Compounds and compositions for the treatment of parasitic disease

1. A compound of Formula Ib:

in which:

R b is selected from hydrogen and C 1-4 alkyl;

R 4 is selected from hydrogen and C 1-6 alkyl;

R 5 is selected from hydrogen and C 1-6 alkyl; or R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached forms C 3-8 cycloalkyl;

R 6 is selected from phenyl, cyclohexyl and pyridinyl; wherein said R 6 is optionally substituted by 1 to 3 radicals independently selected from halo, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;

R 7 is selected from hydrogen and C 1-3 alkyl;

R 8 is selected from phenyl, bicyclo[2.2.1]heptyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl and pyrazolyl; wherein said R 8 is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, hydroxy, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, C 1-6 alkoxy, —C(O)OR 18 , —S(O) 0-2 R 18 , —C(O)NHR 18 , —NHS(O) 0-2 R 18 , phenyl and a saturated, unsaturated or partially unsaturated 5-6 member heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR 30 , S(O) 0-2 and O; wherein R 30 is selected from hydrogen and C 1-6 alkyl; wherein said phenyl or heterocyclic ring substituent of R 8 is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, hydroxy, C 1-6 alkyl and halo-substituted—C 1-6 alkyl; wherein R 18 is selected from hydrogen and C 1-6 alkyl;

R 9 is selected from hydrogen and C 1-6 alkyl;

R 10 is selected from hydrogen and C 1-6 alkyl;

R 11 is selected from hydrogen and C 1-6 alkyl;

R 12 is selected from hydrogen and C 1-6 alkyl; or R 11 and R 12 combine to form C(O);

or the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 in which: R 4 , R 5 , R 9 and R 10 are independently selected from hydrogen and methyl; and R 11 and R 12 are both hydrogen; or R 11 and R 12 combine to form C(O).

3. The compound of claim 2 , wherein said phenyl or pyridinyl of R 6 is optionally substituted by 1 to 3 radicals independently selected from halo, pentyl, hydroxy, methyl and methoxy.

4. The compound of claim 3 in which: R 7 is selected from hydrogen, methyl, ethyl and isopropyl; and R 8 is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, trifluoromethoxy, dimethyl-amino, difluoromethoxy, carboxy, methoxy-carbonyl, methyl-sulfonyl-amino, methyl-sulfonyl, methyl-amino-carbonyl, phenyl, piperidinyl, piperidinyl-methyl, piperazinyl and piperazinyl-methyl.

5. The compound of claim 1 selected from:

2-(4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2]pyrazin -3-amine;

2-(3-fluorophenyl)-N-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2]pyrazin -3-amine;

N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chloro-3-fluorophenyl)-2-(3-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

4-{[2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile;

N-(4-chlorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(3-methylphenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(3,4-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(3-chlorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(2,4-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-fluorophenyl)-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-6-methyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(2,5-difluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-methylphenyl)-2-(pyridin-4-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chloro-3-fluorophenyl)-N-ethyl-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-fluorophenyl)-8,8-dimethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chlorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

4-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile;

N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3-fluorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-ethyl-N-(3-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N,2-bis(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-fluoro-3-methylphenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(3-chloro-4-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-chloro-3-fluorophenyl)-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-fluorophenyl)-8,8-dimethyl-3-{[3-(trifluoromethyl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-3-[(3-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(3,4-dichlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(3,4-difluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

4-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile;

3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(3-chloro-4-fluorophenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

N-(3-fluorophenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-fluorophenyl)-8,8-dimethyl-N-[3-(trifluoromethyl)phenyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzoic acid;

2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile;

5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzoic acid;

5-{[2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile;

5-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile;

N,2-bis(4-fluorophenyl)-5,5,7,8,8-pentamethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-fluoro-5-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile;

2-(4-fluorophenyl)-5,5,7,8,8-pentamethyl-3-[(4-methylphenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-5,5,7,8,8-pentamethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3-fluoro-4-methylphenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3-chloro-4-methylphenyl)-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-fluorophenyl)-8,8-dimethyl-3-[(3,4,5-trifluorophenyl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-3-[(6-methoxypyridin-3-yl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(3-chloro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-8,8-dimethyl-3-[(4-methylpyridin-2-yl)amino]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-chloro-4-{[2-(4-fluorophenyl)-8,8-dimethyl-6-oxo-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile;

(8R)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

(8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-chloro-3-fluorophenyl)amino]-2-(3,4-difluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-8,8-dimethyl-N-(3,4,5-trifluorophenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chlorophenyl)-2-(4-fluorophenyl)-6,6,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chlorophenyl)-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

(8S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

(8S)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

(8S)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

(8R)-3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

(8R)-3-[(4-chlorophenyl)amino]-2-(4-fluorophenyl)-8-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-8,8-dimethyl-3-(quinolin-3-ylamino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-3-[(4-methanesulfonylphenyl)amino]-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-8,8-dimethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-8,8-dimethyl-3-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

2-(4-fluorophenyl)-8,8-dimethyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-(4-fluorophenyl)-6,6-dimethyl-N-(4-methylphenyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N,2-bis(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

2-fluoro-5-{[2-(4-fluorophenyl)-6,6-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}benzonitrile;

3-[(3-fluoro-4-methylphenyl)amino]-2-(4-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(3-fluoro-4-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(3-chloro-4-methylphenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-chloro-3-fluorophenyl)amino]-2-(3-fluorophenyl)-8,8-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

N,2-bis(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chlorophenyl)-2-(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chlorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(4-chloro-3-methylphenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

N-(3,4-difluorophenyl)-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

5-{[2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-yl]amino}-2-methylbenzonitrile;

3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-fluoro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5,7-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-chloro-3-fluorophenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one;

3-[(4-chloro-3-methylphenyl)amino]-2-(4-fluorophenyl)-5,5-dimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-6-one; and

N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-7,8,8-trimethyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-3-amine;

or a pharmaceutically acceptable salt thereof.

6. A method for prevention or treatment of malaria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , and optionally in combination with one or more therapeutic agents.

7. The method of claim 6 , wherein the one or more therapeutic agents are selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent.

8. The method of claim 7 , wherein the anti-malarial drug is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, and pyronaridine.

9. The method of claim 6 , wherein the compound of claim 1 is administered prior to, simultaneously with, or after the one or more therapeutic agents.

10. The method of claim 6 , wherein said subject is a human.

11. A method for prevention or treatment of malaria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 5 , and optionally in combination with one or more therapeutic agents.

12. The method of claim 11 , wherein the one or more therapeutic agents are selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent.

13. The method of claim 12 , wherein the anti-malarial drug is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, and pyronaridine.