Compounds and compositions for the treatment of parasitic diseases

1. A compound of Formula I,

or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, wherein

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

L is selected from the group consisting of *—(CHR 3 ) 1-3 —, *—CHR 3 N(R 2 )—, *—CHR 3 O—, *—CHR 3 S—, *—CHR 3 S(O)—, *—CHR 3 N(R 2 )CHR 3 —, *—C(O)—, *—C(O)N(R 2 )—, *—C(O)N(R 2 )CHR 3 —, *—N(R 2 )—, *—N(R 2 )CHR 3 —, *—N(R 2 )C(O)—, *—N(R 2 )C(O)N(R 2 )—, *—N(R 2 )S(O) 2 —, wherein

* represents the point of attachment of L to the pyrazolo[1,5-a]pyridine fused ring depicted in Formula I;

each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, R—C 0-4 alkylene, and R—C 0-4 alkylene-C(O)—, wherein R is selected from the group consisting of hydroxyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, and C 5-6 heteroaryl, wherein the C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, and C 5-6 heteroaryl of R are each unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of halo, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, oxo, and C 5-6 heteroaryl; and

each R 3 is independently selected from the group consisting of hydrogen and C 1-4 alkyl;

Ring A is selected from the group consisting of C 6-10 aryl and C 3-10 heteroaryl;

Ring C is selected from the group consisting of C 6-10 aryl, C 5-10 heteroaryl, C 5-7 cycloalkyl, C 5-7 heterocycloalkyl, and fused bicyclyl comprising a C 5-6 heterocycloalkyl fused to a phenyl;

each R 1 is independently selected from the group consisting of halo, cyano, amino, C 1-4 alkyl, C 1-4 alkoxyl, halo-C 1-4 alkyl, —C(O)NR 7 R 8 , —NHC(O)R 11 , phenyl, and C 5-6 heteroaryl; wherein

the phenyl and C 5-6 heteroaryl of R 1 are each unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of C 1-4 alkyl, amino, halo, and C 1-4 alkylamino;

R 7 and R 8 are each independently selected from hydrogen, C 1-4 alkyl and haloC 1-4 alkyl;

R 11 is C 1-6 alkyl, unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of amino, C 3-6 cycloalkyl and C 4-6 heterocycloalkyl;

R 17 is selected from the group consisting of cyano, halo, C 1-4 alkyl, halo-C 1-4 alkyl, oxo, C 3-6 cycloalkyl, and —SO 2 —C 1-4 alkyl.

2. The compound of claim 1 , wherein L is selected from the group consisting of *—C(O)N(R 2 )—, and *—N(R 2 )C(O)—, wherein each R 2 is independently selected from hydrogen, C 1-4 alkyl, and R—C 0-4 alkylene, and wherein R is selected from the group consisting of C 4-6 heterocycloalkyl and C 5-6 heteroaryl, each of which is unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of halo, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, oxo, and C 5-6 heteroaryl.

3. The compound of claim 1 , wherein L is selected from the group consisting of *—CH(CH 3 )—, *—CH 2 CH 2 —, *—CH 2 N(CH 3 )—, *—CH 2 N(C(O)(CH 2 ) 1-2 NH(CH 3 ))—, *—CH 2 N(C(O)—(CH 2 ) 1-2 NH 2 )—, *—CH 2 N((C(O)—(CH 2 ) 1-2 N(CH 3 ) 2 )—, *—CH 2 N(C(O)(CH 2 ) 1-2 OH)—, *—CH(CH 3 )N(CH 3 )—, *—CH 2 O—, *—CH 2 S—, *—CH 2 S(O)—, *—C(O)—, *—C(O)N(CH 3 )—, *—C(O)N(CH 2 CH 3 )—, *—C(O)N(CH(CH 3 ) 2 )—, *—C(O)N(C(CH 3 ) 3 )—, *—C(O)N(CH 2 CH(CH 3 ) 2 )—, *—C(O)N(CH(CH 3 )CH 2 CH 3 )—, *—C(O)N(CH 2 CH 2 OCH 3 )—, *—C(O)N(CH 2 CH 2 N(CH 3 ) 2 )—, *—C(O)N(CH 3 )CH 2 —, *—NHCH 2 —, *—N(CH 3 )CH 2 —, *—N(CH 2 -tetrahydropyran-4-yl)-C(O)—,*—N(CH 3 )C(O)—, *—N(CH 3 )C(O)NH—, *—N(CH 3 )S(O) 2 —, *—C(O)N((CH 2 ) 0-1 -cyclopropyl)-, *—C(O)N((CH 2 ) 0-1 -cyclobutyl)-, *—C(O)N((CH 2 ) 0-1 -cyclopentyl)-, *—C(O)N((CH 2 ) 0-1 -cyclohexyl)-, *—C(O)N(CH 2 -tetrahydropyran-4-yl)-, *—C(O)N((CH 2 ) 2 -(1,1-dioxidothiomorpholino-4-yl))-, *—C(O)N(CH 2 -1,1-dioxidothiomorpholino-4-yl)-, *—C(O)N((CH 2 ) 2 -tetrahydropyran-4-yl)), *—C(O)N((CH 2 ) 1-2 -morpholin-4-yl)-, *—C(O)N(oxetan-3-yl)-, *—C(O)N(CH 2 -oxetan-3-yl)-, *—C(O)N(CH(CH 3 )—CH 2 -1-H-pyrazoly-1-yl)-, *—CH 2 N(C(O)—(CH 2 ) 1-2 -morpholinyl))-, *—CH 2 N(C(O)—(CH 2 ) 1-2 -4-methylpiperizin-1-yl)), *—CH 2 N(C(O)—(CH 2 ) 1-2 -tetrahydropyran-4-yl)-, and *—CH 2 N(C(O)(CH 2 ) 1-2 -oxetan-3-yl)-.

4. The compound according to claim 1 , wherein Ring A is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl, and indazolyl, each of which is unsubstituted or substituted by (R 1 ) n .

5. The compound according to claim 1 , wherein Ring C is selected from the group consisting of

each of which is unsubstituted or substituted by (R 17 ) p .

6. The compound according to claim 1 , wherein Ring C is selected from the group consisting of phenyl and pyridinyl, each of which is unsubstituted or substituted by (R 17 ) p .

7. The compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of trifluoromethyl, cyano, —NH 2 —, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , and —NHC(O)CH(NH 2 )(CH 3 ).

8. The compound according to claim 1 , wherein each R 17 is independently selected from the group consisting of cyano, halo, C 1-4 alkyl, haloC 1-4 alkyl, —SO 2 —C 1-4 alkyl, and C 3-6 cycloalkyl.

9. The compound of claim 1 , wherein the compound is of Formula Ia:

or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, wherein

n is 1 or 2;

p is 1 or 2;

Ring A is phenyl, pyridinyl, or pyrimidinyl;

Ring C is phenyl or pyridinyl;

L is *—C(O)NR 2 — or *—NR 2 C(O)—, wherein R 2 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl-(C 0-4 )alkylene, C 4-6 heterocycloalkyl-(C 0-4 )alkylene, wherein the C 4-6 heterocycloalkyl is selected from the group consisting of piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, and oxetanyl, and wherein the C 3-6 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

each R 1 is independently *—C(O)NR 7 R 8 or —NH 2 —, wherein R 7 and R 8 are each independently hydrogen or C 1-4 alkyl; and

R 17 is selected from the group consisting of cyano, halo, —NH 2 —, —C(O)NH 2 , —C(O)NH(CH 3 ), and —C(O)N(CH 3 ) 2 .

10. The compound of claim 1 , wherein the compound, or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, is selected from the group consisting of:

N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)methyl)aniline;

N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)methyl)aniline;

N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)methyl)yridine-2-amine;

5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;

N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;

5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;

N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;

5-(((4-fluorophenyl)sulfinylmethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;

3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzamide;

4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzamide;

4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;

4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;

3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide; N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)yridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-methyl-N-(5-(methylsulfonyl)pyridine-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-amine

N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-amine;

N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)nicotinamide;

N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)picolinamide;

4-cyano-N-((tetrahydro-2H-pyran-4-ylmethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;

N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)urea;

6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;

6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;

4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;

5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide;

N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;

N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;

N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenzamide

4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;

N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;

4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;

N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)phenyl)acetamide;

3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;

4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;

4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;

4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;

N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;

3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide; and

3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide.

11. A pharmaceutical composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

12. The pharmaceutical composition according to claim 11 , further comprising a second agent, wherein the second agent is an antimalarial drug selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.