WO2019040869A1 - Inhibitors of purine import in parasites and uses thereof - Google Patents

Abstract

This invention relates to compounds for treating a protozoan parasitic infection and to pharmaceutical compositions comprising the compounds; and to methods of using the compounds and compositions to treat parasitic infections.

Description

- INHIBITORS OF PURINE IMPORT IN PARASITES AND USES THEREOF

Cross Reference to Related Application

[0001] This application claims the benefit of U.S. Provisional Application No. 62/550,056, filed August 25, 2017, the entire contents of which are hereby incorporated by reference.

Statement of Government Support

[0002] This invention was made with government support under NIH Contract No.

ROl All 16665 awarded by the National Institutes of Health. The government has certain rights in the invention.

Field of the Invention

[0003] This invention relates to compounds that function as inhibitors of purine import in parasites and uses thereof. The compounds are useful in the treatment or prevention of malaria and other diseases or conditions associated with protozoan parasites that are purine auxotrophic. The invention also relates to pharmaceutical compositions comprising the inhibitors disclosed herein.

Background of the Invention

[0004] Protozoan parasites can cause diseases in humans and other animals. Human parasites can cause diseases such as malaria, amoebiasis, giardiasis, toxoplasmosis,

cryptosporidiosis, trichomoniasis, Chagas disease, leishmaniasis, African trypanosomiasis (sleeping sickness), amoebic dysentery, acanthamoeba keratitis, and primary amoebic meningoencephalitis. Although some parasitic diseases can be treated with antiparasitic drugs, the effectiveness of some of the antiparasitic drugs can be compromised as certain parasites become resistant to the drug.

[0005] Malaria is caused by infection with unicellular protozoan parasites from the genus Plasmodium. Five Plasmodium species infect humans, P. falciparum (causes the most lethal form of malaria), P. vivax, P. malariae, P. ovale, and P. knowlesi. The parasite is transmitted to the human via a bite from an infected female Anopheles mosquito. The world has 200 million malaria infections which are estimated to cause 0.5 million deaths every year. The development and spread of drug resistance is causing a growing problem for the treatment of malaria.

Currently drug resistance is common against all classes of antimalarial drugs apart from artemisinins. However, over the past decade resistance to artemisinins has also developed in Southeast Asia. It originated in the Thai-Cambodia border region. Now, malaria stains from Cambodia, Myanmar, Thailand, Vietnam and Laos are resistant to combination therapies that include artemisinins. If resistance to artemisinin-based combination therapies spreads to high transmission regions in sub-Saharan Africa, the results would be disastrous. Thus, there is a need for new generations of antimalarial drugs that are less likely to be subject to ineffectiveness through the development of resistance to the treatment.

Summary of the Invention

[0006] In accordance with one aspect of the present invention, a method of treating protozoan parasite infection in a subject in need thereof is provided. The method comprises administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein V is phenylene or heteroarylene; Ai is CH₂ or NH; each of Yi and Y2 is independently CH2, CO or SO2;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

[0007] In accordance with one aspect of the present invention, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (IA), or a pharmaceutically acceptable salt thereof,

wherein Ai is CH₂ or NH; each of Yi and Y₂ is independently CH₂, CO or S0₂; Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6. [0008] In accordance with one aspect, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (IAa), or a pharmaceutically acceptable salt thereof,

wherein Yi is CH₂, CO or SO2;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaR , or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

[0009] In accordance with some aspects, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (IAb):

[0010] In accordance with another aspect, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (I Ac):

[0011] In accordance with yet another aspect, the method comprises administering to subject a therapeutically effective amount of a compound represented by formula (IAd):

[0012] wherein Re is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)haloalkyl, (CH₂)nORa, or (CH₂)_nNRaRb.

[0013] In accordance with another aspect, the method comprises administering to the a therapeutically effective amount of a compound represented by formula (IAe):

[0014] In accordance with another aspect, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (IAf):

[0015] In accordance with certain aspects, the method comprises administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:

[0016] n accordance with another aspect of the present invention, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (IB), or a pharmaceutically acceptable salt thereof,

wherein V₁ is a thiophendiyl;

Ai is CH₂ or NH; each of Y1 and Y2 is independently CH2, CO or SO2;

R1 and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

[0017] In accordance with one aspect, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (IBa), or a pharmaceutically acceptable salt thereof,

wherein V1 is a thiophendiyl;

Yi is CH₂, CO or SO2;

R1 and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

[0018] In accordance with some aspects, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (IBb):

[0019] In accordance with another aspect, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (IBc):

[0020] In accordance with yet another aspect, the method comprises administering to subject a therapeutically effective amount of a compound represented by formula (IBd):

wherein V1 is a thiophendiyl; and

[0021] Re is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C7)cycloalkyl, (C1-C6)haloalkyl, (CH₂)nORa, or (CH₂)nNRaRb.

[0022] In accordance with another aspect, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (IBe):

[0023] In accordance with another aspect, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (IBf):

wherein R7 is H or (C1-C6)alkyl.

[0024] In accordance with another aspect, the method comprises administering to the subject a therapeutically effective amount of a compound represented by formula (IBg):

wherein R7 is H or (C1-C6)alkyl.

[0025] In accordance with certain aspects, the method comprises administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:

[0026] In accordance with another aspect, the method comprises administering to the subject a therapeutically effective amount of any of the compounds disclosed herein to treat a protozoan parasite infection, wherein the protozoan parasite is selected from the group consisting of Entamoeba histolytica, Cryptosporidium spp, Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp, Trichomonas vaginalis, Toxoplasma gondii, and Plasmodium spp. In accordance with certain aspects, the Plasmodium species is selected from the group consisting of P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. In accordance with certain aspects, the Cryptosporidium species is selected from the group consisting of C. parvum, C. canis, C.felis, C. meleagridis, C. muris and C. hominus. [0027] In accordance with another aspect, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0028] In accordance with one aspect, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein V is phenylene or heteroarylene;

Ai is CH₂ or NH; each of Yi and Y₂ is independently CH₂, CO or S0₂;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaR , or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6; and a pharmaceutically acceptable carrier.

In accordance with certain aspects, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (IA), or a pharmaceutically acceptable salt thereof:

wherein Ai is CH2 or NH; each of Yi and Y2 is independently CH2, CO or SO2;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6; and a pharmaceutically acceptable carrier.

[0029] In accordance with certain aspects, the present invention is directed to a

pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (IAa), or a pharmaceutically acceptable salt thereof:

wherein Yi is CH₂, CO or S0₂; R1 and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)_n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6; and a pharmaceutically acceptable carrier. [0030] In accordance with another aspect, the pharmaceutical composition comprises a compound represented by formula (IAb):

[0031] In accordance with yet another aspect, the pharmaceutical composition comprises a compound represented by formula (IAc):

[0032] In accordance with some aspects, the pharmaceutical composition comprises a compound represented by formula (IAd):

wherein Re is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)haloalkyl, (CH₂)nORa, or (CH₂)nNRaRb.

[0033] In accordance with one aspect, the pharmaceutical composition comprises a compound represented by formula (IAe):

[0034] In accordance with one aspect, the pharmaceutical composition comprises a compound represented by formula (IAf):

Detailed Description of the Invention

Definitions

[0036] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.

[0037] The terms "alkyl" and "alk" refer to a straight or branched chain alkane

(hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "(Ci-C4)alkyl" refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. The term "(Ci-C6)alkyl" refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 6 carbon atoms, such as n-hexyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, in addition to those exemplified for "(Ci-C4)alkyl." "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups:

hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re,

S(=0)₂Re, P(=0)₂Re, S(=0)₂ORe, Ρ(=0)₂0Re, NRbRc, NRbS(=0)₂Re, NRbP(=0)₂Re,

S(=0)₂NRbRc, Ρ(=0)₂NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NR_bRc, NRbC(=0)ORe, NRdC(=0)NRbRc, NRdS(=0)₂NRbRc, NR_dP(=0)₂NR_bR_c, NRbC(=0)Ra, or NRbP(=0)₂Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rt>, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.

[0038] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplaries of such groups include ethenyl or allyl. The term "C2-C6 alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2- methy E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent- 1-enyl, (Z)-hex-l-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-l-enyl, (E)-hex- 1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-l,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,

ORa, SRa, S(=0)Re, S(=0)₂Re, P(=0)₂Re, S(=0)₂ORe, P(=0)₂ORe, NRbRc, NRbS(=0)₂Re,

NRbP(=0)₂Re, S(=0)₂NRbRc, P(=0)₂NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NR_dC(=0)NRbR_c, NRdS(=0)₂NRbRc, NRdP(=0)₂NRbRc, NRbC(=0)Ra, or NRbP(=0)₂Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0039] The term "alkoxy" refers to the group -O-alkyl, including from 1 to 10 carbon atoms of a straight, branched, cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. "Lower alkoxy" refers to alkoxy groups containing one to six carbons. In some embodiments, C1-C4 alkoxy is an alkoxy group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in the specification, an alkoxy group is optionally substituted by one or more substituents.

[0040] The term "alkylthio" means an alkylthio group having from 1 to 12 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio and octylthio; and the term "lower alkylthio " means an alkylthio group having from 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio and hexylthio.

[0041] The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. An exemplary of such groups includes ethynyl. The term "C2-C6 alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon- carbon triple bond, such as ethynyl, prop-l -ynyl, prop-2-ynyl, but-l-ynyl, but-2-ynyl, pent-1 - ynyl, pent-2-ynyl, hex-l-ynyl, hex-2-ynyl, hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cb), cyano, nitro, oxo (i.e. , =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,

ORa, SRa, S(=0)Re, S(=0)₂Re, P(=0)₂Re, S(=0)₂ORe, P(=0)₂ORe, NRbRc, NRbS(=0)₂Re, NRbΡ(=0)₂Re, S(=0)₂NRbRc, P(=0)₂NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NRdC(=0)NRbRc, NRdS(=0)₂NRbRc, NRdP(=0)₂NRbRc, NRbC(=0)Ra, or NRbP(=0)₂Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rt>, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0042] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cb), cyano, nitro, oxo (i.e. , =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,

ORa, SRa, S(=0)Re, S(=0)₂Re, P(=0)₂Re, S(=0)₂ORe, P(=0)₂ORe, NRbRc, NRbS(=0)₂Re,

NRbP(=0)₂Re, S(=0)₂NRbRc, P(=0)₂NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NRdC(=0)NRbRc, NRdS(=0)₂NRbRc, NRdP(=0)₂NRbRc, NRbC(=0)Ra, or NRbP(=0)₂Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cylic substituents, especially spiro-attached cycloalkyl, spiro- attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl,

cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0043] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplaries of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen {e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo {i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,

ORa, SRa, S(=0)Re, S(=0)₂Re, P(=0)₂Re, S(=0)₂ORe, P(=0)₂ORe, NRbRc, NRbS(=0)₂Re,

NRbP(=0)₂Re, S(=0)₂NRbRc, P(=0)₂NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NR_dC(=0)NRbR_c, NRdS(=0)₂NRbRc, NRdP(=0)₂NRbRc, NRbC(=0)Ra, or NRbP(=0)₂Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cylic substituents, especially spiro-attached cycloalkyl, spiro- attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl,

cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0044] The term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). "Substituted aryl" refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR,, SRa, S(=0)Re, S(=0)2Re, P(=0)₂Re, S(=0)₂ORe, P(=0)₂ORe, NRbRc, NRbS(=0)₂Re, NRbΡ(=0)₂Re, S(=0)₂NRbRc, P(=0)₂NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NR_bRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NRdC(=0)NRbRc,

NRdS(=0)₂NRbRc, NRdP(=0)₂NRbRc, NRbC(=0)Ra, or NRbP(=0)₂Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl,

cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0045] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl-radical where aryl and alkyl are as provided herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively. The "aralkyl/arylalkyl" is bonded to the parent molecular structure through the alkyl group. The terms "aralkenyl/arylalkenyl" and "aralkynyl/arylalkynyl" mirror the above description of "aralkyl/arylalkyl" wherein the "alkyl" is replaced with "alkenyl" or "alkynyl" respectively, and the "alkenyl" or "alkynyl" terms are as described herein.

[0046] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., "heteroaryl") cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro- 1 , 1 - dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][l,3]dioxolyl, 2,3- dihydrobenzo[b][l,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl,

tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0047] "Substituted heterocycle" and "substituted heterocyclic" (such as "substituted heteroaryl") refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR,, SRa, S(=0)Re, S(=0)2Re, P(=0)₂Re, S(=0)₂ORe, P(=0)₂ORe, NRbRc, NRbS(=0)₂Re, NRbΡ(=0)₂Re, S(=0)₂NRbRc, P(=0)₂NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NR_bRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NRdC(=0)NRbRc,

NRdS(=0)₂NRbRc, NRdP(=0)₂NRbRc, NRbC(=0)Ra, or NRbP(=0)₂Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cylic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0048] The terms "halogen" or "halo" refer to chlorine, bromine, fluorine or iodine.

[0049] The term "heteroarylene" means a mono- or bicyclic aromatic ring with 5 to 10 ring atoms, which contains up to 3, preferably 1 or 2 heteroatoms selected independently from N, O or S and the remaining ring atoms being carbon atoms. Such heteroarylenes may be optionally substituted one or two times by alkyl which is defined as above. Examples of such

heteroarylenes include, but are not limited to, thiophenediyl, isoxazolediyl, pyrrolidinyl, methylthiophenediyl, furandiyl, imidazoldiyl, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl, triazinediyl, pyrazolediyl, oxazolediyl, methylisoxazolediyl, thiazolediyl, isothiazolediyl, thiadiazolediyl, oxadiazolediyl, triazolediyl, benzothiophenediyl, indolediyl, quinolinediyl, isoquinolinediyl, benzofurandiyl and the like, preferably thiophenediyl, isoxazolediyl, pyrrolediyl, especially thiophenediyl.

[0050] The term "D" refers to a deuterium atom, and is known in the art to refer to a deuterium enriched species, that is, where D is present above its natural isotopic abundance. Hydrogen can be replaced with Deuterium in any of the structures disclosed herein, particularly with respect to the alkyl groups.

[0051] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. [0052] The compounds of the present invention may form salts which are also within the scope of this invention. Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non- toxic, physiologically

acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of a compound of the present invention may be formed, for example, by reacting a compound as disclosed herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0053] The compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxy ethanesulfonates (e.g., 2- hydroxy ethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2- naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3 -phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0054] Compounds of the present invention which contain an acidic moiety, such as but not limited to a carboxylic acid, may form salts with a variety of organic and inorganic bases.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0055] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0056] Compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. [0057] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0058] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to greater than 95%, equal to or greater than 99% pure

("substantially pure" compound I), which is then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also contemplated herein as part of the present invention.

[0059] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings. [0060] Throughout the specifications, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0061] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006, the entire contents of which are incorporated herein by reference.

[0062] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and -S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.

Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0063] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0064] The present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. Compounds of the present invention, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the

aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon- 14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out by conventional procedures, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0065] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. [0066] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether preceded by the term "optionally" or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible

substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of infectious diseases or proliferative disorders. The term "stable", as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0067] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application including, but not limited to, disease treatment, as illustrated below. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells. The specific dose will vary depending on, for example, the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0068] As used herein, the terms "treatment", "treating", "palliating" and "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0069] A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. Compounds

[0070] The compounds of the present invention in accordance with one aspect are inhibitors of purine import into various parasites that are purine auxotrophic. These parasites lack the necessary enzymes for de novo purine biosynthesis and therefore, they must import purines from the host cells via homologues of the equilibrative nucleoside transporter (ENT) family of purine transport proteins. The imported purines are then metabolized through the purine salvage pathway to hypoxanthine, which is used as a starting point for the synthesis of the adenylate and guanalyte purines necessary for cell growth and proliferation.

[0071] Human malaria parasites have four ENT homologues (ENT1, ENT2, ENT3 and ENT4). Based on studies in P. falciparum parasites, the ENT1 homologue (PfENTl) is the primary purine import pathway. Knockout of PfENTl (pfentlΔ) is conditionally lethal, the parasites cannot proliferate in media with purine concentrations found in human blood, i.e., below 10 μΜ. At purine concentrations above 50 μΜ, pfentlΔ parasites can proliferate.

[0072] The compounds disclosed herein are believed to be capable of halting parasite proliferation in patients' blood for the treatment for malaria and other protozoan parasitic infections. By targeting these purine transporters, it is possible to block the parasites' ability to proliferate in human or animal blood.

[0073] Useful compounds in accordance with one aspect of the present invention include compounds of formula (I), or a pharmaceutically acceptable salt thereof,

wherein V is phenylene or heteroarylene; A1 is CH₂ or NH; each of Y1 and Y2 is independently CH2, CO or SO2;

R1 and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

[0074] Useful compounds in accordance with another aspect of the present invention include compounds of formula (IA), or pharmaceutically acceptable salts thereof,

wherein A1 is CH₂ or NH; each of Y1 and Y₂ is independently CH₂, CO or S0₂; Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6. [0075] Useful compounds in accordance with another aspect of the present invention include compounds of formula (IAa), or pharmaceutically acceptable salts thereof,

wherein Y1 is CH₂, CO or SO2;

R1 and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

[0076] In accordance with some aspects, the compound is represented by formula (IAb):

[0077] In accordance with another aspect, the compound is represented by formula (IAc):

[0078] Specific examples of compounds in accordance with this aspect, include, but limited to, the following:

and

[0079] In accordance with yet another aspect, the compound is represented by formula (IAd):

wherein Re is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)haloalkyl, (CH₂)nORa, or (CH₂)nNRaRb.

[0080] In accordance with another aspect, the compound is represented by formula (IAe):

In some embodiments, each R3 is independently (C1-C4)alkyl, or halogen.

[0081] In accordance with another aspect, the compound is represented by formula (IAf):

[0082] Specific examples of compounds in accordance with this aspect, include, but are not limited to, the following:

- 52-

[0085] Exemplary compounds in accordance with yet another aspect of the invention include, but are not limited to, the following:

[0086] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound as described herein and a pharmaceutically-acceptable carrier or diluent.

Utility and Methods of Use

[0087] Provided herein are methods for treating a disorder or disease by inhibiting purine transport. The methods, in general, comprises the step of administering a therapeutically effective amount of at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, to a patient in need thereof to treat the disorder or disease.

[0088] In certain embodiments, this invention provides a use of at least one compound as described herein in the manufacture of a medicament for treating a disorder or disease treatable by inhibition of purine transport.

[0089] The compounds of the present invention inhibit purine transport in purine auxotrophic parasites and may be useful in the treatment of diseases caused by these parasites. The compounds disclosed herein may be used to treat purine auxotrophic parasitic infection in a patient, or for inhibiting a purine auxotrophic parasitic infection in a patient. [0090] In certain embodiments, indications that may be treated with the compounds disclosed herein, either alone or in combination with other drugs, include, but are not limited to, those diseases caused by protozoan purine auxotrophic parasites.

[0091] In certain embodiments, these diseases include, but are not limited to, malaria, amoebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, Chagas disease, leishmaniasis, African trypanosomiasis (sleeping sickness), amoebic dysentery, acanthamoeba keratitis, and primary amoebic meningoencephalitis.

[0092] In certain embodiments, the invention also relates to the use of a compound according to the invention, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.

[0093] In view of the utility of the compounds according to the invention, there is provided a method of treating warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore, and a method of preventing in warm-blooded animals, including humans, any one of the diseases mentioned hereinbefore.

[0094] Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound according to the invention to warm-blooded animals, including humans.

[0095] Therefore, the invention also relates to a method for the prevention and/or treatment of any one of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof.

[0096] The purine transport inhibitors described herein can be used alone, in combination or in combination with other pharmaceutical agents such as other agents used in the treatment of parasitic infections. In such combinations, the compounds of the present invention may be utilized in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds disclosed herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.

[0097] One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to inhibit the purine transport and that this amount varies inter alia, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, an amount of the compounds disclosed herein to be administered as a therapeutic agent for treating diseases in which inhibition of purine transport is beneficial, such as the disorders described herein, will be determined on a case by case by an attending physician.

[0098] Generally, a suitable dose is one that results in a concentration of the purine transport inhibitor at the treatment site in the range of 0.5 nM to 200 uM, and more usually 5 nM to 50 μΜ. To obtain these treatment concentrations, a patient in need of treatment likely will be administered between 0.0001 mg/kg to 70 mg/kg body weight, in particular from 0.001 mg/kg to 25 mg/kg body weight, in particular, from 0.01 to 15 mg/kg body weight, in particular from 0.1 mg/kg to 1.0 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutic effect may vary on case-by-case basis, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to admission. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

Methods of Preparation:

[0099] Following are general synthetic schemes for manufacturing compounds of the present invention.

Scheme 1. General synthetic scheme

Scheme 2. Alternative synthetic scheme

[0100] These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art might use to manufacture compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrations but not limitations of the preparation of some of the starting materials and examples used herein.

[0101] Additional examples of potential schemes for certain compounds are provided below:

Scheme 3-1 Synthetic scheme - example

Scheme 3-3 Synthetic scheme - example

-

Scheme 3-5 Synthetic scheme - example

Scheme 3-6 Synthetic scheme - example

Scheme 3-7 Synthetic scheme - example

Scheme 3-8 Synthetic scheme - example

Scheme 3-9 Synthetic scheme - example

Scheme 3-10 Synthetic scheme - example 10

Scheme 3-11 Synthetic scheme - example 11

Scheme 3-12 Synthetic scheme - example

Scheme 3-13 Synthetic scheme - example 13

Scheme 3-14 Synthetic scheme - example 14 Pharmaceutical Compositions

[0102] This invention also provides a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.

[0103] The phrase "pharmaceutically-acceptable carrier" as used herein means a

pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. 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 which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0104] As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically-acceptable salts. The term "pharmaceutically- acceptable salt", in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al, (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0105] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric,

toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

[0106] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term "pharmaceutically-acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al, supra)

[0107] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. [0108] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient, which 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. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0109] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0110] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a 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 mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. [0111] In solid dosage forms of the invention for oral administration (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: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0112] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets, may be, made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0113] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples are embedding compositions, which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form with one or more of the above- described excipients.

[0114] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, 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, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene 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.

Additionally, cyclodextrins, e.g., hydroxybutyl-.beta.-cyclodextrin, may be used to solubilize compounds. [0115] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0116] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0117] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a 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 pharmaceutical agents of the invention.

[0118] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be apbutriate.

[0119] Dosage forms for the topical or transdermal administration of a compound of this invention 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 butellants which may be required.

[0120] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, 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.

[0121] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary butellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons.

[0122] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving, or dispersing the pharmaceutical agents in the buter medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0123] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more

pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous 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, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0124] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon 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 vehicle. One strategy for depot injections includes the use of polyethylene oxide- polybutylene oxide copolymers wherein the vehicle is fluid at room temperature and solidifies at body temperature.

[0125] Injectable depot forms are made by forming microencapsule 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 tissue.

[0126] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0127] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another anti-malaria agent), or they may achieve different effects (e.g., control of any adverse effects).

[0128] The compounds of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds may be used to treat conditions in mammals (i.e., humans, livestock, and domestic animals), birds, lizards, and any other organism, which can tolerate the compounds.

[0129] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

Equivalents

[0130] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information,

exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof. Examples

[0131] Using a yeast-based high throughput screening assay small molecule inhibitors of PfENTl were identified that killed P. falciparum parasites in culture (Frame et al, 2015 ACS Chem Biol. 10:775-783). In the primary screen the compounds were tested at a concentration of 10 μΜ. Ligand Efficiency is calculated as 1.37 * pIC50/heavy atom count. Results are provided below in Tables 1 and 2:

TABLE 1

- Ill -

N/A = not applicable

TABLE 2

Claims

1. A method of treating protozoan parasite infection in a subject in need thereof comprising administering to the subject of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

(I) wherein V is phenylene or heteroarylene;

Ai is CH₂ or NH; each of Yi and Y2 is independently CH2, CO or SO2;

R1 and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

2. The method of claim 1, wherein the compound is represented by formula (IA):

wherein A1 is CH2 or NH; each of Y1 and Y2 is independently CH2, CO or SO2;

R1 and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

3. The method of claim 1, wherein the compound is represented by formula (IAa):

wherein Yi is CH₂, CO or S0₂. 4. The method of claim 1, wherein the compound is represented by formula (IAb):

The method of claim 1, wherein the compound is represented by formula (IAc):

The method of claim 1, wherein the compound is represented by formula (IAd):

wherein Re is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)haloalkyl, (CH₂)nORa, or (CH₂)nNRaRb.

9. The method of claim 1, wherein the compound is represented by formula (IB), or a pharmaceutically acceptable salt thereof,

wherein Vi is a thiophendiyl;

Ai is CH₂ or NH; each of Yi and Y₂ is independently CH₂, CO or S0₂;

Ri and R₂ are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaR , or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

10. The method of claim 9, wherein the compound is represented by formula (IBa), or a pharmaceutically acceptable salt thereof,

wherein Vi is a thiophendiyl;

Yi is CH₂, CO or S0₂;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaR , or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

11. The method of claim 9, wherein the compound is represented by formula (IBb):

12. The method of claim 9, wherein the compound is represented by formula (IBc):

The method of claim 9, wherein the compound is represented by formula (IBd):

wherein VI is a thiophendiyl; and

R6 is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C7)cycloalkyl, (C1-C6)haloalkyl, (CH2)nORa, or (CH2)nNRaRb.

14. The method of claim 9, wherein the compound is represented by formula (IBe):

15. The method of claim 9, wherein the compound is represented by formula (IBf):

wherein R7 is H or (C1-C6)alkyl.

16. The method of claim 9, wherein the compound is represented by formula (IBg):

wherein R7 is H or (C1-C6)alkyl.

17. The method of claim 9, wherein the compound is selected from the group consisting of:

18. The method of any one of claims 1-17, wherein the protozoan parasite is selected from the group consisting of Entamoeba histolytica, Cryptosporidium spp, Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp, Trichomonas vaginalis, Toxoplasma gondii, and

Plasmodium spp.

19. The method of claim 18, wherein the Plasmodium species is selected from the group consisting of P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi.

20. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein V is phenylene or heteroarylene; Ai is CH₂ or NH; each of Yi and Y2 is independently CH2, CO or SO2;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6; and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20, wherein the compound is represented by formula (IA):

wherein Ai is CH₂ or NH; each of Yi and Y2 is independently CH2, CO or SO2;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R3 and R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; n is 1-6

22. The pharmaceutical composition of claim 20, wherein the compound is represented by formula (IAa):

wherein Yi is CH₂, CO or S0₂.

23. The pharmaceutical composition of claim 20, wherein the compound is represented by formula (IAb):

24. The pharmaceutical composition of claim 20, wherein the compound is represented by formula (IAc):

25. The pharmaceutical composition of claim 20, wherein the compound is represented by formula (IAd):

wherein Re is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)haloalkyl, (CH₂)nORa, or (CH₂)nNRaRb.

26. The pharmaceutical composition of claim 20, wherein the compound is represented by formula (IAe):

27. The pharmaceutical composition of claim 20, wherein the compound is selected from the group consisting of:

28. The pharmaceutical composition of claim 20, wherein the compound is represented by formula (IB), or a pharmaceutically acceptable salt thereof,

wherein Vi is a thiophendiyl;

Ai is CH₂ or NH; each of Y1 and Y₂ is independently CH₂, CO or S0₂;

R1 and R₂ are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaR , or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

29. The pharmaceutical composition of claim 28, wherein the compound is represented by formula (IBa), or a pharmaceutically acceptable salt thereof,

wherein Vi is a thiophendiyl;

Yi is CH₂, CO or S0₂;

Ri and R2 are each independently H, halogen, OH, CN, OCF3, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, 3-12-membered heterocycle, (C1-C6)alkylthio, (C1-C6)haloalkyl, (CH₂)n(C3-C7)cycloalkyl, aryl, arylalkyl, (CH₂)nORa, (CH₂)nSRa, (CH₂)nNRaR , or (CH₂)n(C1-C6)haloalkyl, in which said heterocycle contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of halogen, oxo, OH, OMe, CN, (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)haloalkyl and (C1- C4)alkoxy; each R₄ is independently H, halogen, OH, CN, NO2, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, or haloalkyl; each R5 is independently H, halogen, OH, CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylthio, NRaRb, (C1- C6)haloalkyl, (CH₂)_nORa, (CH₂)nSRa, (CH₂)_nNRaRb, (CH₂)n(C1-C6)haloalkyl; each occurrence of Ra and Rb is independently hydrogen, OMe, or (C1-C6)alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C1- C4)alkyl, phenyl and benzyl; and n is 1-6.

30. The pharmaceutical composition of claim 28, wherein the compound is represented by formula (IBb):

31. The pharmaceutical composition of claim 28, wherein the compound is represented by formula (IBc):

32. The pharmaceutical composition of claim 28, wherein the compound is represented by formula (IBd):

wherein V1 is a thiophendiyl; and

R6 is independently H, C(0)Ra, (C1-C8)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C7)cycloalkyl, (C1-C6)haloalkyl, (CH2)nORa, or (CH2)nNRaRb.

33. The pharmaceutical composition of claim 28, wherein the compound is represented by formula (IBe):

34. The pharmaceutical composition of claim 28, wherein the compound is represented by formula (IBf):

wherein R7 is H or (C1-C6)alkyl.

35. The pharmaceutical composition of claim 28, wherein the compound is represented by formula (IBg):

wherein R7 is H or (C1-C6)alkyl.

36. The pharmaceutical composition of claim 28, wherein the compound is selected from the group consisting of: