HK1260345A1

HK1260345A1 - Compositions and methods for treating infections

Info

Publication number: HK1260345A1
Application number: HK19119808.4A
Authority: HK
Inventors: S·托马斯; A·T·霍普; M·威尔士
Original assignee: 维耶拉制药有限责任公司
Priority date: 2016-02-05
Filing date: 2017-02-02
Publication date: 2019-12-20

Description

Compositions and methods for treating infections

RELATED APPLICATIONS

This application claims benefit of U.S. provisional application No. 62/291,900 filed on 5/2016 and U.S. provisional application No. 62/375,712 filed on 16/8/2016, each of which is incorporated herein by reference in its entirety for all teachings.

Background of the invention

Parasitic protozoan infections are a major concern for human health. Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii (t.gondii). Although toxoplasmosis is most often asymptomatic, people infected with toxoplasmosis can experience severe symptoms (including seizures, poor coordination, lung injury, eye injury, and brain injury); and if left untreated, infections in immunocompromised patients are often fatal. Other parasitic protozoan infections include leishmaniasis (leishmaniasis) (also known as leishmaniasis) caused by protozoan (Trypanosoma brucei) (including Leishmania major) (l.major), Leishmania tropicalis (Leishmania tropica) (l.tropica), Leishmania brasiliensis (Leishmania brasiliensis) (l.brasiliensis) and Leishmania donovani (l.donovani)), chagas disease (leishmaniasis) (also known as leishmaniasis (leishmaniasis)), Trypanosoma cruzi (t.cruzi)) caused by protozoan Trypanosoma cruzi (t.bruzi) (t.cruzi), human african trypanosomiasis (t.brussemia) caused by protozoan (t.brussemia) and plasmodium malaria (plasmodium falciparum), as well as plasmodium malarial parasite (plasmodium).

Existing treatments for toxoplasmosis include administration of pyrimethamine (often combined with DHPS sulfadiazine inhibitors (e.g., sulfadiazine) to improve efficacy and with leucovorin (leucovorin) to improve tolerability). Allergic reactions to sulfonamides are common and therefore some patients cannot receive combination therapy. Pyrimethamine treatment can cause severe side effects and toxicity (including nausea, vomiting, leukopenia, bone marrow toxicity, teratogenicity, and central nervous system toxicity). The mechanism-based toxicity of DHFR inhibition in mammalian (including human) cells can be partially mitigated by administering leucovorin (leucovorin) to selectively replace tetrahydrofolate in mammalian cells.

Pyrimethamine acts by inhibiting the enzyme dihydrofolate reductase (DHFR). IC of pyrimethamine against Toxoplasma gondii DHFR (tgDHFR)₅₀0.76 μ M and pyrimethamine IC for human DHFR (hDHFR)₅₀At 5.8. mu.M. (Allegra et al, J.Clin.Investimation.1987, 79, 478-482). Thus, while pyrimethamine inhibits tgDHFR more potently than hDHFR, the selectivity ratio for tgDHFR (less than 10) is relatively low. Thus, clinically relevant doses of pyrimethamine result in plasma concentrations that effectively inhibit hDHFR, leading to many of the observed mechanism-based side effects of pyrimethamine. In addition, relatively high IC of pyrimethamine for tgDHFR₅₀Greater plasma concentrations are required for efficacy, which can cause additional off-target induced side effects.

Thus, there is a need for compounds that are both more potent and selective inhibitors of tgDHFR compared to hDHFR. Likewise, there is also a need for potent and selective DHFR inhibitors against leishmania, trypanosoma cruzi, trypanosoma brucei and plasmodium for the treatment of leishmaniasis, chagas disease, african trypanosomiasis and malaria, respectively.

Summary of The Invention

In certain embodiments, the present invention relates to compounds having the structure of formula (I) or a pharmaceutically acceptable salt and/or prodrug of said compound:

wherein:

R¹is H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or halogen;

w is N or CR¹⁸And Z is N or CR¹⁷Provided that at least one of W and Z is N;

R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁷and R¹⁸Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy or fluoro; provided that R is²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹At least four of (a) are H; if W is N, R²、R³、R⁶And R⁷None of which is a hydroxyl group; and if Z is N, then R⁴、R⁵、R⁸And R⁹None of which is a hydroxyl group;

R¹⁰is substituted or unsubstituted C_6-10Aryl or 5-to 10-membered heteroaryl.

The invention also relates to pharmaceutical compositions of such compounds, and methods of using such compounds to treat infections, e.g., parasitic infections such as toxoplasmosis.

Detailed description of the invention

In one aspect, the present invention relates to compounds having the structure of formula (I) or a pharmaceutically acceptable salt and/or prodrug of said compound:

in formula (I):

In certain embodiments, W is N, and Z is CR¹⁷. In certain such embodiments, R²、R³、R⁶And R⁷Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or fluoro; and R is⁴、R⁵、R⁸、R⁹And R¹⁷Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy or fluoro.

In certain embodiments, W is CR¹⁸And Z is N. In certain such embodiments, R²、R³、R⁶、R⁷And R¹⁸Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy, or fluoro; and R is⁴、R⁵、R⁸And R⁹Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or fluoro.

In certain preferred embodiments, W is N, and Z is N. In certain such embodiments, R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or fluoro.

In certain embodiments, the compound has the structure of formula (Ia) or is a pharmaceutically acceptable salt and/or prodrug of the structure of formula (Ia):

wherein:

R¹is H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen;

R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or fluoro, with the proviso that R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹At least four of (a) are H;

In certain embodiments, R¹⁰The substituents on (a) are selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, or an aromatic or heteroaromatic moiety. In certain embodiments, R¹⁰The substituents on (a) are selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, or an aromatic or heteroaromatic moiety. In certain preferred embodiments, R¹⁰Not substituted by carbonyl groups. In certain preferred embodiments, R¹⁰Not substituted with vinyl, acyl, amide, ester, carboxylic acid, sulfonamide, sulfate, sulfone, sulfonate, sulfoxide, nitro, oxime, hydrazide, or hydrazone.

In certain embodiments, R¹⁰Substituted with at least one substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In certain embodiments, R¹⁰Substituted with at least one substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In certain preferred embodiments, R¹⁰Substituted with at least one substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxyHeterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In certain preferred embodiments, R¹⁰Not substituted by carbonyl groups. In certain preferred embodiments, R¹⁰Not substituted with vinyl, acyl, amide, ester, carboxylic acid, sulfonamide, sulfate, sulfone, sulfonate, sulfoxide, nitro, oxime, hydrazide, or hydrazone.

In certain embodiments, R¹⁰Is substituted or unsubstituted C_6-10Aryl or 5-to 10-membered heteroaryl, and further with R¹²Or X-R¹²Substitution;

R¹²each instance of (a) is independently selected from substituted or unsubstituted phenyl, 5-or 6-membered heteroaryl, or 4-to 7-membered heterocyclyl;

each instance of X is independently selected from carbonyl, Y, -CH₂Y-, or-YCH₂-；

Each instance of Y is independently selected from-CH₂-, -O-, -S-, or-N (R)¹³) -; and is

R¹³Is independently H or C_1-6An alkyl group.

In certain embodiments, R¹⁰Is optionally independently selected from R¹¹、R¹²Or X-R¹²C substituted by one or more substituents of_6-10Aryl or 5-to 10-membered heteroaryl;

R¹¹each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkyl radical, C_4-8Cycloalkylalkoxy, cyano, or halogen;

each instance of X is independently selected fromCarbonyl, Y, -CH₂Y-, or-YCH₂-；

Each instance of Y is independently selected from-CH₂-, -O-, -S-, or-NR¹³-; and is

R¹³Is independently H or C_1-6An alkyl group.

In certain embodiments, R¹⁰Not more than one R¹²Or X-R¹²And (4) substitution. In certain embodiments, R¹⁰Is substituted by one R¹²And (4) substitution. In certain embodiments, R¹⁰By an X-R¹²And (4) substitution.

In certain embodiments, R¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In certain preferred embodiments, R¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, amino, amidine, cyano, mercapto, or alkylthio, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

In certain embodiments, R¹²The substituents on are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Alkoxyalkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-7Haloalkoxyalkoxy group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, 4-to 7-membered heterocyclyloxy, halogen, cyano, oxoBasic, or alternatively with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino. In certain embodiments, R¹²The substituents on are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino. In certain embodiments, R¹²The substituents on are selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, cyano, or oxo. In certain embodiments, R¹²The substituents on are selected from C_1-6An alkoxy group.

In certain preferred embodiments, R¹⁰Is phenyl. In certain such embodiments, R¹⁰Having at least one substituent in the meta or ortho position (preferably in the meta position). In certain such embodiments, the phenyl ring has at least two substituents.

In certain preferred embodiments, R¹⁰Is a 5-to 10-membered heteroaryl group, such as pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, or thiazolyl.

In certain preferred embodiments, R¹⁰Is a 5-to 10-membered heteroaryl group, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, or thiazolyl. In certain such embodiments, R¹⁰Is pyridyl, pyrimidinyl, or pyrazinyl.

In certain preferred embodiments, R¹²Is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, or thiazolyl. In certain such embodiments, R¹²Is pyridyl, pyrimidinyl, or pyrazinyl.

In certain embodiments, R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is at least one of C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen; r¹Is C_4-6Alkyl radical, C_3-6Cycloalkyl, or fluoro; r¹⁰Is a substituted or unsubstituted 5-to 10-membered heteroaryl or C₁₀An aryl group; r¹⁰Is phenyl substituted in the meta or ortho position with at least one substituent selected from halogen (e.g., fluorine or chlorine), hydroxy, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl; r¹⁰Is made of C_1-6Alkyl-substituted phenyl, said C_1-6Alkyl optionally substituted with C_1-6Alkyl radical, C_3-6Cycloalkyl, halo, carbonyl, cyano, or hydroxy; or R¹⁰Is prepared from R¹²Or X-R¹²(preferably X-R)¹²) A substituted phenyl group.

In certain embodiments, Z is CR¹⁷Or W is CR¹⁸；R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is at least one of C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen; r¹Is C_4-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or fluoro; r¹⁰Is a substituted or unsubstituted 5-to 10-membered heteroaryl or C₁₀An aryl group; r¹⁰Is phenyl substituted in the meta or ortho position with at least one substituent selected from halogen (e.g., fluorine or chlorine), hydroxy, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl; r¹⁰Is made of C_1-6Alkyl-substituted phenyl, said C_1-6Alkyl optionally substituted with C_1-6Alkyl radical, C_3-6Cycloalkyl, halo, carbonyl, cyano, or hydroxy; r¹⁰Is prepared from R¹²Or X-R¹²(preferably X-R)¹²) Substituted phenyl; r¹⁰Is phenyl substituted with fluoro; or R¹Is C_3-6Alkyl, and R¹⁰Is phenyl optionally substituted with halogen (e.g., fluorine or chlorine), hydroxyl, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, azido, sulfhydryl, or alkylthio. In certain embodiments, R¹Is C_4-6Alkyl radical, C_3-6Cycloalkyl, or fluoro.

In certain embodiments, Z is CR¹⁷Or W is CR¹⁸。

In certain embodiments, Z is CR¹⁷。

In certain embodiments, Z and W are N, and R is¹⁰Is phenyl substituted in the meta or ortho position with at least one substituent selected from chlorine, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl.

In certain embodiments, Z and W are N, R¹Is H, and R¹⁰Is phenyl substituted with at least one substituent selected from halogen (e.g., fluoro or chloro), alkyl, trifluoromethyl, cycloalkyl, alkoxy, trifluoromethoxy, or cyano.

In certain embodiments, R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is at least one of C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen.

In certain embodiments, R¹Is C_4-6Alkyl radical, C_3-6Cycloalkyl, or fluoro.

In certain embodiments, R¹Is C_4-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or fluoro.

In certain embodiments, R¹Is C_3-6Alkyl, and R¹⁰Is phenyl optionally substituted with halogen (e.g., fluorine or chlorine), hydroxyl, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, azido, sulfhydryl, or alkylthio.

In certain embodiments, R¹Is methyl, and R¹⁰Is phenyl substituted in the meta or ortho position with halogen (e.g., fluorine or chlorine), alkyl, trifluoromethyl, alkoxy, trifluoromethoxy, or cycloalkyl.

In certain embodiments, R¹Is ethyl, and R¹⁰Is phenyl optionally substituted with halogen (e.g., fluoro or chloro), hydroxy, alkoxy, trifluoromethoxy, amino, alkyl, trifluoromethyl, or cycloalkyl.

In certain embodiments, R¹Is propyl, and R¹⁰Is unsubstituted phenyl or phenyl optionally substituted with halogen (e.g., fluoro or chloro), hydroxy, alkoxy, trifluoromethoxy, amino, alkyl, trifluoromethyl, or cycloalkyl.

In certain embodiments, R¹⁰Is a substituted or unsubstituted 5-to 10-membered heteroaryl or C₁₀And (4) an aryl group.

In certain embodiments, R¹⁰Is prepared from R¹²Or X-R¹²(preferably X-R)¹²) A substituted phenyl group.

In certain embodiments, R¹⁰Is phenyl substituted in the meta or ortho position with at least one substituent selected from halogen (e.g., fluorine or chlorine), hydroxyl, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl.

In certain embodiments, R¹⁰Is made of C_1-6Alkyl-substituted phenyl, said C_1-6Alkyl optionally substituted with C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, carbonyl, cyano, or hydroxy.

In certain embodiments, R¹⁰Is phenyl substituted with fluorine. In certain embodiments, R¹⁰Is fluorophenyl and is not further substituted.

In certain embodiments, R¹⁰Is phenyl substituted with fluorine.

In certain embodiments, if R¹Is H, methyl, ethyl, or chloro, and R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is H, then R¹⁰Is not unsubstituted phenyl. In certain embodiments, if R¹Is methyl, and R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is H, then R¹⁰Is not 4-chlorophenyl, 4-trifluoromethylphenyl, or 4-cyanophenyl. In certain embodiments, if R¹Is ethyl or n-propyl, and R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is H, then R¹⁰Is not 4-cyanophenyl. In certain embodiments, the compounds of the present invention do not comprise compounds represented by the following structures:

in certain embodiments, R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl radical, C_4-8Cycloalkylalkyl, or halogen. In certain embodiments, R¹Is C_4-8A cycloalkylalkyl group.

In certain embodiments, R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl, or halogen.

In certain embodiments, R¹¹Is selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, cyano, or oxo. In further embodiments, R¹¹The substituents on each instance of (a) are limited to methyl, ethyl, cyclopropyl, halogen, cyano, or oxo.

In certain embodiments, R¹Is H, and R¹⁰Is phenyl.

In certain embodiments, R¹⁰With R¹²Is substituted, and R¹⁰Optionally further substituted; and R is¹²Selected from substituted or unsubstituted phenyl, 5-or 6-membered heteroaryl, or 4 to 7-membered heterocyclyl. In certain such embodiments, R¹⁰With R¹²Is substituted, and R¹⁰Optionally with a group independently selected from R¹¹Is further substituted with one or more substituents of (a); and R is¹²Is a substituted or unsubstituted phenyl, 5-or 6-membered heteroaryl, or 4-to 7-membered heterocyclyl. In certain preferred embodiments, R¹²Is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, or tetrahydropyranyl. In certain such embodiments, R¹²Is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or tetrahydropyranyl. In certain embodiments, R¹²Is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, or thiazolyl. In certain embodiments, R¹¹Each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo. In certain preferred embodiments, R¹²The substituents on are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino. In certain preferred embodiments, R¹²The substituents on are selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, cyano, or oxo. In further embodiments, R¹²The substituents on (a) are limited to methoxy, ethoxy, hydroxy, methyl, ethyl, cyclopropyl, cyclobutylamine, dimethylamine, methylamine, trifluoromethyl, halogen, cyano, or oxo. In further embodiments, R¹²The substituents on (A) are limited to methyl, ethyl, cyclopropyl, halogen, cyano, or oxo.

In certain embodiments, R¹²Is a substituted or unsubstituted phenyl, 5-or 6-membered heteroaryl, or 4-to 7-membered heterocyclyl. In certain such embodiments, R¹²Substituted with methyl, ethyl, methoxy, ethoxy or trifluoromethyl. In certain preferred embodiments, R¹Is H. In certain embodiments, R¹²Is phenyl, pyrimidin-5-yl, or pyridin-3-yl. In certain embodiments, R¹²Is pyrimidin-5-yl or pyridin-3-yl. In certain preferred embodiments, R¹²Is 2-methoxy-pyrimidin-5-yl, 3-methoxyphenyl, 2-methoxy-pyridin-3-yl, 2-methyl-pyrimidin-5-yl, or tetrahydropyran-4-yl. In certain preferred embodiments, R¹²Is 2-methoxy-pyrimidin-5-yl, 3-methoxyphenyl, 2-methoxy-pyridin-3-yl, or 2-methyl-pyrimidin-5-yl.

In certain preferred embodiments, the present invention relates to a compound having one of the following structures or a pharmaceutically acceptable salt or prodrug of said compound:

in certain embodiments, R¹²Is a substituted or unsubstituted phenyl group. In further embodiments, R¹²The substituents on are selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, halogen, cyano, or oxo. In further embodiments, R¹²The substituents on are selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, cyano, or oxo. In certain preferred embodiments, R¹²The substituents on (a) are limited to hydroxy, methyl, trifluoromethyl, trifluoromethoxy, ethyl, cyclopropyl, methoxy, ethoxy, halogen, cyano, or oxo. In certain preferred embodiments, R¹²The substituents on (A) are limited to methyl, ethyl, cyclopropyl, halogen, cyano, or oxo.

In certain preferred embodiments, the present invention relates to a compound having the structure:

in certain embodiments, R¹Is C_1-6Alkyl radical, C_3-6Cycloalkyl, or C_4-8A cycloalkylalkyl group; and R is¹⁰Optionally with a group independently selected from R¹¹Is substituted with one or more substituents of (a). In certain preferred embodiments, R¹¹Each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo. In certain preferred embodiments, R¹Is C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or C_1-3An alkyl group.

In certain embodiments, R¹Is C_1-6Alkyl or C_3-6A cycloalkyl group; and R is¹⁰Optionally with a group independently selected from R¹¹Is substituted with one or more substituents of (a). In certain preferred embodiments of the present invention,R¹¹each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo. In certain preferred embodiments, R¹Is C_3-6Cycloalkyl or C_1-3An alkyl group.

in certain embodiments above, Z is CR¹⁷And W is N. In certain such embodiments, R¹Is C_1-6Alkyl or C_3-6A cycloalkyl group; and R is¹⁰Optionally with a group independently selected from R¹¹Is substituted with one or more substituents of (a). In certain preferred embodiments, R¹¹Each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo.

In certain embodiments above, Z is CR¹⁷. In certain embodiments, Z is CR¹⁷；R¹Is C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-8A cycloalkylalkyl group; and R is¹⁰Optionally with a group independently selected from R¹¹Is substituted with one or more substituents of (a). In certain preferred embodiments, R¹¹Each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo.

in certain embodiments, R¹⁰With R¹⁵And R¹⁶Is substituted, and optionally substituted with a substituent independently selected from R¹¹Substituted with one or more substituents of (a); and R is¹⁵And R¹⁶Independently selected from halogens (such as chlorine). In certain preferred embodiments, R¹¹Each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo.

in certain embodiments, R¹⁰With R¹⁵Is substituted, and optionally substituted with a substituent independently selected from R¹¹Substituted with one or more substituents of (a); and R is¹⁵Independently selected from halogen (such as chlorine) or haloalkyl (such as trifluoromethyl). In certain preferred embodiments, R¹¹Each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo.

in another aspect, the invention relates to a pharmaceutical composition comprising a compound as disclosed herein.

In yet another aspect, the invention relates to methods of preventing or inhibiting the growth or proliferation of a microorganism using a compound of formula (I). In certain embodiments, the microorganism is a protozoan. In certain embodiments, the protozoan is of the genus Toxoplasma, Leishmania, Trypanosoma, or Plasmodium. In certain embodiments, the microorganism is Toxoplasma gondii, Trypanosoma cruzi, Trypanosoma brucei, or is a genus Leishmania or Plasmodium. In certain preferred embodiments, the microorganism is Toxoplasma gondii, Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei, or Leishmania macrorrhiza. In certain embodiments, inhibiting the growth or proliferation of a microorganism comprises applying a compound having the structure of formula (I) to a location. The compound may be applied in the form of a spray (e.g., from a spray bottle) or by wiping (e.g., with a pre-soaked rag, mop, or sponge). In certain embodiments, a location is one in which a microorganism is known to be present or suspected to be present. In certain embodiments, the location is a location at risk of having a microorganism. In certain embodiments, the compound of formula (I) is administered prophylactically. In certain embodiments, the compound of formula (I) is applied after suspected contamination by a protozoan. In certain embodiments, the location may be a surface, such as a cooking surface or a surface that has been contacted with a material suspected of containing microorganisms (e.g., a surface that has been contacted with raw meat or animal (e.g., cat) feces). In certain embodiments, the cooking surface is a chopping board, counter, or utensil (e.g., knife or fork). In certain embodiments, the location may be on the surface or within a food item (e.g., meat or vegetables). In certain embodiments, the location may be a liquid, such as water, e.g., potable water. In certain embodiments, the location may be soil. In certain embodiments, the location may be a place where the cat has defecated or is about to defecate, or an area where cat litter or cat litter may be spread or has been spread. In a further embodiment, the location is a trash bin or an area around a trash bin. In certain embodiments, the location is a body surface (e.g., a hand).

In certain embodiments, the compounds of formula (I) are used to prevent the spread of microorganisms between humans and/or animals. In a further embodiment, the transmission is an innate transmission. In further embodiments, the compound of formula (I) is administered to the mother, to the infant, to the skin of the mother, or to the skin of the infant. In certain embodiments, the compound of formula (I) is administered to blood (as illustrated for transfused blood). In certain embodiments, the compound of formula (I) is applied to an organ (as one intended for transplantation). In certain embodiments, the compound of formula (I) is administered to an organ donor prior to transplantation. In certain embodiments, the compound of formula (I) is administered to an animal (e.g., a cat or a mouse).

In yet another aspect, the invention relates to a method of treating an infection comprising administering a compound having the structure of formula (I), a pharmaceutically acceptable salt or prodrug of said compound, or a pharmaceutical composition comprising such a compound, salt or prodrug. In certain embodiments, the infection is caused by a protozoan. In certain embodiments, the protozoan is of the genus Toxoplasma, Leishmania, Trypanosoma, or Plasmodium. In certain embodiments, the microorganism is Toxoplasma gondii, Trypanosoma cruzi, Trypanosoma brucei, or is a genus Leishmania or Plasmodium. In certain preferred embodiments, the infection is caused by Toxoplasma gondii, Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei or Leishmania macrorrhiza.

In yet another aspect, the invention relates to one of the compounds or components disclosed herein, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such a compound, salt or prodrug, for use in the treatment of an infection. In certain embodiments, the infection is caused by a protozoan (e.g., an apicomplexan protozoan). In certain embodiments, the protozoan is of the genus Toxoplasma, Leishmania, Trypanosoma, or Plasmodium. In certain embodiments, the microorganism is Toxoplasma gondii, Trypanosoma cruzi, Trypanosoma brucei, or is a genus Leishmania or Plasmodium. In certain preferred embodiments, the infection is caused by Toxoplasma gondii, Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei, or Leishmania major.

In another aspect, the invention relates to a compound having the structure of formula (I), a pharmaceutically acceptable salt or prodrug of said compound, or a pharmaceutical composition comprising such a compound, salt or prodrug, for use in the treatment of an infection.

The compounds disclosed herein inhibit DHFR and may prevent or reduce infection (including toxoplasmosis). In certain embodiments, the compounds herein preferentially inhibit protozoan DHFR relative to human DHFR. In certain such embodiments, the protozoan is of the genus Toxoplasma, Leishmania, Trypanosoma, or Plasmodium. In certain embodiments, the microorganism is Toxoplasma gondii, Trypanosoma cruzi, Trypanosoma brucei, or is a genus Leishmania or Plasmodium. In certain preferred embodiments, the microorganism is Toxoplasma gondii, Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei, or Leishmania macrorrhiza. In certain such embodiments, the compounds herein are selective for protozoan DHFR (e.g., toxoplasma gondii, trypanosoma cruzi, plasmodium falciparum, trypanosoma brucei, or leishmania gigantea) as compared to human DHFR (e.g., in terms of the IC of the compound for each enzyme₅₀Determined by a ratio of (a) is greater than 3 times, greater than 10 times, greater than 30 times, greater than 50 times, greater than 75 times, greater than 100 times, or greater than 300 times. In certain embodiments, the compounds herein have an IC of less than 1000nM or less than 100nM (preferably less than 10nM) for protozoan DHFR such as Toxoplasma gondii, Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei, or Leishmania macrogola₅₀. In certain embodiments, the compounds herein are selective for toxoplasma gondii, trypanosoma cruzi, plasmodium falciparum, trypanosoma brucei, or leishmania magna (e.g., based on the IC of the compound for each receptor) as compared to human DHFR₅₀Determined by a ratio of (a) is greater than 3 times, greater than 10 times, greater than 30 times, greater than 50 times, greater than 75 times, greater than 100 times, or greater than 300 times. In certain embodiments, the compounds herein are directed against Toxoplasma gondii, Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei, or Leishmania macrorrhiza DHFR has an IC of less than 1000nM or less than 100nM, preferably less than 10nM₅₀。

In certain embodiments, a compound of the invention may be a prodrug of a compound disclosed herein, for example, wherein the hydroxy group in the parent compound is present as an ester or carbonate, or the carboxylic acid present in the parent compound is present as an ester. In certain such embodiments, the prodrug is metabolized in vivo to the active parent compound (e.g., the ester is hydrolyzed to the corresponding hydroxy or carboxylic acid).

In certain embodiments, the compounds of the invention may be racemic. In certain embodiments, the compounds of the present invention may be enriched in one enantiomer. For example, a compound of the invention may have an ee of greater than 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 95% or greater. In certain embodiments, the compounds of the present invention may have more than one stereocenter. In certain such embodiments, the compounds of the present invention may be enriched in one or more diastereomers. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

In certain embodiments, the invention relates to methods of treatment with a compound disclosed herein, or a pharmaceutically acceptable salt of said compound. In certain embodiments, the therapeutic agent may be enriched to provide predominantly one enantiomer of the compound. Enantiomerically enriched mixtures may comprise, for example, at least 60mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99mol percent. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means, for example, that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% of the amount of the other enantiomer in the composition or mixture of compounds. For example, if a composition or mixture of compounds contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it is said to contain 98mol percent of the first enantiomer and only 2% of the second enantiomer.

In certain embodiments, the therapeutic agent may be enriched to provide predominantly one diastereomer of the compound. The diastereomerically enriched mixture may include, for example, at least 60 mole percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mole percent.

In certain embodiments, the invention relates to methods of treatment with a compound disclosed herein, or a pharmaceutically acceptable salt of said compound. In certain embodiments, the therapeutic agent may be enriched to provide predominantly one enantiomer of such a compound. Enantiomerically enriched mixtures may comprise, for example, at least 60mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99mol percent. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means, for example, that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% of the amount of the other enantiomer in the composition or mixture of compounds. For example, if a composition or mixture of compounds contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it is said to contain 98mol percent of the first enantiomer and only 2% of the second enantiomer.

In certain embodiments, the therapeutic agent may be enriched to provide predominantly one diastereomer of a compound disclosed herein. The diastereomerically enriched mixture may include, for example, at least 60 mole percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mole percent.

In certain embodiments, the present invention provides a pharmaceutical formulation suitable for use in a human patient, comprising any of the compounds shown above (e.g., a compound of the invention), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulation may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical formulation has sufficiently low pyrogen activity to be suitable for use in a human patient.

Compounds of any of the above structures may be used in the manufacture of a medicament for the treatment of any of the diseases or conditions disclosed herein.

Definition of

The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbyl C (O) - (preferably alkyl C (O) -).

The term "amido" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C (O) NH-.

The term "acyloxy" is art recognized and refers to a group represented by the general formula hydrocarbyl C (O) O-, preferably alkyl C (O) O-.

The term "alkoxy" refers to an alkyl group (preferably a lower alkyl group) having an oxygen attached thereto. Representative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one double bond, and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," where the latter refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may be present on one or more carbons that are or are not included in one or more double bonds. Further, such substituents include all those contemplated for alkyl groups as discussed below, except where stability is prohibitive. For example, it is contemplated that an alkenyl group is substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

An "alkyl" group or "alkane" is a straight or branched chain nonaromatic hydrocarbon that is fully saturated. Typically, unless otherwise specified, a linear or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10. Examples of linear and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C₁-C₆Straight or branched alkyl groups are also referred to as "lower alkyl" groups.

Furthermore, as used throughout the specification, examples and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyls" and "substituted alkyls", wherein the latter refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. If not otherwise specified, such substituents can comprise, for example, halogen (e.g., fluorine), hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In a preferred embodiment, the substituents on the substituted alkyl groups are selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, carbonyl, cyano, or hydroxy. In a more preferred embodiment, the substituents on the substituted alkyl groups are selected from fluoro, carbonyl, cyano, or hydroxy. It will be understood by those skilled in the art that the substituted moiety on the hydrocarbon chain may itself be substituted (if appropriate). For example, a substituent of a substituted alkyl groupMay contain amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF₃And substituted or unsubstituted forms of, -CN, and the like. Exemplary substituted alkyl groups are described below. Alkyl groups which may be substituted by alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl, -CF₃and-CN, etc. further substituted cycloalkyl.

The term "C" when used in conjunction with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy_x-y"means comprising a group containing from x to y carbons in the chain. For example, the term "C_x-yAlkyl "refers to a substituted or unsubstituted saturated hydrocarbon group (containing straight and branched alkyl groups containing from x to y carbons in the chain, including haloalkyl groups). Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2, 2-trifluoroethyl, and pentafluoroethyl. When the radical is in the terminal position, C₀Alkyl represents hydrogen, if the radical is internal, C₀Alkyl represents a bond. The term "C_2-yAlkenyl "and" C_2-yAlkynyl "refers to a substituted or unsubstituted unsaturated aliphatic hydrocarbon group that is similar in length and possible substituents to the alkyl groups described above, but contains at least one double or triple bond, respectively.

As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group, and may be represented by the general formula alkyl S-.

As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group containing at least one triple bond and is intended to encompass both "unsubstituted alkynyls" and "substituted alkynyls" wherein the latter refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are or are not contained in one or more triple bonds. Further, such substituents include all those intended for alkyl groups as described above, except where stability is prohibitive. For example, it is contemplated that the alkynyl group is substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

As used herein, the term "amide" refers to a group

Wherein each R^AIndependently represent hydrogen or a hydrocarbyl group, or two R^AAnd two R^AThe attached N atoms combine to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., moieties that can be represented by the following formula:

As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

As used herein, the term "aryl" comprises a substituted or unsubstituted, monocyclic aromatic group, wherein each atom of the ring is carbon. Preferably, the ring is a 6-or 10-membered ring, more preferably, a 6-membered ring. The term "aryl" also encompasses polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term "carbamate" is art-recognized and refers to the following groups:

wherein each R^AIndependently represent hydrogen or a hydrocarbyl group (e.g. an alkyl group), or R^ABoth of which are taken together with one or more intervening atoms to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

As used herein, the terms "carbocycle" and "carbocyclic" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings (in which all carbon atoms are saturated) and cycloalkene rings (which contain at least one double bond). "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of the bicyclic carbocycle may be selected from the group consisting of saturated rings, unsaturated rings and aromatic rings. Carbocycles comprise bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two contiguous atoms with the other ring. Each of the fused carbon rings may be selected from saturated rings, unsaturated rings, and aromatic rings. In exemplary embodiments, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated bicyclic rings, unsaturated bicyclic rings, and aromatic bicyclic rings that is valency allowed is encompassed within the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1, 5-cyclooctadiene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decahydronaphthalene, naphthalene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] octane, 4,5,6, 7-tetrahydro-1H-indene and bicyclo [4.1.0] hept-3-ene. The "carbocycle" may be substituted at any one or more positions capable of carrying a hydrogen atom.

A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups have from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of the bicyclic cycloalkyl can be selected from the group consisting of a saturated ring, an unsaturated ring, and an aromatic ring. Cycloalkyl groups comprise bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to bicyclic cycloalkyl groups in which each of the rings shares two contiguous atoms with the other ring. The second ring of the fused bicyclic cycloalkyl can be selected from the group consisting of a saturated ring, an unsaturated ring, and an aromatic ring. "cycloalkenyl" groups are cyclic hydrocarbons containing one or more double bonds.

As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclic group.

The term "carbonate" is art recognized and refers to the group-OCO₂-R^AWherein R is^ARepresents a hydrocarbyl group.

As used herein, the term "carboxy" refers to a compound of the formula-CO₂And H represents a group.

As used herein, the term "ester" refers to the group-C (O) OR^AWherein R is^ARepresents a hydrocarbyl group.

As used herein, the term "ether" refers to a hydrocarbyl group that is linked to another hydrocarbyl group through an oxygen. Accordingly, the ether substituent of the hydrocarbyl group may be hydrocarbyl-O-. The ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers comprise an "alkoxyalkyl" group, which may be represented by the general formula alkyl-O-alkyl.

As used herein, the terms "halogen (halo)" and "halogen (halo)" mean halogen and include chloro, fluoro, bromo, and iodo.

As used herein, the terms "heteroaralkyl" and "heteroaralkyl" refer to an alkyl group substituted with a heteroaryl group.

As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are contiguous.

The terms "heteroaryl" and "heteroaryl" comprise a substituted or unsubstituted aromatic monocyclic ring structure (preferably a 5-to 7-membered ring, more preferably a 5-to 6-membered ring) the ring structure of which comprises at least one heteroatom (preferably one to four heteroatoms, more preferably one or two heteroatoms). The terms "heteroaryl" and "heteroaryl" also encompass polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The terms "heterocyclyl", "heterocycle" and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure (preferably a 3-to 10-membered ring, more preferably a 3-to 7-membered ring) whose ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also encompass polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactones, lactams, and the like.

As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom without an ═ O or ═ S substituent, and typically has at least one carbon-hydrogen bond and a predominant carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl groups for the purposes of this application, but substituents such as acetyl (which has an ═ O substituent on the connecting carbon) and ethoxy (which is connected through oxygen, but not carbon) are not hydrocarbyl groups for the purposes of this application. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

The term "lower", when used in conjunction with a chemical moiety (e.g., acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy), means a group containing ten or fewer non-hydrogen atoms (preferably six or fewer) in the substituent. For example, "lower alkyl" refers to an alkyl group containing ten or fewer carbon atoms (preferably six or fewer). In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent, as defined herein, is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy group, respectively, whether occurring alone or in combination with other substituents, as in the recitation of hydroxyalkyl and aralkyl groups (in the case of aralkyl groups, for example, when calculating the carbon atom in an alkyl substituent, the atom within the aryl group is not calculated).

The terms "polycyclyl," polycyclyl, "and" polycyclic "refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are" fused rings. Each of the rings of the polycyclic rings may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with … …" includes such substitution being according to the allowed valences of the atoms and substituents being substituted, as well as the implicit proviso that the substitution results in a stable compound (e.g., the compound does not spontaneously undergo a transformation, such as by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to encompass all permissible substituents of organic compounds. In a broader aspect, the permissible substituents include acyclic and cyclic substituents of organic compounds, branched and unbranched substituents, carbocyclic and heterocyclic substituents, aromatic and nonaromatic substituents. For suitable organic compounds, the permissible substituents can be one or more and can be the same or different. For the purposes of the present invention, a heteroatom, such as nitrogen, may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatom. The substituent may comprise any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In a preferred embodiment, the substituents on the substituted alkyl groups are selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, carbonyl, cyano, or hydroxy. In a more preferred embodiment, the substituents on the substituted alkyl groups are selected from fluoro, carbonyl, cyano, or hydroxy. It will be appreciated by those skilled in the art that the substituents may themselves be substituted (if appropriate). Unless explicitly stated as "unsubstituted," references herein to chemical moieties are understood to encompass substituted variants. For example, reference to an "aryl" group or moiety implicitly encompasses both substituted and unsubstituted variants.

The term "sulfate" is art-recognized and refers to the group-OSO₃H. Or the group-OSO₃H, a pharmaceutically acceptable salt thereof.

The term "sulfonamide" is art recognized and refers to a group represented by the general formula

Wherein each R^AIndependently represent hydrogen or a hydrocarbyl group (e.g. alkyl), or R^ABoth of which are taken together with one or more intervening atoms to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The term "sulfoxide" is art-recognized and refers to the group-S (O) -R^AWherein R is^ARepresents a hydrocarbon group.

The term "sulfonate" is art-recognized and refers to the group SO₃H. Or a group SO₃H, a pharmaceutically acceptable salt thereof.

The term "sulfone" is art-recognized and refers to the group-S (O)₂-R^AWherein R is^ARepresents a hydrocarbon group.

As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

As used herein, the term "thioester" refers to the group-C (O) SR^Aor-SC (O) R^AWherein R is^ARepresents a hydrocarbon group.

As used herein, the term "thioether" corresponds to an ether, wherein sulfur is substituted for oxygen.

The term "urea" is art recognized and may be represented by the following general formula

Wherein each R^AIndependently represent hydrogen or a hydrocarbyl group (e.g. alkyl), or any occurrence of R^ATogether with one another and one or more intervening atoms, form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

"protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or hinders the reactivity of the functional group. Typically, the protecting group may be selectively removed during the synthesis, as desired. Examples of protecting Groups are found in Greene and Wuts, Protective Groups in Organic Chemistry,3^rdEd.,1999,John Wiley&Sons, NY and Harrison et al, Compendium of Synthetic organic methods, Vols.1-8,1971-1996, John Wiley&Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl("CBZ"), t-butyloxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethylsulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratroxycarbonyl ("NVOC") and the like. Representative hydrocarbyl protecting groups include, but are not limited to, those in which the hydrocarbyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample relative to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

The term "treatment" encompasses prophylactic and/or therapeutic treatment of a disease. The term "prophylactic or therapeutic" treatment is art-recognized and encompasses administration of one or more of the subject compositions to a host. If administered prior to clinical manifestation of a deleterious condition (e.g., disease or other deleterious state of the host animal), the treatment is prophylactic (i.e., it protects the host from developing a deleterious condition), whereas if administered after manifestation of a deleterious condition, the treatment is therapeutic (i.e., it is intended to reduce, alleviate, or stabilize an existing deleterious condition or side effects thereof).

The phrases "co-administration" and "administered in combination" refer to any form of administration of two or more different therapeutic compounds such that a second compound is administered while the previously administered therapeutic compound is still effective in vivo (e.g., both compounds are simultaneously effective in a patient, which may comprise a synergistic effect of both compounds). For example, different therapeutic compounds may be administered concomitantly or sequentially in the same dosage form or in separate dosage forms. In certain embodiments, the different therapeutic compounds may be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or one week of each other. Thus, an individual receiving such treatment may benefit from the combined effects of different therapeutic compounds.

The term "prodrug" is intended to encompass compounds that convert under physiological conditions to the therapeutically active agents of the present invention. Common methods for making prodrugs comprise one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the invention. In certain embodiments, some or all of the compounds of the invention in the dosage forms described above may be replaced with the corresponding suitable prodrugs, for example, where hydroxy groups in the parent compound are present as esters or carbonates, or carboxylic acids present in the parent compound are present as esters.

Use of DHFR inhibitors

Another embodiment of the invention is the use of a compound described herein for the treatment of an infection (e.g., a parasitic infection, such as toxoplasmosis). In certain embodiments, the compounds described herein may be combined with other compounds useful for this purpose (e.g., sulfadiazine, sulfamethoxazole, clindamycin, spiramycin, atovaquone, CDPK1 inhibitors, or cytochrome BC)₁Inhibitors) are used in combination. The compounds of the invention may also be used in combination with leucovorin (leucovorin) to improve tolerability.

Pharmaceutical composition

The compositions and methods of the invention can be employed to treat an individual in need thereof. In certain embodiments, the subject is a mammal, such as a human or non-human mammal. When administered to an animal (e.g., a human), the composition or compound is preferably administered as a pharmaceutical composition that includes, for example, a compound of the invention or a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (such as water or physiological buffered saline) or other solvents or carriers (vehicles) such as glycols, glycerol, oils (such as olive oil) or injectable organic esters. In a preferred embodiment, when such a pharmaceutical composition is for human administration, particularly for invasive routes of administration (i.e., routes that circumvent transport or diffusion through epithelial barriers such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient may be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in the form of dosage units such as tablets, capsules (including dispersion capsules and gelatin capsules), granules, lyophils for reconstitution, powders, solutions, syrups, suppositories, injections and the like. The composition may also be present in a transdermal delivery system, for example, a skin patch. The composition may also be present in a solution suitable for topical administration (e.g., eye drops).

The pharmaceutically acceptable carrier may contain a physiologically acceptable agent that acts, for example, to stabilize, increase solubility, or to increase absorption of a compound, such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymeric matrix into which the compound of the invention may be incorporated (e.g., a compound of the invention). For example, liposomes comprising phospholipids or other lipids are relatively simple nontoxic, physiologically acceptable and metabolizable carriers to manufacture and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier (vehicle) (e.g., a liquid or solid filler, diluent, excipient, solvent, or encapsulating material). Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars (such as lactose, glucose and sucrose); (2) starches (e.g., corn starch and potato starch); (3) cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients (such as cocoa butter and suppository waxes); (9) oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); (10) glycols (e.g., propylene glycol); (11) polyols (such as glycerol, sorbitol, mannitol, and polyethylene glycol); (12) esters (e.g., ethyl oleate and ethyl dodecanoate); (13) agar; (14) buffering agents (such as magnesium hydroxide and aluminum hydroxide); (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) a ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible materials employed in pharmaceutical formulations.

The pharmaceutical composition (formulation) may be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as drenches in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including dispersible capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anal, rectal, or vaginal (e.g., as pessaries, creams, or foams); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally, e.g. as sterile solutions or suspensions); a nasal ground; intraperitoneally; the ground under the skin; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds may also be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for use in such routes of administration can be found, for example, in U.S. Pat. nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, as well as in the patents cited in these patents.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Typically, this amount will vary from about 1% to about 99%, preferably from about 5% to about 70%, most preferably from about 10% to about 30% of the active ingredient in one hundred percent.

The methods of making these formulations or compositions comprise the step of bringing into association an active compound (e.g., a compound of the invention) with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compounds of the invention with liquid carriers or finely divided solid carriers or both, and then shaping the product, if necessary.

Dosage forms of the invention suitable for oral administration may be in the form of: capsules (including dispersible capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, typically sucrose and acacia or tragacanth), lyophilic gels, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia)) and/or as a mouthwash, and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules (including dispersion and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and/or any of the following: (1) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and/or silicic acid); (2) binders (such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia); (3) humectants (such as glycerol); (4) disintegrating agents (such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate); (5) solution retarders (e.g., paraffin); (6) absorption accelerators (such as quaternary ammonium compounds); (7) wetting agents (such as, for example, cetyl alcohol and glycerol monostearate); (8) absorbents (such as kaolin and bentonite); (9) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof); (10) complexing agents (e.g., modified or unmodified cyclodextrins); and (11) a colorant. In the case of capsules (including dispersion-type capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

Tablets may optionally be manufactured by compression or moulding with one or more accessory ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions (e.g., dragees, capsules (including dispersible capsules and gelatin capsules), pills, and granules) can optionally be scored or prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulating art). They may also be formulated with, for example, hydroxypropylmethyl cellulose in varying proportions to provide a desired release profile, other polymer matrices, liposomes and/or microspheres to provide slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient or ingredients only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes. The active ingredient may also be in microencapsulated form with one or more, if appropriate, of the above-mentioned excipients.

Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilic colloids for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art (such as, for example, water or other solvents, cyclodextrins, and derivatives thereof), solubilizing agents and emulsifiers (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof).

In addition to inert diluents, the oral compositions can also contain adjuvants (such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents).

Suspensions, in addition to the active compounds, may contain suspending agents (such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof).

Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration can be presented as a suppository, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, and which is solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or oral spray, or oral ointment.

Alternatively or additionally, the composition may be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Formulations suitable for vaginal administration also include pessary, tampon, cream, gel, paste, foam or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons (e.g. butane and propane).

Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms may be manufactured by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like are also contemplated within the scope of the present invention. Exemplary ophthalmic formulations are described in U.S. publication nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074, and U.S. patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic formulation has properties similar to, or compatible with, tear fluid, aqueous humor, or vitreous humor. A preferred route of administration is topical administration (e.g., topical administration (such as eye drops or administration via an implant)).

As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, typically by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solubilizers or suspending or thickening agents, which render the formulation isotonic with the blood of the intended recipient.

Examples of suitable aqueous and nonaqueous carriers that can be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size for the dispersion and by the use of surfactants.

These compositions may also contain adjuvants (such as preserving, wetting, emulsifying, and dispersing agents). Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents (e.g., methylparaben, chlorobutanol, phenol sorbic acid, and the like). It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil carrier (vehicle).

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

For use in the methods of the invention, the active compound may be administered per se or as a pharmaceutical composition containing, for example, from 0.1% to 99.5% (more preferably, from 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The introduction method may also be provided by a rechargeable or biodegradable device. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including protein biopharmaceuticals. Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds being employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound or compounds being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound or compounds being employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start with a dose of a pharmaceutical composition or compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. By "therapeutically effective amount" is meant a concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age and medical history of the subject. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent that is administered with the compound of the invention. A larger total dose may be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al (1996) Harrison's PCR primers of Internal Medicine 13 ed.,1814-1882, which are incorporated herein by reference).

In general, a suitable daily dose of active compound for use in the compositions and methods of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above.

If desired, an effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered alone, optionally in unit dosage form, at appropriate intervals throughout the day. In certain embodiments of the invention, the active compound may be administered twice or three times daily. In a preferred embodiment, the active compound will be administered once daily.

The patient receiving this treatment is any animal in need thereof, including primates (particularly humans); and other mammals (e.g., horses, cattle, pigs, sheep, cats, and dogs); poultry; and pets in general.

In certain embodiments, the compounds of the present invention may be used alone or administered in combination with another type of therapeutic agent.

The invention encompasses the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benzphetamine, benzathine, betaine, calcium hydroxide, choline, dandol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2-dichloroacetic acid, 2-isethionic acid, 2-ketoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+) -camphoric acid, (+) -camphor-10-sulfonic acid, capric acid (capric acid), caproic acid (caproic acid), caprylic acid (caprylic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, Glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, mandelic acid, methanesulfonic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenate.

The pharmaceutically acceptable acid addition salts may also be present as various solvates (e.g. with water, methanol, ethanol, dimethylformamide, etc.). Mixtures of such solvates may also be prepared. The source of such solvates may be inherent in the solvent from crystallization, the solvent from preparation or crystallization, or extrinsic to such solvents.

Wetting agents, emulsifying agents, and lubricating agents (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, partitioning agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants (e.g., ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.), (2) oil-soluble antioxidants (e.g., ascorbyl palmitate, t-Butylparacresol (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, α -tocopherol, etc.), and (3) metal-chelating agents (e.g., citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.).

In certain embodiments, the invention relates to methods for conducting pharmaceutical transactions by manufacturing dosage forms of the compounds of the invention, or kits described herein, and promoting the benefits of using the dosage forms or kits for treating or preventing any disease or condition described herein to a health care service provider.

Examples of the invention

Examples

Example 1: general procedure

NMR spectra were recorded at Varian 400MHz to obtain¹H NMR. In Shimadzu LCMS 2010 (column:sepax ODS 50 × 2.0mm, 5 μm) or Agilent 1200HPLC, 1956 MSD (column: shim-pack XR-ODS 30X 3.0mm, 2.2 μm) on a quadrupole mass spectrometer.

LC/MS method A: the column (2.0 x 30mm, 3 μm) was run at 40 ℃ on Shimadzu LC-20AB with MS 2010 detector using Luna-C18 (1). Mobile phase a was 0.037% (v/v) aqueous TFA, and mobile phase B was 0.018% (v/v) TFA in acetonitrile. From 0.01 to 1.51min, the flow rate is 0.8mL/min, then from 1.52 to 2.00min, the flow rate is 1.2 mL/min. The gradient ran from 90% mobile phase a to 10% mobile phase a in 1.15min, then remained at 10% mobile phase a until 1.65min, then returned to 90% mobile phase a at 1.66min, and remained at 90% mobile phase a until 2.0 min. UV detection was 220nm and MS was measured in positive ion mode.

LC/MS method B: an Xbridge Shield RP18 column (2.1X 50mm, 5 μm) was used to run at 40 ℃ on Agilent 1200 with MS6120 detector. Mobile phase A was 10mM NH₄HCO₃Aqueous solution, and mobile phase B is acetonitrile. From 0.01 to 2.48min, the flow rate is 1.0mL/min, then from 2.50 to 3.00min, the flow rate is 1.2 mL/min. The gradient ran from 90% mobile phase a to 20% mobile phase a in 2.00min, then remained at 20% mobile phase a until 2.48min, then returned to 90% mobile phase a at 2.50min, and remained at 90% mobile phase a until 3.0 min. UV detection was 220nm and MS was measured in positive ion mode.

LC/MS method C: an Xbridge Shield RP18 column (2.1X 50mm, 5 μm) was used to run at 40 ℃ on Agilent 1200 with MS6120 detector. Mobile phase A was 10mM NH₄HCO₃Aqueous solution, and mobile phase B is acetonitrile. From 0.01 to 2.50min, the flow rate is 1.0mL/min, then from 2.51 to 3.00min, the flow rate is 1.2 mL/min. The gradient ran from 70% mobile phase a to 10% mobile phase a in 1.50min, then remained at 10% mobile phase a until 2.50min, then returned to 70% mobile phase a at 2.51min, and remained at 70% mobile phase a until 3.0 min. UV detection was 220nm and MS was measured in positive ion mode.

LC/MS method D: a Venusil XBP-C18 column (2.1 x 50mm, 5 μm) was used to run at 40 ℃ on Agilent 1200 with MS6120 detector. Mobile phase a was 0.0375% TFA in water and mobile phase B was 0.018% TFA in acetonitrile. From 0.01 to 4.5min, the flow rate was 0.8 mL/min. From 0.00min to 0.40min, the gradient was maintained at 99% mobile phase a, then the gradient was run from 99% mobile phase a to 10% mobile phase a within 3.00min, then to 0% mobile phase a within 0.45 min; then return to 99% mobile phase a in 0.01min and remain there for 0.55 min. UV detection was 220nm and MS was measured in positive ion mode.

Example 2: synthesis Process A

Piperazine intermediate 1001 is generally commercially available or can be prepared by various literature methods (i.e., hong gao and Daniel j. canney.a versatile and reactive microwave-assisted synthesis of synthetic N-arylpiperazines, j. org. chem.,2010,75(21), 7451-53). For example, aniline or aminoheteroaryl starting material 1002 can be reacted with bis (2-chloroethyl) amine in the presence of sulfolane at 140 ℃ to produce intermediate 1001. (Lokesh Ravila et al, An effective scale up process for synthesis of N-arylpiperazines Tetrahefron Letters,2015,56(30), 4541-44). Alternatively, the protected piperazine may be reacted with a bromoaryl or bromoheteroaryl compound 1003 under Buchwald conditions to yield the desired intermediate 1001.

Nucleophilic substitution reaction of 1001 with 5-bromopyrimidine-2, 4(1H,3H) -dione 1004 using KF as a basic catalyst and heating in DMSO yields 5-piperazinylpyrimidine 1005. At 105 ℃ with POCl₃Reaction to give 2, 4-dichloropyrimidine 1006, and reaction by reaction with NH in ethanol at 130 ℃₃The reaction produces the desired 2, 4-diaminopyrimidine 1007. 5-Bromopyrimidine-2, 4(1H,3H) -dione 1004 is generally commercially available or can be prepared by way of the corresponding 6-substituted pyrimidineBromination of diketones.

Alternatively, the compounds of the present invention may be prepared by Suzuki (Suzuki) coupling reactions or Stille (Stille) coupling reactions as shown below.

Synthetic method a is illustrated below in the synthesis of 5- (4- ([1, 1' -biphenyl ] -3-yl) piperazin-1-yl) pyrimidine-2, 4-diamine (compound 2).

Step 1.4- ([1, 1' -biphenyl ] -3-yl) piperazine-1-carboxylic acid tert-butyl ester

3-bromo-1, 1' -biphenyl (10.0g, 42.9mmol, 7.1mL, 1.0 equiv.) was added to sodium 2-methyl-2-propanolate (4.9g, 51.4mmol, 1.2 equiv.) and Pd₂(dba)₃(785.6mg, 858.0. mu. mol, 0.02 eq.) in toluene (100 mL). Reacting 1, 1' -biphenyl at 25 DEG C]-2-Yl dicyclohexylphosphine (2.4g, 6.8mmol, 0.16 equiv.) and piperazine-1-carboxylic acid tert-butyl ester (7.9g, 42.9mmol, 1.0 equiv.) were added to the above mixture, and the reaction vessel was purged with N₂Degassing 3 times, and dissolving in N₂Stirred under atmosphere at 100 ℃ for 16 h. TLC (petroleum ether: ethyl acetate ═ 5:1, Rf ═ 0.51) showed that 3-bromo-1, 1' -biphenyl was consumed and a major new spot with increased polarity was detected. The reaction mixture was concentrated under reduced pressure to give a brown residue, which was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 5:1) to give 4- ([1, 1' -biphenyl) as a white solid]-3-yl) piperazine-1-carboxylic acid tert-butyl ester (7.0g, yield: 48.3%). LCMS method a (ESI +): contemplated M/z 339(M +1)⁺(ii) a Measured (found) M/z 339.1(M +1)⁺，RT：2.19Min。

Step 2.1- ([1, 1' -biphenyl ] -3-yl) piperazine

4- ([1, 1' -biphenyl ] o]A mixture of tert-butyl (3.0g, 8.8mmol, 1.0 equiv.) of (3-yl) piperazine-1-carboxylate in HCl/MeOH (4M, 30.0mL, 13.5 equiv.) was stirred at 15 ℃ for 5 h. TLC (dichloromethane: methanol ═ 10:1, Rf ═ 0.3) showed loss of starting material. The colorless solid was filtered with suction. Redissolving the filter cake in K₂CO₃In aqueous solution (2M, 50mL), stir vigorously for a few minutes, and extract with ethyl acetate (2X 150 mL). In the absence of anhydrous Na₂SO₄The combined organic layers were dried over, and filtered and concentrated under reduced pressure to give 1- ([1, 1' -biphenylyl) oil as a yellow oil]-3-yl) piperazine (2.0g, 8.3mmol, yield: 94.7%). LCMS method B (ESI +): contemplated M/z 239(M +1)⁺(ii) a Actually measured M/z 239.1(M +1)⁺，RT：2.19Min。

Step 3.5- (4- ([1, 1' -biphenyl ] -3-yl) piperazin-1-yl) pyrimidine-2, 4(1H,3H) -dione

To 5-bromo-1H-pyrimidine-2, 4-dione (400.6mg, 2.1mmol, 1.0 equiv.) and 1- ([1, 1' -biphenyl)]Mixture of-3-yl) piperazine (500mg, 2.1mmol, 1.0 equiv) in DMSO (10.00mL) potassium fluoride (182.8mg, 3.15mmol, 1.5 equiv) was added. The resulting mixture was stirred at 110 ℃ for 8 hours, cooled to room temperature, poured into water, and the grey precipitate was collected by suction filtration. The gray solid was washed with 100mL of 1:1 EtOAc: petroleum ether to give 5- (4- ([1, 1' -biphenyl ] e as a gray solid]-3-yl) piperazin-1-yl) pyrimidine-2, 4(1H,3H) -dione (500.0mg, 1.4mmol, yield: 68.3%). LCMS method B (ESI +): expected M/z 349.1(M +1)⁺(ii) a Actually measured M/z 349.1(M +1)⁺，RT：2.16Min。

Step 4.5- (4- ([1, 1' -biphenyl ] -3-yl) piperazin-1-yl) -2, 4-dichloropyrimidine

Mixing 5- (4- ([1, 1' -biphenyl)]-3-yl) piperazin-1-yl) pyrimidine-2, 4(1H,3H) -dione (400.0mg, 1.1mmol, 1.0 equiv.) in POCl₃(26.3g, 171.6mmol, 15.9mL, 149.4 equiv.) the mixture was degassed and treated with N₂Purge 3 times, and then mix in N₂Stirred at 105 ℃ for 5 hours under an atmosphere. LCMS was consistent with the desired product MS (385.1, RT ═ 2.24 Min). The reaction mixture was concentrated under reduced pressure to give a black residue, which was washed with H₂O (50mL) was diluted and extracted with ethyl acetate (2X 50 mL). In Na₂SO₄The organic phase was dried, filtered and concentrated under reduced pressure to give 5- (4- ([1, 1' -biphenylyl) benzene as a yellow solid]-3-yl) piperazin-1-yl) -2, 4-dichloropyrimidine (250.0mg, 649 μmol, yield: 56.4%). LC/MS method C (ESI +): contemplated M/z 385(M +1)⁺(ii) a Actually measured M/z 385.1(M +1)⁺，RT：2.24Min。

Step 5.5- (4- ([1, 1' -biphenyl ] -3-yl) piperazin-1-yl) pyrimidine-2, 4-diamine

Mixing 5- (4- ([1, 1' -biphenyl)]-3-yl) piperazin-1-yl) -2, 4-dichloropyrimidine (100.0mg, 0.26mmol, 1.0 equivalent) in NH₃The mixture solution in EtOH (10mL) was added to the steel reactor. The mixture was stirred at 145 ℃ for 12 hours. The suspension was cooled to room temperature and concentrated under reduced pressure to give a brown residue. The residue was purified by preparative HPLC (TFA conditions) to give 5- (4- ([1, 1' -biphenyl) as a white solid]-3-yl) piperazin-1-yl) pyrimidine-2, 4-diamine (86.5mg, 249.6 μmol, yield: 30.0%). LCMS method D (ESI +): contemplated M/z (347M +1)⁺(ii) a Actually measured M/z347.1(M +1)⁺，Rt：2.60Min。¹H NMR(MeOD 400MHz)δ＝7.64(d,J＝7.4Hz,2H),7.59-7.55(m,2H),7.54-7.49(m,1H),7.46(t,J＝7.4Hz,3H),7.38(d,J＝7.4Hz,1H),7.36-7.30(m,1H),3.66(br.s.,4H),3.18(d,J＝4.3Hz,4H)。

The compounds listed in table 1 were prepared using synthesis method a, for compound 2 above, by reacting 5-bromouracil with an appropriately substituted aryl piperazine.

Table 1: compounds prepared using Synthesis method A

The compounds listed in table 2 were prepared using synthesis method a as above by reacting 5-bromouracil with 1- ([1,1 '-biphenyl ] -3-yl) -3-methylpiperazine or 1- ([1, 1' -biphenyl ] -3-yl) -2-methylpiperazine.

Table 2: compounds prepared using Synthesis method A

The compounds listed in table 3 were prepared using synthesis a as above by reacting 5-bromo-6-ethyluracil with an appropriately substituted aryl piperazine or 4-aryl piperidine.

Table 3: compounds prepared using Synthesis method A (Arylpiperazines or 4-arylpiperidines)

The compounds listed in table 4 were prepared using synthesis a as above by reacting 5-bromo-6-methyluracil with an appropriately substituted arylpiperazine.

Table 4: compounds prepared using Synthesis method A

The compounds listed in table 5 were prepared using synthesis a as above by reacting 5-bromo-6-n-propyluracil with an appropriately substituted arylpiperazine.

Table 5: compounds prepared using Synthesis method A

Example 3: synthesis method B

According to synthesis B, the compounds of the invention can be prepared by suzuki coupling or stille coupling as shown below.

Bromophenyl derivative 1010 may also be converted to a boronic ester 1011 as shown below, and the boronic ester 1011 may then undergo reactions with various aryl or heteroaryl halides under suzuki reaction conditions, as exemplified below for reaction with 4-chloro-2-methylpyrimidine to yield the final target (e.g., 1012).

Synthetic method B is illustrated in the synthesis of 5- (4- (3- (2-methylpyrimidin-5-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (compound 69):

5- (4- (3-bromophenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (Compound 11) (1.0g, 2.8mmol, 1.0 equiv.), 2-methylpyrimidin-5-yl) boronic acid (394.9mg, 2.8mmol, 1.0 equiv.), Cs₂CO₃(1.4g, 4.3mmol, 1.5 equiv.), Pd (PPh)₃)₄(165.4mg, 143.2. mu. mol, 0.05 eq.) in dioxane (32.0mL) and H₂The mixture in O (8.0mL) was degassed and treated with N₂Purge 3 times, and then at N₂Stirring was carried out at 100 ℃ for 12h under an atmosphere. It was then stirred with silica S thiol Met at 20 ℃, filtered and concentrated to yield a residue. The residue was purified by preparative HPLC (TFA conditions) to give 5- (4- (3- (2-methylpyrimidin-5-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine as a white solid (1.2g, 2.5mmol, yield: 88.0%).¹H NMR,400MHz, methanol-d₄)δ＝8.93(s,2H),7.51(s,1H),7.41(t,J＝7.8Hz,1H),7.26-7.24(m,1H),7.16-7.09(m,2H),3.44(br s,4H),3.02(br t,J＝4.8Hz,4H),2.73(s,3H)。

Table 6: compounds prepared using Synthesis method B

Preparation of 5- (4- (4-phenylthiazol-2-yl) piperazin-1-yl) pyrimidine-2, 4-diamine by suzuki coupling of 5- (4- (4-bromothiazol-2-yl) piperazin-1-yl) pyrimidine-2, 4-diamine (prepared by synthesis a) with phenylboronic acid according to synthesis B. The compounds listed in table 7 were prepared analogously.

Table 7: compounds prepared using Synthesis method B

Example 4: synthesis method C

Synthetic method C is illustrated in the synthesis of 5- (4- (3, 5-dimethylphenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (compound 109):

to 5- (4- (3, 5-dibromophenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (50.0mg, 116.7. mu. mol, 1.0 equiv) (prepared according to Synthesis method A) and methylboronic acid (13.9mg, 233.5. mu. mol, 2.0 equiv) in dioxane (2.0mL) and H₂Solution in O (0.5mL) with addition of Cs₂CO₃(114.1mg, 350.3. mu. mol, 3.0 equiv.) and a second generation XPHOS precatalyst (1.8mg, 2.3. mu. mol, 0.02 equiv.). The mixture was stirred at 100 ℃ for 12 hours. The mixture was concentrated and the residue was purified by preparative HPLC (TFA conditions) to give 5- (4- (3, 5-dimethylphenyl) piperazin-1-yl) pyrimidine-2, 4-diamine as a white solid (4.4mg, 14.7 μmol, yield: 12.6%).

Example 5: synthesis method D

Synthetic procedure D is illustrated below for the synthesis of 5- (4- (3- (tetrahydro-2H-pyran-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (compound 110).

Step 1.5- (4- (3- (3, 6-dihydro-2H-pyran-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine

At 20 ℃ in N₂Next, 5- (4- (3-bromophenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (50.0mg, 143.1. mu. mol, 1.0 equiv.) and 1- (3, 6-dihydro-2H-pyran-4-yl) -3,3,4, 4-tetramethylcyclopentaneborane (60.1mg, 286.3. mu. mol, 2.0 equiv.) were added to 1, 4-dioxane (4.0mL) and H₂Mixture in O (1.0mL) with addition of one part of Cs₂CO₃(69.9mg, 214.7. mu. mol, 1.5 eq.) and Pd (PPh)₃)₄(8.2mg, 7.1. mu. mol, 0.05 eq.).The mixture was stirred at 100 ℃ for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions) to give 5- (4- (3- (3, 6-dihydro-2H-pyran-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (30.0mg, 85.1 μmol, yield: 59.4%) as a white solid.¹H NMR (400MHz, methanol-d)₄)δ＝7.53(s,1H),7.32-7.28(m,1H),7.17(s,1H),7.10-7.04(m,2H),6.19(s,1H),4.30(d,J＝2.4Hz,2H),3.94-3.91(m,2H),3.45-3.31(m,4H),3.08-3.06(m,4H),2.53-2.52(m,2H)。

Step 2.5- (4- (3- (tetrahydro-2H-pyran-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine

To 5- (4- (3- (3, 6-dihydro-2H-pyran-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (30.0mg, 85.1. mu. mol, 1.0 equiv) in CH under Ar atmosphere₃Solution in OH (10.0mL) was added Pd/C (10 mg). Degassing the suspension and reacting with H₂Purging 3 times. Mixing the mixture in H₂(15Psi) at 15 ℃ for 1 hour, filtered on celite, and the filtrate was concentrated under reduced pressure to give 5- (4- (3- (tetrahydro-2H-pyran-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (19.0mg, 51.2. mu. mol, yield: 30.0%, purity: 95.53%) as a white solid. LCMS (ESI +): m/z 355.1(M +1)⁺，Rt：2.147Min。¹H NMR (400MHz, methanol-d)₄)δ＝7.52(s,1H),7.25(br t,J＝7.5Hz,1H),7.02-6.92(m,2H),6.88(br d,J＝7.1Hz,1H),4.04(br d,J＝10.6Hz,2H),3.56(br t,J＝11.0Hz,2H),3.40(br s,4H),3.04(br s,4H),2.78(br s,1H),1.88-1.71(m,4H)。

Example 6: synthesis method E

Synthetic method E is illustrated below for the synthesis of 5- (4- (3- (pyrimidin-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (compound 102):

5- (4- (3-bromophenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (100.0mg, 286.3. mu. mol, 1.0 equiv.), tributyl (pyrimidin-4-yl) stannane (105.7mg, 286.3. mu. mol, 1 equiv.), Pd₂(dba)₃A mixture of (7.8mg, 8.6. mu. mol, 0.03 equiv), XPhos (23.2mg, 48.6. mu. mol, 0.17 equiv) in dioxane (8.0mL) was degassed and N was used₂Purge 3 times, and then mix in N₂Stirred at 100 ℃ for 12 hours under an atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (TFA conditions) to give 5- (4- (3- (pyrimidin-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine as a yellow solid (4.5mg, 12.9 μmol, yield: 4.51%). The compounds prepared by method E are listed in table 8.

Table 8: compounds prepared using Synthesis method E

Example 7: synthesis method F

Synthetic method F is illustrated below for the synthesis of 5- (3- (4- (2, 4-diaminopyrimidin-5-yl) piperazin-1-yl) phenyl) pyrimidin-2-ol (compound 111):

to a solution of 5- (4- (3- (2-methoxypyrimidin-5-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (500.0mg, 1.3mmol, 1.0 eq) in dichloromethane (5.0mL) at-30 deg.C was added BBr₃(3.3g, 13.2mmol, 1.2mL, 10.0 equiv.). The mixture was warmed to 15 ℃ and at 15 DEG CStirred for 12 hours. Subjecting the mixture to CH₃OH (10mL) was quenched, concentrated under reduced pressure, and the residue was purified by preparative HPLC (neutral conditions) to give 5- (3- (4- (2, 4-diaminopyrimidin-5-yl) piperazin-1-yl) phenyl) pyrimidin-2-ol as a yellow solid (60.0mg, 154.3 μmol, yield: 11.6%, purity: 93.72%). LCMS (ESI +): m/z 365.2(M +1)⁺，Rt：1.906Min。¹H NMR(DMSO-d₆400MHz)δ＝8.60(br s,2H),7.58(d,J＝0.8Hz,1H),7.31-7.23(m,1H),7.13(s,1H),7.03-6.89(m,2H),3.33(br s,4H),2.87(br t,J＝4.6Hz,4H)。

Example 8: synthesis Process G

According to synthesis method G, the compounds of the present invention may be prepared as described below. Halogenation of an appropriately substituted malonate (e.g., 1013) such as with sulfuryl chloride provides 2-chloromalonate 1014, which 2-chloromalonate 1014 can undergo reaction with an appropriately substituted piperazine to produce 2-piperazinyl malonate intermediate 1015. Reaction with guanidine in a polar protic solvent (e.g., ethanol or methanol) produces 2-amino-4-hydroxypyrimidine 1016. Chlorination, followed by reaction with ammonia, yields the target 2, 4-diaminopyrimidine 1018.

Synthetic method G is illustrated below for the preparation of 6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidine-2, 4-diamine (compound 112):

step 1.2-chloro-3-cyclopropyl-3-oxopropanoic acid methyl ester

3-cyclopropyl-3-oxo-propionic acid methyl ester (5.00g, 35.17mmol, 1.00 equiv.), sulfuryl chloride (5.70g, 42.20mmol, 4.22mL, 1.20 equiv.) in CHCl₃(50.00mL) and degassing the mixture with N₂Purge 3 times, and then mix in N₂Stirred under an atmosphere at 20 ℃ for 2 hours. Removal of the solvent yielded methyl 2-chloro-3-cyclopropyl-3-oxo-propionate (5.00g, crude product) as a yellow oil, which was used in the next step without further purification.

Step 2.3-cyclopropyl-3-oxo-2- (4-phenylpiperazin-1-yl) propionic acid methyl ester

To a solution of 2-chloro-3-cyclopropyl-3-oxo-propionic acid methyl ester (2.50g, 14.16mmol, 1.00 equiv.) and 1-phenylpiperazine (2.30g, 14.16mmol, 2.17mL, 1.00 equiv.) in MeCN (60.00mL) at 25 ℃ was added K₂CO₃(2.94g, 21.24mmol, 1.50 equiv.) and the mixture was stirred for 5 h. The reaction was poured into water (150mL) and extracted with ethyl acetate (3X 50 mL). In Na₂SO₄The combined organic layers were dried, filtered and concentrated in vacuo. By column chromatography (SiO)₂Petroleum ether/ethyl acetate 100/1 to 20:1) to yield methyl 3-cyclopropyl-3-oxo-2- (4-phenylpiperazin-1-yl) propionate as a white solid (1.70g, 5.62mmol, yield: 39.71%).

Step 3.2-amino-6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidin-4-ol

Combine methyl 3-cyclopropyl-3-oxo-2- (4-phenylpiperazin-1-yl) propionate (100.00mg, 330.72 μmol, 1.0 eq), EtOH (3.00mL) and carbonic acid in a microwave bottle; guanidine (40.05mg, 330.72. mu. mol, 1.00 equiv.). The vial was sealed and allowed to react at 120 ℃ while stirring for 5 hours. This was repeated 6 times and the batches were combined and the solvent was removed under reduced pressure. Water (25ml) was added and the mixture was brought to pH 5 via careful addition of acetic acid. The precipitate was isolated via filtration to give a yellow solid. The solid was purified by preparative HPLC (TFA conditions) to give 2-amino-6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidin-4-ol as a yellow solid (300mg, 963 μmol, yield: 48.6%).

Step 4.4-chloro-6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidin-2-amine

In N₂To 2-amino-6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidin-4-ol (150mg, 482. mu. mol, 1.00 equiv), TEBAC (53.7mg, 289. mu. mol, 50.2. mu.L, 0.60 equiv) and PhNMe under an atmosphere₂(58.4mg, 481.7. mu. mol, 60.8. mu.L, 1.00eq) in MeCN (10.0mL) was added POCl₃(739mg, 4.82mmol, 448. mu.L, 10.00 equiv.). The mixture was stirred at 90 ℃ for 1 hour by addition of NaHCO₃The aqueous solution (50mL) was quenched and extracted with dichloromethane (3X 20 mL). In the absence of anhydrous Na₂SO₄The combined organic layers were dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give 4-chloro-6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidin-2-amine (60.0mg, 182 μmol, yield: 37.8%) as a yellow solid. LCMS (ESI +): m/z 330(M +1)⁺，Rt：0.972Min。

Step 5.6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidine-2, 4-diamine

In N₂Under the atmosphere, to NH₃(155mg, 9.10mmol, 50.0 equiv.) to a mixture in ethanol (5.0mL) was added 4-chloro-6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidin-2-amine (60.0mg, 181.9. mu. mol, 1.00 equiv.). The mixture was stirred in a steel reaction vessel at 145 ℃ for 3 days, cooled to 25 ℃ and concentrated under reduced pressure. The solid was collected by filtration, washed with EtOAc (200mL), and purified by preparative HPLC to give 6-cyclopropyl-5- (4-phenylpiperazin-1-yl) pyrimidine-2, 4-diamine as a white solid (3.0mg, 6.44 μmol, yield: 9.03%). LCMS (ESI +): m/z 311.2(M +1)⁺，Rt：2.146Min。¹H NMR (400MHz, methanol-d 4): δ 7.44-7.37(m,2H),7.33-7.25(m,2H),7.18-7.08(m,1H),3.64(br d, J ═ 10.4Hz,4H),3.50-3.34(m,2H),3.30-3.09(m,2H),2.34-2.21(m,1H),1.32-1.25(m,2H),1.14-1.08(m, 2H).

6- (cyclopropylmethyl) -5- (4-phenylpiperazin-1-yl) pyrimidine was prepared in a similar manner to that described in Synthesis procedure G, but starting with 3-cyclopropylmethyl-3-oxo-propionic acid methyl ester. Other compounds similarly prepared by method G are listed in table 9.

Table 9: compounds prepared using Synthesis Process G

Example 9: synthesis Process H

Synthetic procedure H is illustrated below for the preparation of 5- (4- (3- (2-methylpyrimidin-5-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (compound 113):

step 1.5- (4- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine

Reacting 5- (4- (3-bromophenyl) piperazine-1-yl) pyrimidine-2, 4-diamine(1.0g, 2.8mmol, 1.0 equiv.), bis (pinacolato) diboron (1.1g, 4.2mmol, 1.5 equiv.), AcOK (842.0mg, 8.5mmol, 3.0 equiv.), Pd (dppf) Cl₂.CH₂Cl₂(467.1mg, 572.0. mu. mol, 0.2 eq.) A mixture in dioxane (20.0mL) was degassed and treated with N₂Purge 3 times, and then mix in N₂Stirred at 100 ℃ for 12 hours under an atmosphere. The mixture was concentrated under reduced pressure to give 5- (4- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (800.0mg, 1.2mmol, yield: 44.4%) as a black-brown oil, which was used in the next step without further purification. LCMS (ESI +): m/z 397.1(M +1)⁺，Rt：1.271Min。

Step 2.5- (4- (3- (2-methylpyrimidin-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine

5- (4- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-b-oro-2-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine (200.0mg, 504.6. mu. mol, 1.0 equiv.), 4-chloro-2-methyl-pyrimidine (64.8mg, 504.6. mu. mol, 1.0 equiv.), NaHCO₃(127.1mg, 1.5mmol, 3.0 equiv.), Pd (PPh)₃)₄(116.6mg, 100.9. mu. mol, 0.2 eq.) in H₂O (1.0mL) and CH₃The mixture in CN (3.0mL) was degassed and treated with N₂Purge 3 times, and then mix in N₂Stirred at 50 ℃ for 4 hours under an atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions) to give 5- (4- (3- (2-methylpyrimidin-4-yl) phenyl) piperazin-1-yl) pyrimidine-2, 4-diamine as a dark brown solid (20.9mg, 55.3 μmol, yield: 10.9%, purity: 95.9%). LCMS (ESI +): m/z 363.1(M +1)⁺，Rt：2.142Min。¹H NMR(MeOD 400MHz)δ＝8.73(d,J＝5.7Hz,1H),7.90(d,J＝5.5Hz,1H),7.87(s,1H),7.66(d,J＝7.7Hz,1H),7.52(s,1H),7.46(t,J＝7.9Hz,1H),7.26(dd,J＝2.2,8.2Hz,1H),3.48(br s,4H),3.05(br t,J＝4.6Hz,4H),2.79(s,3H)。

Table 10: compounds prepared using Synthesis Process H

Example 10:

certain compounds prepared as described above were assayed to determine their IC for inhibition of hDHFR, Toxoplasma DHFR (tgDHFR), Trypanosoma cruzi DHFR (tcDHFR), Trypanosoma brucei DHFR (tbDHFR), Leishmania major DHFR (lmDHFR) and Plasmodium falciparum DHFR (pfDHFR)₅₀. At least three independent assay replicates were performed for each compound tested. In the assay, DHFR-catalyzed conversion of dihydrofolate + NADPH to tetrahydrofolate + NADP is carried out in the presence of various concentrations of the compound to be assayed⁺The transformation of (3). After an incubation period of 60 minutes, diaphorase and resazurin (resazurin) were added. The mixture was incubated for 10 minutes during which time diaphorase catalyzed the reduction of resazurin to resorufin (resorufin) using NADPH that had not been consumed in the first DHFR catalyzed reaction. The fluorescence of resorufin indicates the amount of unreacted NADPH. Compounds were tested at various concentrations to determine their IC₅₀、pIC₅₀(-log₁₀IC₅₀) And selectivity for parasite DHFR (hDHFR IC)₅₀Parasite DHFR IC₅₀). The results are presented in tables 11-15 below. The DHFR sequences in protozoa of the genera leishmania, trypanosoma, and plasmodium are highly conserved relative to toxoplasma gondii. The compounds described herein that are selective for tgDHFR are expected to be selective for DHFR derived from these genera as well.

Table 11: potency and selectivity against Toxoplasma gondii DHFR

Table 12: potency and selectivity against trypanosoma cruzi DHFR

Table 13: efficacy and selectivity against trypanosoma brucei DHFR

Table 14: potency and selectivity against DHFR of large Leishmania

Table 15: potency and selectivity against plasmodium falciparum DHFR

Is incorporated by reference

All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents of

While specific embodiments of the subject invention have been discussed, the foregoing description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and to the specification, along with such variations.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt or prodrug of said compound:

wherein:

2. The compound of claim 1, wherein the compound has the structure of formula (I) or is a pharmaceutically acceptable salt or prodrug of the structure of formula (I);

wherein:

R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁷and R¹⁸Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy or fluoro; provided that R is²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹At least four of (a) are H;if W is N, R²、R³、R⁶And R⁷None of which is a hydroxyl group; and if Z is N, then R⁴、R⁵、R⁸And R⁹None of which is a hydroxyl group;

R¹⁰is substituted or unsubstituted C_6-10Aryl or 5-to 10-membered heteroaryl;

with the following conditions:

a.Z is CR¹⁷Or W is CR¹⁸；

b.R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is at least one of C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen;

c.R¹is C_4-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or fluoro;

d.R¹⁰is a substituted or unsubstituted 5-to 10-membered heteroaryl or C₁₀An aryl group;

e.R¹⁰is phenyl substituted in the meta or ortho position with at least one substituent selected from halogen (e.g., fluorine or chlorine), hydroxy, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl;

f.R¹⁰is made of C_1-6Alkyl-substituted phenyl, said C_1-6Alkyl optionally substituted with C_1-6Alkyl radical, C_3-6Cycloalkyl, halo, carbonyl, cyano, or hydroxy;

g.R¹⁰is prepared from R¹²Or X-R¹²Substituted phenyl; or

h.R¹⁰Is phenyl substituted with fluoro; or R¹Is C_3-6Alkyl, and R¹⁰Is phenyl optionally substituted with halogen (e.g., fluorine or chlorine), hydroxyl, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, azido, mercapto, or alkylthio; and is

Further wherein:

R¹³Is independently H or C_1-6An alkyl group.

3. The compound of one of claims 1-2, wherein the compound has the structure of formula (I) or is a pharmaceutically acceptable salt or prodrug of the structure of formula (I):

wherein:

R¹⁰is substituted or not substitutedSubstituted C_6-10Aryl or 5-to 10-membered heteroaryl;

with the following conditions:

a.Z is CR¹⁷；

e.Z and W are N, and R¹⁰Is phenyl substituted in the meta or ortho position with at least one substituent selected from chlorine, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl;

g.R¹⁰is prepared from R¹²Or X-R¹²Substituted phenyl;

h.R¹is C_3-6Alkyl, and R¹⁰Is phenyl optionally substituted with halogen (e.g., fluorine or chlorine), hydroxyl, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, azido, mercapto, or alkylthio; or

i.Z and W is N, R¹Is H, and R¹⁰Is phenyl substituted with at least one substituent selected from halogen (e.g., fluoro or chloro), alkyl, trifluoromethyl, cycloalkyl, alkoxy, trifluoromethoxy, or cyano; and is

Further wherein:

R¹²each instance of (a) is independently selected from substituted or unsubstitutedA substituted phenyl, 5-or 6-membered heteroaryl, or a 4 to 7-membered heterocyclyl;

R¹³Is independently H or C_1-6An alkyl group.

4. The compound of one of claims 1-3, wherein W and Z are N.

5. The compound of one of claims 1-4, wherein the compound has the structure of formula (Ia):

wherein:

R¹is H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen;

R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or fluoro, with the proviso that R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹At least four of (a) are H; and is

with the following conditions:

a.R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Is at least one of C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen;

b.R¹is C_4-6Alkyl radical, C_3-6Cycloalkyl, or fluoro;

c.R¹⁰is a substituted or unsubstituted 5-to 10-membered heteroaryl or C₁₀An aryl group;

d.R¹⁰is phenyl substituted in the meta or ortho position with at least one substituent selected from halogen (e.g., fluorine or chlorine), hydroxy, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl;

e.R¹⁰is made of C_1-6Alkyl-substituted phenyl, said C_1-6Alkyl optionally substituted with C_1-6Alkyl radical, C_3-6Cycloalkyl, halo, carbonyl, cyano, or hydroxy; or

f.R¹⁰Is prepared from R¹²Or X-R¹²A substituted phenyl group.

6. The compound of claim 5, wherein the compound has the structure of formula (Ia):

wherein:

R¹is H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen;

R¹⁰Is substituted or unsubstituted C_6-10Aryl radicalsOr 5-to 10-membered heteroaryl;

with the following conditions:

b.R¹is C_4-6Alkyl radical, C_3-6Cycloalkyl, or fluoro;

d.R¹⁰is phenyl substituted in the meta or ortho position with at least one substituent selected from chlorine, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, aryl, or heteroaryl;

f.R¹⁰Is prepared from R¹²Or X-R¹²A substituted phenyl group.

7. The compound of one of claims 1-6, wherein R¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, or an aromatic or heteroaromatic moiety.

8. The compound of one of claims 1-7, wherein R¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, amino, amidine, cyano, mercapto, or alkylthio, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

9. The compound of one of claims 1-8, wherein R¹⁰Substituted with at least one substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, or an aromatic or heteroaromatic moiety.

10. The compound of one of claims 1-9, wherein R¹⁰Substituted with at least one substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

11. The compound of one of claims 1-10, wherein R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl radical, C_4-6Cycloalkylalkyl, or halogen.

12. The compound of one of claims 1-11, wherein R¹Is C_4-6A cycloalkylalkyl group.

13. The compound of one of claims 1-12, wherein R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl, or halogen.

14. The compound of one of claims 1-13, wherein:

R¹⁰is optionally independently selected from R¹¹、R¹²Or X-R¹²C substituted by one or more substituents of_6-10Aryl or 5-to 10-membered heteroaryl;

R¹¹each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkyl radical, C_4-8Cycloalkylalkoxy, cyano, or halogen.

15. The compound of one of claims 1-14, wherein R¹⁰Is substituted or unsubstituted C_6-10Aryl or 5-to 10-membered heteroaryl, and further with R¹²Or X-R¹²And (4) substitution.

16. The compound of claim 12, wherein R¹⁰Is phenyl.

17. The compound of claim 13, wherein R¹⁰Is in the meta position with R¹²A substituted phenyl group.

18. As claimed in one of claims 1 to 17The compound of (1), wherein R¹²The substituents on each instance of (1) are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Alkoxyalkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-7Haloalkoxyalkoxy group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, 4-to 7-membered heterocyclyloxy, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino.

19. The compound of one of claims 1-18, wherein R¹²The substituents on each instance of (1) are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino.

20. The compound of claim 14, wherein R¹²Is selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, cyano, or oxo.

21. The compound of claim 19, wherein R¹²The substituent on each instance of (a) is selected from C_1-6An alkoxy group.

22. A method as claimed in one of claims 1 to 21The compound of (1), wherein R¹Is H, and R¹⁰Is a substituted or unsubstituted phenyl group.

23. The compound of claim 16, wherein:

R¹⁰with R¹²Is substituted, and optionally substituted with a substituent independently selected from R¹¹Substituted with one or more substituents of (a);

R¹¹each instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkoxyalkyl, cyano, or halo.

24. The compound of claim 23, wherein R¹²Is substituted or unsubstituted phenyl, 5-or 6-membered heteroaryl, or 4-to 7-membered heterocyclyl, and is substituted with methyl, ethyl, methoxy, or trifluoromethyl.

25. The compound of any one of claims 23-24, wherein R¹Is H.

26. The compound of any one of claims 18-25, wherein R¹⁰Is prepared from R¹²A substituted phenyl group.

27. The compound of any one of claims 18-25, wherein R¹⁰Is a 5-to 10-membered heteroaryl.

28. The compound of any one of claims 18-27, wherein R¹²Is phenyl.

29. The compound of any one of claims 18-27, wherein R¹²Is pyrimidin-5-yl or pyridin-3-yl.

30. The compound of any one of claims 18-29, wherein R¹²Is 2-methoxy-pyrimidin-5-yl, 3-methoxyphenyl, 2-methoxy-pyridin-3-yl, 2-methyl-pyrimidin-5-yl, or tetrahydropyran-4-yl.

31. The compound of claim 30, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

32. the compound of claim 28, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

33. the compound of claim 14, wherein:

R¹is C_1-6Alkyl radical, C_3-6Cycloalkyl, or C_4-8A cycloalkylalkyl group;

R¹⁰is optionally independently selected from R¹¹C substituted by one or more substituents of_6-10Aryl or 5-to 10-membered heteroaryl;

34. The compound of claim 33, wherein R¹Is C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or C_1-3An alkyl group.

35. The compound of claim 34, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

36. the compound of any one of claims 1-30 or 33-34, wherein Z is CR¹⁷。

37. The compound of claim 36, wherein R¹Is C_1-6Alkyl radical, C_3-6Cycloalkyl, or C_4-8A cycloalkylalkyl group; and R is¹⁰Optionally with a group independently selected from R¹¹Is substituted with one or more substituents of (a).

38. The compound of claim 37, wherein R¹Is C_1-6Alkyl, or C_3-6A cycloalkyl group.

39. The compound of claim 38, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

40. the compound of claim 14, wherein:

R¹⁰is prepared from R¹⁵And R¹⁶Substituted C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally with a substituent independently selected from R¹¹Substituted with one or more substituents of (a);

R¹⁵and R¹⁶Independently selected from halogen; and is

41. The compound of claim 40, wherein R¹⁵And R¹⁶Is chlorine.

42. The compound of claim 41, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

43. the compound of claim 14, wherein:

R¹⁰is prepared from R¹⁵Substituted C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally with a substituent independently selected from R¹¹Substituted with one or more substituents of (a);

R¹⁵selected from halogen or haloalkyl; and is

44. The compound of claim 43, wherein R¹⁵Is trifluoromethyl or chlorine.

45. The compound of claim 44, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

46. the compound of any one of the preceding claims, wherein the compound is more than 10-fold selective for Toxoplasma gondii as compared to human DHFR.

47. The compound of claim 46, wherein the compound is more than 30-fold selective for Toxoplasma gondii as compared to human DHFR.

48. The compound of claim 47, wherein the compound is more than 100-fold selective for Toxoplasma gondii as compared to human DHFR.

49. The compound of any one of the preceding claims, wherein the compound is more than 10-fold selective for trypanosoma cruzi compared to human DHFR.

50. The compound of claim 49, wherein the compound is more than 30-fold selective for Trypanosoma cruzi as compared to human DHFR.

51. The compound of claim 50, wherein the compound is more than 100-fold selective for Trypanosoma cruzi as compared to human DHFR.

52. The compound of any one of the preceding claims, wherein the compound is more than 10-fold selective for plasmodium falciparum as compared to human DHFR.

53. The compound of claim 32, wherein the compound is more than 30-fold selective for plasmodium falciparum compared to human DHFR.

54. The compound of claim 33, wherein the compound is more than 100-fold selective for plasmodium falciparum compared to human DHFR.

55. The compound of any one of the preceding claims, wherein the compound is more than 10-fold selective for Trypanosoma brucei over human DHFR.

56. The compound of claim 55, wherein the compound is more than 30-fold selective for Trypanosoma brucei over human DHFR.

57. The compound of claim 56, wherein the compound is more than 100-fold selective for Trypanosoma brucei over human DHFR.

58. The compound of any one of the preceding claims, wherein the compound is more than 10-fold selective for leishmania major compared to human DHFR.

59. The compound of claim 58, wherein the compound is more than 30-fold selective for Leishmania major compared to human DHFR.

60. The compound of claim 59, wherein the compound is more than 100-fold selective for Leishmania major compared to human DHFR.

61. A pharmaceutical composition comprising a compound of any one of the preceding claims.

62. A method of treating an infection, the method comprising administering a compound having the structure of formula (I), a pharmaceutically acceptable salt or prodrug of the compound, or a pharmaceutical composition comprising the compound, salt, or prodrug:

wherein:

R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁷and R¹⁸Independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy or fluoro; provided that R is²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹At least four of (a) are H; if W is N, R²、R³、R⁶And R⁷None of which is a hydroxyl group; and if Z is N, then R⁴、R⁵、R⁸And R⁹None of which is a hydroxyl group; and is

63. The method of claim 62, wherein W and Z are N.

64. The method of one of claims 62-63, wherein the compound has the structure of formula (Ia):

wherein:

R¹is H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen;

65. The method of one of claims 62-64, wherein the infection is caused by a protozoan.

66. The method of claim 65, wherein said protozoa is an apicomplexan protozoa.

67. The method of claim 66, wherein the protozoan is Toxoplasma gondii.

68. The method of claim 66, wherein the protozoan is Trypanosoma cruzi.

69. The method of claim 66, wherein said protozoa are Leishmania macrolepis.

70. The method of claim 66, wherein the protozoan is Trypanosoma brucei.

71. The method of claim 66, wherein the protozoan is Plasmodium falciparum.

72. The method of one of claims 62-71, wherein R¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, or an aromatic or heteroaromatic moiety.

73. The method of one of claims 62-72, wherein R¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, amino, amidine, cyano, mercapto, or alkylthio, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

74. The method of one of claims 62-73, wherein R¹⁰With at least one substituent selected from the group consisting of alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, substituted aryl,azido, mercapto, or alkylthio, heterocyclic, aralkyl, or a substituent of an aromatic or heteroaromatic moiety.

75. The method of one of claims 62-74, wherein R¹⁰Substituted with at least one substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

76. The method of one of claims 62-75, wherein R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl radical, C_4-6Cycloalkylalkyl, or halogen.

77. The method of one of claims 62-76, wherein R¹Is C_4-6A cycloalkylalkyl group.

78. The method of one of claims 62-76, wherein R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl, or halogen.

79. The method of one of claims 62-78, wherein:

R¹⁰is optionally independently selected from R¹¹、R¹²Or X-R¹²One or more substituents ofSubstituted C_6-10Aryl or 5-to 10-membered heteroaryl;

R¹³Is independently H or C_1-6An alkyl group.

80. The method as recited in claim 79, wherein R¹⁰Is substituted or unsubstituted C_6-10Aryl or 5-to 10-membered heteroaryl, and further with R¹²Or X-R¹²And (4) substitution.

81. The method of claim 80, wherein R¹⁰Is phenyl.

82. The method of claim 81, wherein R¹⁰Is in the meta position with R¹²A substituted phenyl group.

83. The method of one of claims 62-82, wherein R¹²The substituents on each instance of (1) are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Alkoxyalkoxy radical, C_1-6Haloalkyl, C_1-6Alkyl halidesOxy radical, C_3-7Haloalkoxyalkoxy group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, 4-to 7-membered heterocyclyloxy, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino.

84. The method of one of claims 62-83, wherein R¹²The substituents on each instance of (1) are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino.

85. The method as recited in claim 84, wherein R¹²The substituent on each instance of (a) is selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, cyano, or oxo.

86. The method as recited in claim 84, wherein R¹²The substituent on each instance of (a) is selected from C_1-6An alkoxy group.

87. The method of any one of claims 79-86, wherein R¹Is H, and R¹⁰Is a substituted or unsubstituted phenyl group.

88. The method of claim 79, wherein:

89. The method of claim 88, wherein R¹²Is substituted or unsubstituted phenyl, 5-or 6-membered heteroaryl, or 4-to 7-membered heterocyclyl, and is substituted with methyl, ethyl, methoxy, or trifluoromethyl.

90. The method of any one of claims 88-89, wherein R¹Is H.

91. The method of any one of claims 88-90, wherein R¹⁰Is prepared from R¹²A substituted phenyl group.

92. The method of any one of claims 88-90, wherein R¹⁰Is a 5-to 10-membered heteroaryl.

93. The method of claims 88-92, wherein R¹²Is phenyl.

94. The method of any one of claims 88-92, wherein R¹²Is pyrimidin-5-yl or pyridin-3-yl.

95. The method of any one of claims 88-94, wherein R¹²Is 2-methoxy-pyrimidin-5-yl, 3-methoxyphenyl, 2-methoxy-pyridin-3-yl, 2-methyl-pyrimidin-5-yl, or tetraHydropyran-4-yl.

96. The method of claim 95, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

97. the method of claim 93, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

98. the method of claim 79, wherein:

R¹is C_1-6Alkyl radical, C_3-6Cycloalkyl, or C_4-8A cycloalkylalkyl group;

99. The method of claim 98, wherein R¹Is C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or C_1-3An alkyl group.

100. The method of claim 99, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

101. the method of any one of claims 62-95 or 98-99, wherein Z is CR¹⁷。

102. The method as recited in claim 101, wherein R¹Is C_1-6Alkyl radical, C_3-6Cycloalkyl, or C_4-8A cycloalkylalkyl group; and R is¹⁰Optionally with a group independently selected from R¹¹Is substituted with one or more substituents of (a).

103. The method of claim 102, wherein R¹Is C_1-6Alkyl, or C_3-6A cycloalkyl group.

104. The method of claim 103, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

105. the method of claim 79, wherein:

R¹⁰is prepared from R¹⁵And R¹⁶Substituted C_6-10Aryl or 5-A meta to 10-membered heteroaryl, and optionally independently selected from R¹¹Substituted with one or more substituents of (a);

R¹⁵and R¹⁶Independently selected from halogen; and is

106. The method as recited in claim 105, wherein R¹⁵And R¹⁶Is chlorine.

107. The method of claim 106, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

108. the method of claim 79, wherein:

R¹⁵selected from halogen or haloalkyl; and is

109. The method as recited in claim 108, wherein R¹⁵Is trifluoromethyl or chlorine.

110. The method of claim 109, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

111. a compound having the structure of formula (I), a pharmaceutically acceptable salt or prodrug of said compound, or a pharmaceutical composition comprising said compound, salt or prodrug, for use in the treatment of an infection:

wherein:

112. The compound of claim 111, wherein W and Z are N.

113. The compound of one of claims 111-112, wherein the compound has the structure of formula (Ia):

wherein:

R¹is H, C_1-6Alkyl radical, C_3-6Cycloalkyl, or halogen;

114. The compound of one of claims 111-114, wherein the infection is caused by a protozoan.

115. The compound of claim 114, wherein the protozoan is an apicomplexan protozoan.

116. The compound of claim 115, wherein the protozoan is Toxoplasma gondii.

117. The compound of claim 115, wherein the protozoan is trypanosoma cruzi.

118. The compound of claim 115, wherein the protozoan is leishmania magna.

119. The compound of claim 115, wherein the protozoan is trypanosoma brucei.

120. The compound of claim 115, wherein the protozoan is plasmodium falciparum.

121. The compound of one of claims 111-120, wherein R¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkyl, or an aromatic or heteroaromatic moiety.

122. The compound of one of claims 111-121, wherein R is¹⁰Is C_6-10Aryl or 5-to 10-membered heteroaryl, and optionally substituted with a substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, amino, amidine, cyano, mercapto, or alkylthio, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

123. The compound of one of claims 111-122, wherein R¹⁰With at least one member selected from the group consisting of alkyl, cycloalkyl, halogen, hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, mercapto, or alkylthio, heterocyclic, aralkylOr a substituent of an aromatic or heteroaromatic moiety.

124. The compound of one of claims 111-123, wherein R¹⁰Substituted with at least one substituent selected from alkyl, cycloalkyl, halo (e.g., fluoro), hydroxy, alkoxy, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

125. The compound of one of claims 111-124, wherein R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl radical, C_4-6Cycloalkylalkyl, or halogen.

126. The compound of one of claims 111-125, wherein R¹Is C_4-6A cycloalkylalkyl group.

127. The compound of one of claims 111-126, wherein R¹Is H, C_1-3Alkyl radical, C_3-5Cycloalkyl, or halogen.

128. The compound of one of claims 111-127, wherein:

R¹³Is independently H or C_1-6An alkyl group.

129. The compound of claim 128, wherein R¹⁰Is substituted or unsubstituted C_6-10Aryl or 5-to 10-membered heteroaryl, and further with R¹²Or X-R¹²And (4) substitution.

130. The compound of claim 129, wherein R¹⁰Is phenyl.

131. The compound of claim 130, wherein R¹⁰Is in the meta position with R¹²A substituted phenyl group.

132. The compound of one of claims 111-131, wherein R¹²The substituents on each instance of (1) are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Alkoxyalkoxy radical, C_1-6Haloalkyl, C_1-6Alkyl halidesOxy radical, C_3-7Haloalkoxyalkoxy group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, 4-to 7-membered heterocyclyloxy, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino.

133. The compound of any one of claims 111-132, wherein R¹²The substituents on each instance of (1) are selected from hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_4-8Cycloalkylalkoxy radical, C_4-8Cycloalkylalkyl, 4-to 7-membered heterocyclyl, halogen, cyano, oxo, or optionally with up to 2C_1-6Alkyl or C_3-6Cycloalkyl-substituted amino.

134. The compound of claim 133, wherein R¹²The substituent on each instance of (a) is selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, cyano, or oxo.

135. The compound of claim 133, wherein R¹²The substituent on each instance of (a) is selected from C_1-6An alkoxy group.

136. The compound of any one of claims 111-135, wherein R¹Is H, and R¹⁰Is a substituted or unsubstituted phenyl group.

137. The compound of claim 128, wherein:

138. The compound of claim 137, wherein R¹²Is substituted or unsubstituted phenyl, 5-or 6-membered heteroaryl, or 4-to 7-membered heterocyclyl, and is substituted with methyl, ethyl, methoxy, or trifluoromethyl.

139. The compound of any one of claims 137-138, wherein R¹Is H.

140. The compound of any one of claims 137-139, wherein R¹⁰Is prepared from R¹²A substituted phenyl group.

141. The compound of any one of claims 137-139, wherein R¹⁰Is a 5-to 10-membered heteroaryl.

142. The compound of claims 137-141, wherein R¹²Is phenyl.

143. The compound of any one of claims 137-141, wherein R¹²Is pyrimidin-5-yl or pyridin-3-yl.

144. The compound of any one of claims 137-143, wherein R¹²Is 2-methoxy-pyrimidin-5-yl, 3-methoxyphenyl, 2-methoxy-pyridin-3-yl, 2-methyl-pyrimidin-5-yl, or tetrahydropyran-4-yl.

145. The compound of claim 144, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

146. the compound of claim 142, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

147. the compound of claim 128, wherein:

R¹is C_1-6Alkyl radical, C_3-6Cycloalkyl, or C_4-8A cycloalkylalkyl group;

148. The method of claim 147Compound (I) wherein R¹Is C_3-6Cycloalkyl radical, C_4-8Cycloalkylalkyl, or C_1-3An alkyl group.

149. The compound of claim 148, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures:

150. the compound of any one of claims 111-144 or 147-148, wherein Z is CR¹⁷。

151. The compound of claim 150, wherein R¹Is C_1-6Alkyl radical, C_3-6Cycloalkyl, or C_4-8A cycloalkylalkyl group; and R is¹⁰Optionally with a group independently selected from R¹¹Is substituted with one or more substituents of (a).

152. The compound of claim 151, wherein R¹Is C_1-6Alkyl, or C_3-6A cycloalkyl group.

153. The compound of claim 152, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

154. the compound of claim 128, wherein:

R¹⁵and R¹⁶Independently selected from halogen; and is

155. The compound of claim 154, wherein R¹⁵And R¹⁶Is chlorine.

156. The compound of claim 155, wherein the compound has the following structure or is a pharmaceutically acceptable salt or prodrug of the following structure:

157. the compound of claim 128, wherein:

R¹⁵selected from halogen or haloalkyl; and is

158. The compound of claim 157, wherein R¹⁵Is trifluoromethyl orChlorine.

159. The compound of claim 158, wherein the compound has or is a pharmaceutically acceptable salt or prodrug of one of the following structures: