WO2022234069A1

WO2022234069A1 - Novel 2-aminooxazoles derivatives and use thereof for treating infectious diseases

Info

Publication number: WO2022234069A1
Application number: PCT/EP2022/062256
Authority: WO
Inventors: Alain Moussy; Abdellah Benjahad; Didier Pez; Emmanuel Chevenier; Jason Martin; Willy Picoul; Dmytro Atamanyuk; Franck Sandrinelli
Original assignee: Ab Science
Priority date: 2021-05-07
Filing date: 2022-05-06
Publication date: 2022-11-10

Abstract

This invention relates to 2-aminooxazole derivatives of general formula (I) or a pharmaceutically acceptable salt or solvate thereof wherein Y and Z are two different heteroatoms selected from N and O; X is selected from N and CR12; and R1-R5 and R12 may be different chemical groups. According to one embodiment, R1 is -COOH or -CONH2. The 2-aminooxazole derivatives of the invention are useful as PfCDPK1 and/or PfCLK3 inhibitors, in particular in the treatment and/or prevention of infectious diseases such as, for example, malaria.

Description

NOVEL 2-AMINOOXAZOLES DERIVATIVES AND USE THEREOF FOR TREATING INFECTIOUS DISEASES

FIELD OF INVENTION [0001] The present invention relates to novel compounds useful as anti-P/CDPKl

{Plasmodium falciparum CDPK1) agents and/or anti-/^J/CLK3 {Plasmodium falciparum CLK3) agents, especially to novel 2-aminooxazole derivatives as anti-P/CDPKl and/or anti-/^J/CLK3 agents. In particular, the present invention concerns 2-aminooxazole derivatives for use in the treatment and/or prevention of an infectious disease such as malaria.

BACKGROUND OF INVENTION

[0002] Malaria is one of the most prevalent infectious diseases that affects millions and causes significant mortality in the developing world. The World Health Organization (WHO) estimates that from 154 to 289 million cases of malaria caused 660000 associated deaths in 2010. Eighty percent of the estimated cases occur in sub-Saharan Africa and 86% of deaths occur in children less than 5 years of age. One of the problems in overcoming human malaria is the alarming increase in the rate of resistance exhibited by malaria parasites toward currently available drugs. Several species of Plasmodium parasites cause malaria in human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malarieae and the simian Plasmodium knowlesi. The most lethal species is Plasmodium falciparum (P. falciparum), which is found predominantly in Africa. P. falciparum has a complex lifecycle during which it infects both the vector and the human host (Biamonte, MA et al. Bioorganic & Medicinal Chemistry Letters, May 2013, Vol. 23, No. 10, pp. 2829-2843). It first propagates in the liver, followed by invasion and subsequent development in the erythrocytes. In order to eradicate the disease, different stages of infection could be considered for treatment. Liver stage (1): Once the mosquito inoculates the parasites (sporozoites) into the blood stream, the parasites invade the liver within 30 min and start replicating there (schizonts). In addition, P. vivax and P. ovale can remain dormant in the liver (hypnozoites) and cause relapses years after the initial infection. Drugs that target the liver stages are important to prevent the disease from developing (prophylactic effect) and to provide what is known as a “radical cure” for P. vivax and P. ovale. Blood stage (2): After approximately 5-10 days, the liver cells burst and merozoites invade the red blood cells where they rapidly proliferate, causing the symptomatic high fevers and the pathology. In their intraerythrocytic phase, the merozoites go through various forms (rings, trophozoites, schizonts) to form an average of twenty daughter merozoites that are released into the bloodstream and infect new red blood cells. Drugs that target the blood stages are important to control the symptoms of the disease and associated mortality. Transmission stage (3): When ingested by mosquitoes, the male and female gametocytes fuse in the midgut to form a zygote that further develops into new sporozoites ready for the next human host. Drugs that target the transmission (mosquito) stage are important to prevent the infection of the other humans and would benefit to an eradication agenda.

[0003] Most currently approved anti-malarial drugs, including artemisinin-based combination therapies (ACTs), are only effective against blood stages and young gametocytes up to stage III and possibly stage IV of gametocyte maturation. These drugs thus unfortunately do not result in complete clearance of mature gametocytes. To make matters worse, some drug treatment ( e.g ., chloroquine and sulfadoxine-pyrimethamine) were found to induce gametocytogenesis, thus potentially contributing to increased numbers of transmissions and increased rates of new infections. Artemisinin-based combination therapies (ACTs) are the current standard of care for uncomplicated malaria. Artemisinin and its derivatives have a fast onset of action but are cleared rapidly (human ti/2 is about lh) and are therefore combined with slow-clearing drugs to kill residual parasites. Typical partner drugs include lumefantrine (human tm is 3-4 days) and piperaquine (human ti/2 is 8-16 days). The most popular combination consists of tablets containing artemether and lumefantrine (Coartem®, Novartis). In 2011, a combination of dihydroartemisinin and piperaquine (Eurartesim®, Sigma-Tau) was also approved. Parenteral artesunate is the drug of choice for treating severe malaria. For the liver stage, primaquine is the only drug approved to eliminate hypnozoites. As for prophylactic treatment, atovaquone-proguanil (Malarone™, GlaxoSmithKline) is usually preferred because it is well tolerated, but is very expensive. Cycloguanil is the active metabolite of proguanil. About transmission stage, primaquine is the only registered drug active against the mature gametocyte. Resistance against available anti-malaria drugs is well-documented, and especially troubling is the emerging resistance of artemisinin. Combining drugs may limit the emergence of resistance, but this technique is not always efficient: for instance, in parts of Cambodia, the proportion of patients who were still parasitemic after 3 days of treatment with dihydroartemisinin-piperaquine combination increased from 26% in 2008 to 45% in 2010. [0004] Intracellular signalling is involved in almost all stages of parasite development.

Calcium signalling has emerged as a major target in controlling several important signalling pathways in the parasite. These pathways control a wide-range of events in the parasite life cycle such as host cell invasion, sexual differentiation, asexual parasite life cycle and development of hepatic stages. Calcium-dependent protein kinases (CDPKs) are major effectors of calcium signalling in malaria parasite and control some of these processes. CDPKs are present in some species of plants, fungi, and protozoans but absent form mammals. Their importance in parasite signalling and absence in the host have made CDPKs attractive drug targets. CDPKs in Plasmodium are present as a multigene family containing at least five members and different CDPKs are proposed to be functional at different stages of the parasite life cycle.

[0005] P. falciparum CDPK1 (“P/CDPK1”) is expressed in the asexual blood stages of the parasite responsible for malaria. P/CDPK1 has been shown to be encoded by an essential gene and implicated in parasite motility and host cell invasion, where it is able to phosphorylate components of the molecular motor that drive parasite invasion of red blood cells. If this invasion process could be prevented, the parasite lifecycle would be broken, leading the parasites to die and the disease to be cleared. P/CDPK1 has therefore emerged as a key enzyme of the parasite signalling machinery (Kato, N. et al., Nature Chemical Biology, June 2008, Vol. 4, No. 6, pp. 347-356; Green, JL et al., Journal of Biological Chemistry Nov 2008, Vol. 283, No. 45, pp. 30980-30989) and represents a relevant target to design selective anti-malaria treatments. [0006] The protein kinase Plasmodium falciparum CLK3 (“P/CLK3”) plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of P. falciparum at the blood stage. Recently, P/CLK3 was validated as a relevant target to design highly specific anti-malaria treatments for prophylactic, curative, and transmission-blocking use. Various species of malaria parasites at the blood stage and/or liver-stage can be killed through inhibition of the protein kinase CLK3. By preventing gametocyte development, the inhibition of P/CLK3 can also block the transmission of the parasite to mosquitoes (Alam, M. M. etal., Science, August 2019, Vol. 365, Article 884; Mahindra, A. etal., Journal of Medicinal Chemistry, July 2020, Vol. 63, pp. 9300-9315). [0007] Therefore, there is an urgent need for new lines of anti-malarial drugs, especially for solving the problem of drug resistance. New anti-malarial drugs or drug combinations would preferably be acting fast, be safe for children and pregnant women and/or be amenable to a single-dose administration. The new anti-malarial drugs can in particular target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses and/or the transmission stage to avoid transmission to other humans.

SUMMARY

[0008] This invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein Ri, R2, R3, R4, R5, X, Y and Z are as described in the claims. [0009] According to one embodiment, the compound is of formula (II)

or a pharmaceutically acceptable salt or solvate thereof, wherein Ri, R2, R3, R4, R5, Y and Z are as described in the claims. [0010] In one embodiment, the compound is of formula (III)

or a pharmaceutically acceptable salt or solvate thereof, wherein Ri, R2, R3, R4, Y and Z are as described in the claims.

[0011] According to one embodiment, the compound is selected from any one of the individual compounds of formula (I) as listed in the claims, or a pharmaceutically acceptable salt and/or solvate thereof.

[0012] This invention also relates to a pharmaceutical composition comprising the compound of the invention and at least one pharmaceutically acceptable carrier. According to one embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the therapeutic agent is selected from quinine, quinidine, proguanil, mefloquine, chlorproguanil, chloroquine, lumefantrine, atovaquone, pyrimethamine sulfadoxine, cipargamin, ganaplacide, pyrimethamine dapsone, halofantrine, amodiaquine, amopyroquine, trimethoprim, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine and pyronaridine.

[0013] This invention also relates to the compound according to the invention for use as a medicament. This invention also relates to the compound according to the invention for use in the treatment and/or prevention of an infectious disease. According to one embodiment, the infectious disease is malaria. In one embodiment, the malaria is caused by infection from Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malarieae or Plasmodium knowlesi.

[0014] This invention also relates to a process for manufacturing a compound according to the invention, wherein the process comprises at least one of the following steps:

(i) reacting an aryl halide compound with an oxazole compound using Suzuki cross -coupling reaction, thereby obtaining an aryl-substituted oxazole compound;

(ii) reacting an aromatic aldehyde compound with p-toluenesulfonylmethyl isocyanide, thereby obtaining an aryl-substituted oxazole compound and/or (iii) reacting a 5-aryl- 2-chlorooxazole compound with an aminoaryl compound, thereby obtaining a/V-aryl- 5-aryl-oxazole-2-amine compound.

DEFINITIONS

Chemical definitions

[0015] When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise. Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited. For example, an arylalkyl substituent is bound to the rest of the molecule through the alkyl moiety and it may by represented as follows: “aryl-alkyl-”. In this application, all compounds were named using ChemDraw® Professional 15.0 (PerkinElmer), unless otherwise indicated. [0016] “Alkenyl” refers to an alkyl group as defined herein, further comprising one or more carbon-carbon double bonds and two less hydrogen atoms for each double bond. Non-limiting examples of alkenyl groups include ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers and 2,4-pentadienyl. [0017] “Alkoxy” refers to an alkyl-O- group, i.e. , an oxygen atom substituted by an alkyl group as defined herein, wherein the oxygen atom is the point of attachment to other groups.

[0018] “Alkyl” by itself or as part of another substituent refers to a hydrocarbyl group of general formula Cnthn+i wherein n is a number greater than or equal to 1. Typically, alkyl groups comprise from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, more preferably from 1 to 3 carbon atoms, furthermore preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Non-limiting examples of alkyl groups include methyl, ethyl, n -propyl, /-propyl, ₇₇-butyl, /-butyl, 5-butyl and /-butyl, pentyl and its isomers ( e.g ., n-pcntyl, /50-pentyl), and hexyl and its isomers (e.g., 77-hexyl, /50-hexyl). Preferred alkyl groups include methyl, ethyl, 77 -propyl, /-propyl, 77-butyl, 5-butyl and /-butyl. When the suffix “ene” (“alkylene”) is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. Non-limiting examples of alkylene groups include methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene.

[0019] “Alkylamino” refers to a nitrogen atom substituted with one or two alkyl groups as defined herein, including both monoalkylamino and dialkylamino groups.

[0020] “Alkynyl” refers to an alkyl group as defined herein further comprising one or more carbon-carbon triple bonds and four less hydrogen atoms for each triple bond. [0021] “Amido” refers to -CONH2 group.

[0022] “Amino” refers to -NH2 group.

[0023] “Aryl" as used herein refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring. Aryl groups may have a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or linked covalently. Typically, aryl groups have from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2- pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl. Preferred aryl groups include phenyl. “Arylene” refers to a divalent aryl group. [0024] “(Cx-Cy)” preceding a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in chemistry field.

[0025] “Carboxylic acid” refers to -COOH group.

[0026] “Cyano” refers to -CN group.

[0027] “Cycloalkyl” refers to a cyclic, monovalent, saturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups.

Cycloalkyl groups comprise 3 or more carbon atoms in the ring; typically, from 3 to 12 carbon atoms in the ring, more preferably from 3 to 9 carbon atoms, furthermore preferably from 3 to 6 carbon atoms. Typically, a cycloalkyl group is of general formula C_nth_n-i. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When the suffix "ene" is used in conjunction with a cyclic group (e.g., “cycloalkylene” or “heterocycloalkylene”), this is intended to mean the cyclic group as defined has two single bonds as points of attachment to other groups.

[0028] “Halo” or “halogen” refers to fluoro, chloro, bromo or iodo (/._<?., a monovalent fluorine, chlorine, bromine or iodine atom). Preferred halogen groups include fluoro (F) and chloro (Cl).

[0029] “Haloalkyl” refers to an alkyl group as defined herein, wherein one or more hydrogen(s) are replaced with a halogen as defined above. Non-limiting examples of haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl (CH₂), trifluoromethyl (CF₃) and 1,1,1-trifluoroethyl. [0030] “Heterocycloalkyl” refers to a cycloalkyl group as defined herein, wherein at least one carbon atom is replaced with a heteroatom, namely, a non-aromatic, saturated cyclic hydrocarbyl group which has at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulphur atoms, where the nitrogen and sulphur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any one of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of a multi-ring heterocycloalkyl may be fused, bridged and/or joined through one or more spiro atoms. Heterocycloalkyl groups are typically 3- to 7-member monocyclic, 7- to 11-member bicyclic. Heterocycloalkyl groups typically contain a total of from 3 to 10 ring atoms. Non-limiting examples of heterocycloalkyl groups include oxetanyl, oxiranyl, piperidinyl, morpholinyl, thiomorpholinyl azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, indolinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, tetrahydrothiopyranyl sulfoxide, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrofuranyl, dihydrofuranyl-2-one, tetrahydrothienyl, tetrahydro-l,l-dioxothienyl, 2-oxopyrrolidinyl, 4-piperidonyl, pyrrolidinyl, hydantoinyl, tetrahydroquinolinyl, tetrahydroisoquinolin-l-yl, valerolactamyl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1,4-oxathianyl, lH-pyrrolizinyl, tetrahydro-l,l-dioxothiophenyl, N-formylpiperazinyl and morpholin-4-yl. [0031 ] “Heterocyclyl” refers to a group being either an heterocycloalkyl or an heteroaryl group as defined herein. Thus, any occurrence of “heterocyclyl” in this application may be substituted by “heterocycloalkyl or heteroaryl” without changing its meaning or scope.

[0032] “Heteroaryl" refers to an aryl group as defined herein, wherein at least one carbon atom in an aryl group is replaced with a heteroatom. Typically, heteroaryl groups are aromatic rings or ring systems comprising from 5 to 12 carbon atoms, preferably from 5 to 6 carbon atoms; and 1 to 2 rings which are fused together or linked covalently, wherein at least one of the rings is aromatic, wherein one or more carbon atoms of at least one of the aromatic rings is replaced by oxygen, nitrogen and/or sulphur atoms. The nitrogen and sulphur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. The rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring. Non-limiting examples of heteroaryl groups include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l- b][l,3] thiazolyl, thieno [3, 2-b] furanyl, thieno [3, 2-b] thiophenyl, thieno[2,3- d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3- benzoxadiazolyl, 2, 1 ,3 -benzoxadiazolyl, 1 ,2 ,3 -benzothiadiazolyl,

2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo- pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin- l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. “Heteroarylene" refers to a divalent heteroaryl group.

[0033] “Hydroxyl” refers to -OH group.

[0034] “Water-solubilising group” or “solubilising group” refers to a group which has a hydrophilic character sufficient to improve or increase the solubility in water of the compound in which it is included, as compared to an analogue compound that does not include the group. The hydrophilic character can be achieved by any means, for example by the inclusion of functional groups that ionize under the conditions of use to form charged moieties (e.g., carboxylic acids, sulfonic acids, phosphoric acids, amines, etc.); groups that include permanent charges (e.g., quaternary ammonium groups); and/or heteroatoms or heteroatomic groups. Non-limiting examples of solubilising groups include:

[0035] (i) any one of the following structures of formulae (a)-(f):

and

[0036] (ii) any one of the following structures of formulae (g)-(q):

wherein: z is an integer ranging from 0 to 6 (i.e., 0, 1, 2, 3, 4, 5 or 6);

L is selected from CH and N; M is selected from -CH(R^B)-, -CH2-, -0-, -S-, - S(0)₂-, -NH-, -N((CH₂)_Z-R^b)-, -N(-(CH₂)_Z-C(0)R^c)-, -N(-(CH₂)_Z-C(0)OR^c)-, - N(-(CH₂)_Z-S(0)₂R^c)-, -N(-(CH₂)_Z-S(0)₂0R^c)- and -N(-(CH₂)_Z- C(0)N(R^C)(R^d))-; with the proviso that L and M are not simultaneously CH and Cf , respectively;

R^A is selected from hydrogen, (Ci-Cio) alkyl and (Ci-Cio) alkoxy;

R^B is selected from hydrogen, hydroxyl, (Ci-Cio) alkyl, (Ci-Cio) alkoxy, unsubstituted aryl and unsubstituted heteroaryl; wherein the (Ci-Cio) alkyl is optionally substituted and/or interrupted by at least one heteroatom selected from halogen, oxygen and nitrogen; and

R^c and R^D are each independently selected from hydrogen, (Ci-Cio) alkyl, unsubstituted aryl and unsubstituted heteroaryl; wherein the (Ci-Cio) alkyl is optionally substituted and/or interrupted by at least one cyano, hydroxyl or heteroatom selected from halogen, oxygen and nitrogen.

[0037] In formulae (a)-(q) above, the waving line ^ represents the point of attachment of the water-solubilising group to the main molecule or group.

[0038] Preferred solubilising groups include morpholinyl, piperidinyl, pyrrolidinyl, N-(C_I-C₆) alkyl piperidinyl (in particular N-methyl piperidinyl and N-ethyl piperidinyl), hydroxy piperidinyl (in particular 4-hydroxy piperidinyl), N-(4-piperidinyl)piperidinyl, 4-(l-piperidinyl)piperidinyl, 1-pyrrolidinylpiperidinyl, 4-morpholinopiperidinyl, 4-(N- methyl-l-piperazinyl) piperidinyl, piperazinyl, N-iCi-Ce) alkyl piperazinyl (in particular N-methyl piperazinyl and N-ethyl piperazinyl), N-(C3-C6) cycloalkyl piperazinyl (in particular N-cyclohexyl piperazinyl), pyrrolidinyl, N-(Ci-Ce) alkyl pyrrolidinyl (in particular N-methyl pyrrolidinyl and N-ethyl pyrrolidinyl), diazepinyl, N-(Ci-Ce) alkyl azepinyl (in particular N-methyl azepinyl and N-ethyl azepinyl), homopiperazinyl, N-methyl homopiperazinyl, N-ethyl homopiperazinyl and imidazolyl.

General definitions [0039] In the present application, the following terms have the following meanings.

[0040] “About” is used herein to mean approximately, roughly, around, or in the region of. The term “about” preceding a figure means plus or less 10 % of the value of the figure. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by 10%.

[0041] “Administration", or a variant thereof ( e.g ., “administering”), means providing a therapeutic agent (e.g., a compound of the invention) alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated and/or prevented.

[0042] “Human” refers to a male or female subject at any stage of development, including neonate, infant, juvenile, adolescent and adult.

[0043] “Patient” refers to an animal, typically a warm-blooded animal, preferably a human, who/which is awaiting the receipt of, or is receiving medical care, or is/will be the object of a medical procedure. A patient may also be the subject of preventive care or procedure.

[0044] “Pharmaceutically acceptable” meant that the ingredients of a composition are compatible with each other and not deleterious to the patient to which/whom it is administered.

[0045] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA. Non-limiting examples of pharmaceutically acceptable carriers are ion exchangers, alumina, aluminium stearate, lecithin, serum proteins (such as, for example, human serum albumin), buffer substances (such as, for example, phosphates, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as, for example, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate or sodium chloride), zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (such as, for example, sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat. [0046] “Prevent”, “preventing” and “prevention” refer to delaying or precluding the onset of a condition and/or disease and/or any one of its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing the risk for a patient of acquiring a condition and/or disease and/or any one of its attendant symptoms. [0047] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent ( e.g ., a compound of the invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo into the active compounds. Non-limiting examples of prodmgs include amide prodmgs and carboxylic acid ester prodmgs, in particular alkyl esters, cycloalkyl esters and aryl esters.

[0048] “Solvate” refers to molecular complex comprising a compound along with stoichiometric or sub- stoichiometric amounts of one or more molecule(s) of one or more solvent(s), typically the solvent is a pharmaceutically acceptable solvent such as, for example, ethanol. The term “hydrate” refers to when the solvent is water (H2O). [0049] “Therapeutic agent” and “active pharmaceutical ingredient” and “active ingredient” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound of the invention) may be indicated for treating and/or preventing a disease, preferably an infectious disease. An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent. [0050] “Therapeutically effective amount” (in short “effective amount”) refers to the amount of a therapeutic agent (e.g., a compound of the invention) that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered.

[0051] “Treat”, “treating” and “treatment” refers to alleviating, attenuating or abrogating a condition and/or disease and/or any one of its attendant symptoms. DETAILED DESCRIPTION Compounds

[0052] This invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt and/or solvate thereof.

[0053] In formula (I), Ri is selected from cyano, -COOR6, -CONR6R7 and heteroaryl; wherein R6 and R7 are each independently selected from hydrogen and (C₁-C₁₀) alkyl; wherein the (C₁-C₁₀) alkyl is optionally substituted by at least one (C₁-C₁₀) alkoxy or water-solubilising group. From the definitions of Ri herein, it stems that Ri is not an haloalkyl group such as, for example, trifluoromethyl. According to one embodiment, Ri is cyano. According to another embodiment, Ri is selected from -COOR6, -CONR6R7 and heteroaryl, i.e., Ri is not cyano. According to another embodiment, Ri is selected from cyano, -COOR6 and -CONR6R7, i.e., Ri is not heteroaryl.

[0054] According to one embodiment, Ri is selected from -COOR6 and -CONR6R7; wherein R6 and R7 are as defined hereinabove. In one embodiment, R6 and R7 are each independently selected from hydrogen and (C₁-C₅) alkyl; wherein the (C₁-C₅) alkyl is optionally substituted by at least one (C₁-C₅) alkoxy or water- solubilising group. In one embodiment, R6 and R7 are each independently selected from hydrogen and (C₁-C₅) alkyl. In one embodiment, R6 is (C₁-C₅) alkyl optionally substituted by at least one (C₁-C₅) alkoxy such as, for example, methoxy. In one embodiment, R6 is (C₁-C₃) alkyl, preferably ethyl or methyl; wherein the (C₁-C₃) alkyl is optionally substituted by at least one (C1-C5) alkoxy or water- solubilising group. In one embodiment, R7 is hydrogen.

[0055] According to one embodiment, both R6 and R7 are hydrogen, i.e., Ri is selected from carboxylic acid (-COOH) and amido (-CONH2). In one embodiment, Ri is -COOH. In one embodiment, Ri is -CONH2.

[0056] According to one embodiment, R6 is (C₁-C₁₀) alkyl, preferably (C₁-C₅) alkyl, more preferably (C₁-C₃) alkyl. In this embodiment, the alkyl is unsubstituted. According to one embodiment, Ri is -CONR6R7, wherein R6 is (C₁-C₁₀) alkyl and R7 is hydrogen. In one embodiment, R6 is selected from methyl and ethyl. In one embodiment, R6 is methyl.

[0057] According to one embodiment, Ri is -COOR6 and R6 is (C₁-C₁₀) alkyl, preferably (C1-C5) alkyl, more preferably (C1-C3) alkyl, wherein the (C1-C10) alkyl is substituted by at least one water-solubilising group. According to one embodiment, Ri is -CONR6R7, wherein R6 is (C₁-C₁₀) alkyl substituted by at least one water-solubilising group and R7 is hydrogen. In one embodiment, R6 is

(C₁-C₁₀) alkyl substituted by at least one water- solubilising group, wherein the water-solubilising group is an heterocycloalkyl optionally substituted by at least one amino, cyano, halogen, hydroxyl, trifluoromethyl, methyl, ethyl, methoxy or ethoxy; such as, for example, methylpiperazinyl, piperazinyl, methylpiperidinyl or piperidinyl.

[0058] It is well-known in the art that carboxylic esters are prodrugs of carboxylic acid. Therefore, a compound of formula (I) wherein Ri is -COOR6 and R6 is (C1-C10) alkyl, optionally substituted by at least one solubilizing group, is expected to be metabolised in vivo by the action of esterase enzymes into a carboxylic acid (-COOH), thereby showing a similar biological activity to an analogue compound wherein Ri is -COOH. It is also well-known in the art that secondary amides are prodrugs of primary amides. Therefore, a compound of formula (I) wherein Ri is -CONHR6 (secondary amide) and R6 is (C1-C10) alkyl, optionally substituted by at least one solubilizing group, is expected to be converted in vivo into a primary amide (-CONH2), thereby showing a similar biological activity to an analogue compound wherein Ri is -CONH2. [0059] According to one embodiment, Ri is a heteroaryl. According to one embodiment, Ri is a five-membered heteroaryl. According to one embodiment, Ri is selected from pyrrolyl, imidazolyl (1,3-diazolyl), pyrazolyl (1,2-diazolyl), triazolyl, thiazolidinedionyl, oxazolidinedionyl, 5-oxo-l,2,4-oxadiazolyl, 5-oxo-l,2,4-thiadiazolyl, 5-thioxo- 1,2,4-oxadiazolyl, isothiazolyl, isoxazolyl, 3-hydroxyisothiazol-5-yl, 3-hydroxyisooxazol-5-yl and tetrazolyl. In one embodiment, Ri is tetrazolyl such as, for example, lH-tetrazolyl and 2H-tetrazolyl. In one embodiment, Ri is tetrazol-5-yl. Tetrazole is known in the art as a bioisostere of carboxylic acid. Therefore, a compound of formula (I) wherein Ri is tetrazolyl is expected to show a similar biological activity to an analogue compound wherein Ri is -COOH.

[0060] In formula (I), R2 is selected from hydrogen, cyano, halogen, hydroxyl, (C1-C10) alkyl, (C1-C10) haloalkyl, (C1-C10) alkoxy and -NR8R9; wherein the (C₁-C₁₀) alkyl or (C₁-C₁₀) alkoxy is optionally substituted by at least one (C₁-C₁₀) alkoxy or water- solubilising group; wherein Rs and R9 are each independently selected from hydrogen and (C₁-C₁₀) alkyl; wherein the (C₁-C₁₀) alkyl is optionally substituted by at least one amino, hydroxyl or (C₁-C₁₀) alkoxy.

[0061] According to one embodiment, R2 is selected from hydrogen, cyano, halogen, hydroxyl, (C1-C5) alkyl, (C1-C5) haloalkyl and (C1-C5) alkoxy. In one embodiment, R2 is selected from hydrogen, cyano, halogen, hydroxyl, (C1-C3) alkyl, (C1-C3) haloalkyl and (C1-C3) alkoxy. In one embodiment, R2 is selected from hydrogen, halogen, (C1-C3) alkyl and (C1-C3) alkoxy. In one embodiment, R2 is selected from hydrogen, fluoro, chloro, bromo, methyl and methoxy. In one preferred embodiment, R2 is hydrogen. In one embodiment, R2 is selected from fluoro, chloro and bromo. In one embodiment, R2 is chloro. In one embodiment, R2 is selected from ethyl and methyl. In one embodiment, R2 is methyl. In one embodiment, R2 is selected from ethoxy and methoxy. In one embodiment, R2 is methoxy.

[0062] From the definitions of Ri and R2 herein, it stems that Ri and R2 do not form together with the phenyl group to which they are bound a polycyclic aryl or heteroaryl group. In other words, Ri and R2 are not fused together. [0063] In formula (I), R3 and R are each independently selected from hydrogen, cyano, halogen, hydroxyl, trifluoromethyl, (C₁-C₁₀) alkyl,

(C1-C10) alkoxy, -COR10, -NR10R11, -NR10-COR11, -CONR10R11 and -SO2NR10R11; wherein the (C₁-C₁₀) alkyl or (C₁-C₁₀) alkoxy is optionally substituted by at least one (C₁-C₁₀) alkoxy, heterocyclyl or water- solubilising group; wherein Rio and R11 are each independently selected from hydrogen, hydroxyl, (C₁-C₁₀) alkyl, (C₁-C₁₂) cycloalkyl, heterocyclyl and water-solubilising group; wherein the (C₁-C₁₀) alkyl or (C₁-C₁₂) cycloalkyl is optionally substituted by at least one cyano, amino, (C₁-C₁₀) alkylamino, (C₁-C₁₀) alkoxy, aryl, heterocyclyl or water- solubilising group; wherein the aryl is optionally substituted by at least one amino, cyano, halogen, hydroxyl, trifluoromethyl, methyl, ethyl, methoxy or ethoxy; wherein the heterocyclyl is optionally substituted by at least one amino, cyano, halogen, hydroxyl, trifluoromethyl, methyl, ethyl, methoxy or ethoxy. According to one embodiment, the aryl is phenyl. According to one embodiment, the heterocyclyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and pyridinyl.

[0064] From the definitions of R3 and R4 herein, it stems that R3 or R4 are not a sulphonamide group (-NR-SO₂R’) such as, for example, -NH-SO₂CH₃. From the definitions of Rio and R11 herein, it stems that Rio and R11 do not form together with the nitrogen atom to which they are bound an heterocyclyl group such as, for example, morpholinyl. In other words, Rio and R11 are not fused together.

[0065] According to one embodiment, R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, trifluoromethyl, (C₁-C₅) alkyl, (C₁-C₅) alkoxy, -COR10 and -CONR10R11; wherein the (C₁-C₅) alkyl or (C₁-C₅) alkoxy is optionally substituted by at least one (C₁-C₅) alkoxy, heterocyclyl or water-solubilising group; and wherein Rio and R11 are each independently selected from hydrogen, hydroxyl, (C₁-C₅) alkyl,

(C₁-C₉) cycloalkyl, heterocyclyl and water- solubilising group; wherein the (C₁-C₅) alkyl or (C₁-C₉) cycloalkyl is optionally substituted by at least one cyano, amino, (C₁-C₅) alkylamino, (C₁-C₅) alkoxy, aryl (preferably phenyl), heterocyclyl or water-solubilising group; wherein the aryl (preferably phenyl) is optionally substituted by at least one amino, cyano, halogen, hydroxyl, trifluoromethyl, methyl, ethyl, methoxy or ethoxy; wherein the heterocyclyl is optionally substituted by at least one amino, cyano, halogen, hydroxyl, trifluoromethyl, methyl, ethyl, methoxy or ethoxy. According to one embodiment, at least one among Ra or R is -COR10, wherein Rio is heterocyclyl or water-solubilising group such as, for example, methylpiperazinyl or morpholinyl. [0066] According to one embodiment, R3 and R4 are identical. According to another embodiment, R3 and R4 are different. In one particular embodiment, R3 and R4 are not each hydrogen. In one particular embodiment, R3 and R4 are not each an alkoxy group. In one embodiment, R3 is not halogen. In one embodiment, R3 is not hydroxyl. In one embodiment, R3 is not hydrogen. In one embodiment, R3 is not -NR10R11 as defined herein. In one embodiment, R3 is not -SO₂NR10R11 as defined herein. In one embodiment, R3 is not an alkoxy group substituted at least one water- solubilising as defined herein. In one particular embodiment, R3 is not an alkoxy group. In one embodiment, R4 is not halogen. In one embodiment, R4 is not hydroxyl. In one embodiment, R4 is not hydrogen. In one embodiment, R4 is not -NR10R11 as defined herein. In one embodiment, R4 is not -SO₂NR10R11 as defined herein. In one embodiment, R4 is not an alkoxy group substituted at least one water-solubilising as defined herein. In one particular embodiment, R4 is not an alkoxy group.

[0067] In formula (I), Rs is selected from hydrogen, halogen, (C₁-C₁₀) alkyl and (C₁-C₁₀) alkoxy. According to one embodiment, Rs is selected from hydrogen, (C₁-C₁₀) alkyl and (C₁-C₁₀) alkoxy, i.e. , Rs is not halogen. According to one embodiment,

Rs is selected from hydrogen, halogen and (C₁-C₁₀) alkyl, i.e., Rs is not (C₁-C₁₀) alkoxy. In one embodiment, Rs is selected from hydrogen and (C₁-C₁₀) alkyl. In one embodiment, Rs is hydrogen. In one embodiment, Rs is halogen. In one embodiment, Rs is fluoro. In another embodiment, Rs is not fluoro. In one embodiment, Rs is (C₁-C₁₀) alkyl, preferably (C₁-C₅) alkyl, more preferably (C₁-C₃) alkyl. In one embodiment, Rs is methyl.

[0068] According to one embodiment, R3, R4 and Rs are not each hydrogen, i.e., the phenyl group to which R3, R4 and Rs are bond is not an unsubstituted phenyl.

[0069] In formula (I), X is selected from N and CR12; wherein R12 is selected from hydrogen, cyano, halogen, hydroxyl, (C1-C10) alkyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, heteroaryl and -NR13R14; wherein the (C₁-C₁₀) alkyl or (C₁-C₁₀) alkoxy is optionally substituted by at least one (C₁-C₁₀) alkoxy or water- solubilising group; wherein R13 and Ri4 are each independently selected from hydrogen and (C₁-C₁₀) alkyl; wherein the (C₁-C₁₀) alkyl is optionally substituted by at least one amino, hydroxyl or (C₁-C₁₀) alkoxy. According to one embodiment, X is selected from N and CH. In one embodiment, X is N. In one preferred embodiment, X is CH.

[0070] In formula (I), Y and Z are two different heteroatoms selected from N and O, i. e. , one heteroatom is N and the other heteroatom is O, /._<?., the five-membered heteroaryl in which Y and Z are encompassed is an oxazolyl group. The dotted line in formula (I) represents the fact that the bond is a double C=N bond when Y or Z is N and a simple C-0 bond when Y or Z is O, in accordance with the chemical structure of oxazole. According to one preferred embodiment, Y is N and Z is O. According to one embodiment, Y is O and Z is N.

[0071] In one preferred embodiment, Ri is -COOH, R2 is halogen (preferably chloro), R3 and R4 are methyl, Rs is hydrogen, X is CH, Y is N and Z is O.

[0072] According to one embodiment, the compound is of formula (II)

or a pharmaceutically acceptable salt and/or solvate thereof; wherein Ri, R2, R3, R4, Rs, Y and Z are as defined hereinabove. In this embodiment, X is CH. [0073] In one embodiment, the compound is of formula (III)

or a pharmaceutically acceptable salt and/or solvate thereof; wherein Ri, R2, R3, R4, Y and Z are as defined hereinabove. In this embodiment, Rs is hydrogen. [0074] According to one embodiment, when one group among R3 and R4 is halogen, then the other group is not hydrogen. In one embodiment, R3 is not an ethoxy group substituted at least one water-solubilising as defined herein such as, for example, -0-CH₂CH₂-morpholin-4-yl. In one embodiment, R3 is not an alkoxy group substituted by morpholin-4-yl, preferably substituted by morpholinyl. In one embodiment, R3 is not fluoro. In one embodiment, R3 is not chloro. In one embodiment, R3 is not bromo. In one embodiment, R3 is not methoxy. In one embodiment, R3 is not ethoxy. In one embodiment, R4 is not an ethoxy group substituted at least one water-solubilising as defined herein such as, for example, -0-CH₂CH₂-morpholin-4-yl. In one embodiment, R4 is not an alkoxy group substituted by morpholin-4-yl, preferably substituted by morpholinyl. In one embodiment, R4 is not fluoro. In one embodiment, R4 is not chloro. In one embodiment, R4 is not bromo. In one embodiment, R4 is not methoxy. In one embodiment, R4 is not ethoxy.

[0075] According to one embodiment, the compound of formula (I) is not 4-(2-((3- hydroxyphenyl)amino)oxazol-5-yl)benzonitrile. According to one embodiment, the compound of formula (I) is not 4-(2-((3,5-dimorpholinophenyl)amino)oxazol-5- yl)benzonitrile. According to one embodiment, the compound of formula (I) is not 4-(2- ((3-fluoro-5-morpholinophenyl)amino)oxazol-5-yl)benzonitrile. According to one embodiment, the compound of formula (I) is not 4-(2-((3-fluoro-5-(2- morpholinoethoxy)phenyl)amino)oxazol-5-yl)benzonitrile. According to one embodiment, the compound of formula (I) is not 4-(2-((3-fluorophenyl)amino)oxazol-5- yl)benzoic acid. According to one embodiment, the compound of formula (I) is not 4-(2- ((4-fluorophenyl)amino)oxazol-5-yl)benzoic acid. According to one embodiment, the compound of formula (I) is not methyl 4-(2-((3-fluorophenyl)amino)oxazol-5- yl)benzoate. According to one embodiment, the compound of formula (I) is not methyl 4-(2-((4-fluorophenyl)amino)oxazol-5-yl)benzoate. According to one embodiment, the compound of formula (I) is not 4-[2-(3,5-dimethoxy-phenylamino)-oxazol-5-yl]- benzonitrile.

[0076] According to one embodiment, the compound of formula (I) according to the invention is selected from:

[0077] Table 1: Compounds of formula (I)

[0078] According to one embodiment, the compound of formula (I) according to the invention is selected from compounds 001-075 and 078-109 as shown on Table 1 above.

[0079] All references to a compound of the invention (e.g., a compound of formula (I) herein) include references to salts (preferably pharmaceutically acceptable salts), solvates, multi component complexes and liquid crystals thereof. All references to a compound of the invention include references to polymorphs and crystal habits thereof. All references to a compound of the invention include references to pharmaceutically acceptable prodrugs thereof. All references to a compound of the invention include references to isotopically-labelled compounds, including deuterated compounds.

[0080] A compound of the invention ( e.g ., a compound of formula (I) herein) and subformulae thereof contain at least one asymmetric centre(s) and thus may exist as different stereoisomeric forms. Accordingly, all references to a compound of the invention include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.

[0081] The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of a compound of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. When the compound of formula (I) contains an acidic group as well as a basic group the compound may also form internal salts, and such compounds are within the scope of the invention. When the compound of formula (I) contains a hydrogen-donating heteroatom (e.g., NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods: (i) by reacting the compound of formula (I) with the desired acid; (ii) by reacting the compound of formula (I) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or (iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

Pharmaceutical composition

[0082] This invention also relates to a pharmaceutical composition comprising a compound of the invention as described herein and at least one pharmaceutically acceptable carrier. According to one embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the therapeutic agent is an antimalaria agent. In one embodiment, the therapeutic agent is selected from quinine, quinidine, proguanil, mefloquine, chlorproguanil, chloroquine, lumefantrine, atovaquone, pyrimethamine sulfadoxine, cipargamin (KAE-609), ganaplacide (KAF- 156), pyrimethamine dapsone, halofantrine, amodiaquine, amopyroquine, trimethoprim, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine and pyronaridine. Methods of inhibition

[0083] This invention also relates to the use as an P/CDPK1 inhibitor of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein. This invention also relates to a method for inhibiting P/CDPK1. [0084] This invention also relates to the use as an /CLK3 inhibitor of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein. This invention also relates to a method for inhibiting /CLK3.

[0085] According to one embodiment, the use or the method comprise a step of administration of the compound or the pharmaceutical composition to a subject in need thereof.

Medical use and methods of treatment

[0086] This invention also relates to a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, for use as a medicament. This invention also relates to a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, for use in the treatment and/or prevention of an infectious disease.

[0087] According to one embodiment, the infectious disease is malaria. In one embodiment, malaria is caused by infection from Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malarieae or Plasmodium knowlesi. In one embodiment, malaria is caused by infection from Plasmodium falciparum.

[0088] The compound of the invention may be administered by oral, parenteral ( e.g ., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration. The compound of the invention may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In the treatment and/or prevention of infectious diseases an appropriate dosage level may be from about 0.01 to 500 mg per kg patient body weight per day (mg/kg/day), which can be administered in single or multiple doses. Typically, the dosage level will be from about 0.1 to about 250 mg/kg/day, preferably from about 0.5 to about 100 mg/kg/day, more preferably from about 2.5 to about 20 mg/kg/day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular diseases and the host undergoing therapy.

[0089] This invention also relates to the use of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, for the treatment and/or prevention of an infectious disease. This invention also relates to the use of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, in the manufacture of a medicament for the treatment and/or prevention of an infectious disease. This invention also relates to a method for the treatment and/or prevention of an infectious disease in a subject in need thereof, comprising a step of administrating to the subject a therapeutically effective amount of a compound of the invention as described herein, or of a pharmaceutical composition of the invention as described herein.

Manufacturing process

[0090] The invention also relates to a process for manufacturing a compound of the invention as described herein. The compounds of the invention such as, for example, compounds of formula (I), may be prepared using the general protocol as described hereinafter. The synthesis of the aminooxazole derivatives is undergone by firstly reacting aryl halides A (X is Cl, Br or I) with oxazoles B to prepare the corresponding aryl-substituted oxazole derivatives C using Suzuki cross-coupling reaction (Scheme 1). Compounds B may be prepared according the method of Primas, N. et al. (Tetrahedron, August 2010, Vol. 66, pp. 8121-8136). The silyl group in compounds C can be cleaved under acid conditions to give compounds D as described by Miller, R. A. et al. (Journal of Organic Chemistry, 2005, Vol. 70, pp. 9074-9076) (Scheme 1). Compounds D can also be prepared by reacting aromatic aldehydes E with p-toluenesulfonylmethyl isocyanide (TosMIC) using the method of Van Leusen, A. M. et al. (Tetrahedron Letters, 1972, Vol. 23, pp. 2369-2372). Secondly, those compounds D are further functionalised by deprotonation of the oxazole moiety by a suitable organic base and subsequent electrophilic chlorination is used to prepare the 2-chlorooxazole compounds F. A direct nucleophilic displacement reaction by aniline compounds G (wherein R’ is hydrogen), in the presence of a suitable solvent such as alcohol and with heating in elevated temperature, generally affords the final target compounds H. Compounds H may also be obtained by reacting compounds G (wherein R’ is an acetyl group) and compounds F in the presence of sodium hydride and in a suitable solvent such as tetrahydrofuran or dimethylformamide using the method of Benjahad, A. (WO 2007/131953 Al).

[0091] However, the synthetic methods described herein are merely exemplary, and the compounds of the invention may be synthesized by alternate routes as appreciated by one skilled in the art. EXAMPLES

[0092] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

Example 1: Synthesis of the compounds Materials and Methods

[0093] General: All chemicals used were commercial reagent grade products. Solvents were of anhydrous commercial grade and were used without further purification. The progress of the reactions was monitored by thin layer chromatography (TLC) using precoated silica gel 60F 254, Merck TLC plates, which were visualized under UV light. Multiplicities in ¹ H NMR spectra are indicated as singlet (s), broad singlet (br s), doublet (d), triplet (t), quadruplet (q), and multiplet (m) and the NMR spectrum were performed either on a Bruker Avance 300, 360 or 400 MHz spectrometer.

[0094] Abbreviations

C₂C1₆ Hexachloroethane

CDCb Chloroforme-d

DCM Dichloromethane

DMF N,N-Dimethylformamide

DMSO-d6 Hexadeuterodimethyl sulfoxide

EDCI l-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide

Et₂0 Diethylether

EtOAc Ethyl acetate hr Hour(s)

HC1 Hydrogen chloride

HOBT N- H y dro x y hen zo t ri azo 1 c

K₂C0 Potassium carbonate

LiHMDS Lithium bis(trimethylsilyl)amide

MeOH Methanol

MgS0₄ Magnesium sulfate min Minutes nBuLi n-Butyllithium NaCl Sodium chloride NaOH Sodium hydroxy de NMR Nuclear Magnetic Resonance NaN₃ Sodium azide zPrOH 2-Propanol TosMIC p- T oluenesulfonylmethyl isocyanide THF Tetrahydrofuran RT Room Temperature ZnCli Zinc Chloride

[0095] The detailled synthesis of representative compounds of the invention is described hereinafter (Scheme 2 and Scheme 3).

Scheme 2: Synthetic approach for example compounds Oil, 012 and 060

Scheme 3: Synthetic approach of intermediate I-a

[0096] Synthesis of intermediate I-e: 2-(triisopropylsilyl)-l,3-oxazole: To a stirred solution of oxazole (1.147 g, 16.6 mmol) in THF (40 mL) was added n-BuLi (11.5 mL, 18.3 mmol, 1.6 M in hexane) dropwise at -20°C under inert atmosphere. After stirring for an additional 10 min at -20°C, triisopropylsilyl trifluoromethanesulfonate (4.9 mL, 18.3 mmol) was added slowly to reaction mixture at -20°C. After completion of addition, the reaction mixture was slowly allowed to warm to RT and was stirred for 30 min at room temperature. The mixture was quenched with EtOAc (150 mL) and H2O (50 mL). The organic phase was washed with brine, dried over anhydrous MgSCL and concentrated under reduced pressure to afford intermediate I-e (3.7 g) as an orange oil.

[0097] Synthesis of intermediate I-a: 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 2-(triisopropylsilyl)oxazole: To a solution of 2-(triisopropylsilyl)-l,3-oxazole (3.7 g) in THF (120 mL) was added dropwise n-BuLi in hexane solution (2.5M, 22.3 mL) at -30°C. The reaction mixture was stirred at -30°C for 30 min. under nitrogen atmosphere, triisopropyl borate (4.6 mL, 19.9 mmol) was added and the mixture was stirred at -30°C for 2 hr. The reaction mixture was then slowly allowed to warm to RT and was stirred for 45 min. at room temperature. To the reaction mixture were added a solution of 2,3-dimethylbutane-2,3-diol (2 g, 16.6 mmol) in THF (10 mL), and acetic acid (2 mL), and the mixture was stirred at room temperature for 1 hr. After evaporation of solvent under reduced pressure ethyl acetate was added, and the mixture was washed with water and saturated brine, and the solvent was evaporated under reduced pressure to give the title compound (6.7 g) as a brown oil which was used for next step without further purifications. [0098] Synthesis of intermediate I-b: methyl 2-chloro-4-(2-(triisopropylsilyl)oxazol-5- yl)benzoate : In a sealed tube, to a solution of methyl 2-chloro-4-iodobenzoate (3 g, 10.11 mmol) in dioxanc/FLO (120 mL / 40 mL), were added successively intermediate I-a (14 mmol) and sodium carbonate (3 g), Pd(PPh3)4 (600 mg). The reaction mixture was stirred at 80°C for 4 hr. Water was added, the crude product was extracted with EtOAc (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSC and concentrated. The final product was purified by silica gel chromatography using DCM/Cyclohexane: 1/1 as eluent to give intermediate I-b as a yellow solid in 93% yield.

NMR (400 MHz, DMSO-d6) d 8.00 (d, 7 = 3.1 Hz, 1H), 7.98-7.87 (m, 2H), 7.81-7.73 (m, 1H), 3.88 (s, 3H), 1.39 (m, m 3H), 1.12 (dd, /= 7.3, 3.1

Hz, 18H).

[0099] Synthesis of intermediate I-c: Methyl 2-chloro-4-(oxazol-5-yl)benzoate: To a stirred solution of I-b (3.7 g, 9.39 mmol) in THF (40 mL), was added dropwise HC1 IN (4 mL). The reaction mixture was stirred at room temperature for 1 hr. Water was added, the crude product was extracted with EtOAc and the organic layer was washed with brine, then dried over MgS04 and concentrated. The final product was purified by silica gel chromatography using 5 to 20% EtOAc/cyclohexane as eluent to give intermediate I-c as white solid in 75% yield.

NMR (400 MHz, DMSO-d6) d 8.58 (s, 1H), 8.02-7.90 (m, 3H), 7.81 (d, J = 6.5 Hz, 1H), 3.89 (s, 3H). [0100] Synthesis of intermediate I-d: methyl 2-chloro-4-(2-chlorooxazol-5-yl)benzoate:

To a solution of I-c (712,5 mg, 3 mmol) in dry THF (25 mL) under inert atmosphere was added dropwise at -78°C a solution of LiHMDS 1M in dry THF (3.3 mL, 3.3 mmol). The reaction mixture was stirred at -78°C for 0.5 hr. Then, C2CI6 (820 mg, 3.45 mmol) was added at -78°C and the reaction mixture was stirred at room temperature for lhr. Water was added and the crude product was extracted with EtOAc (2 times), the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgS0₄ and concentrated. The final product was purified by silica gel chromatography using 0 to 10% EtOAc/cyclohexane as eluent to give intermediate I-d as a beige solid in 83% yield. ¹ H NMR (400 MHz, DMSO-d6) d 8.06 (s, 1H), 7.99-7.87 (m, 2H), 7.76 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H). [0101] Synthesis of compound Oil: methyl 2-chloro-4-(2-((3,5- dimethylphenyl)amino)oxazol-5-yl)benzoate: To a solution of I-d (600 mg, 2.2 mmol) in z^'-PrOH (24 mL) under inert atmosphere was added 3,5-dimethylaniline (320 mg, 2.64 mmol). The reaction mixture was stirred at 110°C for 24 hr. The formed precipitate was collected by filtration, washed with Et₂0 and dried under vacuum to give compound Oil as a yellow solid in 82% yield. ^XH NMR (400 MHz, DMSO) d 10.41 (s, 1H), 7.93 (d, /= 8.2 Hz, 1H), 7.79 (s, 1H), 7.76 (d, /= 1.6 Hz, 1H), 7.60 (dd, 7= 8.2, 1.7 Hz, 1H), 7.27 (s, 2H), 6.63 (s, 1H), 3.86 (s, 3H), 2.26 (s, 6H).

[0102] Synthesis of compound 012: 2-chloro-4-(2-((3,5-dimethylphenyl)amino)oxazol- 5-yl)benzoic acid: To a stirred solution of 011 (120 mg, 0.35 mmol) in MeOH (10 mL), was added dropwise aqueous NaOH 32% (0.6 mL). The reaction mixture was stirred at 80°C for 2 h. Water was added (10 ml) and reaction mixture acidified by HC137% until pH = 2. The formed Precipitate is collected by filtration, washed with diethyl ether to give compound 012 as a yellow solid in 61% yield (72 mg). ^XH NMR (400 MHz, DMSO) d 13.34 (s, 1H), 10.36 (s, 1H), 7.91 (d, / = 8.0 Hz, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.58 (d,

/= 8.0 Hz, 1H), 7.27 (s, 2H), 6.63 (s, 1H), 2.26 (s, 6H).

[0103] Synthesis of compound 060: 2-chloro-4-(2-((3,5-dimethylphenyl)amino)oxazol- 5-yl)benzamide : To the solution of compound 012 (50 mg, 0.15 mmol) and HOBT (26 mg, 0.19 mmol) in DML (3 mL) was added EDCI (43 mg, 0.225 mmol) and 30% ammonia solution (0.2 ml). The mixture was stirred at ambient temperature for 24 hr. The reaction mixture is poured into ice cold water and the precipitate formed is filtered, washed with water and dried under vacuum to afford compound 060 as a yellow solid (48 mg,

10.25 (s, 1H), 7.87 (s, 1H), 7.73-7.42 (m, 5H), 7.27 (s, 2H), 6.63 (s, 1H), 2.26 (s, 6H). [0104] Alternative synthesis of representative compounds of the invention is described hereinafter (Scheme 4 and Scheme 5).

Scheme 4: Synthetic approach for example compound 029

[0105] Synthesis of intermediate Il-a: Methyl 4-(oxazol-5-yl)benzoate: To a solution of methyl 4-formylbenzoate (1.37 g, 8.35 mmol) in MeOH (40ml) were added K2CO3 (1.38 g, 10 mmol) and TosMIC (1.79 g, 9.18 mmol). The reaction mixture was stirred at

95 °C for 1 hour. Water (200 mL) was then added and the formed precipitate is collected by filtration, washed with water and dried under vacuum to give intermediate Il-a as a beige solid in 94% (1.59 g).

NMR (400 MHz, CDC13) d 8.12 (d, J = 8.3 Hz, 2H), 7.99 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.50 (s, 1H), 3.96 (s, 3H). [0106] Synthesis of intermediate Il-b: methyl 4-(2-chlorooxazol-5-yl)benzoate:

Prepared as described for intermediate I-d above, starting from intermediate I-a, followed by silica gel chromatography using 0 to 20 % EtOAc/cyclohexane as eluent to give intermediate Il-b as yellow solid (741 mg, 35%). ¹ H NMR (400 MHz, DMSO-d6) d 8.04 (d, J = 8.4 Hz, 2H), 7.97 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 3.87 (d, J = 2.1 Hz, 3H).

[0107] Synthesis _ of _ intermediate _ II-c: 3-methoxy-5-((5-(4-

(methoxycarbonyl)phenyl)oxazol-2-yl)amino)benzoic acid: Prepared as described for compound Oil above, starting from intermediate Il-b, to give intermediate II-c as yellow solid (717 mg,

13.03 (s, 1H), 10.71 (s, 1H), 8.06-7.99 (m, 2H), 7.85 (dd, J = 2.0, 1.3 Hz, 1H), 7.75-7.69 (m, 3H), 7.58 (t, J = 2.2 Hz, 1H), 7.09 (dd, J = 2.4, 1.3 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H).

[0108] Synthesis of intermediate Il-d: methyl 4-(2-((3-methoxy-5-((2- methoxyethyl)carbamoyl)phenyl)amino)oxazol-5-yl)benzoate: To the solution of intermediate II-c (200 mg, 0.54 mmol) and HOBT (125 mg, 0.92 mmol) in DMF (13 mL) was added EDCI (208 mg, 1.09 mmol), 2-methoxyethan- 1 -amine (61 mg, 0,81 mmol) and triethylamine (380 mL, 2.71 mmol). The reaction mixture was stirred at room temperature for 20h. DMF was removed under reduced pressure and obtained residue was diluted with EtOAc and the formed precipitate is collected by filtration and dried under vacuum to give intermediate Il-d as a yellow solid.

[0109] Synthesis _ of _ compound _ 029: 4-(2-((3-methoxy-5-((2- methoxyethyl)carbamoyl)phenyl)amino)oxazol-5-yl)benzoic acid: Prepared as described for compound 012 above, starting from intermediate Il-d to give compound 029 as a yellow solid (42 mg, 81%).

NMR (400 MHz, DMSO-d6) d 12.95 (s, 1H), 10.59 (s, 1H), 8.46 (t, J = 5.4Hz, 1H), 8.00 (d, J = 8.5Hz, 2H), 7.73-7.66 (m, 3H), 7.63 (s, 1H), 7.52 (t, J = 1.9Hz, 1H), 7.03 (s, 1H), 3.82 (s, 3H), 3.50-3.38 (m, 4H), 3.29 (s, 3H).

Scheme 5: Synthetic approach for example compound 073 [0110] Synthesis of intermediate Ill-b: 4-(2-((3-methoxyphenyl)amino)oxazol-5- yl)benzonitrile: To a solution of Ill-a (prepared according to preparation described in WO2007131953) (500 mg, 2.44 mmol) in i-PrOH (15 mL) under inert atmosphere was added 3 -methoxy aniline (330 mg, 2.68 mmol). The reaction mixture was stirred at 110°C for 16 hr. The formed precipitate was collected by filtration, washed with i-PrOH and dried under vacuum to give intermediate Ill-b as a yellow solid in 58% yield. ¹ H NMR (400 MHz, DMSO-d6) d 10.56 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.79 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.25 (t, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.1, 1.0 Hz, 1H), 6.59 (dd, J = 8.1, 2.4 Hz, 1H), 3.77 (s, 3H). [0111] Synthesis of compound 073: (3-Methoxy-phenyl)-{5-[4-(lH-tetrazol-5-yl)- phenyl]-oxazol-2-yl] -amine: To a solution of intermediate Ill-b (200 mg, 0.69 mmol) in DMF (3 ml) were added ZnCh (187 mg, 1.38 mmol) and NaN3 (90 mg, 1.38 mmol). The reaction mixture was stirred at 130°C for 16 hour. Water (10 mL) and 4M HC1 (6 mL) were then added. The mixture was stirred at room temperature for 2 h and the formed precipitate is collected by filtration, washed with water and dried under vacuum to give compound 073 as a yellow solid (200 mg, 83% yield). ^XH NMR (400 MHz, DMSO-d6) d 10.48 (s, 1H), 8.12 (d, J = 8.4 Hz, 3H), 7.79 (d, J = 8.3 Hz, 2H), 7.67 (s, 1H), 7.36 (s, 1H), 7.31-7.08 (m, 2H), 6.57 (d, J = 7.3 Hz, 1H), 3.76 (s, 3H).

Results [0112] Example compounds 001-078 were prepared based on the synthetic strategy presented hereinabove. Analytical data for example compounds 001-078 is provided on Table 2 below.

Table 2: Analytical data of the synthesised compounds

Example 2: In vitro CDPK1 inhibition assays

Materials and Methods

[0113] The cDNA coding for protein full length PfCDPKl kinase (Amino-acids 1-524) was obtained by gene synthesis (Genewiz) and cloned into the pDEST17 expression vector. This vector allows the expression of hexa-histidine-tagged (His6) protein at the N-terminus. His6-CDPK1 was expressed BL21(DE3) cells and purified near homogeneity by Nickel affinity chromatography followed by a size exclusion chromatography step. The kinase assays were performed using the HTRF (Homogeneous Time Resolved Fluorescence) SI Kinase assay provided by Cisbio International. Enzymatic assays were carried out at room temperature in 384-wells low volume black plates in a final volume of 20 pi in a buffer containing 10 mM MgCh, 50 mM Sodium-HEPES pH 7.8, BRIJ-35 0,01%, 1 mM SI substrate supplemented with 100 mM ATP and 0.1 nM PfCDPKl. Concentration of ATP and kinase were determined to ensure a linear reaction rate. Reactions were initiated upon introduction of the enzyme and terminated with the addition of one reaction volume (20 mΐ) of HTRF detection buffer. Plates were incubated for one hour at room temperature and the time resolved Fluorescence resonance energy transfer signal was measured on a Pherastar FS microplate reader (BMG Labtech). All data are the average of triplicate results with a standard deviation lower than 10%.

Results [0114] The experimental results for tested compounds using the above-described method are presented on Table 3 below.

Table 3: Results of the in vitro CDPK1 inhibition assays

IC50: concentration for inhibiting 50% of the protein kinase (micromolar).

[0115] The above results evidence very effective inhibition of PfCDPKl by the class of compounds of the invention. The specific compounds listed on Table 3 are well-representing the general class of compounds the invention.

Example 3: In vitro PfCLK3 inhibition assays

Materials and Methods

[0116] The TR-FRET assays, a high-throughput inhibition assay, was used to determine the potency of the small molecules generated against full-length PfCLK3 full length (1-699) recombinant protein in a kinase buffer (containing 50 mM HEPES, 10 mM MgCh, 5 mM DTT, 0.01% BRIJ, and 1 mM DTT). A ULight™-labelled peptide substrate MBP peptide (sequence: CFFKNIVTPRTPPPSQGK) was used and a recombinant protein purified internally. First, in a 10 pL reaction volume, 5 pL of twice the required enzyme concentration (50 nM) and 2.5 pL of four times the required substrate concentration mix containing cold ATP, and the serially diluted drugs were mixed in a black 384-plate well plate and incubated at 37 °C for 1 h. The reaction was stopped after incubation by adding the stopping/detection solution (containing 10 mM EDTA in lx Lance® detection buffer and 2 nM Europium-labelled antiphospho specific antibody) and incubated for another hour at RT before phosphorylation signals were measured using the PHERAStar (END POINT module HTRF PHERASTAR (337-665-615).

Results

[0117] The experimental results for tested compounds using the above-described method are presented on Table 4 below.

Table 4: Results of the in vitro PfCLK3 inhibition assays

IC50: concentration for inhibiting 50% of the protein kinase (micromolar).

[0118] The above results evidence very effective inhibition of PfCLK3 by the class of compounds of the invention. The specific compounds listed on Table 4 are well-representing the general class of compounds the invention.

[0119] Inhibition of PfCDPKl and PfCLK3 by the compounds of the invention as evidenced in Example 2 and Example 3 herein is very relevant for the treatment of infectious diseases, in particular malaria. Indeed, this “dual” activity allows targeting the parasite at different stages of its development and/or avoiding drug resistance by acting on different biological targets.

Claims

or a pharmaceutically acceptable salt and/or solvate thereof, wherein:

Ri is selected from cyano, -COOR6, -CONR6R7 and tetrazolyl; wherein R6 and R7 are each independently selected from hydrogen and (C₁-C₁₀) alkyl; wherein said (C₁-C₁₀) alkyl is optionally substituted by at least one (C₁-C₁₀) alkoxy or water-solubilising group; R2 is selected from hydrogen, cyano, halogen, hydroxyl, (C₁-C₁₀) alkyl,

(C1-C10) haloalkyl, (C1-C10) alkoxy and -NR8R9; wherein said (C₁-C₁₀) alkyl or (C₁-C₁₀) alkoxy is optionally substituted by at least one (C₁-C₁₀) alkoxy or water-solubilising group; wherein Rs and R9 are each independently selected from hydrogen and (C₁-C₁₀) alkyl; wherein said (C₁-C₁₀) alkyl is optionally substituted by at least one amino, hydroxyl or (C₁-C₁₀) alkoxy;

R3 and R4 are each independently selected from hydrogen, cyano, halogen, hydroxyl, trifluoromethyl, (C₁-C₁₀) alkyl,

(C1-C10) alkoxy, -COR10, -NR10R11, -NR10-COR11, -CONR10R11 and -SO2NR10R11; wherein said (Ci-Cio) alkyl or (Ci-Cio) alkoxy is optionally substituted by at least one (Ci-Cio) alkoxy, heterocyclyl or water-solubilising group; wherein Rio and Rn are each independently selected from hydrogen, hydroxyl, (Ci-Cio) alkyl, (C₁-C₁₂) cycloalkyl, heterocyclyl and water-solubilising group; wherein said (C₁-C₁₀) alkyl or (C₁-C₁₂) cycloalkyl is optionally substituted by at least one cyano, amino, (C1-C10) alkylamino, (C1-C10) alkoxy, aryl, heterocyclyl or water-solubilising group; wherein said aryl is optionally substituted by at least one amino, cyano, halogen, hydroxyl, trifluoromethyl, methyl, ethyl, methoxy or ethoxy;

R5 is selected from hydrogen, (C₁-C₁₀) alkyl and (C₁-C₁₀) alkoxy;

X is selected from N and CR12; wherein R12 is selected from hydrogen, cyano, halogen, hydroxyl, (C1-C10) alkyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, heteroaryl and -NR13R14; wherein said (C₁-C₁₀) alkyl or (C₁-C₁₀) alkoxy is optionally substituted by at least one (C₁-C₁₀) alkoxy or water-solubilising group; wherein R13 and R14 are each independently selected from hydrogen and (C₁-C₁₀) alkyl; wherein said (C₁-C₁₀) alkyl is optionally substituted by at least one amino, hydroxyl or (C₁-C₁₀) alkoxy;

Y and Z are two different heteroatoms selected from N and O; and

each water- solubilising group is independently selected from: (i) any one of the following structures of formulae (a)-(f):

and

(ii) any one of the following structures of formulae (g)-(q):

wherein z is an integer ranging from 0 to 6;

L is selected from CH and N; M is selected from -CH(R^B)-, -CH2-, O, S, -S(0)₂-, -NH-, -N((CH₂)_Z-R^bK -N(-(CH₂)_Z-C(0)R^cK -N(-(CH₂)_z-

C(0)0R^c)-, -N(-(CH₂)_Z-S(0)₂R^c)-, -N(-(CH₂)_Z-S(0)₂0R^c)- and -N(-(CH₂)_Z-C(0)N(R^C)(R^d))-; provided that L and M are not simultaneously CH and CH2, respectively;

R^A is selected from hydrogen, (C1-C10) alkyl and (C1-C10) alkoxy; R^B is selected from hydrogen, hydroxyl, (Ci-Cio) alkyl, (Ci-Cio) alkoxy, unsubstituted aryl and unsubstituted heteroaryl; wherein the (Ci-Cio) alkyl is optionally substituted and/or interrupted by at least one heteroatom selected from halogen, oxygen and nitrogen; and

R^c and R^D are each independently selected from hydrogen, (Ci-Cio) alkyl, unsubstituted aryl and unsubstituted heteroaryl; wherein the (Ci-Cio) alkyl is optionally substituted and/or interrupted by at least one cyano, hydroxyl or heteroatom selected from halogen, oxygen and nitrogen; provided that the compound of formula (I) is not selected from: 4-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)benzonitrile; 4-(2-((3-fluoro-5-(2-morpholinoethoxy)phenyl)amino)oxazol-5-yl)benzonitrile; 4-(2-((3-fluorophenyl)amino)oxazol-5-yl)benzoic acid; methyl 4-(2-((3-fluorophenyl)amino)oxazol-5-yl)benzoate; and

4-[2-(3,5-dimethoxy-phenylamino)-oxazol-5-yl]-benzonitrile.

2. The compound according to claim 1, wherein:

Ri is selected from -COOR6, -CONR6R7 and tetrazolyl; wherein R6 and R7 are each independently as defined in claim 1;

R3 is selected from hydrogen, cyano, halogen, hydroxyl, trifluoromethyl, (C1-C10) alkyl, (C1-C10) alkoxy, -COR10, -NR10R11, -NR10-COR11, -

CONR10R11 and -SO2NR10R11; and

R4 is selected from hydrogen, cyano, hydroxyl, trifluoromethyl, (C1-C10) alkyl, (C1-C10) alkoxy, -COR10, -NR10R11, -NR10-COR11, - CONR10R11 and -SO2NR10R11; wherein said (C₁-C₁₀) alkyl or (C₁-C₁₀) alkoxy present in R3 or R4 is optionally substituted by at least one (C₁-C₁₀) alkoxy, heterocyclyl or water- solubilising group; and wherein Rio and Rn present in R3 or R4 are each independently as defined in claim 1.

3. The compound according to claim 1 or claim 2, wherein X is selected from N and CH.

4. The compound according to any one of claims 1 to 3, wherein said compound is of formula (II)

or a pharmaceutically acceptable salt and/or solvate thereof, wherein Ri, R2, R3, R4, Rs, Y and Z are as defined in claim 1.

5. The compound according to claim 4, wherein said compound is of formula (III)

or a pharmaceutically acceptable salt and/or solvate thereof, wherein Ri, R2, R3, R4, Y and Z are as defined in claim 1.

6. The compound according to any one of claims 1 to 4, wherein Ri is selected from -COOR6 and -CONR6R7; wherein R6 and R7 are as defined in claim 1.

7. The compound according to claim 6, wherein R6 and R7 are each independently selected from hydrogen and (C₁-C₅) alkyl.

8. The compound according to claim 7, wherein both R6 and R7 are hydrogen.

9. The compound according to any one of claims 1 to 8, wherein R2 is selected from hydrogen, cyano, halogen, hydroxyl, (C₁-C₅) alkyl, (C₁-C₅) haloalkyl and (C₁-C₅) alkoxy; preferably wherein R2 is selected from hydrogen, fluoro, chloro, bromo, methyl and methoxy.

10. The compound according to any one of claim 1 to 9, wherein R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, trifluoromethyl, (C1-C5) alkyl, (C1-C5) alkoxy, -COR10 and -CONR10R11; wherein said (C1-C5) alkyl or (C1-C5) alkoxy is optionally substituted by at least one (C1-C5) alkoxy, heterocyclyl or water-solubilising group as defined in claim 1; and wherein Rio and R11 are each independently selected from hydrogen, hydroxyl,

(C1-C5) alkyl, (C1-C9) cycloalkyl, heterocyclyl and water- solubilising group as defined in claim 1; wherein said (C1-C5) alkyl or (C1-C9) cycloalkyl is optionally substituted by at least one cyano, amino, (C1-C5) alkylamino, (C1-C5) alkoxy, aryl, heterocyclyl or water- solubilising group as defined in claim 1; wherein said aryl is optionally substituted by at least one amino, cyano, halogen, hydroxyl, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.

11. The compound according to any one of claims 1 to 10, wherein said compound is selected from:

and pharmaceutically acceptable salts and/or solvates thereof.

12. Pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12, wherein said pharmaceutical composition further comprises at least another therapeutic agent; preferably said therapeutic agent is selected from quinine, quinidine, proguanil, mefloquine, chlorproguanil, chloroquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, cipargamin, ganaplacide, pyrimethamine-dapsone, halofantrine, amodiaquine, amopyroquine, trimethoprim, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine and pyronaridine.

14. Compound according to any one of claims 1 to 11 for use as a medicament; preferably for use in the treatment and/or prevention of an infectious disease; more preferably said infectious disease is malaria; more preferably said malaria is caused by infection from Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malarieae or Plasmodium knowlesi.

15. Process for manufacturing a compound according to any one of claims 1 to 11, wherein said process comprises at least one of the following steps:

(i) reacting an aryl halide compound with an oxazole compound using Suzuki cross -coupling reaction, thereby obtaining an aryl- substituted oxazole compound;

(ii) reacting an aromatic aldehyde compound with p-toluenesulfonylmethyl isocyanide, thereby obtaining an aryl-substituted oxazole compound; and/or

(iii) reacting a 5-aryl 2-chlorooxazole compound with an aminoaryl compound, thereby obtaining a /V-aryl-5-aryl-oxazole-2-amine compound.