Furopyrimidine derivatives

Abstract

The present invention relates to novel compounds having valuable properties, in particular those useful for the preparation of pharmaceuticals, as well as their use and process for their preparation. The compounds are particularly useful as PI4K inhibitors and are useful in the treatment or prevention of PI4K-related conditions such as protozoal infections (e.g., malaria) and viral infections.

Description

Background of the Invention Technical Field

[0002] The present invention relates to novel compounds having valuable properties, in particular those compounds which can be used for the preparation of medicaments, and methods for their use and preparation. The compounds are particularly useful as PI4K inhibitors and for the treatment or prevention of PI4K-related disorders, such as protozoan infections (e.g. malaria) and viral infections.

[0003] Related technical notes

[0004] Malaria represents a significant global health burden, with an estimated 229 million new cases and nearly 409,000 deaths in 2019, primarily affecting young children and pregnant women (World Malaria Report 2020; World Health Organization: Geneva, Switzerland, 2020). It is a vector-borne infectious disease caused by hematoprotozoan parasites of the genus Plasmodium (Phillips, MA et al., Malaria. Nat. Rev. Dis. Prim. 2017, 3, 17050). According to the World Health Organization (WHO), Plasmodium falciparum is responsible for the vast majority of malaria-related morbidity and mortality in sub-Saharan Africa.

[0005] At present, WHO recommends artemisinin-based combination therapy (ACT). In addition, vector control measures are a key factor in reducing the burden of malaria. However, reports of resistance to ACT (Dondorp, AM et al., Artemisinin Resistance in Plasmodium falciparum Malaria. N. Engl. J. Med. 2009, 361, 455-467) illustrate the necessity of a new generation of drugs to combat resistance and improve the standard of care for millions of affected patients. In recent years, studies have identified new druggable target structures that can affect malarial parasite viability. The availability of a limited number of validated drug targets (such as dihydrofolate reductase, cytochrome c-oxidoreductase, and hemozoin formation) is a promising starting point for the development of new antimalarial compounds, and emphasizes the need to expand chemical substances to more effective drugs with new modes of action and multi-stage antiparasitic activity.

[0006] In this context, plasmodium kinases are attractive targets for the new generation of antimalarial drugs because both protein and lipid kinases are involved in key signaling pathways at various stages of the parasite life cycle and have been genetically or phenotypically validated to a certain extent (Arendse, LB et al., Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities, ACS Infect Dis. 2021, 7(3): 518-534. doi: 10.1021 / acsinfecdis.0c00724).

[0007] For example, lipid kinases are important at all stages of the malarial parasite life cycle; this includes phosphatidylinositol-4-kinase (PI4K) that catalyzes the conversion of phosphatidylinositol (PI) to phosphatidylinositol-4-phosphate (PI4P). Phosphatidylinositol 4-kinase type III β (PI4KIIIβ) is a ubiquitous eukaryotic enzyme that phosphorylates lipids to regulate intracellular signaling and transport. Imidazolopyrazines are known PI4K inhibitors. In the blood stage of malaria, imidazopyrazines block the later steps of parasite development by destroying the plasma membrane invagination around the developing daughter merozoites. This may be due to the altered d1 phosphatidylinositol 4-phosphate (PI4P) pool and the disturbed Rab11A-mediated membrane transport. (McNamara, CW et al., Targeting Plasmodium PI (4) K to Eliminate Malaria. Nature 2013, 504 (7479), 248-253). Therefore, Plasmodium PI4K is very important for signal transduction and membrane trafficking and has been demonstrated to be an effective drug target for the prevention, treatment and elimination of malaria.

[0008] Several drugs have been recently reported as Plasmodium PI4K inhibitors, and the 2-aminopyridine MMV390048 has reached Phase IIa clinical trials (Paquet, T. et al., Antimalarial Efficacy of MMV390048, an Inhibitor of Plasmodium Phosphatidylinositol 4-Kinase. Sci. Transl. Med. 2017, 9(387), 1-14), and further related compounds are shown below (PvPI4K, Pv = Plasmodium vivax).

[0009]

[0010]

[0011] Although PI4K has been identified as a useful target for the treatment of protozoan infections, it is well known that human PI4K is also hijacked by viruses. In particular, human PI4KIIIβ is an important host target for viruses such as RNA viruses [PMID: 20510927; PMID: 33022924]. Therefore, PI4K inhibitors show great potential in the treatment of PI4K-related conditions such as viral or malarial infections.

[0012] WO 2012 025187 A1 discloses heterocyclic compounds used as Syk inhibitors, which can be applied to treat rheumatoid arthritis and / or systemic lupus erythematosus.

[0013] WO 2013 117285 A1 discloses heterocyclic compounds useful as TBK1 and IKKε inhibitors, which can be applied to treat cancer and inflammatory diseases.

[0014] WO 2013 124025 A1 discloses heterocyclic compounds useful as Syk inhibitors, which can be used to treat rheumatoid arthritis and / or systemic lupus erythematosus.

[0015] WO 2017 003995 A1 discloses heterocyclic compounds useful as TBK / IKKε inhibitors.

[0016] WO 2011 086531 A1 and WO 2013 121387 A1 disclose the use of aminopyridine derivatives in the manufacture of a medicament for preventing or treating malaria. In particular, the present disclosure relates to aminopyridine derivatives for inhibiting the proliferation of malarial parasites.

[0017] Although many new compounds are under development, the need for a wider range of effective drugs targeting PI4K is high in order to allow combination therapy to inhibit the development of resistance to single compounds. In addition, several lead structures that have demonstrated acceptable PI4K inhibition require high doses to be effective in vivo. There is a need to continuously develop and improve compounds to adapt the biophysical properties of the compounds to improve bioavailability and tolerability in the clinical setting. Therefore, the object of the present invention is to overcome the disadvantages associated with the prior art as described above and to provide an alternative with high effectiveness. Summary of the invention

[0018] The present invention provides compounds according to formula (I). The compounds have been shown to be useful for preventing and / or treating PI4K-related disorders, such as malaria or viral infections, and further relate to pharmaceutical compositions comprising the compounds. In particular, the compounds according to the present invention show high selectivity in inhibiting Plasmodium PI4K while affecting human PI4K to a lesser extent, thus providing drugs with potentially lower side effects due to human PI4K inhibition.

[0019]

[0020] In another aspect, the present invention provides compounds of formula (I) which are suitable as PI4K inhibitors. The compounds preferably inhibit Plasmodium PI4K and significantly reduce growth.

[0021] In certain embodiments, the present invention provides compounds of formula (I) that are selective PI4K inhibitors. In certain embodiments, the present invention provides compounds of formula (I) that are selective for Plasmodium PI4K.

[0022] In certain embodiments, the present invention provides compounds of formula (I) that inhibit human PI4K, more preferably human PI4KIIIβ.

[0023] In certain embodiments, the present invention provides compounds of formula (I) for use in preventing and / or treating viral infections, most preferably viral infections caused by RNA viruses.

[0024] In a further embodiment, the present invention relates to a pharmaceutical composition for preventing and / or treating a PI4K-related disorder, comprising at least one compound of formula (I).

[0025] In another aspect, the present invention provides a method for treating and / or preventing malaria, said method comprising administering a compound of formula (I). In another aspect, the present invention provides a compound capable of modulating, in particular inhibiting, PI4K activity in a disease state in a mammal.

[0026] For convenience, certain terms used in the specification, examples and accompanying embodiments are collected here and provide definitions of the various chemical moieties that make up the compounds according to the invention, and are intended to apply uniformly throughout the specification and embodiments unless an otherwise expressly set out definition provides a more comprehensive definition.

[0027] The term "pharmaceutically acceptable salt or complex" refers to a salt or complex of a compound according to the present invention. Examples of such salts include, but are not limited to, base addition salts formed by reacting a compound of the present invention with an organic or inorganic base, such as a hydroxide, carbonate or bicarbonate of a metal cation, such as one selected from alkali metals (sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium). Also included are salts formed by acid addition, salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with organic acids (such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid and polygalacturonic acid).

[0028] "Pharmaceutically active compound" refers to any compound that can directly or indirectly provide the activity disclosed herein after administration to a recipient. The term "indirectly" also includes prodrugs that can be converted into pharmaceutically active forms by endogenous enzymes or metabolism. The prodrug is a derivative of a compound according to the present invention, and exhibits antimalarial activity, has a group that can be chemically or metabolically decomposed, and is a compound that can be converted into a pharmaceutically active compound according to the present invention in vivo by solvent decomposition under physiological conditions. The prodrug is converted into a compound according to the present invention by reacting with an enzyme, gastric acid, etc. (e.g., by oxidation, reduction, hydrolysis, etc., each of which is enzymatically carried out) under physiological conditions in vivo. These compounds can be produced by the compounds of the present invention according to well-known methods.

[0029] The term "solvate" of a compound is understood to mean an addition of inert solvent molecules to the compound which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alkoxides.

[0030] The term "indirectly" also includes metabolites of the compounds according to the invention.

[0031] The term "metabolites" refers to all molecules derived from any compound according to the invention in a cell or an organism, preferably a mammal.

[0032] The term "malaria" includes diseases and conditions associated with infection with plasmodium protozoa.

[0033] As used herein, "treatment" and "treating" and the like generally refer to obtaining a desired pharmacological and physiological effect. The effect may be prophylactic in terms of preventing or partially preventing a disease, its symptoms or condition, and / or the effect may be therapeutic in terms of partially or completely curing a disease, condition, symptom or side effect caused by the disease. The term "treatment" as used herein includes any treatment of a mammal, particularly a human disease, including: (a) preventing the onset of the disease in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease, i.e., preventing its development; or alleviating the disease, i.e., causing regression of the disease and / or its symptoms or condition. The term "effective amount" includes "prophylactically effective amount" and "therapeutically effective amount".

[0034] The term "prophylactically effective amount" refers to a concentration of the compound of the present invention that, when administered prior to infection (i.e., before, during and / or slightly after the period of exposure to Plasmodium), can effectively inhibit, reduce the likelihood of Plasmodium-induced disease, or prevent malaria infection or prevent the delayed onset of disease caused by Plasmodium.

[0035] The term "prevention" includes etiological prevention (i.e., antimalarial activity that includes prevention of the development of the pre-erythrocytic stage of the parasite), suppressive prevention (i.e., antimalarial activity that includes inhibition of the development of blood-stage infection), and terminal prevention (i.e., antimalarial activity that includes inhibition of the development of intrahepatic stage infection). This term includes primary prevention (i.e., prevention of initial infection), in which the antimalarial compound is administered before, during and / or after the exposure period of the Plasmodium; and terminal prevention (i.e., prevention of recurrence or delayed onset of clinical symptoms of malaria), in which the antimalarial compound is administered at the end of the exposure period of the Plasmodium and / or slightly later but before the onset of clinical symptoms. In addition, this term includes inhibition of dormant forms of parasites in the liver (intrahepatic or pre-erythrocytic stages) and activation and elimination of dormant forms (awakening and killing concepts). Typically, suppressive prevention is used for infection with Plasmodium falciparum protozoa, while terminal prevention is used for Plasmodium ovale, Plasmodium vivax, or a combination of Plasmodium falciparum and Plasmodium vivax. Inhibition of dormancy is particularly useful for Plasmodium ovale and Plasmodium vivax.

[0036] The expression "effective amount" denotes the amount of a drug or a pharmaceutically active ingredient that elicits in a tissue, system, animal or human the biological or medical response that is sought or desired, for example, by a researcher or physician.

[0037] Likewise, the term "therapeutically effective amount" or "therapeutically effective amount" refers to an amount of a compound that has the following results: improved treatment, cure, prevention or elimination of a disease, syndrome, condition, discomfort, disorder or side effect, or reduced progression of a disease, disorder or condition, as compared to a corresponding subject not receiving that amount.

[0038] The expression "therapeutically effective amount" or "therapeutically effective amount" also includes an amount effective to increase normal physiological function, as well as an amount effective to treat a disease such as malarial infection, for example, when administered after infection has occurred, resulting in a decrease in the number of parasites in the blood after microscopic examination.

[0039] The expression "PI4K-associated disorder" refers to a disorder affected by PI4K interactions, such as inhibition or overexpression of PI4K caused by, for example, pathogens, genetic susceptibility, use of PI4K for viral replication, and disorders that can be treated and / or prevented by inhibiting PI4K in a patient or a parasite such as Plasmodium. Examples of PI4K-associated disorders include, but are not limited to, viral infections (such as infections caused by RNA viruses) or protozoan infections (such as malaria).

[0040] The term "subject" as used herein refers to a mammal. For example, mammals contemplated by the present invention include humans and the like.

[0041] The term "pharmaceutically acceptable carrier, adjuvant or excipient" refers to a non-toxic carrier, adjuvant or excipient that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or excipients used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0042] "Pharmaceutically acceptable derivative" refers to any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or its inhibitory active metabolite or residue.

[0043] A wavy line at the end of a bond line usually appears perpendicular to the bond line and has the same meaning as a wavy line that bisects the bond line.

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] The aim of the present invention is to develop and identify novel compounds for inhibiting PI4K and treating PI4K-related disorders such as malaria or viral infections in order to expand, provide alternatives and improve limited treatment options for physicians and veterinarians, thus ensuring efficient treatment for patients.

[0046] Surprisingly, it has been found that the compounds according to the invention are inhibitors of PI4K, which is found in various organisms.

[0047] Therefore, the present invention relates to compounds according to formula (I)

[0048] or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof,

[0049] in:

[0050] R indicates AR1 or HT1;

[0051] AR1 represents phenyl which is unsubstituted or substituted by:

[0052] - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN and / or NO2 (preferably Alk2, OAlk2, Hal and / or Cyc); and / or

[0053] - a substituent selected from the group consisting of: A, NH2, OH, (CR a R b ) n HetCyc1, (CR a R b ) n HetAr1、(CR a R b ) n Aryl, (CR a R b ) n CO(R a R b ) m HetCyc1, (CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl, (CR a R b ) n COCyc, (CR a R b ) n COA, (CR a R b ) nCONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CRa R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) nSO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、(CR a R b ) n SOHetCyc1(NA)、(CR a R b ) n SOHetAr1(NA)、(CR a Rb ) n SOA(NCyc),(CR a R b ) n SOCyc(NCyc),(CR a R b ) n SOAryl(NCyc),(CR a R b ) n SOHetCyc1(NCyc),(CR a R b ) n SOHetAr1(NCyc),(CR a R b ) n SO2NA2, (CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA and (CR a R b ) n POA2;

[0054] HT1 represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 3 to 9 carbon atoms and 1, 2, 3 or 4 N, O and / or S atoms, wherein the heterocycle is unsubstituted or substituted by:

[0055] - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN, =O and / or NO2 (preferably Alk2, OAlk2, Hal and / or Cyc); and / or

[0056] - a substituent selected from the group consisting of:

[0057] A、NH2、OH、(CR a R b ) n HetCyc1, (CR a R b ) n HetAr1、(CR a R b ) n Aryl, (CR a R b ) n CO(R a R b ) m HetCyc1, (CRa R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl、(CR a R b ) n COCyc、(CR a R b ) n COA、(CR a R b ) n CONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a Rb ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(Ra R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) nSOA(NA),(CR a R b ) n SOR Cyc1 (NR Cyc2 ), (CR a R b ) n SOCyc(NA),(CR a R b ) n SOAryl(NA),(CR a R b ) n SOHetCyc1(NA),(CR a R b ) n SOHetAr1(NA),(CR a R b ) n SOA(NCyc),(CR a R b ) n SOCyc(NCyc),(CR a R b ) n SOAryl(NCyc),(CR a R b ) n SOHetCyc1(NCyc),(CR a R b ) n SOHetAr1(NCyc),(CR a R b ) n SO2NA2, (CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA and (CR a R b ) n POA2,;

[0058] Q represents a structure according to formula (II)

[0059] R 1 Indicates AR2 or HT2;

[0060] R 2 , R 3 and R 4 independently of each other, expressed H, Hal, or CAlk2;

[0061] Y represents CH, CHal, CAlk2, CCHal3 or N;

[0062] AR2 represents phenyl which is unsubstituted or substituted by:

[0063] - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN and / or NO2 (preferably Alk2, OAlk2, Hal and / or Cyc); and / or

[0064] - a substituent selected from the group consisting of: A, NH2, OH, (CR a R b ) n HetCyc1, (CR a R b ) n HetAr1、(CR a R b ) n Aryl, (CR a R b ) n CO(R a R b ) m HetCyc1, (CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl, (CR a R b ) n COCyc, (CR a R b ) n COA, (CR a R b ) n CONA2, (CR a R b ) n CONH2, (CR a R b ) n CONHA, (CR a R b ) n CONH(CR a R b )m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) mAryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b )n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、(CR a R b ) n SOHetCyc1(NA)、(CR a R b ) n SOHetAr1(NA)、(CR a R b ) n SOA(NCyc)、(CR a R b ) n SOCyc(NCyc)、(CR a R b ) n SOAryl(NCyc)、(CR a R b ) nSOHetCyc1(NCyc),(CR a R b ) n SOHetAr1(NCyc),(CR a R b ) n SO2NA2, (CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA and (CR a R b ) n POA2;

[0065] HT2 represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 3 to 9 carbon atoms and 1, 2, 3 or 4 N, O and / or S atoms, wherein the heterocycle is unsubstituted or substituted by:

[0066] - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN, =O and / or NO2 (preferably Alk2, OAlk2, Hal and / or Cyc); and / or

[0067] - a substituent selected from the group consisting of: A, NH2, OH, (CR a R b ) n HetCyc1, (CR a R b ) n HetAr1、(CR a R b ) n Aryl, (CR a R b ) n CO(R a R b ) m HetCyc1, (CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl, (CR a R b )n COCyc、(CR a R b ) n COA、(CR a R b ) n CONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONR Cyc3 R Cyc4 、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a Rb ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) mHetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) nSOCyc(NA),(CR a R b ) n SOAryl(NA),(CR a R b ) n SOHetCyc1(NA),(CR a R b ) n SOHetAr1(NA),(CR a R b ) n SOA(NCyc),(CR a R b ) n SOCyc(NCyc),(CR a R b ) n SOAryl(NCyc),(CR a R b ) n SOHetCyc1(NCyc),(CR a R b ) n SOHetAr1(NCyc),(CR a R b ) n SO2NA2, (CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA and (CR a R b ) n POA2;

[0068] A represents a straight-chain or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, wherein:

[0069] - one or two non-adjacent CH2 groups may be replaced by O, NAlk2 or NH; and / or

[0070] - 1, 2, 3, 4 or 5 hydrogens may be replaced by Hal; and / or

[0071] - one hydrogen may be replaced by OH or NH2 or a cyclic alkyl group having 3, 4, 5 or 6 carbon atoms which is mono-, di- or tri-substituted by Hal, OH, Alk2, NHAlk2, N(Alk2)2 and / or NH2;

[0072] Alk1 represents a straight-chain or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, in which one or two CH2 groups may be replaced by O, NAlk2 or NH; and / or

[0073] - 1 hydrogen can be replaced by OH, NHAlk2, N(Alk2)2 or NH2; and / or

[0074] -1, 2, 3, 4 or 5 hydrogens can be replaced by Hal;

[0075] Alk2 represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, in which 1, 2, 3, 4 or 5 hydrogen atoms may be replaced by Hal;

[0076] Aryl represents phenyl, which is unsubstituted or mono-, di- or poly-substituted by Hal, Alk2, OAlk2, OH, NH2 or Cyc;

[0077] HetCyc1 represents a monocyclic or bicyclic, optionally bridged, saturated or unsaturated 4- to 10-membered heterocycle having 1 or 2 heteroatoms selected from N, O, S and / or Si, wherein the heterocycle may be unsubstituted or mono- or disubstituted by Hal, OH, A, SO2Alk2 and / or =O;

[0078] Cyc represents a cyclic alkyl group having 3 to 6 carbon atoms, in which 1, 2 or 3 hydrogens may be replaced by Hal and 1 additional hydrogen may be replaced by Alk2, NH2 and / or OH;

[0079] Hal means F or Cl;

[0080] HetAr1 represents a monocyclic or bicyclic aromatic 4- to 12-membered heterocycle having 1, 2, 3 or 4 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by Hal, Alk2, SOAlk2, SO2Alk2, OH or NH2;

[0081] R a and R b Each independently represents H, Alk2 or Cyc;

[0082] or

[0083] R a and R b Common Representative - (CH2) x -, wherein x = 2, 3, 4 or 5, thus forming together with the carbon atoms to which they are attached a (3-, 4-, 5- or 6-membered) cycloalkyl ring;

[0084] R Cyc1 and R Cyc2Together they form -(CH2) x -, where x = 3 or 4, thus forming together with the atoms to which they are attached a (5- or 6-membered) ring, where -(CH2) x -1 or 2 H atoms in can be replaced by Hal or Alk1 independently;

[0085] R Cyc3 and R Cyc4 Together they form -(CH2) x -, wherein x = 3, 4 or 5, thus forming together with the nitrogen atom to which they are attached a (4-, 5- or 6-membered) ring, wherein -(CH2) x -1 or 2 H atoms in can be replaced by Hal or Alk1 independently;

[0086] n represents 0, 1 or 2 (preferably 0 or 1); and

[0087] m represents 0 or 1 (preferably 0).

[0088] Compounds of formula (I) according to the present invention may have one or more chiral centers, which also depends on the properties of the substituents they may carry. Therefore, as the case may be, they may appear in the form of various enantiomers and diastereomers, and may be racemic or optically active forms. Therefore, the present invention also relates to optically active forms, enantiomers, racemates, diastereomers and mixtures of all proportions thereof, collectively referred to as "stereoisomers". It may be desirable to use specific stereoisomers, such as a specific enantiomer or diastereomer of a certain compound. In these cases, the compounds according to the present invention obtained as racemates or even their intermediates can be separated into stereoisomers (enantiomers, diastereomers) compounds by chemical or physical measures known to those skilled in the art. The compounds of the present invention having one or more chiral centers and existing as racemates or enantiomers or diastereoisomer mixtures can be fractionated or split into their optically pure or enriched isomers, i.e. enantiomers or diastereomers, for example, by methods known per se. Isolation of the compounds of the invention can be carried out by chromatography, such as column separation on a chiral or achiral phase, or by recrystallization from an optionally optically active solvent, or by using an optically active acid or base, or by derivatization with an optically active reagent, such as an optically active alcohol, followed by elimination of a free radical. Another method that can be used to obtain one or more specific stereoisomers of the compounds of the invention in enriched or pure form utilizes stereoselective synthetic procedures, such as using starting materials in stereoisomerically enriched or pure form (e.g., using a pure or enriched (R)- or (S)-enantiomer of a specific starting material bearing a chiral center) or using a chiral reagent or catalyst, particularly an enzyme.

[0089] Examples of compounds according to the invention having a stereocenter are:

[0090]

[0091] In this specific example, the sulfur atom represents a stereocenter, and in other examples of the invention, the compound may of course have other or additional stereocenters located on different atoms, such as carbon atoms. As indicated above, if a compound having one or more stereocenters is shown without indicating the stereoconfiguration of the stereocenter(s), this refers to a mixture of the corresponding stereoisomers.

[0092] In a particular embodiment of the invention, the residue R of the compound according to formula (I) represents a structure according to formula (IV), (V), (Va) or (VI)

[0093]

[0094] in

[0095] R 6 represents OH, A or Cyc (preferably OH, cyclopropyl, OCH3, OCF3, OCHF2, CH3, C2H5, CH2F, CHF2, OC2H5, OiPr, OtBu, NH2, NHCH3, N(CH3)2, N(C2H5)2, N(iPr)2, N(CH3)(nPr) or N(CH3)(tBu)), or a substituent according to formula (VII) to (X)

[0096]

[0097] in

[0098] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 each independently represents H, OH, Hal, CH3, C2H5, CHal3, OCH3, OCHal3, OCHal2, OCH2Hal, CH2Hal and / or CHHal2;

[0099] R 15 Indicates NR 17 or O;

[0100] R 16 Indicates A or Cyc;

[0101] R 17represents H, Alk1 or a cyclic alkyl group having 3 to 6 carbon atoms, wherein 1, 2 or 3 hydrogen atoms of the cyclic alkyl group may be replaced by Hal;

[0102] X 1 represents N or CH; and

[0103] X 2 Represents NH, NAlk1, or O.

[0104] For the avoidance of doubt, the residues R of formulae (IV), (V) and (VI) as shown above are 7 , R 8 COR 6 , SOR 16 (NR 15 ) and SOR 16 And the cyclic S-residue of formula (Va) can be attached to each carbon atom of the aromatic ring. In an important embodiment, the residue COR 6 , SOR 16 (NR 15 ) and SOR 16 Attached to the para position of the carbon atom, this connects the residue R to the annulated ring system (furanopyrimidine residue), as shown in the following formulae (IVb)-(VIb),

[0105]

[0106] And the residue R 7 and R 8 Each is preferably bonded in the ortho- or meta-position to the carbon atom which links the residue R to the fused ring system.

[0107] Another particular embodiment relates to compounds according to formula (I) as defined above, wherein Q represents a residue according to formula (XI)

[0108]

[0109] in

[0110] Y represents N or CH;

[0111] And the residue R 2 , R 3 and R 4 One or two of the residues independently represent Hal, CH3, CHal3, OCH3, OCHal3, OCHHal2, OCH2Hal, CH2Hal and / or CHHal2, and the remaining residue(s) represent H.

[0112] In this embodiment, R 2 and R 4Preferably, independently of one another, they represent a residue selected from the group consisting of: F, CH3, CF3, OCH3, OCF3, OCHF2, OCH2F, CH2F and / or CHF2, and R 3 represents H. In another important embodiment according to formula (XI) as described above, R 2 represents a residue selected from the group consisting of F, CH3, CF3, OCH3, OCF3, OCHF2, OCH2F, CH2F and / or CHF2, and R 3 and R 4 In other important embodiments of the residues, R 4 represents a residue selected from the group consisting of F, CH3, CF3, OCH3, OCF3, OCHF2, OCH2F, CH2F and / or CHF2, and R 3 and R 2 Indicates H.

[0113] Other particular embodiments relate to compounds according to formula (I), wherein Z represents N.

[0114] In the context of the present invention, "hydroxyalkyl" means a straight or branched hydrocarbon residue having 1, 2, 3, 4, 5 or 6 carbon atoms (preferably 1, 2, 3 or 4 carbon atoms) substituted by one or two (preferably one) hydroxyl groups. Examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyprop-2-yl, 1-hydroxyethyl, 2-hydroxy-2-methylpropyl, etc.

[0115] Throughout the invention, all residues occurring more than once may be identical or different, i.e. independent of one another. a R b ) n CONH(CR a R b ) m HetCyc1" or "(CR a R b ) n SO2NA2”, R a , R b Each instance of and A may have a different meaning (within the scope of the corresponding definition).

[0116] In a particularly important embodiment, A represents a straight-chain or branched alkyl group having 1, 2, 3 or 4 carbon atoms, in which (if applicable) one or two non-adjacent CH2 groups may be replaced by O, NCH3, NC2H5, NiPr or NH; and / or 1, 2, 3, 4 or 5 hydrogens may be replaced by Hal, and / or one hydrogen may be replaced by OH, NH2 or a cyclic alkyl group having 3, 4, 5 or 6 carbon atoms, in which the cyclic alkyl group may be mono- or disubstituted by Hal, Alk2NHAlk2(NAlk2)2 and / or NH2.

[0117] AR1 represents preferably 3,4,5-trimethoxyphenyl or phenyl, which is:

[0118] - substituted by: one or two residues selected from Hal, CH3, CHal3 and / or OCH3; and / or

[0119] - a residue selected from the group consisting of: (CR a R b ) n HetCyc1, (CR a R b ) n HetAr1、(CR a R b ) n Aryl, (CR a R b ) n CO(R a R b ) m HetCyc1, (CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl, (CR a R b ) n COCyc, (CR a R b ) n COA, (CR a R b ) n CONA2, (CR a R b ) n CONH2, (CRa R b ) n CONHA、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a Rb ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、((CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CRa R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、(CR a R b ) n SOHetCyc1(NA)、(CR a R b ) n SOHetAr1(NA)、(CR a R b ) n SOA(NCyc)、(CR a R b) n SOCyc(NCyc),(CR a R b ) n SOAryl(NCyc),(CR a R b ) n SOHetCyc1(NCyc),(CR a R b ) n SOHetAr1(NCyc),(CR a R b ) n SO2NA2, (CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA or (CR a R b ) n POA2.

[0120] HT1 preferably represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, isoindolyl, benzimidazolyl, indazolyl (most preferably pyridinyl) or one of the following residues:

[0121]

[0122] Each of the residues is independently unsubstituted or substituted with (the following optional substituents (which may be attached to the carbon atom or to another atom provided that the atom yields the appropriate valence) not shown in the above residues):

[0123] - 1, 2 or 3 substituents independently selected from: A, Hal; and / or

[0124] - a substituent selected from the group consisting of:

[0125] NH2、OH、(CR a R b ) n HetCyc1, (CR a R b ) n HetAr1、(CR a R b ) n Aryl, (CR a R b ) n CO(R a R b )m HetCyc1、(CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl、(CR a R b ) n COCyc、(CR a R b ) n COA、(CR a R b ) n CONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) mHetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a Rb ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a Rb ) n SOA(NA),(CR a R b ) n SOR Cyc1 (NR Cyc2 ), (CR a R b ) n SOCyc(NA),(CR a R b ) n SOAryl(NA),(CR a R b ) n SOHetCyc1(NA),(CR a R b ) n SOHetAr1(NA),(CR a R b ) n SOA(NCyc),(CR a R b ) n SOCyc(NCyc),(CR a R b ) n SOAryl(NCyc),(CR a R b ) n SOHetCyc1(NCyc),(CR a R b ) n SOHetAr1(NCyc),(CR a R b ) n SO2NA2, (CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA,(CR a R b ) n POA2, and an azaspirocycle which is unsubstituted or monosubstituted with at least one Hal, Alk2 or OAlk2 group.

[0126] HT2 preferably represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, isoindolyl, benzimidazolyl, indazolyl (most preferably pyridinyl) or one of the following residues:

[0127]

[0128] Each of the residues is independently unsubstituted or substituted with (the following optional substituents (which may be attached to the carbon atom or to another atom provided that the atom yields the appropriate valence) not shown in the above residues):

[0129] - 1, 2 or 3 substituents independently selected from: A, Hal; and / or

[0130] - a substituent selected from the group consisting of:

[0131] NH2、OH、(CR a R b ) n HetCyc1, (CR a R b ) n HetAr1、(CR a R b ) n Aryl, (CR a R b ) n CO(R a R b ) m HetCyc1, (CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl, (CR a R b ) n COCyc, (CR a R b ) n COA, (CR a R b ) n CONA2, (CR a R b ) n CONH2, (CR a R b ) n CONHA, (CR a R b ) n CONH(CR a R b )m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) mAryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b )n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、(CR a R b ) n SOHetCyc1(NA)、(CR a R b ) n SOHetAr1(NA)、(CR a R b ) n SOA(NCyc)、(CR a R b ) n SOCyc(NCyc)、(CR a R b ) n SOAryl(NCyc)、(CR a R b ) nSOHetCyc1(NCyc),(CR a R b ) n SOHetAr1(NCyc),(CR a R b ) n SO2NA2, (CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA,(CR a R b ) n POA2 and an azaspirocycle which is unsubstituted or monosubstituted with at least one Hal, Alk2 or OAlk2 group.

[0132] Cyc preferably denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0133] In a specific embodiment of the invention, the residue R of the compound according to formula (I) represents a structure according to formula (IV)

[0134]

[0135] in

[0136] R 6 It is Alk1, Alk2, -OH, -CH3, -OCH3, -OC(CH3)3, -N(CH3)2,

[0137]

[0138] W is O, -NCH3, NR 18 or CR 18 R 19 ;

[0139] R 7 , R 8 Each is independently selected from -H or Hal;

[0140] R 18 , R 19 Each is independently selected from -H, -CH3 or Alk1;

[0141] X 1 Yes CR 7 or N.

[0142] In this embodiment of the invention, the residue Q of the compound represents a structure according to formula (II) above, wherein

[0143] R1 It's H, Hal,

[0144] R 2 , R 3 , R 4 Each independently selected from H or Hal;

[0145] R 28 It is Alk1, Alk2, -NH2,

[0146] R 29 , R 30 are each independently selected from -H or -CH3; and

[0147] Y is N, CH or CHal.

[0148] Furthermore, in a preferred embodiment of the present invention,

[0149] R 6 are -CH3, -OH, -N(CH3)2; W is O;

[0150] R 7 , R 8 It is H;

[0151] R 18 , R 19 are each independently selected from -H or -CH3; and

[0152] X 1 It is CH or N.

[0153] Furthermore, in a preferred embodiment of the present invention,

[0154] R 6 yes And R 1 yes

[0155] In a specific embodiment of the invention, the residue R of the compound according to formula (I) represents a structure according to formula (V)

[0156] in

[0157] X 1 Yes CR 7 or N;

[0158] R 7 , R 8 Each independently selected from H, Hal or CHal3;

[0159] R 15 is O or NH;

[0160] R 16 It is H, -CH3, -NH2, -N(CH3)2 or Alk1.

[0161] In this embodiment of the invention, the residue Q of the compound represents a structure according to formula (II) above, wherein

[0162] R 1 It's H, Hal,

[0163] R 2 , R 3 , R 4 Each independently selected from H or Hal;

[0164] R 28 It is Alk1, Alk2, -NH2,

[0165]

[0166] R 29 , R 30 are each independently selected from H or CH3; and

[0167] Y is N, CH or CHal.

[0168] Furthermore, in a preferred embodiment of the present invention,

[0169] R 1 Selected from H, Hal or

[0170] R 2 , R 3 , R 4 , R 7 , R 8 Each independently selected from H or Hal;

[0171] R 16 is -CH3 or Alk1;

[0172] X 1 is CH; and

[0173] Y is CH or CHal.

[0174] Furthermore, in a preferred embodiment of the present invention,

[0175] R 1 yes

[0176] R2 , R 7 , R 8 Each independently selected from H or Hal;

[0177] R 3 , R 4 It is H;

[0178] R 15 It is NH;

[0179] R 16 is -CH3 or Alk1;

[0180] X 1 is CH; and

[0181] Y is CH.

[0182] Furthermore, in a preferred embodiment of the present invention, the SOR of formula V 15 R 16 The group is located in the ortho position to the bond of Formula I. In some embodiments, R 3 and R 4 is H. In some embodiments, X 1 It is CH.

[0183] Furthermore, in a preferred embodiment of the present invention,

[0184] R 1 yes

[0185] R 2 , R 7 , R 8 Each independently selected from H or Hal;

[0186] R 3 , R 4 It is H;

[0187] R 15 It is NH;

[0188] R 16 is -CH3;

[0189] X 1 is CH; and

[0190] Y is CH.

[0191] Furthermore, in a very specific embodiment of the invention, the compound is

[0192]

[0193] Furthermore, in a very specific embodiment of the invention, the compound is

[0194]

[0195] Furthermore, in a very specific embodiment of the invention, the compound is

[0196]

[0197] In a specific embodiment of the invention, the residue R of the compound according to formula (I) represents one of the following structures

[0198] in

[0199] R 18 , R 19 are each independently selected from H, -CH3 or Alk1; and

[0200] R 27 It is -CH3 or -C((CH3)2OH).

[0201] In this embodiment of the invention, the residue Q of the compound represents a structure according to formula (II) above, wherein

[0202] R 1 It's H, Hal,

[0203] R 2 , R 3 , R 4 Each independently selected from H or Hal;

[0204] R 28 It is Alk1, Alk2, -NH2,

[0205] R 29 , R 30 are each independently selected from H or CH3; and

[0206] Y is N, CH or CHal.

[0207] In some embodiments, the compounds according to the present invention are selected from:

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

[0221] Surprisingly, in vitro studies have shown that small amounts of the compounds according to the invention are potent PI4K inhibitors.The present invention therefore relates to compounds according to the invention for use in inhibiting PI4K.

[0222] These multifunctional PI4K inhibitory properties make the compounds according to the present invention ideal candidates for the treatment and / or prevention of PI4K-associated disorders such as, but not limited to, protozoan infections and viral infections.

[0223] Surprisingly, small amounts of the compounds according to the invention are sufficient to reduce Plasmodium viability and growth. Additional data indicate the high inhibitory potential of the compounds on Plasmodium PI4K activity. Therefore, the present invention also relates to the use of the compounds according to the invention for the treatment and / or prevention of protozoan infections such as malaria.

[0224] The compounds according to the invention inhibit PI4K of protozoa such as, but not limited to, Plasmodium ssp, Toxoplasma ssp, Babesia ssp, Cryptosporidium ssp.

[0225] Human PI4K is a well-known druggable target for the treatment and prevention of viral infections. Surprisingly, the disclosed compounds were additionally found to inhibit human PI4KIIIβ, which is an important target for viruses such as, but not limited to, RNA viruses.

[0226] Therefore, some embodiments of the present invention relate to the use of a compound according to the present invention for treating and / or preventing a PI4K-associated disorder selected from the list of protozoan infections and viral infections. In a preferred embodiment, the PI4K-associated disorder is a protozoan infection, more preferably malaria.

[0227] Viral infections can be caused by viruses such as RNA or DNA viruses. In a preferred embodiment, the compounds according to the invention are used for the treatment and / or prevention of viral infections caused by RNA viruses.

[0228] In a preferred embodiment, the viral infection is caused by a virus selected from the family Orthomyxoviridae, Adenoviridae, Paramyxoviridae, and Coronaviridae. Viruses of the family Orthomyxoviridae include influenza A virus, influenza B virus, influenza C virus, infectious salmon anemia virus (Isavirus), Thogoto virus, and Dhori virus. Members of the family Adenoviridae include human adenovirus types A, B, C, D, E, and F; bovine adenovirus types A, B, and C; canine adenovirus; equine adenovirus types A and B; murine adenovirus type A; ovine adenovirus types A and B; porcine adenovirus types A, B, and C; and tree shrew adenovirus. Members of the Paramyxoviridae family include bovine parainfluenza virus type 3 (BPIV-3), human parainfluenza virus type 1 (HPIV-1), human parainfluenza virus type 3 (HPIV-3); Sendai virus (murine parainfluenza virus type 1); simian parainfluenza virus type 10 (SPIV-10), bovine respiratory syncytial virus (BRSV), human respiratory syncytial virus (HRSV), pneumonia virus of mice (PVM), canine distemper virus (CDV), dolphin distemper virus (DMV), measles virus (MeV), peste des petits ruminants virus (PPRV), phocine (seal) distemper virus (PDV), porpoise distemper virus, rinderpest virus (RPV), avian paramyxovirus type 2 (APM V-2), avian paramyxovirus 3 (APMV-3), avian paramyxovirus 4 (APMV-4), avian paramyxovirus 5 (APMV-5), avian paramyxovirus 6 (APMV-6), avian paramyxovirus 7 (APMV-7), avian paramyxovirus 8 (APMV-8), avian paramyxovirus 9 (APMV-9), human parainfluenza virus type 2 (HPIV-2), human parainfluenza virus type 4a (HPIV-4a), human parainfluenza virus type 4b (HPIV-4-b), mumps virus, Newcastle disease virus (avian paramyxovirus type 1) (NDV; APMV-1), swine measles virus, simian parainfluenza virus type 5 (SV-5) and simian parainfluenza virus type 41 (SV-41). Members of the Coronaviridae family include infectious bronchitis virus, bovine coronavirus, canine coronavirus, feline coronavirus, human coronavirus and SARS-coronavirus, SAR2-coronavirus-2, MERS-CoV. In a more preferred embodiment, the compounds according to the invention are used to treat and / or prevent SARS-CoV2.

[0229] Although the compounds according to the invention are able to inhibit both protozoan and human PI4K, surprisingly, protozoan PI4K is preferentially inhibited. Human PI4K does show inhibition when treated with the compounds according to the invention. However, since protozoan PI4K is inhibited at very low concentrations, the compounds according to the invention are particularly suitable for treating protozoan infections using low amounts without or with low cross-inhibition of human PI4K. These properties have considerable pharmacological potential, since inhibition of human PI4K can lead to significant side effects in some patients. The excellent inhibitory properties of the compounds according to the invention allow the use of very low amounts to treat and / or prevent PI4K-related diseases, thereby reducing the possibility of toxic effects caused by the compound and allowing the use of lower concentrations of additional approved antimalarials in combination therapy.

[0230] Composition

[0231] The invention further relates to pharmaceutical compositions comprising at least one compound of formula (I) according to the invention.

[0232] In another particular embodiment, a pharmaceutical formulation is provided, which contains at least one compound of formula (I) according to the present invention and a pharmaceutically acceptable carrier, diluent or excipient thereof.

[0233] The present invention further relates to the pharmaceutical composition for preventing and / or treating PI4K-related disorders.

[0234] In some embodiments, the present invention further relates to a pharmaceutical composition for preventing and / or treating a PI4K-related disorder, comprising at least one compound of formula (I) according to the present invention, wherein the PI4K-related disorder is selected from the list of protozoan infections and viral infections. In a preferred embodiment, the PI4K-related disorder is caused by an RNA virus. In another preferred embodiment, the PI4K-related disorder is malaria.

[0235] combination

[0236] According to the present invention, the compound according to formula (I) or its pharmaceutical composition can be administered alone or in combination with other active ingredients (co-agents), such as pharmaceutically active compounds that can be used to treat and / or prevent PI4K-related disorders.

[0237] Therefore, the present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) and at least one other active ingredient (co-agent) different from formula (I). In certain embodiments, the co-agent is an antimalarial agent different from formula (I). Preferably, the additional active ingredient (antimalarial co-agent) is selected from: pyronaridine (free base or tetraphosphate), quinacrine, chloroquine, ferrocene chloroquine, primaquine, tafenoquine, doxycycline, atovaquone, proguanil, cycloguanil, cabamiquine (free base or succinate), cipargamin, ganaplacide, sulfadoxine, pyrimethamine, artemisinin, dihydroartemisinin, artesunic acid, artesunate, arterolane, artefenomel, lumefantrine, DSM 265 (CAS No. 1282041-94-4), (OC-6-21)-[4-[[2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino]phenyl]pentafluorosulfur, SAR121 (CAS No. 2260904-47-8), benzamide, 5-[2-[3-[[(aminoiminomethyl)amino]carbonyl]-5-(trifluoromethyl)phenyl]ethynyl]-N-2-pyridinyl-2-(trifluoromethyl), INE963 (CAS No. 2640567-43-5), 4-piperidinol, 4-(aminomethyl) [(3R)-3-(4-fluorophenyl)-1-pyrrolidinyl]-1-yl]-1-[(3R)-3-(4-fluorophenyl)-1-pyrrolidinyl]-2-yl]-1-[(3R)-3-(4-fluorophenyl) ...

[0238] In another embodiment, the pharmaceutical composition comprises at least one compound of formula (I) and at least one additional antiviral agent (antiviral co-agent) different from formula (I).

[0239] The antiviral active auxiliary agent according to the present invention can be any antiviral agent known in the art, for example, but not limited to, an antiviral agent selected from the following: Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Umifenovir (Arbidol), Atazanavir, Atripla, Baloxavir Dipivoxil (Xofluza), Bituowei, Boceprevir, Bulevirtide, Cidofovir, Cobivir Tybost, Double Taizhi, Daklinza, Darunavir, Delavirdine, Dacohui, Didanosine, Docosanol, Dolutegravir, Pifeltro, Edoxuridine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Ensitrelvir, Entecavir, Intelence, Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Cytovene, Etravirine Ibacitabine, Ibalizumab (Trogarzo), Iodoxuridine, Imiquimod, Imunovir, Indinavir, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviramide, Maraviroc, Metixazone, Morphoguanidine, Nelfinavir, Nevirapine, Nexavir (Kutapressin), Nitazoxanide, Ritonavir (Norvir), Oseltamiflu, Penciclovir, Peramivir, Penciclovir, Peramivir (Rapivab), Pruconaril, Podophyllotoxin, Raltegravir, Remdesivir, Ribavirin, Rilpivirine Edurant, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir (Olysio), sofosbuvir, stavudine, taliprine (Viramidine), telaprevir, telbivudine (Tyzeka), tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, tipranavir, trifluridine, Trizivir, tromantadine, Truvada, arbidol, valacyclovir (Valtrex), valganciclovir (Valcyte), Vicriviroc, adenosine, zalcitabine, zanamivir (Relenza), zidovudine.

[0240] Drug administration

[0241] The present invention includes the administration of a compound according to the present invention or a pharmaceutical formulation thereof (=pharmaceutical preparation, pharmaceutical composition), wherein the compound or pharmaceutical formulation thereof is administered to an individual in an effective amount before, simultaneously or sequentially with other therapeutic regimens or active adjuvants (e.g., multiple drug regimens) that can be used to treat PI4K-related diseases such as malaria or viral infections. The compound according to the present invention or a pharmaceutical formulation thereof administered simultaneously with the active adjuvant can be administered in the same or different compositions by the same or different routes of administration.

[0242] In a further embodiment, the present invention relates to a method for preventing or treating a PI4K-related disorder, wherein the method comprises the following steps:

[0243] (i) providing at least one compound and / or pharmaceutical composition according to the present invention; and

[0244] (ii) administering an effective amount of the at least one compound or the composition to a patient in need thereof.

[0245] In a preferred embodiment, the PI4K-associated disorder is selected from the following list: protozoan infection and viral infection, more preferably viral infection caused by RNA virus, most preferably malaria.

[0246] The other preferred embodiments listed above also apply to the method according to the invention.

[0247] The present invention also relates to a medicament for treating and / or preventing PI4K-related disorders, comprising at least one compound of formula (I) and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and optional excipients and / or adjuvants.

[0248] The pharmaceutical composition can be administered in the form of a dosage unit (which contains a predetermined amount of active ingredient per dosage unit). Such a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg of a compound according to the invention, depending on the condition being treated, the method of administration, and the age, weight and condition of the patient, or a pharmaceutical formulation can be administered in the form of a dosage unit (which contains a predetermined amount of active ingredient per dosage unit). Preferred dosage unit formulations are those formulations containing a daily dose or a partial dose as described above or an active ingredient of a corresponding fraction thereof. In addition, this type of pharmaceutical formulation can be prepared using methods known in the pharmaceutical field

[0249] The pharmaceutical composition may be suitable for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared by all methods known in the pharmaceutical art, for example by mixing the active ingredient with excipient(s) or adjuvant(s).

[0250] In some embodiments, administration according to the methods of the invention is by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal).

[0251] Pharmaceutical compositions suitable for oral administration may be administered as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0252] Thus, for example, in the case of oral administration in tablet or capsule form, the active ingredient components may be combined with oral, non-toxic and pharmaceutically acceptable inert excipients (e.g., ethanol, glycerol, water, etc.). Powders are prepared by crushing the compound into a suitable fine size and mixing it with a pharmaceutical excipient crushed in a similar manner, such as an edible carbohydrate, such as starch or mannitol. Flavoring agents, preservatives, dispersants and dyes may also be present.

[0253] Capsules are produced by preparing a powder mixture as described above and filling a gelatin shell formed therefrom. Before the filling operation, glidants and lubricants such as highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol (in solid form) may be added to the powder mixture. Disintegrants or solubilizers such as agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after the capsule is taken.

[0254] In addition, if desired or necessary, suitable binders, lubricants and disintegrants and dyes can be incorporated into the mixture equally. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum, etc. Tablets are prepared by, for example, preparing a powder mixture, granulating or dry pressing a mixture, adding lubricants and disintegrants and compressing the entire mixture to obtain tablets. By mixing the compound crushed in a suitable manner with a diluent or alkali (as described above), and optionally with a binder (e.g., carboxymethylcellulose, alginate, gelatin or polyvinyl pyrrolidone), a dissolution retardant (e.g., paraffin), an absorption promoter (e.g., a quaternary ammonium salt) and / or an absorbent (e.g., bentonite, kaolin or dicalcium phosphate), a powder mixture is prepared. The powder mixture can be wetted with a binder such as syrup, starch paste, acacia or a solution of cellulose or polymer material and pressed through a sieve to form granules. As an alternative to granulation, the powder mixture can be passed through a tablet press to obtain a mass of uneven shape, which is broken into granules. The granules can be lubricated by adding stearic acid, stearate, talcum or mineral oil to prevent adhesion to the tablet casting mold. The lubricated mixture is then pressed to obtain a tablet. The compound according to the present invention can also be combined with a free-flowing inert excipient and then directly pressed to obtain a tablet without granulation or dry pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a sugar or polymer material layer and a wax gloss layer may be present. Dyestuffs may be added to these coatings to allow for differentiation of different dosage units.

[0255] Oral liquids, such as solutions, syrups and elixirs, can be prepared in the form of dosage units so that a given amount contains a predetermined amount of compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, and elixirs are prepared using non-toxic alcoholic carriers. Suspensions can be prepared by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives, such as peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, etc. can also be added. If necessary, the dosage unit formulation for oral administration can be encapsulated in microcapsules. The formulation can also be prepared in a manner that the release is extended or delayed, for example, by coating or embedding the granular material in a polymer, wax, etc.

[0256] The compounds of formula (I) and their salts, solvates and physiologically functional derivatives can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

[0257] Formula (I) compound and its salt, solvate and physiological function derivative can also use delivery reagent such as monoclonal antibody, nucleic acid or nanoparticle to deliver as a single carrier, and compound molecule is coupled on the carrier or surrounded by the carrier.Compound can also be coupled with soluble polymer as targeted drug carrier.This polymer can contain polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethyl asparagine phenol or polyethylene oxide polylysine, which is replaced by palmitoyl group.These compounds can also be coupled with a class of biodegradable polymers suitable for realizing controlled release of drugs, such as crosslinking or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylate and hydrogel.

[0258] Pharmaceutical compositions suitable for transdermal administration can be administered as independent patches for prolonged close contact with the recipient's epidermis. Thus, for example, the active ingredient can be released from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318(1986). Pharmaceutical compounds suitable for topical administration can be formulated into ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0259] For treatment of the eye or other external tissues, for example mouth and skin, the formulation is preferably used as a topical ointment or cream. In the case of formulation to give an ointment, the active ingredient may be used with a paraffinic or water-miscible cream base. Alternatively, the active ingredient may be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.

[0260] Pharmaceutical compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[0261] Pharmaceutical compositions suitable for topical application in the mouth include lozenges, pastilles and mouthwashes.

[0262] Pharmaceutical compositions adapted for rectal administration may be administered in the form of suppositories or enemas.

[0263] Pharmaceutical compositions suitable for intranasal administration (wherein the carrier substance is a solid) comprise coarse powders having a particle size, for example, in the range of 20-500 microns, which are administered as a snuff, i.e., by rapid inhalation through the nasal passages from a container containing the powder close to the nose. Suitable formulations for administration as nasal sprays or nose drops with a liquid as carrier substance include solutions of the active ingredient in water or oil. Pharmaceutical formulations suitable for administration by inhalation include fine particulate dusts or mists, which can be generated by various types of pressurized dispensers with aerosols, nebulizers or insufflators.

[0264] Pharmaceutical compositions adapted for vaginal administration may be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0265] Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which contain antioxidants, buffers, antibacterial agents and solutes, by which the formulation is made isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may contain a suspension medium and a thickener. The formulation can be administered in single-dose or multiple-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, so that only a sterile carrier, such as water for injection, needs to be added immediately before use. Injections and suspensions prepared according to prescriptions can be prepared from sterile powders, granules and tablets.

[0266] It will be appreciated that in addition to the ingredients particularly mentioned above the compositions may include other agents conventional in the art having regard to the particular type of formulation; thus, for example, formulations suitable for oral administration may include flavoring agents.

[0267] The therapeutically effective amount of formula (I) compound depends on many factors, including, for example, the age and body weight of the subject (such as animals and people), the exact condition to be treated and its severity, the nature and administration of the formulation, and is ultimately determined by the treating doctor or veterinarian. However, the effective amount of the compound according to the present invention is generally in the range of 0.01 to 100mg / kg recipient (mammal) body weight per day, particularly typically in the range of 1 to 100mg / kg body weight per day. Therefore, the actual amount of an adult mammal with a body weight of 70kg is generally between 70-700mg, wherein the amount can be administered in a single dose per day, or generally in a series of partial doses (for example, twice, three times, four times, five times or six times) per day, so that the total dose is the same per day. The effective amount of its salt or solvate or physiological function derivative can be determined as the fraction of the effective amount of the compound itself according to the present invention. It can be assumed that similar dosage is applicable to the treatment of other conditions mentioned above.

[0268] Preparation of reactants and compounds according to the invention

[0269] Compounds according to the present invention and derivatives thereof can be prepared from readily available starting materials using methods and procedures known to the skilled person. It should be understood that typical or preferred experimental conditions (i.e., reaction temperature, time, number of moles of reagents, solvent, etc.) are given, and other experimental conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by those skilled in the art using conventional optimization procedures.

[0270] Scheme 1 below describes a general synthetic method for obtaining compounds of formula (I).

[0271]

[0272] Scheme 1: General synthesis of the furano-pyrimidine core

[0273] If the above-mentioned synthetic methods are not suitable for obtaining the furano-pyridine or furano-pyrimidine derivatives and / or necessary intermediates according to the present invention, suitable preparation methods known to those skilled in the art should be used. In general, the synthetic route of any individual furano-pyridine or furano-pyrimidine derivative will depend on the specific substituents of the respective molecule and the ready availability of the necessary intermediates; again, such factors are understood by those of ordinary skill in the art.

[0274] Further examples illustrating different synthetic strategies to obtain compounds or reactants according to the invention can be found in the examples disclosed below. Example

[0275] HPLC:

[0276] Perform LC purity trace using one of the following methods:

[0277] Method 1:

[0278] A Kinetex 2.6 μM C-18 column was used with a 2 μL injection volume and a flow rate of 0.7 mL / min; gradient: 15-100% B in 1.2 min (held for 3.3 min), 100-15% in 0.3 min (held for 1.2 min) (mobile phase A: 10 mM buffer (ammonium acetate / acetic acid) in H2O, mobile phase B: 10 mM buffer (ammonium acetate / acetic acid) in methanol).

[0279] Method 2:

[0280] A Kinetex 1.7 μM C-18 column was used with 1 μL injection volume and a flow rate of 1.2 mL / min; gradient: 5-100% B in 1.5 min (held for 0.4 min), 100-5% in 0.3 min (held for 0.5 min) (mobile phase A: 0.1% formic acid in H2O, mobile phase B: 0.1% formic acid in acetonitrile).

[0281] The present invention will be illustrated, but not limited, by reference to specific embodiments described in the following examples.

[0282] Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise stated, all temperatures are in °C and all reactions were performed at room temperature. Compounds were purified by silica gel chromatography or preparative HPLC.

[0283] Unless otherwise indicated, all structures below that do not indicate a specific stereochemistry refer to a mixture of stereoisomers (preferably a racemic mixture of stereoisomers).

[0284] Example 1: Synthesis of furano-pyrimidine core:

[0285]

[0286] Step-1: A mixture of methyl 3-aminothiophene-2-carboxylate (5 g, 0.035 mol), formamidine acetate (7.3 g, 0.070 g) and 2-methoxyethanol (50 mL) was stirred and heated at reflux for 3 hours. The mixture was cooled to ambient temperature and water (50 ml) was added. The resulting solid was separated, washed thoroughly with water and with ether and dried under vacuum to obtain furano[3,2-d]pyrimidin-4(3H)-one 2 (4.1 g, 85.06%). LCMS: Calculated for C6H6N6O2 136.11, Observed 137.1 (M+H), RT. 0.934 min, 94.28% (max). 1H NMR (400MHz, DMSO-d6): δ 12.60 (s, 1H), 8.23 ​​(d, J = 1.60 Hz, 1H), 8.07 (s, 1H), 6.99 (d, J = 2.00 Hz, 1H).

[0287] Step-2: Furano[3,2-d]pyrimidin-4(3H)-one 2(4.1 g) was placed in thionyl chloride (20 ml) and DMF (0.2 ml). Stir and reflux for 5 h. After completion of the reaction, the reaction mixture was concentrated to remove thionyl chloride, water was added to the reaction mixture, extracted with dichloromethane, and dried over anhydrous sodium sulfate. After concentration under vacuum, trituration was performed with hexane to obtain 4-chlorofurano[3,2-d]pyrimidine 3(4.1 g, 89.1%). LCMS: Calculated for C6H3ClN2O 154.55, Observed 155.1(M+H), RT.1.41 min, 97.42%(max). 1H NMR (400MHz, DMSO-d6): δ 8.92 (s, 1H), 8.68 (d, J = 2.40 Hz, 1H), 7.40 (d, J = 2.00 Hz, 1H).

[0288] Step-3: To 4-chlorofurano[3,2-d]pyrimidine 3 (2 g, 0.013 mol) in THF stirred at -78°C, 1.6 M solution of n-butyllithium (12.1 ml, 0.019 mol) in THF was added dropwise over 15 minutes. After stirring at -78°C for 2 hours, ICl (1.01 ml, 0.019 mol) was added dropwise and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phase was washed with 10% sodium thiosulfate solution, dried over sodium sulfate, and dried under reduced pressure after filtration. The obtained solid was washed with ether and dried to obtain 4-chloro-6-iodofurano[3,2-d]pyrimidine 4 (2 g, 55.2%) as a reddish orange solid. LCMS: Calculated for C6H2ClIN2O 280.45, observed 280.9 (M+H), RT. 1.94 min, 95.31% (max). 1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 7.72 (s, 1H).

[0289] General procedure for step 4:

[0290] To a stirred solution of 4-chloro-6-iodofuro[3,2-d]pyrimidine (0.285 mmol), R1-B(OH)2 (67.0 mg, 0.285 mmol) in 1,4-dioxane (3 ml) and water (1.00 ml) was added K2CO3 (0.571 mmol). The reaction mixture was then degassed for 5 minutes, followed by the addition of Pd(PPh3)4 (0.029 mmol). The reaction mixture was stirred at 90°C for about 3 hours. The solvent was evaporated to give a crude mixture of compound 5, which was used as is in the next step.

[0291] Manufacturing Example

[0292]

[0293] 4-(4-{4-chlorofuro[3,2-d]pyrimidin-6-yl}benzoyl)morpholine (building block): LCMS: calcd. 343.77; observed 344.0 (M+H).

[0294]

[0295] 4-Chloro-6-(4-methanesulfonylphenyl)furo[3,2-d]pyrimidine (building block): LCMS: calculated for C13H9ClN2O3S, exact mass: 308.73, observed 309.1 (M+H).

[0296]

[0297] (1R,4R)-5-(4-{4-chlorofuro[3,2-d]pyrimidin-6-yl}benzoyl)-2-oxa-5-azabicyclo[2.2.1]heptane (building block): LCMS: calculated for C18H14ClN3O3, exact mass 355.07, observed 356.0 (M+H).

[0298]

[0299] 4-Chloro-6-(4-methanesulfonylphenyl)furo[3,2-d]pyrimidine (building block): LCMS: calcd for C21H18FN304S 308.0, observed 309.0 (M+H).

[0300]

[0301] (2R,6S)-4-(4-{4-chlorofuro[3,2-d]pyrimidin-6-yl}benzoyl)-2,6-dimethylmorpholine (building block): LCMS: Calculated for C19H18ClN3O3 371.82, 372.0 (M+H).

[0302] General procedure for step 5:

[0303] To a stirred solution of compound 5 (0.233 mmol), R2-B(OH)2 (0.233 mmol) in 1,4-dioxane (4 ml) and water (1 ml) was added potassium carbonate (0.465 mmol). The reaction mixture was then degassed for 5 minutes, followed by the addition of Pd(PPh3)4 (0.029 mmol) and stirred at 110°C for about 16 hours. The resulting residue was purified by preparative HPLC to give compound 6.

[0304]

[0305] 2-(4-{6-[4-(morpholine-4-carbonyl)phenyl]furo[3,2-d]pyrimidin-4-yl}pyridin-2-yl)propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 8.20 (s, 1H), 8.03 (d, J = 5.60 Hz, 1H), 7.72-7.70 (m, 1H), 7.50 (d, J = 8.40 Hz, 2H), 6.90 (s, 3H), 3.01-2.52 (m, 8H), 0.90 (s, 6H). LCMS: Calculated for C25H24N4O4 343.77, observed 444.49 (M+H).

[0306] Manufacturing Example

[0307]

[0308] 2-{2-Fluoro-3-[6-(4-methanesulfonylphenyl)furo[3,2-d]pyrimidin-4-yl]phenyl}propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ9.20 (s, 1H), 8.28 (d, J=8.40 Hz, 2H), 8.15 (d, J=8.80 Hz, 2H), 8.10 (s, 1H), 7.95-7.91 (m, 1H), 7.84-7.80 (m, 1H), 7.46 (t, J=7.60 Hz, 1H), 5.50 (s, 1H), 3.31 (s, 3H), 1.62 (s, 6H). LCMS: calculated for C22H19FN2O4S, molecular weight: 426.1, observed 427.1 (M+H).

[0309] (4-(4-(2-fluoro-3-(2-hydroxypropyl-2-yl)phenyl)furo[3,2-d]pyrimidin-6-yl)phenyl)(imino)(methyl)-λ 6 -thioketone (D203): 1H NMR (400 MHz, DMSO): δ 9.18 (s, 1H), 8.23-8.21 (d, J = 8.4 Hz, 2H), 8.12-8.10 (d, J = 8.4 Hz, 2H), 8.045 (s, 1H), 7.94-7.91 (m, 1H), 7.83-7.80 (t, J = 6.8 Hz, 1H), 7.47-7.43 (t, J = 7.8 Hz, 1H), 5.48 (s, 1H), 4.39 (s, 1H), 3.14 (s, 3H), 1.61 (s, 6H). LCMS: Calculated for C22H20FN3O3S, 425.478, observed 426.2 (M+H).

[0310] The (S)- and (R)-enantiomers (D209 and D210, respectively) were separated using a Waters 2545 Quaternary Gradient Module with MassLynx software (version 4.1), a Waters 2424ELS detector, a Waters 2767 Sample Manager, and a Chiralpak IC 5 μM, (20 mm × 250 mm) chiral column using the following method. Isocratic elution: Hexane / CH2Cl2 / EtOH (50:25:25) D209 t R = 20.18 minutes (purity 100%), D210 t R = 29.02 minutes (purity 100%).

[0311] (S)-(4-(4-(2-fluoro-3-(2-hydroxypropyl-2-yl)phenyl)furo[3,2-d]pyrimidin-6-yl)phenyl)(imino)(methyl)-λ 6 -Thione (D209). Synthesis: See D203 above. Yield 43%. 1 H NMR (300MHz, MeOD-d4) δ = 9.11 (s, 1H), 8.19 (q, J = 8.4Hz, 4H), 7.95 (t, J = 7.8Hz, 1H), 7.80 ( d, J=7.1Hz, 1H), 7.71 (s, 1H), 7.44 (t, J=7.7Hz, 1H), 3.23 (s, 3H), 1.72 (s, 6H); analysis RP-HPLC t R = 2.34 min (method 2, purity 100%); LC-MS: m / z = 426.2 [M+H] + (For C 22 H 20 FN3O3S + Analytical calculation: m / z = 426.1).

[0312] (R)-(4-(4-(2-fluoro-3-(2-hydroxypropyl-2-yl)phenyl)furo[3,2-d]pyrimidin-6-yl)phenyl)(imino)(methyl)-λ 6 -Thione (D210). Synthesis: see D203 above. Yield 46%. 1 H NMR (300 MHz, DMSO-d6) δ = 9.25 (s, 1H), 8.29 (overlapping s, 2H), 8.22-8.09 (m, 3H), 7.99 (t, J = 7.8 Hz, 1H), 7.88 (t, J = 6.7 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 5.59 (s, 1H), 3.20 (s, 3H), 1.68 (s, 6H); analytical RP-HPLC tR = 2.34 min (method 2, purity 99%); LC-MS: m / z = 426.2 [M+H] + (For C 22 H 20 FN3O3S + Analytical calculation: m / z = 426.1).

[0313]

[0314] 2-(2-Fluoro-3-{6-[4-(4-methylpiperazine-1-carbonyl)phenyl]furo[3,2-d]pyrimidin-4-yl}phenyl)propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ9.81 (s, 1H), 9.18 (s, 1H), 8.12 (d, J=8.00 Hz, 2H), 7.98 (s, 1H), 7.93-7.80 (m, 1H), 7.67 (d, J=8.00 Hz, 2H), 7.45 (t, J=8.00 Hz, 1H), 3.13 (s, 4H), 2.84 (s, 4H), 1.62 (s, 6H). LCMS: calcd. for C26H27FN4O3 474.5, observed 475.2 (M+H).

[0315]

[0316] 2-[2-Fluoro-3-(6-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]phenyl}furo[3,2-d]pyrimidin-4-yl)phenyl]propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.08 (d, J = 8.40 Hz, 2H), 7.95-7.91 (m, 1H), 7.81-7.78 (m, 2H), 7.71 (d, J = 8.00 Hz, 2H), 7.43 (t, J = 7.60 Hz, 1H), 5.21 (s, 1H ), 4.63 (s, 2H), 3.88 (d, J = 7.20 Hz, 1H), 3.75 (s, 1H), 3.54 (dd, J = 1.20, 11.00 Hz, 1H), 3.35 (d, J = 9.60 Hz, 1H), 1.92 (d, J = 8.80 Hz, 1H), 1.83 (s, 1H), 1.64 (s, 6H). LCMS: calculated for C27H24FN3O4, exact mass 473.18, observed 474.2 (M+H).

[0317]

[0318] 2-{6-Fluoro-4-[6-(4-methanesulfonylphenyl)furo[3,2-d]pyrimidin-4-yl]pyridin-2-yl}propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.78 (s, 1H), 8.45 (d, J = 8.00 Hz, 2H), 8.19 (d, J = 7.20 Hz, 3H), 7.97 (s, 1H), 7.65-7.56 (m, 1H), 5.69 (s, 1H), 3.44 (s, 3H), 1.53 (s, 6H). LCMS: Calculated for C21H18FN304S 427.45, observed 428.0 (M+H).

[0319]

[0320] 2-[4-(6-{4-[(3S)-3-methylmorpholine-4-carbonyl]phenyl}furo[3,2-d]pyrimidin-4-yl)pyridin-2-yl]propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.85-8.83 (m, 1H), 8.56-8.56 (m, 1H), 8.35-8.33 (m, 1H), 8.08-8.06 (m, 1H), 7.63-7.61 (m, 3H), 7.38 (s, 1H), 4.88 (s, 1H), 3.95 (s, 1H), 3.72-3.69 (m, 2H), 3.58-3.45 (m, 2H), 1.72 (s, 6H), 1.44 (d, J = 6.80 Hz, 3H). LCMS: Calculated for C26H26N4O4 458.52, observed 459.1 (M+H).

[0321]

[0322] 2-(4-{6-[4-(4-methylpiperazine-1-carbonyl)phenyl]furo[3,2-d]pyrimidin-4-yl}pyridin-2-yl)propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ9.20 (s, 1H), 8.84-8.83 (m, 2H), 8.32-8.26 (m, 3H), 7.99 (s, 1H), 7.64 (d, J=8.40 Hz, 2H), 5.50 (s, 1H), 3.66 (s, 2H), 3.32-3.36 (m, 2H), 2.38 (s, 3H), 2.33-2.34 (m, 1H), 2.22 (s, 3H), 1.55 (s, 6H). LCMS: calcd. for C26H27N5O3 457.53, observed 458.1 (M+H).

[0323]

[0324] 2-(2-Fluoro-3-{6-[4-(morpholine-4-carbonyl)phenyl]furo[3,2-d]pyrimidin-4-yl}phenyl)propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.09 (d, J = 8.40 Hz, 2H), 7.93 (d, J = 6.00 Hz, 2H), 7.81 (s, 1H), 7.63 (d, J = 8.00 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 5.50 (s, 1H), 3.65 (s, 8H), 1.61 (s, 6H). LCMS: Calculated for C26H24FN3O4 461.493, observed 462.1 (M+H).

[0325]

[0326] 2-[4-(6-{4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]phenyl}furo[3,2-d]pyrimidin-4-yl)pyridin-2-yl]propan-2-ol: 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.84-8.82 (m, 2H), 8.33-8.27 (m, 3H), 7.99 (s, 1H), 7.66 (d, J=8.40 Hz, 2H), 5.50 (s, 1H), 4.43-4.40 (m, 1H), 3.59-3.50 (m, 2H), 3.44-3.27 (m, 1H), 2.68-2.56 (m, 1H), 1.55 (s, 6H), 1.40-1.10 (m, 6H). LCMS: Calculated for C27H28N4O4 472.55, observed 473.3 (M+H).

[0327]

[0328] 2-(3-Fluoro-4-(6-(4-(methylsulfonyl)phenyl)furo[3,2-d]pyrimidin-4-yl)pyridin-2-yl)propan-2-ol. Yield 51% as a white solid. 1H NMR (300 MHz, MeOD-d4) δ = 9.22 (s, 1H), 8.64 (dd, J = 4.9, 1.1 Hz, 1H), 8.37-8.26 (m, 2H), 8.21-8.11 (m, 2H), 7.95 (t, J = 4.9 Hz, 1H), 7.83 (s, 1H), 3.21 (s, 3H), 1.75 (d, J = 1.4 Hz, 6H); analytical RP-HPLC tR = 0.959 min (method 2, purity 99%); LC-MS ESI: m / z = 428.1 [M+H]+ (calculated for C21H19F3O4S+: m / z = 428.1).

[0329]

[0330] (4-(4-(3-Fluoro-2-(2-hydroxypropan-2-yl)pyridin-4-yl)furo[3,2-d]pyrimidin-6-yl)phenyl)(morpholinyl)methanone. Yield 24% as a white solid. 1H NMR (300 MHz, MeOD-d4) δ = 9.12 (s, 1H), 8.60 (d, J = 4.9 Hz, 1H), 8.10 (s, 2H), 7.89 (dd, J = 4.8, 4.8 Hz, 1H), 7.61 (s, 3H), 3.77 (s, 4H), 3.64 (s, 2H), 3.48 (s, 2H), 1.71 (s, 6H); analytical RP-HPLC tR = 0.941 min (method 2, purity 99%); LC-MS ESI: m / z = 463.2 [M+H]+ (calculated for C25H24F4O4+: m / z = 463.2).

[0331]

[0332] ((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)(4-(4-(3-fluoro-2-(2-hydroxypropan-2-yl)pyridin-4-yl)furo[3,2-d]pyrimidin-6-yl)phenyl)methanone. Yield 27% as a white solid. 1H NMR (300MHz, MeOD-d4) δ=9.17 (s, 1H), 8.63 (dd, J=4.8, 1.0Hz, 1H), 8.15 (d, J=9.9, 8.2Hz, 2H), 7.93 (dd, J=4.8, 4.8Hz, 1H), 7.80-7.66 (m, 3H), 4.7 9-4.40 (m, 2H), 4.02 (dd, J=10.1, 7.7Hz, 1H), 3.94-3.78 (m, 1H), 3.68-3. 60(m, 1H), 3.57-3.35(m, 1H), 2.12-1.88(m, 2H), 1.74(s, 6H); analytical RP-HPLC tR = 0.920 min (method 2, purity 100%); LC-MS ESI: m / z = 475.2 [M+H] + (calculated for C26H24F4O4 +: m / z = 475.2).

[0333] Biological Activity

[0334] Example 2: Effects of Compounds on the Growth of Plasmodium

[0335] Plasmodium PI4K is a recently identified drug target for anti-malarial drugs. The compounds according to the invention were tested for properties related to inhibition of Plasmodium growth, in which PI4K plays an important role. Low concentrations of the compounds required to inhibit Plasmodium growth are preferred.

[0336] In vitro Plasmodium falciparum assay

[0337] The compounds according to the invention were screened in vitro against a sensitive (NF54) strain of Plasmodium falciparum using a modified [3H] hypoxanthine incorporation assay (Vennerstrom, JL; Arbe-Barnes, S.; Brun, R.; Charman, S.A.; Chiu, F.C.K.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Tomas, J.S.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S. and Charman, W.N. Dentistry of an Antimalarial Synthetic Trioxolane Drug Development Candidate. Nature, 2004, 430, 900-904).

[0338] The compound concentration that inhibited the growth of P. falciparum by 50% compared to untreated controls was expressed in nM (IC 50 ) is the measurement.

[0339] Table 1: Growth inhibition of Plasmodium falciparum by compounds according to the invention

[0340]

[0341]

[0342] IC50: <10nM=A, 10-50nM=B, >50nM=C

[0343] These data demonstrate the potency of the compounds according to the invention in inhibiting the growth of P. falciparum and underscore their usefulness as a new generation of antimalarial drugs.

[0344] Example 3: Compound pairs Human PI4K The influence of activity

[0345] Although Plasmodium PI4K is a desirable drug target, many compounds known in the art that target this enzyme show cross-inhibitory properties with closely related enzymes from other species. In this context, human PI4K may be a problematic off-target because it is involved in essential processes in animals. Therefore, in the case of antimalarials, it would be desirable to specifically inhibit Plasmodium PI4K while only mildly affecting human PI4K.

[0346] To further test the effects of the compounds according to the present invention on human PI4Kβ, the HuPI4Kβ inhibition of the selected compounds was tested and compared with the results of the inhibition of the PfNF54 strain described in the above examples.

[0347] The lipid kinase reaction was performed by incubating the lipid substrate (PI:3PS or PIP2:3PS) with the recombinant enzyme and ATP and using ADP-Glo TM Kinase assays are used to measure kinase activity. First, the kinase reaction is terminated and any ATP remaining after the reaction is consumed, leaving only ADP. A kinase detection reagent is then added to convert ADP to ATP for the coupled luciferin / luciferase reaction. The luminescent output is measured and correlated with kinase activity. This assay can be performed in 96 or 384 well plates and can be used for enzyme characterization, inhibitor screening, or compound profiling.

[0348] The results of measuring the effects of compounds on HuPI4Kβ are shown in Table 2 in nM (IC 50 ) reports describing the concentration required to inhibit 50% of the enzyme activity (HuPI4Kβ IC50 (nM)).

[0349] As mentioned above, nM (IC 50 )(PfNF54 IC50 (nM)) measures the concentration of compound that inhibits the growth of P. falciparum by 50% compared to untreated controls.

[0350] Table 2: Inhibitory properties of compounds

[0351]

[0352]

[0353] IC50: <10nM=A,10-50nM=B,>50nM

[0354] IC50: <50nM=+++, 50-100nM=++, 100-500nM=+, >500=-

[0355] As shown in Table 2, in addition to Plasmodium-derived PI4K, several compounds also showed high potency in inhibiting human PI4K. However, most compounds showed low inhibitory properties against human PI4K while strongly inhibiting Plasmodium growth. Therefore, these data illustrate the excellent use of the compounds according to the present invention in the treatment and / or prevention of malaria.

[0356] Example 4: Effects of Compounds on Sensitive Plasmodium Strains

[0357] Other compounds according to the invention have been tested for growth inhibition of the NF54 strain in order to evaluate the concentrations required to reduce parasite viability and to test the efficiency of different compounds according to the invention in preventing parasite growth.

[0358] In vitro anti-plasmodium activity—Assay A

[0359] The test samples were screened for in vitro anti-plasmodial activity against a chloroquine-sensitive (CQS) strain (NF54) of the malarial parasite Plasmodium falciparum. Continuous in vitro cultures of asexual erythrocytic stages of P. falciparum were maintained using a modified version of the method of Trager and Jensen (1976).1. The in vitro anti-plasmodial activity was quantitatively assessed by the parasite lactate dehydrogenase assay using a modified method described by Makler (1993). The test samples were tested in triplicate on two different occasions. On the day of the experiment, further dilutions were prepared in complete medium. If the sample was not completely dissolved, it was tested as a suspension. Chloroquine and artesunate were used as reference drugs.

[0360] In vitro anti-plasmodium activity—Assay B

[0361] Compounds were screened in vitro against a CQC-sensitive strain (NF54) of P. falciparum as described by Vennerstrom et al. (2004).

[0362] A full dose response was performed starting at a concentration of 3000 nM, followed by a 2-fold serial dilution in complete medium to yield 10 concentrations; the lowest concentration was approximately 6 nM. The same dilution technique was used for all samples. The reference was tested at a starting concentration of 1000 ng / mL. The highest concentration of solvent to which the parasites were exposed had no measurable effect on parasite viability (data not shown).

[0363] Table 3: Inhibitory properties of compounds on malarial parasite growth

[0364]

[0365]

[0366]

[0367] IC50: <15nM=A, 15-50nM=B, >50nM=C

[0368] The above data further provide clear evidence for the use of compounds according to the present invention for the treatment and / or prevention of malaria. Concentrations as low as <1 nM are able to inhibit Plasmodium growth by 50%.

[0369] Example 5: In vitro Plasmodium vivax liver stage assay

[0370] Compounds were evaluated for their efficacy against P. vivax liver schizonts and hypnozoites in infected primary human hepatocytes (PHH). Compound screening was performed in 384-well plates in a 12-point dose response starting at 50 μM. All compounds were tested in free radical curing mode (RCM).

[0371] Two days before Plasmodium vivax sporozoite infection, PHH was inoculated into 384-well plates. In RCM, starting from the 5th day after infection, compounds were added to the culture in two duplicate wells for three days. Nigericin and PI4K inhibitor (KDU691) were used as positive controls in each assay, while solvent (DMSO) without adding compounds was used as negative controls. Culture medium was changed every day, and culture was fixed on the 12th day after infection to ensure complete removal of parasites. Fixed cells were permeabilized and stained with anti-UIS4 first antibody and fluorescent second antibody. Liver stage schizonts and dormant schizonts were then quantified by high content imaging.

[0372] Roth, A. et al., A comprehensive model for assessment of liver stagetherapies targeting Plasmodium vivax and Plasmodium falciparum. Nat. Commun. 2018, 9(1), 1837.doi.org / 10.1038 / s41467-018-04221-9.

[0373] Table 4: In vitro assay data for the liver stage of Plasmodium vivax

[0374] Compound ID / Structure <![CDATA[Pv Sleep Sub-IC 50 (nM)]]> <![CDATA[Pv schizont IC 50 (nM)]]> D149 A A D183 A A D201 B A D203 B A D213 C A

[0375] IC50: <15nM=A, 15-50nM=B, >50nM=C.

Claims

1. A compound according to formula (I), or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof, wherein: R indicates AR1 or HT1; AR1 represents phenyl which is unsubstituted or substituted by: - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN and / or NO2; and / or - a substituent selected from the group consisting of: A、NH2、OH、(CR a R b ) n HetCyc1、(CR a R b ) n HetAr1、(CR a R b ) n Aryl、(CR a R b ) n CO(R a R b ) m HetCyc1、(CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl、(CR a R b ) n COCyc、(CR a R b ) n COA、(CR a R b ) n CONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、(CR a R b ) n SOHetCyc1(NA)、(CR a R b ) n SOHetAr1(NA)、(CR a R b ) n SOA(NCyc)、(CR a R b ) n SOCyc(NCyc)、(CR a R b ) n SOAryl(NCyc)、(CR a R b ) n SOHetCyc1(NCyc)、(CR a R b ) n SOHetAr1(NCyc)、(CR a R b ) n SO2NA2、(CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA and (CR a R b ) n POA2; HT1 represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 3 to 9 carbon atoms and 1, 2, 3 or 4 N, O and / or S atoms, wherein the heterocycle is unsubstituted or substituted by: - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN, =O and / or NO2; and / or - substituents selected from the group consisting of: A、NH2、OH、(CR a R b ) n HetCyc1、(CR a R b ) n HetAr1、(CR a R b ) n Aryl、(CR a R b ) n CO(R a R b ) m HetCyc1、(CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl、(CR a R b ) n COCyc、(CR a R b ) n COA、(CR a R b ) n CONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、(CR a R b ) n SOHetCyc1(NA)、(CR a R b ) n SOHetAr1(NA)、(CR a R b ) n SOA(NCyc)、(CR a R b ) n SOCyc(NCyc)、(CR a R b ) n SOAryl(NCyc)、(CR a R b ) n SOHetCyc1(NCyc)、(CR a R b ) n SOHetAr1(NCyc)、(CR a R b ) n SO2NA2、(CR a R b ) n SO2NH2、(CR a R b ) n SO2NHA or (CR a R b ) n POA2; Q represents a structure according to formula (II) R 1 Indicates AR2 or HT2; R 2 , R 3 and R 4 independently of each other, expressed H, Hal, or CAlk2; Y represents CH, CHal, CAlk2, CCHal3 or N; AR2 represents phenyl which is unsubstituted or substituted by: - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN and / or NO2 (preferably Alk2, OAlk2, Hal and / or Cyc); and / or - a substituent selected from the group consisting of: A、NH2、OH、(CR a R b ) n HetCyc1、(CR a R b ) n HetAr1、(CR a R b ) n Aryl、(CR a R b ) n CO(R a R b ) m HetCyc1、(CR a R b ) n CO(R a R b ) m HetAr1、(CR a R b ) n CO(R a R b ) m Aryl、(CR a R b ) n COCyc、(CR a R b ) n COA、(CR a R b ) n CONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、 (CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、 (CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、 (CR a R b ) n SOHetCyc1(NH)、 (CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、 (CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、 (CR a R b ) n SOHetCyc1(NA), (CR a R b ) n SOHetAr1(NA)、(CR a R b ) n SOA(NCyc)、(CR a R b ) n SOCyc(NCyc)、(CR a R b ) n SOAryl(NCyc)、(CR a R b ) n SOHetCyc1(NCyc)、 (CR a R b ) n SOHetAr1(NCyc)、(CR a R b ) n SO2NA2、 (CR a R b ) n SO2NH2, (CR a R b ) n SO2NHA and (CR a R b ) n POA2; HT2 represents a moiety having 3 to 9 carbon atoms and 1, 2, 3 or 4 N, A monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle containing O and / or S atoms, wherein the heterocycle is unsubstituted or substituted by: - 1, 2 or 3 substituents independently selected from: Alk2, OAlk2, Hal, Cyc, CN, =O and / or NO2 (preferably Alk2, OAlk2, Hal and / or Cyc); and / or - a substituent selected from the group consisting of: A、NH2、OH、(CR a R b ) n HetCyc1、 (CR a R b ) n HetAr1、(CR a R b ) n Aryl、 (CR a R b ) n CO(R a R b ) m HetCyc1、 (CR a R b ) n CO(R a R b ) m HetAr1、 (CR a R b ) n CO(R a R b ) m Aryl、(CR a R b ) n COCyc、 (CR a R b ) n COA、(CR a R b ) n CONA2、(CR a R b ) n CONH2、(CR a R b ) n CONHA、(CR a R b ) n CONR Cyc3 R Cyc4 、(CR a R b ) n CONH(CR a R b ) m HetCyc1、(CR a R b ) n CONH(CR a R b ) m HetAr1、(CR a R b ) n CONH(R a R b ) m Aryl、(CR a R b ) n CONHCyc、(CR a R b ) n COOA、(CR a R b ) n COOH、(CR a R b ) n COO(CR a R b ) m HetCyc1、(CR a R b ) n COO(CR a R b ) m HetAr1、(CR a R b ) n COO(R a R b ) m Aryl、(CR a R b ) n COOCyc、(CR a R b ) n NHCO(R a R b ) m HetCyc1、(CR a R b ) n NHCO(R a R b ) m HetAr1、(CR a R b ) n NHCO(R a R b ) m Aryl、(CR a R b ) n NHCOCyc、(CR a R b ) n NHCOA、(CR a R b ) n S(R a R b ) m HetCyc1、(CR a R b ) n S(R a R b ) m HetAr1、(CR a R b ) n S(R a R b ) m Aryl、(CR a R b ) n SA、(CR a R b ) n SO(R a R b ) m HetCyc1、(CR a R b ) n SO(R a R b ) m HetAr1、(CR a R b ) n SO(R a R b ) m Aryl、(CR a R b ) n SOA、(CR a R b ) n SO2(R a R b ) m HetCyc1、(CR a R b ) n SO2(R a R b ) m HetAr1、(CR a R b ) n SO2(R a R b ) m Aryl、(CR a R b ) n SO2Cyc、(CR a R b ) n SO2A、(CR a R b ) n SOA(NH)、(CR a R b ) n SOCyc(NH)、(CR a R b ) n SOAryl(NH)、(CR a R b ) n SOHetCyc1(NH)、(CR a R b ) n SOHetAr1(NH)、(CR a R b ) n SOA(NA)、(CR a R b ) n SOR Cyc1 (NR Cyc2 )、(CR a R b ) n SOCyc(NA)、(CR a R b ) n SOAryl(NA)、(CR a R b ) n SOHetCyc1(NA), (CR a R b ) n SOHetAr1(NA)、(CR a R b ) n SOA(NCyc)、(CR a R b ) n SOCyc(NCyc)、(CR a R b ) n SOAryl(NCyc)、(CR a R b ) n SOHetCyc1(NCyc)、 (CR a R b ) n SOHetAr1(NCyc)、(CR a R b ) n SO2NA2、 (CR a R b ) n SO2NH2, (CR a R b ) n SO2NHA and (CR a R b ) n POA2; A represents a straight-chain or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, wherein: - one or two non-adjacent CH2 groups may be replaced by O, NAlk2 or NH; and / or - 1, 2, 3, 4 or 5 hydrogens may be replaced by Hal; and / or - one hydrogen may be replaced by OH or NH2 or a cyclic alkyl group having 3, 4, 5 or 6 carbon atoms which is mono-, di- or tri-substituted by Hal, OH, Alk2, NHAlk2, N(Alk2)2 and / or NH2; Alk1 represents a straight-chain or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, wherein - one or two CH2 groups may be replaced by O, NAlk2 or NH; and / or - 1 hydrogen can be replaced by OH, NHAlk2, N(Alk2)2 or NH2; and / or -1, 2, 3, 4 or 5 hydrogens can be replaced by Hal; Alk2 represents a straight or branched alkyl group having 1 to 6 carbon atoms, 1, 2, 3, 4 or 5 of the hydrogens may be replaced by Hal; Aryl represents phenyl which is unsubstituted or mono-, di- or tri-substituted by Hal, Alk2, OAlk2, OH, NH2 or Cyc; HetCyc1 represents a mono- or bi-cyclic, optionally bridged, saturated or unsaturated 4- to 10-membered heterocycle having 1 or 2 heteroatoms selected from N, O, S and / or Si, wherein the heterocycle may be unsubstituted or mono- or di-substituted by Hal, OH, A, SO2Alk2 and / or =O; Cyc represents a cyclic alkyl group having 3 to 6 carbon atoms, in which 1, 2 or 3 hydrogens may be replaced by Hal and 1 additional hydrogen may be replaced by Alk2, NH2 and / or OH; Hal means F or Cl; HetAr1 represents a monocyclic or bicyclic aromatic 4- to 12-membered heterocycle having 1, 2, 3 or 4 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by Hal, Alk2, SOAlk2, SO2Alk2, OH or NH2; R a and R b Each independently represents H, Alk2 or Cyc; or R a and R b Common Representative - (CH2) x -, wherein x = 2, 3, 4 or 5, thus forming together with the carbon atoms to which they are attached a (3-, 4-, 5- or 6-membered) cycloalkyl ring; R Cyc1 and R Cyc2 Together they form -(CH2) x -, wherein x = 3 or 4, thus forming together with the atoms to which they are attached a (5- or 6-membered) ring, wherein in -(CH2) x -1 or 2 H atoms in can be replaced by Hal or Alk1 independently; R Cyc3 and R Cyc4 Together they form -(CH2) x , wherein x = 3, 4 or 5, thus forming together with the nitrogen atom to which they are attached a (4-, 5- or 6-membered) ring, wherein in -(CH2) x -1 or 2 H atoms can be replaced by Hal or Alk1 independently; n represents 0, 1 or 2; and m represents 0 or 1.

2. The compound according to claim 1, wherein R represents a structure according to formula (IV), (V), (Va) or (VI) in R 6 represents OH, A or Cyc or a substituent according to formula (VII) to (X) in R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 each independently represents H, OH, Hal, CH3, C2H5, CHal3, OCH3, OCHal3, OCHal2, OCH2Hal, CH2Hal and / or CHHal2; R 15 Indicates NR 17 or O; R 16 Indicates A or Cyc; R 17 represents H, Alk1 or a cyclic alkyl group having 3 to 6 carbon atoms, wherein 1, 2 or 3 hydrogen atoms of the cyclic alkyl group may be replaced by Hal; X 1 represents N or CH; and X 2 represents NH, NAlk1, or O.

3. The compound according to any one of claims 1 or 2, wherein Q represents a structure according to formula (XI) The residue R 2 , R 3 and R 4 One or two of the residues independently represent Hal, CH3, CHal3, OCH3, OCHal3, OCHHal2, OCH2Hal, CH2Hal and / or CHHal2, and the remaining one or more residues represent H.

4. The compound according to claim 1, which is selected from: and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5. A compound according to any one of claims 1 to 4 for use in inhibiting PI4K.

6. The compound according to any one of claims 1 to 4 for use in the treatment and / or prevention of PI4K-related disorders.

7. The compound of claim 6, wherein the PI4K-related disorder is a protozoan infection or a viral infection.

8. The composition of claim 7, wherein the protozoan infection is malaria.

9. The compound of claim 8, wherein the viral infection is an RNA viral infection.

10. A pharmaceutical composition comprising at least one compound of formula (I). The pharmaceutical composition according to claim 10 , for use in treating and / or preventing a PI4K-related disorder.

12. The pharmaceutical composition according to any one of claims 10 or 11, further comprising at least one other active ingredient, wherein the other active ingredient is at least one antimalarial agent different from formula (I).

13. The pharmaceutical composition according to any one of claims 10 to 12, further comprising a pharmaceutically acceptable carrier, diluent or excipient thereof.

14. A method for preventing or treating a PI4K-related disorder, wherein the method comprises the following steps: (i) providing at least one compound according to any one of claims 1 to 4 and / or a pharmaceutical composition according to any one of claims 10 to 13; and (ii) administering an effective amount of the at least one compound or the composition to a patient in need thereof.

15. The method of claim 14, wherein the PI4K-related disorder is malaria.

16. The compound according to claim 1, wherein R has the structure of formula (IV): in R 6 Alk1、Alk2、-OH、-CH3、-OCH3、-OC(CH3)3、-N(CH3)2、 W is O, NR 18 or CR 18 R 19 ; R 7 , R 8 Each is independently selected from -H or Hal; R 18 , R 19 Each is independently selected from -H, -CH3 or Alk1; X 1 Yes CR 7 or N; and wherein Q is of formula II, and R 1 It's H, Hal, R 2 , R 3 , R 4 Each independently selected from H or Hal; R 28 is Alk1, Alk2, -NH2, R 29 , R 30 Each is independently selected from -H or -CH3; Y is N, CH or CHal.

17. The compound according to claim 1, wherein R has the structure of formula (V): X 1 Yes CR 7 or N; R 7 , R 8 Each independently selected from H, Hal or CHal3; R 15 is O or NH; R 16 is H, -CH3, -NH2, -N(CH3)2, or Alk1; and wherein Q is of formula II, and R 1 It's H, Hal, R 2 , R 3 , R 4 Each independently selected from H or Hal; R 28 It is Alk1, Alk2, -NH2, R 29 , R 30 Each independently selected from H or CH3; Y is N, CH or CHal.

18. The compound according to claim 1, wherein R has the following structure: R 18 , R 19 are each independently selected from H, -CH3 or Alk1; and R 27 is -CH3 or -C((CH3)2OH); wherein Q is of formula II, and R 1 It's H, Hal, R 2 , R 3 , R 4 Each independently selected from H or Hal; R 28 It is Alk1, Alk2, -NH2, R 29 , R 30 Each independently selected from H or CH3; Y is N, CH or CHal.

19. The compound according to claim 16, wherein R 6 are -CH3, -OH, -N(CH3)2; W is O; R 7 , R 8 It is H; R 18 , R 19 Each is independently selected from -H or -CH3; X 1 It is CH or N.

20. The compound according to claim 19, wherein R 6 yes and R 1 yes 21. The compound according to claim 17, wherein R 1 Selected from H, Hal or R 2 , R 3 , R 4 , R 7 , R 8 Each independently selected from H or Hal; R 16 is -CH3 or Alk1; X 1 is CH; and Y is CH or CHal.

22. The compound according to claim 21, wherein R 1 yes R 2 , R 7 , R 8 Each independently selected from H or Hal; R 3 , R 4 It is H; R 15 It is NH; R 16 is -CH3 or Alk1; X 1 is CH; and Y is CH.

23. The compound according to claim 22, wherein SOR of formula V 15 R 16 The groups are orthogonal to the bonds of formula I.

24. The compound according to claim 23, wherein R 3 and R 4 It's H.

25. The compound according to claim 24, wherein X 1 It is CH.

26. The compound according to claim 25, wherein R 1 yes R 2 , R 7 , R 8 Each independently selected from H or Hal; R 3 , R 4 It is H; R 15 It is NH; R 16 is -CH3; X 1 is CH; and Y is CH.

27. The compound according to claim 26, wherein the compound is 28. The compound according to claim 26, wherein the compound is 29. The compound according to claim 26, wherein the compound is

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