5-aminopyrazole-4-carboxamide inhibitors of CDPK1 from T. gondii and C. parvum

A method for treating an apicomplexan protozoan related disease, wherein the disease is caused by Cryptosporidium parvum, Cryptosporidium hominus, Toxoplasma gondi, Neospora caninum, or Plasmodium spp., the method comprising providing to a patient in need of such treatment a therapeutically effective amount of either a compound of formula:

• or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein
• R1 is one of the formulas:
• wherein
• R8 is, halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, or -Q-R8′;
• Q is —O—, —S—, —NH—, or —N(C1-6 alkyl)-;
• R8′ is hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-8 cycloalkyl, heterocyclyl, aryl, arylC1-6 alkyl, heteroaryl, or heteroarylC1-6 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, C1-6 alkyl, C1-6 haloalkyl, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —S(O)2R14, —OC(O)R14, —OC(O)OR14, —OC(O)N(R14)2, —N(R14)C(O)R14, —N(R14)C(O)OR14, or —N(R14)C(O)N(R14)2, wherein each R14 is independently hydrogen or C1-6 alkyl;
• and
• R2 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, —C1-4alkyl-R12, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, monocyclic heterocyclyl, monocyclic heteroaryl, or phenyl, wherein the alkyl, cycloalkyl, heterocyclyl, heteroaryl, and phenyl groups are each optionally substituted with one or two R13 groups;
• each R13 is independently C1-6 alkyl, C1-6 haloalkyl, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, or —S(O)2R;
• and
• where R12 is —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2R, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR2, phenyl, monocyclic heteroaryl, C3-8 cycloalkyl, or monocyclic heterocyclyl, wherein the aryl, heteroaryl, C3-8 cycloalkyl, and heterocyclyl groups are each optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2R, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR2;
• and each R is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-8 cycloalkyl, heterocyclyl, aryl, arylC1-6 alkyl, heteroaryl, or heteroarylC1-6 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, C1-6 alkyl, C1-6 haloalkyl, —OR0, —SR0,) —N(R0)2, —C(O)R0, —C(O)OR0, —C(O)N(R0)2, —S(O)2R0, —OC(O)R0, —OC(O)OR0, —OC(O)N(R0)2, —N(R0)C(O)R0, —N(R0)C(O)OR0, or —N(R0)C(O)N(R0)2, wherein each R0 is independently hydrogen or C1-6 alkyl;
• or R2 and R3 together with the atoms to which they are attached form 2-oxo-2,3 -dihydro-imidazolyl ring;
• R3 and R4 are independently hydrogen;
• and
• R5 and R6 are independently hydrogen.

A method for inhibiting activity of an apicomplexan calcium dependent protein kinase (CDPK) in a patient, comprising providing to the patient in need of such treatment a therapeutically effective amount of either a compound of formula:

• or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein R1 is one of the formulas:
• wherein
• R8 is, halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, or -Q-R8′;
• Q is —O—, —S—, —NH—, or —N(C1-6 alkyl)-;
• R8′ is hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-8 cycloalkyl, heterocyclyl, aryl, arylC1-6 alkyl, heteroaryl, or heteroarylC1-6 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, C1-6 alkyl, C1-6 haloalkyl, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —S(O)2R14, —OC(O)R14, —OC(O)OR14, —OC(O)N(R14)2, —N(R14)C(O)R14, —N(R14)C(O)OR14, or —N(R14)C(O)N(R14)2, wherein each R14 is independently hydrogen or C1-6 alkyl;
• and
• each R9 is independently hydrogen or C1-6 alkyl;
• R2 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, —C1-4 alkyl-R12, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, monocyclic heterocyclyl, monocyclic heteroaryl, or phenyl, wherein the alkyl, cycloalkyl, heterocyclyl, heteroaryl, and phenyl groups are each optionally substituted with one or two R13 groups;
• each R13 is independently C1-6 alkyl, C1-6 haloalkyl, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, or —S(O)2R;
• and
• where R12 is —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2R, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR2, phenyl, monocyclic heteroaryl, C3-8 cycloalkyl, or monocyclic heterocyclyl, wherein the aryl, heteroaryl, C3-8 cycloalkyl, and heterocyclyl groups are each optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2R, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR2;
• and each R is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-8 cycloalkyl, heterocyclyl, aryl, arylC1-6 alkyl, heteroaryl, or heteroarylC1-6 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, C1-6 alkyl, C1-6 haloalkyl, —OR0, —SR0, —N(R0)2, —C(O)R0, —C(O)OR0, —C(O)N(R0)2, —S(O)2R0, —OC(O)R0, —OC(O)OR0, —OC(O)N(R0)2, —N(R0)C(O)R0, —N(R0)C(O)OR0, or —N(R0)C(O)N(R0)2, wherein each R0is independently hydrogen or C1-6 alkyl;
• or R2 and R3 together with the atoms to which they are attached form 2-oxo-2,3-dihydro-imidazolyl ring;
• R3 and R4 are independently hydrogen;
• and
• R5 and R6 are independently hydrogen.