Compounds and methods for blocking the transmission of malaria parasites

Description

BACKGROUND OF THE INVENTION

[0001] Malaria cases and deaths have dropped 50% in 29 countries since 2000 due to the combined effects of long-lasting insecticidal bed nets, indoor residual spraying, and artemisinin-based combination therapies (ACTs) [Kilama W. et al., Lancet, 2009, 374: 1480-1482]. This success has raised hopes for malaria eradication and consequently stimulated interest in developing new reagents that block gametocyte transmission, such as novel and safe gametocytocidal drugs [Buchholz K. et al., The Journal of Infectious Diseases, 2011, 203: 1445-1453]. Previous drug development efforts have focused primarily on the asexual parasites that cause symptoms but not malaria transmission. To be transmitted from person to person via mosquitoes, the parasites must switch from asexual to sexual development and produce male and female gametocytes. Once gametocytes are taken up in a blood meal by a mosquito, fertilization is stimulated and the resulting zygote differentiates into a motile ookinete that migrates across the midgut epithelium of the mosquito and forms an oocyst. Over the course of the next 2 weeks, tens of thousands of infectious sporozoites are generated and sequestered in the mosquito salivary glands until released into a vertebrate host for transmission during the next blood meal.

[0002] Sexual stage P. falciparum gametocytes have a lifespan of over 3 weeks and are not cleared effectively by current antimalarial agents, except primaquine (PQ) [Sweeney AW et al., American Journal of Tropical Medicine and Hygiene, 2004, 71: 187-189; Peatey CL et al., Journal of Infectious Diseases, 2009, 200: 1518-1521] which is not widely used because it causes hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency [Baird JKet al., Trends in Parasitology, 2011, 27: 11-16]. Consequently, treatment with current antimalarial drugs often results in asymptomatic carriers who remain infectious for weeks after the clearance of asexual parasites. Despite the risks of PQ, its efficacy with artemisinin combination therapy (ACT) in reducing malaria transmission in the PQ-tolerant patients was recently demonstrated in test regions. Other than PQ, the only other gametocytocidal candidate being tested is methylene blue.

[0003] Moreover, also WO2015 / 073804 discloses compounds with antimalarial activity.

[0004] Thus, a new generation of antimalarial agents with potent activities against both sexual and asexual parasites is urgently needed for better therapeutic effect and eradication of malarial infection globally.BRIEF SUMMARY OF THE INVENTION

[0005] The invention provides a compound of formula (I): wherein A is CR 5< or N, B is CR 3< =CR 4< , R 1< is C 6-10 aryl or heteroaryl substituted with at least one substituent selected from -CN, cyanomethyl, -SO 2 R 13< , -SO 2 NHR 15< , and -CONR 11< R 12< , optionally further in combination with one or more substituents selected from halo, C 1-12 alkyl, alkoxy, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolidinyl, and diazepinyl, or an aryl bicyclic lactam of the formula: wherein the aryl group of the aryl bicyclic lactam is optionally substituted with at least one substituent selected from -CN, cyanomethyl, -SO 2 R 13< , -SO 2 NH 2 , and -CONR 11< R 12< , optionally further in combination with one or more substituents selected from halo, C 1-12 alkyl, alkoxy, 2-(dimethylamino)ethyl)amino, dimethylamino, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolidinyl, azetidinyl and diazepinyl, R 2< is selected from 4-pyridinyl, 2-amino-5-pyrimidinyl, 3-pyridyl, quinolin-3-yl, 5-pyrimidinyl, 2-acetylamino-5-pyridyl, 2-amino-4-methylpyrimidin-5-yl, 1-piperazinyl, indol-5-yl, 1H-imdazol-5-yl, 4-aminophenyl, 1,2,3,6-tetrahydropyridin-4-yl, 1H-pyrazol-4-yl, N-methyl-pyrazol-4-yl, 1H-benzo[d]imidazol-5-yl, 4-sulfonylaminophenyl, 2-dimethylaminopyrimidin-5-yl, 3-trifluoromethylphenyl, bromo, 3-aminophenyl, 4-aminophenyl, vinyl, 4-aminocarbonylphenyl, 3-cyanophenyl, 3-hydroxyphenyl, 3-trifluoromethyl-5-pyridyl, tetrazolyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-aminocarbonylphenyl, 3-acetylphenyl, 3-cyano-4-chlorophenyl, 3-cyano-5-methylphenyl, 3-hydroxy-4-chlorophenyl, 4-hydroxymethylphenyl, 3-amino-4-chlorophenyl, 2,3-dihydrobenzofuran-6-yl, 1-methyl-1H-indol-5-yl, benzo[d][1,3]dioxo-5-yl, 4-hydroxyphenyl, morpholin-1-yl, benzo[b]thiophen-1-yl, 4-methylsulfonylphenyl, benzo[c][1,2,5]oxadiazol-5-yl, 2-(piperidin-1-yl)-3-pyridinyl, 4-carboxyphenyl, 2-methyl-5-pyridyl, 4-methylsulfonylphenyl, 4-dimethylaminocarbonylphenyl, 4-phenylphenyl, 4-methylphenyl, 3-chloro-5-pyridyl, (3-pyrrolidin-1-yl)phenyl, 4-([piperizin-1-yl]carbonyl)phenyl, 4-([morpholin-1-yl]carbonyl)phenyl, 2-hydroxypyrimidin-5-yl, 3-aminosulfonylphenyl, 2-oxo-1,2,3,4,tetrahydroisoquinolin-6-yl, 2-oxo-1,2,3,4,-tetrahydroquinolin-6-yl, 4-(methylaminocarbonyl)phenyl, 1-oxoindolin-5-yl, 2-oxoindolin-5-yl, 1-oxoisoindolin-5-yl, 2-amino-4-pyridyl, 3-amino-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 4-aminophenyl, 3-methylphenyl, 3-methoxyphenyl, phenyl, 5-indolinonyl, 5-isoindolinonyl, 3-aminophenyl, 2-hydroxy-4-chlorophenyl, 4-cyanophenyl, 4-azetidinylphenyl, 4-ethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-cyano-4-fluorophenyl, 3-amino-4-fluorophenyl, 4-(1-hydroxy-1-ethyl)phenyl, 3-methyl-5-pyridyl, 2-acetylamio-5-pyridyl, 2-oxoindolin-5-yl, benzimidazolin-5-yl, 3-dimethylamino-1-propargyl, 2-pyrrolyl, N-methyl-2-pyrrolyl, 2-thiopheneyl, 3-thiopheneyl, 3-furanyl, and 3-aminosulfonylphenyl, R 3< and R 4< are independently selected from hydrogen, hydroxyl, OR 5< , halogen, optionally substituted C 6-10 aryl, and optionally substituted C 1-6 alkyl, R 5< is hydrogen, C 1-12 alkyl, C 6-10 aryl, halogen, hydroxyl, or OR 16< , R 6< is hydrogen, C 1-12 alkyl, C 2-12 hydroxyalkyl, C 1-6 acyl-C 1-6 alkyl, or C 6-10 aryl, R 7< -R 10< are independently selected from hydrogen, C 1-12 alkyl, C 3-8 cycloalkyl, CH 2 COOR 13< , and H 2 N(CH 2 ) n - wherein n is an integer of 2-6, R 11< and R 12< selected from the group consisting of hydrogen, C 1-12 alkyl and C 3-10 cycloalkyl or, taken together with the N to which they are bound, form an optionally substituted 4-7 membered heterocyclyl ring containing O or N atoms, and R 13< is C 1-12 alkyl, R 15< is hydrogen or C 1-12 alkyl, R 16< is hydrogen, C 1-12 alkyl or C 6-10 aryl, or a pharmaceutically acceptable salt thereof.

[0006] The invention further provides a pharmaceutical composition comprising a compound or salt of formula (I) and a pharmaceutically acceptable carrier.

[0007] The invention additionally provides the mentioned compound for use in blocking transmission of a Plasmodium parasite comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a first compound of formula (I), optionally in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat.

[0008] The invention also provides the mentioned compound for use in treating malaria by killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in a gametocyte stage, the method comprising administering to a mammal a therapeutically effective amount of a first compound of formula (I), optionally in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat.

[0009] Advantageously, the compounds and methods of the invention compounds kill all stages of malaria parasites.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0010] Figure 1 (drawing sheets 1 / 85 and 2 / 85) depicts the structures of compounds in accordance with an embodiment of the invention. Figure 2 (drawing sheets 3 / 85 through 85 / 85) depicts the structures of additional compounds 1 to 395 in accordance with an embodiment of the invention and the structures of additional reference compounds 396 to 640. DETAILED DESCRIPTION OF THE INVENTION

[0011] In an embodiment, the invention provides a compound of formula (I): wherein A is CR 5< or N, B is CR 3< =CR 4< , R 1< is C 6-10 aryl or heteroaryl substituted with at least one substituent selected from -CN, cyanomethyl, -SO 2 R 13< , -SO 2 NHR 15< , and -CONR 11< R 12< , optionally further in combination with one or more substituents selected from halo, C 1-12 alkyl, alkoxy, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolidinyl, and diazepinyl, or an aryl bicyclic lactam of the formula: wherein the aryl group of the aryl bicyclic lactam is optionally substituted with at least one substituent selected from -CN, cyanomethyl, -SO 2 R 13< , -SO 2 NH 2 , and -CONR 11< R 12< , optionally further in combination with one or more substituents selected from halo, C 1-12 alkyl, alkoxy, 2-(dimethylamino)ethyl)amino, dimethylamino, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolidinyl, azetidinyl and diazepinyl, R 2< is selected from 4-pyridinyl, 2-amino-5-pyrimidinyl, 3-pyridyl, quinolin-3-yl, 5-pyrimidinyl, 2-acetylamino-5-pyridyl, 2-amino-4-methylpyrimidin-5-yl, 1-piperazinyl, indol-5-yl, 1H-imdazol-5-yl, 4-aminophenyl, 1,2,3,6-tetrahydropyridin-4-yl, 1H-pyrazol-4-yl, N-methyl-pyrazol-4-yl, 1H-benzo[d]imidazol-5-yl, 4-sulfonylaminophenyl, 2-dimethylaminopyrimidin-5-yl, 3-trifluoromethylphenyl, bromo, 3-aminophenyl, 4-aminophenyl, vinyl, 4-aminocarbonylphenyl, 3-cyanophenyl, 3-hydroxyphenyl, 3-trifluoromethyl-5-pyridyl, tetrazolyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-aminocarbonylphenyl, 3-acetylphenyl, 3-cyano-4-chlorophenyl, 3-cyano-5-methylphenyl, 3-hydroxy-4-chlorophenyl, 4-hydroxymethylphenyl, 3-amino-4-chlorophenyl, 2,3-dihydrobenzofuran-6-yl, 1-methyl-1H-indol-5-yl, benzo[d][1,3]dioxo-5-yl, 4-fluorophenyl, 4-hydroxyphenyl, morpholin-1-yl, benzo[b]thiophen-1-yl, 4-methylsulfonylphenyl, benzo[c][1,2,5]oxadiazol-5-yl, 2-(piperidin-1-yl)-3-pyridinyl, 4-carboxyphenyl, 2-methyl-5-pyridyl, 4-methylsulfonylphenyl, 4-dimethylaminocarbonylphenyl, 4-phenylphenyl, 4-methylphenyl, 3-chloro-5-pyridyl, (3-pyrrolidin-1-yl)phenyl, 4-([piperizin-1-yl]carbonyl)phenyl, 4-([morpholin-1-yl]carbonyl)phenyl, 2-hydroxypyrimidin-5-yl, 3-aminosulfonylphenyl, 2-oxo-1,2,3,4,tetrahydroisoquinolin-6-yl, 2-oxo-1,2,3,4,-tetrahydroquinolin-6-yl, 4-(methylaminocarbonyl)phenyl, 1-oxoindolin-5-yl, 2-oxoindolin-5-yl, 1-oxoisoindolin-5-yl, 2-amino-4-pyridyl, 3-amino-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 4-aminophenyl, 3-methylphenyl, 3-methoxyphenyl, phenyl, 5-indolinonyl, 5-isoindolinonyl, 3-aminophenyl, 2-hydroxy-4-chlorophenyl, 4-cyanophenyl, 4-azetidinylphenyl, 4-ethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-cyano-4-fluorophenyl, 3-amino-4-fluorophenyl, 4-(1-hydroxy-1-ethyl)phenyl, 3-methyl-5-pyridyl, 2-acetylamio-5-pyridyl, 2-oxoindolin-5-yl, benzimidazolin-5-yl, 3-dimethylamino-1-propargyl, 2-pyrrolyl, N-methyl-2-pyrrolyl, 2-thiopheneyl, 3-thiopheneyl, 3-furanyl, and 3-aminosulfonylphenyl, R 3< and R 4< are independently selected from hydrogen, hydroxyl, OR 5< , halogen, optionally substituted C 6-10 aryl, and optionally substituted C 1-6 alkyl, R 5< is hydrogen, C 1-12 alkyl, C 6-10 aryl, halogen, hydroxyl, or OR 16< , R 6< is hydrogen, C 1-12 alkyl, C 2-12 hydroxyalkyl, C 1-6 acyl-C 1-6 alkyl, or C 6-10 aryl, R 7< -R 10< are independently selected from hydrogen, C 1-12 alkyl, C 3-8 cycloalkyl, CH 2 COOR 13< , and H 2 N(CH 2 ) n - wherein n is an integer of 2-6, R 11< and R 12< selected from the group consisting of hydrogen, C 1-12 alkyl and C 3-10 cycloalkyl or, taken together with the N to which they are bound, form an optionally substituted 4-7 membered heterocyclyl ring containing O or N atoms, and R 13< is C 1-12 alkyl, R 15< is hydrogen or C 1-12 alkyl, R 16< is C 1-12 alkyl or C 6-10 aryl or a pharmaceutically acceptable salt thereof,

[0012] In any of the above embodiments, B is CR 3< =CR 4< .

[0013] In certain embodiments, R 1< is C 6-10 aryl substituted with -CN.

[0014] In certain of these embodiments, R 2< is selected from 4-chlorophenyl, 4-dimethylaminomethylphenyl, 4-diethylaminomethylphenyl, 2-amino-4-pyridyl, 2-amino-5-pyridyl, and 4-fluorophenyl.

[0015] In certain of these embodiments, R 1< is selected from 3-cyanomethylphenyl, 3-cyano-6-methylphenyl, 3-cyano-4-morpholinylphenyl, 3-cyano-2-methylphenyl, 3-cyano-4-piperazinyl-6-methylphenyl, and 3-cyano-4-piperazinylmethylphenyl.

[0016] In certain embodiments, R 1< is C 6-10 aryl substituted with -SO 2 R 13< .

[0017] In certain of these embodiments, R 2< is selected from 4-chlorophenyl, 3-hydroxy-4-chlorophenyl, 3-amino-4-chlorophenyl, 4-fluorophenyl, 4-dimethylaminomethylphenyl, 4-aminomethylphenyl, 3-methyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 3-cyano-4-chlorophenyl, and 4-pyrrolidinomethylphenyl.

[0018] In certain of these embodiments, R 1< is selected from 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 2-methyl-4-methylsulfonylphenyl, and 3-piperazinylmethyl-4-methylsulfonylphenyl.

[0019] In certain particular embodiments, the compound is selected from:

[0020] In certain embodiments, R 1< is C 6-10 aryl substituted with -SO 2 NH 2 .

[0021] In certain of these embodiments, R 2< is 4-chlorophenyl or 2-amino-5-pyridiyl.

[0022] In certain of these embodiments, R 1< is 4-aminosulfonylphenyl or 3-aminosulfonylphenyl.

[0023] In certain embodiments, R 1< is C 6-10 aryl substituted with -CONR 11< R 12< .

[0024] In certain of these embodiments, R 2< is selected from 4-chlorophenyl, 4-fluorophenyl, 4-dimethylaminomethylphenyl, 4-aminomethylphenyl, 3-amino-4-chlorophenyl, 3-hydroxy-4-chlorophenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-hydroxymethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-cyanophenyl, phenyl, 5-indolinonyl, 3-hydroxyphenyl, 5-isoindolinonyl, 3-aminophenyl, 2-hydroxy-4-chlorophenyl, 3-cyano-4-chlorophenyl, 4-cyanophenyl, 4-(2-aminoethyl)phenyl, 4-(2-dimethylaminoethyl)phenyl, 4-azetidinylphenyl, 4-ethylphenyl, 2-amino-5-pyridyl, and 4-(1-aminocycloprop-1-yl)phenyl.

[0025] In certain of these embodiments, R 1< is selected from 4-methylcarbonylaminophenyl, 4-morpholinocarbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-(3,5-dimethylaminomorpholino)carbonylphenyl, 4-(4-methylpiperazinyl)carbonylphenyl, 4-piperazinylcarbonylphenyl, 4-piperidinylcarbonylphenyl, 4-[N,N-bis(2-hydroxyethyl]carbonylphenyl, 4-cyclopentylaminocarbonylphenyl, 4-azetidinylcarbonylphenyl, 4-(4-hydroxyethylpiperazinyl)carbonylphenyl, 2-methyl-4-methylaminocarbonylphenyl, 3-chloro-4-methylaminocarbonylphenyl, 4-cyclopropylaminocarbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)carbonylphenyl, 4-1-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)carbonylphenyl, 1-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonylphenyl, 1-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)carbonylphenyl, 4-(N-cyclopropyl-N-cyclohexylamino)carbonylphenyl, 4-(N-methyl-N-cyclopropylamino)carbonylphenyl, 4-cyclobutylaminocarbonylphenyl, 2trifluoroethylaminocarbonylphenyl, 4-(2-dimethylaminoethylaminocarbonyl)phenyl, 4-(4-[2-dimethylaminoethyl]piperazin-1-yl-carbonyl)phenyl, 4-cyclopropylaminocarbonylphenyl 4-(1-[2-dimethylaminoethyl]piperidin-4-amino)carbonylphenyl, 4-(N-(1-(2-hydroxyethyl)azetidin-3-ylamino)carbonylphenyl, 4-(pyrrolidinyl-3-amino)carbonylphenyl.

[0026] In certain particular embodiments, the compound is selected from:

[0027] In certain embodiments, R 1< is a aryl bicyclic lactam of the formula:

[0028] In certain of these embodiments, R 7< , R 8< , R 9< , and R 10< are hydrogen, C 1-12 alkyl, or H 2 N(CH 2 ) n - wherein n is an integer of 2-6.

[0029] In certain of these embodiments, R 2< is selected from 4-chlorophenyl, 4-dimethylaminomethylphenyl, 4-diethylaminomethylphenyl, 4-fluorophenyl, 2-amino-5-pyridyl, and 4-(1-aminocycloprop-1-yl)phenyl.

[0030] In certain particular embodiments, the compound is selected from: Chemistry

[0031] The compounds of the invention can be synthesized using any suitable route. In an embodiment, the compounds of formula (I) wherein A is CH and B is CR 3< =CR 4< can be synthesized by the route shown in Scheme 1.

[0032] A substituted 4-amino-6-bromoquinoline-3-carbaldehyde 1 can be reacted with an acetyl chloride in the presence of a base such as diethylaminopropylamine in a solvent such as tetrahydrofuran, optionally under microwave irradiation, to give a 9-bromobenzo[h][1,6]naphthyridin-2(1H)-one 1'. Suzuki coupling of 1' with an arylboronic acid R 1< B(OR") 2 in the presence of a catalyst such as Pd(Ph 3 P) 4 and a base such as NaHCO 3 in a solvent such as DMF / water under microwave irradiation gives the desired compound 2.

[0033] In an embodiment, a compound of formula (I) wherein A is CH and B is NR 6< can be synthesized by the route shown in Scheme 2. Reagents and conditions. (i) 150 °C, 1,4-dioxanes; (ii) SnCl 2 , 65 °C, 3.5 h; (iii) ClCO 2 CCl 3 , Et 3 N; (iv) Mel, NaH,THF

[0034] Reaction of a substituted aniline such as, for example, 3-trifluoromethylaniline with 6-bromo-4-chloro-3-nitroquinoline in a solvent such as 1,4-dioxane gives the substituted quinoline 17. Reduction of the nitro group with a reducing agent such as SnCl 2 gives the amino compound 18. Cyclization of compound 18 with a carbonylation reagent such as triphogene gives the substituted 8-bromo-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one 19. N-alkylation of compound 19 can be performed using an alkylating agent such as methyl iodide in the presence of a base such as NaH in a solvent such as tetrahydrofuran to give the N-alkylated compound 20. Suzuki coupling of compounds 19 and 20 gives 8-functionalized 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones.

[0035] The compounds of formula (II) can be prepared by the route shown in Scheme 3.

[0036] Reaction of 1-(6-bromo-4-hydroxyquinolin-3-yl)ethan-1-one 1 with substituted hydrazine 2 in a solvent such as acetic acid gives substituted 8-bromo-1H-pyrazolo[4,3-c]quinoline 3. Suzuki coupling of 3 with an arylboronic acid 4 in the presence of a catalyst such as Pd(Ph 3 P) 4 and a base such as NaHCO 3 in a solvent such as DMF / water under microwave irradiation gives the desired compound 5.

[0037] In an embodiment, the invention provides a method for the preparation of heteroaryl-fused imidazolidin-2-ones. In an embodiment, the method comprises the steps of (a) providing a compound of formula 100: wherein X 2< is F, Cl, Br, or I, V is CR 104< or N, W is CR 105< or N, Y is CR 106< or N, Z is CR 107< or N, wherein optionally Y and Z, wherein R 104< -R 107< are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or when Y is CR 106< and Z is CR 107< , R 106< and R 106< , taken together with the carbons to which they are bound, form a fused 5- to 8-membered carbocyclic, aryl, heterocyclyl, or heteroaryl ring, wherein the heterocyclyl contains one or more atoms selected from N, O, and S, wherein at least one of V, W, Y, and Z is N, wherein R 100< is alkyl or aryl, wherein R 101< is hydrogen, alkyl, or aryl, and (b) reacting the compound of formula 100 with an amine of the formula: R 102< NH 2 to give a compound of the formula 101: wherein R 102< is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heteroarylalkyl.

[0038] The method comprises mixing ortho-halo heteroaryl carbamates and a primary amine under conditions such that an imidazolidin-2-one ring is formed. In typical embodiments, an ortho-halo heteroaryl carbamate 100 reacts with a primary amine to give a heteroaryl-fused imidazolidin-2-one 101 as the product (Scheme 4). The reaction usually takes place in preferred acidic conditions under conventional heat or microwave heat. When a polycyclic ortho-halo heteroaryl carbamate 100' is used as the starting material, a polycyclic imidazolidin-2-one product 101' is formed (Scheme 5). The acid used here can be an organic or inorganic acid such as hydrochloric acid (HCl), nitric acid (HNO 3 ), phosphoric acid (H 3 PO 4 ), sulphuric acid (H 2 SO 4 ), boric acid (H 3 BO 3 ), hydrofluoric acid (HF), hydrobromic acid (HBr), perchloric acid (HClO 4 ), formic acid (HCOOH), acetic acid (CH 3 COOH), propanoic acid (CH 3 CH 2 COOH), and trifluoroacetic acid (TFA). The solvent used here can be a high boiling point solvent such as 2-pentanol, 3-pentanol, cyclohexanol, polyethylene glycol (PEG), 2-methyl-2-butanol, tert-butanol, MeCN, 1,2-dimethoxyethane (DME), 1,2-dichloroethane (DCE), 1,4-dioxane, toluene, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP), xylenes, dimethylsulfoxide (DMSO), o-dichlorobenezene (o-DCB) and ionic liquid. The reaction temperature is between 25° C to 250° C.

[0039] In an embodiment, the method is useful for the synthesis of compounds of formula (I) wherein B is NR 6< .

[0040] The synthesis of carbamate 104 and N-alkyl carbamate 105 can be accomplished as shown in Scheme 6. Reduction of nitro quinoline 102 wherein X 1< and X 2< are independently halo or OSO 2 R wherein R is alkyl, CF 3 , or optionally substituted aryl with a suitable reducing agent such as SnCl 2 or under catalytic hydrogenation conditions provides amino quinoline 103. Reaction of amino quinolone 103 with an alkyl or aryl chloroformate provides carbamate 104. Carbamate 104 can be alkylated, for example, using an alkyl halide or alkyl sulfonate in the presence of a base such as sodium hydride provides N-alkyl carbamate 105. Reagents and conditions: (a) SnCl 2 *H 2 O, AcOH, EtOH, rfx, 3 h, 64%; (b) CICOOiPr, pyr, DCM, rt, 4 h, 66%; (c) MeI, NaH, THF, rt, 18 h, 93%.

[0041] Reaction of N-alkyl carbamate 105 with an optionally substituted arylamine or alkylamine in a solvent such as 3-pentanol under microwave irradiation provides 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one 106 as shown in Scheme 7. 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one 106 reacts with aryl boronic acids R 103< B(OH) 2 under Suzuki coupling conditions in the presence of a catalyst such as Pd(PPh 3 ) 4 and a base such as K 3 PO 4 in a solvent or solvent mixture such as DMF / H 2 O / i-PrOH under microwave irradiation to give 8-arylated 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one 107.

[0042] Heteroaryl-fused imidazolidin-2-ones are important motifs in the biologically active compounds. For example, the dual PI3K / mTOR inhibitors, NVP-BEZ235 and NVP-BGT226, have both been studied in clinic trials for their potential as future anti-cancer agents. The synthesis of heteroaryl-fused imidazolidin-2-ones usually involves the reaction of phosgene or its derivatives with heteroaryl 1,2-diamines to form the cyclic urea rings. Alternatively, heteroaryl-fused imidazolidin-2-ones were prepared from their corresponding ortho-chloro heteroaryl amines via Pd-catalyzed Buchwald-Hartwig C-N bond formation followed by an intramolecular cyclization. These methods use either toxic phosgene derivatives or expensive transition-metal catalysts. A general, metal-free method using nontoxic reagents is desired for the synthesis of biologically interesting molecules containing polycyclic imidazolidin-2-ones.

[0043] NVP-BEZ235 and NVP-BGT226 have both been studied in clinical trials for their potential as future anti-cancer agents. The N-methyl i-Pr carbamate 110 could react satisfactorily with two equivalents of aniline 111 and three equivalents of HCl, subsequent one-pot coupling gave desired 112 (NVP-BEZ235) in 85% yield (Scheme 8). When Boc-protected CF 3 -substituted aniline 113 was used under optimal condition, the desired product 114 (NVP-BGT226) was obtained as a free base in 42% yield. Additionally, such transformation has been effected on a gram scale under conventional heating. N-methyl i-Pr carbamate 110 reacts with two equivalents of Boc-protected CF 3 -substituted aniline 113 and ten equivalents of HCl in high boiling point solvent such as N-Methyl-pyrrolidone (NMP), subsequent one-pot coupling furnished desired 114 (NVP-BGT226) in 77% yield (Scheme 8).

[0044] The described new method for the synthesis of heteroaryl-fused imidazolidin-2-ones can be applied to the construction of other pharmaceutically active molecules such as I-BET151 (GSK1210151A), a novel small molecule inhibitor of the BET family, which has been investigated substantially in preclinical models for the treatment of mixed lineage leukemia (MLL). Telcagepant, also known as MK0974, is an orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist under development for the acute treatment and prevention of migraine (Scheme 9).

[0045] In accordance with an embodiment of the invention, any of the compounds or salts thereof can be administered in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

[0046] The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.

[0047] The choice of carrier will be determined in part by the particular active agent, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and are in no way limiting.

[0048] Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.

[0049] The compounds of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.

[0050] Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0051] Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.

[0052] The parenteral formulations typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multidose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0053] The compounds of the present invention may be made into injectable formulations. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

[0054] Additionally, the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0055] Suitable carriers and their formulations are further described in A.R. Gennaro, ed., Remington: The Science and Practice of Pharmacy (19th ed.), Mack Publishing Company, Easton, PA (1995).

[0056] The compound of the invention or a composition thereof can be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases, such as mono-, di-, trialkyl, and aryl amines and substituted ethanolamines. The conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent. The mixture is maintained at a suitable temperature (e.g., between 0 °C and 50 °C). The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.

[0057] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0058] It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

[0059] It is further understood that the above compounds and salts may form solvates, or exist in a substantially uncomplexed form, such as the anhydrous form. As used herein, the term "solvate" refers to a molecular complex wherein the solvent molecule, such as the crystallizing solvent, is incorporated into the crystal lattice. When the solvent incorporated in the solvate is water, the molecular complex is called a hydrate. Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrilates and the like. These compounds can also exist in polymorphic forms.

[0060] In an embodiment, the invention provides a method of blocking transmission of a Plasmodium parasite comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the invention. In another embodiment, the invention provides a method of treating malaria by killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in a gametocyte stage, the method comprising administering to a mammal a therapeutically effective amount of a compound of the invention.

[0061] The Plasmodium parasite can be any suitable Plasmodium parasite. Non-limiting examples of suitable Plasmodium parasites include Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. In a preferred embodiment, the Plasmodium parasite is Plasmodium falciparum.

[0062] In an embodiment, the Plasmodium parasite is a Plasmodium gametocyte.

[0063] In embodiments, the Plasmodium gametocyte is a mature stage II-V gametocyte. In a preferred embodiment, the Plasmodium gametocyte is a stage III-V gametocyte, e.g., a mature stage III-V gametocyte. In another preferred embodiment, the Plasmodium gametocyte is a mature stage V gametocyte.

[0064] In certain preferred embodiments, the compound effectively kills Plasmodium gametocytes.

[0065] In embodiments, the Plasmodium parasite is a drug-resistant strain. Examples of drug-resistant strains of Plasmodium are described in Kun, J.F.J. et al., Antimicrob Agents Chemother., 1999 September; 43(9): 2205-2208, and references cited therein.

[0066] In embodiments, the Plasmodium parasite is in an asexual stage. For example, the Plasmodium parasite can be a sporozoite, a liver stage parasite, a merozoite, an asexual erythrocyte-stage parasite, a zygote, an ookinete, or an oocyst.

[0067] The amount or dose of a compound of the invention or a salt thereof, or a composition thereof should be sufficient to effect a therapeutic or prophylactic response in the mammal. The appropriate dose will depend upon several factors. For instance, the dose also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular compound or salt. Ultimately, the attending physician will decide the dosage of the compound of the present invention with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compound or salt to be administered, route of administration, and the severity of the condition being treated. By way of example and not intending to limit the invention, the dose of the compound(s) described herein can be about 0.1 mg to about 1 g daily, for example, about 5 mg to about 500 mg daily. Further examples of doses include but are not limited to: 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.6 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 17 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 140 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg / kg body weight per day.

[0068] In certain embodiments, the method further comprises administering to the mammal at least one additional antimalarial compound. Any suitable antimalarial compound can be used, many of which are well known in the art. Non-limiting examples of suitable antimalarial compounds include primaquine, bulaquine, artemisinin and derivatives thereof, chloroquine, mefloquine, amodiaquine, piperaquine, pyronaridine, atovaquone, tafenoquine, methylene blue, trioxaquines, endoperoxides such as OZ 439 and OZ 277, decoquinate, 9-anilinoacridines, HIV-protease inhibitors, and natural products such as neem, epoxomicin, harmonine, and riboflavin. In certain preferred embodiments, the compound of the invention is administered in combination with elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, panobinostat, or any combination thereof.Illustrative Examples of Embodiments

[0069] The present application further refers to the following aspects: 1. A compound of formula (I): wherein A is CR 5< or N, B is CR 3< =CR 4< or NR 6< , R 1< is C 6-10 aryl or heteroaryl substituted with at least one substituent selected from -CN, cyanomethyl, -SO 2 R 13< , -SO 2 NHR 15< , and -CONR 11< R 12< , optionally further in combination with one or more substituents selected from halo, C 1-12 alkyl, alkoxy, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolinidyl, and diazepinyl, or an aryl bicyclic lactam of the formula: wherein the aryl group of the aryl bicyclic lactam is optionally substituted with at least one substituent selected from -CN, cyanomethyl, -SO 2 R 13< , -SO 2 NH 2 , and -CONR 11< R 12< , optionally further in combination with one or more substituents selected from halo, C 1-12 alkyl, alkoxy, 2-(dimethylamino)ethyl)amino, dimethylamino, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolinidyl, azetidinyl and diazepinyl, R 2< is selected from 2-amino-5-pyridinyl, 4-pyridinyl, 2-amino-5-pyrimidinyl, 3-pyridyl, quinolin-3-yl, 5-pyrimidinyl, 2-acetylamino-5-pyridyl, 2-amino-4-methylpyrimidin-5-yl, 1-piperazinyl, indol-5-yl, 1H-imdazol-5-yl, 4-aminophenyl, 1,2,3,6-tetrahydropyridin-4-yl, 1H-pyrazol-4-yl, N-methyl-pyrazol-4-yl, 1H-benzo[d]imidazol-5-yl, 4-sulfonylaminophenyl, 2-dimethylaminopyrimidin-5-yl, 3-trifluoromethylphenyl, bromo, 3-aminophenyl, 4-aminophenyl, vinyl, 4-aminocarbonylphenyl, 3-cyanophenyl, 3-hydroxyphenyl, 3-trifluoromethyl-5-pyridyl, tetrazolyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-aminocarbonylphenyl, 3-acetylphenyl, 3-cyano-4-chlorophenyl, 3-cyano-5-methylphenyl, 3-hydroxy-4-chlorophenyl, 4-hydroxymethylphenyl, 3-amino-4-chlorophenyl, 2,3-dihydrobenzofuran-6-yl, 1-methyl-1H-indol-5-yl, benzo[d][1,3]dioxo-5-yl, 4-fluorophenyl, 4-hydroxyphenyl, morpholin-1-yl, benzo[b]thiophen-1-yl, 4-methylsulfonylphenyl, benzo[c][1,2,5]oxadiazol-5-yl, 2-(piperidin-1-yl)-3-pyridinyl, 4-carboxyphenyl, 2-methyl-5-pyridyl, 4-methylsulfonylphenyl, 4-dimethylaminocarbonylphenyl, 4-phenylphenyl, 4-methylphenyl, 3-chloro-5-pyridyl, (3-pyrrolidin-1-yl)phenyl, 4-([piperizin-1-yl]carbonyl)phenyl, 4-([morpholin-1-yl]carbonyl)phenyl, 2-hydroxypyrimidin-5-yl, 3-aminosulfonylphenyl, 2-oxo-1,2,3,4,tetrahydroisoquinolin-6-yl, 2-oxo-1,2,3,4,-tetrahydroquinolin-6-yl, 4-(aminomethyl)phenyl, 4-(dimethylaminomethyl)phenyl, 4-(diethylaminomethyl)phenyl, 4-(methylaminocarbonyl)phenyl, 1-oxoindolin-5-yl, 2-oxoindolin-5-yl, 1-oxoisoindolin-5-yl, 2-amino-4-pyridyl, 3-amino-4-chlorophenyl, 4-aminomethylphenyl, 3-methyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 4-aminophenyl, 3-methylphenyl, 3-methoxyphenyl, phenyl, 5-indolinonyl, 5-isoindolinonyl, 3-aminophenyl, 2-hydroxy-4-chlorophenyl, 4-cyanophenyl, 4-(2-aminoethyl) phenyl, 4-(2-dimethylaminoethyl) phenyl, 4-azetidinylphenyl, 4-ethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-dimethylaminomethylphenyl, 3-cyano-4-fluorophenyl, 3-amino-4-fluorophenyl, 4-(1-hydroxy-1-ethyl)phenyl, 3-methyl-5-pyridyl, 2-acetylamio-5-pyridyl, 2-oxoindolin-5-yl, benzimidazolin-5-yl, 3-dimethylamino-1-propargyl, 2-pyrrolyl, N-methyl-2-pyrrolyl, 2-thiopheneyl, 3-thiopheneyl, 3-furanyl, 3-aminosulfonylphenyl, 4-dimethylaminomethylphenyl, and 4-pyrrolidinomethylphenyl, R 3< and R 4< are independently selected from hydrogen, hydroxyl, OR 5< , halogen, optionally substituted C 6-10 aryl, and optionally substituted C 1-6 alkyl, R 5< is hydrogen, C 1-12 alkyl, C 6-10 aryl, halogen, hydroxyl, or OR 16< , R 6< is hydrogen, C 1-12 alkyl, C 2-12 hydroxyalkyl, C 1-6 acyl-C 1-6 alkyl, or C 6-10 aryl, R 7< -R 10< are independently selected from hydrogen, C 1-12 alkyl, C 3-8 cycloalkyl, CH 2 COOR 13< , and H 2 N(CH 2 ) n - wherein n is an integer of 2-6, R 11< and R 12< selected from the group consisting of hydrogen, C 1-12 alkyl and C 3-10 cycloalkyl or, taken together with the N to which they are bound, form an optionally substituted 4-7 membered heterocyclyl ring containing O or N atoms, and R 13< is C 1-12 alkyl, R 15< is hydrogen or C 1-12 alkyl, R 16< is C 1-12 alkyl, C 1-6 acyl, or C 6-10 aryl, or a pharmaceutically acceptable salt thereof, with the provisos that when A is CH, B is CR 3< =CR 4< , R 3< and R 4< are each hydrogen, and R 2< is 2-amino-5-pyridyl, R 1< is not 3-cyanophenyl or 3-aminosulfonylphenyl. 2. The compound or salt of embodiment 1, wherein A is CR 5< . 3. The compound or salt of embodiment 2, wherein B is CR 3< =CR 4< . 4. The compound or salt of embodiment 3, wherein R 1< is C 6-10 aryl substituted with -CN. 5. The compound or salt of embodiment 4, wherein R 2< is selected from 4-chlorophenyl, 4-dimethylaminomethylphenyl, 4-diethylaminomethylphenyl, 2-amino-4-pyridyl, 2-amino-5-pyridyl, and 4-fluorophenyl. 6. The compound or salt of embodiment 4 or 5, wherein R 1< is selected from 3-cyanomethylphenyl, 3-cyano-6-methylphenyl, 3-cyano-4-morpholinylphenyl, 3-cyano-2-methylphenyl, 3-cyano-4-piperazinyl-6-methylphenyl, and 3-cyano-4-piperazinylmethylphenyl. 7. The compound or salt of any one of embodiments 3-6, wherein the compound is selected from: and 8. The compound or salt of embodiment 3, wherein R 1< is C 6-10 aryl substituted with -SO 2 R 13< . 9. The compound or salt of embodiment 8, wherein R 2< is selected from 4-chlorophenyl, 3-hydroxy-4-chlorophenyl, 3-amino-4-chlorophenyl, 4-fluorophenyl, 4-dimethylaminomethylphenyl, 4-aminomethylphenyl, 3-methyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 3-cyano-4-chlorophenyl, and 4-pyrrolidinomethylphenyl. 10. The compound or salt of embodiment 8 or 9, wherein R 1< is selected from 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 2-methyl-4-methylsulfonylphenyl, and 3-piperazinylmethyl-4-methylsulfonylphenyl. 11. The compound or salt of any one of embodiments 8-10, wherein the compound is selected from: 12. The compound or salt of embodiment 3, wherein R 1< is C 6-10 aryl substituted with -SO 2 NH 2 . 13. The compound or salt of embodiment 12, wherein R 2< is 4-chlorophenyl or 2-amino-5-pyridiyl. 14. The compound or salt of embodiment 12 or 13, wherein R 1< is 4-aminosulfonylphenyl or 3-aminosulfonylphenyl. 15. The compound or salt of embodiment 3, wherein R 1< is C 6-10 aryl substituted with -CONR 11< R 12< . 16. The compound or salt of embodiment 15, wherein R 2< is selected from 4-chlorophenyl, 4-fluorophenyl, 4-dimethylaminomethylphenyl, 4-aminomethylphenyl, 3-amino-4-chlorophenyl, 3-hydroxy-4-chlorophenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-hydroxymethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-cyanophenyl, phenyl, 5-indolinonyl, 3-hydroxyphenyl, 5-isoindolinonyl, 3-aminophenyl, 2-hydroxy-4-chlorophenyl, 3-cyano-4-chlorophenyl, 4-cyanophenyl, 4-(2-aminoethyl)phenyl, 4-(2-dimethylaminoethyl)phenyl, 4-azetidinylphenyl, 4-ethylphenyl, 2-amino-5-pyridyl, and 4-(1-aminocycloprop-1-yl)phenyl. 17. The compound or salt of embodiment 15 or 16, wherein R 1< is selected from 4-methylcarbonylaminophenyl, 4-morpholinocarbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-(3,5-dimethylaminomorpholino)carbonylphenyl, 4-(4-methylpiperazinyl)carbonylphenyl, 4-piperazinylcarbonylphenyl, 4-piperidinylcarbonylphenyl, 4-[N,N-bis(2-hydroxyethyl]carbonylphenyl, 4-cyclopentylaminocarbonylphenyl, 4-azetidinylcarbonylphenyl, 4-(4-hydroxyethylpiperazinyl)carbonylphenyl, 2-methyl-4-methylaminocarbonylphenyl, 3-chloro-4-methylaminocarbonylphenyl, 4-cyclopropylaminocarbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)carbonylphenyl, 4-1-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)carbonylphenyl, 1-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonylphenyl, 1-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)carbonylphenyl, 4-(N-cyclopropyl-N-cyclohexylamino)carbonylphenyl, 4-(N-methyl-N-cyclopropylamino)carbonylphenyl, 4-cyclobutylaminocarbonylphenyl, 2trifluoroethylaminocarbonylphenyl, 4-(2-dimethylaminoethylaminocarbonyl)phenyl, 4-(4-[2-dimethylaminoethyl]piperazin-1-yl-carbonyl)phenyl, 4-cyclopropylaminocarbonylphenyl 4-(1-[2-dimethylaminoethyl]piperidin-4-amino)carbonylphenyl, 4-(N-(1-(2-hydroxyethyl)azetidin-3-ylamino)carbonylphenyl, 4-(pyrrolidinyl-3-amino)carbonylphenyl. 18. The compound or salt of any one of embodiments 15-17, wherein the compound is selected from: and 19. The compound or salt of embodiment 3, wherein R 1< is a aryl bicyclic lactam of the formula: 20. The compound or salt of embodiment 19, wherein R 7< , R 8< , R 9< , and R 10< are hydrogen, C 1-12 alkyl, or H 2 N(CH 2 ) n - wherein n is an integer of 2-6. 21. The compound or salt of embodiment 19 or 20, wherein R 2< is selected from 4-chlorophenyl, 4-dimethylaminomethylphenyl, 4-diethylaminomethylphenyl, 4-fluorophenyl, 2-amino-5-pyridyl, and 4-(1-aminocycloprop-1-yl)phenyl. 22. The compound or salt of any one of embodiments 19-21, wherein the compound is selected from: 23. The compound or salt of embodiment 3, wherein B is NR 6< . 24. The compound or salt of embodiment 23, wherein R 1< is C 6-10 aryl substituted with -CN. 25. The compound or salt of embodiment 24, wherein R 6< is hydrogen or methyl. 26. The compound or salt of embodiment 24 or 25, wherein R 2< is selected from 4-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxy-4-chlorophenyl, 3-aminophenyl, 3-methylphenyl, 3-dimethylaminomethylphenyl, 3-cyano-4-fluorophenyl, 3-hydroxy-4-fluorophenyl, 3-methoxy-4-fluorophenyl, 3-cyano-4-chlorophenyl, 3-hydroxy-4-chlorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-hydroxyphenyl, 3-amino-4-fluorophenyl, 4-dimethylaminophenyl, 3-cyanophenyl, 4-methylphenyl, 4-aminophenyl, 4-(1-hydroxy-1-ethyl)phenyl, 4-(2-aminoethyl)phenyl, 2-amino-5-pyridyl, 2-amino-5-pyrimidyl, 2-methyl-5-pyridyl, 2-acetylamino -5-pyridyl, 2-oxoindolin-5-yl, benzimidazolin-5-yl, 3-dimethylamino-1-propargyl, 4-(2-dimethylaminoethyl)phenyl, 2-pyrrolyl, N-methyl-2-pyrrolyl, 2-thiopheneyl, 3-thiopheneyl, 3-furanyl, 3-aminosulfonylphenyl, and 4-dimethylaminomethylphenyl. 27. The compound or salt of any one of embodiments 24-26, wherein R 1< is selected from 3-cyano-6-methyl phenyl, 3-cyano-4-piperazinyl-6-methylphenyl, 3-cyanophenyl, 3-cyano-4-piperazinylphenyl, 3-cyano-4-morpholinylphenyl, 4-(4-(2-hydroxyethylpiperazinyl-3-cyanophenyl, 3-cyano-4-(1,4-diazepan-1-yl)phenyl, 3-cyano-4-(4-acetylaminopiperazin-1-yl), 2-methyl-3-cyanophenyl, 3-cyano-4-(3-aminoazetidinyl)-6-methylphenyl, 3-cyano-4-(2-dimethylaminoethyl)-6-methylphenyl, 2-piperazinyl-3-cyano-6-methyl-5-pyridyl, 2-piperazinyl-3-cyano-5-pyridyl, 3-cyano-4-methoxyphenyl, 3-cyano-4-(4-hydroxypiperidinyl)phenyl, 3-cyano-4-(4-aminopiperidinyl)phenyl, and 2-methyl-3-cyanophenyl. 28. The compound or salt of any one of embodiments 24-27, wherein the compound is selected from: and 29. The compound or salt of embodiment 23, wherein R 1< is C 6-10 aryl substituted with -SO 2 R 13< . 30. The compound or salt of embodiment 29, wherein R 2< is 2-amino-5-pyridyl or 4-chlorophenyl. 31. The compound or salt of embodiment 29 or 30 wherein R 1< is 4-aminosulfonylphenyl. 32. The compound or salt of any one of embodiments 29-31, wherein the compound is: 33. The compound or salt of embodiment 23, wherein R 1< is C 6-10 aryl substituted with -CONR 11< R 12< . 34. The compound or salt of embodiment 33, wherein R 2< is selected from 4-chlorophenyl, 2-amino-5-pyridyl, 3-hydroxy-4-chlorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-dimethylaminomethylphenyl, and 4-methylphenyl. 35. The compound or salt of embodiment 33 or 34, wherein R 1< is 4-morpholinocarbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-(N-methyl-N-cyclopropyl)aminocarbonylphenyl, or 4-piperidinocarbonylphenyl. 36. The compound or salt of any one of embodiments 33-35, wherein the compound is selected from: and 37. The compound or salt of embodiment 23, wherein R 1< is: 38. The compound or salt of embodiment 37, wherein R 2< is 4-chlorophenyl or 4-dimethylaminophenyl. 39. The compound or salt of embodiment 38, wherein R 1< is or 40. A pharmaceutical composition comprising a compound or salt of any one of embodiments 1-39 and a pharmaceutically acceptable carrier. 41. A method of blocking transmission of a Plasmodium parasite comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a first compound of any one of embodiments 1-39, optionally in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 42. A method of treating malaria by killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in a gametocyte stage, the method comprising administering to a mammal a therapeutically effective amount of a first compound of any one of embodiments 1-39, optionally in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 43. A compound of any one of embodiments 1-39 for use in blocking transmission of a Plasmodium parasite in a mammal in need of therefore, optionally for use in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 44. A compound of any one of embodiments 1-39 for use in killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in a gametocyte stage, optionally for use in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 45. A compound of formula (II): wherein A is CR 5< or N, wherein R 1< is C 6-10 aryl or heteroaryl substituted with one or more substituents selected from the group consisting of C 1-12 alkyl, C 3-10 cycloalkyl, alkoxy, -CF 3 , heterocyclyl, -CONR 11< R 12< , -SO 2 NHR 16< , and CN, R 2< is selected from 2-amino-5-pyridinyl, 4-pyridinyl, 2-amino-5-pyrimidinyl, 3-pyridyl, quinolin-3-yl, 5-pyrimidinyl, 2-acetylamino-5-pyridyl, 2-amino-4-methylpyrimidin-5-yl, 1-piperazinyl, indol-5-yl, 1H-indazol-5-yl, 4-aminophenyl, 1,2,3,6-tetrahydropyridin-4-yl, 1H-pyrazol-4-yl, 1H-benzo[d]imidazol-5-yl, 4-sulfonylaminophenyl, 2-dimethylaminopyrimidin-5-yl, 3-trifluoromethylphenyl, bromo, 3-aminophenyl, vinyl, 4-aminocarbonylphenyl, 3-cyanophenyl, 3-trifluoromethyl-5-pyridyl, tetrazolyl, 4-chlorophenyl, 4-methoxyphenyl, 3-aminocarbonylphenyl, 3-acetylphenyl, 2,3-dihydrobenzofuran-6-yl, 1-methyl-1H-indol-5-yl, benzo[d][1,3]dioxo-5-yl, 4-fluorophenyl, 4-hydroxyphenyl, morpholin-1-yl, benzo[b]thiophen-1-yl, 4-methylsulfonylphenyl, benzo[c][1,2,5]oxadiazol-5-yl, 2-(piperidin-1-yl)-3-pyridinyl, 4-carboxyphenyl, 2-methyl-5-pyridyl, 4-methylsulfonylphenyl, 4-dimethylaminocarbonylphenyl, 4-phenylphenyl, 4-methylphenyl, 3-chloro-5-pyridyl, (3-pyrrolidin-1-yl)phenyl, 4-([piperizin-1-yl]carbonyl)phenyl, 4-([morpholin-1-yl]carbonyl)phenyl, 2-hydroxypyrimidin-5-yl, 3-aminosulfonylphenyl, 2-oxo-1,2,3,4,tetrahydroisoquinolin-6-yl, 2-oxo-1,2,3,4,-tetrahydroquinolin-6-yl, 4-(aminomethyl)phenyl, 4-(dimethylaminomethyl)phenyl, 4-(methylaminocarbonyl)phenyl, 1-oxoindolin-5-yl, 2-oxoindolin-5-yl, and 1-oxoisoindolin-5-yl, R 11< and R 12< selected from the group consisting of hydrogen, C 1-12 alkyl and C 3-10 cycloalkyl or, taken together with the N to which they are bound, form an optionally substituted 4-7 membered heterocyclyl ring containing O or N atoms, R 14< is hydrogen or C 1-12 alkyl, and R 16< is hydrogen or C 1-12 alkyl, or a pharmaceutically acceptable salt thereof. 46. The compound or salt of embodiment 45, wherein R 14< is methyl. 47. The compound or salt of embodiment 45 or 46, wherein R 2< is 2-amino-5-pyridyl or 4-chlorophenyl. 48. The compound or salt of any one of embodiments 45-47, wherein R 1< is selected from 3-trifluoromethylphenyl, 4-methylphenyl, 3-cyanophenyl, 3-pyridyl, 4-pyrrolidinylcarbonylphenyl, 4-cyclopropylaminocarbonylphenyl, 4-(3-dimethylaminopropylaminocarbonyl)phenyl, and 3-trifluoromethyl-4-morpholinocarbonylphenyl. 49. A pharmaceutical composition comprising a compound or salt of any one of embodiments 45-48 and a pharmaceutically acceptable carrier. 50. A method of blocking transmission of a Plasmodium parasite comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a first compound of any one of embodiments 45-48, optionally in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 51. A method of treating malaria by killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in a gametocyte stage, the method comprising administering to a mammal a therapeutically effective amount of a first compound of any one of embodiments 45-48 and / or a second compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 52. A compound of any one of embodiments 45-48 for use in blocking transmission of a Plasmodium parasite in a mammal in need of therefore, optionally for use in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 53. A compound of any one of embodiments 45-48 for use in killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in a gametocyte stage, optionally for use in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 54. A method of synthesizing a compound of formula 101, comprising the steps of: (a) providing a compound of formula 100: wherein X 2< is F, Cl, Br, or I, V is CR 104< or N, W is CR 105< or N, Y is CR 106< or N, Z is CR 107< or N, wherein optionally Y and Z, wherein R 104< -R 107< are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or when Y is CR 106< and Z is CR 107< , R 106< and R 106< , taken together with the carbons to which they are bound, form an optionally substituted fused 5- to 8-membered carbocyclic, aryl, heterocyclyl, or heteroaryl ring, wherein the heterocyclyl contains one or more atoms selected from N, O, and S, wherein at least one of V, W, Y, and Z is N, wherein R 100< is alkyl or aryl, and wherein R 101< is hydrogen, alkyl, or aryl, (b) reacting the compound of formula 100 with an amine of the formula: R 102< NH 2 to give a compound of the formula 101: wherein R 102< is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heteroarylalkyl. 55. The method of embodiment 54, wherein the reacting step (b) is conducted in the presence of an acid. 56. The method of embodiment 55, wherein the acid is selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid, formic acid, acetic acid, propanoic acid, and trifluoroacetic acid. 57. The method of any one of embodiments 54-56, wherein the reacting is conducted in an aliphatic alcohol solvent.

[0070] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.Materials and Methods

[0071] Cell culture. Asexual parasites of P. falciparum strain 3D7 were cultured as described previously [Trager W, et al., Journal of Parasitology 2005, 91: 484-486]. Stage III-V gametocytes were selected and enriched with 3-day treatment with 50 mM N-acetylglucosamine (NAG) and the following Percoll density gradient centrifugation after gametocyte production [Tanaka TQ, et al., Molecular and Biochemical Parasitology, 2011, 177: 160-163]. Gametocytes of HB3 and Dd2 strains were produced and then set up for assay in a similar process. HepG2 cells (ATCC, cat. no. 77400) were cultured in 175-cm 2< tissue culture flasks with 30 ml growth medium at 37 °C in a 5% CO 2 humidified atmosphere. Growth medium was made with Dulbecco's Modified Eagle Medium with 10% fetal bovine serum (FBS). Growth medium was replaced every other day and cells were passed at 75% confluence.

[0072] Compound library and gametocyte assay screen. The approved drug library was collected with 4,265 compounds from traditional chemical suppliers, specialty collections, pharmacies and custom synthesis [Huang R et al., Science Translational Medicine, 2011, 3: 80ps16] that included 49% drugs approved for human or animal use by the US Food and Drug Administration (FDA), 23% approved in Canada / UK / EU / Japan, and the remaining 28% either in clinical trials or research tool compounds. The Malaria Box contained 400 drugs or tool compounds with the confirmed activities on blood-staged P. falciparum and assessed cytotoxicity against mammalian cells [Gamo FJ et al., Nature, 2010 465: 305-U356; Guiguemde WA et al., Nature, 2010, 465: 311-315]. The MIPE library was an internal collection of 550 kinase inhibitors, which contain approved drugs and drug candidates in preclinical and clinical stages [Mathews LA et al., Journal of Biomolecular Screening, 2012, 17: 1231-1242]. Compounds from all libraries were obtained as powder samples and dissolved in DMSO as 10 mM stock solutions, except several hundreds from the approved drug library that were prepared as 4.47 mM stock solutions due to solubility limitations.

[0073] Compound screening experiments were performed as previously described [Tanaka TQ et al., Molecular and Biochemical Parasitology, 2013, 3188: 20-25]. Briefly, 2.5 µl / well incomplete medium was dispensed into each well of 1,536-well plates using the Multidrop Combi followed by 23 nl compound transferring using the NX-TR Pintool (WAKO Scientific Solutions, San Diego, CA). 2.5 µl / well of gametocytes was dispensed with a seeding density of 20,000 cells / well using the Multidrop Combi. The assay plates were incubated for 72 h at 37 °C with 5% CO 2 . After addition of 5 µl / well of 2X AlamarBlue dye (Life Technologies, cat. no. DAL1100), the plates were incubated for 24 h at 37 °C with 5% CO 2 and were read in a fluorescence detection mode (Ex = 525 nm, Em = 598 nm) on a ViewLux plate reader (PerkinElmer).

[0074] Small molecule pull-down. Affinity matrix: To make a bead-connected affinity probe of Torin 2, a tetraethylene glycol linker was attached to 1-(piperazin-1-yl)propan-1-one of HWW030 and then coupled to Affi-Gel 10 resin (Bio-Rad Laboratories, cat. no. 153-6046) under mild basic conditions to afford Torin 2 matrix (T2M). See detailed version in Example 7. Torin 1 was similarly immobilized to resin and used as a negative control (T1M). The resultant affinities probes were incubated with gametocyte lysates, the bound proteins were eluted from resin by boiling in SDS-PAGE sample loading buffer. The eluted fractions were separated by SDS-PAGE and visualized by silver staining. RBC infected with gametocytes (3D7 strain: Stage III-V) were washed 3 times with PBS and then lysed by 0.05% saponin treatment in PBS for 5 min at room temperature. The prepared gametocytes were washed 3 times with PBS and frozen at -80° C. The affinity precipitation experiment was processed as previously described [Zhang Q et al., Proceedings of the National Academy of Sciences of the United States of America, 2007, 104: 7444-7448; Arastu-Kapur S et al., Nature Chemical Biology, 2008, 4: 203-213]. The frozen samples were lysed with homogenization buffer (60 mM glycerophosphate, 15 mM p-nitrophenyl phosphate, 25 mM MOPS (pH 7.2), 15 mM EGTA, 15 mM MgCl2, 1mM DTT, protease inhibitors (Roche Diagnostics, cat. no. 11836170001), and 0.5% Nonidet P-40). Cell lysates were centrifuged at 16,000 x g for 20 min at 4°C, and the supernatant was collected. Protein concentration in the supernatant was determined by using a BCA protein assay kit (Pierce Chemical, cat. no. 23225). The lysate (0.5 mg) was then added to the packed affinity matrix, and bead buffer (50 mM Tris HCl (pH 7.4), 5 mM NaF, 250 mM NaCl, 5 mM EDTA, 5 mM EGTA, protease inhibitors, and 0.1% Nonidet P-40) was added to a final volume of 1 ml. After rotating at 4°C for 2 h, the mixture was centrifuged at 16,000 x g for 2 min at 4°C, and the supernatant was removed. The affinity matrix was then washed (six times) with cold bead buffer and eluted by boiling with SDS-PAGE sample loading buffer at 95°C for 5 min. Supernatants were separated on a 10% Bis-Tris gel (Life Technologies, cat. no. NP0315BOX) and visualized by silver staining using a Pierce Silver Stain Kit for Mass Spectrometry (Pierce Chemical, cat. no. 24600).

[0075] DARTS (drug affinity responsive target stability). The 3D7 gametocytes were lysed with M-PER supplemented with protease and phosphatase inhibitors as previously described [Lomenick B et al., Proceedings of the National Academy of Sciences of the United States of America, 2009, 106: 21984-21989]. After centrifugation at 16,000 x g for 20 min, protein concentration in the supernatant was quantified and 2 µg / µl proteins were treated with 600 nM of Torin 2 or 600 nM of Torin 1 for 2 h at room temperature. The samples were treated with 46 µg / ml pronase (Sigma-Aldrich, cat. no. P6911) for 30 min at room temperature. The digestion was stopped by adding the SDS-PAGE sample loading buffer and boiled at 70 °C for 10 min. The samples were separated on a 10% Bis-Tris gel and visualized by silver staining.

[0076] Malaria Mouse Model. Plasmodium berghei ANKA (Pb) parasites were maintained by serial passage by intraperitoneal (i.p.) injection in outbred mice. Two days before feeding, female mice were infected i.p. with 200-400 µl whole blood from a Pb-infected mouse with >10% parasitemia. On the day of feeding, the mice were checked for exflagellation and injected intravenously (i.v.) with drug vehicle alone (10% N-methylpyrrolidnone, 40% PEG 400 in water), or (a) 2-4 mg / kg Torin 2 (one or two doses), (b) 8 mg / kg NVP-AUY922 (two doses), or (c) 8 mg / kg Alvespimycin (two doses). Two hours post treatment, mice were anesthetized and Anopheles stephensi mosquitoes were allowed to feed on infected mice for 15 minutes. Parasitemia, gametocytemia, and presence of exflagellation were examined as described previously [Blagborough AM et al., Nature Communications, 2013, 4: 1812]. Mosquitoes were maintained on 5% (w / v) glucose at 19 °C and 80% relative humidity. At day 10 post feeding, mosquito midguts were dissected and transmission was measured by staining mosquito midguts with 0.2% mercurochrome and counting the numbers of oocysts per midgut.

[0077] Data analysis. The primary screen data was analyzed using customized software developed internally [Wang Y et al., Current Chemical Genomics 2010, 4: 57-66]. IC 50 values were calculated using the Prism software (Graphpad Software, Inc. San Diego, CA). Data were presented as means ± SEM with n = 3 independent experiments.

[0078] General materials and methods for chemical synthesis. All commercially available reagents, compounds, and solvents were purchased and used without further purification. 9-Bromo-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one was prepared according to the method described by Liu and coworkers (Liu, Q. et. al., J. Med. Chem., 2011, 1473-1480). Column chromatography on silica gel was performed on Biotage KPSil pre-packed cartridges using the Biotage SP-1 automated chromatography system. Reverse phase column chromatography was performed on RediSep preparative C-18 column using the Teledyne ISCO combiflash Rf system. 1< H spectra were recorded using an Inova 400 MHz spectrometer (Varian). Samples were analyzed on an Agilent 1200 series LC / MS. Method A used an Enomenex Kinetex 1.7 micron column and a flow rate of 1.1 mL / min. The mobile phase was a mixture of acetonitrile and H 2 O each containing 0.05% trifluoroacetic acid. A gradient of 4% to 100% acetonitrile over 4 minutes was used during analytical analysis. Method B used a Zorbax ™< Eclipse XDB-C18 reverse phase (5 micron, 4.6 x 150 mm) column and a flow rate of 1.1 mL / min. The mobile phase was a mixture of acetonitrile and H 2 O each containing 0.05% trifluoroacetic acid. A gradient of 5% to 100% acetonitrile over 8 minutes was used during analytical analysis.EXAMPLE 1

[0079] This example demonstrates an In vitro drug activity on gametocytes.

[0080] Stage III-V gametocytes (blood stage P. falciparum parasites) were enriched with treatment with 50 mM N-acetylglucosamine (NAG) and Percoll density gradient centrifugation as described previously 1< . Briefly, 2.5 µl / well incomplete medium was dispensed into each well of 1,536-well plates using the Multidrop Combi followed by 23 nl compound transfer using the NX-TR Pintool (WAKO Scientific Solutions, San Diego, CA). Then, 2.5 µl / well of gametocytes was dispensed with a seeding density of 20,000 cells / well using the Multidrop Combi. The assay plates were incubated for 72 h at 37 °C with 5% CO 2 . After addition of 5 µl / well of 2X AlamarBlue dye (Life Technologies, cat. no. DAL1100), the plates were incubated for 24 h at 37 °C with 5% CO 2 and then were read in a fluorescence detection mode (Ex = 525 nm, Em = 598 nm) on a ViewLux plate reader (PerkinElmer).EXAMPLE 2

[0081] This example demonstrates In vitro drug activity on asexual parasites in accordance with an embodiment of the invention.

[0082] Asexual parasites of P. falciparum strain 3D7 were cultured as described previously (Trager, W. et al., J. Parasitol. 2005, 91(3): 484-486). Drug activity on asexual stage parasites was tested using a SYBR Green assay as described previously (Eastman, R.T. et al., Antimicrob. Agents Chemother. 2013, 57(1): 425-435; Smilkstein, M. et al., Antimicrob. Agents Chemother. 2004, 48(5): 1803-1806). Briefly, parasites were diluted to 0.5% parasitemia in complete culture medium with 2% hematocrit and drugs diluted in DMSO (≤0.5%) and were loaded into a 96-well plate (200 µl / well). No drug and RBC alone wells were included as positive and background controls, respectively, and each testing condition was examined in duplicated. After 72 h incubation under the standard culture condition and a freeze-thaw lysis step at -80°C and room temperature, 100 µl / well of lysis buffer containing SYBR Green I was added to the parasite culture and incubated for 30 min at room temperature. The fluorescence of each well was measured at 520 nm following excitation at 490 nm using a FLUOstar Optima ™< microplate reader (BMG Labtech).EXAMPLE 3

[0083] This example demonstrates a synthesis of compounds, in accordance with an embodiment of the invention.

[0084] A general procedure for the synthesis of compound 2 is shown in Scheme 1.

[0085] Aldehydes 1 were prepared using a reported procedure (J. Med. Chem. 2011, 54(5): 1473-1480). A solution of 1 (300 µmole) in 3 mL of THF were added 300 µL of Et 2 NiPr and R'CH 2 COCl (3000 µmole). The mixture was heated in a microwave between 100 to 150 °C for 15 min. The crude product was purified by column chromatography on silica gel using dichloromethane in methanol (0-20%) as eluent to give 1'. A mixture of 1' (1.0 equiv), boronic acid or boronic acid pinacol ester (3.0 equiv), tetrakis(triphenylphosphine)palladium (0.05 equiv), DMF (1.5 mL) and saturated NaHCO 3 aqueous solution (0.5 mL) was charged in a microwave vial. Nitrogen was bubbled through the mixture for 3 min. The vial was capped and heated in a microwave at 120-150 °C for 15 min. The reaction mixture was filtered through a plug of Celite and the filtrate was purified by reverse phase column chromatography using acetonitrile (containing 0.1% TFA) / water (containing 0.1% TFA) as an eluent to give 2. 9-(4-chlorophenyl)-1-(4-(morpholine-4-carbonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0086] LC / MS (Method B): (electrospray +ve), m / z 496.1 (MH) +< , t R = 4.712, UV 254 = 100%9-(4-((dimethylamino)methyl)phenyl)-1-(4-(morpholine-4-carbonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0087] LC / MS (Method B): (electrospray +ve), m / z 519.2 (MH) +< , t R = 3.462, UV 254 = 100%4-(9-(4-chlorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-cyclopropylbenzamide

[0088] LC / MS (Method B): (electrospray +ve), m / z 466.1 (MH) +< , t R = 4.659, UV 254 = 100%4-(9-(4-chlorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-cyclopropyl-3-methylbenzamide

[0089] LC / MS (Method B): (electrospray +ve), m / z 480.1 (MH) +< , t R = 4.765, UV 254 = 100%4-(9-(4-chlorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0090]

[0091] White solid, isolated yield: 18.3% . 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.42 (t, J = 6.2 Hz, 1H), 9.17 (s, 1H), 8.35 (d, J = 9.5 Hz, 1H), 8.23 - 8.17 (m, 2H), 8.12 (dd, J = 8.6, 0.5 Hz, 1H), 8.01 (dd, J = 8.7, 2.0 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.35 - 7.28 (m, 2H), 7.09 - 7.05 (m, 3H), 6.95 (d, J = 9.4 Hz, 1H), 4.30 - 4.16 (m, 2H); LC / MS (Method B): (electrospray +ve), m / z 508.0 (MH) +< , t R = 4.992, UV 254 = 100%4-(9-(4-chlorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-(2-(dimethylamino)ethyl)benzamide

[0092]

[0093] Off-white solid, isolated yield: 28.4%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (s, 1H), 8.95 (t, J = 5.7 Hz, 1H), 8.36 (d, J = 9.5 Hz, 1H), 8.19 - 8.10 (m, 3H), 8.02 (dd, J = 8.7, 1.9 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.38 - 7.31 (m, 2H), 7.14 - 7.08 (m, 2H), 7.06 (dd, J = 1.9, 0.5 Hz, 1H), 6.96 (d, J = 9.4 Hz, 1H), 3.73 (q, J = 6.0 Hz, 2H), 3.34 (q, J = 6.0 Hz, 2H), 2.90 (d, J = 4.8 Hz, 7H); LC / MS (Method B): (electrospray +ve), m / z 497.3 (MH) +< , t R = 3.667, UV 254 = 100%N-cyclopropyl-4-(9-(4-fluorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)benzamide

[0094] Off-white solid, isolated yield: 19.25% . 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.16 (s, 1H), 8.70 (d, J = 4.4 Hz, 1H), 8.34 (d, J = 9.5 Hz, 1H), 8.11 (dd, J = 8.5, 6.3 Hz, 3H), 7.99 (dd, J = 8.7, 2.0 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.16 - 7.08 (m, 4H), 6.97 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 9.4 Hz, 1H), 3.02 - 2.94 (m, 1H), 0.79 (td, J = 7.0, 4.6 Hz, 2H), 0.69 - 0.59 (m, 2H); LC / MS (Method B): (electrospray +ve), m / z 450.1 (MH) +< , t R = 4.372, UV 254 = 100%4-(9-(4-chlorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)benzamide

[0095] 4-(9-(4-chlorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-(1-(2-hydroxyethyl)azetidin-3-yl)benzamide

[0096] LC / MS (Method B): (electrospray +ve), m / z 525.2 (MH)+, t R = 2.666, UV 254 = 100%9-(4-chlorophenyl)-1-(4-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0097] LC / MS (Method B): (electrospray +ve), m / z 566.3 (MH)+, t R = 2.731, UV 254 = 100%4-(9-(4-chlorophenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-(pyrrolidin-3-yl)benzamide

[0098] LC / MS (Method B): (electrospray +ve), m / z 495.2 (MH) +< , t R = 2.713, UV 254 = 100%4-(9-(4-(1-aminocyclopropyl)phenyl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-cyclopropylbenzamide

[0099] LC / MS (Method B): (electrospray +ve), m / z 487.3 (MH) +< , t R = 2.264, UV 254 = 100%9-(4-chlorophenyl)-1-(1-oxoisoindolin-5-yl)benzo[h][1,6]naphthyridin-2(1H)-one

[0100] LC / MS (Method B): (electrospray + ve), m / z 438.1 (MH) +< , t R = 4.145, UV 254 = 100%9-(4-((dimethylamino)methyl)phenyl)-1-(1-oxoisoindolin-5-yl)benzo[h][1,6]naphthyridin-2(1H)-one

[0101] LC / MS (Method B): (electrospray + ve), m / z 461.2 (MH) +< , t R = 3.149, UV 254 = 100%9-(4-chlorophenyl)-1-(2-methyl-1-oxoisoindolin-5-yl)benzo[h][1,6]naphthyridin-2(1H)-one

[0102] LC / MS (Method B): (electrospray + ve), m / z 452.1 (MH) +< , t R = 4.309, UV 254 = 100%9-(4-((dimethylamino)methyl)phenyl)-1-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)benzo[h][1,6]naphthyridin-2(1H)-one

[0103] Isolated yield: 30.1%. LC / MS (Method B): (electrospray +ve), m / z 475.1 (MH) +< , t R = 3.257, UV 254 = 100%1-(2-(3-aminopropyl)-1-oxoisoindolin-5-yl)-9-(4-chlorophenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0104] Off-white solid, isolated yield: 24.83% . 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (s, 1H), 8.36 (d, J = 9.5 Hz, 1H), 8.12 (dd, J = 8.7, 0.5 Hz, 1H), 8.00 (dd, J = 8.7, 2.0 Hz, 1H), 7.96 (dd, J = 8.0, 0.6 Hz, 1H), 7.89 (dd, J = 1.8, 0.7 Hz, 1H), 7.74 (s, 4H), 7.64 (dd, J = 8.0, 1.8 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.05 - 7.00 (m, 2H), 6.97 (d, J = 9.5 Hz, 1H), 6.91 (dd, J = 2.0, 0.6 Hz, 1H), 4.75 - 4.55 (m, 2H), 3.83 (dt, J = 14.3, 7.3 Hz, 1H), 3.63 (dt, J = 13.6, 6.5 Hz, 1H), 2.89 (s, 2H), 2.02 - 1.91 (m, 2H); LC / MS (Method B): (electrospray +ve), m / z 495.0 (MH) +< , t R = 3.783, UV 254 = 100%9-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0105] LC / MS (Method B): (electrospray + ve), m / z 461.1 (MH) +< , t R = 4.389, UV 254 = 100%9-(4-chloro-3-hydroxyphenyl)-1-(4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0106] LC / MS (Method B): (electrospray + ve), m / z 477.1 (MH) +< , t R = 4.178, UV 254 = 100%9-(4-chlorophenyl)-1-(4-(ethylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0107] LC / MS (Method B): (electrospray + ve), m / z 475.1 (MH) +< , t R = 4.982, UV 254 = 100%9-(3-amino-4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0108] LC / MS (Method B): (electrospray + ve), m / z 476.1 (MH) +< , t R = 4.331, UV 254 = 100%9-(4-fluorophenyl)-1-(4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0109] LC / MS (Method B): (electrospray + ve), m / z 445.1 (MH) +< , t R = 4.478, UV 254 = 100%9-(4-((dimethylamino)methyl)phenyl)-1-(4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0110] LC / MS (Method B): (electrospray + ve), m / z 484.2 (MH) +< , t R = 3.264, UV 254 = 100%9-(4-chloro-3-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0111] Off-white solid, isolated yield: 38.6%. LC / MS (Method B): (electrospray +ve), m / z 491.1 (MH) +< , t R = 4.866, UV 254 = 100%2-chloro-5-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydrobenzo[h][1,6]naphthyridin-9-yl)benzonitrile

[0112] Yellow solid, isolated yield: 9.67%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.22 (s, 1H), 8.37 (d, J = 9.5 Hz, 1H), 8.23 (dt, 2H), 8.18 - 8.14 (m, 2H), 8.10 (dd, J = 8.7, 1.9 Hz, 1H), 7.86 (dt, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.98 (d, J = 9.4 Hz, 1H), 6.92 (dd, J = 8.6, 2.3 Hz, 1H), 3.36 (s, 3H); LC / MS (Method B): (electrospray +ve), m / z 486.1 (MH) +< , t R = 4.634, UV 254 = 100%1-(4-(methylsulfonyl)phenyl)-9-(4-(pyrrolidin-1-ylmethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0113] Off-white solid, isolated yield: 2.405% . 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.17 (s, 1H), 8.35 (d, J = 9.5 Hz, 1H), 8.28 - 8.22 (m, 2H), 8.12 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.7, 1.9 Hz, 1H), 7.88 - 7.83 (m, 2H), 7.34 (d, J = 7.7 Hz, 2H), 7.12 - 7.09 (m, 1H), 7.02 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 9.4 Hz, 1H), 2.44 (s, 5H), 1.72 (s, 5H); LC / MS (Method B): (electrospray +ve), m / z 510.4 (MH) +< , t R = 3.302, UV 254 = 100%9-(4-chlorophenyl)-1-(2-methyl-4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0114] Yellow solid, isolated yield: 2.89%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.21 (s, 1H), 8.40 (d, J = 9.5 Hz, 1H), 8.23 (dd, J = 1.9, 0.7 Hz, 1H), 8.15 (dd, J = 8.6, 0.5 Hz, 1H), 8.11 - 8.03 (m, 2H), 7.77 - 7.73 (m, 1H), 7.49 - 7.44 (m, 2H), 7.13 - 7.06 (m, 2H), 7.05 - 7.03 (m, 1H), 7.00 (d, J = 9.5 Hz, 1H), 3.36 (s, 3H), 2.12 (s, 3H); LC / MS (Method B): (electrospray +ve), m / z 475.1 (MH) +< , t R = 4.966, UV 254 = 100%9-(4-chlorophenyl)-1-(4-(methylsulfonyl)-3-(piperazin-1-ylmethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0115] LC / MS (Method B): (electrospray + ve), m / z 559.1 (MH) +< , t R = 4.318, UV 254 = 100%9-(4-(1-aminocyclopropyl)phenyl)-1-(4-(methylsulfonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one

[0116] Off-white solid, isolated yield: 3.24% . 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (s, 1H), 8.36 (d, J = 9.5 Hz, 1H), 8.26 - 8.20 (m, 2H), 8.14 (dd, J = 8.6, 0.5 Hz, 1H), 8.03 (dd, J = 8.7, 1.9 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.46 - 7.41 (m, 2H), 7.15 - 7.09 (m, 2H), 7.05 (dd, J = 2.0, 0.6 Hz, 1H), 6.97 (d, J = 9.4 Hz, 1H), 3.34 (s, 4H), 1.38 - 1.32 (m, 2H), 1.22 - 1.16 (m, 2H); LC / MS (Method B): (electrospray +ve), m / z 482.1 (MH) +< , t R = 3.459, UV 254 = 100%EXAMPLE 4

[0117] This example demonstrates a synthesis of compounds, in accordance with an embodiment of the invention.

[0118] A reaction scheme for the synthesis of compounds 13 and 14 is shown in Scheme 2.8-(4-chloro-3-hydroxyphenyl)-3-methyl-1-(4-(morpholine-4-carbonyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0119] Off-white solid, isolated yield: 24%. LC / MS (Method B): (electrospray + ve), m / z 515.2 (MH) +< , t R = 3.995, UV 254 = 100%4-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N,N-dimethylbenzamide

[0120] Off-white solid, isolated yield: 18%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.16 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.78 - 7.72 (m, 4H), 7.46 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H), 3.64 (s, 3H), 3.08 (s, 3H), 2.98 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 457.1 (MH) +< , t R = 4.153, UV 254 = 100%4-(8-(4-chloro-3-hydroxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N-cyclopropyl-N-methylbenzamide

[0121] Off-white solid, isolated yield: 18%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 9.12 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.36 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 6.95 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 3.63 (s, 3H), 3.02 (s, 3H), 2.93 - 2.87 (m, 1H), 0.33 (d, J = 70.3 Hz, 3H); LC / MS (Method B): (electrospray + ve), m / z 499.2 (MH) +< , t R = 4.162, UV 254 = 100%4-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N-(3-(dimethylamino)propyl)benzamide

[0122] LC / MS (Method B): (electrospray + ve), m / z 514.1 (MH) +< , t R = 3.492, UV 254 = 100%N-cyclopropyl-4-(8-(4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzamide

[0123] LC / MS (Method B): (electrospray + ve), m / z 453.2 (MH) +< , t R = 3.894, UV 254 = 100%3-(8-(3-(dimethylamino)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0124] LC / MS (Method B): (electrospray + ve), m / z 382.1 (MH) +< , t R = 2.916, UV 254 = 100%3-(8-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0125] LC / MS (Method B): (electrospray + ve), m / z 397.1 (MH) +< , t R = 4.452, UV 254 = 100%3-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0126] LC / MS (Method B): (electrospray + ve), m / z 411.1 (MH) +< , t R = 4.626, UV 254 = 100%3-(8-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0127] Off-white solid, isolated yield: 22%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.16 (s, 1H), 8.94 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.12 (dd, J = 8.0, 1.8 Hz, 1H), 7.99 (dd, J = 9.0, 2.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.37 - 7.33 (m, 2H), 6.98 (d, J = 2.0 Hz, 1H), 2.21 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 411.1 (MH) +< , t R = 4.666, UV 254 = 100%3-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0128] Off-white solid, isolated yield: 9%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.16 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.13 (dd, J = 8.0, 1.7 Hz, 1H), 7.98 (dd, J = 8.9, 2.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.37 - 7.33 (m, 2H), 6.98 (d, J = 2.0 Hz, 1H), 3.65 (s, 3H), 2.20 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 425.1 (MH+), t R = 4.847, UV 254 = 100%3,3'-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline-1,8-diyl)dibenzonitrile

[0129] Off-white solid, isolated yield: 37%. LC / MS (Method B): (electrospray + ve), m / z 402.1 (MH) +< , t R = 4.011, UV 254 = 100%3-(8-(4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0130] Off-white solid, isolated yield: 20%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 8.33 (s, 1H), 8.18 - 8.12 (m, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.93 (t, J = 8.0 Hz, 2H), 7.42 (dd, J = 8.7, 5.4 Hz, 2H), 7.27 (t, J = 8.7 Hz, 2H), 7.16 (s, 1H), 3.62 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 395.1 (MH) +< , t R = 4.262, UV 254 = 100%3-(8-(4-chloro-3-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0131] Off-white solid, isolated yield: 7%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.03 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.07 (dd, J = 7.6, 1.9 Hz, 1H), 7.93 (dd, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.2, 2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 3.85 (s, 3H), 3.60 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 441.1 (MH) +< , t R = 4.583, UV 254 = 100%3-(8-(4-chlorophenyl)-3-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0132] Off-white solid, isolated yield: 12%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.17 (t, J = 8.1 Hz, 2H), 8.10 (dd, J = 7.7, 1.8 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.52 - 7.48 (m, 2H), 7.42 - 7.39 (m, 2H), 7.21 (d, J = 2.0 Hz, 1H), 4.19 (t, J = 5.3 Hz, 2H), 3.81 (d, J = 5.4 Hz, 2H), 3.48 (s, 1H); LC / MS (Method B): (electrospray + ve), m / z 441.1 (MH) +< , t R = 4.389, UV 254 = 100%3-(3-acetyl-8-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0133] Off-white solid, isolated yield: 8%. LC / MS (Method B): (electrospray + ve), m / z 439.1 (MH) +< , t R = 5.215, UV 254 = 100%5-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(piperazin-1-yl)benzonitrile

[0134] LC / MS (Method B): (electrospray + ve), m / z 495.2 (MH) +< , t R = 3.337, UV 254 = 1003-(8-(4-chloro-3-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0135] Off-white solid, isolated yield: 17%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.12 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.12 (dd, J = 8.0, 1.8 Hz, 1H), 7.99 (dd, J = 8.9, 2.1 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.02 - 6.99 (m, 1H), 6.93 (d, J = 2.1 Hz, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 2.19 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 455.1 (MH) +< , t R = 4.581, UV 254 = 100%5-(1-(5-cyano-2-methylphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)-2-fluorobenzonitrile

[0136] Off-white solid, isolated yield: 19%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (s, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.08 (dd, J = 8.0, 1.8 Hz, 1H), 7.97 (dd, J = 8.9, 2.1 Hz, 1H), 7.88 (dd, J = 6.1, 2.3 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.21 - 6.95 (m, 1H), 6.94 (s, 1H), 3.65 (s, 3H), 2.19 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 434.2 (MH) +< , t R = 4.248, UV 254 = 100%3-(8-(4-fluoro-3-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0137] Off-white solid, isolated yield: 19%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.12 (dd, J = 8.0, 1.8 Hz, 1H), 7.99 (dd, J = 9.0, 2.0 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.27 (dd, J = 11.3, 8.4 Hz, 1H), 7.00 - 6.93 (m, 3H), 3.86 (s, 3H), 3.65 (s, 3H), 2.20 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 439.1 (MH) +< , t R = 4.290, UV 254 = 100%2-chloro-5-(1-(5-cyano-2-methylphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)benzonitrile

[0138] Off-white solid, Isolated yield: 15%. LC / MS (Method B): (electrospray + ve), m / z 450.1 (MH) +< , t R = 4.462, UV 254 = 100%3-(8-(4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0139] Off-white solid, isolated yield: 23%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.12 (dd, J = 8.0, 1.8 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.27 (t, J = 8.8 Hz, 2H), 6.97 (d, J = 2.1 Hz, 1H), 3.65 (s, 3H), 2.21 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 409.1 (MH) +< , t R = 4.279, UV 254 = 100%3-(8-(3-cyanophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0140] Off-white solid, isolated yield: 16%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.09 (dd, J = 8.0, 1.8 Hz, 1H), 7.99 (dd, J = 8.9, 2.1 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 1.4 Hz, 1H), 7.63 (dd, 2H), 6.99 (d, J = 2.1 Hz, 1H), 3.65 (s, 3H), 2.20 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 416.1 (MH) +< , t R = 4.052, UV 254 = 100%3-(8-(4-(2-aminoethyl)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0141] Off-white solid, isolated yield: 28%. LC / MS (Method B): (electrospray + ve), m / z 420.1 (MH) +< , t R = 3.131, UV 254 = 100%5-(8-(4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(piperazin-1-yl)benzonitrile

[0142] LC / MS (Method B): (electrospray + ve), m / z 479.2 (MH) +< , t R = 3.135, UV 254 = 100%5-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(piperazin-1-yl)benzonitrile

[0143] LC / MS (Method B): (electrospray + ve), m / z 509.2 (MH) +< , t R = 3.378, UV 254 = 100%5-(8-(4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(piperazin-1-yl)benzonitrile

[0144] LC / MS (Method B): (electrospray + ve), m / z 493.3 (MH) +< , t R = 3.195, UV 254 = 100%5-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzonitrile

[0145] LC / MS (Method B): (electrospray + ve), m / z 539.3 (MH) +< , t R = 3.401, UV 254 = 100%5-(8-(3-cyanophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(piperazin-1-yl)benzonitrile

[0146] LC / MS (Method B): (electrospray + ve), m / z 486.1 (MH) +< , t R = 3.282, UV 254 = 100%4-methyl-3-(3-methyl-2-oxo-8-(1H-pyrrol-2-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0147] LC / MS (Method B): (electrospray + ve), m / z 380.1 (MH) +< , t R = 3.645, UV 254 = 100%4-methyl-3-(3-methyl-8-(1-methyl-1H-pyrrol-2-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0148] LC / MS (Method B): (electrospray + ve), m / z 394.1 (MH) +< , t R = 4.004, UV 254 = 100%4-methyl-5-(3-methyl-2-oxo-8-(thiophen-2-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(piperazin-1-yl)benzonitrile

[0149] LC / MS (Method B): (electrospray + ve), m / z 481.1 (MH) +< , t R = 2.962, UV 254 = 100%2-(4-acetylpiperazin-1-yl)-5-(8-(4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0150] LC / MS (Method B): (electrospray + ve), m / z 535.1 (MH) +< , t R = 4.093, UV 254 = 100%2-(4-acetylpiperazin-1-yl)-5-(8-(3-cyanophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0151] LC / MS (Method B): (electrospray + ve), m / z 542.1 (MH) +< , t R = 3.954, UV 254 = 100%4-methyl-3-(3-methyl-2-oxo-8-(thiophen-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0152] LC / MS (Method B): (electrospray + ve), m / z 397.1 (MH) +< , t R = 3.920, UV 254 = 100%3-(8-(furan-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0153] LC / MS (Method B): (electrospray + ve), m / z 381.1 (MH) +< , t R = 3.845, UV 254 = 100%2-(3-aminoazetidin-1-yl)-5-(8-(3-cyanophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0154] LC / MS (Method B): (electrospray + ve), m / z 486.1 (MH) +< , t R = 3.290, UV 254 = 100%5-(8-(3-cyano-4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(piperazin-1-yl)benzonitrile

[0155] LC / MS (Method B): (electrospray + ve), m / z 518.1 (MH) +< , t R = 3.455, UV 254 = 100%2-(3-aminoazetidin-1-yl)-5-(8-(4-fluorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0156] LC / MS (Method B): (electrospray + ve), m / z 479.1 (MH) +< , t R = 3.380, UV 254 = 100%2-(4-acetylpiperazin-1-yl)-5-(8-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile

[0157] LC / MS (Method B): (electrospray + ve), m / z 551.1 (MH) +< , t R = 4.309, UV 254 = 100%5-(8-(3-cyanophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-((2-(dimethylamino)ethyl)amino)-4-methylbenzonitrile

[0158] LC / MS (Method B): (electrospray + ve), m / z 502.1 (MH) +< , t R = 3.348, UV 254 = 100%8-(4-chlorophenyl)-3-methyl-1-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0159] Off-white solid, isolated yield: 12%. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.05 (s, 1H), 8.28 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.92 (dd, J = 8.9, 2.1 Hz, 1H), 7.43 - 7.36 (m, 4H), 7.11 (d, J = 2.0 Hz, 1H), 3.62 (s, 3H), 3.41 (s, 3H); LC / MS (Method B): (electrospray + ve), m / z 464.1 (MH) +< , t R = 4.238, UV 254 = 100%8-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0160] LC / MS (Method B): (electrospray + ve), m / z 450.1 (MH) +< , t R = 4.119, UV 254 = 100%EXAMPLE 5

[0161] This example demonstrates a synthesis of compounds, in accordance with an embodiment of the invention.

[0162] A representative synthesis is shown in Scheme 3. To a 10 mL microwave tube charged with bromide 1 (2.25 mmol) in acetic acid (5 mL) were added hydrazine 2 (4.5 mmol, 2.0 equiv). The reaction was heated under MW at 180 oC for 25 min, and was monitored by LC-MS. Then the reaction mixture was concentrated in vacuo, and the product was triturated with water to afford the product 3 in 75% yield.

[0163] To a 10 mL microwave tube charged with bromide 3 (0.3 mmol in DMF (1.5 mL) were added i-PrOH (0.75 mL) and 0.75 mL aqueous K3PO4 solution (0.8 M, 2 equiv). The mixture was stirred for 5 min. Nitrogen gas was bubbled through the reaction solution for 1-2 min, then Pd(PP3)4 (0.05 equiv) and boronic acid / ester 4 (2 equiv) were added. The mixture was heated in a MW at 150 °C for 10 min. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The crude was treated with 50% TFA in CH 2 Cl 2 at room temperature for 2 h, then the solvent was removed under vacuum, and the crude was purified by silica gel chromatograph with DCM / 10% NH 4 OH in MeOH.(4-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)phenyl)(pyrrolidin-1-yl)methanone

[0164] LC / MS (Method B): (electrospray + ve), m / z 467.2 (MH) +< , t R = 4.705, UV 254 = 100%4-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)-N-cyclopropylbenzamide

[0165] LC / MS (Method B): (electrospray + ve), m / z 453.1 (MH) +< , t R = 4.536, UV 254 = 100%4-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)-N-(3-(dimethylamino)propyl)benzamide

[0166] LC / MS (Method B): (electrospray + ve), m / z 498.2 (MH) +< , t R = 3.795, UV 254 = 100%.(4-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)phenyl)(morpholino)methanone

[0167] LC / MS (Method B): (electrospray + ve), m / z 483.1 (MH) +< , t R = 4.350, UV 254 = 100%.(4-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)(morpholino)methanone

[0168] LC / MS (Method B): (electrospray + ve), m / z 551.1 (MH) +< , t R = 4.830, UV 254 = 100%N-cyclopropyl-3-(8-(4-((dimethylamino)methyl)phenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)benzamide

[0169] LC / MS (Method B): (electrospray + ve), m / z 476.2 (MH) +< , t R = 3.265, UV 254 = 100%.(3-(8-(4-((dimethylamino)methyl)phenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)phenyl)(morpholino)methanone

[0170] LC / MS (Method B): (electrospray + ve), m / z 506.2 (MH) +< , t R = 3.193, UV 254 = 100%.3-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)-N-cyclopropylbenzamide

[0171] LC / MS (Method B): (electrospray + ve), m / z 453.2 (MH) +< , t R = 4.659, UV 254 = 100%.(3-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)phenyl)(morpholino)methanone

[0172] LC / MS (Method B): (electrospray + ve), m / z 483.2 (MH) +< , t R = 4.503, UV 254 = 100%.4-(8-(4-chlorophenyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-N-cyclopropylbenzamide

[0173] LC / MS (Method B): (electrospray + ve), m / z 438.2 (MH) +< , t R = 5.765, UV 254 = 100%.3-(8-(6-aminopyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)-N-cyclopropylbenzamide

[0174] LC / MS (Method B): (electrospray + ve), m / z 435.2 (MH) +< , t R = 3.107, UV 254 = 100%.(3-(8-(6-aminopyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)phenyl)(morpholino)methanone

[0175] LC / MS (Method B): (electrospray + ve), m / z 465.2 (MH) +< , t R = 3.061, UV 254 = 100%.3-(8-(4-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)benzonitrile

[0176] LC / MS (Method B): (electrospray + ve), m / z 395.1 (MH) +< , t R = 5.027, UV 254 = 100%.3-(8-(3-(1-aminocyclopropyl)phenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)benzonitrile

[0177] 3-(8-(4-((dimethylamino)methyl)phenyl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)benzonitrile

[0178] LC / MS (Method B): (electrospray + ve), m / z 418.2 (MH) +< , t R = 3.387, UV 254 = 100%.3-(8-(6-aminopyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-c]quinolin-1-yl)benzonitrile

[0179] LC / MS (Method B): (electrospray + ve), m / z 377.1 (MH) +< , t R = 3.219, UV 254 = 100%.4-methyl-3-(3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0180] LC / MS (Method B): (electrospray +ve), m / z 395.2 (MH) +< , t R = 3.376, UV 254 = 100%.4-methyl-3-(3-methyl-2-oxo-8-(1H-pyrazol-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0181] LC / MS (Method B): (electrospray +ve), m / z 381.1 (MH) +< , t R = 3.100, UV 254 = 100%.1-(4-methoxyphenyl)-3-methyl-8-(thiophen-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0182] LC / MS (Method B): (electrospray +ve), m / z 388.1 (MH) +< , t R = 4.054, UV 254 = 100%.4-(dimethylamino)-3-(3-methyl-2-oxo-8-(thiophen-2-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0183] LC / MS (Method B): (electrospray +ve), m / z 426.1 (MH) +< , t R = 4.021, UV 254 = 100%.4-(dimethylamino)-3-(3-methyl-2-oxo-8-(thiophen-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0184] LC / MS (Method B): (electrospray +ve), m / z 426.1 (MH) +< , t R = 4.082, UV 254 = 100%.3-(3-methyl-2-oxo-8-(thiophen-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0185] LC / MS (Method B): (electrospray +ve), m / z 383.1 (MH) +< , t R = 3.893, UV 254 = 100%.4-fluoro-3-(3-methyl-2-oxo-8-(thiophen-2-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0186] LC / MS (Method B): (electrospray +ve), m / z 401.1 (MH) +< , t R = 4.139, UV 254 = 100%.3-(3-methyl-2-oxo-8-(thiophen-2-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0187] LC / MS (Method B): (electrospray +ve), m / z 383.1 (MH) +< , t R = 4.019, UV 254 = 100%.4-(dimethylamino)-3-(8-(furan-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0188] LC / MS (Method B): (electrospray +ve), m / z 410.1 (MH) +< , t R = 3.867, UV 254 = 100%.4-methyl-3-(3-methyl-2-oxo-8-(1H-pyrrol-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0189] LC / MS (Method B): (electrospray +ve), m / z 380.2 (MH) +< , t R = 3.486, UV 254 = 100%.EXAMPLE 6

[0190] This example demonstrates the gametocytocidal activity and activity against asexual parasites in accordance with an embodiment of the invention.

[0191] Compounds were screened against gametocytes and asexual parasites as described in Examples 1 and 2. The results are set forth in Tables 1-8. Table 1#Gametocyte EC50 (nM)Asexual EC50 (nM)mTOR (nM)Microsomal Stability (rat) T 1 / 2 (min)Sol @ pH 7.4 (ug / mL)PAMPA Permeability (x10 6< cm / s)188.8527.95643.6---2427.52914316>30.0>64.01040.63264.3111.41282012.1<0.1621.2454.9914.92128209.6<1215507.5N / A3557-7.03725.276101.7N / A100000-0.02ND725.0713.051433->66.00-8139.360.32130514.5<1<192570667.75000010.958.61492.310469.272.19207718>6601154.9914.92128209.6<12112125.555.8250000---13135.180.365000000014425113114300---15521.2730.450000---1669.3923.746175---17------18------19------2022.5911.6542.71>30.0<1.0505.62117.0213.79232.512.71.160622114.734.56101.7>30.0<1.0ND2340.3522.47182.93.51.4858.152423.355.87675.31195.7547.9 Table 2 # Gametocyte EC50 (nM) Asexual EC50 (nM) mTOR (nM) Microsomal Stability (rat) T 1 / 2 (min) Sol @ pH 7.4 (ug / mL) PAMPA Permeability (x10 6< cm / s) 2511714.726251>30.0<1.0<1.526177.637.8327290>30.01.2ND27107.80178.9>30.0<1.0<1.02895.3116.1757.76>30.0<1.033.92988.4819.75119.2>30.0<1.0-30336.3117.92902>30.030.4677.93122233.47458>30.0<1.040.73292.7685.5350000>30.0<1.039.633-288.46606>3061439.234-59.4426817.1<1<135-75.770>304.33536-187.71083>305.96.537------38187.1219.7111612.7<1.032.539426413.7469.21.7<1.0-4051.7314.6174.3>30.0<1.0<1.04189.4123.12189.56.3<1.0ND42118.537.36254.74.9<1.097.443Inactive438501642>30.0>74.0<1.044135.431.1786.364.6<1.034.845208.877.8332.88.9<1.0144.446259.762.5112758.3<1.0ND47377.366.37399.4>30.02.1<2.948560.9200.21315>30.0<1.0<1.04919943192448.24.3<1.0235.8501826932.4269832.7164.451291.3202.91658>30.04.343.152352101473025790<1.057.2200.85368503791110602.89.6115.954393.1145.9167851.7>69.00-555335N / A35379.45>71.00788.14561548N / A440.7>30.000.01716.9857839.9380.63371>30.07.9527.858890.4N / A1057013.5<0.101527.985925.369.069345.512.8<0.10<1.00601951N / A18480>30.0021.281646.44618.486211.6>302.3<1621325558.511610>30.00>84.00-63342.1147.34738---641046488.7350>301.4<12.36546143.08756.22.9<15.466350.4-13081.4<1135671338-61171.7<11449.168-131.48033>3015.7148.769-1940100000>30>73828.370-20.1373.931.31.2148.471-56.652106>302133.572------73------74------75------76------77294.681.6717.03>30.033.6<1.07811.576.11610.15>30.0<1.0ND7922.814.75632.37>30.0<1.0<11.880213.6N / A33.297.149.6850.858133.86N / A81.93-105.182166.7150.4231.4---8374.74N / A173.6>30.005.6258.3184------ Table 3 # Gametocyte EC50 (nM) Asexual EC50 (nM) mTOR (nM) Microsomal Stability (rat) T 1 / 2 (min) Sol @ pH 7.4 (ug / mL) PAMPA Permeability (x10 6< cm / s) 8577.586.895-9<1.0793.886211.5177.23776>30.061.645987139.224.36241.1>30.02.633.188141.356.71841-0.51117.4989-52.142689>30<1<190-74.1119840>3013.680291-33.024415>30<154.292-27.2613.8>3013.33.993-27.9450.7>30<176.394-24.924188>3013.61.995-15.671731>3054.767496-37.291291>3011.47.897-100.61400>307.135.898-19.34994>30009913046.68-16.9<1.01054.510045.5114.7815313.8<1.0314.6101305.410717804.5<1.0-102116.5185.8519157.51083.410371.3474.26299710.56.376.1104193.7214.726801.4<1.0388.810594.3347.9779.95.914.8284.6106125.663.9917352.1<1.062110765.932.29541.46.9<1.010.110859.0661.431165<1.0<1.0119.310917.9760.7326012.34.2226.8110138.940.7594592.21.1-111284.8240.81135>30.019.8-112178.976.78358155-11375.9429.93137013.6<1.0-11413.576.953431.323.3<1.0-1156.2138.144229.49<1.0<1.011665.0222.02454.6<1.0<1.0383.1117Inactive144104734>30.0>80.0-11829.616.603269.1>30.0<1.0-11932.397.54775.3918.4<1.0-12035.857.498224.6>30.0<1.0-121443.1221522.65.4-242.7122370.9261.213035.4-822.3123442.4145.28577.3--124349144.2135719.7-20.412539.768.083506.1---126118.224.04372.41.7<1.01238.7127169.1105.3338.712.27.39.112831.456.054310.612.71.5735.41296801445856.7>30.020.35.413072.220.17202.1>30.09.2467.213117360174801557>30.0>75.01.9132344.163.1736.2<1.0<1.02316133101203997inactive>30.0<1.0<5.4134255.772.67200710.5<1.0142.113510000077800inactive>30.0>80.03136732.794.5235917.88.61292.91371004187.915181.6<1.0-138276.8173.212784.8<1.0890.6139152.920.63405.14.3<1.0238.4140272.259.2463739.6>77.01393.8141260.147.4780434.266.51500.61425000013770461701.4<1.0ND143242.163.12671.61.6<1.01421.51441761367.720834.1<1.01470.8145266.360.6512144.9<1.0362.81461814535.857329.66398.3147183004809212203.1>90.0108.61484575601.118170>30.021.8-149839.5408.66235>30.08.8-1506229382478732.43.9-15152.6719.0537203.5<1.0-15240382205796.23.3<1.0-15352.91126.8183609.4<1.057.9154101.7159.9765.78<1.0<1.0155311312352797010.7<1.0<1.01561576686.7676305.6<1.0<1.015774303350500006.8<1.0<1.015835561555789918.8<1.0<2.4159320.591.593523---160270.196.069278>30.0>79.0<1.01611536512.547050>30.0>82.05.4162894.736832080>30.0>83.0<1.0163246.593.886497>30.0>72.0231.9164809594.440420>30.0>79.0238.31654091933.750000>30.0>80.01.8166179.472.738762>30.0>70.0426.6167469223.222690>30.0>76.01.5168224.385.971194>30.017.31.4169629.7301631.5-2.8204.2170168.1122.2377313.32.7591171240.447.51154.32.8>72.031.3172202.8121967.8>30.02.312.31732526-100000->77.00365.72174265132.77636>30.00>68.0049.89175161873111780>30.0066.62-176282.790.23556.2-<0.10ND177902.1-9038->74.00-178918444.95312---1791696451.110000019.4<1<11801821931.42454>3043.73.818119231584830.4>3017.336.31821479459143910.81.10183131.149.84794.5>3028.4<1184820.6171.318050>3056.1292.51851144352.55000015.13.435.5186572.8207.212440---18745881605724.6000188601.5-720121.5<11247189357.9-6514>30>78212.5190248.5-10680>30>770191172.3-433726.72.4606.4192174.41199024.7<10193813.6-8290>30>81161.6194701.5-1000006.9<11078.4195275.8-781.48.8<1148196100000-10000018<185.919765140-2384>30>773.5198263.613840>30>756.1199108.8165105.61.41442.820060.031537007.21070.120116191728012.6<113.8202120.43267>3057.8415.120317.23512.829.31.2749.520414.26257.1>30<1<1205177.2106102.2455.620648.9196407.144.1427.6207145.4168.8>3058.1<120865.922175013.235.5247.9209537.724924<1<1210144701000002.7<10211387843090>30>83227212388815800>30>79188.7213130.2129918.9<1<121418.82339.421.2<1333.1215177.5763.86.3<1492.121642.23832.16.7<11.1217531.317830>30>83130218168416250>30>69100.4219370.73288>306.33.3220156.1424712.69.4127.422145.47150422.2<1133.122222.83820.627.27.1757.622358.027119-3.41178.5224460001000000>74<122519.75916.923.3<1735.2226208.18446---22766.4516000---228194.911220---229232.419250---23098.1750000---23122.74850.518<1364.423253.431065>309.27.6233162.46306>30>76155.12342219189201.4<1874.2235244501000003.4<1563.9236119850000>30>78<123739510100000>30>653.323856.84214.8>30<1438.923917.47242.2>30<179.924052.88443.6>3031.6<1241334.76061>30>7418.6242488.7373>30>74<1243676.914600>30>76382.224416357873>30>76216.2245381710410>30>6111.72461257645.9>30>721.524781.83190316.7<1846248329.22338010.651.2ND249575.5147607.9>821066.32505492911>309.514.325123741000001.3<1<1252100000100000---253257.88463>30>80352.9254206.23012>3053.15.7255181.9129502.3>881044.2256500.787763.5<1663.625760.782719>30>841.525834.3254124.40025924.18655.92.60026062.4150242.10026160.0318711.700262213.853994.30026358.821512>300026456.5613214.50026513220641.90026658.2830132.80026758.153878800268211.14985200269389.93874>3000270348.43254>3000271612.616140140027252.07522721.911.8625.827318.94164>30<1027440.61490021.463.81007.127544.22403919.965.6426.8276222.2217605.834.8973.227782.4836313.819.9354278110.280002.6>831383.727950.5131715.8>8449.1280152.41609>3073.649.128127.3821803>8633.428271.445364.1>86598.228369.1150902.770.71184.7284182.993547.536.6280.628559.711506>3041.6159.428653.68117702.435.6863.428758.4420834.3<121.7288283.912581.2<118.828986.7392161.7<1141.129064.384806363.1310.7291210.949753.10772.92921137155601.703.4293146.3610322.90241.2294204645868.400295162.22374010.60638.9296477.2186007.10509.8297150.1110201.60936.2298949.5500001.50148.229955.345830---30032.743792---301205.550000>30<1030216.37159512<103036.446237.6>300.7030419.2853.5---305483.34727---306100.28864---307190.939900---30823.562099---309553.93824---310413.73373---31153.26198.2---3121853500000---31339.031429---314429.4780---315137100000---316412.18154---317201.78572---318------319------320------321------322------323------324------325------326------327------328------329------330------331------3321519859494.9>30.0>64.031.9333411.2238.7213.5---33419.738.21388.72>30.03014.933517.7414.4428.21>30.02.8<2.233640.9910.1719.71>30.0<1.0<3.6337623215743229>30.0>68.0-33865.86N / A150.5-0.32140.79 Table 4 # Gametocyte EC50 (nM) Asexual EC50 (nM) mTOR (nM) Microsomal Stability (rat) T 1 / 2 (min) Sol @ pH 7.4 (ug / mL) PAMPA Permeability (x10 6< cm / s) 3399.190299.9>30.0<1.0<1.0340616.5266.115200>30.0>68.05.234182.9569.08620.512.4<1.0ND342349.8129.96710>30.0031.0112.72343-20.85447.6>3013.4<2.534415050353919.2<1.0238.834538322.3427622<1.0--34648.3818.57574.1---3471719667.714370>30.0>70.0317.63482446145823930>30.0>72.0289.4349267801422016230>30.0>68.02.53501003546.210110->68.0-3512162155.9433---3521000001875011480->72.0343.63532514588.750000>30.00NOT_DETERMINED3541907687.415790>30.0>74.0292.33552875020222516>30.0>77.0-35665.4924.981044>30.00<0.10NOT_DETERMINED3572197862.98193>30.00>70.0040.533582184878.56888->72.001209.2359129.723.44132814.90.06-360736170.2169619.20.73635.0536164411575100000>30.00<0.10199.8436281.718.8612787.40.698.56363860.2449.64610-57.748.76364100000458250000>302.775.936530610481.5126.9055.9<1.83663759123512120014.847.8367104.729326.512.80ND368219512833401>306.52.936929421228178202615.7553704115296.21456>3027.3<13712473471.631140>3045.31.23721049540.250000>30<1<137345.72349.61735>303.3<6.337412930418350000>3052.5<1.6375714.8389.150000>3013.1<1.1376198.6115460.1000377384.13.84111770003781546-17200>30>702.3379-2956740023<131380-310.51365>302.6<10.7381-263.8652.7>3044.94381-8.4382938---383-62.311837---384-1322100000---385------386------3871838315.8262.6>30.01.4<4.138888.1528.19120-11.8238965.2721.8390.23-<1.0<9.7390115.875.1660.97>30.04.22539156.2812.26126.8>30.0010ND39246.0822.04122.6>30.0033.81133.3939330.719.30519.62-6.26<1.10394438.5129.8107.5>30<1<139546000-53.39>3011.33.9 Table 5 #Gametocyte EC50 (nM)Asexual EC50 (nM)mTOR (nM)Microsomal Stability (rat) T 1 / 2 (min) Sol @ pH 7.4 (ug / mL) PAMPA Permeability (x10 6< cm / s) 396-144.115140>3046.4207.8397232.3267.8Inactive>30.0<1.0-398194.1104.92471>30.0<1.0-399522.2219.3100000>30.0<1.0ND400294165.2100000>30.0<1.01464.6401190.286.71271>30.0<1.0296.7402343.1139.953210>30.01.9222.8403262.2125.3100000>30.03.1ND4041644681.450000>30.00.919.5405665.7298.41000002.4<0.1ND40613.078.463216.519.4<1ND407104.252.4150000>30<10408304.710.04100000000409105.752.895000000041036.32.488100000000411108.761.410000000041239.886.57410000000041353.9929.35273000041438.7114.21584.2---41518.6321.4315870---41621.6439.63930.6---41736.45-3190<1<1418-7.934700.2---419-82.9430380---420-144.230220---421-18.9118940---422-5.8661870---423-50.4215400---424-22.9912510---425-48.435000---426-29.436418---427-75.1630600---428-27.7711000---429-10.5212570---430-58.454622---431------432------433-17.076100---434Inactive45000>46000 uM11.3<1.0ND4353657364.6>3030.8114361966891.912450>30.052.9767.243744.3414.4529.3>30.0<1.03.1438169.3174.110000027.2<1.0<1.0439843.937.93714.1>30.01.418.44402179786.6100000>30.0<1.0ND441685.5319.1516.2>30.0<1.0<1.04421992449.1100000---44368.2744.55302.4>30.03.3644.7444279.7106.1427.812.8<1.0406.6445734.7269.4630.3---446-16696805>301<16.2447-139.31634026.77.41377.34485000020020100000>30.00.4ND44910000063461000002.90.2ND450312.888.3110817.9<0.10-451500008408100000-<0.10ND45229171186100000>30<0.1ND4531000003996479.614.929.3<0.54541627301.21000000<0.1ND455206010136581---4563156931.41313397.43.9<0.94572543667.950000>30<1<13.5458456.722.0542820---45944388.47100000---460100000147.7500009.8<1927.1461-17661000009.943.8ND462-569.11000008.2<12112.3463-341710000017.1<1306.8464137.245.31068018.5<11021.6465525.5113.450000>30<1953.846618.313.6267762>306.6174.146723.6915.04177617.6<179246811460.197448000469125.552.9610000018.642.7814.3470217.2163.620420000471156.360.34603000047271.5620.6476400047339.316.87311500047424.9917.6338200047524.511.1459.7000476473.8231.319430---477237116154288000478292.5-49380>30>660479141.1-125011.2<1<13.34808715-325811.9<10481851.2-34621035.9<14822749-6901039.735.8484306-13120<181.648581.01-562.60<11348677.87-299.50<1<4.6487-469.410000030.537.9804.3488-4845100000>30<1ND489-55.86100000>30<10490-2984100000>30<1ND491-51.4229904.7531585.7492-944.12384>30<1<1493-805.4100000>30<1ND494-433.3100000>30<1ND495-2972100000>30<1192.2496-130.12358>30<1<5.3497-132.1648512.9<10498-373610000030.457.51434.3500-1499100000-48.11393.2501-259.71000007.453.6993.7502-18.53682.27.2<1ND503-542.74788023.3<1ND504-187.8500000>3027.4960.1505-16.7812320>30<10506-27.174579>301.1<1507-221.88798>3056.7720.1508-75.143176>3058.41010.7509-100.343950>30>681289510-25.331000008.5<11361511-8.5100000---512-19.7518500---513-26.53907022.5<10514-147.41000005.2<1ND515-7.0825000012.101471.9516-465.9100000701285.5517-12.33100000---518-28191876---519-5.728722---520-38.0321200---521-117.84237---522-260.1100000---523-10339590---524-40.016470---525-191.529140---526------527------528------529------530------531------532------533------534------535------536------537------538------539------540------541------542------543------544482.5385.6174.1>30.0<1.0<17.5545118.198.4499.1>30.0<1.02054663.137.0728.44-<1.0<6.25474.1012.6946.71>30.0<1.0-54827.946.836490.2>30.043.53.35497.2323.995541.4>30.043.8199.1550310.3140.95548ND2.5145.955131.921.51111>30.01.612.7552111197.772908>30.02.34.655392.8577.96553.9>30.01.3<1.0554707.9298.812330>30.08.6543.6555706.730150000---55621400633250000-20.7100.755758.1613.61420.425.91.4529.2558372.3101.7126420.83.40559655386.8289.65.35.32755601837377.184.97>3011.5056122.079.82344.49>30.001.51377.44562500001285100000>30.00<0.10<30.205633562897.250000011.3056418.295.258985.5000626-23.3326260>3047.978.6627-17.143535>3029.980.3628-97.97557.914<1876.8629-163.622780>30<1983.9630-57.228400>30<1810.6631-45.161000009.1<12.5632-12.9693847.6<11241.2633-48.495000012.1<1382634-12212200002.811339.4635-19.1626730--- Table 6 # Gametocyte EC50 (nM) Asexual EC50 (nM) mTOR (nM) Microsomal Stability (rat) T 1 / 2 (min) Sol @ pH 7.4 (ug / mL) PAMPA Permeability (x10 6< cm / s) 5651332445.719430>30.0<1.0ND566816.352615670>30.0<1.0ND567373778052906>3056.7056814570437050000---569100000146806560---57028740-2694>303.71.7571228.368.11170.8>30.0427.8572557.867.7525.37--- Table 7 # Gametocyte EC50 (nM) Asexual EC50 (nM) mTOR (nM) Microsomal Stability (rat) T 1 / 2 (min) Sol @ pH 7.4 (ug / mL) PAMPA Permeability (x10 6< cm / s) 573237.254.66794.5>30.0<1.0>1625.0574536.5115.5147725.8<1.0222.9575337.5218.1105922.73.33576-153.78427---577-197.2100000---578276921741808018.5<1.0<4.8579719.3418.228100---580111812314304-5.4654.65811060632.21824-5.2ND5821850992100205.5<1.0ND58337450Inactive357500012.2<1.0ND5842619494.9145217.8<1.031.658576471092171.419<1.079.35868025480210510>30.0>77.0220.3587688.6245670218.2<1.0ND5885312142410000018.5<1.083.1589100000913.8100000---5901083217.847615.321345.45911909106620956.2<1.01336.259250140-37960>3012.7<1593100000-100000---594-427510000019.6<1144.8595-683.3100000---596-349.926820---597-490.1100000---598-5124100000---599-438406384---600-251.414470---601-431.37223---6023348302.4127.4>30.0<1.0<3.1603107.582.18195.4>30.01.1<6.4604374107.433.566.5<1.0<12.3605159.460.87111.315.6<1.0231.660612050.7379.18>30.01.970.96075635113.9116.2>30.04.9<1.960810634.84210>30.0712.260928990351.9335>30.04.5ND610150.450.9257>303.906112232225.6234>30.01.6<3.6 Table 8 # Gametocyte EC50 (nM) Asexual EC50 (nM) mTOR (nM) Microsomal Stability (rat) T 1 / 2 (min) Sol @ pH 7.4 (ug / mL) PAMPA Permeability (x10 6< cm / s) 612168705660114102.254.4-6131000001408013650>30.037.72.961411290353412050>30.058.6-615100000380029840>30.0403.1 EXAMPLE 7

[0192] This example demonstrates a synthesis of compounds, in accordance with an embodiment of the invention.

[0193] N-methyl isopropyl carbamate 4 of 6-bromo-4-chloroquinolin-3-amines 2, one example of the key intermediate, can be synthesized from commercially available 6-bromo-4-chloroquinolin-3-amine 1 in three steps: stannous chloride mediated reduction of 1 followed by carbamate synthesis through isopropyl chloroformate gave 3, subsequent methylation provided 4, as shown in Scheme 6. Reagents and conditions: (a) SnCl 2* 2H 2 O, AcOH, EtOH, rfx, 3 h, 64%; (b) CICOOiPr, pyr, DCM, rt, 4 h, 66%; (c) MeI, NaH, THF, rt, 18 h, 93%.

[0194] One aspect of the invention provides a process of making a compound of structure 6 in a high boiling point organic reaction medium under microwave irradiation, further coupling the compound of structure 6 with the boronic species to obtain the compound of structure 7, as shown in Scheme 7. Preparation of 6-bromo-4-chloroquinolin-3-amine 2

[0195] To a mixture of 25 g (85 mmol) of 6-bromo-4-chloro-3-nitroquinoline 1 with 500 mL of EtOH and 75 mL of AcOH was added 98 g (435 mmol) SnCl 2 dihydrate as one portion. The reaction mixture was then refluxed for 3 hours. The reaction mixture was cooled to 0 °C and the pH was adjusted to basic with saturated NaHCO 3 . The mixture was extracted with 1L of EtOAc three times. The EtOAc layers were combined, dried over MgSO4 and concentrated. The resulting solid was triturated with Et 2 O to provide 14.3 g of 2 as a pale-yellow solid.Preparation of isopropyl (6-bromo-4-chloroquinolin-3-yl)carbamate 3

[0196] Under an inert atmosphere, to a stirred solution of 2 (7.98 g, 31 mmol) in anhydrous DCM (140 mL) at 0 °C was added pyridine (37.2 mmol), followed by 34.1 mL isopropyl chloroformate (34.1 mmol, as 1M solution in PhMe) dropwise. The solution was stirred at 0 °C for a further 15 min before the ice bath was removed and stirring continued at rt for 4 hours. Then 200 mL DCM was added at 0 °C, followed by an equal volume of saturated NaHCO 3 and several drops of MeOH. The mixture was extracted with 200mL of DCM three times. The organic layers were combined, dried (MgSO 4 ) and concentrated. The resulting orange red mixture was triturated with Et 2 O (100 mL X 3), providing 7.0 g pure product 3 as a pale-orange solid.Preparation of isopropyl (6-bromo-4-chloroquinolin-3-yl)(methyl)carbamate 4

[0197] Under an inert atmosphere, to a stirred solution of 3 (7 g, 20.3 mmol) in anhydrous THF (100 mL) at 0 °C , was added portion-wise NaH (1.63 g, 40.7 mmol, 60% dispersion in mineral oil). After 15 min, iodomethane (3.8 mL, 61.1 mmol) was added dropwise and the resulting mixture was stirred at 0 °C for 60 min and then at rt for 18 hours. At 0 °C, 200 mL saturated NH 4 Cl was added. The mixture was extracted with 200 mL of EtOAc three times. The EtOAc layers were combined, dried (MgSO 4 ) and concentrated. The residual mixture was then passed through a silica gel column, and the product eluted with DCM and MeOH. The resulting pale orange oil was left under vacuum, providing 6.7 g product 4 as pale-yellow solid.Preparation of compound 7 through one-pot two step synthesis

[0198] In a 0.5 mL-2.0 mL conical shaped microwave reaction vial, isopropyl (6-bromo-4-chloroquinolin-3-yl)(methyl)carbamate 4 (36 mg, 0.1 mmol) and 1.0 mL of 3-pentanol were mixed, followed by aniline 5 (0.2 mmol) and 75 uL HCl (0.3 mmol, 4.0 M in dioxane). The mixture was microwave irradiated at 230 °C for several minutes. 0.5 mL DMF and 0.5 mL 1M K 3 PO 4 (106mg K 3 PO 4 in 0.5mL H 2 O) a< were added. With stirring, the air was displaced with nitrogen. Boronic acid / ester (0.2 mmol) and Pd(PPh 3 ) 4 (0.003 mmol) were introduced. The mixture was microwave heated at 150 °C for 10 minutes. The reaction mixture was cooled and 5 mL of saturated NaHCO 3 was introduced. The reaction mixture was extracted with three 7 mL portions of DCM. The organic extract was dried (MgSO 4 ), filtered and concentrated. To obtain a pure product, the residual mixture was passed through a silica gel column, and the product 7 was eluted with DCM and MeOH.

[0199] a< Note: For difficult examples, molar ratio (4 : 5 : HCl) = 1 : 4 : 5, volumeof 1M K 3 PO 4 = 0.7 mL.Preparation of compound 6 through conventional reflux

[0200] In a round bottomed flask, N-methyl carbamate 4 (3 mmol) and 10 mL cyclohexanol were mixed, followed by aniline 5 (9 mmol) and HCl (12 mmol, 4.0 M in dioxane). The mixture was refluxed for 4 hours (or until reaction was complete). Then at 0 °C, 30 mL of saturated NaHCO 3 was introduced. The mixture was then extracted with three 30 mL portions of DCM. The organic extract was dried (MgSO 4 ), filtered and concentrated. The resulting mixture was passed through a silica gel column, and product 6 was eluted with DCM and MeOH.

[0201] The use of the term "at least one" followed by a list of one or more items (for example, "at least one of A and B") is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0202] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. A compound of formula (I): wherein A is CR5 or N, B is CR3=CR4, R1 is C6-10 aryl or heteroaryl substituted with at least one substituent selected from -CN, cyanomethyl, -SO2R13, -SO2NHR15, and -CONR11R12, optionally further in combination with one or more substituents selected from halo, C1-12 alkyl, alkoxy, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolidinyl, and diazepinyl, or an aryl bicyclic lactam of the formula: wherein the aryl group of the aryl bicyclic lactam is optionally substituted with at least one substituent selected from -CN, cyanomethyl, -SO2R13, -SO2NH2, and -CONR11R12, optionally further in combination with one or more substituents selected from halo, C1-12 alkyl, alkoxy, 2-(dimethylamino)ethyl)amino, dimethylamino, a heterocyclyl group selected from the group consisting of optionally substituted piperazinyl, morpholinyl, pyrrolidinyl, azetidinyl and diazepinyl, R2 is selected from 4-pyridinyl, 2-amino-5-pyrimidinyl, 3-pyridyl, quinolin-3-yl, 5-pyrimidinyl, 2-acetylamino-5-pyridyl, 2-amino-4-methylpyrimidin-5-yl, 1-piperazinyl, indol-5-yl, 1H-imdazol-5-yl, 4-aminophenyl, 1,2,3,6-tetrahydropyridin-4-yl, 1H-pyrazol-4-yl, N-methyl-pyrazol-4-yl, 1H-benzo[d]imidazol-5-yl, 4-sulfonylaminophenyl, 2-dimethylaminopyrimidin-5-yl, 3-trifluoromethylphenyl, bromo, 3-aminophenyl, 4-aminophenyl, vinyl, 4-aminocarbonylphenyl, 3-cyanophenyl, 3-hydroxyphenyl, 3-trifluoromethyl-5-pyridyl, tetrazolyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-aminocarbonylphenyl, 3-acetylphenyl, 3-cyano-4-chlorophenyl, 3-cyano-5-methylphenyl, 3-hydroxy-4-chlorophenyl, 4-hydroxymethylphenyl, 3-amino-4-chlorophenyl, 2,3-dihydrobenzofuran-6-yl, 1-methyl-1H-indol-5-yl, benzo[d][1,3]dioxo-5-yl, 4-hydroxyphenyl, morpholin-1-yl, benzo[b]thiophen-1-yl, 4-methylsulfonylphenyl, benzo[c][1,2,5]oxadiazol-5-yl, 2-(piperidin-1-yl)-3-pyridinyl, 4-carboxyphenyl, 2-methyl-5-pyridyl, 4-methylsulfonylphenyl, 4-dimethylaminocarbonylphenyl, 4-phenylphenyl, 4-methylphenyl, 3-chloro-5-pyridyl, (3-pyrrolidin-1-yl)phenyl, 4-([piperizin-1-yl]carbonyl)phenyl, 4-([morpholin-1-yl]carbonyl)phenyl, 2-hydroxypyrimidin-5-yl, 3-aminosulfonylphenyl, 2-oxo-1,2,3,4,tetrahydroisoquinolin-6-yl, 2-oxo-1,2,3,4,-tetrahydroquinolin-6-yl, 4-(methylaminocarbonyl)phenyl, 1-oxoindolin-5-yl, 2-oxoindolin-5-yl, 1-oxoisoindolin-5-yl, 2-amino-4-pyridyl, 3-amino-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 4-aminophenyl, 3-methylphenyl, 3-methoxyphenyl, phenyl, 5-indolinonyl, 5-isoindolinonyl, 3-aminophenyl, 2-hydroxy-4-chlorophenyl, 4-cyanophenyl, 4-azetidinylphenyl, 4-ethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-cyano-4-fluorophenyl, 3-amino-4-fluorophenyl, 4-(1-hydroxy-1-ethyl)phenyl, 3-methyl-5-pyridyl, 2-acetylamio-5-pyridyl, 2-oxoindolin-5-yl, benzimidazolin-5-yl, 3-dimethylamino-1-propargyl, 2-pyrrolyl, N-methyl-2-pyrrolyl, 2-thiopheneyl, 3-thiopheneyl, 3-furanyl, and 3-aminosulfonylphenyl, R3 and R4 are independently selected from hydrogen, hydroxyl, OR5, halogen, optionally substituted C6-10 aryl, and optionally substituted C1-6 alkyl, R5 is hydrogen, C1-12 alkyl, C6-10 aryl, halogen, hydroxyl, or OR16, R6 is hydrogen, C1-12 alkyl, C2-12 hydroxyalkyl, C1-6 acyl-C1-6 alkyl, or C6-10 aryl, R7-R10 are independently selected from hydrogen, C1-12 alkyl, C3-8 cycloalkyl, CH2COOR13, and H2N(CH2)n- wherein n is an integer of 2-6, R11 and R12 selected from the group consisting of hydrogen, C1-12 alkyl and C3-10 cycloalkyl or, taken together with the N to which they are bound, form an optionally substituted 4-7 membered heterocyclyl ring containing O or N atoms, and R13 is C1-12 alkyl, R15 is hydrogen or C1-12 alkyl, R16 is C1-12 alkyl, C1-6 acyl, or C6-10 aryl, or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1, wherein the compound is selected from:

3. The compound or salt of claim 1, wherein the compound is selected from:

4. The compound or salt of claim 1, wherein the compound is selected from:

5. A pharmaceutical composition comprising a compound or salt of any one of claims 1-4 and a pharmaceutically acceptable carrier.

6. A compound of any one of claims 1-4 or the pharmaceutical composition of claim 5, for use in blocking transmission of a Plasmodium parasite or treating malaria by killing or arresting the growth of Plasmodium organisms in a mammal.