Aminoisoquinoline compounds and methods of using thereof

Abstract

The present invention relates to a compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. The invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating plasmodium related diseases such as malaria.

Description

[0001] AMINOISOQUINOLINE COMPOUNDS AND METHODS OF USING THEREOF

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. provisional application serial no.: 63 / 673,363 filed 19 July 2024, which is incorporated by reference herein in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The invention provides aminoisoquinoline compounds, compositions comprising such compounds and their use for the treatment of parasitic diseases such as malaria.

[0006] BACKGROUND OF THE INVENTION

[0007] Malaria in humans is caused by five species of Plasmodium parasite: Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), Plasmodium ovale (P. ovale), Plasmodium malaria (P. malaria) and Plasmodium knowlesi (P. knowlesi). The parasites are transmitted to humans by mosquito bites, particularly bites by Anopheles mosquitoes. Malaria is typically classified as asymptomatic, uncomplicated and complicated / severe.

[0008] A patient suffering from “asymptomatic malaria” has circulating parasites but not symptoms. “Uncomplicated malaria” usually presents within 7-10 days after a bite by an infectious mosquito; symptoms are non-specific and can include fever, chills, shaking, profuse sweating, headache, nausea, vomiting, diarrhea and anemia. “Complicated / severe malaria” is usually caused by infection with P. falciparum, although it can be caused by infection with P. vivax or P. knowlesi. It is accompanied by severe anemia and signs of severe organ dysfunction, including cerebral malaria (e.g., abnormal behavior, impaired consciousness, seizures, coma and other neurologic abnormalities); pulmonary complications (e.g., edema and hyperpneic syndrome); hypoglycemia and acute kidney injury. Often, complicated / severe malaria is associated with hyperparasitemia (e.g., >5% infected erythrocytes or >250,000 parasites / pL; and often results in death).

[0009] Malaria is a problem in many parts of the world and has steadily increased over the last decades. An estimated 1-3 million people die every year from malaria, mostly children below 5 years old. This increase in malaria mortality is due in part to the fact that P. falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs; even resistance to artemisinins is emerging. Thus, there remains a need for novel and effective compounds for the treatment of malaria.

[0010] SUMMARY OF THE INVENTION

[0011] In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein:

[0012] R1is H, C1-C4 alkyl or C3-C6 cycloalkyl(Ci-4 alkyl);

[0013] R2is C1-C4 alkyl, C1-C4 haloalkyl unsubstituted or substituted by hydroxy; C3-C6cycloalkyloxy(Ci-4alkyl); -(CR2)I-4-NR3R4; C5-C7 cycloalkyl; or a 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(Co-4 alkyl), each comprising 1-3 heteroatoms selected from N, O and S; wherein said C5-C7 cycloalkyl, 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl) is unsubstituted or substituted by 1 -2 Raindependently selected from C1-C4 alkyl, C1-C4 alkoxy and -S(=O)2R5wherein R5is C1-C4 alkyl or C1-C4 haloalkyl; alternatively, R1and R2together with the atom to which they are attached to form ring B;

[0014] Ring B is a 4-12 membered monocyclic or bicyclic heterocycle having 1-4 heteroatoms selected from N, O and S; and is unsubstituted or substituted by 1-4 Rx; each Rxis independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -O-(Ci-C4haloalkyl), C1-C4 alkoxy, C1-C4 alkoxyCi.4alkyl, halo, hydroxy, hydroxyCi-4alkyl, -(CR2)0.2-C(=O)OR, oxo, - S(=O)2; -S(=O)2-R6wherein R6is C1-C4 alkyl, C3-C6cycloalkyl or -NRR7wherein R7is hydrogen or C1-C4 alkyl or R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; -C(=O)-R8wherein R8is halo, C1-C4 alkyl, C1-C4 haloalkyl or -NR3R4; - (CR2)O.2NRR9wherein R9is hydrogen, C1-C4 alkyl or Ci-C4alkoxy(Ci-3alkyl); hydroxyCi-4alkyl unsubstituted or substituted with halo or -NR3R4; and C3-C6cycloalkyl(C0-4 alkyl), C3-C6cycloalkyloxy(C0-4 alkyl) and 4-6 membered heterocyclyl(C0-4 alkyl) comprising 1-3 heteroatoms selected from N, O and S, wherein said C3-Ce cycloalkyl(Co-4 alkyl), C3-Ce cycloalkyloxy(Co-4 alkyl) and 4-6 membered heterocyclyl(Co-C4alkyl) is unsubstituted or substituted with 1-4 Rcselected from oxo, -S(=O)2, C1-C4 alkyl, C1-C4 alkoxy and halo; and each R is hydrogen or C1-C4 alkyl unless R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; each R3and R4is independently hydrogen or C1-C4 alkyl.

[0015] In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0016] In yet another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a Plasmodium related disease. In yet another aspect, the invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a Plasmodium related disease.

[0017] In yet another aspect, the invention provides a method of treating a Plasmodium related disease, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] In yet another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0019] BRIEF DESCRIPTION OF THE FIGURES

[0020] Figure 1 depicts the1D NMR spectrum for 7-(8-((1 R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)imidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine (Example 1).

[0021] DETAILED DESCRIPTION OF THE INVENTION Definitions

[0022] As used herein, the terms "a,” "an,” "the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. By way of example, “an element” means one element or more than one element.

[0023] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-C10 alkyl means an alkyl group or radical having 1 to 10 carbon atoms. In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, “alkylaryl” means a monovalent radical of the formula alkyl-aryl-, while “arylalkyl” means a monovalent radical of the formula aryl-alkyl-. Furthermore, the use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.

[0024] As used herein, the term “and / or” means either “and” or “or” unless indicated otherwise.

[0025] As used herein, the term “optionally substituted” means that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(Ci-C6)alkyl, Ci-C6alkyl, Ci-C6alkoxy and Ci-C6 haloalkyl. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0026] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0027] As used herein, the term “unsubstituted” means that the specified group bears no substituents. As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation, and which is attached to the rest of the molecule by a single bond. The term “Ci-C6alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Terms such as “C1-4 alkyl” are to be construed accordingly. Examples of Ci-6alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl (-CH2CH(CH3)2), sec-butyl (-CH(CH3)CH2CH3), f-butyl (-C(CH3)3), n- pentyl, isopentyl (-(CH2)2CH(CH3)2), neopentyl (-CH2C(CH3)3), te / Y-pentyl (-C(CH3)2CH2CH3), 2- pentan-yl (-CH(CH3)(CH2)2CH3), n-hexyl, and the like. When an alkyl is represented along with another radical like arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxyalkyl, alkylamino, the alkyl portion shall have the same meaning as described above and is bonded to the other radical. For example, C6-io aryl(Ci.3alkyl) includes, benzyl, phenylethyl, 1 -phenylethyl, 3-phenylpropyl and the like.

[0028] As used herein, the term “-(CR2)I.4” refers to a straight or branched alkyl having from one to four carbon atoms. Depending on the definition of R2, said straight or branched alkyl may be substituted or unsubstituted. In case R2, is hydrogen, the term refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to four carbon atoms, and which is attached to the rest of the molecule by a single bond. Terms such as “-(CR2)0.2-C(=O)OR” are to be construed accordingly. Thereby, in case of “-(CR2)0-C(=O)OR”, the -CR2radical is absent such that the term “-(CR2)0-C(=O)OR” refers to “-C(=O)OR".

[0029] As used herein, the term "Ci-C6alkoxy" refers to a radical of the formula -ORa, where Rais a C1-6 alkyl radical as generally defined above. Examples of C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy. Terms such as "C1-C4 alkoxy" are to be construed accordingly.

[0030] As used herein, the term “C1-C4 alkoxyCi.4 alkyl” refers to a radical of the formula -Ra-O-Rawhere each Rais independently a C1-C4 alkyl radical as defined above. The oxygen atom may be bonded to any carbon atom in either alkyl radical. Examples of C1-C4 alkoxyCi.4alkyl include, but are not limited to, methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1 -ethoxy-propyl and 2- methoxy-butyl. Terms such as “Ci-C4alkoxyCi-3alkyl" are to be construed accordingly.

[0031] As used herein, the term "hydroxyCi.4alkyl” refers to a Ci-4alkyl radical as defined above, wherein one of the hydrogen atoms of the Ci-4alkyl radical is replaced by OH. Examples of hydroxyCi.4alkyl include, but are not limited to, ethan-1-olyl, 2-methylpropan-1-olyl, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxy-propyl and 3-hydroxy-propyl.

[0032] As used herein, “cycloalkyl” or “carbocyclyl” means a monocyclic or polycyclic saturated carbon ring containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A “C3-C8cycloalkyl” is a cycloalkyl group containing from 3 to 8 carbon atoms. An example of polycyclic cycloalkyl is a bicyclic cycloalkyl. A bicyclic cycloalkyl can be fused (e.g., decalin) or bridged (e.g., norbomane). A further example of a polycyclic saturated carbon ring is spirocyclic cycloalkyl. The term “C5-C7cycloalkyl” refers to a cycloalkyl radical as defined above having from five to seven carbon atoms. Terms such as “C3-C6cycloalkyl” are to be construed accordingly.

[0033] As used herein, the term “C3-C6cycloalkyl(C0-4alkyl)” refers to a stable monocyclic saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to six carbon atoms, and which is attached to the rest of the molecule by a single bond (i.e., C3-C6cycloalkyl) or by a Ci.4alkyl radical as defined above. Examples of C3-C6cycloalkyl(C0-4alkyl) include, but are not limited to, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclobutyl-ethyl, cyclopentyl, cyclopentyl-propyl and cyclohexyl. Terms such as “C3-C6cycloalkyl(Ci-4alkyl)” are to be construed accordingly.

[0034] As used herein, the term “C3-C6cycloalkyloxy(Ci-4alkyl)” refers to a radical of the formula -Ra-O-Rb where each Rais a Ci-C4alkyl radical as defined above and where Rb is a C3-C6cycloalkyl radical as generally defined above. Terms such as “C3-C6cycloalkyloxy(C0-4alkyl)” are to be construed accordingly.

[0035] As used herein, the term “cyano” means the radical - C^ .

[0036] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom or to a sulfur atom. “=O” means an oxo substituent.

[0037] As used herein, the term “halo” refers to bromo, chloro, fluoro or iodo; preferably fluoro, chloro or bromo.

[0038] As used herein, “amino” means a substituent containing at least one nitrogen atom (e.g., - NH2). The substituent -NH2is often referred to as an amino group. /

[0039] As used herein, “alkylamino” means an amino or -NH2group where one of the hydrogens is replaced with an alkyl group, e.g., -NH(alkyl). Examples of alkylamino groups include, but are not limited to, methylamino (e.g., -NH(CH3)), ethylamino, propylamino, iso-propylamino, n- butylamino, sec-butylamino, te / Y-butylamino, etc. As used herein, the term, “dialkylamino” means an amino or -NH2group where both of the hydrogens are replaced with alkyl groups, e.g., -N(alkyl)2. The alkyl groups on the amino group are the same or different alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino (e.g., -N(CH3)2), diethylamino, dipropylamino, diiso-propylamino, di-n- butylamino, di-sec-butylamino, di-te / Y-butylamino, methyl(ethyl)amino, methyl(butylamino), etc.

[0040] As used herein, the term “-NRR7” refers to a radical of the formula -NRaRb where Rais R and Rbis R7. In case R and R7are both defined as alkyl, the term refers to a dialkylamino. In case R and R7are both defined as hydrogen, the term refers to amino. Terms such as “-NRR9" and “-NR3R4” are to be construed accordingly.

[0041] As used herein, the term “-(CR2)I-4-NR3R4” refers to a radical of the formula -Ra-NR3R4, where -Ra- is a -(CR2)M- radical as generally defined above. Terms such as “-(CR2)0.2NRR9” are to be construed accordingly. Thereby, in case of “-(CR2)0NRR9”, the -CR2- radical is absent such that the term “-(CR2)oNRR9” refers to “-NRR9" as generally defined above.

[0042] As used herein, the term “Ci-C6haloalkyl" refers to a Ci.6alkyl radical as defined above, substituted by one or more halo radicals as defined above. Examples of Ci-6haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1 ,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and 1 ,4,4-trifluorobutan-2-yl. Terms such as “Ci-C4haloalkyl" are to be construed accordingly.

[0043] As used herein, the term "-O-(Ci-C4haloalkyl)" refers to a radical of the formula -ORa, where Rais a Ci-C4haloalkyl radical as generally defined above.

[0044] As used herein, the term “heterocyclyl” or “heterocycle” refers to a non-aromatic monocyclic or polycyclic ring radical containing carbon and at least one heteroatom selected from nitrogen, oxygen and sulfur. An example of a polycyclic heterocycle is a bicyclic heterocycle. A bicyclic heterocycle can be fused or bridged. A further example of a bicyclic heterocycle is a spirocyclic heterocycle. The heterocyclyl radical may be bonded via a carbon atom or heteroatom. The terms such as “4-7 membered heterocycle”, “7-8 membered heterocycle” and “4-12 membered heterocycle” are to be construed accordingly. Heterocycles may monocyclic or bicyclic. Examples of 4-12 membered monocyclic or bicyclic heterocycles include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, piperidyl, piperazinyl, tetrahydropyranyl (oxanyl), morpholinyl, azepanyl; 2-5-diazabicyclo[2.2.1]heptan-2-yl; 3,8- diazabicyclo[3.2.1]octan-3-yl; 3,8-diazabicyclo[3.2.1]octan-8-yl; 3,6-diazabicyclo[3.1 ,1]heptan-6- yl; 3,6-diazabicyclo[3.1 ,1]heptan-3-yl; 2-oxa-5-bicyclo[2.2.1]heptan-5-yl; 3- azabicyclo[3.1 ,1]heptan-6-yl; 8-oxa-3-azabicyclo[3.2.1]octan-3-yl; 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl; and 7-azabicyclo[2.2.1]heptan-7-yl; 2,6-diazaspiro[3.4]octan-6-yl; 2,7-diazaspiro[3.5]nonan-2-yl; 2,7-diazaspiro[4.4]nonan-2-yl; 2,6-diazaspiro[3.3]heptan-2-yl; 2- oxa-6,9-diazaspiro[4.5]decan-9-yl; 1-oxa-8-azaspiro[4.5]decan-3-yl; 2-oxa-7- azaspiro[4.4]nonan-7-yl; 3-oxa-9-azaspiro[5.5]undecane-9-yl; 7-oxa-2-azapiro[3.5]nonan-yl; 7- azaspiro[3.5]nonan-7-yl; 2-oxa-8-azaspiro[4.5]decan-8-yl; 2,8-diazaspiro[4.5]decan-8-yl; 6- azaspiro[2.5]octan-6-yl and 7-azaspiro[3.5]nonan-2-yl. Terms such as “5-6 membered heterocycle”, “4-7 membered heterocycle”, “7-9 membered bridged heterocyle” and “7-11 membered spirocyclic heterocycle” are to be construed accordingly. Examples of 4-7 membered heterocycles include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1 ,4- diazepan-1-yl and imidazolidinyl. Examples of 7-9 membered bridged heterocyle include, but are not limited to 2-5-diazabicyclo[2.2.1]heptan-2-yl; 3,8-diazabicyclo[3.2.1]octan-3-yl, 3,8- diazabicyclo[3.2.1]octan-8-yl, 3,6-diazabicyclo[3.1 ,1]heptan-6-yl, 3,6-diazabicyclo[3.1 ,1]heptan- 3-yl; 2-oxa-5-bicyclo[2.2.1]heptan-5-yl; 3-azabicyclo[3.1 ,1]heptan-6-yl, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and 7- azabicyclo[2.2.1]heptan-7-yl. Examples of 7-11 membered spirocyclic heterocycle include, but are not limited to 2,6-diazaspiro[3.4]octan-6-yl, 2,7-diazaspiro[3.5]nonan-2-yl; 2,7- diazaspiro[4.4]nonan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-oxa-6,9-diazaspiro[4.5]decan-9-yl, 1 -oxa-8-azaspiro[4.5]decan-3-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl, 3-oxa-9- azaspiro[5.5]undecane-9-yl, 7-oxa-2-azapiro[3.5]nonan-yl, 7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[4.5]decan-8-yl, 2,8-diazaspiro[4.5]decan-8-yl, 6-azaspiro[2.5]octan-6-yl and 7- azaspiro[3.5]nonan-2-yl.

[0045] As used herein, the term “heterocyclyl(C0-C4alkyl)” refers to a heterocyclic ring as defined above, which is attached to the rest of the molecule by a single bond or by a Ci.4alkyl radical as defined above. Terms such as “5-9 membered heterocyclyl(C0-4alkyl)” and “4-6 membered heterocyclyl(C0-4alkyl)” are to be construed accordingly.

[0046] As used herein, the term “heteroaryl” refers to aromatic moieties containing at least one heteroatom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 10-membered aromatic ring system. The heteroaromatic moiety may consist of a single or fused ring system. A typical single heteroaryl ring is a 5- to 6-membered ring containing one to four heteroatoms independently selected from N, O and S and a typical fused heteroaryl ring system is a 9- to 10- membered ring system containing one to four heteroatoms independently selected from N, O and S. The fused heteroaryl ring system may consist of two heteroaryl rings fused together or a heteroaryl fused to an aryl (e.g., phenyl). Examples of 9-10 membered fused heteroaryl include, but are not limited to quinolinyl, isoquinolinyl, indazolyl, quinazolinyl, quinoxalinyl, benzofuranyl, benzothiazolyl, benzimidazolyl, 1 H-pyrazolo[3,4-b]pyridinyl, 1 H-pyrazolo[3,4-c]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, imidazo[1 ,2-a]pyridinyl or 1 H-pyrrolo[2,3-b]pyridinyl.

[0047] As used herein, the term “5-6 membered heteroaryl(Co-4alkyl)” refers to a 5-6 membered heteroaryl as defined above, and which is attached to the rest of the molecule by a single bond or by a Ci.4alkyl radical as generally defined above.

[0048] As used herein, the term "ECso" refers to the molar concentration of an inhibitor or modulator that produces 50% efficacy. As used herein, the term “pharmaceutical composition” refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for topical or parenteral administration.

[0049] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22ndEd. Pharmaceutical Press, 2013, pp. 1049-1070).

[0050] As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0051] As used herein, the term “prevent”, “preventing" or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0052] As used herein, the term “subject” refers to primates (e.g., humans, male or female, dogs, rabbits, guinea pigs, pigs, rats and mice). In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0053] As used herein, the term “treat”, “treating" or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0054] As used herein, the term “Plasmodium related disease” refers to a disease caused by a Plasmodium parasite; more particularly, by Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), Plasmodium ovale (P. ovale), Plasmodium malaria (P. malaria), Plasmodium knowlesi (P. knowlesi) or a combination thereof.

[0055] As used herein, the term "a therapeutically effective amount" of a compound of the invention refers to an amount of the compound of the invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and / or ameliorate a condition, or a disorder or a disease caused by a parasite; or (2) reduce or inhibit the proliferation of a parasite, such as malaria. As used herein, the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within experimental error, typical of standard methods used for the measurement and / or determination of a given value or range.

[0056] Unless specified otherwise, the terms “compounds of the present invention” and “compounds of the invention” refer to compounds of Formula I and subformulae thereof, salts of the compound, hydrates or solvates of the compounds, salts, as well as all stereoisomers (including diastereoisomers, enantiomers or enantiomeric mixtures), and isotopically labeled compounds (including deuterium substitutions). Compounds of the invention further comprise polymorphs of compounds of Formula (I) (or subformulae thereof) and salts thereof. When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be unsubstituted or substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.

[0057] Description of the Embodiments

[0058] The invention relates to compounds having anti-parasitic activity and more particularly, for treating malaria. In further embodiments, the invention relates to compounds for treating complicated or severe malaria.

[0059] One embodiment of the invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein:

[0060] R1is H, C1-C4 alkyl or C3-C6cycloalkyl(Ci-4alkyl);

[0061] R2is C1-C4 alkyl, C1-C4 haloalkyl unsubstituted or substituted by hydroxy; C3-C6cycloalkyloxy(Ci-4alkyl); -(CR2)I-4-NR3R4; C5-C7 cycloalkyl; or a 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(Co-4 alkyl), each comprising 1-3 heteroatoms selected from N, O and S; wherein said C5-C7 cycloalkyl, 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl) is unsubstituted or substituted by 1-2 Raindependently selected from C1-C4 alkyl, C1-C4 alkoxy and -S(=O)2R5wherein R5is C1-C4 alkyl or C1-C4 haloalkyl; alternatively, R1and R2together with the atom to which they are attached to form ring B;

[0062] Ring B is a 4-12 membered monocyclic or bicyclic heterocycle having 1-4 heteroatoms selected from N, O and S; and is unsubstituted or substituted by 1-4 Rx; each Rxis independently selected from Ci-C4alkyl, Ci-C4haloalkyl, -O-(Ci-C4haloalkyl), Ci-C4alkoxy, Ci-C4alkoxyCi.4alkyl, halo, hydroxy, hydroxyCi-4alkyl, -(CR2)0.2-C(=O)OR, oxo, - S(=O)2; -S(=O)2-R6wherein R6is Ci-C4alkyl, C3-C6cycloalkyl or -NRR7wherein R7is hydrogen or Ci-C4alkyl or R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; -C(=O)-R8wherein R8is halo, Ci-C4alkyl, Ci-C4haloalkyl or -NR3R4; - (CR2)O.2NRR9wherein R9is hydrogen, Ci-C4alkyl or Ci-C4alkoxy(Ci-3alkyl); hydroxyCi-4alkyl unsubstituted or substituted with halo or -NR3R4; and C3-C3cycloalkyl(Co-4alkyl), C3-C3cycloalkyloxy(C0-4alkyl) and 4-6 membered heterocyclyl(C0-4alkyl) comprising 1-3 heteroatoms selected from N, O and S, wherein said C3-C6cycloalkyl(C0-4alkyl), C3-C6cycloalkyloxy(C0-4alkyl) and 4-6 membered heterocyclyl(Co-C4alkyl) is unsubstituted or substituted with 1-4 Rcselected from oxo, -S(=O)2, Ci-C4alkyl, Ci-C4alkoxy and halo; and each R is hydrogen or Ci-C4alkyl unless R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; each R3and R4is independently hydrogen or Ci-C4alkyl.

[0063] In one embodiment of the invention, ring B is monocyclic. In another embodiment of the invention, ring B is bicyclic. In case ring B is bicyclic, ring B may be bridged or fused, or ring B may be a spirocyclic heterocycle.

[0064] Ring B may be a 4-12 membered monocyclic or bicyclic heterocycle. In one embodiment of the invention, ring B is monocyclic and is a 4-7 membered heterocycle. In another embodiment of the invention, ring B is bicyclic and is a 7-9 membered bridged heterocycle. In yet another embodiment of the invention, ring B is bicyclic and is a 7-11 membered spirocyclic heterocycle. In yet another embodiment, ring B is bicyclic and is a 5-6 membered heterocycle comprising 1-2 heteroatoms selected from N, O and S heteroatoms, wherein said 5-6 membered heterocycle is fused to a 5-6 membered saturated, unsaturated or partially saturated ring.

[0065] Ring B may have 1 -4 heteroatoms selected from N, O and S. In one embodiment, ring B is monocyclic and has 1 -2 nitrogen heteroatoms. In another embodiment of the invention, ring B is a 7-9 membered bridged heterocycle having 1 -2 heteroatoms selected from N and O. In yet another embodiment of the invention, ring B is a 7-1 1 membered spirocyclic heterocycle having 1-2 heteroatoms selected from N, O and S. In yet another embodiment of the invention, ring B is fused bicyclic heterocycle having 1-2 heteroatoms selected from N, O and S.

[0066] Ring B may be unsubstituted or may be substituted by 1 -4 Rx. In one embodiment, ring B is monocyclic and is substituted by 1 -4 Rx. In another embodiment of the invention, ring B is a 7-9 membered bridged heterocycle and is substituted by 1 -2 Rx. In yet another embodiment of the invention, ring B is a 7-1 1 membered spirocyclic heterocycle and is substituted by 1-2 Rx. In yet another embodiment of the invention, ring B is fused bicyclic heterocycle and is substituted by 1-2 Rx.

[0067] One embodiment of the invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein:

[0068] R1and R2together with the atom to which they are attached to form ring B;

[0069] Ring B is a 4-12 membered bicyclic heterocycle having 1 -4 heteroatoms selected from N, O and S; and is unsubstituted or substituted by 1-4 Rx; each Rxis independently selected from Ci-C4alkyl, Ci-C4haloalkyl, -O-(Ci-C4haloalkyl), Ci-C4alkoxy, Ci-C4alkoxyCi.4alkyl, halo, hydroxy, -(CR2)0.2-C(=O)OR, oxo, -S(=O)2; and each R is hydrogen or Ci-C4alkyl.

[0070] One embodiment of the invention relates to a compound of Formula (II) or a pharmaceutically acceptable salt thereof: wherein: ring B is a 4-12 membered bicyclic heterocycle comprising at least one nitrogen atom attached to the C atom marked with *; and is substituted by 1 -2 Rx;

[0071] Rxis selected from the group consisting of Rxis selected from the group consisting of Ci-C4alkyl, Ci-C4haloalkyl, -O-(Ci-C4haloalkyl), Ci-C4alkoxy, Ci-C4alkoxyCi.4alkyl, halo, hydroxy, hydroxyCi-4alkyl, -(CR2)0.2-C(=O)OR, oxo, and -S(=O)2; or Rxis selected from the group consisting of Rxselected from the group consisting of methyl, ethyl, prop-1 -yl, prop-2-yl, methoxy, methoxyethyl, hydroxymethyl, 2,2-difluoroethyl, trifluoromethoxy, trifluoromethyl, 2-hydroxy-3-trifluoro-propyl, dimethylaminomethyl, methylaminomethyl, (methoxyethyl)amino and 2-hydroxy-3-dimethylamino-propyl; and each R is hydrogen or Ci-C4alkyl. One embodiment of the invention relates to a compound of Formula (II) or a pharmaceutically acceptable salt thereof: wherein: ring B is a 4-12 membered bridged bicyclic heterocycle comprising at least one nitrogen atom attached to the C atom marked with *; and is substituted by 1 -2 Rx;

[0072] Rxis selected from the group consisting of Rxis selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, -O-(Ci-C4 haloalkyl), C1-C4 alkoxy, C1-C4 alkoxyCi-4 alkyl, halo, hydroxy, - (CR2)O-2-C(=0)OR, OXO and -S(=O)2; or Rxis selected from the group consisting of Rxselected from the group consisting of methyl, ethyl, prop-1-yl, prop-2-yl, methoxy, methoxyethyl, hydroxymethyl, 2,2-difluoroethyl, trifluoromethoxy, trifluoromethyl, 2-hydroxy-3-trifluoro-propyl, dimethylaminomethyl, methylaminomethyl, (methoxyethyl)amino and 2-hydroxy-3-dimethylamino-propyl; and each R is hydrogen or C1-C4 alkyl.

[0073] Various (enumerated) embodiments of the invention are described herein. Features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0074] Embodiment 1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein:

[0075] R1is H, C1-C4 alkyl or C3-C6cycloalkyl(Ci-4alkyl);

[0076] R2is C1-C4 alkyl, C1-C4 haloalkyl unsubstituted or substituted by hydroxy; C3-C6cycloalkyloxy(Ci-4alkyl); -(CR2)I-4-NR3R4; C5-C7 cycloalkyl; or a 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl), each comprising 1-3 heteroatoms selected from N, O and S; wherein said C5-C7 cycloalkyl, 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl) is unsubstituted or substituted by 1 -2 Raindependently selected from C1-C4 alkyl, C1-C4 alkoxy and -S(=O)2R5wherein R5is C1-C4 alkyl or C1-C4 haloalkyl; alternatively, R1and R2together with the atom to which they are attached to form ring B;

[0077] Ring B is a 4-12 membered monocyclic or bicyclic heterocycle having 1-4 heteroatoms selected from N, O and S; and is unsubstituted or substituted by 1-4 Rx; each Rxis independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -O-(Ci-C4haloalkyl), C1-C4 alkoxy, C1-C4 alkoxyCi.4alkyl, halo, hydroxy, hydroxyCi-4alkyl, -(CR2)0.2-C(=O)OR, oxo, - S(=O)2; -S(=O)2-R6wherein R6is C1-C4 alkyl, C3-C6cycloalkyl or -NRR7wherein R7is hydrogen or C1-C4 alkyl or R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; -C(=O)-R8wherein R8is halo, C1-C4 alkyl, C1-C4 haloalkyl or -NR3R4; - (CR2)O.2NRR9wherein R9is hydrogen, C1-C4 alkyl or Ci-C4alkoxy(Ci-3alkyl); hydroxyCi-4alkyl unsubstituted or substituted with halo or -NR3R4; and C3-C6cycloalkyl(C0-4 alkyl), C3-C6cycloalkyloxy(Co-4 alkyl) and 4-6 membered heterocyclyl(Co-4 alkyl) comprising 1-3 heteroatoms selected from N, O and S, wherein said C3-C6cycloalkyl(C0-4 alkyl), C3-C6cycloalkyloxy(C0-4 alkyl) and 4-6 membered heterocyclyl(Co-C4alkyl) is unsubstituted or substituted with 1-4 Rcselected from oxo, -S(=O)2, C1-C4 alkyl, C1-C4 alkoxy and halo; and each R is hydrogen or C1-C4 alkyl unless R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; each R3and R4is independently hydrogen or C1-C4 alkyl.

[0078] Embodiment 2. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein said compound is of Formula (II): wherein ring B is a 4-12 membered monocyclic or bicyclic heterocycle comprising at least one nitrogen atom attached to the C atom marked with *; and is substituted by 1-4 Rx.

[0079] Embodiment 3. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring B is a 4-7 membered monocyclic heterocycle.

[0080] Embodiment 4. The compound according to any one of Embodiments 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ring B is a 4-7 membered heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1 ,4-diazepan-1-yl and imidazolidinyl; wherein said 4-7 membered heterocycle is substituted by 1 -4 Rx. Embodiment 5. The compound according to any one of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

[0081] Embodiment 6. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring B is a bridged bicyclic heterocycle.

[0082] Embodiment 7. The compound according to any one of Embodiments 1-2 and 6 or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-9 membered bridged bicyclic heterocycle.

[0083] Embodiment 8. The compound according to any one of Embodiments 1 -2 and 6-7 or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-9 membered bridged bicyclic heterocycle that is substituted by 1-2 Rxor by 1 Rx. Embodiment 9. The compound according to any one of Embodiments 1-2 and 6-8 or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-9 membered bridged heterocycle selected from 2-5-diazabicyclo[2.2.1]heptan-2-yl; 3,8-diazabicyclo[3.2.1]octan-3-yl; 3,8- diazabicyclo[3.2.1]octan-8-yl; 3,6-diazabicyclo[3.1 ,1]heptan-6-yl; 3,6-diazabicyclo[3.1 ,1]heptan- 3-yl; 2-oxa-5-bicyclo[2.2.1]heptan-5-yl; 3-azabicyclo[3.1 ,1]heptan-6-yl; 8-oxa-3- azabicyclo[3.2.1]octan-3-yl; 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl; and 7- azabicyclo[2.2.1]heptan-7-yl; and wherein said 7-9 membered bridged heterocycle is substituted by 1-2 Rxor by 1 Rx.

[0084] Embodiment 10. The compound according to any one of Embodiments 1-2 and 6-9 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

[0085] Embodiment 11 . The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring B is a bicyclic heterocycle, and wherein the two rings of the bicyclic heterocycle are linked by one common atom.

[0086] Embodiment 12. The compound according to any one of Embodiments 1-2 and 11 or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-11 membered spirocyclic heterocycle. Embodiment 13. The compound according to Embodiment 12 or a pharmaceutically acceptable salt thereof, wherein said 7-11 membered spirocyclic heterocycle is substituted by 1-2 Rx.

[0087] Embodiment 14. The compound according to any one of Embodiments 1 -2 and 11 -13 or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-11 membered spirocyclic heterocycle selected from 2,6-diazaspiro[3.4]octan-6-yl; 2,7-diazaspiro[3.5]nonan-2-yl; 2,7- diazaspiro[4.4]nonan-2-yl; 2,6-diazaspiro[3.3]heptan-2-yl; 2-oxa-6,9-diazaspiro[4.5]decan-9-yl;

[0088] 1 -oxa-8-azaspiro[4.5]decan-3-yl; 2-oxa-7-azaspiro[4.4]nonan-7-yl; 3-oxa-9- azaspiro[5.5]undecane-9-yl; 7-oxa-2-azapiro[3.5]nonan-yl; 7-azaspiro[3.5]nonan-7-yl; 2-oxa-8- azaspiro[4.5]decan-8-yl; 2,8-diazaspiro[4.5]decan-8-yl; 6-azaspiro[2.5]octan-6-yl and 7- azaspiro[3.5]nonan-2-yl; wherein said 7-11 membered spirocyclic heterocycle is substituted by 1-2 Rx.

[0089] Embodiment 15. The compound according to any one of Embodiments 1 -2 and 11 -14 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

[0090]

[0091] Embodiment 16. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring B is a fused bicyclic heterocycle.

[0092] Embodiment 17. The compound according to Embodiment 16 or a pharmaceutically acceptable salt thereof, wherein said fused bicyclic heterocycle B is substituted by 1-2 Rx.

[0093] Embodiment 18. The compound according to any one of Embodiments 1 -2 and 16-17 or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-6 membered heterocycle comprising 1-2 heteroatoms selected from N, O and S heteroatoms; wherein said 5-6 membered heterocycle is fused to a 5-6 membered saturated, unsaturated or partially saturated ring comprising 1-2 heteroatoms selected from N, O and S; wherein ring B is substituted by 1-2

[0094] Rx.

[0095] Embodiment 19. The compound according to any one of Embodiments 1 -2 and 16-18 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

[0096]

[0097] Embodiment 20. The compound according to any one of the preceding Embodiments or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of Ci-C4alkyl, Ci-C4haloalkyl, -O-(Ci-C4haloalkyl), Ci-C4alkoxy, Ci-C4alkoxyCi.4alkyl, halo, hydroxy, -(CR2)0.2-C(=O)OR, oxo and -S(=O)2.

[0098] Embodiment 21 . The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of -S(=0)2-R6wherein R6is Ci-C4alkyl, C3-C6cycloalkyl or -NRR7, wherein R7is hydrogen or Ci-C4alkyl or R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle.

[0099] Embodiment 22. The compound according to any one of the preceding Embodiments or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of C(=O)-R8, wherein R8is halo, Ci-C4alkyl, Ci-C4haloalkyl or -NR3R4; -(CR2)o-2NRR9wherein R9is hydrogen, Ci-C4alkyl or Ci-C4alkoxy(Ci-3alkyl).

[0100] Embodiment 23. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of hydroxyCi-4alkyl unsubstituted or substituted with halo or -NR3R4.

[0101] Embodiment 24. The compound according to any one of the preceding Embodiments or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of C3-C6cycloalkyl(C0-4alkyl), C3-C6cycloalkyloxy(C0-4alkyl) and 4-6 membered heterocyclyl(C0-4alkyl) comprising 1-3 heteroatoms selected from N, O and S, wherein said C3-C6cycloalkyl(C0-4alkyl), C3-C6cycloalkyloxy(C0-4alkyl) and 4-6 membered heterocyclyl(Co-C4alkyl) is unsubstituted or substituted with 1-4 Rcselected from oxo, -S(=O)2, Ci-C4alkyl, Ci-C4alkoxy and halo.

[0102] Embodiment 25. The compound according to any one of the preceding Embodiments or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rx selected from the group consisting of methyl, ethyl, prop-1 -yl, prop-2-yl, methoxy, methoxyethyl, hydroxymethyl, 2,2-difluoroethyl, trifluoromethoxy, trifluoromethyl, 2-hydroxy-3-trifluoro-propyl, dimethylaminomethyl, methylaminomethyl, (methoxyethyl)amino and 2-hydroxy-3-dimethylamino-propyl.

[0103] Embodiment 26. The compound according to any one of the preceding Embodiments and 25 or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting cyclopropyl, tetrahydropyranyl, tetrahydropyranylmethyl, tetra hydro furanyl, oxetanyl, piperidinyl, oxopiperidinyl, azolidinyl, azolidinylsulfonyl, azetidinyl, morpholinyl, oxomorpholinyl and 1 ,1-dioxo-tetrahydro-thiopyranyl, each substituted with 0, 1 , 2 or 3 Ry, and wherein each Ryis independently selected from the group consisting of oxo, halo, Ci-C3alkoxy and Ci-C3alkyl.

[0104] Embodiment 27. The compound according to any one of the preceding Embodiments or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of halo, fluorocarbonyl, methylcarbonyl, trifluoromethylcarbonyl, 2-amino-2-methylpropylcarbonyl, hydroxycarbonyl, methylsulfonyl, dimethylaminosulfonyl, cyclopropylsulfonyl and difluoromethylsulfonyl.

[0105] Embodiment 28. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein:

[0106] R1is H, C1-C4 alkyl or C3-C6cycloalkyl(Ci-4alkyl); and

[0107] R2is C1-C4 alkyl, C1-C4 haloalkyl unsubstituted or substituted by hydroxy; C3-C6cycloalkyloxy(Ci-4alkyl); -(CR2)I-4-NR3R4; C5-C7 cycloalkyl; or a 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl), each comprising 1-3 heteroatoms selected from N, O and S; wherein said C5-C7 cycloalkyl, 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(Co-4 alkyl) is unsubstituted or substituted by 1 -2 Raindependently selected from C1-C4 alkyl, C1-C4 alkoxy and -S(=O)2R5wherein R5is C1-C4 alkyl or C1-C4 haloalkyl.

[0108] Embodiment 29. The compound according to Embodiment 1 or 28 or a pharmaceutically acceptable salt thereof, wherein R1is H, C1-C4 alkyl or C3-C6cycloalkyl(Ci-4alkyl).

[0109] Embodiment 30. The compound according to any one of Embodiments 1 and 28-29 or a pharmaceutically acceptable salt thereof, wherein R2is C1-C4 alkyl, C1-C4 haloalkyl unsubstituted or substituted by hydroxy.

[0110] Embodiment 31 . The compound according to any one of Embodiments 1 and 28-29 or a pharmaceutically acceptable salt thereof, wherein R2is C3-C6cycloalkyloxy(Ci-4alkyl), -(CR2)i-4- NR3R4.

[0111] Embodiment 32. The compound according to any one of Embodiments 1 and 28-29 or a pharmaceutically acceptable salt thereof, wherein R2is C5-C7 cycloalkyl, a 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl), each comprising 1-3 heteroatoms selected from N, O and S; wherein said C5-C7 cycloalkyl, 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl) is unsubstituted or substituted by 1 -2 Raindependently selected from C1-C4 alkyl, C1-C4 alkoxy or -S(O)2R5wherein R5is C1-C4 alkyl or C1-C4 haloalkyl. Embodiment 33. The compound according to any one of the preceding Embodiments, wherein halo is fluoro.

[0112] Embodiment 34. A compound or a pharmaceutically acceptable salt thereof, selected from Compounds 1 -153 in Table 1 :

[0113] Table 1

[0114] Embodiment 35. The compound according to Embodiment 34, wherein said compound is 7- (8-(5-methyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)imidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine or a pharmaceutically acceptable salt thereof.

[0115] Embodiment 36. The compound according to Embodiment 34, wherein said compound is 7- (8-((1 R,4R)-5-methyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)imidazo[1 ,2-a]pyrazin-2-yl)isoquinolin- 1 -amine or a pharmaceutically acceptable salt thereof.

[0116] Embodiment 37. The compound according to Embodiment 34, wherein said compound is 7- (8-((1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)imidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 - amine or a pharmaceutically acceptable salt thereof.

[0117] Embodiment 38. A compound or pharmaceutically acceptable salt thereof according to any of the embodiments herein, for use as a medicament.

[0118] Embodiment 39. A compound or pharmaceutically acceptable salt thereof according to any of the embodiments herein, for use in treating a Plasmodium related disease.

[0119] Embodiment 40. Use of a compound or pharmaceutically acceptable salt thereof according to any of the embodiments herein, in the manufacture of a medicament for treating a Plasmodium related disease.

[0120] Embodiment 41 . A method of treating a Plasmodium related disease, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to any of the embodiments herein.

[0121] Embodiment 42. The compound for use according to any of the embodiments herein, the use according to any of the embodiments herein, wherein the Plasmodium related disease is malaria.

[0122] Embodiment 43. The compound for use according to any of the embodiments herein, the use according to any of the embodiments herein, or the method according to any of the embodiments herein, wherein the compound according to any of the embodiments herein is administered in combination with one or more therapeutically active agent(s).

[0123] Embodiment 44. The compound for use according to any of the embodiments herein, the use according to any of the embodiments herein, or the method according to any of the embodiments herein, wherein the compound according to any of the embodiments herein is administered prior to, simultaneously with, or after the therapeutically active agent.

[0124] Embodiment 45. The compound for use, the use, or the method according to any of the embodiments herein, wherein the therapeutically active agent is selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent.

[0125] Embodiment 46. The compound for use, the use according, or the method according to any of the embodiments herein, wherein the active agent is an anti-malarial drug selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine, KAE-609, KAF-156 and INE963.

[0126] Embodiment 47. The method according to any of the embodiments herein, wherein the subject is human.

[0127] Embodiment 48. A pharmaceutical composition comprising the compound according to any of the embodiments herein, and one or more pharmaceutically acceptable carriers.

[0128] Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as stereoisomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms. Optically active ( / ?)- and (S)- stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.

[0129] As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0130] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0131] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0132] In another aspect, the present invention provides compounds according to any one of embodiments 1 to 37 in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form.

[0133] In another aspect, the present invention provides compounds according to any one of embodiments 1 to 37, in sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt form.

[0134] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen.

[0135] Further, incorporation of certain isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability. It is understood that deuterium in this context is regarded as a substituent of a compound of the present invention. The concentration of deuterium may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term “isotopic enrichment factor” can be applied to any isotope in the same manner as described for deuterium.

[0136] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as3H,11C,13C,14C,15N,18F31P,32P,35S,36CI,123l,124l,125l respectively. Accordingly, it should be understood that the invention includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as3H and14C, or those into which non-radioactive isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labeled reagents in place of the non-labeled reagent previously employed.

[0137] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the invention can be present in racemic or enantiomerically enriched, for example the ( / ?)-, (S)- or (Reconfiguration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the ( / ?)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.

[0138] Accordingly, as used herein a compound of the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

[0139] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0140] Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p- toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0141] In one aspect, the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof: wherein ring B is a 7-9 membered bridged bicyclic heterocycle comprising at least one nitrogen atom attached to the C atom marked with *; and is substituted by 1-2 Rxor is substituted by 1 Rx; and wherein Rxis selected from the group consisting of Rxis selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, -O-(Ci-C4haloalkyl), C1-C4 alkoxy, C1-C4 alkoxyCi.4alkyl, halo, hydroxy, hydroxyCi-4alkyl, -(CR2)0.2-C(=O)OR, oxo and -S(=O)2; or Rxis selected from the group consisting of Rxselected from the group consisting of methyl, ethyl, prop-1 -yl, prop-2-yl, methoxy, methoxyethyl, hydroxymethyl, 2,2-difluoroethyl, trifluoromethoxy, trifluoromethyl, 2-hydroxy-3-trifluoro-propyl, dimethylaminomethyl, methylaminomethyl, (methoxyethyl)amino and 2-hydroxy-3-dimethylamino-propyl.

[0142] In a further aspect, the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof: wherein ring B is selected from 2-5-diazabicyclo[2.2.1]heptan-2-yl; 3,8- diazabicyclo[3.2.1 ]octan-3-yl; 3,8-diazabicyclo[3.2.1 ]octan-8-yl; 3,6-diazabicyclo[3.1 ,1]heptan-6- yl; 3,6-diazabicyclo[3.1 ,1]heptan-3-yl; 2-oxa-5-bicyclo[2.2.1]heptan-5-yl; 3- azabicyclo[3.1 ,1]heptan-6-yl; 8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl; 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl; and 7-azabicyclo[2.2.1]heptan-7-yl; wherein said ring B is substituted by 1-2 Rx; and wherein Rxis selected from the group consisting of Rxis selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, -O-(Ci-C4haloalkyl), C1-C4 alkoxy, C1-C4 alkoxyCi.4alkyl, halo, hydroxy, -(CR2)0.2-C(=O)OR, oxo, and -S(=O)2; or Rxis selected from the group consisting of Rxselected from the group consisting of methyl, ethyl, prop-1 -yl, prop-2-yl, methoxy, methoxyethyl, hydroxymethyl, 2,2-difluoroethyl, trifluoromethoxy, trifluoromethyl, 2-hydroxy-3-trifluoro-propyl, dimethylaminomethyl, methylaminomethyl, (methoxyethyl)amino and 2-hydroxy-3-dimethylamino-propyl.

[0143] In a further aspect, the invention provides a compound of Formula (III) or a pharmaceutically acceptable salt thereof: wherein Rxis selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, -O-(Ci-C4haloalkyl), C1-C4 alkoxy, C1-C4 alkoxyCi.4alkyl, halo, hydroxy, -(CR2)0.2-C(=O)OR, oxo, -S(=O)2; or, wherein Rxis selected from the group consisting of methyl, ethyl, prop-1-yl, prop-2-yl, methoxy, methoxyethyl, hydroxymethyl, 2,2-difluoroethyl, trifluoromethoxy, trifluoromethyl, 2-hydroxy-3-trifluoro-propyl, dimethylaminomethyl, methylaminomethyl, (methoxyethyl)amino and 2-hydroxy-3-dimethylamino-propyl.

[0144] Pharmacology and Utility

[0145] The compounds of formulae (I), (II) and (III) in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example in the treatment of Plasmodium related diseases (for example, malaria) or in in vitro tests as provided in the next sections, and are therefore indicated for therapy or for use as research chemicals, e.g. as tool compounds.

[0146] Compounds of the invention may have activity against protein kinases, but are relatively inactive against certain protein kinases, e.g. ataxia telangiectasia mutated (ATM) and Rad3 related (together, ATR) kinase. Compounds of the invention are useful in the treatment and / or prevention of infections such as those caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malaria, Trypanosoma cruzi and parasites of the Leishmania genus, such as, for example, Leishmania donovani.

[0147] In accordance with the foregoing, the present invention further provides a method for preventing or treating malaria in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of a compound of Formula (I) and subformulae thereof, a compound of the Examples or a pharmaceutically acceptable salt thereof. The required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.

[0148] Pharmaceutical Compositions, Dosage and Administration

[0149] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application. The pharmaceutical compositions of the invention can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0150] Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). The compound of the invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound of the invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the invention.

[0151] Products provided as a combined preparation include a composition comprising a compound of the present invention and another therapeutic agent(s) together in the same pharmaceutical composition, or in separate form, e.g. in the form of a kit. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt stereoisomer thereof, and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above. In another embodiment, the invention provides a product comprising a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.

[0152] In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.

[0153] In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.

[0154] Accordingly, the invention provides the use of a compound of the present invention for treating a disease or condition caused by the growth and proliferation of a plasmodium parasite, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition caused by the growth and proliferation of a plasmodium parasite, wherein the medicament is administered with a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof. The invention also provides the use of a compound of the present invention for treating a plasmodium related disease, wherein the patient has previously {e.g., within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition caused by the growth and proliferation of a plasmodium parasite, wherein the patient has previously e.g., within 24 hours) been treated with a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0155] In one embodiment, the other therapeutic agent is selected from a kinase inhibitor, an anti- malarial drug and an anti-inflammatory agent. The anti-malarial drug is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine, KAE-609, KAF-156 and INE963. Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

[0156] PREPARATION OF COMPOUNDS

[0157] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis in view of the methods, reaction schemes and examples provided herein. For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. All methods described herein can be performed in any suitable order, unless otherwise indicated or otherwise clearly contradicted by context.

[0158] Compounds of Formula (I) can be prepared as generally illustrated in Scheme 1 below, wherein R1and R2are as defined in the Summary of the Invention.

[0159]

[0160] Scheme 1

[0161] Scheme I depicts a general method for synthesizing compounds of Formula (I). The synthesis begins from commerically-available 7-bromoisoquinolin-1 -amine, which is exhaustively protected with two N-tert-butyloxycarbonyl groups under standard conditions. The boc-protected aminoisoquinoline is then subjected to a Stille reaction with tributyl(1 - ethoxyvinyl)tin. The resulting ethyl vinyl ether is not isolated, but reacted with NBS in one-pot fashion to afford a-bromoketone via electrophilic bromination. This intermediate is then heated with either 3-bromopyrazin-2-amine or 3-chloropyrazin-2-amine in acetonitrile at 90 °C to effect a cyclocondensation reaction to yield 7-halo-imidazopyrazines A1 (X = Br) or A2 (X = Cl). Both intermediates are equally competent in the final reaction to install either secondary or primary amines via nucleophilic aromatic substitution (SNr) in the presence of Hunig’s base (DIPEA) at elevated temperature. Detailed descriptions of the synthesis of compounds of the Invention are given in the Examples below, vide infra.

[0162] EXAMPLES

[0163] The disclosure is further illustrated by the following examples and synthetic methods, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0164] The compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. Unless otherwise noted, reagents and solvents were used as received from commercial suppliers.

[0165] The chemical names were generated using ChemDraw (e.g., Professional version 22.0.0.22) from PerkinElmer.

[0166] Temperatures are given in degrees Celsius. As used herein, unless specified otherwise, the term “room temperature” or “ambient temperature” means a temperature of from 15°C to 30°C, such as from 20°C to 30°C, such as from 20°C to 25°C. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20 - 133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0167] ABBREVIATIONS

[0168] Abbreviations used in the following examples and elsewhere herein are:

[0169] (BOC)20 Di-te / Y-butyl dicarbonate

[0170] DCM Dichloromethane

[0171] DMAP 4-Dimethylaminopyridine

[0172] DIPEA N,N-Diisopropylethylamine

[0173] DMSO Dimethylsulfoxide

[0174] EtOAc Ethyl acetate

[0175] Me Methyl

[0176] NBS N-bromo succinimide

[0177] LC-MS Methods

[0178] LC-MS Method 1 :

[0179] Column: Xbridge C18 (75 mm x 4.6 mm, 3.5 pm) Column Temperature: 35°C, Mobile phase: A - 10mM Ammonium Bicarbonate in water, B - acetonitrile, Flow rate: 1 .3 ml / min, Gradient: Time (min) / %ACN: 5%-98% Solvent B in 4.0min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0180] LC-MS Method 2:

[0181] Column: Kinetex C18, 50 mm x 2.1 mm, 2.6 pm) Column Temperature: °C, Mobile phase: A - Water + 0.1 %TFA, B - acetonitrile + 0.1%TFA, Flow rate: 1.2 ml / min, Gradient: 2%-88% Solvent B in 9.29min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 220 nm, Detector: SQD.

[0182] LC-MS Method 3: Column: BEH C18, 50 mm x 2.1 mm, 1 .9 pm) Column Temperature: 35°C, Mobile phase: A

[0183] - Water + 0.05%Formic Acid, B - acetonitrile + 0.05%Formic Acid, Flow rate: 0.6 ml / min, Gradient: 3%-98% Solvent B in 9.5min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0184] LC-MS Method 4:

[0185] Column: BEH C18, 50 mm x 2.1 mm, 1 .7 pm) Column Temperature: 35°C, Mobile phase: A

[0186] - Water + 0.05%Formic Acid, B - acetonitrile + 0.05%Formic Acid, Flow rate: 0.6 ml / min, Gradient: 3%-98% Solvent B in 3.4min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0187] LC-MS Method 5:

[0188] Column: Kinetex C18, 50 mmx 2.1 mm, 2.6 pm) Column Temperature: 50°C, Mobile phase: A - Water + 0.1%TFA, B - acetonitrile + 0.1%TFA, Flow rate: 1 .2 ml / min, Gradient: 2%-88% Solvent B in 9.29min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 220 nm, Detector: QDa.

[0189] LC-MS Method 6:

[0190] Column: Kinetex C18, 50 mmx 2.1 mm, 2.6 pm) Column Temperature: 50°C, Mobile phase: A - Water + 0.1%TFA, B - acetonitrile + 0.1%TFA, Flow rate: 1 .2 ml / min, Gradient: 2%-99% Solvent B in 1.5min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0191] LC-MS Method 7:

[0192] Column: Xbridge C18, 50 mmx 4.6 mm, 3.5 pm) Column Temperature: 35°C, Mobile phase: A - 5mM Ammonium Bicarbonate in water, B - acetonitrile, Flow rate: 0.8 ml / min, Gradient: 3%- 98% Solvent B in 4.0min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0193] LC-MS Method 8:

[0194] Column: Xbridge C18, 50 mmx 4.6 mm, 3.5 pm) Column Temperature: 35°C, Mobile phase: A - 5mM Ammonium Acetate in water, B - acetonitrile, Flow rate: 0.8 ml / min, Gradient: 3%-98% Solvent B in 4.0min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0195] LC-MS Method 9:

[0196] Column: Xbridge C18, 50 mmx 4.6 mm, 3.5 pm) Column Temperature: 25°C, Mobile phase: A - 10mM Ammonium Bicarbonate in water, B - acetonitrile, Flow rate: 1 .0 ml / min, Gradient: 5%-98.16% Solvent B in 11.0min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0197] LC-MS Method 10:

[0198] Column: Agilent Poroshell 120 SB-C18, 30 mm x 4.6 mm, 2.7 pm) Column Temperature: 60°C, Mobile phase: A - water + 0.1%formic acid, B - acetonitrile + 0.1 %formic acid, Flow rate: 3.0 ml / min, Gradient: 1 %-100% Solvent B in 1.73min, MS Ionization mode: Electrospray ionization (ESI), UV detection: 215 nm.

[0199] Purification by preparative HPLC:

[0200] Instrument: Waters, HPLC-2767-MS (3100) Column: Sunfire C18, 30 mm x 50 mm Mobile phase: A - water + 0.1 %TFA, B - acetonitrile + 0.1 %TFA, Flow rate: 75 ml / min, UV detection: 220 nm.

[0201] SYNTHESIS OF THE INTERMEDIATES

[0202] Intermediate A1-2: te / Y-butyl (7-(2-bromoacetyl)isoquinolin-1-yl)(tert-butoxycarbonyl)carbamate

[0203] The title compound was prepared in the following way:

[0204] To a solution of 7-bromoisoquinolin-1-amine (5.00 g, 22.41 mmol) and DMAP (0.27 g, 2.24 mmol) in THF (56 mL) were added DIPEA (8.69 g, 67.2 mmol) and B0C2O (12.23 g, 56.0 mmol). The reaction was stirred at rt open to air as a large volume of gas rapidly evolves and subsides within the first 5 min after Boc20 addition. The reaction was stirred at rt for 1 h before a second portion of B0C2O (12.23 g, 56.0 mmol) was added. The reaction was stirred for 18 h. The reaction was concentrated in vacuo, re-dissolved in EtOAc, and washed with a sat. solution of NHCO3. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (EtOAc I heptane gradient 0 to 25%) to afford te / Y-butyl (7- bromoisoquinolin-1-yl)(tert-butoxycarbonyl)carbamate (5.37 g, 56.6%) as a white solid.1H NMR (500 MHz, CDCI3) 6 8.46 (d, J = 5.7 Hz, 1 H), 8.13 (dt, J = 1.7, 0.8 Hz, 1 H), 7.82 - 7.74 (m, 2H), 7.63 (dd, J = 5.7, 1.0 Hz, 1 H), 1 .34 (s, 16H). LCMS (ESI) m / z calc’d for CigH23BrN2O4422.1 , found 423.2 (M+H)+.

[0205] To a suspension of A1-1 (5.00g, 12.0 mmol) and bis-(triphenylphosphino)-palladous chloride (0.41 g, 0.59 mmol) in 1 ,4-dioxane (50 mL) was added tributyl(1-ethoxyvinyl)stannane (6.40 g, 18.0 mmol). The resulting mixture was degassed under a balloon of N2for 15 min and then heated to 80 °C for 1 .6 h. The reaction mixture was diluted with 30 mL of 2:1 THF / Water and cooled to 0 °C before / V-bromosuccinimide (4.20 g, 24 mmol) was added. The reaction was allowed to stir at 0 °C for 30 min. The reaction was diluted with EtOAc and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (EtOAc I heptane gradient 0 to 35%) to afford te / Y-butyl (7- (2-bromoacetyl)isoquinolin-1-yl)(tert-butoxycarbonyl)carbamate (5.10 g, 93% yield) as yellow solid.1H NMR (500 MHz, CDCI3) 6 8.59 (dt, J = 1 .7, 0.9 Hz, 1 H), 8.57 (d, J = 5.8 Hz, 1 H), 8.27 (dd, J = 8.6, 1 .7 Hz, 1 H), 7.98 (d, J = 8.6 Hz, 1 H), 7.72 (dd, J = 5.7, 1 .1 Hz, 1 H), 7.27 (d, J = 1 .0 Hz, 1 H), 4.52 (d, J = 1.0 Hz, 2H), 1.36 (d, J = 1.0 Hz, 16H). LCMS (ESI) m / z ca Ic’d for C2iH25BrN2O5464.1 , found 465.1 (M+H)+.

[0206] Intermediate A1 : 7-(8-bromoimidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine

[0207] A suspension of A1 -2 (5.50 g, 11.8 mmol) and 3-bromopyrazin-2-amine (3.08 g, 17.7 mmol) in CH3CN (40 mL) was stirred at 90 °C for 18 h. The resulting black suspension was filtered to afford 7-(8-bromoimidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine (3.50 g, 39% yield).1H NMR (500 MHz, DMSO-c / e) 6 12.94 (s, 2H), 9.23 - 9.21 (m, 1 H), 8.88 (s, 1 H), 8.78 (d, J = 4.5 Hz, 1 H), 8.59 (dd, J = 8.4, 1 .6 Hz, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 4.5 Hz, 1 H), 7.71 (d, J = 6.9 Hz, 1 H), 7.28 (d, J = 6.9 Hz, 1 H). LCMS (ESI) m / z calc’d for Ci5Hi0BrN5339.0, found 340.1 (M+H)+.

[0208] Intermediate A2: 7-(8-chloroimidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine

[0209] A suspension of A1 -2 (4.18 g, 10.0 mmol) and 3-chloropyrazin-2-amine (2.0 g, 15.0 mmol) in CH3CN (40 mL) was stirred at 90 °C for 18 h. The resulting black suspension was filtered to afford 7-(8-bromoimidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine (2.81 g, 72% yield). LCMS (ESI) m / z calc’d for CI5HI0CIN5295.1 , found 296.1 (M+H)+.

[0210] SYNTHESIS OF THE EXAMPLES

[0211] Example 1 : 7-(8-((1 R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)imidazo[1 ,2-a]pyrazin-2- yl)isoquinolin-1-amine

[0212] The title compound was prepared in the following way:

[0213] Compound A1 (1 .20 g, 3.53 mmol), (1 R,4R)-2-methyl-2,5-diazabicyclo[2.2.1 ]heptane, 2AA - Hydrochloride (1.11 g, 6.00 mmol), were placed in a 20 mL microwave vials. To this mixture was added CH3CN (12 mL) followed by DIPEA (4.92 mL, 28.22 mmol). The reaction mixture was stirred at 90 °C for 18 h. After dilution with EtOAc, the resulting precipitate was filtered off and dissolved in a minimal of 10% MeOH / DCM and applied to the top of an SiO2solid loading cartridge and was purified by flash chromatography over silica gel (MeOH I DCM gradient 0 to 20%) followed with a prepared mixture of 15% MeOH / DCM + 1 % Et3N to afford the coupling product. The resulting product was dissolved in 3:1 EtOAc / EtOAc, washed with a sat. aq. NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. The neutralized product was re-dissolved in 2:1 water / CH3CN, frozen with liquid N2, and lyophilized to afford the title compound (663.4 mg, 49% yield).1H NMR (500 MHz, MeOD) 6 8.59 (s, 1 H), 8.19 (dd, J = 8.4, 1.6 Hz, 1 H), 8.12 (s, 1 H), 7.70 (d, J = 5.9 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.60 (d, J = 4.6 Hz, 1 H), 7.18 (d, J = 4.6 Hz, 1 H), 6.95 (d, J = 6.0 Hz, 1 H), 6.55 - 5.72 (br s, 1 H), 4.05 (br s, 1 H), 3.74 (br s, 1 H), 3.62 (s, 1 H), 2.99 (d, J = 10.2 Hz, 1 H), 2.81 (d, J = 10.2 Hz, 1 H), 2.44 (s, 3H), 2.08 (d, J = 10.1 Hz, 1 H), 1 .95 (d, J = 10.0 Hz, 1 H). LC-MS method 5 rt = 1 .03 min, MS m / z calc’d for C2IH2IN7371 .2, found 372.2 [M+H]+.

[0214] Figure 1 depicts the1D NMR spectrum of Example 1 with low integrals for broad signals at 6.5 - 5.7 and 4.2 - 3.6 ppm. As one skilled in the art would understand,1H NMR data that contain significantly broadened signals with low integrations may be due to short T2 relaxation for these protons, caused by quadruple nitrogen nuclei in the configuration. As a result, some protons appear to be missing in the1D spectra for Example 1 and other examples herein, but can be observed directly or indirectly by TOCSY 1 D experiments with overall structure confirmation using2D NMR techniques. Example 2: 7-(8-(4-isopropylpiperazin-1 -yl)imidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine

[0215] The title compound was prepared in the following way: A suspension of Compound A1 (213.0 mg, 626 pmol), 1 -isopropylpiperazine (240.8 mg, 1.01 mmol) and DIPEA (485.5 mg, 3.76 mmol) in CH3CN (11 mL) was irradiated in the Biotage microwave to 100 °C for 2 h. The reaction mixture was diluted further with CH3CN, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography over silica gel (MeOH I DCM gradient 0 to 20%) to afford the title compound (176.0 mg, 63%) as a light brown solid at 87% purity. This solid was purified by SFC. The product was re-dissolved in 2:1 water / CH3CN to afford the title compound.1H NMR (500 MHz, MeOD) 6 8.70 (dd, J = 1 .7, 0.9 Hz, 1 H), 8.32 - 8.24 (m, 2H), 7.83 (d, J = 4.5 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H), 7.73 (d, J = 6.0 Hz, 1 H), 7.36 (d, J = 4.5 Hz, 1 H), 7.03 (dd, J = 6.1 , 0.9 Hz, 1 H), 4.40 (s, 4H), 2.92 (t, J = 5.3 Hz, 5H), 1 .22 (d, J = 6.5 Hz, 6H). LC-MS method 6 rt = 0.46 min, MS m / z calc’d for C22H25N7 387.2, found 388.3 [M+H]+.

[0216] Example 3: 7-(8-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)imidazo[1 ,2-a]pyrazin-2- yl)isoquinolin-1-amine To a mixture of Compound A2 (80 mg, 0.21 mmol) and 1-(tetrahydro-2H-pyran-4- yl)piperazine, Hydrochloride (0.13 g, 0.53 mmol) in CH3CN (3 mL) was added DIPEA (0.26 g, 2.0 mmol). The reaction was heated to 90 °C for 4.5 h. The reaction was concentrated in vacuo. The residue was purified by reverse preparative HPLC to afford the title compound (22.9 mg, 23%).1H NMR (500 MHz, DMSO-c / 6) 6 8.74 (s, 1 H), 8.42 (s, 1 H), 8.22 (dd, J = 8.4, 1 .5 Hz, 1 H),

[0217] 8.17 (s, 2H), 7.97 (d, J = 4.4 Hz, 1 H), 7.82 - 7.73 (m, 2H), 7.37 (d, J = 4.4 Hz, 1 H), 6.97 (s, 2H), 6.92 (d, J = 5.8 Hz, 1 H), 4.27 (d, J = 5.7 Hz, 4H), 3.90 (dd, J = 11 .6, 4.0 Hz, 2H), 3.29 (td, J = 11.8, 1.9 Hz, 2H), 2.68 (t, J = 5.1 Hz, 4H), 2.47 - 2.41 (m, 1 H), 1.77 (dd, J = 12.2, 3.5 Hz, 2H), 1 .45 (qd, J = 12.1 , 4.5 Hz, 2H). LC-MS method 6 rt = 0.46 min, MS m / z calc’d for C24H27N7O 429.2, found 430.2 [M+H]+.

[0218] Examples 4-153 were prepared from Intermediate A1 or Intermediate A2 and appropriate amines and in a manner analogous to Examples 1-3.

[0219]

[0220]

[0221]

[0222]

[0223] BIOLOGICAL ASSAYS AND DATA

[0224] The activity of a compound according to the present invention can be assessed by the following in vitro methods. A compound of formula (I), or a pharmaceutically acceptable salt thereof, exhibits valuable pharmacological properties, e.g. as indicated in tests as provided in the next sections, and are therefore indicated for therapy, e.g. in the treatment of plasmodium related diseases, e.g. malaria.

[0225] The following assay illustrates the invention without in any way limiting the scope of the invention. This parasite proliferation assay measures the increase in parasite DNA content using a DNA intercalating dye, SYBR Green®.

[0226] 3D7 P. falciparum strain is grown in complete culturing media until parasitemia reaches 3% to 8% with O+ human erythrocytes. 20 pl of screening media is dispensed into 384 well assay plates. 50 nl of compounds of the invention (in DMSO), including antimalarial controls (mefloquine, pyrimethamine and artemisinin), are then transferred into the assay plates, as well as DMSO alone to serve as a negative control for inhibition. Then 30 pl of a suspension of a 3D7 P. falciparum infected erythrocytes in screening media is dispensed into the assay plates such that the final hematocrit is 2.5% with a final parasitemia of 0.3%. The plates are placed in a 37 °C incubator for 72 hours in the presence of 5% CO2. 10 pl of lysis buffer (saponin, triton-X, EDTA) containing a 10X solution of SYBR Green I® in RPMI media is dispensed into the plates. The plates are covered and kept at room temperature overnight for the lysis of the infected red blood cells. The fluorescence intensity is measured (excitation 425nm, emission 530nm) using the Envision™ system (Perkin Elmer).

[0227] As shown in Table 2, compounds of the invention have on target activity and can delay the increase in parasitemia. Biological activity is represented as follows: “+” > 0.1 pM (EC50); 0.1 pM (EC50) > “++” > 0.01 pM (EC50); “+++” < 0.01 pM (EC50).

[0228] Table 2

[0229] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

WHAT IS CLAIMED IS:1 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein:R1is H, C1-C4 alkyl or C3-C6cycloalkyl(Ci-4alkyl);R2is C1-C4 alkyl, C1-C4 haloalkyl unsubstituted or substituted by hydroxy; C3-C6cycloalkyloxy(Ci-4alkyl); -(CR2)I-4-NR3R4; C5-C7 cycloalkyl; or a 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(Co-4 alkyl), each comprising 1-3 heteroatoms selected from N, O and S; wherein said C5-C7 cycloalkyl, 5-6 membered heteroaryl(C0-4 alkyl) or 5-9 membered heterocyclyl(C0-4 alkyl) is unsubstituted or substituted by 1 -2 Raindependently selected from C1-C4 alkyl, C1-C4 alkoxy and -S(=O)2R5wherein R5is C1-C4 alkyl or C1-C4 haloalkyl; alternatively, R1and R2together with the atom to which they are attached to form ring B;Ring B is a 4-12 membered monocyclic or bicyclic heterocycle having 1-4 heteroatoms selected from N, O and S; and is unsubstituted or substituted by 1-4 Rx; each Rxis independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -O-(Ci-C4haloalkyl), C1-C4 alkoxy, C1-C4 alkoxyCi.4alkyl, halo, hydroxy, hydroxyCi-4alkyl, -(CR2)0.2-C(=O)OR, oxo, - S(=O)2; -S(=O)2-R6wherein R6is C1-C4 alkyl, C3-C3cycloalkyl or -NRR7wherein R7is hydrogen or C1-C4 alkyl or R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; -C(=O)-R8wherein R8is halo, C1-C4 alkyl, C1-C4 haloalkyl or -NR3R4; - (CR2)O.2NRR9wherein R9is hydrogen, C1-C4 alkyl or Ci-C4alkoxy(Ci-3alkyl); hydroxyCi-4alkyl unsubstituted or substituted with halo or -NR3R4; and C3-C6cycloalkyl(C0-4 alkyl), C3-C6cycloalkyloxy(C0-4 alkyl) and 4-6 membered heterocyclyl(C0-4 alkyl) comprising 1-3 heteroatoms selected from N, O and S, wherein said C3-C6cycloalkyl(C0-4 alkyl), C3-C6cycloalkyloxy(C0-4 alkyl) and 4-6 membered heterocyclyl(Co-C4alkyl) is unsubstituted or substituted with 1-4 Rcselected from oxo, -S(=O)2, C1-C4 alkyl, C1-C4 alkoxy and halo; and each R is hydrogen or C1-C4 alkyl unless R and R7together with the nitrogen atom they are attached to form a 5-6 membered heterocycle; each R3and R4is independently hydrogen or C1-C4 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is of Formula (II):wherein ring B is a 4-12 membered monocyclic or bicyclic heterocycle comprising at least one nitrogen atom attached to the C atom marked with *; and is substituted by 1-4 Rx.

3. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein ring B is monocyclic and is a 4-7 membered heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1 ,4-diazepan-1-yl and imidazolidinyl; wherein said 4-7 membered heterocycle is substituted by 1-4 Rx.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

5. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein ring B is bicyclic and is a 7-9 membered bridged heterocyle selected from 2-5- diazabicyclo[2.2.1]heptan-2-yl; 3,8-diazabicyclo[3.2.1]octan-3-yl; 3,8-diazabicyclo[3.2.1]octan-8- yl; 3,6-diazabicyclo[3.1 ,1]heptan-6-yl; 3,6-diazabicyclo[3.1 ,1]heptan-3-yl; 2-oxa-5- bicyclo[2.2.1]heptan-5-yl; 3-azabicyclo[3.1 ,1]heptan-6-yl; 8-oxa-3-azabicyclo[3.2.1]octan-3-yl; 2- oxa-5-azabicyclo[2.2.1]heptan-5-yl; and 7-azabicyclo[2.2.1]heptan-7-yl; wherein said 7-9 membered bridged heterocycle is substituted by 1-2 Rx.

6. The compound according to any one of claims 1-2 and 5 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

7. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein ring B is bicyclic and is a 7-11 membered spirocyclic heterocycle selected from 2,6-diazaspiro[3.4]octan-6-yl; 2,7-diazaspiro[3.5]nonan-2-yl; 2,7-diazaspiro[4.4]nonan-2-yl; 2,6- diazaspiro[3.3]heptan-2-yl; 2-oxa-6,9-diazaspiro[4.5]decan-9-yl; 1-oxa-8-azaspiro[4.5]decan-3- yl; 2-oxa-7-azaspiro[4.4]nonan-7-yl; 3-oxa-9-azaspiro[5.5]undecane-9-yl; 7-oxa-2- azapiro[3.5]nonan-yl; 7-azaspiro[3.5]nonan-7-yl; 2-oxa-8-azaspiro[4.5]decan-8-yl; 2,8- diazaspiro[4.5]decan-8-yl; 6-azaspiro[2.5]octan-6-yl and 7-azaspiro[3.5]nonan-2-yl; wherein said 7-11 membered spirocyclic heterocycle is substituted by 1-2 Rx.

8. The compound according to any one of claims 1-2 and 7 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

9. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein ring B is bicyclic and is a 5-6 membered heterocycle comprising 1-2 heteroatoms selected from N, O and S heteroatoms; wherein said 5-6 membered heterocycle is fused to a 5-6 membered saturated, unsaturated or partially saturated ring comprising 1-2 heteroatoms selected from N, O and S; wherein ring B is substituted by 1-2 Rx.

10. The compound according to any one of claims 1-2 and 9 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:1 1 . The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of methyl, ethyl, prop-1-yl, prop-2-yl, methoxy, methoxyethyl, hydroxymethyl, 2,2-difluoroethyl, trifluoromethoxy, trifluoromethyl, 2-hydroxy-3-trifluoro-propyl, dimethylaminomethyl, methylaminomethyl, (methoxyethyl)amino and 2-hydroxy-3-dimethylamino-propyl.

12. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of cyclopropyl, tetrahydropyranyl, tetrahydropyranylmethyl, tetrahydrofuranyl, oxetanyl, piperidinyl, oxopiperidinyl, azolidinyl, azolidinylsulfonyl, azetidinyl, morpholinyl, oxomorpholinyl and 1 ,1-dioxo-tetrahydro-thiopyranyl, each substituted with 0, 1 , 2 or 3 Ry, and wherein each Ryis independently selected from the group consisting of oxo, halo, Ci-C3alkoxy and Ci-C3alkyl.

13. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring B is substituted with one or more Rxselected from the group consisting of halo, fluorocarbonyl, methylcarbonyl, trifluoromethylcarbonyl, 2-amino-2-methylpropylcarbonyl, hydroxycarbonyl, methylsulfonyl, dimethylaminosulfonyl, cyclopropylsulfonyl and difluoromethylsulfonyl.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1is H, Ci-C4alkyl or C3-C6cycloalkyl(Ci-4alkyl); and R2is Ci-C4alkyl, Ci-C4haloalkyl unsubstituted or substituted by hydroxy; C3-C6cycloalkyloxy(Ci-4alkyl); -(CR2)I-4-NR3R4; C5-C7 cycloalkyl or a 5-6 membered heteroaryl(Co-4alkyl) or 5-9 membered heterocyclyl(Co-4alkyl), each comprising 1-3 heteroatoms selected from N, O and S; wherein said C5-C7 cycloalkyl, 5-6 membered heteroaryl(C0-4alkyl) or 5-9 membered heterocyclyl(C0-4alkyl) is unsubstituted or substituted by 1-2 Raindependently selected from Ci-C4alkyl, Ci-C4alkoxy or -S(O)2R5wherein R5is Ci-C4alkyl or Ci-C4haloalkyl.

15. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein said compound is selected from Table 1 .

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is 7-(8-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)imidazo[1 ,2- a]pyrazin-2-yl)isoquinolin-1 -amine; 7-(8-((1 R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)imidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine; or 7-(8-((1 S,4S)-5-methyl-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)imidazo[1 ,2-a]pyrazin-2-yl)isoquinolin-1 -amine.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, and one or more pharmaceutically acceptable carriers.

18. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, for use in treating a Plasmodium related disease.

19. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, in the manufacture of a medicament for treating a Plasmodium related disease.

20. A method of treating a Plasmodium related disease, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to any one of claims 1 to 16.21 . The compound for use according to claim 18, the use according to claim 19, or the method according to claim 20, wherein the Plasmodium related disease is malaria.

22. The compound for use according to claim 18, the use according to claim 19, or the method according to claim 20, wherein the Plasmodium related disease is complicated or severe malaria.

23. The compound for use according to claim 18, the use according to claim 19, or the method according to claim 20, wherein the compound is administered in combination with at least one other therapeutically active agent.

24. The compound for use according to claim 18, the use according to claim 19, or the method according to claim 20, wherein the other therapeutically active agent is selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent.

25. The compound for use, the use according, or the method according to claim 24, wherein the other therapeutically active agent is an anti-malarial drug selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine, KAE-609,KAF-156 and INE963.-I OS-

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