Quinazoline Compounds and Uses

Abstract

Novel heterocyclic compounds, such as novel quinazoline compounds, and pharmaceutical compositions thereof, that can be used in the treatment or prevention of malaria, HIV infection, and cancer are disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 447,180, filed February 21, 2023, the entire contents of which are incorporated herein by reference.

[0002] Novel heterocyclic compounds, such as novel quinazoline compounds, and pharmaceutical compositions thereof, that can be used in the treatment or prevention of malaria, HIV infection, and cancer are disclosed. [Background technology]

[0003] Current treatments for malaria, HIV infection, and cancer need improvement. Thus, there is a need for new classes of compounds that can be used to treat and / or prevent malaria, HIV infection, and cancer. Summary of the Invention

[0004] In one aspect, these and other needs are met by a compound of structural formula (I): [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, During the ceremony, X is substituted heteroaryl or -C(O)-R1, where R1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Y is [ka] and Z is H, -C(O)R 10 , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; R 10is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

[0005] Also provided are derivatives of the compounds described herein, such as salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs. Additionally provided are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable vehicle.

[0006] In yet another aspect, there is provided a method for treating, preventing, or alleviating the symptoms of a medical disorder, such as, for example, malaria, HIV infection, or cancer, comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of structural formula (I) or a pharmaceutically acceptable composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0007] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0008] Unless otherwise specified, when the terms "about" and "approximately" are used herein in connection with a property having a numerical value or a numerical range, they indicate that the value or range of values ​​may deviate to an extent that would be reasonably recognized by one of ordinary skill in the art, within the scope of the expression of that particular property. Specifically, the terms "about" and "approximately," as used in this context, indicate that the numerical value or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the stated value or range of values. Also, unless the context clearly indicates otherwise, the singular forms "a" and "the" include plural references. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those of ordinary skill in the art.

[0009] A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes before or after a chemical group are for convenience; a chemical group may be written with or without one or more dashes without losing its normal meaning. A wavy line through a straight line in a structure indicates the point of attachment of the group. No directionality is given or implied by the order in which chemical groups are written or named unless chemically or structurally required.

[0010] Prefix “C” u~v indicates that the subsequent group has u to v carbon atoms. The u to v carbon atoms include carbon numbers u+1 to v, u+2 to v, u+3 to v, etc., u+1 to u+3 to v, u+1 to u+4 to v, u+2 to u+4 to v, etc., and should be understood to encompass all possible permutations of u and v.

[0011] "Alkyl," by itself or as part of another substituent, refers to a saturated, branched or straight-chain monovalent hydrocarbon radical derived by the removal of a hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl, such as propan-1-yl, propan-2-yl; butyl, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl; and the like. In some embodiments, an alkyl group contains 1 to 20 carbon atoms (C1-C 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1 to C 10 In yet other embodiments, the alkyl group comprises 1 to 6 carbon atoms (C1-C6 alkyl).

[0012] "Alkenyl," by itself or as part of another substituent, refers to an unsaturated, branched, or straight-chain group having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl groups such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl; butenyl groups such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl; and the like. In some embodiments, an alkenyl group contains 2 to 20 carbon atoms (C 20 alkenyl). In other embodiments, the alkenyl group contains 2 to 10 carbon atoms (C 10 In yet other embodiments, the alkenyl group contains 2 to 6 carbon atoms (C2-C6 alkenyl).

[0013] "Alkynyl," by itself or as part of another substituent, refers to an unsaturated, branched, or straight chain alkyl group having at least one carbon-carbon triple bond, derived by the removal of a hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl and prop-2-yn-1-yl; butynyl groups such as but-1-yn-1-yl, but-1-yn-3-yl, and but-3-yn-1-yl; and the like. In some embodiments, an alkynyl group contains from 2 to 20 carbon atoms (C2-C6). 20 In other embodiments, the alkynyl group contains 2 to 10 carbon atoms (C 10 In yet other embodiments, the alkynyl group contains from 2 to 6 carbon atoms (C2-C6 alkynyl).

[0014] "Aryl," by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon radical derived by the removal of a hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In some embodiments, an aryl group contains 6 to 30 carbon atoms (C6-C8). 30 In other embodiments, the aryl group contains 6 to 20 carbon atoms (C6-C 20 In yet other embodiments, the aryl group contains 6 to 15 carbon atoms (C6-C 15 In yet another embodiment, the aryl group contains 6 to 10 carbon atoms (C 10 aryl).

[0015] "Arylalkyl," by itself or as part of another substituent, means an alkyl group, as defined herein, containing at least one carbon atom (typically a terminal or sp 3 The arylalkyl group refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a (C7-C8 carbon atom) is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 1-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 1-naphthylethene-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl. In some embodiments, the arylalkyl group is a (C7-C8 carbon atom) 40 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C 10 ) alkyl, and the aryl portion is (C6-C 30 In other embodiments, the arylalkyl group is (C7-C 30 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C 10 ) alkyl, and the aryl portion is (C6-C 20 In other embodiments, the arylalkyl group is (C7-C 20 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C8) alkyl and the aryl portion is (C6-C 12 In yet another embodiment, the arylalkyl group is (C7-C 15 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C5) alkyl and the aryl portion is (C6-C 10 ) aryl.

[0016] "Arylalkenyl," by itself or as part of another substituent, refers to an acyclic alkenyl group, as defined herein, in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group. In some embodiments, an arylalkenyl group is a (C8-C 40 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C10 ) alkenyl, and the aryl moiety is (C6-C 30 In other embodiments, the arylalkenyl group is (C8-C 30 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C 10 ) alkenyl, and the aryl portion is (C8-C 20 In other embodiments, the arylalkenyl group is (C8-C 20 )arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C2-C8)alkenyl and the aryl portion is (C6-C 12 In yet another embodiment, the arylalkenyl group is (C8-C 15 )arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C2-C5)alkenyl and the aryl portion is (C6-C 10 ) aryl.

[0017] "Arylalkynyl," by itself or as part of another substituent, refers to an acyclic alkynyl group, as defined herein, in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group. In some embodiments, an arylalkynyl group is a (C8-C 40 ) arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C 10 ) alkynyl, and the aryl moiety is (C6-C 30 In other embodiments, the arylalkynyl group is (C8-C 30 ) arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C 10 ) alkynyl, and the aryl moiety is (C6-C 20 In other embodiments, the arylalkynyl group is (C8-C 20 )arylalkynyl, for example, the alkynyl portion of the arylalkenyl group is (C2-C8)alkynyl and the aryl portion is (C6-C 12In yet another embodiment, the arylalkynyl group is (C8-C 15 )arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C2-C5)alkynyl and the aryl portion is (C6-C 10 ) aryl.

[0018] "Compound" refers to a compound encompassed by the structural formulas disclosed herein, and includes any specific compound within these formulas whose structures are disclosed herein. A compound may be identified by its chemical structure and / or chemical name. The chemical structure defines the identity of the compound. The compounds described herein may contain one or more asymmetric centers and / or double bonds and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Thus, chemical structures depicted herein encompass stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure forms) depicted in the structure. Chemical structures depicted herein also encompass enantiomeric and stereoisomeric derivatives of the depicted compound. Enantiomeric and stereoisomeric mixtures can be separated into their constituent enantiomers or stereoisomers using separation or asymmetric synthesis techniques well known to those skilled in the art. Compounds may exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the depicted compounds. The compounds may also be atropisomers. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17Examples include, but are not limited to, O. Compounds may exist in unsolvated as well as solvated forms, for example, hydrated forms. In general, compounds may be hydrated or solvated. Some compounds may exist in multiple crystalline or amorphous forms. In general, for the uses contemplated herein, all physical forms are equivalent and intended to be within the scope of the present disclosure. Furthermore, when a substructure of a compound is depicted, it should be understood that the brackets indicate the point of attachment at which the substructure is attached to the remainder of the molecule.

[0019] "Cycloalkyl," by itself or as part of another substituent, refers to a saturated cyclic monovalent hydrocarbon radical derived by the removal of a hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and the like. In some embodiments, cycloalkyl groups contain from 3 to 20 carbon atoms (C3 to C6). 15 In other embodiments, the cycloalkyl group contains 3 to 10 carbon atoms (C 10 In yet other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C3-C8 cycloalkyl). The term "cyclic monovalent hydrocarbon radical" also includes polycyclic hydrocarbon ring systems having a single radical and containing 5 to 12 carbon atoms. Examples of polycyclic cycloalkyl rings include norbornyl, vinyl, and adamantyl.

[0020] "Cycloalkenyl," by itself or as part of another substituent, refers to an unsaturated cyclic monovalent hydrocarbon radical derived by the removal of a hydrogen atom from a single carbon atom of a parent cycloalkene. Typical cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, and the like. In some embodiments, cycloalkenyl groups contain from 3 to 20 carbon atoms (C3 to C6). 20 In other embodiments, the cycloalkenyl group contains 3 to 10 carbon atoms (C 10In yet other embodiments, the cycloalkenyl group comprises from 3 to 8 carbon atoms (C3-C8 cycloalkenyl).

[0021] "Cycloheteroalkyl" by itself or as part of another substituent refers to a cycloalkyl group, as defined herein, in which one or more carbon atoms (and optionally any hydrogen atoms attached thereto) are each independently replaced with the same or different heteroatom or heteroatom group as defined below under "heteroalkyl." In some embodiments, a cycloheteroalkyl group contains from 3 to 20 carbon atoms and heteroatoms ( 3~20 In other embodiments, the cycloheteroalkyl group contains 3 to 10 carbon atoms and heteroatoms (cycloheteroalkyl). 3~10 In yet another embodiment, the cycloheteroalkyl group contains 3 to 8 carbon atoms and heteroatoms (cycloheteroalkyl). 3~8 Cycloheteroalkyl). The term "cyclic monovalent heteroalkyl radical" also includes polycyclic heteroalkyl ring systems having a single radical and having 3 to 12 carbon atoms and at least one heteroatom. Examples of cycloheteroalkyl groups include azetidine, pyrrolidine, piperazine, piperidine, morpholine, and tetrahydrofuran.

[0022] "Cycloheteroalkenyl" by itself or as part of another substituent refers to a cycloalkenyl group, as defined herein, in which one or more carbon atoms (and optionally any hydrogen atoms bonded thereto) are each independently replaced with the same or different heteroatom or heteroatom group defined below under "heteroalkenyl." In some embodiments, the cycloheteroalkenyl group contains 3 to 20 carbon atoms and heteroatoms ( 3~20 In other embodiments, the cycloheteroalkenyl group contains 3 to 10 carbon atoms and heteroatoms ( 3~10) In yet another embodiment, the cycloheteroalkenyl group contains 3 to 8 carbon atoms and heteroatoms (cycloheteroalkenyl). 3~8The term "cyclic monovalent heteroalkenyl radical" also encompasses polycyclic heteroalkenyl ring systems having a single radical and having 2 to 12 carbon atoms and at least one heteroatom.

[0023] "Halo" by itself or as part of another substituent refers to a radical -F, -Cl, -Br, or -I.

[0024] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and optionally any hydrogen atoms bonded thereto) are each independently replaced with the same or different heteroatoms or heteroatom groups. Typical heteroatoms or heteroatom groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, and -S(O)2NH-, and combinations thereof. These heteroatoms or heteroatom groups may be located at any interior position of the alkyl, alkenyl, or alkynyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 , =NN=, -N=N-, -N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2- and -SnR 507 R 508 Examples include, but are not limited to, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkyl group contains 1 to 20 carbon atoms and heteroatoms ( 1~20In other embodiments, the heteroalkyl group contains 1 to 10 carbon atoms and heteroatoms (heteroalkyl). 1~10 In yet other embodiments, the heteroalkyl group contains 1 to 6 carbon atoms and heteroatoms (heteroalkyl). 1~6 heteroalkyl).

[0025] "Heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and optionally any hydrogen atoms bonded thereto) are each independently replaced with the same or different heteroatoms or heteroatom groups. Typical heteroatoms or heteroatom groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, and -S(O)2NH-, and combinations thereof. These heteroatoms or heteroatom groups may be located at any position within the alkyl, alkenyl, or alkynyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 , =NN=, -N=N-, -N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2- and -SnR 507 R 508 Examples include, but are not limited to, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, heteroalkenyl groups contain 1 to 20 carbon atoms and heteroatoms (e.g., 1~20 In other embodiments, heteroalkenyl groups contain 1 to 10 carbon atoms and heteroatoms (heteroalkenyl). 1~10In yet other embodiments, heteroalkenyl groups contain 1 to 6 carbon atoms and heteroatoms (heteroalkenyl). 1~6 heteroalkenyl).

[0026] "Heteroaryl," by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of a hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and xanthene. In some embodiments, heteroaryl groups contain 5 to 20 ring atoms (5-20 membered heteroaryls). In other embodiments, heteroaryl groups contain 5 to 10 ring atoms (5-10 membered heteroaryls). Examples of heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0027] "Heteroarylalkyl" by itself or as part of another substituent means a heteroaryl group containing a carbon atom (typically a terminal or sp 3"Heteroarylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6- to 21-membered heteroarylalkyl, e.g., the alkyl portion of the heteroarylalkyl is a (C1-C6)alkyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkyl group is a 6- to 13-membered heteroarylalkyl, e.g., the alkyl portion is a (C1-C3)alkyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0028] "Heteroarylalkenyl," by itself or as part of another substituent, refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, a heteroarylalkenyl group is a 7- to 21-membered heteroarylalkenyl, e.g., the alkenyl portion of the heteroarylalkenyl is a (C2-C6)alkenyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, a heteroarylalkenyl is a 7- to 13-membered heteroarylalkenyl, e.g., the alkenyl portion is a (C2-C3)alkenyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0029] "Heteroarylalkynyl," by itself or as part of another substituent, refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, the heteroarylalkynyl group is a 7- to 21-membered heteroarylalkynyl, e.g., the alkynyl portion of the heteroarylalkynyl is a (C2-C6)alkynyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkynyl is a 7- to 13-membered heteroarylalkynyl, e.g., the alkynyl portion is a (C2-C3)alkynyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0030] The term "hydrate" refers to a form of a compound described herein that incorporates water in a stoichiometric ratio to form an adduct. Hydrates can be produced by storage in an atmosphere containing water vapor; by forming a dosage form containing water; or by conventional pharmaceutical manufacturing processes such as crystallization (i.e., from water or mixed aqueous solvents), lyophilization, wet granulation, aqueous film coating, or spray drying. Under certain conditions, hydrates may also form when crystalline solvates are exposed to water vapor or when anhydrous materials are suspended in water. Hydrates may crystallize in multiple forms, resulting in polymorphic hydrates. See, for example, (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above-described methods for preparing hydrates are well within the skill of those in the art and are completely standard, requiring no experimentation beyond that typical in the art. Hydrates may be characterized and / or analyzed by methods well known to those skilled in the art, such as single crystal X-ray diffraction, powder X-ray diffraction, polarized light microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy (Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). Furthermore, many commercial companies, such as HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil (France) (http: / / www.holodiag.com), routinely offer services that include the preparation and / or characterization of hydrates.

[0031] "N-oxide" refers to a compound containing an NO bond with three additional hydrogens or side chains attached to the N, or a compound containing an NO bond with two additional hydrogens or side chains attached to the N, where a positive charge is present at the nitrogen. The N-oxides of the present disclosure can be synthesized by oxidation procedures well known to those of skill in the art.

[0032] "Parent Aromatic Ring System" refers to an unsaturated monocyclic or polycyclic ring system having a conjugated π-electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indane, indene, phenalene, etc. Exemplary parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0033] "Parent heteroaromatic ring system" refers to a parent aromatic ring system in which one or more carbon atoms (and optionally, hydrogen atoms bonded thereto) are each independently replaced with the same or different heteroatoms. Typical heteroatoms that can replace carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specific examples included within the definition of "parent heteroaromatic ring system" include fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Exemplary parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, b-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and xanthene.

[0034] "Pharmaceutically acceptable salt" refers to a salt of a compound that retains the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbiphenylsulfonic acid, 4-methylbenzyl ... (2) acid addition salts formed with organic acids such as cyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (3) salts formed by replacing the acidic proton present in the parent compound with a metal ion such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, or by coordination with an organic base such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine.

[0035] "Preventing" or "prevention" refers to a reduction in the risk of developing a disease or disorder (i.e., preventing the development of at least one clinical symptom of the disease in a patient who may have been exposed to or been predisposed to the disease, but who has not yet experienced or exhibited symptoms of the disease). The application of a therapeutic agent for the prevention of a disease or disorder is known as "prophylaxis." In some embodiments, the compounds provided herein may provide superior preventative therapy due to fewer long-term side effects over time.

[0036] As used herein, the term "prodrug" refers to a derivative of a drug molecule that must undergo a transformation within the body to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the parent drug.

[0037] As used herein, a "promoiety" refers to a type of protecting group that is used to mask functional groups in a drug molecule, converting the drug into a prodrug. Typically, a promoiety is attached to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means.

[0038] A "protecting group" refers to a group of atoms attached to a reactive functional group in a molecule to mask, reduce, or prevent the reactivity of that functional group during chemical synthesis. Examples of protecting groups are described in Green et al., "Protective Groups in Organic Chemistry" (Wiley, 2007). nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino-protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitro-veratryloxycarbonyl ("NVOC"). Representative hydroxy-protecting groups include, but are not limited to, acylated or alkylated hydroxy groups, such as benzyl, trityl ethers, and alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0039] A "solvate" refers to the incorporation of a solvent into the crystalline lattice of a compound described herein in a stoichiometric ratio to form an adduct. Methods for preparing solvates include, but are not limited to, storage in a solvent-containing atmosphere, a solvent-containing dosage form, or standard pharmaceutical manufacturing processes such as crystallization (i.e., crystallization from a solvent or solvent mixture), vapor diffusion, etc. Under certain circumstances, a solvate may form from other crystalline solvates or hydrates upon exposure to a solvent or when a material is suspended in a solvent. A solvate may crystallize in more than one form, resulting in solvate polymorphs. See, for example, (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above methods for preparing solvates are well within the skill of one in the art and are entirely standard, requiring no experimentation beyond that typical in the art. Solvates may be characterized and / or analyzed by methods well known to those skilled in the art, such as single crystal X-ray diffraction, powder X-ray diffraction, polarized light microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy (Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). Furthermore, a number of commercial companies, such as, for example, HOLODIAG, Pharmaparc II, Voie de l Innovation, 27 100 Val de Reuil (France) (http: / / www.holodiag.com), routinely offer services that include the preparation and / or characterization of solvates.

[0040] "Substituted," when the term is used in reference to modifying a particular group or radical, means that one or more hydrogen atoms of the particular group or radical are each independently replaced with the same or different substituent(s). Substituents useful for replacing saturated carbon atoms in a particular group or radical include R a , halo, -O - , =O, -OR b , -SR b , -S - , =S, -NR c R c , =NR b , =N-OR b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b , -N-NR c R c , -NR b S(O)2R b , =N2, -N3, -S(O)2R b , -S(O)NR b R b , -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2O - , -OS(O)2OR b , -OS(O)2NR c NR c , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(O)NR b -OR b -C(S)R b , -C(NR b )R b , -C(O)O - , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b, -OC(S)R b , -OC(O)O - , -OC(O)OR b , -OC(O)NR c R c , -OC(NCN)NR c R c , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O - , -NR b C(O)OR b , -NR b C(NCN)OR b , -NR b S(O)NR c R c , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(S)NR c R c , -NR b C(S)NR b C(O)R a , -NR b S(O)2OR b , -NR b S(O)2R b , -NR b C(NCN)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c where each R ais independently substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, or substituted heteroaryl; each R b is independently hydrogen, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, aryl alkyl, substituted aryl alkyl, aryl alkenyl, substituted aryl alkenyl, aryl alkynyl, substituted aryl alkynyl, heteroaryl alkyl, substituted heteroaryl alkyl, heteroaryl alkenyl, substituted heteroaryl alkenyl, heteroaryl alkynyl, or substituted heteroaryl alkynyl; each R c are independently R b Or, two R c together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, or substituted cycloheteroalkenyl ring, or form a cycloheteroalkyl or cycloheteroalkenyl fused with an aryl group, which optionally contains 1 to 4 identical or different additional heteroatoms selected from the group consisting of O, N, and S. For example, specifically, -NR c R c is meant to include -NH, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, substituents useful for replacing saturated carbon atoms in particular groups or radicals include R a , halo, -OR b , -NR c R c , trihalomethyl, -CN, -NR b S(O)2R b , -C(O)R b , -C(O)NR b -OR b, -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -OC(O)NR c R c and -NR b C(O)OR b where R a , R b and R c is as defined above. In yet another embodiment, substituents useful for substituting saturated carbon atoms in particular groups or radicals include R a , halo, -OR b , -NR c R c , trihalomethyl, -CN, -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)NR c R c and -NR b C(O)OR b where R a , R b and R c has the same meaning as above.

[0041] Substituents useful for replacing unsaturated carbon atoms in certain groups or radicals include substituted alkyl, -R a , halo, -O - , -OR b , -SR b , -S ー , -NR c R c , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2OR b , -OS(O)2O - , -P(O)(O- ) 2, -P(O)(OR b )(O - )、-P(O)(OR b )(OR b )、-C(O)R b 、-C(S)R b 、-C(NR b )R b 、-C(O)O - 、-C(O)OR b 、-C(S)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-OC(S)R<从 b 、-OC(O)O - 、-OC(O)OR b 、-OC(S)OR b 、-OC(O)NR c R c 、-OS(O)2NR c NR c 、-NR b C(O)R b 、-NR b C(S)R b 、-NR b C(O)O - 、-NR b C(O)OR b 、-NR b S(O)2OR a 、-NR b S(O)2R a 、-NR b C(S)OR b 、-NR b C(O)NR c R c 、-NR b C(NR b )R b 、-NR b C(NR b )NR c R c 、及び -C(NR b )NR b C(NR b )NR c R c が挙げられ、ここで、R It should be noted that there may be some inaccuracies in the original text, especially in the chemical formula part. The above translation is for reference only based on the requirements. You may need to further verify and correct it according to the specific chemical knowledge.a , R b and R c is as defined above. In other embodiments, substituents useful for replacing unsaturated carbon atoms in certain groups or radicals include substituted alkyl, -R a , halo, -OR b , -SR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R c is as defined above. In yet another embodiment, substituents useful for substituting unsaturated carbon atoms in certain groups or radicals include substituted alkyl, -R a , halo, -OR b , -NR c R c , trihalomethyl, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R c is as defined above.

[0042] Useful substituents for substituting a nitrogen atom in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, alkyl, -R a , -O - , -OR b , -SR b , -S - , -NR c R c , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R b , -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2O - , -OS(O)2OR b , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(S)R b , -C(NR b )R b , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)OR b , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)OR b , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b , -NR b C(NR b )NRc R c and -C(NR b )NR b C(NR b )NR c R c where R a , R b and R c is as defined above. In some embodiments, substituents useful for substituting a nitrogen atom in heteroalkyl and cycloheteroalkyl groups include alkyl, R a , halo, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -OS(O)2R b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R c is as defined above. In yet another embodiment, useful substituents for substituting a nitrogen atom in heteroalkyl and cycloheteroalkyl groups include alkyl, R a , halo, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -NR bC(O)R b and -NR b C(O)OR b where R a , R b and R c is as defined above.

[0043] Of the substituents listed above, those useful to substitute other particular groups or atoms will be apparent to those skilled in the art.

[0044] The substituents used to substituted a particular group can be further substituted, typically with one or more groups that are the same or different and selected from the various groups described above.

[0045] The terms "subject," "individual," or "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, rodents, primates, humans, farm animals, sport animals, and pets. In some embodiments, the subject, individual, or patient belongs to the species Homo sapiens. In other embodiments, the subject, individual, or patient includes all mammals other than Homo sapiens.

[0046] "Treating" or "treatment" of any disease or disorder, in some embodiments, refers to alleviating the disease or disorder (i.e., halting or alleviating the progression of the disease or at least one of its clinical symptoms). Treatment may be considered to include preemptive or prophylactic administration to alleviate, halt, or prevent the disease or at least one clinical symptom. As an additional feature, the administered treatment is unlikely to produce long-term side effects over multiple years. In other embodiments, "treating" or "treatment" refers to the improvement of at least one physical parameter, which may not be discernible by the patient. In yet other embodiments, "treating" or "treatment" refers to the inhibition of the disease or disorder, which may be physical inhibition (e.g., stabilization of discernible symptoms), physiological inhibition (e.g., stabilization of physical parameters), or both. In yet other embodiments, "treating" or "treatment" refers to the delay in the onset of the disease or disorder.

[0047] A "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism, excretion, etc. of the patient being treated.

[0048] "Vehicle" refers to a diluent, excipient, or carrier used in administering a compound to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.

[0049] compound In some embodiments, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[0050] wherein X is a substituted heteroaryl or —C(O)—R1, where R1 is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and Y is [ka] and Z is H, -C(O)R 10 , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; R 10 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

[0051] In other embodiments, X is [ka] R2 is H, alkyl, or -C(O)R3; R4 is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, -C(O)R5, or R2 and R4 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R3 and R5 are independently alkyl; and A is -N- or -CH-.

[0052] In yet other embodiments, Z is [ka] R6 is H, alkyl, or -C(O)R7; R8 is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, -C(O)R9, or R6 and R8 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R7 and R9 are independently alkyl; and B is -N- or -CH-.

[0053] In yet other embodiments, X is [ka] R2 is H, alkyl, or -C(O)R3; R4 is H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, or -C(O)R5, or R2 and R4 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R3 and R5 are independently alkyl; A is -N- or -CH-; Z is [ka] R6 is H, alkyl, -C(O)R7; R7 is alkyl; R8 is H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, -C(O)R9, or R6 and R8 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R7 and R9 are independently alkyl; B is -N- or -CH-, with the proviso that when R3 is -C(O)R5, R2 is not -C(O)R3; and when R8 is -C(O)R9, R6 is not -C(O)R7.

[0054] In some embodiments of the above, Y is [ka] In another embodiment of the above, A and B are -N-.

[0055] In some embodiments of the above, R2 and R6 are -H, and R4 and R8 are independently arylalkyl or substituted arylalkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0056] In some embodiments of the above, R2 and R6 are -H, R4 is arylalkyl, and R8 is alkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0057] In some embodiments of the above, R2 and R6 are -H, R4 is substituted heteroalkyl, and R8 is arylalkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0058] In some embodiments, R2 and R6 are -H, and R4 and R8 are independently heteroarylalkyl or substituted heteroarylalkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0059] In some embodiments of the above, R2 and R6 are -H, and R4 is alkyl, and / or R8 is heteroarylalkyl or substituted heteroarylalkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0060] In some embodiments of the above, R2 and R6 are -H, and R4 and R8 are alkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0061] In some embodiments of the above, R2 is alkyl, R6 is -H, and R4 and R8 are alkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0062] In some embodiments of the above, R2 and R6 are alkyl, and R4 and R8 are alkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0063] In some embodiments of the above, R2 and R6 are alkyl and R4 and R8 are heteroalkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0064] In some embodiments of the above, R2 and R6 are -H, and R4 and R8 are heteroalkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0065] In some embodiments of the above, R2 and R6 are -H, R4 is alkyl, and R8 is heteroalkyl or substituted heteroalkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0066] In some embodiments of the above, R2 is -H, R4 is alkyl, and R6 and R8 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring. In some embodiments, the following structure: [ka] Compounds having the formula:

[0067] In some embodiments of the above, R2 and R4 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring, and R6 and R8 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring. In some embodiments, the following structure: [ka] Compounds having the formula:

[0068] In some embodiments of the above, R2 and R6 are -H, R4 is substituted alkyl, and R8 is substituted alkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0069] In some embodiments of the above, R2 and R6 are alkyl, R4 is -C(O)R5, and R8 is -C(O)R9. In some embodiments, the following structure: [ka] Compounds having the formula:

[0070] In some embodiments of the above, R2 and R6 are -H, R4 is -C(O)R5, and R8 is -C(O)R9. In some embodiments, the following structure: [ka] Compounds having the formula:

[0071] In some embodiments, Y is [ka] In other embodiments, R2 and R6 are -H, R4 is substituted alkyl, and R8 is arylalkyl. In yet other embodiments, the following structure: [ka] Compounds having the formula:

[0072] In some embodiments of the above, R2 and R6 are -H, and R4 and R8 are alkyl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0073] In some embodiments, Y is [ka] In other embodiments, R2 is -H, R4 is alkyl, and Z is heteroaryl. In yet other embodiments, the following structure: [ka] Compounds having the formula:

[0074] In some embodiments, X is [ka] and C is halo or -NR 11 R 12 and R 11 is H, alkyl, -C(O)R13 and;R 12 is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, -C(O)R 14 or R 11 and R 12 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R 13 and R 14 are independently alkyl; A is -N- or -CH-.

[0075] In some embodiments, Z is [ka] and D is halo or -NR 15 R 16 and R 15 is H, alkyl, -C(O)R 17 and;R 15 is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, -C(O)R 18 or R 15 and R 16 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R 17 and R 18 are independently alkyl; A is -N- or -CH-.

[0076] In some embodiments, X is [ka] and C is halo or -NR 11 R 12 and;R 11 is H, alkyl, -C(O)R 13 and;R 12is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, -C(O)R 14 or R 11 and R 12 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R 13 and R 14 are independently alkyl; A is -N- or -CH-; Z is [ka] and D is halo or -NR 15 R 16 and;R 15 is H, alkyl, -C(O)R 17 and;R 15 is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, -C(O)R 18 or R 15 and R 16 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R 17 and R 18 are independently alkyl; A is -N- or -CH-; B is -N- or -CH-, provided that R 12 -C(O)R 14 If R 11 HA-C(O)R 13 rather than ;R 15 -C(O)R 18 If R 15 HA-C(O)R 17 isn't it.

[0077] In some embodiments, Y is [ka] In some other embodiments, C is —NR 11 R12 and D is -NR 15 R 16 In some other embodiments, the following structure: [ka] In yet another embodiment, C is halo and D is halo. In yet another embodiment, a compound having the following structure: [ka] Compounds having the formula:

[0078] In some embodiments of the above, Z is substituted heteroaryl. In some embodiments, Z is substituted heteroaryl. [ka] Compounds having the formula:

[0079] In some embodiments of the above, Z is -H. In other embodiments, Z is a compound having the following structure: [ka] Compounds having the formula:

[0080] In some embodiments of the above, X and Z are substituted heteroaryl. In some embodiments, the following structure: [ka] Compounds having the formula:

[0081] In some embodiments of the above, Z is —C(O)R 10 In other embodiments, R2 is -H and R4 is alkyl or substituted heteroarylalkyl. In yet other embodiments, the following structure: [ka] Compounds having the formula:

[0082] In some embodiments, Y is [ka] In other embodiments, R2 and R6 are -H and R4 and R8 are alkyl. In yet other embodiments, the following structure: [ka] Compounds having the formula:

[0083] In some embodiments, Y is [ka] In other embodiments, R2 and R6 are -H and R4 and R8 are alkyl. In yet other embodiments, the following structure: [ka] Compounds having the formula:

[0084] In some embodiments, Y is [ka] In other embodiments, R2 and R6 are -H and R4 and R8 are alkyl. In yet other embodiments, the following structure: [ka] Compounds having the formula:

[0085] In some embodiments, Y is [ka] In other embodiments, R2 and R6 are -H and R4 and R8 are alkyl. In yet other embodiments, the following structure: [ka] Compounds having the formula:

[0086] Examples of compounds are provided in Table 1 below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0087] The above compounds can be prepared by well-known procedures, some of which are illustrated in the Examples.

[0088] Compositions and Methods of Administration The compositions provided herein comprise a therapeutically effective amount of one or more compounds provided herein useful for preventing, treating, or alleviating one or more symptoms of a disease or disorder described herein, and a vehicle. Vehicles suitable for administering the compounds provided herein include any carrier known to those skilled in the art as suitable for the particular mode of administration. Furthermore, the compounds may be formulated as the sole active ingredient in the composition or may be combined with other active ingredients.

[0089] The disclosed compounds may be administered by any method of administration. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, intranasal, topical, intrauterine, intrahepatic, intravaginal, ophthalmic, buccal, optic, intracerebral, rectal, sublingual, buccal, and parenteral administration of injectable solutions, including intravenous, intraCSF, intraarterial, intramuscular, and subcutaneous administration. Administration may also include administration into the hepatic artery or via the hepatic portal vein (HPV). Administration of the disclosed compounds, disclosed therapeutic agents, disclosed pharmaceutical compositions, or combinations thereof can include direct administration to the CNS (e.g., intraparenchymal, intraventricular, intracisternal, intrathecal (lumbar), delivery to deep gray matter, delivery to deep gray matter via convection-enhanced delivery) or direct administration to the PNS. Administration can be continuous or intermittent.

[0090] The composition comprises one or more compounds provided herein. In some embodiments, the compound can be formulated into a suitable formulation for oral administration, such as a solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained-release formulation, or elixir, or a sterile solution or suspension for parenteral administration, as well as for topical administration, transdermal administration, and oral inhalation via nebulizer, pressurized metered-dose inhaler, and dry powder inhaler. In some embodiments, the compound is formulated into a composition using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0091] In the composition, one or more compounds or derivatives thereof are mixed with a suitable vehicle at an effective concentration. As described above, the compound may be derivatized as the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate, or prodrug prior to formulation. The concentration of the compound in the composition is such that, upon administration, an amount effective to treat, prevent, or alleviate one or more symptoms of the diseases or disorders described herein is delivered. In some embodiments, the composition is formulated for single-dose administration. To formulate the composition, the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at a mass fraction that results in an effective concentration such that the condition to be treated is alleviated, prevented, or one or more symptoms are alleviated.

[0092] The active compound is contained in the vehicle in an amount sufficient to exert a therapeutically useful effect without causing undesirable side effects in the treated patient.The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then extrapolated to determine the dosage for humans.The human dosage is typically fine-tuned in clinical trials and adjusted according to response.

[0093] The concentration of the active compound in the composition will depend on the absorption, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the administration schedule and dosage, and other factors known to those skilled in the art, for example, the amount delivered will be sufficient to alleviate one or more symptoms of a disease or disorder, as described herein.

[0094] If the compound is not sufficiently soluble, methods for solubilizing the compound may be used, such as liposomes, prodrugs, complexation / chelation, nanoparticles, emulsions, or tertiary templating. These techniques are well known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO), surfactants or surface modifiers such as TWEEN®, complexing agents such as cyclodextrins, or ionization-assisted dissolution (i.e., dissolution in aqueous sodium bicarbonate). Derivatives of the compound, such as prodrugs of the compound, may also be used to formulate active compositions.

[0095] Upon mixing or addition of the compounds, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is a concentration sufficient to alleviate the symptoms of the disease, disorder, or condition being treated and may be empirically determined.

[0096] The compositions are provided in dosage forms suitable for the indication for administration to humans and animals, including dry powder inhalers (DPIs), pressurized metered-dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / bioerodible strips, tablets or capsules, powders, granules, lozenges, lotions, ointments, suppositories, fast melts, transdermal patches or other transdermal application devices / formulations, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions, containing an appropriate amount of the compounds or derivatives thereof. In some embodiments, the therapeutically active compounds and derivatives thereof are formulated and administered in unit-dose or multi-dose forms. As used herein, "unit-dose form" refers to physically discrete units suitable for human and animal administration, individually packaged as known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, together with the necessary vehicle. Examples of unit-dose forms include ampoules, syringes, and individually packaged tablets or capsules. A unit-dose form may be administered in a fractional or multiple dose. A multi-dose form refers to a single container containing a plurality of identical unit-dose forms, packaged to be administered individually as unit-dose forms. Examples of multi-dose forms include vials; bottles of tablets or capsules; or bottles of pints or gallons. Thus, a multi-dose form is a plurality of unit doses in undivided packaging.

[0097] Liquid compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active compound and any adjuvants defined above in a vehicle such as water, saline, aqueous glucose, glycerol, glycols, and ethanol, thereby forming a solution or suspension, a colloidal dispersion, an emulsion, or a liposomal preparation. If desired, the composition to be administered may contain small amounts of nontoxic auxiliary substances such as wetting agents, emulsifiers, solubilizing agents, and pH buffering agents, including, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other similar agents.

[0098] Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975, or later editions.

[0099] Dosage forms or compositions may be prepared containing the active ingredient in the range of 0.005% to 100%, with the remainder consisting of a vehicle or carrier. Methods for preparing these compositions are known to those skilled in the art. The contemplated compositions may contain the active ingredient in the range of 0.001% to 100%, in one embodiment 0.1 to 95%, and in another embodiment 0.4 to 10%.

[0100] In some embodiments, the composition is lactose-free and contains excipients well known in the art, such as those described in US Pharmacopeia (USP) 25-NF20 (2002). Generally, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in appropriate amounts. A particular lactose-free dosage form contains the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0101] Furthermore, anhydrous compositions and dosage forms containing active ingredients are also provided, since water can accelerate the decomposition of some compounds. For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine properties such as shelf life or stability of a formulation over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be extremely important because formulations are often exposed to moisture and / or humidity during production, handling, packaging, storage, transportation, and use.

[0102] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and under low moisture or low humidity conditions.

[0103] Anhydrous compositions should be prepared and stored such that their anhydrous nature is maintained. Accordingly, anhydrous compositions are generally packaged using materials known to prevent exposure to water such that they can be incorporated into suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0104] Oral dosage forms can be either solid, gel, or liquid. Solid dosage forms include tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed tablets, chewable lozenges, and tablets that may be enteric-coated, sugar-coated, or film-coated. Capsules can be hard or soft gelatin capsules, and granules and powders can be provided in non-effervescent or effervescent form by combining them with other ingredients known to those skilled in the art.

[0105] In some embodiments, the formulation is in a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, and lozenges may contain one or more of the following ingredients or compounds with similar properties: binders, lubricants, diluents, flow agents, disintegrants, colorants, sweeteners, flavorings, wetting agents, enteric coatings, film coatings, and controlled-release agents. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidone, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopodium, and stearic acid. Excipients include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol, and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include, for example, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, approved water-soluble FD&C dyes, mixtures thereof, and water-insoluble FD&C dye suspensions on hydrated alumina, as well as advanced color additives or anti-counterfeit color / opalescent additives known to those skilled in the art. Sweetening agents include sucrose, lactose, mannitol, and artificial sweeteners such as saccharin, as well as various spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds which produce a pleasant sensation or mask an unpleasant taste, such as, but not limited to, peppermint and methyl salicylate. Humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Enteric coating agents include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coating agents include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Release-controlling agents include polymers such as the Eudragit® series and cellulose esters.

[0106] The compound or its derivative can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated with an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other similar ingredient.

[0107] When the dosage unit is a capsule, it may contain, in addition to the above-mentioned materials, a liquid carrier such as fatty oil. Furthermore, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, such as sugar coatings and other enteric agents. The compound can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, or the like. The syrup may contain, in addition to the active compound, sucrose as a sweetener, as well as certain preservatives, dyes, colorings, and flavorings.

[0108] The active materials may be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a derivative thereof. High concentrations, for example, up to about 98% by weight, of the active ingredient may be included.

[0109] In all aspects, tablet and capsule formulations may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient, for example, with conventional enteric coatings such as phenylsalicylate, waxes, and cellulose acetate phthalate.

[0110] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0111] Elixirs are clear, sweetened hydroalcoholic preparations. Vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of tiny droplets throughout another liquid. Carriers used in emulsions include non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances for use in non-effervescent granules to be reconstituted into liquid oral dosage forms include fillers, sweeteners, and wetting agents. Acceptable substances for use in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[0112] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol. Non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Emulsifiers include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and gum arabic. Sweeteners include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water-soluble FD&C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds which produce a pleasant taste sensation.

[0113] For solid dosage forms, the solution or suspension, for example, in propylene carbonate, vegetable oils, or triglycerides, is in some embodiments encapsulated in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, the solution, such as in polyethylene glycol, may be diluted with a sufficient quantity of a liquid vehicle, such as water, to be easily measured for administration.

[0114] Alternatively, the active compound or its salt may be dissolved or dispersed in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other similar carriers, and these solutions or suspensions may be encapsulated in hard or soft gelatin capsule shells to prepare oral liquid or semisolid formulations. Other useful formulations include those described in U.S. Patent Nos. RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, formulations comprising a compound described herein; a dialkylated mono- or polyalkylene glycol, such as, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol); and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0115] Other formulations include, but are not limited to, aqueous alcohol solutions containing acetals. The alcohols used in these formulations are any water-miscible solvents having one or more hydroxy groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0116] Parenteral administration, in some embodiments, is characterized by injection, either subcutaneously, intramuscularly, or intravenously, and is also contemplated herein. Injectables can be prepared in conventional forms, as liquid solutions or suspensions, as solids suitable for dissolution or suspension in liquid prior to injection, or as emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients include, for example, water, saline, dextrose, glycerol, or ethanol. If desired, the compositions to be administered may also contain small amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other similar agents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0117] Implantation of a slow-release or sustained-release system such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, the compounds provided herein are dispersed in a solid inner matrix, e.g., a hydrophilic polymer such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate; this inner matrix is ​​dispersed in an outer The parenteral composition is surrounded by a polymeric membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, and this outer polymeric membrane is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate-controlling process. The percentage of active compound contained in such parenteral compositions largely depends on the specific nature of the composition, as well as the activity of the compound and the needs of the subject.

[0118] Parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Formulations for parenteral administration include sterile solutions ready for injection; sterile dry soluble products, such as lyophilized powders, which can be combined with a solvent immediately before use, for example, tablets for subcutaneous injection; sterile suspensions ready for injection; sterile dry insoluble products, which can be combined with a vehicle immediately before use; and sterile emulsions. The solutions can be aqueous or non-aqueous.

[0119] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS); solutions containing viscosity enhancing and solubilizing agents such as dextrose, polyethylene glycol and polypropylene glycol; and mixtures thereof.

[0120] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other substances.

[0121] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water for injection, dextrose, and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Parenteral formulations packaged in multi-dose containers require the addition of bacteriostatic or fungistatic concentrations of antibacterial agents, such as phenol or cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonicity agents include sodium chloride and glucose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween® 80). Sequestering or chelating agents for metal ions include EDTA. Carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0122] The concentration of the compound is adjusted so that injection provides an amount effective to produce the desired pharmacological effect. The exact dose depends on the age, weight, body surface area and condition of the patient or animal, as is known in the art.

[0123] Unit dose parenteral preparations are packaged in ampoules, vials or syringes with needles. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[0124] For example, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile, aqueous or oily solution or suspension containing an active material, injected as necessary to produce the desired pharmacological effect.

[0125] Injectables are designed for local and systemic administration and are formulated in some embodiments to provide a therapeutically effective dose of the active compound to the tissue to be treated at a concentration of at least about 0.01% w / w to about 90% w / w or more, and in some embodiments, greater than 0.1% w / w.

[0126] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to alleviate the symptoms of the condition and may be empirically determined.

[0127] The active ingredients provided herein can be administered by controlled-release means or delivery devices known to those skilled in the art, for example, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5 ,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634. These dosage forms can be used to provide sustained or controlled release of one or more active ingredients, using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, in various proportions to provide the desired release profile. Controlled-release formulations suitable for use with the active ingredients provided herein can be readily selected from controlled-release formulations known to those skilled in the art, including those described herein.

[0128] All controlled-release products share a common goal: to achieve improved drug therapy over their non-controlled counterparts. Ideally, the use of optimally designed controlled-release formulations in medical practice is characterized by the smallest amount of drug used and the shortest time required to cure or control a condition. Advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to affect the onset of action and other characteristics, such as blood levels of the drug, and therefore the occurrence of side effects (e.g., adverse effects).

[0129] Many controlled-release formulations are designed to initially release an amount of drug (active ingredient) that quickly produces the desired therapeutic effect, and then gradually and continuously release a different amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the rate of release of the drug from the dosage form must be at a rate that compensates for the amount of drug metabolized and excreted in the body. Controlled-release of an active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0130] In certain embodiments, agents may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials may be used. In other embodiments, a controlled-release system may be placed in proximity to the therapeutic target, i.e., requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments, a controlled-release device is introduced in proximity to the site of aberrant immune activation or tumor site in a subject. Other controlled-release systems are discussed in the review by Langer (Science 249: 1527-1533 (1990)).The active ingredient may be dispersed in a solid inner matrix, such as a hydrophilic polymer such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which inner matrix is ​​surrounded by an outer polymeric membrane, For example, polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene copolymer, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer are surrounded by an outer polymer membrane that is insoluble in body fluids.The active ingredient then diffuses through the outer polymer membrane in a release rate-controlling process.The percentage of the active ingredient contained in such parenteral compositions largely depends on its specific nature and the needs of the subject.

[0131] Also of interest herein are lyophilized powders that can be reconstituted and administered as solutions, emulsions, and other mixtures, which can also be reconstituted and formulated as solids or gels.

[0132] Sterile lyophilized powders are prepared by dissolving a compound provided herein or a derivative thereof in a suitable solvent. The solvent may contain excipients to improve the stability or other pharmacological components of the powder or a reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the excipient is selected from the group consisting of dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain citrate buffer, sodium phosphate or potassium phosphate buffer, or other similar buffers known to those of skill in the art at approximately neutral pH. The solution is then sterile filtered and lyophilized under standard conditions known to those of skill in the art to obtain the desired formulation. In some embodiments, the resulting solution is dispensed into vials for lyophilization. Each vial contains a single or multiple doses of the compound. The lyophilized powder may be stored under appropriate conditions, such as at about 4°C to room temperature.

[0133] This lyophilized powder is reconstituted with water for injection to provide a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected and can be determined empirically.

[0134] Topical mixtures are prepared as described for local and systemic administration, and the resulting mixture may be a solution, suspension, or emulsion, and may be formulated into a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, wash, spray, suppository, bandage, skin patch, or any other formulation suitable for topical administration.

[0135] The compounds or derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for the delivery of steroids useful in the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract may be in the form of aerosols or solutions for nebulizers, or fine powders for inhalants, and may be used alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation have a mass median geometric diameter of less than 5 μm in some embodiments, and less than 10 μm in other embodiments.

[0136] Oral inhalation formulations of the compound or derivative suitable for inhalation include metered dose inhalers, dry powder inhalers, and liquid formulations for administration from a nebulizer or metered dose liquid dispensing system. In both metered dose inhalers and dry powder inhalers, the physical form of the compound or derivative is preferably a crystalline form of the drug to maintain longer product stability.

[0137] In addition to size reduction methods known to those skilled in the art, crystalline particles of the compound or derivative can also be produced using supercritical fluid processing, which offers important advantages in the manufacture of such particles for inhalation delivery because it allows for the production of inhalable particles of a desired size in a single step (e.g., WO 2005 / 025506). Selecting a controlled particle size for the crystallites ensures that a substantial portion of the compound or derivative is deposited in the lungs. In some embodiments, these particles have a mass median aerodynamic diameter of about 0.1 to about 10 μm, in other embodiments about 1 to about 5 μm, and in yet other embodiments about 1.2 to about 3 μm.

[0138] Inert, non-flammable HFA propellants are selected from HFA134a (1,1,1,2-tetrafluoroethane) and HFA227e (1,1,1,2,3,3,3-heptafluoropropane), provided singly or in ratios that match the crystalline particle density of the compound or derivative. Furthermore, the ratios are selected to ensure the avoidance of deleterious settling or creaming in the product suspension (which can induce irreversible clumping) and to promote a loosely fluctuating system that disperses easily upon shaking. Loosely fluctuating systems are generally considered to provide optimal stability in pMDI cans. As a result of the formulation's properties, the formulation was free of ethanol and surfactants / stabilizers.

[0139] The compound may be formulated in the form of gel, cream, and lotion for local or topical application, for example, for topical application to the skin and mucous membranes such as the eyes, and may also be formulated for application to the eyes, or for intracisternal or intrathecal administration.External administration is intended for transdermal delivery, as well as for administration to the eyes or mucous membranes, or for inhalation therapy.Nasal solutions of the active compound may also be administered alone or in combination with other excipients.

[0140] For intranasal administration, the formulation may contain the esterified phosphonate compound dissolved or suspended in a liquid carrier, especially an aqueous carrier, for aerosol application. The carrier may contain a solubilizing or suspending agent such as propylene glycol, a surfactant, an absorption enhancer such as lecithin or cyclodextrin, or a preservative.

[0141] Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions at a pH of about 5 to 7.4, with appropriate salts.

[0142] Other routes of administration such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration are also contemplated herein.

[0143] Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

[0144] For example, dosage forms for rectal administration include rectal suppositories, capsules, and tablets intended for systemic action. As used herein, a rectal suppository refers to a solid object inserted into the rectum that melts or softens at body temperature and releases one or more pharmacologically or therapeutically active ingredients. The materials used in rectal suppositories are a base or vehicle and an agent to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), and appropriate mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of these various bases may also be used. Agents to raise the melting point of the suppository include spermaceti and wax. Rectal suppositories may be prepared by compression or molding. In one embodiment, the weight of a rectal suppository is approximately 2 to 3 g. Rectal tablets and capsules are manufactured using the same materials and by the same methods as oral formulations.

[0145] The compounds provided herein or derivatives thereof may also be formulated to target specific tissues, receptors, or other areas of the body to be treated. Many targeting techniques of this type are known to those skilled in the art. All such targeting techniques are contemplated for use in the compositions herein. For non-limiting examples of targeting approaches, see, e.g., U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0146] In some embodiments, liposome suspensions, including tissue-targeted liposomes such as tumor-targeted liposomes, may also be suitable as carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) may be formed by drying phosphatidylcholine and phosphatidylserine (molar ratio 7:3) in a flask. A solution of a compound provided herein in phosphate-buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0147] The compound or derivative may be packaged as an article comprising packaging material, a compound or derivative thereof provided herein within the packaging material that is effective for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder, and a label indicating that the compound or composition or derivative thereof is used for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder.

[0148] The articles of manufacture provided herein include packaging materials. Packaging materials used to package products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging suitable for the selected formulation and intended mode of administration and treatment. Various formulations of the compounds and compositions provided herein are contemplated, as are various treatments for any disease or disorder described herein.

[0149] dose When used to treat or prevent infectious diseases, the compounds described herein or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount. In human treatment, the physician will determine the most appropriate dosing regimen depending on whether prophylactic or curative treatment is required, and on the age, weight, stage of the disease, and other factors specific to the subject being treated. The amount of active ingredient in the formulations provided herein that is effective for preventing or treating infectious diseases will vary depending on the nature and severity of the disease or condition, and the route of administration of the active ingredient. The frequency and dosage will also vary depending on factors specific to each subject, and will depend on the specific treatment (e.g., therapeutic or prophylactic) administered, the severity of the infection, the route of administration, and the age, weight, response, and medical history of the subject.

[0150] Examples of dosage forms include milligram or microgram amounts of active compound per 1 kg of subject (e.g., about 1 μg / kg to about 50 mg / kg, about 10 μg / kg to about 30 mg / kg, about 100 μg / kg to about 10 mg / kg, or about 100 μg / kg to about 5 mg / kg).

[0151] In some embodiments, a therapeutically effective dose results in a serum concentration of the active ingredient of about 0.001 ng / mL to about 50-200 μg / mL. In other embodiments, the composition provides a daily dose of about 0.0001 mg to about 70 mg of compound per kg of body weight. Unit dosage forms are prepared to provide about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg of the active ingredient or combination of essential ingredients, per unit dosage form, and in some embodiments, about 10 mg to about 500 mg. Suitable non-limiting examples of dosages of the disclosed compounds according to the present disclosure include about 1 ng / kg to about 5000 mg / kg. In some embodiments, the dose may range from 0.0001 mg / kg / day to 0.0010 mg / kg / day, 0.0010 mg / kg / day to 0.010 mg / kg / day, 0.010 mg / kg / day to 0.10 mg / kg / day, 0.10 mg / kg / day to 1.0 mg / kg / day, 1.00 mg / kg / day to about 200 mg / kg / day, or 200 mg / kg / day to about 5000 mg / kg / day. For example, the dose may be from about 1 mg / kg / day to about 100 mg / kg / day, e.g., 2 to 10 mg / kg / day, 10 to 50 mg / kg / day, or 50 to 100 mg / kg / day.The doses are also approximately 1mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 60mg / kg, 70mg / kg, 80mg / kg, 90mg / kg kg, 100mg / kg, 125mg / kg, 150mg / kg, 175mg / kg, 200mg / kg, 250mg / kg, 300mg / kg, 400mg / kg, 500mg / kg, 600mg / kg, 700mg / kg, 800mg / kg, 900mg / kg, 100 0 mg / kg, 1100 mg / kg, 1200 mg / kg, 1300 mg / kg, 1400 mg / kg, 1500 mg / kg, 1600 mg / kg, 1700 mg / kg, 1800 mg / kg, 1900 mg / kg, 2000 mg / kg, 2100 mg / kg, 2200 mg / kg, 2300 mg / kg, 2400 mg / kg, 2500 mg / kg, 2600 mg / kg, 2700 mg / kg, 2800 mg / kg, 2900 mg / kg, 3000 mg / kg, 3500 mg / kg, 4000 mg / kg or 5000 mg / kg. In certain embodiments, the dose is about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg / kg. The dose and administration interval may be individually adjusted to provide plasma concentrations of the compound and / or active metabolite compound sufficient to maintain therapeutic or prophylactic effect. For example, the compound may be administered once a week, several times a week (e.g., every other day), once a day, or multiple times a day, depending, inter alia, on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. In cases of local administration or selective uptake, e.g., topical administration, the effective local concentration of the compound and / or active metabolite compound may not be related to plasma concentration. One of ordinary skill in the art will be able to optimize the effective dose without undue experimentation.

[0152] The active ingredient may be administered at once or divided into several smaller doses to be administered at intervals. It is understood that the precise dosage and duration of treatment are a function of the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data or subsequent clinical trials. It should be noted that concentrations and dosage values ​​may also vary depending on the severity of the condition to be alleviated. It should also be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and further, that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0153] As will be apparent to those skilled in the art, in some cases it may be necessary to use doses of the active ingredients outside the ranges disclosed herein. Furthermore, it should be noted that the clinician or attending physician will know when and how to interrupt, adjust, or terminate treatment depending on the subject's response.

[0154] For systemic administration, the therapeutically effective dose can be estimated initially from in vitro assays, e.g., in animal models, IC determined in cell culture, 50 (i.e., the concentration of test compound that is lethal to 50% of the cultured cells), or the IC determined in cell culture. 100 The compound can be formulated at a dose to achieve a circulating concentration range that includes the compound (i.e., the concentration of the compound that is lethal to 100% of the cells in culture). Such information can be used to more accurately determine useful doses in humans.

[0155] Initial doses can also be estimated from in vivo data (e.g., animal models) using techniques well known in the art. Those skilled in the art can readily optimize human administration based on animal data.

[0156] Alternatively, the IC of certain compounds disclosed herein50 , MIC and / or I 100 The initial dose can be determined from the administered dose of the known drug by comparing the initial dose of the known drug with that of the known drug and adjusting the initial dose accordingly. The optimal dose may be obtained from these initial values ​​by routine optimization.

[0157] In cases of local administration or selective uptake, the effective local concentration of the compound used may not be related to plasma concentration, and one skilled in the art can optimize a therapeutically effective local dose without undue trial and error.

[0158] Ideally, a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing substantial toxicity. Compound toxicity can be assessed using standard pharmaceutical procedures in cell culture or animal studies, e.g., LD 50 (the dose that is lethal to 50% of the population) or LD 100 The therapeutic index can be measured by determining the therapeutic dose (the dose at which 100% of the population is lethal). The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds that exhibit a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a dosage range that will not cause toxicity when used in subjects. The dosage of the compounds described herein preferably lies within a range of circulating concentrations that includes the effective dose with little or no toxicity. Dosage can vary within this range depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).

[0159] Treatment may be repeated intermittently. In some embodiments, administration of the same formulation provided herein may be repeated, with administration occurring at intervals of at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0160] Methods of Use of the Compounds and Compositions Symptoms of medical disorders such as malaria, HIV infection, and cancer can be ameliorated by administering to a subject a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X is substituted heteroaryl or —C(O)—R1, wherein R1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Y is [ka] and Z is H, -C(O)R 10 , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; R 10 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

[0161] In practicing the method, a therapeutically effective amount of the compound or composition described herein is administered to a patient having the disorder or condition.

[0162] The compounds provided herein can be used to treat or prevent malaria caused by species belonging to the Plasmodium group (i.e., P. falciparum, P. vivaz, P. ovale, P. malariae, and P. knowleski). In some aspects, treating malaria can be reducing the severity or duration of one or more malaria symptoms, suppressing, reducing, lowering, or otherwise mitigating the severity of malaria, delaying the onset of malaria, and / or inactivating species belonging to the Plasmodium group. Signs or symptoms of the early stages of malaria include chills, fever, headache, fatigue, abdominal discomfort, muscle pain, cramps, convulsions, and the like. Symptoms of cerebral malaria include neurological symptoms such as abnormal posture, nystagmus, conjugate gaze palsy, opisthotonus, seizures, or coma.

[0163] The present disclosure also provides methods for treating or preventing HIV infection and / or AIDS. The HIV infection can be HIV-1 infection or HIV-2 infection. The HIV can be an A, B, C, D, F, G, H, J, K, M, N, O, or P strain.

[0164] In some embodiments, treatment of HIV infection can be a reduction in the severity or duration of one or more HIV- or AIDS-related symptoms, suppression, reduction, decrease, or otherwise alleviation of the severity of HIV infection, delay in the onset of AIDS, and / or inactivation of HIV. Signs or symptoms of the early stages of HIV infection include fever, swollen lymph nodes, sore throat, rash, muscle pain, fatigue, and oral and esophageal pain. AIDS, the final stage of HIV infection, can present with symptoms of various opportunistic infections, as is well known to those skilled in the art. Symptoms at this stage can include unexplained weight loss, recurrent respiratory tract infections, prostatitis, skin rash, and oral ulcers.

[0165] In some embodiments, the present disclosure provides methods for treating and preventing cancer. The methods include administering to a subject in need thereof a therapeutically effective amount of one or more disclosed compounds. As will be appreciated by those skilled in the art, "cancer," as used throughout this disclosure, can refer to one or more neoplasms or cancers. Neoplasms can be malignant or benign, cancers can be primary or metastatic, and neoplasms or cancers can be at an early or advanced stage. Non-limiting examples of neoplasms or cancers that may be treated include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma (pediatric cerebellar or cerebral), basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumors (cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic tract and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, Burkitt's lymphoma, and the like. Cancer, carcinoid tumor (childhood, gastrointestinal), cancer of unknown primary, central nervous system lymphoma (primary), cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma of Ewing family tumors, extracranial germ cell tumor (childhood), extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer (intraocular melanoma) , retinoblastoma), gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor (pediatric extracranial, extragonadal, ovarian), gestational trophoblastic tumor, glioma (adult, pediatric brainstem, pediatric cerebral astrocytoma, pediatric visual pathway and hypothalamus), gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular (liver) carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, glioma of the hypothalamus and visual pathway (pediatric), intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, kidney cancer (renal cell carcinoma), laryngeal cancer, leukemia (acute lymphoma) blastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cell), lip and oral cavity cancer, liver cancer (primary), lung cancer (non-small cell, small cell), lymphoma (AIDS-related, Burkitt's, cutaneous T-cell, Hodgkin, non-Hodgkin, primary central nervous system), macroglobulinemia (Waldenstrom), malignant fibrous histiocytoma / osteosarcoma of bone, medulloblastoma (childhood), melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma (adult malignant, childhood), metastatic squamous cell carcinoma of the neck of unknown primary, oral cancer,Multiple endocrine neoplasia syndrome (childhood), multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, myeloid leukemia (chronic), myeloid leukemia (acute in adults, acute in children), multiple myeloma, myeloproliferative disorders (chronic), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian cancer Focal epithelial carcinoma (superficial epithelial stromal tumor), ovarian germ cell tumor, low-grade ovarian tumor, pancreatic cancer, pancreatic cancer (islet cell), paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germ cell tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor (childhood), pituitary adenoma, plasma cell tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma (kidney cancer), renal pelvis and Transitional cell carcinoma of the ureter, retinoblastoma, rhabdomyosarcoma (childhood), salivary gland cancer, sarcoma (Ewing family tumors, Kaposi's tumors, soft tissue tumors, uterine tumors), Sezary syndrome, skin cancer (non-melanoma, melanoma), skin cancer (Merkel cell), small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell carcinoma of the cervix of unknown primary origin (metastatic), gastric cancer, supratentorial primitive neuroectodermal tumor (childhood), T-cell lymphoma (skin), testicular cancer, These include throat cancer, thymoma (childhood), thymoma and thymic carcinoma, thyroid cancer, thyroid cancer (childhood), transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor (gestational), cancer of unknown primary origin (adult, child), transitional cell carcinoma of the ureter and renal pelvis, urethral cancer, uterine cancer (endometrium), uterine sarcoma, vaginal cancer, glioma of the visual tract and hypothalamus (childhood), vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor (childhood).

[0166] In some embodiments, treating cancer can be inhibiting cancer progression and / or metastasis, inhibiting tumor volume increase, reducing tumor volume, reducing tumor growth, eradicating tumors and / or cancer cells, or any combination thereof. The disclosed treatments can also result in an increase in subject survival or an improvement in a subject's prognosis.

[0167] Combination therapy The compounds and compositions disclosed herein may be used in combination with one or more other active ingredients. In some embodiments, the compounds may be administered in combination with or sequentially with other therapeutic agents. Such other therapeutic agents include known therapeutic agents for treating, preventing, or alleviating one or more symptoms of malaria, HIV infection, and cancer. Many such therapeutic agents are known in the art.

[0168] It should be understood that any suitable combination of the compounds and compositions provided herein, one or more therapeutic agents described above, and, optionally, one or more additional pharmacologically active agents, is considered within the scope of the present disclosure. In some embodiments, the compounds and compositions provided herein are administered before or after the one or more additional active ingredients.

[0169] Finally, it should be noted that there are alternative ways of practicing the invention, and therefore these aspects should be considered illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents.

[0170] All publications and patents cited herein are hereby incorporated by reference in their entirety.

[0171] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0172] Scheme 1 shows the preparation of compound 6. [ka]

[0173] Preparation of 7-chloro-N-isopentyl-quinazolin-4-amine (102) [ka] A mixture of 4,7-dichloroquinazoline (0.811 g (4.1 mmol)) (100) and isopentylamine (1 g (12 mmol)) (102) in 5 mL of CH3CN was briefly sonicated and then stirred at room temperature for 20 min before diluting with EtOAc. The EtOAc solution was then washed with water, dried over (Na2CO4), and the solvent removed. The crude product was subjected to column chromatography (ISCO (EtOAc / CHCl3)) to afford 1 g (97%) of 7-chloro-N-isopentyl-quinazolin-4-amine (102).

[0174] Example 1: Preparation of Compound 6 [ka] To a mixture of 7-chloro-N-isopentyl-quinazolin-4-amine (1 g, 4 mmol) (102), RuPhosPd (150 mg, 0.2 mmol), RuPhos (90 mg, 0.2 mmol), CsCO (3.93 g, 10 mmol), and 20 mL of t-BuOH was added piperazine (172 mg, 2 mmol). The mixture was heated and stirred at 87 °C for 20 h. After cooling to room temperature, the mixture was diluted with 20 mL of saturated NaCl solution and extracted twice with EtOAc. The extracts were dried over (NaSO), and the solvent was removed. The crude product was purified (ISCO (10% NH in MeOH / CHCl)) to give 600 mg (60%) of dimer 3. LCMS, M+1 = 513.

[0175] Scheme 2 shows the preparation of key intermediate 106. [ka]

[0176] Synthesis of Compound 105 [ka] A mixture of Boc-piperazine (223 mg (1.2 mmol)) (104), CsCO (600 mg (1.5 mmol)), PdRuPhos (37 mg (0.05 mmol)), RuPhos (23 mg (0.05 mmol)), and 7-chloro-N-isopentyl-quinazolin-4-amine (250 mg (1 mmol)) (100) in 2–3 mL of t-BuOH was heated and stirred at 87 °C for 20 h under an argon atmosphere. After cooling, the mixture was diluted with 20 mL of 10% MeOH / DCM and filtered through a short pad of Celite. The filtrate was evaporated to dryness, and the residue was purified (Isco (hexane / EtOAc)) to give 384 mg (96%) of the Boc-piperazine adduct 105.

[0177] Synthesis of Compound 106 [ka] To the Boc-piperazine adduct (223 mg (1.2 mmol)) (105) was added 3 mL of 30% TFA / DCM, the mixture was stirred at room temperature for 1 h, evaporated to dryness, and the residue was partitioned between 1 N NaOH and DCM. The DCM layer was dried over (NaSO) and the solvent was removed to give 228 mg of the piperazine adduct 106, which was used directly in the next step.

[0178] Scheme 3 shows the preparation of key intermediate 109. [ka]

[0179] Preparation of Compound 109 [ka] A mixture of 4,7-dichloroquinazoline (0.189 g (0.95 mmol)) (107) and tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (0.433 g (1.9 mmol)) in 3 mL of acetonitrile was sonicated briefly, stirred at room temperature for 20 min, and then diluted with EtOAc. The EtOAc solution was washed with water, dried over (Na2CO4), and the solvent removed. The crude product was chromatographed (ISCO (EtOAc / CHCl3)) to give 296 mg (80%) of 109.

[0180] Scheme 4 shows the preparation of compound 2. [ka]

[0181] Example 2: Preparation of Compound 2 [ka] A mixture of 228 mg (0.76 mmol) of piperazine compound 106, 376 mg (1.15 mmol) of CsCO, 33 mg (0.04 mmol) of PdRuPhos, 19 mg (0.04 mmol) of RuPhos, and 296 mg (0.76 mmol) of chloroquinazoline 109 in 3 mL of t-BuOH was heated at 87 °C with stirring under argon for 20 h. After cooling, the mixture was diluted with 20 mL of 10% MeOH / DCM and filtered through a short pad of Celite. The filtrate was evaporated to dryness, and the residue was purified (Isco (10% NH in MeOH / CHCl)) to give 375 mg (75%) of the desired compound 2. Scheme 5 shows the preparation of key intermediate 111. [ka]

[0182] Preparation of Compound 111 [ka] A mixture of 4,7-dichloroquinazoline (0.189 g (0.95 mmol)) (107) and n-butylamine (0.139 g (1.9 mmol)) (110) in 3 mL of acetonitrile was sonicated briefly and then stirred at room temperature for 20 min before diluting with EtOAc. The EtOAc solution was washed with water, dried over (Na2CO4), and the solvent removed. The crude product was purified (ISCO (EtOAc / CHCl3)) to give 190 mg (85%) of compound 111.

[0183] Scheme 6 shows the preparation of compound 22. [ka]

[0184] Example 3: Preparation of Compound 22 [ka] A mixture of 228 mg (0.76 mmol) of piperazine compound 106, 376 mg (1.15 mmol) of CsCO, 33 mg (0.04 mmol) of PdRuPhos, 19 mg (0.04 mmol) of RuPhos, and 172 mg (0.76 mmol) of chloroquinazoline compound 111 in 3 mL of t-BuOH was heated and stirred at 87 °C for 20 h under an argon atmosphere. After cooling, the mixture was diluted with 20 mL of 10% MeOH / DCM and filtered through a short pad of Celite. The filtrate was evaporated to dryness, and the residue was purified (Isco (10% NH in MeOH / CHCl)) to give 310 mg (82%) of the desired compound 22.

[0185] Scheme 7 shows the preparation of compound 53. [ka]

[0186] Example 4: Preparation of Compound 53 [ka] To a mixture of 7-chloro-N-butyl-quinazolin-4-amine (235 mg (1 mmol)) (111), Pd2dba3 (46 mg (0.05 mmol)), RuPhos (47 mg (0.1 mmol)), Cs2CO3 (652 g (10 mmol)), and 5 mL of DMF was added methylpiperazine (50 mg (0.5 mmol)) (112). The mixture was heated and stirred at 140 °C for 2 h. After cooling to room temperature, the mixture was diluted with 10 mL of 10% MeOH in DCM. The mixture was then filtered through Celite, and the filtrate was rotary evaporated to dryness. The residue was dissolved in approximately 2 mL of 0.1% TFA / ACN and subsequently purified by reverse-phase ISCO using 0.1% TFA in ACN / 0.1% TFA in water to give 188 mg (40%) of dimer 53.

[0187] Scheme 8 shows the preparation of compound 67. [ka]

[0188] Preparation of N-butyl-7-(3-methylpiperazin-1-yl)quinazolin-4-amine (113) [ka] To a mixture of 7-chloro-N-butyl-quinazolin-4-amine (235 mg (1 mmol)) (111), Pd2dba3 (23 mg (0.025 mmol)), RuPhos (23 mg (0.05 mmol)), Cs2CO3 (326 g (1 mmol)), and 2 mL of DMF was added methylpiperazine (300 mg (3 mmol)) (112). The mixture was heated and stirred at 140 °C for 2 h. After cooling to room temperature, the mixture was diluted with 10 mL of 10% MeOH in DCM. The mixture was then filtered through Celite, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was dissolved in approximately 2 mL of 0.1% TFA / ACN and then purified by reverse-phase ISCO using 0.1% TFA in ACN / 0.1% TFA in water to give 480 mg (quantitative) of N-butyl-7-(3-methylpiperazin-1-yl)quinazolin-4-amine (113).

[0189] Example 5: Preparation of Compound 67 [ka] To a mixture of N-butyl-7-(3-methylpiperazin-1-yl)quinazolin-4-amine (480 mg (1 mmol)) (113), Pd2dba3 (23 mg (0.025 mmol)), RuPhos (23 mg (0.05 mmol)), Cs2CO3 (326 g (1 mmol)), and 4 mL of DMF was added 7-chloro-N-isopentyl-quinazolin-4-amine (250 mg (1 mmol)) (114) (prepared using the same procedure as for (111)). The mixture was heated and stirred at 140 °C for 2 h. After cooling to room temperature, the mixture was diluted with 10 mL of 10% MeOH in DCM. The mixture was then filtered through Celite, and the filtrate was rotary evaporated to dryness. The residue was dissolved in approximately 2 mL of 0.1% TFA / ACN and then purified by reverse-phase ISCO using 0.1% TFA in ACN / 0.1% TFA in water to give 156 mg (30%) of dimer 67.

[0190] Scheme 9 shows the preparation of compound 92. [ka]

[0191] tert-Butyl N-[2-[[4-(butylamino)quinazolin-7-yl]-ethyl-amino]ethyl]-N-methylcarbamate (116) [ka] To a mixture of 7-chloro-N-butyl-quinazolin-4-amine (118 mg (0.5 mmol)) (111), Pd2dba3 (23 mg (0.025 mmol)), RuPhos (23 mg (0.05 mmol)), Cs2CO3 (326 g (1 mmol)), and 2 mL of DMF, tert-butyl N-[2-(ethylamino)ethyl]-N-methylcarbamate (101 mg (0.5 mmol)) (115) was added. The mixture was heated and stirred at 140 °C for 2 h. After cooling to room temperature, the mixture was diluted with 10 mL of 10% MeOH in DCM. The mixture was then filtered through Celite, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was dissolved in approximately 2 mL of 0.1% TFA / ACN and then purified by reverse-phase ISCO using 0.1% TFA in ACN / 0.1% TFA in water to afford 100 mg (50%) of tert-butyl N-[2-[[4-(butylamino)quinazolin-7-yl]-ethyl-amino]ethyl]-N-methylcarbamate (116).

[0192] Example 6: Preparation of Compound 92 [ka] tert-Butyl N-[2-[[4-(butylamino)quinazolin-7-yl]-ethyl-amino]ethyl]-N-methylcarbamate (100 mg, 0.25 mmol) (116) was added to 1 mL of 60% TFA in DCM. After standing at room temperature for 30 minutes, the mixture was rotary evaporated to dryness to a tan residue, which was then placed under high vacuum overnight. To the residue was added Pd2dba3 (12 mg, 0.0125 mmol), RuPhos (12 mg, 0.025 mmol), Cs2CO3 (163 g, 0.5 mmol), and 2 mL of DMF, followed by 7-chloro-N-isopentyl-quinazolin-4-amine (70 mg, 0.25 mmol) (114). The mixture was heated and stirred at 140 °C for 2 hours. After cooling to room temperature, the mixture was diluted with 10 mL of 10% MeOH in DCM. The mixture was then filtered through Celite, and the filtrate was rotary evaporated to dryness. The residue was dissolved in approximately 2 mL of 0.1% TFA / ACN and then purified by reverse-phase ISCO using 0.1% TFA in ACN / 0.1% TFA in water to give 90 mg (70%) of the dimer 92).

[0193] MS data of selected compounds [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0194] Example 4: Oncological screening All compounds that were described as active were tested in Hennes. Selected hits from the Hennes screen were further tested in anti-cancer studies.

[0195] Hennes To screen compounds for oncological activity, Hennes-20 cells were seeded at low density (500 cells / well) and high density (15,000 cells / well) and treated with DMSO (vehicle) or a dose titration of compound. The rationale for this screen is that compounds with inherent toxicity should kill cells regardless of density, such as Hennes-20 cells. However, compounds that selectively cause growth arrest will inhibit cell proliferation when seeded at low density and appear cytotoxic due to cell growth inhibition at low density, while appearing non-toxic when seeded at high density, when cells are approaching confluence and the readout detected by the cell viability assay is already near maximum.

[0196] To perform the Hennes-20 screening, two 96-well plates were seeded with Hennes-20 cells in parallel, one at 500 cells / well and the other at 15,000 cells / well. 90 μL of minimal essential medium was added to each well, and the plates were placed in a 37°C incubator for 24 hours. The next day, 10 μL of medium containing a compound diluted in DMSO was added to each plate. Six wells on each plate received 10 μL of medium containing DMSO alone. Each well was gently mixed five times with a 100 μL pipette. The plates were incubated at 37°C for 72 hours, after which 10 μL of Alamar Blue was added to each well. Each well was mixed five times, followed by an incubation period of 72 hours at 37°C. The plates were then read at 530 / 590°C.

[0197] The rationale for this screen is as follows: Hennes-20 cells lack intrinsic apoptosis. Cells seeded at low density proliferate and approach confluence by 72 hours. Drugs that arrest growth can mask their growth-inhibitory effects by inducing intrinsic apoptosis. However, in the Hennes system, which lacks intrinsic apoptosis, such arrest manifests as a dose-dependent maintenance at low cell densities. Because high-density cells are seeded near confluence, differences in Alamar Blue cell viability readings after 72 hours reflect the drug's ability to inhibit growth in cells seeded at low density. In cells seeded at high density, any decrease in Alamar Blue readings compared to vehicle controls is due to intrinsic toxicity rather than growth arrest, since the cells are already confluent. Therefore, compounds that appear toxic on low-density plates (low Alamar Blue readings after 72 hours) and non-toxic on high-density plates (high Alamar Blue readings after 72 hours) should arrest growth. This is because the intrinsic toxicity of a compound should be observed at both low and high cell densities, rather than being selectively observed only in low density plates.

[0198] The results for selected compounds are shown in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0199] Oncopanel A panel of human tumor cell lines (A172, BFTC-905, COR-L105, DB, FaDu, H9, Hs 294T, MCF7, MDA MB 436, MeWo, MHH-PREB-1, SJSA1-OSA, SW1353, and U2OS) was grown in RPMI 1640, 10% FBS, 2 mM L-alanyl-L-glutamine, and 1 mM sodium pyruvate. Cells were seeded into 384-well plates and incubated at 37°C in a humidified atmosphere of 5% CO2. After 24 h of incubation, DMSO or compounds were added, and the plates were incubated for 3 days. Cells were then lysed with CellTiter-Glo (Promega), which generates a bioluminescent signal proportional to ATP levels and is used to measure viable cells. Bioluminescence was read using a PerkinElmer Envision microplate reader. Bioluminescence intensity was measured on a PerkinElmer Envision microplate reader and converted to percent of control (POC) using the following formula: POC = (Ix / I0) × 100; where Ix is the signal intensity across wells for a given treatment condition, and I0 is the average intensity of untreated vehicle wells.

[0200] Example 5: HIV screening MT-2 cells were pre-seeded in a 96-well plate in 100 μL of complete RPMI. Multiple concentrations of PAV-951 were serially diluted in DMSO and then added to infection medium prepared by diluting NL4-3 Rluc virus stock to 400 IU / 100 μL in complete RPMI. This mixture was added to MT-2 cells to achieve a final MOI of 0.02 and a final DMSO concentration of 1% in the infection field. One well contained DMSO alone instead of PAV-951, and one well contained medium alone for normalization and background detection. Cells were incubated at 37°C for 96 hours. 100 μL of medium was removed and discarded, and 10 μL of 15 μM EnduRen luciferase substrate was added to each well and incubated at 37°C for 1.5 hours. Plates were read using a luminescence plate reader. Bioluminescence intensity was measured using a Synergy H1 BioTek plate reader. The mean and standard deviation of the viral titers observed under various treatment conditions were calculated using Microsoft Excel and graphed as the percent inhibition of PAV-951-treated cells compared to untreated cells. Results for selected compounds are shown in Table 3. [Table 3] Example 6: Malaria screening Compounds were added to 0.5% Plasmodium parasitemia cultures and incubated for 48 hours. After incubation, the cells were treated with SYBR Green (a dye whose fluorescence increases significantly upon contact with Plasmodium DNA) and the fluorescence of treated and untreated cells was measured to determine inhibitory effects (Smilkstein, et al., "Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening," Antimicrob Agents Chemother. 2004 May;48(5):1803-6. doi: 10.1128 / AAC.48.5.1803-1806.2004. PMID: 15105138; PMCID: PMC400546). Table 4

Claims

1. Compounds of structural formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate or hydrate thereof (In the formula, X is a substituted heteroaryl or —C(O)—R １ and R １ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Y is 【Chemistry 2】 and Z is H, —C(O)R １０ , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; R １０ is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl).

2. X is 【Transformation 3】 and R ２ is H, alkyl or —C(O)R ３ and R ４ is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R ５ or R ２ and R ４ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R ３ and R ５ are independently alkyl; A is —N— or —CH—; The compound of claim 1.

3. Z is 【Chemistry 4】 and R ６ is H, alkyl, —C(O)R ７ and R ８ is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R ９ or R ６ and R ８ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R ７ and R ９ are independently alkyl; B is —N— or —CH—; The compound of claim 1.

4. X is 【Transformation 5】 and R ２ is H, alkyl, —C(O)R ３ and R ４ is H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R ５ or R ２ and R ４ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R ３ and R ５ are independently alkyl; A is —N— or —CH—; and Z is 【Transformation 6】 and R ６ is H, alkyl, —C(O)R ７ and R ７ is alkyl, and R ８ is H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R ９ or R ６ and R ８ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R ７ and R ９ are independently alkyl; B is —N— or —CH—, provided that R ３ -C(O)R ５ If R ２ Ha-C(O)R ３ rather than; However, R ８ -C(O)R ９ If R ６ Ha-C(O)R ７ isn't it, The compound of claim 1.

5. Y is 【Transformation 7】 That is, The compound of claim 4.

6. A and B are —N—; The compound of claim 5.

7. R ２ and R ６ is -H, and R ４ and R ８ is independently arylalkyl or substituted arylalkyl; The compound of claim 6.

8. The following structure: 【Transformation 8】 having The compound of claim 7.

9. R ２ and R ６ is -H, and R ４ is arylalkyl, and R ８ is alkyl, The compound of claim 6.

10. The following structure: 【Chemistry 9】 having The compound of claim 9.

11. R ２ and R ６ is -H, and R ４ is a substituted heteroalkyl, and R ８ is arylalkyl; The compound of claim 6.

12. The following structure: 【Chemistry 10】 having The compound of claim 11.

13. R ２ and R ６ is -H, and R ４ and R ８ is independently heteroarylalkyl or substituted heteroarylalkyl; The compound of claim 6.

14. The following structure: 【Chemistry 11】 having The compound of claim 13.

15. R ２ and R ６ is —H, and R ４ is alkyl, and / or R ８ is heteroarylalkyl or substituted heteroarylalkyl; The compound of claim 6.

16. The following structure: 【Chemistry 12】 having 16. The compound of claim 15.

17. R ２ and R ６ is -H, and R ４ and R ８ is alkyl, The compound of claim 6.

18. The following structure: 【Chemistry 13】 having 18. The compound of claim 17.

19. R ２ is alkyl, and R ６ is -H, and R ４ and R ８ is alkyl, The compound of claim 6.

20. The following structure: 【Chemistry 14】 having 20. The compound of claim 19.

21. R ２ and R ６ is alkyl, and R ４ and R ８ is alkyl, The compound of claim 6.

22. The following structure: 【Chemistry 15】 having 22. The compound of claim 21.

23. R ２ and R ６ is alkyl, and R ４ and R ８ is heteroalkyl; The compound of claim 6.

24. The following structure: 【Chemistry 16】 having 24. The compound of claim 23.

25. R ２ and R ６ is -H, and R ４ and R ８ is heteroalkyl; The compound of claim 6.

26. The following structure: 【Chemistry 17】 having 26. The compound of claim 25.

27. R ２ and R ６ is -H, and R ４ is alkyl, and R ８ is heteroalkyl or substituted heteroalkyl; The compound of claim 6.

28. The following structure: [Chemistry 18] having 28. The compound of claim 27.

29. R ２ is -H, and R ４ is alkyl, and R ６ and R ８ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; The compound of claim 6.

30. The following structure: 【Chemistry 19】 having 30. The compound of claim 29.

31. R ２ and R ４ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring, and R ６ and R ８ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; The compound of claim 6.

32. The following structure: 【Chemistry 20】 having 32. The compound of claim 31.

33. R ２ and R ６ is -H, and R ４ is a substituted alkyl, and R ８ is a substituted alkyl; The compound of claim 6.

34. The following structure: 【Chemistry 21】 having 34. The compound of claim 33.

35. R ２ and R ６ is alkyl, and R ４ Ha-C(O)R ５ and R ８ Ha-C(O)R ９ That is, The compound of claim 6.

36. The following structure: 【Chemistry 22】 having 36. The compound of claim 35.

37. R ２ and R ６ is -H, and R ４ Ha-C(O)R ５ and R ８ Ha-C(O)R ９ That is, The compound of claim 6.

38. The following structure: 【Chemistry 23】 having 38. The compound of claim 37.

39. Y is 【Chemistry 24】 That is, The compound of claim 4.

40. R ２ and R ６ is -H, and R ４ is a substituted alkyl, and R ８ is arylalkyl; 40. The compound of claim 39.

41. The following structure: 【Chemistry 25】 having 41. The compound of claim 40.

42. R ２ and R ６ is -H, and R ４ and R ８ is alkyl, 42. The compound of claim 41.

43. The following structure: 【Chemistry 26】 having 43. The compound of claim 42.

44. Y is 【Chemistry 27】 That is, The compound of claim 2.

45. R ２ is -H, and R ４ is alkyl and Z is heteroaryl; 45. The compound of claim 44.

46. The following structure: 【Chemistry 28】 having 46. ​​The compound of claim 45.

47. X is 【Chemistry 29】 and C is halo or -NR １１ R １２ and R １１ is H, alkyl, —C(O)R １３ and R １２ is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R １４ or R １１ and R １２ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R １３ and R １４ are independently alkyl; A is —N— or —CH—; The compound of claim 1.

48. Z is 【Transformation 30】 and D is halo or -NR １５ R １６ and R １５ is H, alkyl, -C(O)R １７ and R １５ is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R １８ or R １５ and R １６ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R １７ and R １８ are independently alkyl; A is —N— or —CH—; The compound of claim 1.

49. X is 【Chemistry 31】 and C is halo or -NR １１ R １２ and R １１ is H, alkyl, -C(O)R １３ and R １２ is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R １４ or R １１ and R １２ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R １３ and R １４ are independently alkyl; A is —N— or —CH—; and Z is 【Chemistry 32】 and D is halo or -NR １５ R １６ and R １５ is H, alkyl, -C(O)R １７ and R １５ is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, —C(O)R １８ or R １５ and R １６ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted heteroarylalkyl ring; R １７ and R １８ are independently alkyl; A is —N— or —CH—; B is —N— or —CH—, provided that R １２ -C(O)R １４ If R １１ Ha-C(O)R １３ rather than; However, R １５ -C(O)R １８ If R １５ Ha-C(O)R １７ isn't it, The compound of claim 1.

50. Y is 【Transformation 33】 That is, 50. The compound of claim 49.

51. C is -NR １１ R １２ and D is -NR １５ R １６ That is, 51. The compound of claim 50.

52. The following structure: 【Transformation 34】 having 52. The compound of claim 51.

53. C is halo and D is halo; 51. The compound of claim 50.

54. The following structure: 【Chemistry 35】 having 54. The compound of claim 53.

55. Z is a substituted heteroaryl; The compound of claim 2.

56. The following structure: 【Transformation 36】 having 56. The compound of claim 55.

57. Z is —H; The compound of claim 2.

58. The following structure: 【Chemistry 37】 having 58. The compound of claim 57.

59. X and Z are substituted heteroaryl; The compound of claim 1.

60. The following structure: 【Transformation 38】 having 60. The compound of claim 59.

61. Z is -C(O)R １０ That is, The compound of claim 2.

62. R ２ is -H, and R ４ is alkyl or substituted heteroarylalkyl; 62. The compound of claim 61.

63. The following structure: 【Chemistry 39】 having 63. The compound of claim 62.

64. 10. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle. Pharmaceutical compositions.

65. A method for preventing or treating cancer in a mammal not belonging to the species Homo sapiens, comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of claim 1 or a pharmaceutical composition of claim 64.

66. A method for preventing or treating cancer in Homo sapiens, comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of claim 1 or a pharmaceutical composition of claim 64.

67. A method for preventing or treating HIV infection in a patient, comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of claim 1 or a pharmaceutical composition of claim 64.

68. 65. A method for preventing or treating malaria in a patient, comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of claim 1 or a pharmaceutical composition of claim 64.

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