Compositions and methods for treating toxoplasmosis, cryptosporidiosis, and other apicomplexan protozoan related diseases

1. A method for treating an apicomplexan protozoan related disease comprising providing to a patient in need of such treatment a therapeutically effective amount of a compound of formula:

or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, carrier, or diluent, wherein

X, Y, and Z are defined by either: (i) X is N, Y is C, and Z is N; or (ii) X is C, Y is N, and Z is C(H);

R 1 is C 2-6 alkyl, C 1-6 haloalkyl, —C 1-4 alkyl—R 12 , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, monocyclic heterocyclyl, monocyclic heteroaryl, or phenyl, wherein

the cycloalkyl, heterocyclyl, heteroaryl, and phenyl groups are each optionally substituted with one or two R 11 groups;

each R 11 is independently C 1-6 alkyl, C 1-6 haloalkyl, —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , or —S(O) 2 R;

and

R 12 is —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR 2 , phenyl, monocyclic heteroaryl, C 3-8 cycloalkyl, or monocyclic heterocyclyl, wherein the aryl, heteroaryl, C 3-8 cycloalkyl, and heterocyclyl groups are each optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR 2 ;

R 3 is one of the formulas,

wherein

n is 0, 1, or 2;

Q is —O—, —S—, or —N(R Q )—, wherein R Q is hydrogen or C 1-6 alkyl; and

R 33 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 20 , —SR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —S(O) 2 R 20 , —OC(O)R 20 , —OC(O)OR 20 , —OC(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , or —N(R 20 )C(O)N(R 20 ) 2 , wherein each R 20 is independently hydrogen or C 1-6 alkyl,

each R 32 is independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 34 , —SR 34 , —N(R 34 ) 2 , —C(O)R 34 , —C(O)OR 34 , —C(O)N(R 34 ) 2 , —S(O) 2 R 34 , —OC(O)R 34 , —OC(O)OR 34 , —OC(O)N(R 34 ) 2 , —N(R 34 )C(O)R 34 , —N(R 34 )C(O)OR 34 , or —N(R 34 )C(O)N(R 34 ) 2 wherein each R 34 is independently hydrogen or C 1-6 alkyl; and

R 35 is hydrogen or C 1-6 alkyl; and

each R is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 R 0 , —OC(O)R 0 , —OC(O)OR 0 , —OC(O)N(R 0 ) 2 , —N(R 0 )C(O)R 0 , —N(R 0 C(O)OR 0 , or —N(R 0 )C(O)N(R 0 ) 2 , wherein each R 0 is independently hydrogen or C 1-6 alkyl, provided that the compound is not

1-cyclopentyl-3-(1-methyl-1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-cyclopentyl-3-(1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-cyclopentyl-3-(1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-3-carbaldehyde,

3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-isopropyl-3-(1-methyl-1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

3-(1H-indol-6-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

2-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol,

3-(1H-indol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, and

1-cyclopentyl-3-(1H-indol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.

2. The method of claim 1 , wherein the apicomplexan protozoan related disease is toxoplasmosis, cryptosporidiosis, coccidiosis, or malaria.

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

3-(6-isopropoxynaphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

1-(piperidin-4-ylmethyl)-3-(6-propoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(benzyloxy)naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-butoxynaphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(allyloxy)naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(2-chlorobenzyloxy)naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(3-chlorobenzyloxy)naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(4-chlorobenzyloxy)naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(benzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(allyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-butoxynaphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-isobutoxynaphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-isobutoxynaphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(2-chlorobenzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(3-chlorobenzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(2,5-dimethylbenzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

1-isopropyl-3-(6-(2-methylbenzyloxy)naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

1-isopropyl-3-(6-(2-methyl-5-(trifluoromethyl)benzyloxy)naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(3-chloro-4-(2,2,2-trifluoroethyl)benzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(3-chloro-5-fluorobenzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d] pyrimidin-4-amine;

1-isopropyl-3-(6-(1-phenylethoxy)naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(4-tert-butylbenzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

1-isopropyl-3-(6-(pyridin-4-ylmethoxy)naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

3-(6-(4-chlorobenzyloxy)naphthalen-2-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

6-(4-amino-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,N-dimethylquinolin-2-amine;

3-tert-butyl-1-(6-ethoxynaphthalen-2-yl)imidazo[1,5-a]pyrazin-8-amine;

3-(6-ethoxynaphthalen-2-yl)-1-((l-methylpiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

and pharmaceutically acceptable salts thereof.

4. The method of claim 1 , wherein the compound is of the formula:

5. The method of claim 1 , wherein the compound is of the formula:

6. The method of claim 1 , wherein R 3 is

7. The method of claim 6 , wherein Q is —O— or —N(R Q )—.

8. The method of claim 7 , wherein R 33 is C 1-6 alkyl, C 2-6 alkenyl, arylC 1-6 alkyl, or heteroarylC 1-6 alkyl, wherein the arylalkyl and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 20 , δR 20 N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —S(O) 2 R 20 , —OC(O)R 20 , —OC(O)OR 20 , —OC(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , or —N(R 20 )C(O)N(R 20 ) 2 , wherein each R 20 is independently hydrogen or C 1-6 alkyl.

9. The method of claim 1 , wherein R 1 is C 2-6 alkyl or —C 1-4 alkyl-R 12 .

10. The method of claim 9 , wherein R 1 is —CH 2 —R 12 .

11. The method of claim 9 , wherein R 12 is phenyl, monocyclic heteroaryl, C 3-8 cycloalkyl, or monocyclic heterocyclyl, wherein the phenyl, heteroaryl, C 3-8 cycloalkyl, and heterocyclyl groups are each optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR 2 .

12. The method of claim 9 , wherein R 12 is piperidinyl optionally substituted by one or two groups that are each independently C 1-6 alkyl, —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR 2 .

13. The method of claim 7 , wherein R 33 is C 1-6 alkyl or C 3-8 cycloalkyl.

14. The method of claim 13 , wherein R 1 is —C 1-4 alkyl-R 12 .

15. The method of claim 13 , wherein R 12 is —OR or monocyclic heterocyclyl optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR 2 .

16. The method of claim 15 , wherein R 1 is —C 4 alkyl-R 12 and R 33 is C 3-8 cycloalkyl.

17. The method of claim 16 , wherein R 12 is —OR.