Furopyrimidine derivatives

Abstract

The present invention relates to novel compounds with valuable properties, particularly compounds that can be used in the preparation of pharmaceuticals, and methods for their use and preparation. The compounds are particularly useful as PI4K inhibitors and in the treatment or prevention of PI4K-associated disorders, such as protozoal and viral infections, including malaria.

Description

[Technical Field]

[0001] Background of the Invention Field of invention The present invention relates to novel compounds with valuable properties, particularly compounds that can be used in the preparation of pharmaceuticals, and methods for their use and preparation. The compounds are particularly useful as PI4K inhibitors and for the treatment or prevention of PI4K-associated disorders, such as protozoal infections, including malaria and viral infections.

[0002] 2. Description of Related Art Malaria poses a significant global health burden, with an estimated 229 million new cases and approximately 409,000 deaths in 2019, most of which affect young children and pregnant women (World Malaria Report 2020, World Health Organization: Geneva, Switzerland, 2020). It is a vector-borne infectious disease caused by blood protozoan parasites of the genus Plasmodium (Phillips, MA et al., Malaria. Nat. Rev. Dis. Prim. 2017, 3, 17050). According to World Health Organization (WHO) data, the majority of malaria-related morbidity and mortality in sub-Saharan Africa was caused by Plasmodium falciparum.

[0003] Currently, the WHO recommends artemisinin-based combination therapy (ACT). Furthermore, vector control measures play an important role in reducing the burden of malaria. However, reports of the emergence of resistance to ACTs (Dondorp, A. M et al., Artemisinin Resistance in Plasmodium falciparum Malaria. N. Engl. J. Med. 2009, 361, 455-467) indicate that a new generation of drugs is needed to combat resistance and improve standard treatment for the millions of affected patients. In recent years, research has identified novel drug target structures that may affect the viability of the malaria parasite. The limited number of validated drug targets, such as dihydrofolate reductase, cytochrome c oxidoreductase, and hemozoin formation, represents a promising starting point for the development of new antimalarial compounds, highlighting the need to expand the chemistry toward more effective drugs with novel mechanisms of action and multiphase antiparasitic activity.

[0004] Within this context, Plasmodium kinases are attractive targets for a new generation of antimalarial drugs, as both protein and lipid kinases are involved in key signaling pathways at different stages of the parasite life cycle and have undergone some genetic or phenotypic validation (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).

[0005] For example, lipid kinases are important in all stages of the malaria parasite life cycle. This includes phosphatidylinositol-4-kinase (PI4K), which catalyzes the conversion of phosphatidylinositol (PI) to phosphatidylinositol-4-phosphate (PI4P). Phosphatidylinositol 4-kinase type III beta (PI4KIIβ) is a ubiquitous eukaryotic enzyme that phosphorylates lipids to regulate intracellular signaling and transport. Imidazopyrazines are known inhibitors of PI4K. In the blood stage of malaria, imidazopyrazines block the later stages of parasite development by interfering with the invasion of the surrounding plasma membrane by developing daughter merozoites. This may be due to alterations in the phosphatidylinositol-4-phosphate (PI4P) pool and disruption of Rab11A-mediated membrane trafficking. (McNamara, CW et al., Targeting Plasmodium PI(4)K to Eliminate Malaria. Nature 2013, 504 (7479), 248-253). Therefore, Plasmodium PI4K is important for signal transduction and membrane trafficking, and has been shown to be an effective drug target for the prevention, treatment, and eradication of malaria.

[0006] Recently, several drugs have been reported as Plasmodium PI4K inhibitors, including the 2-aminopyridine MMV390048, which has entered 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 other related compounds (PvPI4k, Pv = Plasmodium vivax) are listed below. [ka]

[0007] Although PI4K has been identified as a useful target for treating protozoan infections, human PI4K is also well known to be hijacked by viruses. In particular, human PI4KIIβ is an important host target of viruses, including RNA viruses [PMID:20510927; PMID:33022924]. Therefore, PI4K inhibitors show great potential for the treatment of PI4K-related disorders, such as viral and malaria infections.

[0008] WO 2012 025187 A1 discloses heterocyclic compounds useful as inhibitors of Syk that can be used to treat rheumatoid arthritis and / or systemic lupus. WO 2013 117285 A1 discloses heterocyclic compounds useful as inhibitors of TBK1 and IKKε that can be used to treat cancer and inflammatory diseases. WO 2013 124025 A1 discloses heterocyclic compounds useful as inhibitors of Syk that can be used to treat rheumatoid arthritis and / or systemic lupus. WO 2017 003995 A1 discloses heterocyclic compounds useful as TBK / IKK inhibitors. WO 2011 086531 A1 and WO 2013 121387 A1 disclose the use of aminopyridine derivatives in the manufacture of medicaments for the prevention or treatment of malaria. Specifically, the disclosure relates to aminopyridine derivatives useful for inhibiting the growth of malaria parasites.

[0009] While many new compounds are under development, there is a growing need for broader, more effective agents that target PI4K to enable combination therapy that suppresses the development of resistance to single compounds. Furthermore, several lead structures that have demonstrated acceptable PI4K inhibition require high doses to be effective in vivo. Continuous development and refinement of compounds is necessary to adapt their biophysical properties and increase their bioavailability and tolerability in clinical settings. Therefore, the objective of the present invention was to overcome the drawbacks associated with the state-of-the-art technology and provide a highly effective alternative.

[0010] Summary of the Invention The present invention provides compounds according to formula (I), which have been shown to be useful in the prevention and / or treatment of PI4K-related disorders, such as malaria or viral infections, and further relates to pharmaceutical compositions comprising said compounds. In particular, the compounds according to the present invention have shown high selectivity in inhibiting human PI4K, but only to a limited extent, thereby providing drugs with potentially fewer side effects due to human PI4K inhibition. [ka] (I) In another aspect, the present invention provides compounds of formula (I) suitable as PI4K inhibitors, which preferably inhibit malaria parasite PI4K and significantly reduce proliferation.

[0011] 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. In certain embodiments, the present invention provides compounds of formula (I) that inhibit human PI4K, more preferably human PI4KIIβ.

[0012] In one embodiment, the present invention provides a compound of formula (I) for use in the prevention and / or treatment of a viral infection, most preferably a viral infection caused by an RNA virus. In a further aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) for use in the prevention and / or treatment of a PI4K-associated disorder. In another embodiment, the present invention provides a method for the treatment and / or prevention of malaria comprising administering a compound of formula (I). In another aspect, the present invention provides compounds that are capable of modulating, and in particular inhibiting, the activity of PI4K in disease states in mammals.

[0013] For convenience, certain terms used in the specification, examples, and accompanying embodiments are collected here to provide definitions of the various chemical moieties that make up the compounds in accordance with the invention, and are intended to be applied uniformly throughout the specification and embodiments, unless a definition expressly set forth otherwise provides a broader definition.

[0014] 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 hydroxides, carbonates, or bicarbonates of a metal cation, such as those selected from the group consisting of alkali metals (sodium, potassium, or lithium), alkaline earth metals (e.g., calcium or magnesium). Also included are salts formed by acid addition, salts formed with inorganic acids (e.g., hydrochloric acid, oleic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as 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, naphthalenedisulfonic acid, and polygalacturonic acid.

[0015] A "pharmaceutically active compound" refers to any compound capable of directly or indirectly providing the activity disclosed herein upon administration to a recipient. The term "indirectly" also encompasses prodrugs that can be converted to active drug forms by endogenous enzymes or metabolism. Prodrugs are derivatives of compounds according to the present invention and exhibit antimalarial activity by possessing chemically or metabolically degradable groups, and can be converted in vivo to pharmaceutically active compounds according to the present invention upon dissolution under physiological conditions. Prodrugs are converted to compounds according to the present invention under physiological conditions in vivo by reaction with enzymes or gastric acid, for example, by oxidation, reduction, hydrolysis, or the like, each of which is enzymatic. These compounds can be prepared from compounds of the present invention according to well-known methods.

[0016] The term "solvates" of a compound is understood to mean adductions of inert solvent molecules onto the compound which form owing to their mutual attractive forces. Solvates are, for example, mono- or dihydrates or alkoxides. The term "indirectly" also includes metabolites of the compounds according to the invention. The term "metabolite" refers to any molecule derived from any of the compounds according to the invention in a cell or organism, preferably a mammal. The term "malaria" includes diseases and conditions associated with infection with the malaria parasite.

[0017] As used herein, "treating" and "treatment" generally refer to obtaining a desired pharmacological and physiological effect. The effect may be prophylactic, in that a disease, symptom, or condition is prevented or partially prevented, or therapeutic, in that a disease, condition, symptom, or side effect resulting from the disease is partially or completely cured. As used herein, the term "treatment" refers to the treatment of mammalian, particularly human, disease, and includes (a) preventing the onset of disease in a subject who may be susceptible to the disease but has not yet been diagnosed with it, and (b) suppressing the disease, i.e., preventing its onset, or alleviating the disease, i.e., causing regression of the disease and / or its symptoms or condition. The term "effective amount" includes a "prophylactically effective amount" and a "therapeutically effective amount." The term "prophylactically effective amount" refers to a concentration of a compound of the invention that, when administered pre-infection, i.e., before, during, and / or shortly after the period of exposure to the malaria parasite, is effective in suppressing, reducing the likelihood of developing, or preventing malaria infection or delaying the onset of malaria parasite disease.

[0018] The term "prophylaxis" encompasses causal prophylaxis, i.e., antimalarial activity involving prevention of pre-erythrocytic development of the parasite; suppressive prophylaxis, i.e., antimalarial activity involving inhibition of the development of blood-stage infection; and terminal prophylaxis, i.e., antimalarial activity involving inhibition of the development of intrahepatic stage infection. This term encompasses primary prophylaxis (i.e., prevention of initial infection), in which an antimalarial compound is administered before, during, and / or after the period of exposure to the malaria parasite, and terminal prophylaxis (i.e., prevention of recurrence of malaria or delayed onset of clinical symptoms), in which an antimalarial compound is administered near the end of and / or shortly after the period of exposure to the malaria parasite, but before the onset of clinical symptoms. Additionally, this term encompasses the inhibition of dormant forms of the parasite (intrahepatic or pre-erythrocytic stages) in the liver, as well as the activation and elimination of dormant forms (the "wake-and-kill" concept). Suppressive prophylaxis is typically used against P. falciparum infections, while terminal prophylaxis is used against P. ovale, P. vivax, or a combination of P. falciparum and P. vivax. Dormant stage suppression is particularly effective against P. ovale and P. vivax.

[0019] The expression "effective amount" refers to the amount of a drug or active pharmaceutical ingredient that elicits the biological or medical response sought or desired, for example, by a researcher or physician, in a tissue, system, animal or human.

[0020] Similarly, the term "therapeutically effective amount" or "therapeutically effective amount" refers to that amount of a compound that results in improved treatment, cure, prevention or elimination of a disease, syndrome, condition, complaint, disorder or side effect, or attenuation of the progression of a disease, complaint or disorder, compared to a corresponding subject who is not administered that amount.

[0021] The phrase "therapeutically effective amount" or "therapeutically effective amount" also encompasses an amount necessary for effective treatment of a disease such as a malaria infection, such as an amount effective to enhance normal physiological function and, when administered after infection, reducing the number of parasites in the blood after microscopic examination. The phrase "PI4K-associated disorder" refers to disorders affected by PI4K interactions, such as, for example, pathogen-induced inhibition or overexpression of PI4K, genetic predisposition, and use of PI4K for viral replication, as well as diseases that can be treated and / or prevented by inhibiting PI4K in a patient or a parasite, such as Plasmodium falciparum. Examples of PI4K-associated disorders include, but are not limited to, viral infections, such as infections with RNA viruses, and protozoan infections, such as malaria.

[0022] As used herein, the term "subject" refers to a mammal. For example, mammals contemplated by the present invention include humans and the like. 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 with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or excipients that can be 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, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0023] "Pharmaceutically acceptable derivatives" refers to non-toxic salts, esters, ester salts or other derivatives of the compounds of the invention which, upon administration to a recipient, are capable of yielding, directly or indirectly, the compounds of the invention or their inhibitory active metabolites or residues.

[0024] 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 bisecting the bond line.

[0025] Detailed Description of the Invention The objective of the present invention was to develop and identify novel compounds useful for inhibiting PI4K and treating PI4K-associated disorders such as malaria and viral infections, thereby expanding, providing alternatives to, and improving upon limited treatment options for physicians and veterinarians, allowing for highly effective treatment for patients.

[0026] Surprisingly, it has been discovered that compounds according to the present invention are inhibitors of PI4K, which is found in several organisms. Thus, the present invention provides a compound of formula (I) [ka] Medium R represents AR1 or HT1, AR1 is - 1, 2 or 3 substituents independently selected from Alk2, OAlk2, Hal, Cyc, CN and / or NO2, and / or -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 ) nCOOCyc、(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; represents a phenyl group substituted or unsubstituted by a substituent selected from the group comprising: HT1 represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle containing 3 to 9 carbon atoms and 1, 2, 3 or 4 N, O and / or S atoms, wherein the aromatic heterocycle is unsubstituted or - 1, 2 or 3 substituents independently selected from Alk2, OAlk2, Hal, Cyc, CN, ═O and / or NO2 and / or A, NH2, OH, (CR a R b ) n HetCyc1, (CR a R b ) n HetAr1, (CR a R b ) n Aryl, (CR a Rb ) 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、(CRa 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 aR 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 substituted by a substituent selected from the group comprising POA2, Q represents a structure according to formula (II), [ka] R 1 indicates AR2 or HT2, R 2 , R 3 and R 4 each independently represents H, Hal, or CAlk2, Y represents CH, CHal, CAlk2, CCHal3 or N; AR2 is - 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, 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 ) nCONHA、(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、(CRa 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 ) nSO2(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)、(CRa 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 A substituent selected from the group comprising: POA2; represents phenyl substituted or unsubstituted by HT2 represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle containing 3 to 9 carbon atoms and 1, 2, 3 or 4 N, O and / or S atoms, wherein the aromatic heterocycle is unsubstituted or - 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, 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 ) mHetAr1、(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 Rb ) 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)、(CRa 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 or branched alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, where: 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 -1 hydrogen may be replaced by OH or NH2, or a cyclic alkyl having 3, 4, 5, or 6 carbon atoms, which is mono-, di-, or tri-substituted with Hal, OHalk2, NHalk2, N(Alk2)2, and / or NH2; Alk1 represents a straight or branched alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, one or two CH2 groups may be replaced by O, NAlk2 or NH, and / or -1 hydrogen may be replaced by OH, NHalk2, N(Alk2)2 or NH2, and / or 1, 2, 3, 4 or 5 hydrogens may be replaced by Hal; Alk2 represents a linear or branched alkyl having 1 to 6 carbon atoms, in which 1, 2, 3, 4 or 5 hydrogen atoms may be replaced by Hal; Aryl represents phenyl, which is unsubstituted or mono-, di- or trisubstituted Hal, Alk2, OAlk2, OH, NH2 or Cyc, HetCyc1 represents a monocyclic or bicyclic, optionally bridged, saturated or unsaturated 4-10 membered heterocycle having one or two heteroatoms selected from N, O, S and / or Si, said heterocycle being unsubstituted or mono- or di-substituted by Hal, OH, A, SO2Alk2 and / or ═O. Cyc represents a cyclic alkyl having 3 to 6 carbon atoms, in which 1, 2 or 3 hydrogens are replaced by Hal and 1 additional hydrogen may be replaced by Alk2, NH2 and / or OH; Hal represents F or Cl; HetAr1 represents a monocyclic or bicyclic aromatic 4-12 membered heterocycle having 1, 2, 3 or 4 N, O and / or S atoms, said heterocycle being unsubstituted or mono- or disubstituted by Hal, Alk2, SOAlk2, SO2Alk2, OH or NH2; Ra and Rb each independently represent Halk2 or Cyc; or Ra and Rb together represent -(CH2)x- (x=2, 3, 4 or 5) and form a (3-, 4-, 5- or 6-membered) cycloalkyl ring together with the carbon atom to which they are attached; RCyc1 and RCyc2 together form -(CH2)x- (x=3 or 4), which together with the atoms to which they are attached form a 5- or 6-membered ring, wherein one or two H atoms in -(CH2)x- may be independently replaced by Hal or Alk1; RCyc3 and RCyc4 together form -(CH2)x- (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 one or two H atoms in -(CH2)x- may be independently replaced by Hal or Alk1; n represents 0, 1 or 2; m represents 0 or 1; or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof.

[0027] The compounds of formula (I) according to the present invention may have one or more chiral centers, depending on the nature of the substituents they possess. Therefore, they may occur in various enantiomeric and diastereomeric forms, optionally in racemic or optically active form. The present invention therefore also relates to optically active forms, enantiomers, racemates, diastereomers, and mixtures thereof in all ratios, collectively referred to as "stereoisomers." It may be desirable to use a specific stereoisomer, e.g., a specific enantiomer or diastereomer of a specific compound. In such cases, compounds according to the present invention obtained as a racemate or an intermediate thereof may be separated into stereoisomeric (enantiomers, diastereoisomers) compounds by chemical or physical means known to those skilled in the art. Compounds of the present invention having one or more chiral centers and occurring as a racemate or as a mixture of enantiomers or diastereoisomers may be separated or resolved into optically pure or enriched isomers, i.e., enantiomers or diastereomers, by methods known per se. The compounds of the present invention can be separated by chromatographic methods, such as column separation on chiral or non-chiral phases, optionally recrystallization from optically active solvents, the use of optically active acids or bases, or derivatization with optically active reagents such as optically active alcohols, followed by removal of radicals. Another method that can be applied to obtain one or more specific stereoisomers of the compounds of the present invention in enriched or pure form is to use stereoselective synthesis. For example, stereoisomerically enriched or pure starting materials are used (e.g., pure or enriched (R) or (S)-enantiomers of specific starting materials having chiral centers are used). Or chiral reagents or catalysts, particularly enzymes, are used.

[0028] Examples of compounds according to the invention that have a stereocenter are: [ka] In this particular example, the sulfur atom represents a stereocenter; in other examples of the invention, the compounds may of course have other or additional stereocenters located on other atoms, e.g., carbon atoms. Thus, when a compound having one or more stereocenters is depicted without specifying the configuration of the stereocenters, it refers to a mixture of the corresponding stereoisomers. In some embodiments of the invention, residue R of the compound according to formula (I) exhibits a structure according to formula (IV), (V), (Va) or (VI).

[0029] [ka] where R 6 denotes OH, A or Cyc (preferably OH, cyclopropyl, OCH3, OCH3, OCHF3, OCHF2, CH3, C2F, CHF2, CHF2, OC2H5, OiPr, OtBu, NH2, NHCH3, N(CH3)2, N(CH3)2, N(iPr)2, N(CH3)(nPr) or N(CH3)(tBu)) or a substituent according to formulae (VII) to (X) [ka] where R 7 , R8, R9, R10, R11, R12, R13, and R14 each represent H, OH, Hal, CH3, C2H5, CHal3, OCH3, CoCHal2, OCH2Hal, CH2Hal, CH2Hal, CH2Hal, CH2Hal, CH2Hal, and / or ChHal2; R 15 is NR 17 or O, R 16 indicates A or Cyc, R 17 represents HALk1 or cyclic alkyl having 3 to 6 carbon atoms, wherein 1, 2 or 3 hydrogen atoms of the cyclic alkyl group may be substituted by Hal; X 1 represents N or CH, X 2indicates NH, NaLk1, or O.

[0030] For the avoidance of doubt, the formula (NR 15 Residues R7, R8, C0r6, S0r16 (NR15), and S0r16 of formulas (IV), (v), and (VI) and the cyclic S-residue (VA) of the above formula may be attached to each carbon atom of the aromatic ring. In an important embodiment, C0r6, S0r16 (NR15), and S0r16 are attached to the carbon atom in the para position. This connects the ring system (furopyrimidine residue) with residue R removed, as shown in formulas (IVB) to (VIB). [ka] residue R 7 and R 8 are each preferably attached in the ortho or meta position to the carbon atom connecting the residue R with the ring system. Another particular embodiment relates to compounds according to formula (i) as defined above. [ka] (XI) where Y represents N or CH. One or two of residues R2, R3, R4 independently represent Hal, CHal3, OCHal3, OCHal3, OCHal2, OCHal2, OCHal2, CHal2, and / or CHal2, and the remaining residues represent H.

[0031] In such embodiments, R2 and R4 preferably represent independently of one another, and a residue selected from F, CH3, CH3, OCH3, OCH3, OCHF2, OCH2F, CH2F and / or CHF2 and R3 represents H. In another important embodiment of the residue according to formula (XI) above, R2 represents a residue selected from F, CH3, CF3, OCH3, OCH3, OCHF2, OCH2F, CH2F and / or CHF2 and R3 and R4 represent H. In a further important embodiment of said residue, R4 represents a residue selected from F, CH3, CF3, OCH3, OCH3, OCH3, OCH3, OCH2F, CH2F and / or CHF. 2, R3 and R2 represent H. A further particular embodiment relates to compounds according to formula (I) wherein Z represents N.

[0032] In the context of the present invention, "hydroxyalkyl" denotes a straight-chain or branched hydrocarbon residue having 1, 2, 3, 4, 5, or 6 carbon atoms (preferably 1, 2, 3, or 4 carbon atoms) and substituted with one or two (preferably one) hydroxy 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-hydroxypropan-2-yl, 1-hydroxyethyl, 2-hydroxy2-methylpropyl, etc.

[0033] Throughout the present invention, all residues occurring multiple times may be identical or different, i.e., independent of each other. For example, "(CR a R b ) n CONH(CR a R b ) m HetCyc1" or "(CRa R b ) n SO 2NA2 "In R a , R b , each instance of A may have a different meaning (within the corresponding definition).

[0034] A particularly important aspect A represents a linear or branched alkyl group having 1, 2, 3, or 4 carbon atoms, in which one or two non-adjacent CH groups may be replaced by O, NCH, NC, H, NIPR, or NH, and / or one, two, three, four, or five hydrogens may be replaced by HALON, and / or one hydrogen may be replaced by OH, NH, or a cyclic alkyl group having 3, 4, 5, or 6 carbon atoms. AR1 is preferably 3,4,5-trimethoxyphenyl or phenyl, selected from Hal, CH3, CHal3, and / or OCH3, and / or (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 ) nNHCO(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 Rb ) 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 a substitution of one or two residues from one residue selected from POA2; Preferably, HT1 denotes pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, isoindolyl, benzimidazolyl, indazolyl (most preferably pyridinyl) or any of the following residues: [ka] Each of the above residues is, independently of the other, unsubstituted or substituted (any of the following substituents may be attached to a carbon atom or other atom, but not shown in the above residues, provided that the appropriate valence of that atom is obtained).

[0035] - 1, 2 or 3 substituents are independently selected from A, HAL, and / or 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 ) nCONHCyc、(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 Rb ) 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 ) nSOCyc(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、(CR a R b) n POA2, and an azaspiro ring, which is substituted or unsubstituted by at least one HAL, ALK2, or OALK2 group; HT2 is preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, isoindolyl, benzimidazolyl, indozolyl (most preferably pyridinyl), or one of the following residues: [ka] Each of the above residues, independent of each other, is unsubstituted or substituted (following any subsequent substituents, may be attached to a carbon atom or another atom, provided that the resulting appropriate valence of the atom is not shown in the residue): - 1, 2 or 3 substituents are independently selected from A, HAL, and / or 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 ) nNHCO(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 Rb ) 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, an azaspirocycle, which is substituted or unsubstituted by at least one HAL, ALK2, or OALK2 group; Cyc preferably denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0036] In one embodiment of the invention, the residue R of the compound according to formula (I) exhibits a structure according to formula (IV). [ka] During the ceremony, R 6 is Alk1, Alk2, -OH, -CH3, -OCH3, -OC(CH3)3, -N(CH3)2, or; [ka] W is O, -NCH3, NR18, or CR18R19; R7 and R8 are each independently selected from H or Hal; R18 and R19 are each independently selected from -H, -CH3, or Alk1; X1 is CR7 or N.

[0037] In this embodiment of the invention, residue Q of the compound represents a structure according to formula (II) above, R1 is H, Hal, [ka] R2, R3, and R4 are each independently selected from H or Hal; R28 is Alk1, Alk2, -NH2, [ka] R 29 , R 30 are each independently selected from -H or -CH3, and Y is N, CH, or CHal.

[0038] Furthermore, in a preferred embodiment of the present invention, R 6 is -CH3, -OH, -N(CH3)2, or; [ka] W is O, R 7 , R 8 is,,H, R 18 , R 19 are each independently selected from -H or -CH3; and X 1 is CH or N. Furthermore, in a preferred embodiment of the present invention, R 6 teeth [ka] and R 1 teeth [ka] is.

[0039] In one embodiment of the invention, the residue R of the compound according to formula (I) exhibits a structure according to formula (V). [ka] During the ceremony, X 1 is CR 7 or N, R 7 , R 8 are each independently selected from H, Hal, and CHal3; R 15 is O or NH, R 16 is H, -CH3, -NH2, -N(CH3)2, or Alk1.

[0040] In this embodiment of the invention, residue Q of the compound represents a structure according to formula (II) above, R 1 H, Hal, [ka] R 2 , R 3 , R 4 are each independently selected from H or Hal. R28 is Alk1, Alk2, -NH2, [ka] R 29 , R 30 are each independently selected from H or CH3; and Y is N, CH, or CHal.

[0041] Furthermore, in a preferred embodiment of the present invention, R 1 is H, Hal, or [ka] is selected from R 2 , R 3 , R 4 , R 7 , R 8 are each independently selected from H or Hal; R 16 is -CH3 or Alk1, X 1 is CH, Y is CH or CHal.

[0042] Furthermore, in a preferred embodiment of the present invention, R 1 teeth, [ka] R 2 , R 7 , R 8 are each independently selected from H or Hal; R 3 , R 4 is hydrogen, R 15 is NH, R 16 is -CH3 or Alk1, X 1 is CH, Y is CH.

[0043] Furthermore, in a preferred embodiment of the present invention, the SOR of formula V 15 R 16 The group is ortho to the bond to Formula I. In some embodiments, R 3 and R 4 is H, and in some embodiments X 1 is CH. Furthermore, in a preferred embodiment of the present invention, R 1 teeth, [ka] and R 2 , R 7 , R 8 are each independently selected from H or Hal; R 3 , R 4 is hydrogen, R 15 is NH, R 16 is -CH3, X 1 is CH, Y is CH.

[0044] Furthermore, in a very particular aspect of the invention, the compound [Table 1]

[0045] Furthermore, in a very particular aspect of the invention, the compound [Table 2]

[0046] Furthermore, in a very particular aspect of the invention, the compound [Table 3]

[0047] In one embodiment of the invention, the residue R of the compound according to formula (I) exhibits any of the following structures: [ka] where R 18 , R 19 are each independently selected from H, —CH3, or Alk1; and R 27 is -CH3 or -C((CH3)2OH).

[0048] In this embodiment of the invention, residue Q of the compound represents a structure according to formula (II) above, R 1 H, Hal, [ka] R 2 , R 3 , R 4 are each independently selected from H or Hal;

[0049] R 28 are Alk1, Alk2, -NH2, [ka] R 29 , R 30 are each independently selected from H or CH3; and Y is N, CH, or CHal.

[0050] In certain embodiments, the compound according to the present invention is selected from the group consisting of: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] Also, pharmaceutically acceptable solvates, salts, tautomers, and stereoisomers (including mixtures in all ratios)

[0051] Surprisingly, in vitro studies have shown that small amounts of compounds according to the invention are potent PI4K inhibitors.Accordingly, the present invention relates to compounds according to the invention for use in inhibiting PI4K.

[0052] These versatile 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, protozoal and viral infections.

[0053] Surprisingly, a small amount of compound according to the present invention is sufficient to reduce the survival rate and suppress the proliferation of malaria parasites.Additional data suggests that said compound has a high inhibitory effect on the PI4K activity of malaria parasites.Therefore, the present invention also relates to the use of compound according to the present invention for treating and / or preventing protozoan infections such as malaria.

[0054] The compounds of the present invention inhibit PI4K in protozoa such as, but not limited to, Plasmodium ssp, Toxoplasma ssp, Babesia ssp, and Cryptosporidium ssp.

[0055] Human PI4K is a well-known drug target for the treatment and prevention of viral infections. Surprisingly, the disclosed compounds have further been found to inhibit human PI4KIIβ, an important target of viruses, including RNA viruses.

[0056] Therefore, some embodiments of the present invention relate to the use of compounds according to the present invention for the treatment and / or prevention of a PI4K-related disorder selected from the list of protozoal infections and viral infections. In a preferred embodiment, said PI4K-related disorder is a protozoal infection, more preferably malaria.

[0057] Viral infections can be caused by viruses such as RNA viruses and DNA viruses. In a preferred embodiment, the compounds according to the present invention are used for the treatment and / or prevention of viral infections caused by RNA viruses.

[0058] In preferred embodiments, the viral infection is caused by a virus selected from the Orthomyxoviridae, Adenoviridae, Paramyxoviridae, and Coronaviridae families. Viruses of the Orthomyxoviridae family include influenza A, influenza B, influenza C, infectious salmon anemia virus (isavirus), Thogotovirus, and Dorivirus. Members of the Adenoviridae family include human adenoviruses A, B, C, D, E, and F, bovine adenoviruses A, B, and C, canine adenovirus, equine adenoviruses A and B, murine adenovirus A, ovine adenoviruses A and B, porcine adenoviruses A, B, and C, and tupai adenovirus.Members of the Paramyxoviridae family include bovine parainfluenza virus 3 (BPIV-3), human parainfluenza virus 1 (HPIV-1), human parainfluenza virus 3 (HPIV-3); Sendai virus (murine parainfluenza virus 1); simian parainfluenza virus 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), plague of small ruminants virus (PPRV), phocine distemper virus (PDV), dolphin distemper virus, rinderpest virus (RPV), avian paramyxovirus 2 (APMV-2), and avian paramyxovirus 1 (AVMV-1). These include 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 2 (HPIV-2), Human Parainfluenza Virus 4a (HPIV-4a), Human Parainfluenza Virus 4b (HPIV-4-b), Mumps Virus, Newcastle Disease Virus (Avian Paramyxovirus 1) (NDV; APMV-1), Butalubula Virus, Simian Parainfluenza Virus 5 (SV-5), and Simian Parainfluenza Virus 41 (SV-41). Members of the Coronaviridae family include Infectious Bronchitis Virus, Bovine Coronavirus, Canine Coronavirus, Feline Coronavirus, Human Coronavirus, SARS-CoV, SAR2-CoV-2, and MERS-CoV. In a more preferred embodiment, the compounds of the invention are used for the treatment and / or prevention of SARS-CoV2.

[0059] The compounds of the present invention were able to inhibit both protozoan and human PI4K, although surprisingly, protozoan PI4K was preferentially inhibited. Human PI4K was inhibited by treatment with the compounds of the present invention. However, because protozoan PI4K was inhibited at very low concentrations, the compounds of the present invention are particularly useful for treating low-dose protozoan infections in combination with no or low cross-inhibition of human PI4K. These properties have great pharmacological potential, as inhibition of human PI4K can cause significant side effects in some patients. The excellent inhibitory properties of the compounds of the present invention allow for the treatment and / or prevention of PI4K-related disorders at very low doses, thereby reducing the potential for toxic effects caused by the compounds and allowing for lower concentrations of additional established antimalarial drugs useful in combination therapy.

[0060] composition The present invention further relates to pharmaceutical compositions comprising at least one compound according to formula (I) of the present invention. In another embodiment, there is provided a pharmaceutical formulation comprising at least one compound according to formula (I) of the present invention and a pharmaceutically acceptable carrier, diluent or excipient thereof.

[0061] The present invention further relates to said pharmaceutical composition for use in the prevention and / or treatment of PI4K-associated disorders. In one embodiment, the present invention further relates to a pharmaceutical composition for use in the prevention and / or treatment of PI4K-related disorders, 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.

[0062] combination According to the present invention, the compound according to formula (I) or a pharmaceutical composition thereof can be administered alone or in combination with further active ingredients (adjuvants), such as pharmaceutically active compounds useful in the treatment and / or prevention of PI4K-associated disorders. Therefore, the present invention also refers to a pharmaceutical composition comprising at least one compound of formula (I) and at least one further active ingredient (auxiliary agent) different from formula (I). In one embodiment, the auxiliary agent is an antimalarial agent, which is an antimalarial agent different from formula (I). Preferably, the further active ingredient (antimalarial auxiliary agent) is pyronaridine (free base or tetraphosphate), quinacrine, chloroquine, ferroquine, primaquine, tafenoquine, doxycycline, atovaquone, proguanil, cycloguanil, kabamyquine (free base or succinate), cypargamine, ganaplacid, sulfadoxine, pyrimethamine, artemisinin, dihydroartemisinin, artesunic acid, arte Sunate, Arterolane, Artefenomel, Lumefantrine, DSM265 (CAS number: 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 number: 2260904-47-8), Benzamide, 5-[2-[3-[[(amino (aminomethyl)amino]carbonyl]-5-(trifluoromethyl)phenyl]ethynyl]-N-2-pyridinyl-2-(trifluoromethyl), INE963 (CAS no. 2640567-43-5), 4-piperidinol, 4-(aminomethyl)-1-[5-[2-methoxy-6-(1-methylethyl)-3-pyridinyl]imidazo[2,1-b]-1,3,4-thiadiazol-2-yl], ZY19489 (CAS no. No.: 1821293-405)-6), 2,4-pyrimidinediamine, N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridinyl)-5-[(3R)-3,4-dimethyl-1-piperazinyl]-N4-(1,5-dimethyl-1H-pyrazol-3-yl), and GSK701 (CAS No.: 2366983-10-8) methanone, [(3R)-3-(4-fluorophenyl)-1-pyrrolidinyl].

[0063] In another embodiment, the pharmaceutical composition comprises at least one compound of formula (I) and at least one additional antiviral agent (antiviral adjunct) different from formula (I).

[0064] Antiviral adjuvants according to the present invention include abacavir, acyclovir (acyclovir), adefovir, amantadine, ampligen, amprenavir (agenerase), umifenovir (arbidol), atazanavir, atripla, baloxavir Marboxil (Xofluza), Biktarvy, Boceprevir, Brevirtide, Cidofovir, Cobicistat (Tyvost), Combivir, Daclatasvir (Daclinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Encitrervir, Entecavir, Etravirine (Intelence), Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Ganciclovir (Cytoven), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Immunovir , indinavir, lamivudine, letermovir (Previmis), lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfinavir, nevirapine, nexavir (formerly ctapressin), nitazoxanide, norvir, oseltamivir (Tamiflu), penciclovir, peramivir, penciclovir, peramivir (Rapivab), pleconaril, podophyllotoxin, raltegravir, remdesivir, ribavirin, rilpivirine (Edurant), rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir (Olysio), sofosbuvir, stavudine, taribavirin (Viramidine), telaprevir, telbivudine (Taizeka), tenofovir The antiviral agent may be any antiviral agent known in the art, such as, but not limited to, an antiviral agent selected from the list of alafenamide, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, Truvada, umifenovir, valacyclovir (Valtrex), valganciclovir (Valcyte), vicriviroc, vidarabine, zalcitabine, zanamivir (Relenza), zidovudine.

[0065] Administration The present invention encompasses the administration of a compound according to the invention or a pharmaceutical formulation thereof (= pharmaceutical preparation, pharmaceutical composition) administered to an individual in an effective amount together with, prior to, simultaneously with, or sequentially to, other treatment regimens or adjuncts useful in the treatment of PI4K-related disorders such as malaria or viral infections (e.g., multiple drug therapies). Compounds according to the invention or pharmaceutical formulations thereof administered simultaneously with said adjuncts can be administered in the same or different compositions and by the same or different routes of administration.

[0066] In a further aspect, the present invention relates to a method for preventing or treating a PI4K-associated disorder, the method comprising the steps of: (i) providing at least one compound and / or pharmaceutical composition according to the present invention; and (ii) administering an effective amount of said at least one compound or said composition to a patient in need thereof. In a preferred embodiment, the PI4K-associated disorder is selected from the list of protozoal infections and viral infections, more preferably including viral infections caused by RNA viruses, most preferably malaria.

[0067] The above further preferred embodiments also apply to the method according to the invention. The present invention further relates to a medicament comprising at least one compound of formula (I) and / or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof (including mixtures in all ratios), and optionally excipients and / or adjuvants for the treatment and / or prevention of PI4K-associated disorders.

[0068] Pharmaceutical compositions can be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Such units can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 100 mg, of the compound according to the present invention, depending on the condition to be treated, the method of administration, and the patient's age, weight, and condition. Pharmaceutical preparations can be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit preparations are those containing the daily dose or partial dose, as described above, or a corresponding proportion of the active ingredient. Furthermore, such pharmaceutical preparations can be prepared using methods commonly known in the pharmaceutical art.

[0069] The pharmaceutical compositions can be adapted for administration in any suitable manner, for example, orally (including buccal or sublingually), rectally, nasally, topically (including buccal, sublingually or transdermally), vaginally or parenterally (including subcutaneously, intramuscularly, intravenously or intradermally). Such formulations can be prepared, for example, by combining the active ingredient with an excipient or adjuvant, using any process known in the pharmaceutical art.

[0070] In some embodiments, administration according to the methods of the present invention is by oral administration, including buccal or sublingual administration, rectal administration, nasal administration, topical administration, including buccal or sublingual administration, local administration, including sublingual or transdermal administration, vaginal administration, or parenteral administration, including subcutaneous, intramuscular, intravenous or intradermal administration.

[0071] Pharmaceutical compositions suitable for oral administration can be administered as discrete units, for example, capsules or tablets, powders or granules, aqueous or non-aqueous liquid solutions or suspensions, edible foams or effervescent food products, or oil-in-water or water-in-oil liquid emulsions.

[0072] For example, for oral administration in the form of tablets or capsules, the active ingredient can be combined with an orally non-toxic, pharmaceutically acceptable inert excipient such as ethanol, glycerol, water, etc. Powders are prepared by grinding the compound to a suitable fine size and mixing it with a pharmaceutical additive ground in a similar manner, such as an edible carbohydrate, for example, starch or mannitol. Flavors, preservatives, dispersants, and dyes may also be present.

[0073] Capsules are produced by preparing a powder mixture as described above and filling it into formed gelatin shells.Before filling, glidants and lubricants such as highly dispersed silicic acid, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture.Similarly, disintegrants or solubilizers such as agar, calcium carbonate, sodium carbonate, etc. can be added to increase the availability of the drug after taking the capsule.

[0074] Additionally, suitable binders, lubricants, disintegrants, and dyes can be incorporated into the mixture as needed or desired. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums such as acacia, tragacanth, and sodium halates, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets can be formulated, for example, by preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and disintegrant, and compressing the entire mixture to form tablets. Powder mixtures are prepared by mixing the compound, milled as described above, with a diluent or base, and, optionally, a binder, such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone; a dissolution inhibitor, such as paraffin; an absorption enhancer, such as a quaternary salt; and / or an absorbent, such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, acacia mucilage, or a solution of cellulose or polymeric materials, and forcing it through a screen. Instead of granulating, the powder mixture can be passed through a tablet press to produce lumps of uneven shape, which are then broken down to form granules. The granules can be lubricated with the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent sticking to the tablet dies. The lubricated mixture is then compressed to form tablets. The compounds of the present invention can also be directly compressed into tablets by combining them with a free-flowing inert excipient, without the granulation or dry-pressing steps. A clear or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymeric material, and a gloss layer of wax may be present.Dyes can be added to these coatings to make it possible to distinguish between different dosage units.

[0075] For example, oral liquid preparations such as solutions, syrups, and elixirs can be pre-paired in dosage units so that a given volume contains a pre-specified amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs can be prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives, such as peppermint oil, natural sweeteners or saccharin, or other artificial sweeteners, can also be added. Dosage unit preparations for oral administration can be encapsulated in microcapsules, if desired. Preparations can also be prepared in a manner that extends or delays release, for example, by coating or embedding particulate matter in polymers, wax, or the like.

[0076] 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 a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines, and the like.

[0077] The compounds of Formula (I) and their salts, solvates, and physiologically functional derivatives can also be delivered using delivery agents such as monoclonal antibodies, nucleic acids, or nanoparticles as individual carriers to which the compound molecules are bound or encapsulated. These compounds can also be conjugated to soluble polymers as targeted drug carriers. Such polymers may include palmitoyl-substituted polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide polylysine. The compounds can also be conjugated to suitable types of biodegradable polymers to achieve controlled drug release, such as polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, crosslinked hydrogels, or amphiphilic block copolymers.

[0078] Pharmaceutical compositions suitable for transdermal administration can be administered as independent plasters for prolonged, intimate contact with the recipient's epidermis. Thus, for example, the active ingredient can be delivered from the plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical compounds suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

[0079] For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. In formulations formulated as an ointment, the active ingredient can be employed in either a paraffinic or water-miscible cream base. Alternatively, the active ingredient can be formulated to give an oil-in-water cream base or a water-in-oil base cream.

[0080] Pharmaceutical compositions adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent. Pharmaceutical compositions adapted for topical application in the mouth include lozenges, pastilles and mouthwashes. Pharmaceutical compositions adapted for rectal administration can be administered in the form of suppositories or enemas.

[0081] Pharmaceutical compositions suitable for nasal administration in which the carrier substance is solid include, for example, coarse powders with particle sizes in the range of 20 to 500 microns, which are administered by snuffing, i.e., rapid inhalation through the nasal passages from a container containing the powder held close to the nose. Formulations suitable for administration as nasal sprays or nasal drops, which contain a liquid as the carrier substance, include solutions of the active ingredient in water or oil. Pharmaceutical formulations suitable for inhalation administration include fine particle dusts or mists that can be generated by various types of pressurized dispensers, including aerosols, nebulizers, or inhalers.

[0082] Pharmaceutical compositions adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams, or spray formulations. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats, and solutes (the formulations render the formulation isotonic with the blood of the intended recipient), as well as aqueous and non-aqueous sterile suspensions, which may contain suspending media and thickening agents. The formulations may be dispensed in single-dose or multi-dose containers, such as sealed ampoules or vials, and stored in a lyophilized (lyophilized) state, requiring only the addition of a sterile carrier liquid, such as water for injection, immediately prior to use. Recipe-prepared injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0083] Of course, in addition to the ingredients specifically mentioned above, the compositions may include other agents commonly used in the art for the particular type of formulation. Thus, for example, formulations suitable for oral administration may include flavors.

[0084] The therapeutically effective amount of a compound of Formula (I) will depend on many factors, including, for example, the age and weight of the animal or human subject, the exact condition requiring treatment, its severity, the nature of the formulation, and the method of administration, and is ultimately determined by the treating physician or veterinarian. However, an effective amount of a compound of the present invention will generally be in the range of 0.01 to 100 mg / kg of recipient (mammal) per day, and more particularly, in the range of 1 to 100 mg / kg per day. Thus, the practical daily dose for an adult mammal weighing 70 kg will typically be 70 to 700 mg, which can be administered as a single daily dose or, typically, in a series of partial doses (e.g., 2, 3, 4, 5, 6, etc.) per day, resulting in the same total daily dose. An effective amount of a salt or solvate, or a physiologically functional derivative thereof, according to the present invention, can be determined as a percentage of the effective amount of the compound. Similar doses are believed to be appropriate for treating the other conditions listed above.

[0085] Preparation of reactants and compounds according to the present invention The compounds according to the present invention and their derivatives can be prepared from readily available starting materials using methods and procedures known to those skilled in the art. Where typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvent, etc.) are given, it is understood that other experimental conditions can also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures.

[0086] A general synthetic approach to obtain compounds of formula (I) is shown in Scheme 1 below. [ka] Scheme 1: General synthesis of the furopyrimidine core

[0087] If the above synthetic methods are not applicable to obtain the furopyridine or furopyrimidine derivatives and / or the necessary intermediates according to the present invention, appropriate preparative methods known to those skilled in the art should be used. In general, the synthetic route to a particular furopyridine or furopyrimidine derivative will depend on the specific substituents of each molecule and the ready availability of the necessary intermediates. Again, such factors will be appreciated by those of ordinary skill in the art.

[0088] Further examples illustrating various synthetic strategies for obtaining compounds or reactants according to the present invention can be found in the examples disclosed below.

[0089] example High-Performance Liquid Chromatography: LC purity traces were performed using one of the following methods:

[0090] Method 1: A Kinetex 2.6 μM C-18 column was used, with an injection volume of 2 μL and a flow rate of 0.7 mL / min. The gradient was 15–100% B in 1.2 min (hold for 3.3 min), followed by 100–15% B in 0.3 min (hold for 1.2 min). (Mobile phase A: 10 mM buffer (ammonium acetate / acetic acid) in HO; mobile phase B: 10 mM buffer (ammonium acetate / acetic acid) in methanol.

[0091] Method 2: A Kinetex 1.7µM C-18 column was used, injection volume 1µL, flow rate 1.2mL / min, gradient: 5-100% B in 1.5min (hold for 0.4min), 100-5% B in 0.3min (hold for 0.5min) (mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile).

[0092] The present invention will now be described, but not limited to, with reference to specific embodiments illustrated in the following examples. Unless otherwise noted, all raw materials were obtained from commercial suppliers and used without further purification. All temperatures are in °C and all reactions are performed at rt unless otherwise specified. Compounds were purified by either silica chromatography or preparative HPLC. Unless otherwise specified, all structures shown below where a particular stereochemistry is not indicated refer to a mixture of stereoisomers (preferably a racemic mixture of stereoisomers).

[0093] Example 1: Synthesis of the furopyrimidine core: [ka] 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 to reflux for 3 hours. The mixture was cooled to ambient temperature, and water (50 mL) was added. The resulting solid was isolated, washed thoroughly with water and diethyl ether, and dried under vacuum to give furo[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 (400 MHz, DMSO-d6): δ 12.60 (s, 1 H), 8.23 ​​(d, J = 1.60 Hz, 1 H), 8.07 (s, 1 H), 6.99 (d, J = 2.00 Hz, 1 H).

[0094] Step 2: Furo[3,2-d]pyrimidin-4(3H)-one 2 (4.1 g) was dissolved in thionyl chloride (20 ml) and DMF (0.2 ml). The mixture was stirred at reflux for 5 hours. After the reaction was completed, the reaction mixture was concentrated to remove thionyl chloride, water was added, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration in vacuo, the mixture was triturated with hexane to give 4-chlorofuro[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 (400 MHz, DMSO-d6): δ 8.92 (s, 1 H), 8.68 (d, J = 2.40 Hz, 1 H), 7.40 (d, J = 2.00 Hz, 1 H).

[0095] Step 3: To a solution of 4-chlorofuro[3,2-d]pyrimidine 3 (2 g, 0.013 mol) in THF at -78 °C, a 1.6 M solution of n-butyllithium in THF (12.1 mL, 0.019 mol) was added dropwise over 15 min. After stirring at -78 °C for 2 h, iCl (1.01 mL, 0.019 mol) was added dropwise and stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with 10% sodium thiosulfate solution, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The resulting solid was washed with diethyl ether and dried to give 4-chloro-6-iodofuro[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, 1 H), 7.72 (s, 1 H).

[0096] General instructions for Step 4: 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, after which Pd(PPh3)4 (0.029 mmol) was added. The reaction mixture was stirred at 90 °C for approximately 3 hours. The solvent was evaporated to give compound 5 as a crude mixture, which was carried directly to the next step.

[0097] Manufacturing example [ka] 4-(4-{4-chlorofuro[3,2-d]pyrimidin-6-yl}benzoyl)morpholine (building block): LCMS: Calculated 343.77; Observed 344.0 (M+H). [ka] 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).

[0098] [ka] (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). [ka] 4-Chloro-6-(4-methanesulfonylphenyl)furo[3,2-d]pyrimidine (building block): LCMS: Calculated for C21H18FN304S 308.0, Observed 309.0 (M+H).

[0099] [ka] (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).

[0100] General instructions for Step 5: To a stirred solution of compound 5 (0.233 mmol), R2-B(OH)2 (0.233 mmol), and water (1 mL) in 1,4-dioxane (4 mL) was added potassium carbonate (0.465 mmol). The reaction mixture was then degassed for 5 minutes, after which Pd(PPh3)4 (0.029 mmol) was added and stirred at 110 °C for approximately 16 hours. The resulting residue was purified by preparative HPLC to give compound 6. [ka] 2-(4-{6-[4-(morpholine-4-carbonyl)phenyl]furo[3,2-d]pyrimidin-4-yl}pyridin-2-yl)propan-2-ol: H NMR (400 MHz, DMSO-D): 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 C H NO 343.77, Observed 444.49 (M+H).

[0101] Manufacturing example [ka] 2-{2-Fluoro-3-[6-(4-methanesulfonylphenyl)furo[3,2-d]pyrimidin-4-yl]phenyl}propan-2-ol: H NMR (400 MHz, DMSO-D): δ 9.20 (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 C H FNO S, Molecular Weight: 426.1, Observed 427.1 (M+H) (4-(4-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)furo[3,2-d]pyrimidin-6-yl)phenyl)(imino)(methyl)-λ 6 -Sulfanone (D203): 1HNMR (400MHz, DMSO): δ9.18(s, 1H), 8.23-8.21(d, J=8.4Hz, 2H), 8.12-8.10(d, J=8.4Hz, 2H), 8.045(s, 1H), 7. 94-7.91(m, 1H), 7.83-7.80(t, J=6.8Hz, 1H), 7.47-7.43(t, J=7.8Hz, 1H), 5.48(s, 1H), 4.39(s, 1H)H), 3.14(s, 3H), 1.61(s, 6H). LCMS: Calculated for C22H20FN3O3S, 425.478, Observed 426.2 (M+H).

[0102] Separation of the (S)- and (R)-enantiomers (D209 and D210, respectively) was achieved using a Waters 2545 quaternary gradient module with Mass Lynx software (version 4.1), a Waters 2424 ELS detector, a Waters 2767 sample manager, and a Chiralpak IC 5 μM (20 mm x 250 mm) chiral column as follows: Isocratic elution: hexane / Ch₂Cl₂ / EtOH (50:25:25). D209 tR = 20.18 min (100% purity), D210 tR = 29.02 min (100% purity).

[0103] (S)-(4-(4-(2-Fluoro-3-(2-hydroxypropan-2-yl)phenyl)furo[3,2-d]pyrimidin-6-yl)phenyl)(imino)(methyl)-λ-sulfanone (D209). Synthesis: See D203 above. Yield 43%. 1H NMR (300 MHz, MeOD-d4) δ = 9.11 (s, 1H), 8.19 (q, J = 8.4 Hz, 4H), 7.95 (t, J = 7.8 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.71 (s, 1H), 7.44 (t, J = 7.7 Hz, 1H), 3.23 (s, 3H), 1.72 (s, 6H); Anal. RP-HPLC tR = 2.34 min (method 2, purity 100 %); LC-MS: m / z = 426.2 [M+H]+ (anal. calcd for C22H20FN3O3S+: m / z = 426.1

[0104] (R)-(4-(4-(2-Fluoro-3-(2-hydroxypropan-2-yl)phenyl)furo[3,2-d]pyrimidin-6-yl)phenyl)(imino)(methyl)-λ-sulfanone (D210). Synthesis: See D203 above. Yield 46%. 1H 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); Anal. RP-HPLC tR = 2.34 min (method 2, purity 99%); LC-MS: m / z = 426.2 [M+H]+ (anal. calcd for C22H20FN3O3S+: m / z = 426.1) [ka] 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): δ 9.81 (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: Calculated for C26H27FN4O3 474.5, Observed 475.2 (M+H).

[0105] [ka] 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).

[0106] [ka] 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).

[0107] [ka] 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, 1 H), 8.85-8.83 (m, 1 H), 8.56-8.56 (m, 1 H), 8.35-8.33 (m, 1 H), 8.08-8.06 (m, 1 H), 7.63-7.61 (m, 3 H), 7.38 (s, 1 H), 4.88 (s, 1 H), 3.95 (s, 1 H), 3.72-3.69 (m, 2 H), 3.58-3.45 (m, 2 H), 1.72 (s, 6 H), 1.44 (d, J = 6.80 Hz, 3 H). LCMS: Calculated for C26H26N4O4 458.52, Observed 459.1 (M+H).

[0108] [ka] 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): δ 9.20 (s, 1 H), 8.84-8.83 (m, 2 H), 8.32-8.26 (m, 3 H), 7.99 (s, 1 H), 7.64 (d, J = 8.40 Hz, 2 H), 5.50 (s, 1 H), 3.66 (s, 2 H), 3.32-3.36 (m, 2 H), 2.38 (S, 3 H), 2.33-2.34 (m, 1 H), 2.22 (s, 3 H), 1.55 (s, 6 H). LCMS: Calculated for C26H27N5O3 457.53, Observed 458.1 (M+H).

[0109] [ka] 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, 1 H), 8.09 (d, J = 8.40 Hz, 2 H), 7.93 (d, J = 6.00 Hz, 2 H), 7.81 (s, 1 H), 7.63 (d, J = 8.00 Hz, 2 H), 7.45 (t, J = 8.0 Hz, 1 H), 5.50 (s, 1 H), 3.65 (s, 8 H), 1.61 (s, 6 H). LCMS: Calculated for C26H24FN3O4 461.493, Observed 462.1 (M+H). [ka] 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).

[0110] [ka] 2-(3-Fluoro-4-(6-(4-(methylsulfonyl)phenyl)furo[3,2-d]pyrimidin-4-yl)pyridin-2-yl)propan-2-ol. 51% yield 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); Anal. RP-HPLC tR = 0.959 min (method 2, purity 99%); LC-MS ESI: m / z = 428.1 [M+H]+ (anal. calcd for C21H19FN3O4S+: m / z = 428.1).

[0111] [ka] (4-(4-(3-Fluoro-2-(2-hydroxypropan-2-yl)pyridin-4-yl)furo[3,2-d]pyrimidin-6-yl)phenyl)(morpholino)methanone. 24% yield 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); Anal. RP-HPLC tR = 0.941 min (method 2, purity 99%); LC-MS ESI: m / z = 463.2 [M+H]+ (anal. calcd for C25H24FN4O4+: m / z = 463.2).

[0112] [ka] ((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(3-fluoro-2-(2-hydroxypropan-2-yl)pyridin-4-yl)furo[3,2-d]pyrimidin-6-yl)phenyl)methanone. 27% yield as a white solid. 1H NMR (300 MHz, MeOD-d4) δ = 9.17 (s, 1H), 8.63 (dd, J = 4.8, 1.0 Hz, 1H), 8.15 (d, J = 9.9, 8.2 Hz, 2H), 7.93 (dd, J = 4.8, 4.8 Hz, 1H), 7.80-7.66 (m, 3H), 4.79-4.40 (m, 2H), 4.02 (dd, J = 10.1, 7.7 Hz, 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); Anal. RP-HPLC tR = 0.920 min (method 2, purity 100%); LC-MS ESI: m / z = 475.2 [M+H]+ (anal. calcd for C26H24FN4O4+: m / z = 475.2).

[0113] biological activity Example 2: Effects of compounds on malaria parasite proliferation Malaria parasite PI4K has recently been identified as a drug discovery target for antimalarial drugs. Compounds according to the present invention have been tested for properties related to the inhibition of malaria parasite proliferation, in which PI4K plays an important role. Compounds that require low concentrations to inhibit malaria parasite proliferation are preferred.

[0114] In vitro Plasmodium falciparum assay Compounds according to the present invention were screened in vitro against a susceptible (NF54) strain of Plasmodium falciparum using a modified [H]hypoxanthine incorporation assay. (Vennerstrom, JL; Arbe-Barnes, S.; Brun, R.; Charman, SA; Chiu, FCK; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Tomas, JS; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S. and Charman, WN. Identification of an Antimalarial Synthetic Trioxolane Drug Development Candidate. Nature, 2004, 430, 900-904.) The compound concentration at which P. falciparum growth was inhibited by 50% compared to untreated controls was measured in nM (IC50).

[0115] [Table 5]

[0116] Example 3: Effect of compounds on PI4K activity in humans Although Plasmodium PI4K is a desirable drug target, many compounds known in the art that target this enzyme exhibit cross-inhibitory properties with closely related enzymes from other species. In this context, off-targeting of human PI4K may be problematic because it is involved in essential processes in animals. Therefore, for antimalarial drugs, it is desirable to specifically inhibit Plasmodium PI4K while only mildly affecting human PI4K. To further test the effect of compounds according to the invention on human PI4Kβ, selected compounds were tested for Hupi4Kβ inhibition and compared with the results of inhibiting the PFNF54 line described in the examples above.

[0117] The lipid kinase reaction is performed by incubating the lipid substrate (PI:3PS or PIP2:3PS) with recombinant enzyme and ATP, and kinase activity is measured using the ADP-Glo® Kinase Assay. First, the kinase reaction is terminated, and any remaining ATP is depleted, leaving only ADP. Next, kinase detection reagent is added to convert ADP to ATP, which is used in the luciferin / luciferase binding reaction. Luminescence output is measured and correlated with kinase activity. The assay can be performed in 96- or 384-well plates and can be used for enzyme characterization, inhibitor screening, or compound profiling.

[0118] The results of measuring the effect of compounds on HUPI4Kβ are shown in Table 2 in nM (IC50), which describes the concentration required to inhibit 50% of the enzyme activity (HUPI4Kβ IC50 (nM)). The compound concentration at which P. falciparum growth was inhibited by 50% compared to untreated controls was determined in nM (IC50) as described above (pFNF54 IC50 (nM)).

[0119] [Table 6]

[0120] As shown in Table 2, in addition to PI4K derived from malaria parasites, some compounds showed high potency in inhibiting human PI4K. However, while most compounds strongly inhibited the growth of malaria parasites, they had poor inhibitory properties against human PI4K. Therefore, these data indicate the excellent utility of the compounds according to the present invention for the treatment and / or prevention of malaria.

[0121] Example 4: Effect of compounds on susceptible Plasmodium strains In order to assess the concentration required to reduce the viability of malaria parasites and to test the effectiveness of various compounds according to the invention in preventing the growth of malaria parasites, further compounds according to the invention were tested for growth inhibition of the NF54 strain.

[0122] In vitro antimalarial activity—Assay A Test samples were screened for in vitro antimalarial activity against a chloroquine-susceptible (CQS) strain (NF54) of the malaria parasite Plasmodium falciparum. Continuous in vitro cultures of asexual erythrocytic stages of P. falciparum were maintained using a modified version of the method by Trager and Jensen (1976). Quantitative assessment of in vitro antimalarial activity was determined by a parasite lactate dehydrogenase assay using a modified method described by Makler (1993). Test samples were tested in triplicate in duplicate. Further dilutions were prepared in complete medium on the day of the experiment. Samples were tested as suspensions if not completely dissolved. Chloroquine and artesunate were used as reference drugs.

[0123] In vitro antimalarial activity - Assay B Screening of compounds was performed in vitro against a CQC-susceptible strain of Plasmodium falciparum (NF54) as described by Vennerstrom et al. (2004).

[0124] A full dose response was performed starting at a concentration of 3000 nM, which was serially diluted two-fold in complete medium to 10 concentrations. The lowest concentration was approximately 6 nM. The same dilution technique was used for all samples. References were tested at a starting concentration of 1000 ng / mL. The highest solvent concentrations to which the parasites were exposed had no measurable effect on parasite viability (data not shown).

[0125] [Table 7-1] [Table 7-2] [Table 7-3]

[0126] The above data further provide clear evidence for the use of compounds according to the invention for the treatment and / or prevention of malaria: at concentrations as low as less than 1 nM, the proliferation of malaria parasites was inhibited by 50%.

[0127] Example 5: In vitro Plasmodium vivax liver stage assay The efficacy of compounds against Plasmodium vivax liver-stage schizonts and hypnozoites is evaluated in infected primary human hepatocytes (PHHs). Compound screening is performed in 384-well plates with a 12-point dose response starting from 50 μM. All compounds are tested in the radical cure mode (RCM). PHHs are seeded in 384-well plates two days before infection with Plasmodium vivax sporozoites. For RCM, compounds are added to the culture medium in duplicate wells for three days, starting on day 5 postinfection. Nigericin and a PI4K inhibitor (KDU691) are used as positive controls in each assay, while solvent (DMSO) without compound is used as a negative control. The medium is changed daily, and the cultures are fixed on day 12 postinfection to ensure complete parasite removal. Fixed cells are permeabilized and stained with anti-UIS4 primary and fluorescent secondary antibodies. Liver-stage schizonts and hypnozoites are then quantified by high-content imaging. Roth, A., et al. A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum. Nat. Commun. 2018, 9(1), 1837. doi.org / 10.1038 / s41467-018-04221-9.

[0128] [Table 8]

Claims

1. Formula (I) 【Chemical 1】 During the ceremony R represents AR1 or HT1; AR1 represents phenyl, which is unsubstituted, or Alk2, OAlk2, Hal, Cyc, CN and / or NO ２ and / or 1, 2 or 3 substituents independently selected from - A、NH ２ 、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 CONA ２ 、(CR ａ R ｂ ) ｎ CONH ２ 、(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 SO ２ (R ａ R ｂ ) ｍ HetCyc1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ HetAr1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ Aryl、(CR ａ R ｂ ) ｎ SO ２ Cyc、(CR ａ R ｂ ) ｎ SO ２ A、(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 SOHetA1NNH), (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 SOHetA1NNA), (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 SOHetA1NNCyc), (CR ａ R ｂ ) ｎ 2000 ２ NA ２ 、(CR ａ R ｂ ) ｎ 2000 ２ NH ２ 、(CR ａ R ｂ ) ｎ 2000 ２ NHAおよび(CR ａ R ｂ ) ｎ 2000 ２ ; a substituent selected from the group comprising is replaced by HT1 represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle containing 3 to 9 carbon atoms and 1, 2, 3 or 4 N, O and / or S atoms, wherein the aromatic heterocycle is unsubstituted or Alk2, OAlk2, Hal, Cyc, CN, ═O and / or NO ２ and / or 1, 2 or 3 substituents independently selected from - A、NH ２ 、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 CONA ２ 、(CR ａ R ｂ ) ｎ CONH ２ 、(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 SO ２ (R ａ R ｂ ) ｍ HetCyc1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ HetAr1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ Aryl、(CR ａ R ｂ ) ｎ SO ２ Cyc、(CR ａ R ｂ ) ｎ SO ２ A、(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 SOHetA1NNH), (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 SOHetA1NNA), (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 SOHetA1NNCyc), (CR ａ R ｂ ) ｎ SO ２ N.A. ２ , (CR ａ R ｂ ) ｎ SO ２ NH ２ , (CR ａ R ｂ ) ｎ SO ２ NHAor (CR ａ R ｂ ) ｎ POA ２ a substituent selected from the group comprising is replaced by Q represents a structure according to formula (II), 【Chemistry 2】 R １ indicates AR2 or HT2, R ２ , R ３ and R ４ each independently represents H, Hal, or CAlk2; Y is CH, CHal, CAlk2, CCHal ３ or N, AR2 represents phenyl, which is unsubstituted, or Alk2, OAlk2, Hal, Cyc, CN and / or NO ２ (preferably Alk2, OAlk2, Hal and / or Cyc); and / or - A、NH ２ 、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 CONA ２ 、(CR ａ R ｂ ) ｎ CONH ２ 、(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 SO ２ (R ａ R ｂ ) ｍ HetCyc1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ HetAr1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ Aryl、(CR ａ R ｂ ) ｎ SO ２ Cyc、(CR ａ R ｂ ) ｎ SO ２ A、(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 SOHetA1NNH), (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 SOHetA1NNA), (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 SOHetA1NNCyc), (CR ａ R ｂ ) ｎ SO ２ N.A. ２ , (CR ａ R ｂ ) ｎ SO ２ NH ２ , (CR ａ R ｂ ) ｎ SO ２ NHA and (CR ａ R ｂ ) ｎ POA ２ a substituent selected from the group comprising: is replaced by HT2 represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle containing 3 to 9 carbon atoms and 1, 2, 3 or 4 N, O and / or S atoms, the aromatic heterocycle being unsubstituted or Alk2, OAlk2, Hal, Cyc, CN, ═O and / or NO ２ (preferably Alk2, OAlk2, Hal and / or Cyc); and / or - A、NH ２ 、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 CONA ２ 、(CR ａ R ｂ ) ｎ CONH ２ 、(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 SO ２ (R ａ R ｂ ) ｍ HetCyc1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ HetAr1、(CR ａ R ｂ ) ｎ SO ２ (R ａ R ｂ ) ｍ Aryl、(CR ａ R ｂ ) ｎ SO ２ Cyc、(CR ａ R ｂ ) ｎ SO ２ A、(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 SOHetA1NNH), (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 SOHetA1NNA), (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 SO ２ N.A. ２ , (CR ａ R ｂ ) ｎ SO ２ NH ２ , (CR ａ R ｂ ) ｎ SO ２ NHA and (CR ａ R ｂ ) ｎ POA ２ substituted by a substituent selected from the group comprising: A represents a straight or branched alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, where: - 1 or 2 non-adjacent CH ２ The group 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 is OH or NH ２ or cyclic alkyl having 3, 4, 5, or 6 carbon atoms, which are Hal, OHalk2, NHalk2, N(Alk2), ２ and / or mono-, di-, or tri-substituted with NH2; Alk1 represents a straight or branched alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, - 1 or 2 CH ２ The group may be replaced by O, NAlk2 or NH, and / or - One hydrogen is OH, NHAlk2, N(Alk2) ２ or NH ２ and / or 1, 2, 3, 4 or 5 hydrogens may be replaced by Hal; Alk2 represents a straight or branched alkyl having 1 to 6 carbon atoms, in which 1, 2, 3, 4 or 5 hydrogens may be replaced by Hal. Aryl is unsubstituted or mono-, di- or trisubstituted Hal, Alk2, OAlk2, OH, NH ２ or Cyc, HetCyc1 represents a monocyclic or bicyclic, optionally bridged, saturated or unsaturated 4- to 10-membered heterocycle having one or two heteroatoms selected from N, O, S and / or Si, the heterocycle being unsubstituted or optionally substituted with Hal, OH, A, SO ２ optionally mono- or disubstituted by Alk2 and / or ═O; Cyc represents a cyclic alkyl having 3 to 6 carbon atoms, in which 1, 2 or 3 hydrogens are replaced by Hal and one additional hydrogen is Alk2, NH ２ and / or may be replaced by OH, Hal represents 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, said heterocycle being unsubstituted or optionally substituted with Hal, Alk2, SOAlk2, SO ２ Alk2, OH or NH ２ may be mono- or disubstituted with R ａ and R ｂ each independently represents H, Alk2, or Cyc; or R ａ and R ｂ Let's get together-(CH ２ ) ｘ -(x=2, 3, 4, or 5), which together with the carbon atom to which they are attached form a (3-, 4-, 5-, or 6-membered) cycloalkyl ring; R Ｃｙｃ１ and R Ｃｙｃ２ Let's get together-(CH ２ ) ｘ -(x=3 or 4) and together with the atoms to which they are attached form a (5- or 6-membered ring). ２ ) ｘ one or two H atoms in - may be independently replaced by Hal or Alk1; R Ｃｙｃ３ and R Ｃｙｃ４ Let's get together-(CH ２ ) ｘ -(x=3, 4 or 5), which together with the nitrogen atom to which they are attached form a (4-, 5- or 6-membered ring), where -(CH ２ ) ｘ one or two H atoms in - may be independently replaced by Hal or Alk1; n represents 0, 1 or 2; m represents 0 or 1; or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof.

2. R represents a structure according to formula (IV), (V), (Va) or (VI); 【Chemistry 3】 During the ceremony, R ６ represents OH, A, Cyc, or a substituent according to formula (VII) to (X), 【Chemistry 4】 During the ceremony R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ and R １４ are each independently H, OH, Hal, or CH ３ , C ２ H ５ , CHal ３ , OCH ３ , OCHal ３ , OCHal ２ , OCH ２ Hal, C.H. ２ Hal and / or CHHal ２ represents R １５ is NR １７ or O, R １６ represents A or Cyc, R １７ Halk represents 1 or a cyclic alkyl 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, X ２ represents NH, NAlk1, or O.

3. Q represents a structure according to formula (XI): 【Chemistry 5】 In the formula, the residue R ２ , R ３ , R ４ One or two of the groups are independently Hal, CH ３ , CHal ３ , OCH ３ , OCHal ３ , OCHHal ２ , OCH ２ Hal, C.H. ２ Hal, and / or CHHal ２ and the remaining residue(s) represent H.

4. Selected from the following 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 10. A compound according to claim 1, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer (including mixtures in any ratio).

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

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

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

8. 8. The compound of claim 7, wherein the protozoal 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).

11. 11. The pharmaceutical composition of claim 10 for use in the treatment and / or prevention of a PI4K-associated disorder.

12. 12. The pharmaceutical composition according to claim 10 or 11, comprising at least one further active ingredient, and said further active ingredient is at least one antimalarial agent different from formula (I).

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

14. 1. A method for preventing or treating a PI4K-associated disorder, comprising: The method is as follows: (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 said at least one compound or said composition to a patient in need thereof. The method comprises the steps of:

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

16. R has the structure of formula (IV): 【Chemistry 6】 During the ceremony, R ６ は、Alk1、Alk2、-OH、-CH ３ ,-OCH ３ ,-OC(EH ３ ) ３ 、-N(CH ３ ) ２ 、 【Chemistry 7】 and W is O, NR １８ , or CR １８ R １９ and R ７ , R ８ are each independently selected from H or Hal; R １８ , R １９ are each independently —H, —CH ３ or Alk1, X １ is CR ７ or N, wherein Q is of formula II, and R １ But, H, Hal, 【Chemistry 8】 and R ２ , R ３ , R ４ are each independently selected from H or Hal; R ２８ is Alk1, Alk2, -NH ２ , 【Chemistry 9】 and R ２９ , R ３０ are each independently H or —CH ３ is selected from Y is N, CH, or CHal; The compound of claim 1.

17. R has the structure of formula (V): 【Chemistry 10】 X １ is CR ７ or N, R ７ , R ８ are each independently H, Hal, or CHal ３ is selected from either R １５ is O or NH, R １６ is H, -CH ３ , -NH ２ , -N(CH ３ ) ２ or Alk1, wherein Q is of formula II, and R １ But, H, Hal, 【Chemistry 11】 and R ２ , R ３ , R ４ are each independently selected from H or Hal; R ２８ Alk1, Alk2, -NH ２ , 【Chemistry 12】 and R ２９ , R ３０ are each independently H or CH ３ is selected from 2. The compound of claim 1, wherein Y is N, CH, or CHal.

18. R is, 【Chemistry 13】 or 【Chemistry 14】 having the structure R １８ , R １９ are each independently H, —CH ３ or Alk1, and R ２７ is -CH ３ or -C((CH ３ ) ２ OH), wherein Q is of formula II, and R １ H, Hal, 【Chemistry 15】 and R ２ , R ３ , R ４ are each independently selected from H or Hal; R ２８ is Alk1, Alk2, -NH ２ , 【Chemistry 16】 and R ２９ , R ３０ are each independently H or CH ３ is selected from 2. The compound of claim 1, wherein Y is N, CH, or CHal.

19. R ６ But -CH ３ , -OH, -N(CH ３ ) ２ ,or 【Chemistry 17】 and W is O, R ７ , R ８ is hydrogen, R １８ , R １９ are each independently —H or —CH ３ is selected from X １ is CH or N.

20. R ６ but, 【Chemistry 18】 and R １ but, 【Chemistry 19】 20. The compound of claim 19, wherein:

21. R １ is H, Hal, or 【Chemistry 20】 is selected from R ２ , R ３ , R ４ , R ７ , R ８ are each independently selected from H or Hal; R １６ But -CH ３ or Alk1, X １ is CH, 18. The compound of claim 17, wherein Y is CH or CHal.

22. R １ but, 【Chemical 21】 and R ２ , R ７ , R ８ are each independently selected from H or Hal; R ３ , R ４ is H, R １５ is NH, R １６ But -CH ３ or Alk1, X １ is CH, 22. The compound of claim 21, wherein Y is CH.

23. SOR of Formula V １５ R １６ 23. The compound of claim 22, wherein the group is ortho to the bond of formula I.

24. R ３ and R ４ 24. The compound of claim 23, wherein is H.

25. X １ 25. The compound of claim 24, wherein is CH.

26. R １ but, 【Chemical Formula 22】 R ２ , R ７ , R ８ are each independently selected from H or Hal; R ３ , R ４ is H, R １５ is NH, R １６ But -CH ３ and X １ is CH, 26. The compound of claim 25, wherein Y is CH.

27. The compound 【Table 2】 27. The compound of claim 26, wherein:

28. The compound 【Table 3】 27. The compound of claim 26, wherein:

29. The compound 【Table 4】 27. The compound of claim 26, wherein:

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