Phenothiazinyl compounds and uses thereof

Abstract

Novel heterocyclic compounds, such as novel phenothiazinyl compounds, and pharmaceutical compositions thereof are disclosed that can be used to treat or prevent bacterial infections, including gram-positive bacterial infections, skin infections, endocarditis, osteomyelitis, pneumonia, HIV infections, cancer, Alzheimer's disease, pox, rabies, and coronavirus infections. Also disclosed are general uses of known phenothiazinyl compounds and pharmaceutical compositions thereof for treating or preventing bacterial infections, including gram-positive bacterial infections, skin infections, endocarditis, osteomyelitis, pneumonia, HIV infections, cancer, Alzheimer's disease, and coronavirus infections.

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 / 447,183, filed February 21, 2023, which is incorporated herein by reference in its entirety.

[0002] Novel heterocyclic compounds, such as novel phenothiazinyl compounds, and pharmaceutical compositions thereof are disclosed that can be used to treat or prevent bacterial infections, including gram-positive bacterial infections, skin infections, endocarditis, osteomyelitis, pneumonia, HIV infections, cancer, Alzheimer's disease, pox, rabies, and coronavirus infections. Also disclosed are general uses of known phenothiazinyl compounds and pharmaceutical compositions thereof for treating or preventing bacterial infections, including gram-positive bacterial infections, skin infections, endocarditis, osteomyelitis, pneumonia, HIV infections, cancer, Alzheimer's disease, and coronavirus infections. [Background technology]

[0003] MRSA and Staphylococcus aureus cause skin infections, endocarditis, osteomyelitis, and pneumonia, but are becoming increasingly difficult to treat due to the rise in antimicrobial resistance worldwide, resulting in fewer and fewer treatment options. The effectiveness of current treatments is further undermined by side effects. The lack of new classes of antibiotics in the pharmaceutical pipeline is an additional concern.

[0004] Similarly, current treatments for HIV infection, cancer, Alzheimer's disease, pox, rabies, and coronavirus infections are inadequate.

[0005] Therefore, there is a need for new classes of compounds that can be used to treat and / or prevent bacterial infections, including gram-positive infections and infections caused by MRSA, MDR, and Staphylococcus aureus, HIV infection, cancer, Alzheimer's disease, pox, rabies, and coronavirus infections. Summary of the Invention

[0006] In one aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, that meets these and other needs: [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof: R1 is H, -NR7R8, -OR9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; and R2 is -H, -NR 10 R 11 ,or [ka] and R3 is -H, halo, -OR 12 , alkyl, or substituted alkyl; R4 is -H, -NR 13 R 14 ,or [ka] and R5 is -H, halo, -OR 15 , alkyl, or substituted alkyl; R6 is -H, -NR 16 R 17 , -OR 18 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; R7 and R8 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R 10 and R 11are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R 16 and R 17 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, a substituted cycloheteroalkenyl ring, a bicycloheteroalkyl ring, a substituted bicycloheteroalkyl ring, a spirocycloheteroalkyl ring, or a substituted spirocycloheteroalkyl ring; R, R 12 , R 15 , and R 18 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted aryl, heteroalkyl, or substituted heteroalkyl; and X- is a pharmaceutically acceptable salt.

[0007] In some embodiments, the following compounds are excluded: with the proviso that when R2 and R4 together form a C5-C7 cycloheteroalkyl ring or a C5-C7 substituted cycloheteroalkyl ring, when R6 is t-butyl, R1 is not H, when R6 is H, except when R5 is -CH2Boc or -OMe, R1 is not H or methyl, when R6 is ethyl, R1 is not methyl or ethyl; with the proviso that R 10 and R 11 or R 13 and R 14 When any of R and R forms a C5-C7 cycloheteroalkyl ring or a C5-C7 substituted cycloheteroalkyl ring, when R and R are independently -H, alkyl, alkenyl, or haloalkyl, R10 , R 11 , R 13 , or R 14 is alkyl or substituted alkyl; with the proviso that when one of R2 and R4 is -H, then at least one of R1 and R6 is not -H; and with the proviso that when R2 is -NR 10 R 11 and R4 is -NR 13 R 14 and R 10 , R 11 , R 13 , or R 14 When either of R is substituted alkyl, 10 , R 11 , R 13 , or R 14 -OR 19 , -SR 20 , or -NR 21 is not replaced by R 19 , R 20 , or R 21 is independently alkyl, alkenyl, or aryl. It should be understood that the above conditions may operate simultaneously, independently, or not at all.

[0008] In another aspect, there is provided a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or hydrate thereof: [ka] R 15 is H, alkyl, or halo; R 16 Ha-NR 19 R 20 and;R 17 Ha-NR 21 R 22 and;R 18 is -H, alkyl, or halo; R 19 and R 20are alkyl or together with the atom to which they are attached form a saturated pyrrolidinyl-1-yl ring, a saturated substituted pyrrolidinyl-1-yl ring, an unsaturated pyrrolidinyl-1-yl ring, an unsaturated substituted pyrrolidinyl-1-yl ring, a saturated piperazin-1-yl ring, a saturated substituted piperazin-1-yl ring, an unsaturated piperazin-1-yl ring, or an unsaturated substituted piperazin-1-yl ring; R 21 and R 22 are alkyl or together with the atom to which they are attached form a saturated pyrrolidinyl-1-yl ring, a saturated substituted pyrrolidinyl-1-yl ring, an unsaturated pyrrolidinyl-1-yl ring, an unsaturated substituted pyrrolidinyl-1-yl ring, a saturated piperazin-1-yl ring, a saturated substituted piperazin-1-yl ring, an unsaturated piperazin-1-yl ring, or an unsaturated substituted piperazin-1-yl ring; X- is a pharmaceutically acceptable salt; provided that the compound of formula (II) [ka] (R 23 and R 24 are -CH2F, F, Cl, or C2H5) or [ka] No.

[0009] Also provided are derivatives, including salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs, of the compounds described herein. Additionally, provided are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable vehicle.

[0010] In yet another aspect, there is provided a method for treating, preventing, or ameliorating symptoms of a medical disorder, such as, for example, a bacterial infection, including a gram-positive bacterial infection, a skin infection, endocarditis, osteomyelitis, pneumonia, an HIV infection, cancer, Alzheimer's disease, pox, rabies, and a coronavirus infection, 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.

[0011] In some embodiments, when treating or preventing cancer, the patient is a mammal other than Homo sapiens. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the time-kill kinetics of Compound 1 against MSSA ATCC25923. [Figure 2] FIG. 2 shows the time-kill kinetics of Compound 1 against MSSA ATCC43300. [Figure 3] FIG. 3 shows the time-kill kinetics of Compound 1 against MDR Staphylococcus aureus. [Figure 4] FIG. 4 shows the sustained antibacterial effect of Compound 1 against MRSA. [Figure 5] FIG. 5 shows the sustained antibacterial effect of Compound 1 against MDR Staphylococcus aureus. [Figure 6] FIG. 6 shows the biofilm removal against MRSA by Compound 1. [Figure 7] FIG. 7 shows the mean serum concentration time profile following a single intravenous administration of Compound 1 to mice. [Figure 8] FIG. 8 shows tumor volume versus time during treatment with control, gemcitabine, and Compound 68. DETAILED DESCRIPTION OF THE INVENTION

[0013] 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 multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0014] As used herein, unless otherwise specified, the terms "about" and "approximately" when used in connection with a property having a numerical value or range of values ​​indicates that the value or range of values ​​may deviate to an extent that would be reasonable for one of ordinary skill in the art while still describing the 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% from the stated value or range of values. Also, unless the context clearly dictates otherwise, the singular forms "a" and "the" include the plural. Thus, for example, a reference to "the compound" includes the plural of that compound, and a reference to "the assay" includes a reference to one or more assays and equivalents thereof known to those of ordinary skill in the art.

[0015] A dash ("-") that is 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 a carbon atom. Dashes at the front or end of a chemical group are for convenience, and the chemical group may be depicted with or without one or more dashes without losing its normal meaning. A wavy line across a line in a structural formula indicates the point of attachment of the group. No direction is indicated or implied in the order in which chemical groups are written or listed unless chemically or structurally necessary.

[0016] "C u~v " prefix indicates that the following group has u to v carbon atoms. It should be understood that u to v carbons includes u+1 to v, u+2 to v, u+3 to v, etc. carbons, u+1 to u+3 to v, u+1 to u+4 to v, u+2 to u+4 to v, etc., encompassing all combinations of u and v.

[0017] "Alkyl," alone or as part of another substituent, refers to a saturated, branched, or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Representative 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-C6). 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1-C 10 In yet other embodiments, the alkyl group comprises 1 to 6 carbon atoms (C1-C6 alkyl).

[0018] "Alkenyl," alone or as part of another substituent, refers to an unsaturated, branched, 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 configuration about the double bond(s). Representative 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. In some embodiments, the alkenyl group contains 2 to 20 carbon atoms (C 20 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).

[0019] "Alkynyl," alone or as part of another substituent, refers to an unsaturated branched, straight-chain group having at least one carbon-carbon triple bond, derived by removing a hydrogen atom from a single carbon atom of a parent alkyne. Representative alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl and prop-2-yn-1-yl; butynyl, 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 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 2 to 6 carbon atoms (C2-C6 alkynyl).

[0020] "Aryl," alone 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. Representative aryl groups include, but are not limited to, radicals derived from 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. 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 another embodiment, 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 (C6-C 10 aryl).

[0021] "Arylalkyl," alone or as part of another substituent, refers to an alkyl group containing a carbon atom, typically a terminal or sp 3 This refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to the carbon atom is replaced by an aryl group, as defined herein. Representative 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, 2-naphthophenylethan-1-yl, and the like. In some embodiments, the arylalkyl group is (C7-C 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.

[0022] "Arylalkenyl," 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 by an aryl group, as defined herein. In some embodiments, an arylalkenyl group is an alkyl group (C8-C 40 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C 10 ) alkenyl, and the aryl moiety is (C6-C 30In 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.

[0023] "Arylalkynyl," by itself or as part of another substituent, refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group, as defined herein. In some embodiments, an arylalkynyl group is an aryl group (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 12 In 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.

[0024] "Bicycloheteroalkyl," by itself or as part of another substituent, refers to a bicyclic alkyl structure which shares two atoms and contains at least one heteroatom independently selected from the group consisting of N, O, and S within the ring.

[0025] "Compound" refers to a compound encompassed by the structural formulas disclosed herein, including any specific compound within these formulas having a structure disclosed herein. Compounds may be identified by their chemical structure and / or chemical name. The identity of a compound is determined by its chemical structure. The compounds described herein may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereoisomers. Thus, the chemical structures depicted herein encompass stereomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereoisomerically pure) forms depicted in the structural formulas. The chemical structures depicted herein also encompass enantiomeric and stereoisomeric derivatives of the depicted compounds. Enantiomeric and stereoisomeric mixtures can be separated into their component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in multiple tautomeric forms, including enol forms, keto forms, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the depicted compounds. Compounds may also be atropisomers. The compounds described also include isotopically labeled compounds in which the atomic mass of one or more atoms differs from the atomic mass normally 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.17 Examples include, but are not limited to, O. Compounds can exist in unsolvated forms and solvated forms, including hydrated forms. In general, compounds can be in a hydrated or solvated state. A particular compound can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure. Furthermore, when depicting a substructure of a compound, it should be understood that square brackets indicate the point of attachment of the substructure to the remainder of the molecule.

[0026] "Cycloalkyl," alone or as part of another substituent, refers to a saturated cyclic monovalent hydrocarbon group derived by the removal of a hydrogen atom from a single carbon atom of a parent cycloalkane. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and the like. In some embodiments, cycloalkyl groups contain 3 to 20 carbon atoms (C3-C6). 15 In other embodiments, the cycloalkyl group contains 3 to 10 carbon atoms (C3-C 10 In still other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C3-C8 cycloalkyl). The term "cyclic monovalent hydrocarbon group" also includes polycyclic hydrocarbon ring systems having a single radical and 5 to 12 carbon atoms. Exemplary polycyclic cycloalkyl rings include, for example, norbornyl, vinyl, and adamantyl.

[0027] "Cycloalkenyl," alone or as part of another substituent, refers to an unsaturated cyclic monovalent hydrocarbon group derived by the removal of a hydrogen atom from a single carbon atom of a parent cycloalkene. Representative 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-C6). 20 In other embodiments, the cycloalkenyl group contains 3 to 10 carbon atoms (C 10In yet other embodiments, the cycloalkenyl group contains from 3 to 8 carbon atoms (C3-C8 cycloalkenyl).

[0028] "Cycloheteroalkyl," alone or as part of another substituent, refers to a cycloalkyl group, as defined herein, in which one or more of the carbon atoms (and optionally associated hydrogen atoms) have been replaced, each independently of the other, with the same or different heteroatoms or heteroatom groups 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 (e.g., 3~10 In yet other embodiments, the cycloheteroalkyl group contains 3 to 8 carbon atoms and heteroatoms (e.g., 3~8 cycloheteroalkyl). The term "cyclic monovalent heteroalkyl group" includes both monocyclic and polycyclic heteroalkyl ring systems having 3 to 12 carbon atoms and at least one heteroatom. Exemplary cycloheteroalkyl groups include, for example, azetidine, pyrrolidine, piperazine, piperidine, morpholine, and tetrahydrofuran.

[0029] "Cycloheteroalkenyl," alone or as part of another substituent, refers to a cycloalkenyl group, as defined herein, in which one or more of the carbon atoms (and optionally associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatom groups defined below under "heteroalkenyl." In some embodiments, a cycloheteroalkenyl group contains from 3 to 20 carbon atoms and heteroatoms ( 3~20 In other embodiments, the cycloheteroalkenyl group contains 3 to 10 carbon atoms and heteroatoms (e.g., 3~10 In yet another embodiment, the cycloheteroalkenyl group contains 3 to 8 carbon atoms and heteroatoms (cycloheteroalkenyl). 3~8The term "cyclic monovalent heteroalkenyl group" also includes monocyclic and polycyclic heteroalkenyl ring systems having 2 to 12 carbon atoms and at least one heteroatom.

[0030] "Halo," by itself or as part of another substituent, refers to the groups -F, -Cl, -Br, or -I.

[0031] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) have been replaced, each independently, with the same or different heteroatoms or heteroatomic groups. Representative heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatom or heteroatom group can be located at any interior position of the alkyl, alkenyl, or alkynyl group. Representative 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-, -SnR 507 R 508 These include, but are not limited to, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 is 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 ( 1~20 In 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).

[0032] "Heteroalkenyl" refers to an alkenyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) have been replaced, each independently, with the same or different heteroatoms or heteroatom groups. Representative heteroatoms or heteroatom groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatom or heteroatom group can be located at any interior position of the alkyl, alkenyl, or alkynyl group. Representative 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-, -SnR 507 R 508 These include, but are not limited to, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 is 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 (e.g., 1~10 In still other embodiments, heteroalkenyl groups contain 1 to 6 carbon atoms and heteroatoms (e.g., 1~6 heteroalkenyl).

[0033] "Heteroaryl," alone or as part of another substituent, refers to a monovalent heteroaromatic group derived by the removal of a hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Representative heteroaryl groups include, but are not limited to, 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, xanthene, and the like. In some embodiments, heteroaryl groups contain 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, heteroaryl groups contain 5 to 10 ring atoms (5-10 membered heteroaryl). Exemplary heteroaryl groups are those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0034] "Heteroarylalkyl," alone or as part of another substituent, refers to an alkyl 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 (C1-C6)alkyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkyl is a 6- to 13-membered heteroarylalkyl, e.g., the alkyl portion is (C1-C3)alkyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0035] "Heteroarylalkenyl," alone 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 by a heteroaryl group. In some embodiments, a heteroarylalkenyl group is a 7- to 21-membered heteroarylalkenyl, e.g., the alkenyl moiety of the heteroarylalkenyl is a (C2-C6)alkenyl and the heteroaryl moiety is a 5- to 15-membered heteroaryl. In other embodiments, a heteroarylalkenyl is a 7- to 13-membered heteroarylalkenyl, e.g., the alkenyl moiety is a (C2-C3)alkenyl and the heteroaryl moiety is a 5- to 10-membered heteroaryl.

[0036] "Heteroarylalkynyl," alone 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 by a heteroaryl group. In some embodiments, the heteroarylalkynyl group is a 7- to 21-membered heteroarylalkynyl, e.g., the alkynyl moiety of the heteroarylalkynyl is a (C2-C6)alkynyl and the heteroaryl moiety is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkynyl is a 7- to 13-membered heteroarylalkynyl, e.g., the alkynyl moiety is a (C2-C3)alkynyl and the heteroaryl moiety is a 5- to 10-membered heteroaryl.

[0037] "Hydrate" refers to an adduct formed by incorporating water in a stoichiometric ratio into a form of a compound described herein. Methods for producing hydrates include, but are not limited to, storage in an atmosphere containing water vapor, a dosage form containing water, or conventional formulation processes such as crystallization (i.e., from water or a mixed water solvent), lyophilization, wet granulation, aqueous film coating, or spray drying. Hydrates can also form under certain conditions when a crystalline solvate is exposed to water vapor or when an anhydrous form is suspended in water. Hydrates can also crystallize in multiple forms, resulting in hydrate 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-described methods for preparing hydrates are within the skill of those in the art and are completely conventional, requiring no experimentation beyond that typical of the art. Hydrates can be characterized and / or analyzed by methods well known to those skilled in the art, such as, for example, single crystal X-ray diffraction, X-ray powder 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). Additionally, many companies, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27100 Val de Reuil, France (http: / / www.holodiag.com), routinely offer services that include the preparation and / or characterization of hydrates.

[0038] "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, resulting in a positive charge on the nitrogen. The N-oxides of the present disclosure can be synthesized by oxidation procedures well known to those of skill in the art.

[0039] "Parent aromatic ring system" refers to an unsaturated cyclic 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 of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as fluorene, indane, indene, phenalene, etc. Representative 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.

[0040] "Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms. Representative heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, and Si. Specifically included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as benzodioxanes, benzofurans, chromanes, chromenes, indoles, indolines, xanthenes, and the like. Representative parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-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, xanthene, and the like.

[0041] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) 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, (2) acid addition salts formed with organic acids such as 4-methylbicyclo[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, muconic acid, and the like; or (3) acid addition salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordination salts with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0042] "Preventing" or "prevention" refers to a reduction in the risk of developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from manifesting in a patient who may be exposed to or predisposed to the disease, but who has not yet experienced or displayed 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 are superior prophylaxis due to their reduced long-term side effects.

[0043] As used herein, "prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are often, though not necessarily, pharmacologically inactive until converted to the parent drug.

[0044] As used herein, a "promoiety" refers to a form of protecting group that, when used to mask a functional group in a drug molecule, converts 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.

[0045] A "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents 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, 2009). 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"), nitro-veratryloxycarbonyl ("NVOC"). Representative hydroxy-protecting groups include, but are not limited to, acylated or alkylated hydroxy groups, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0046] "Spirocycloheteroalkyl," by itself or as part of another substituent, refers to bicyclic alkyl structures that share one atom within the ring and that contain at least one heteroatom independently selected from the group consisting of N, O, and S.

[0047] "Solvate" refers to an adduct formed by incorporating a solvent in a stoichiometric ratio into the crystalline lattice of a compound described herein. Methods for preparing solvates include, but are not limited to, storage in a solvent-containing atmosphere, formulations containing a solvent, or conventional formulation processes such as crystallization (i.e., from a solvent or solvent mixture), vapor diffusion, etc. Solvates may also form from other crystalline solvates or hydrates under certain conditions when exposed to or suspended in a solvent. Solvates may crystallize in multiple forms, 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-described methods for preparing solvates are within the skill of those in the art and are completely conventional, requiring no experimentation beyond that typical in the art. Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as, for example, single crystal X-ray diffraction, X-ray powder 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). Additionally, many companies, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27100 Val de Reuil, France (http: / / www.holodiag.com), routinely offer services that include the preparation and / or characterization of solvates.

[0048] "Substituted," when used to modify 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). A group of substituents useful for replacing saturated carbon atoms in a particular group or radical includes 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 b , -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 b , -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)Rb 、 -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)2NR 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 、および -NR b C(NR b )NR c R c があり、各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, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; and each R c is independently R b or alternatively, two R c together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, a substituted cycloheteroalkenyl ring, or a cycloheteroalkyl or cycloheteroalkenyl fused to an aryl group which may optionally contain 1 to 4 identical or different additional heteroatoms selected from the group consisting of O, N, and S. Specific examples include -NR c R c is intended 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 There is R a , R b , and R c is defined above. In still other embodiments, substituents useful for substituting saturated carbon atoms in certain 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 There is R a , R b , and R c is defined as above.

[0049] Substituents useful for replacing unsaturated carbon atoms in certain groups or radicals include substituted alkyl, -R a , halo, -O - , -OR b , -SR b , -S - , -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 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 、および-C(NR b )NR b C(NR b )NR c R c があり、R a 、Rb , and R c is defined above. In other aspects, 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 There is R a , R b , and R c is defined above. In still other embodiments, substituents useful for replacing 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 There is R a , R b , and R c is defined as above.

[0050] Useful substituents for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include alkyl, -R a , -O- 、-OR b 、-SR b 、-S - 、-NR c R c 、トリハロメチル、-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 )NR c R c 、および-C(NR b )NR b C(NR b )NRc R c These include, but are not limited to, R a , R b , and R c is defined above. In some embodiments, 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 , -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 There is R a , R b , and R c is 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 b C(O)R b , and -NR b C(O)OR b There is R a , R b, and R c is defined as above.

[0051] The above-listed substituents useful for substituting other particular groups or atoms will be apparent to those skilled in the art.

[0052] The substituents used to substituted a particular group may be further substituted, typically with one or more of the same or different groups selected from the various groups identified above.

[0053] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to vertebrates, preferably mammals. Mammals include, but are not limited to, rodents, apes, 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 except Homo sapiens.

[0054] "Treating" any disease or disorder or "treatment" of any disease or disorder, in some embodiments, refers to ameliorating the disease or disorder (i.e., preventing or alleviating the onset of the disease or at least one of its clinical symptoms). Treatment may also be considered to include preemptive or prophylactic administration to ameliorate, prevent, or prevent the onset of at least one disease or clinical symptom. As an additional feature, the administered treatment has a low likelihood of long-term side effects over multiple years. In other embodiments, "treating" or "treatment" refers to ameliorating at least one physical parameter, which may be imperceptible to the patient. In still other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In still other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0055] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat that disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism, and excretion of the patient being treated.

[0056] "Vehicle" refers to a diluent, excipient, or carrier used in administering a compound to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.

[0057] compound In some embodiments, the compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1 is H, -NR7R8, -OR9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; and R2 is -H, -NR 10 R 11 ,or [ka] and R3 is -H, halo, -OR 12 , alkyl, or substituted alkyl; R4 is -H, -NR 13 R 14 ,or [ka] and R5 is -H, halo, -OR 15 , alkyl, or substituted alkyl; R6 is -H, -NR 16 R 17 , -OR 18, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; R7 and R8 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R 10 and R 11 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R 16 and R 17 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, a substituted cycloheteroalkenyl ring, a bicycloheteroalkyl ring, a substituted bicycloheteroalkyl ring, a spirocycloheteroalkyl ring, or a substituted spirocycloheteroalkyl ring; R, R 12 , R 15 , and R 18 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted aryl, heteroalkyl, or substituted heteroalkyl; and X- is a pharmaceutically acceptable salt.

[0058] In some embodiments, the following compounds are excluded: with the proviso that when R2 and R4 together form a C5-C7 cycloheteroalkyl ring or a C5-C7 substituted cycloheteroalkyl ring, when R6 is t-butyl, R1 is not H, when R6 is H, except when R5 is -CH2Boc or -OMe, R1 is not H or methyl, when R6 is ethyl, R1 is not methyl or ethyl; with the proviso that R 10 and R 11 or R 13 and R 14 When any of R and R forms a C5-C7 cycloheteroalkyl ring or a C5-C7 substituted cycloheteroalkyl ring, when R and R are independently -H, alkyl, alkenyl, or haloalkyl, R 10 , R 11 , R 13 , or R 14 is alkyl or substituted alkyl; with the proviso that when one of R2 and R4 is -H, then at least one of R1 and R6 is not -H; and with the proviso that when R2 is -NR 10 R 11 and R4 is -NR 13 R 14 and R 10 , R 11 , R 13 , or R 14 When either of R is substituted alkyl, 10 , R 11 , R 13 , or R 14 -OR 19 , -SR 20 , or -NR 21 is not replaced by R 19 , R 20 , or R 21 is independently alkyl, alkenyl, or aryl. It should be understood that the above conditions may operate simultaneously, independently, or not at all.

[0059] In some embodiments, R2 is -NR9R 10 and R4 is -NR 11 R12 In other embodiments, R and R 10 together with the atoms to which they are attached form a bicycloheteroalkyl ring or a substituted bicycloheteroalkyl ring, and R 11 and R 12 together with the atoms to which they are attached form a bicycloheteroalkyl ring or a substituted bicycloheteroalkyl ring.

[0060] In some embodiments, R1, R3, R5, and R6 are -H. In other embodiments, the structure: [ka] In yet another embodiment, the compound of the present disclosure has structure 1. In yet another embodiment, the compound of the present disclosure has structure 2. In yet another embodiment, the compound of the present disclosure has structure 3.

[0061] In some embodiments, R3, R5, and R6 are -H. In other embodiments, the structure: [ka] In yet another embodiment, the compound of the present disclosure has structure 4. In yet another embodiment, the compound of the present disclosure has structure 5. In yet another embodiment, the compound of the present disclosure has structure 6. In yet another embodiment, the compound of the present disclosure has structure 15.

[0062] In some embodiments, R1, R3, and R6 are -H. In other embodiments, the structure: [ka] In yet other embodiments, compounds of the present disclosure have structure 7. In yet other embodiments, compounds of the present disclosure have structure 8. In some embodiments, compounds of the present disclosure have structure 9. In still other embodiments, R3 and R5 are -H.

[0063] In some embodiments, the structure: [ka] In another embodiment, the compound of the present disclosure has structure 10. In yet another embodiment, the compound of the present disclosure has structure 11. In yet another embodiment, the compound of the present disclosure has structure 12. In yet another embodiment, the compound of the present disclosure has structure 13.

[0064] In some embodiments, R5 is -H. In other embodiments, R5 is a compound having the structure: [ka] Compounds having the formula:

[0065] In some embodiments, R and R 10 together with the atoms to which they are attached form a spirocycloheteroalkyl ring or a substituted spirocycloheteroalkyl ring, and R 11 and R 12 together with the atoms to which they are attached form a spirocycloheteroalkyl ring or a substituted spirocycloheteroalkyl ring. [ka] Compounds having the formula:

[0066] In some embodiments, R2 is [ka] In another aspect, the structure: [ka] In yet another embodiment, the compound of the present disclosure has structure 18. In another embodiment, the compound of the present disclosure has structure 19.

[0067] In some embodiments, R and R 10together with the atoms to which they are attached form a cycloheterocycloalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring, and R 11 and R 12 together with the atoms to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring. [ka] In yet another embodiment, compounds of the present disclosure have structure 20. In yet another embodiment, compounds of the present disclosure have structure 21. In yet another embodiment, compounds of the present disclosure have structure 22. In yet another embodiment, compounds of the present disclosure have structure 23. In yet another embodiment, compounds of the present disclosure have structure 24. In yet another embodiment, compounds of the present disclosure have structure 25. In yet another embodiment, compounds of the present disclosure have structure 27. In yet another embodiment, compounds of the present disclosure have structure 28. In yet another embodiment, compounds of the present disclosure have structure 29.

[0068] In some embodiments, R and R 10 together with the atoms to which they are attached form a bicycloheteroalkyl ring or a substituted bicycloheteroalkyl ring, and R 11 and R 12 are alkyl or together with the atom to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring. [ka] In yet another embodiment, the compound of the present disclosure has structure 30. In yet another embodiment, the compound of the present disclosure has structure 31. In yet another embodiment, the compound of the present disclosure has structure 32.

[0069] In some embodiments, R and R10 is alkyl and R 11 and R 12 together with the atoms to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring. [ka] In yet another embodiment, the compound of the present disclosure has structure 33. In yet another embodiment, the compound of the present disclosure has structure 34. In yet another embodiment, the compound of the present disclosure has structure 35. In yet another embodiment, the compound of the present disclosure has structure 36.

[0070] In some embodiments, R and R 10 together with the atoms to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring, and R 11 and R 12 is -H. In another embodiment, the structure: [ka] In yet another embodiment, the compound of the present disclosure has structure 37. In yet another embodiment, the compound of the present disclosure has structure 38.

[0071] In some embodiments, R 11 and R 12 together with the atoms to which they are attached form a saturated substituted pyrrolidinyl-1-yl ring, and R 13 and R 14 together with the atoms to which they are attached form a saturated substituted pyrrolidinyl-1-yl ring. [ka] In yet another embodiment, the compound of the present disclosure has structure 75. In yet another embodiment, the compound of the present disclosure has structure 76. In yet another embodiment, the compound of the present disclosure has structure 82. In yet another embodiment, the compound of the present disclosure has structure 84.

[0072] In some embodiments, the compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and R 15 is H, alkyl, or halo; R 16 Ha-NR 19 R 20 and;R 17 Ha-NR 21 R 22 and;R 18 is -H, alkyl, or halo; R 19 and R 20 are alkyl or together with the atom to which they are attached form a saturated pyrrolidinyl-1-yl ring, a saturated substituted pyrrolidinyl-1-yl ring, an unsaturated pyrrolidinyl-1-yl ring, an unsaturated substituted pyrrolidinyl-1-yl ring, a saturated piperazin-1-yl ring, a saturated substituted piperazin-1-yl ring, an unsaturated piperazin-1-yl ring, or an unsaturated substituted piperazin-1-yl ring; R 21 and R 22 are alkyl or together with the atom to which they are attached form a saturated pyrrolidinyl-1-yl ring, a saturated substituted pyrrolidinyl-1-yl ring, an unsaturated pyrrolidinyl-1-yl ring, an unsaturated substituted pyrrolidinyl-1-yl ring, a saturated piperazin-1-yl ring, a saturated substituted piperazin-1-yl ring, an unsaturated piperazin-1-yl ring, or an unsaturated substituted piperazin-1-yl ring; and X- is a pharmaceutically acceptable salt; provided that the compound of formula (II) is [ka] (R 23 and R 24 are —CH2F, F, Cl, or C2H5), or [ka] No.

[0073] In some embodiments, R 19 and R 20 form a saturated pyrrolidinyl-1-yl ring together with the atoms to which they are attached, and R 21 and R 22 together with the atoms to which they are attached form a saturated pyrrolidinyl-1-yl ring. [ka] In yet another embodiment, compounds of the present disclosure have structure 39. In yet another embodiment, compounds of the present disclosure have structure 40. In yet another embodiment, compounds of the present disclosure have structure 41. In yet another embodiment, compounds of the present disclosure have structure 42. In yet another embodiment, compounds of the present disclosure have structure 43. In yet another embodiment, compounds of the present disclosure have structure 44. In yet another embodiment, compounds of the present disclosure have structure 45. In yet another embodiment, compounds of the present disclosure have structure 46.

[0074] In some embodiments, R 19 and R 20 together with the atoms to which they are attached form a saturated substituted pyrrolidinyl-1-yl ring, and R 21 and R 22 together with the atoms to which they are attached form a saturated substituted pyrrolidinyl-1-yl ring. [ka] In yet another embodiment, compounds of the present disclosure have structure 47. In yet another embodiment, compounds of the present disclosure have structure 48. In yet another embodiment, compounds of the present disclosure have structure 49. In yet another embodiment, compounds of the present disclosure have structure 50. In yet another embodiment, compounds of the present disclosure have structure 51. In yet another embodiment, compounds of the present disclosure have structure 52. In yet another embodiment, compounds of the present disclosure have structure 53. In yet another embodiment, compounds of the present disclosure have structure 54.

[0075] In some embodiments, R 19 and R 20 form a saturated pyrrolidinyl-1-yl ring together with the atoms to which they are attached, and R 21 and R 22 together with the atoms to which they are attached form a saturated substituted pyrrolidinyl-1-yl ring. [ka] In yet another embodiment, the compound of the present disclosure has structure 55. In yet another embodiment, the compound of the present disclosure has structure 56. In yet another embodiment, the compound of the present disclosure has structure 57. In yet another embodiment, the compound of the present disclosure has structure 58.

[0076] In some embodiments, R 19 and R 20 is alkyl and R 21 and R 22 is alkyl. In another aspect, the structure: [ka] In yet another embodiment, the compound of the present disclosure has structure 59. In yet another embodiment, the compound of the present disclosure has structure 60.

[0077] In some embodiments, R 19 and R 20together with the atoms to which they are attached form an unsaturated substituted pyrrolidinyl-1-yl ring, and R 21 and R 22 together with the atoms to which they are attached form an unsaturated substituted pyrrolidinyl-1-yl ring. [ka] Compounds having the formula:

[0078] In some embodiments, R 19 and R 20 together with the atoms to which they are attached form a saturated piperazin-1-yl, and R 21 and R 22 together with the atoms to which they are attached form a saturated piperazin-1-yl ring. [ka] Compounds having the formula:

[0079] Exemplary compounds are shown in Table 1 below.

[0080] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

[0081] The above compounds can be prepared by well known procedures, some of which are exemplified in the experimental section.

[0082] Compositions and Methods of Administration The compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein, which are useful for preventing, treating, or ameliorating one or more symptoms of the diseases or disorders described herein, and a vehicle.Vehicles suitable for administering the compounds provided herein include any carrier known to those skilled in the art to be suitable for a particular administration method.In addition, the compounds may be formulated as the only active ingredient in the composition, or may be combined with other active ingredients.

[0083] Any administration method may be used to administer the compounds of the present disclosure. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, intranasal administration, topical administration, intrauterine administration, intrahepatic administration, intravaginal administration, eye drop administration, buccal administration, intraocular administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injection administration such as intravenous administration, intracerebrospinal fluid administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration may also be via the hepatic artery or hepatic portal vein (HPV). The disclosed compounds, disclosed therapeutic agents, disclosed pharmaceutical compositions, or combinations thereof may be administered to the CNS (e.g., intraparenchymal administration, intraventricular administration, intracisternal administration, intrathecal (lumbar) administration, delivery to deep gray matter, convection-enhanced delivery to deep gray matter) or directly to the PNS. Administration may be continuous or intermittent.

[0084] Compositions contain one or more compounds provided herein.In some embodiments, compounds are prepared into suitable formulations, such as solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained-release preparation or elixir for oral administration, or sterile solution or suspension for parenteral administration, and suitable formulations for topical administration, transdermal administration, and oral inhalation by nebulizer, pressurized metered dose inhaler and dry powder inhaler.In some embodiments, the above-mentioned compounds are prepared into compositions using well-known techniques and procedures in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0085] In the composition, an effective concentration of one or more compounds or their derivatives is mixed with a suitable vehicle.As described above, the compound can be derivatized as the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate, or prodrug before formulation.The concentration of the compound in the composition is effective to deliver an amount that, when administered, treats, prevents, or alleviates one or more symptoms of the disease or disorder described herein.In some embodiments, the composition is formulated for single administration.To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in the selected vehicle at an effective concentration that alleviates, prevents, or alleviates one or more symptoms of the condition to be treated.

[0086] The active compound is placed 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 human doses can be extrapolated therefrom.The human dose is then usually fine-tuned in clinical trials and titrated according to response.

[0087] The concentration of the active compound in the composition depends 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, an amount sufficient to ameliorate one or more symptoms of the diseases or disorders described herein is delivered.

[0088] If the solubility of the compound is insufficient, methods for solubilizing the compound can be used, such as the use of liposomes, prodrugs, complexation / chelating, nanoparticles, or emulsions, or tertiary template methods. Such methods 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), the use of surfactants or surface modifiers such as TWEEN®, the use of complexing agents such as cyclodextrins, or dissolution by enhanced ionization (i.e., dissolution in aqueous sodium bicarbonate). Compound derivatives, such as prodrugs of the compound, can also be used to formulate effective compositions.

[0089] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on several factors, such as the intended method of administration and the solubility of the compound in the selected vehicle. The effective concentration sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated may be empirically determined.

[0090] For administration to humans and animals, the compositions are provided in dosage forms appropriate for the indication, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / biodegradable strips, tablets or capsules, powders, granules, lozenges, lotions, ointments, suppositories, fast-dissolving tablets, transdermal application devices / formulations such as transdermal patches, sterile injectable solutions or suspensions, and oral solutions or suspensions, as well as oil-in-water emulsions containing an appropriate amount of the compound or its derivatives. In some embodiments, the therapeutically active compound or its derivatives are formulated and administered in unit-dosage or multiple-dosage forms. As used herein, unit-dosage form refers to a physically discrete unit suitable for human and animal subjects, packaged individually as is well known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, along with the necessary vehicle. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets or capsules. Unit-dosage forms can be administered in separate or multiple doses. A multiple-dosage form consists of a plurality of identical unit-dosage forms packaged in a single container for separate administration in unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple-dosage form is a plurality of unit-dosage forms that are not segregated within the package.

[0091] Liquid compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active compound and any auxiliary agents defined above in a vehicle such as water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a solution or suspension, colloidal dispersion, emulsion, or liposomal preparation. If necessary, the composition to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, solubilizing agents, pH buffering agents, and the like, for example, acetate salts, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other similar agents.

[0092] Actual methods for preparing such dosage forms will be well known or apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions.

[0093] Dosage forms or compositions can be prepared containing 0.005 to 100% of the active ingredient, with the remainder being made up with a vehicle or carrier. Methods for preparing these compositions are well known to those skilled in the art. The contemplated compositions may contain 0.001 to 100% of the active ingredient, in one embodiment 0.1 to 95%, and in another embodiment 0.4 to 10%.

[0094] In certain embodiments, the composition is a lactose-free composition containing excipients well known in the art, such as those listed in the United States Pharmacopoeia 25-NF20, 2002. Generally, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in compatible amounts. A specific lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0095] In addition, because water can accelerate the decomposition of some compounds, anhydrous compositions and dosage forms containing active ingredients are provided.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 long-term formulation stability.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.Therefore, the effect of water on formulations can be very important, since moisture and / or humidity usually occur during the production, handling, packaging, storage, transportation, and use of formulations.

[0096] Anhydrous compositions and dosage forms provided herein can be prepared under low moisture or low humidity conditions using anhydrous or low moisture containing ingredients.

[0097] Anhydrous compositions should be prepared and stored so as to maintain their anhydrous nature.Therefore, anhydrous compositions are generally packaged using materials known to prevent exposure to water, so that they can be included in suitable formulary kits.Suitable packaging examples include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0098] Oral dosage forms can be 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 can 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 forms in combination with other ingredients known to those skilled in the art.

[0099] In certain embodiments, the formulation is in a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, troches, etc. may contain one or more of the following ingredients or compounds of similar nature: binders; lubricants; diluents; flow agents; disintegrants; colorants; sweeteners; flavoring agents; wetting agents; enteric coatings; film coatings; and release-modifying agents. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, tragacanth gum, glucose solution, arabic mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidone, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lysine, and stearic acid. Diluents include 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 croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, any of the approved water-soluble FD&C dyes, mixtures thereof, and water-insoluble FD&C dyes suspended in alumina hydrate, as well as modern coloring agents or anti-counterfeiting dyes / opacifiers 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 that provide a pleasant sensation or mask unpleasant tastes, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Enteric-coatings include fatty acids, oils, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Release-modifying agents include polymers and cellulose esters such as the Eudragit® series.

[0100] The compounds or their derivatives can be provided in a composition that protects them 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.

[0101] When the dosage unit is a capsule, in addition to the above-mentioned materials, it can contain liquid carriers such as fatty oils.In addition, the dosage unit can contain various other materials that modify the physical form of dosage form, such as sugar coating and other enteric agents.The compound can also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc.Syrups can contain sucrose as a sweetener, certain preservatives, dyes, colorings, and flavorings in addition to active compounds.

[0102] The active ingredients may be mixed with other active substances that do not impair the desired action, or with substances that complement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a derivative thereof. The active ingredient may be present in a high concentration of up to about 98% by weight.

[0103] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to control or sustain dissolution of the active ingredient, and thus may be coated with conventional enteric coatings such as phenylsalicylate, waxes, and cellulose acetate phthalate.

[0104] 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.

[0105] Elixirs are clear, sweetened, hydroalcoholic preparations. The vehicle used in elixirs contains a solvent. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain a preservative. Emulsions are two-phase systems in which one liquid is dispersed in the form of small droplets in another liquid. The carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules to be reconstituted into a liquid oral dosage form include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules to be reconstituted into a liquid oral dosage form include organic acids and a carbon dioxide source. Colorings and flavorings are used in all of the above dosage forms.

[0106] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and gum arabic. Sweetening agents include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Humectants 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 water-soluble FD&C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds that produce a pleasant taste sensation.

[0107] For solid dosage forms, in some embodiments, the solution or suspension, for example, in propylene carbonate, vegetable oil, or triglyceride, is 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, for example, in polyethylene glycol, can be sufficiently diluted with a liquid vehicle such as water so that it can be easily measured at the time of administration.

[0108] Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other similar carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those described in U.S. Patents RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, a compound provided herein, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, dialkylated mono- or polyalkylene glycols, including but not limited to, 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, but not limited to, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0109] Other formulations include, but are not limited to, aqueous alcohol solutions containing acetals. The alcohols used in these formulations are any water-miscible solvents containing one or more hydroxyl 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.

[0110] Parenteral administration, in some embodiments, is characterized by subcutaneous, intramuscular, or intravenous injection, and is also contemplated herein. Injectables can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable additives include, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if necessary, the administered composition may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other similar agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0111] Provision 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 of 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 acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which matrix is ​​surrounded by an outer highly The composition is enveloped in 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 and 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 the polymeric membrane is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a step that controls the release rate. The content of the active compound in such parenteral compositions largely depends on their properties, the activity of the compound, and the needs of the subject.

[0112] Parenteral administration of the composition includes intravenous administration, subcutaneous administration, and intramuscular administration.Preparations for parenteral administration include sterile solution for injection, sterile dry soluble product such as freeze-dried powder that is mixed with a solvent immediately before use, including tablets for subcutaneous injection, sterile suspension for injection, sterile dry insoluble product that is mixed with a vehicle immediately before use, and sterile emulsion.The solution can be either aqueous or non-aqueous.

[0113] For intravenous administration, suitable carriers include saline or phosphate buffered saline (PBS) and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0114] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, external anesthetics, suspending agents, dispersing agents, emulsifying agents, sequestering or chelating agents, and other substances.

[0115] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, and 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 multidose containers require the addition of bacteriostatic or antifungal concentrations of antibacterial agents, such as phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, p-hydroxybenzoic acid methyl and propyl esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. 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. Emulsifiers include polysorbate 80 (Tween® 80). Sequestering or chelating agents for metal ions include EDTA. Carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol as water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid as pH adjusters.

[0116] The concentration of the compound is adjusted to provide an effective amount to produce the desired pharmacological effect upon injection, and the exact dose depends on the age, weight, body surface area, and condition of the patient or animal, as is well known in the art.

[0117] Unit dosage 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.

[0118] For example, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective method of administration. In another embodiment, a sterile aqueous or oily solution or suspension containing the active material is injected as needed to achieve the desired pharmacological effect.

[0119] Injectables are designed for local and systemic administration. In some embodiments, a therapeutically effective dose is formulated to contain at least about 0.01% to about 90% or more by weight of the active compound relative to the tissue to be treated, and in certain embodiments, greater than 0.1% by weight.

[0120] The compound can be suspended in a suitable form, such as micronized, or derivatized to produce a more soluble active product or prodrug. The form of the resulting mixture depends on several factors, such as the intended method of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to improve the symptoms of the condition and can be empirically determined.

[0121] The active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. See, for example, U.S. Pat. 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, Nos. 6,972,891, 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. Such dosage forms can achieve delayed 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. Suitable controlled-release formulations known to those of skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0122] All controlled-release products share a common goal of improving drug therapy over non-controlled-release products. Ideally, the use of an optimally designed controlled-release formulation in therapy is characterized by utilizing the minimum amount of drug to treat or control a disease in the minimum amount of time. Advantages of controlled-release formulations include extended drug activity, reduced dosing frequency, and improved patient compliance. Additionally, controlled-release formulations can be used to affect properties such as time to onset of action and blood levels, which may affect the occurrence of side effects (e.g., adverse effects).

[0123] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that quickly produces the desired therapeutic effect, followed by a gradual and continuous release of another amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant drug level in the body, the drug must be released from the dosage at a rate that will replace the amount of drug being metabolized or excreted from the body. Controlled-release of an active ingredient can be stimulated by a variety of conditions, including, but not limited to, physiological conditions and compounds such as pH, temperature, enzymes, and water.

[0124] In certain embodiments, the agent may be administered using methods such as intravenous infusion, an implantable osmotic pump, a transdermal patch, or liposomes. 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, thereby 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 into the vicinity of a site of inappropriate immune activation or a tumor in a subject. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).The active ingredient can be 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 acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which matrix is ​​surrounded by an outer polymeric membrane, e.g., a polymeric membrane. The active ingredient is enveloped in polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and 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 polymer membrane is insoluble in body fluids.Then, the active ingredient diffuses through the outer polymer membrane in a step that controls the release rate.The content of the active ingredient in such parenteral compositions largely depends on their properties, the activity of the compound, and the needs of the patient.

[0125] Lyophilized powders are also of interest herein and can be reconstituted and administered as solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0126] Sterile lyophilized powders are prepared by dissolving the compounds provided herein or their derivatives in a suitable solvent. The solvent may contain excipients to improve the pharmacological properties, such as stability, of the powder or a reconstituted solution prepared from the powder. Possible excipients include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the excipient is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain a buffer, such as citrate, sodium phosphate, potassium phosphate, or other similar buffers known to those skilled in the art, at a near-neutral pH. The solution is then sterilized and lyophilized under standard conditions known to those skilled 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 can be stored under appropriate conditions, such as at about 4°C to room temperature.

[0127] The lyophilized powder is reconstituted with water for injection to provide a formulation for parenteral administration. To reconstitute, the lyophilized powder is added to a suitable carrier, such as sterile water. The exact amount will depend on the compound selected and can be determined empirically.

[0128] Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, wash, spray, suppository, bandage, skin patch, or other formulation suitable for topical administration.

[0129] Compounds or their derivatives can be formulated as aerosols for topical application, such as by inhalation (see, for example, U.S. Pat. No. 4,044,126, U.S. Pat. No. 4,414,209 and U.S. Pat. No. 4,364,923, which describe aerosols for delivering steroids useful for treating inflammatory diseases, particularly asthma). These formulations for respiratory administration can be in the form of aerosols or solutions for nebulizers, or in the form of fine powders for inhalation, alone or in combination with inert carriers such as lactose. In such cases, the particles of the formulation have a mass median geometric diameter of less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0130] 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. For both metered dose inhalers and dry powder inhalers, a crystalline form of the compound or derivative is preferred as the physical form of the drug to provide longer product stability.

[0131] In addition to micronization methods well known to those skilled in the art, supercritical fluid processing can be used to produce crystalline particles of a compound or derivative. This process offers significant advantages in producing 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). The controlled particle size of the microcrystals can be selected so that the majority of the compound or derivative is deposited in the lungs. In some embodiments, the mass median aerodynamic diameter of these particles is about 0.1 to about 10 microns, in other embodiments about 1 to about 5 microns, and in still other embodiments about 1.2 to about 3 microns.

[0132] The 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. The ratios are also selected so that the product suspension does not undergo undesirable settling or creaming (which can cause irreversible clumping), but instead forms a loosely cohesive system that disperses easily upon shaking. A loosely cohesive system is considered to provide optimal stability in pMDI containers. Due to this formulation property, the formulation is ethanol-free and surfactant / stabilizer-free.

[0133] Compound can be formulated for topical or external application, such as application to mucous membranes such as skin and eyes in gel, cream and lotion form, and application to eyes, or intracisternal or intrathecal application.External administration is intended for transdermal delivery, and administration to eyes or mucous membranes, or for inhalation therapy.Nasal drops of active compound alone or combined with other excipients can also be administered.

[0134] For nasal administration, the formulation may contain the esterified phosphonate compound dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol application. The carrier may contain absorption enhancers such as propylene glycol, surfactants, lecithin or cyclodextrin, or solubilizing or suspending agents such as preservatives.

[0135] Solutions, particularly those intended for ophthalmic administration, may be formulated as 0.01-10% isotonic solutions at a pH of about 5-7.4 with appropriate salts.

[0136] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein.

[0137] Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art and are disclosed, for example, 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.

[0138] For example, dosage forms for rectal administration include rectal suppositories, capsules, and tablets intended for systemic administration. As used herein, a rectal suppository refers to a solid body inserted into the rectum that melts or softens at body temperature to release 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 various bases may also be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared by compression or molding. In one embodiment, a rectal suppository weighs approximately 2 to 3 g. Tablets and capsules for rectal administration are manufactured using materials and methods similar to those used for oral administration.

[0139] The compounds provided herein or their derivatives can also be formulated to target specific tissues, receptors, and other body regions of the subject to be treated.Many of these targeting methods are well known to those skilled in the art.All of these targeting methods are contemplated herein for use in the present compositions.Non-limiting examples of targeting methods are described in, for example, U.S. Patent No. 6,316,652, U.S. Patent No. 6,274,552, U.S. Patent No. 6,271,359, U.S. Patent No. 6,253,872, U.S. Patent No. 6,139,865, U.S. Patent No. 6,131,570, U.S. Patent No. 6,120,751, U.S. Patent No. 6,071,495, U.S. Patent No. 6,060,000. See U.S. Patent Nos. 82, 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.

[0140] In some embodiments, liposome suspensions, including tissue-targeted liposomes such as tumor-targeted liposomes, may also be suitable as carriers. These may be prepared according to methods well known to those skilled in the art. For example, liposome formulations may be prepared according to the method described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLVs), may be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) inside a flask. A solution of a compound provided herein dissolved in phosphate-buffered saline (PBS) without divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, pelleted by centrifugation, and then resuspended in PBS.

[0141] The compound or derivative may be packaged as an article of manufacture comprising packaging material, a compound provided herein or a derivative thereof in 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.

[0142] The products provided herein include packaging materials. Packaging materials used in packaged products are well known to those skilled in the art. For example, see U.S. Patent No. 5,323,907, U.S. Patent No. 5,052,558 and U.S. Patent No. 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 material suitable for the selected formulation and intended administration method and treatment. A wide range of formulations of the compounds and compositions provided herein are contemplated for various treatments for any disease or disorder described herein.

[0143] Dosage When used for the treatment or prevention of infectious diseases, the compounds provided herein or their pharmaceutical compositions are administered or applied in a therapeutically effective amount.In human treatment, the doctor will determine the most appropriate dosage regimen according to the preventive or therapeutic treatment, and according to the age, weight, stage of disease and other specific factors of the patient to be treated.The amount of active ingredient in the formulations provided herein that is effective for the prevention or treatment of infectious diseases varies depending on the nature and severity of the disease or condition and the administration route of the active ingredient.Frequency and dosage also vary depending on the treatment (e.g., therapeutic or prophylactic agent) to be administered, the severity of infection, the administration route, and the patient's age, weight, response and medical history, which are specific to each patient.

[0144] Exemplary dosages of the formulations include milligram or microgram amounts of active compound per kilogram 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).

[0145] In some embodiments, a therapeutically effective dosage should result 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 should provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. 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, and in some embodiments, about 10 mg to about 500 mg of the active ingredient or combination of essential ingredients per unit dosage form. Suitable, non-limiting examples of dosages for compounds according to the present disclosure can be about 1 ng / kg to about 5000 mg / kg. In some embodiments, the dosage can range from 0.0001 mg to 0.0010 mg / kg / day, 0.0010 mg to 0.010 mg / kg / day, 0.010 mg to 0.10 mg / kg / day, 0.10 mg to 1.0 mg / kg / day, 1.00 mg to about 200 mg / kg / day, or 200 mg to about 5000 mg / kg / day. For example, the dosage can be from about 1 mg to about 100 mg / kg / day, e.g., 2 mg to 10 mg / kg / day, 10 mg to 50 mg / kg / day, or 50 mg to 100 mg / kg / day.Dosage is 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 , 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, 1000m g / 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 dosage 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 dosage and administration interval can be individually adjusted to ensure that the plasma concentration of the compound(s) and / or active metabolite(s) is sufficient to maintain therapeutic or prophylactic effects. 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 on the method of administration, the specific indication being treated, and the judgment of the prescribing physician. In cases of selective uptake, such as local administration or topical administration, the effective local concentration of the compound(s) and / or active metabolite(s) may not be related to plasma concentration. Those skilled in the art can optimize the effective dosage without undue experimentation.

[0146] The active ingredient may be administered at once or divided into several small doses to be administered at intervals. It is understood that the exact dosage and duration of treatment depend on the disease to be 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 also be noted that concentrations and dosages may vary depending on the severity of the condition to be alleviated. Furthermore, it should be understood that for any individual subject, specific dosing regimens should be adjusted over time based on the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0147] As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredient that exceed the ranges disclosed herein. Furthermore, it should be noted that the clinician or treating physician will understand how and when to interrupt, adjust, or terminate treatment in relation to the subject's response.

[0148] For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays, e.g., IC determined in cell culture, animal models, or 50 (i.e., the concentration of test compound that is lethal to 50% of the cell cultures) or IC determined in cell culture 100 A dose can be formulated to achieve a circulating concentration range that includes the compound (i.e., the concentration of the compound that is lethal to 100% of the cell cultures). Such information can be used to more accurately determine useful doses in humans.

[0149] Initial dosages may be estimated from in vivo data (e.g., animal models) using techniques well known in the art, and those skilled in the art can readily optimize human administration based on animal data.

[0150] Alternatively, the IC of certain compounds disclosed herein 50 , MIC, and / or I 100The initial dosage can be determined from the dosages of known drugs by comparing the initial dose of the known drug with that of the known drug and adjusting the initial dosage accordingly. From these initial values, the optimal dosage can be obtained by routine optimization.

[0151] In cases of local administration or selective uptake, the effective local concentration of the compound used may not be related to plasma concentration. One skilled in the art can optimize the therapeutically effective local dosage without undue experimentation.

[0152] Ideally, a therapeutically effective dose of the compounds described herein will provide a therapeutic effect without causing substantial toxicity. Compound toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 (the dose lethal to 50% of the population) or LD 100 The therapeutic index can be determined by determining the dose (lethal dose in 100% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds with a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a non-toxic dosage range for use in subjects. The dosage of the compounds described herein preferably lies within a blood concentration range that includes the effective dose with little or no toxicity. Dosages can vary within this range depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (see, for example, Fingl et al., In: The Pharmacological Basis of Therapeutics, 1975, Ch. 1, p. 1).

[0153] Treatment may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated, and administration may occur 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.

[0154] Methods of Use of the Compounds and Compositions Methods are provided for treating, preventing, or ameliorating symptoms of medical disorders such as bacterial infections and diseases, including gram-positive bacterial infections, skin infections, endocarditis, osteomyelitis, or pneumonia, HIV infection, cancer, Alzheimer's disease, and coronavirus infections using compounds of structural formula (I): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1 is H, -NR7R8, -OR9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; and R2 is -H, -NR 10 R 11 ,or [ka] and R3 is -H, halo, -OR 12 , alkyl, or substituted alkyl; R4 is -H, -NR 13 R 14 ,or [ka] and R5 is -H, halo, -OR 15 , alkyl, or substituted alkyl; R6 is -H, -NR 16 R 17 , -OR 18 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; R7 and R8 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R 10 and R 11are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R 16 and R 17 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, a substituted cycloheteroalkenyl ring, a bicycloheteroalkyl ring, a substituted bicycloheteroalkyl ring, a spirocycloheteroalkyl ring, or a substituted spirocycloheteroalkyl ring; R, R 12 , R 15 , and R 18 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted aryl, heteroalkyl, or substituted heteroalkyl; and X- is a pharmaceutically acceptable salt; with the proviso that when R2 and R4 together form a C5-C7 cycloheteroalkyl ring or a C5-C7 substituted cycloheteroalkyl ring, when R6 is t-butyl, R1 is not H, and when R6 is H, except when R5 is -CH2Boc or -OMe, R1 is not H or methyl, and when R6 is ethyl, R1 is not methyl or ethyl; with the proviso that R 10 and R 11 or R 13 and R 14 When any of R and R forms a C5-C7 cycloheteroalkyl ring or a C5-C7 substituted cycloheteroalkyl ring, when R and R are independently -H, alkyl, alkenyl, or haloalkyl, R 10 , R 11 , R 13 , or R 14is alkyl or substituted alkyl; with the proviso that when one of R2 and R4 is -H, then at least one of R1 and R6 is not -H; and with the proviso that when R2 is -NR 10 R 11 and R4 is -NR 13 R 14 and R 10 , R 11 , R 13 , or R 14 When either of R is substituted alkyl, 10 , R 11 , R 13 , or R 14 -OR 19 , -SR 20 , or -NR 21 is not replaced by R 19 , R 20 , or R 21 is independently alkyl, alkenyl, or aryl.

[0155] In practicing the method, a therapeutically effective amount of a compound or composition described herein is administered to a patient having the disorder or condition.

[0156] The compounds provided herein can be used to treat or prevent bacterial infections caused by Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, Enterococcus faecalis, Staphylococcus epidermidis, Group A hemolytic streptococcus, Streptococcus pneumoniae, or Clostridium difficile. The bacterial strains can be antibiotic-susceptible or antibiotic-resistant. Resistant strains include, for example, MRSA ATCC43300, macrolide-resistant Staphylococcus aureus, vancomycin-resistant E. faecium, ciprofloxacin-resistant E. faecium, tetracycline-resistant Staphylococcus aureus, MDR Staphylococcus aureus, or any ampicillin-, chloramphenicol-, or kanamycin-resistant strain. The bacteria can be Gram-positive or Gram-negative.

[0157] Examples of bacterial infections include, but are not limited to, surgical site infections, urinary tract infections, bloodstream infections (sepsis), pneumonia (hospital-acquired or community-acquired), diabetic foot infections, and skin infections such as cellulitis, boils, abscesses, styes, carbuncles, and impetigo.

[0158] Treatment or prevention of bacterial infection can include administering a compound of the present disclosure to a subject having an infection, symptoms of an infection, or predisposed to such an infection, for the purpose of treating, curing, alleviating, mitigating, altering, correcting, ameliorating, or affecting the infection, symptoms of the infection, or predisposition to the infection. Treatment can result in the death or inactivation of bacteria. Treatment can inhibit biofilm formation or reduce the bacterial load in the subject's body.

[0159] The present disclosure also provides a method for treating HIV infection and / or AIDS. The HIV infection may be HIV-1 infection or HIV-2 infection. The HIV infection may be subtype A, B, C, D, F, G, H, J, K, M, N, O, or P strain.

[0160] In some embodiments, treatment of HIV infection may be a reduction in the severity or duration of one or more HIV- or AIDS-related symptoms, suppression, reduction, amelioration, or otherwise reducing the severity of HIV infection, delaying the onset of AIDS, and / or inactivating HIV. Signs or symptoms of the early stage of HIV infection include fever, swollen lymph nodes, sore throat, rash, muscle pain, fatigue, stomatitis, and esophageal sores. AIDS, the final stage of HIV infection, may present with symptoms of various opportunistic infections, as is well known in the art. Symptoms of this stage may include unexplained weight loss, recurrent respiratory infections, prostatitis, skin rash, and mouth ulcers.

[0161] In some embodiments, the present disclosure provides a method for treating or preventing cancer. The method comprises administering to a subject in need thereof one or more of the compounds of the present disclosure in a therapeutically effective amount. As those skilled in the art will recognize, the term "cancer" 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 early or late stage. Non-limiting examples of neoplasms or cancers that may be treated include acute lymphocytic 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, visual pathway and hypothalamic glial tumor), breast cancer, bronchial adenoma / carcinoid, Burkitt's disease Lymphoma, 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 the Ewing's tumor family, extracranial germ cell tumor (childhood), extragonadal germ cell tumor, extrahepatic bile duct cancer, eye Cancer (intraocular melanoma, retinoblastoma), gallbladder cancer, stomach 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 hypothalamic), gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma (pediatric), intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, kidney cancer (renal cell ), laryngeal cancer, leukemia (acute lymphoblastic, 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), bone malignant fibrous histiocytoma / osteosarcoma, medulloblastoma (pediatric), melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma (adult malignant, pediatric),Metastatic squamous cell neck cancer of unknown primary, oral cavity cancer, multiple endocrine neoplasia syndrome (pediatric), multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, myeloid leukemia (chronic), myeloid leukemia (acute adult, acute childhood), multiple myeloma, myeloproliferative disorders (chronic), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma / bone malignancy Fibrous histiocytoma, ovarian cancer, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, pancreatic cancer (islet cell), paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma and supratentorial primitive neuroectodermal tumor (childhood), pituitary adenoma, plasma cell neoplasm, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell Cancer (renal cancer), renal pelvis and ureter transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma (childhood), salivary gland cancer, sarcoma (Ewing's family of tumors, Kaposi's, soft tissue, uterine), Sézary 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 neck cancer of unknown primary (metastatic), gastric cancer, supratentorial primitive neuroectodermal tumor (childhood), T-cell lymphoma (skin) ), testicular cancer, pharyngeal cancer, thymoma (childhood), thymoma and thymic carcinoma, thyroid cancer, thyroid cancer (childhood), transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor (gestational), unknown primary (adult, child), transitional cell carcinoma of the ureter and renal pelvis, urethral cancer, uterine cancer (endometrium), uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma (childhood), vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor (childhood).

[0162] In some embodiments, treating cancer can be inhibiting cancer progression and / or metastasis, inhibiting tumor volume increase, reducing tumor volume, inhibiting 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.

[0163] Combination therapy The compounds and compositions disclosed herein can also be used in combination with one or more other active ingredients.In certain embodiments, the compounds can be administered in combination or sequentially with another therapeutic agent.Such other therapeutic agents include those known to treat, prevent, or ameliorate one or more symptoms associated with various bacterial infections, including gram-positive bacterial infections, skin infections, endocarditis, osteomyelitis, or pneumonia, HIV infection, cancer, Alzheimer's disease, and coronavirus infection.Many of these therapeutic agents are well known in the art.

[0164] It should be understood that any suitable combination of the compounds and compositions provided herein with one or more of the above therapeutic agents, and optionally one or more additional pharmacologically active substances, is within the scope of the present disclosure. In some embodiments, the compounds and compositions provided herein are administered before or after one or more additional active ingredients.

[0165] Finally, it should be noted that there are alternative ways of implementing the invention. Accordingly, the present aspects are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details set forth herein, but may be modified within the scope of the appended claims and their equivalents.

[0166] All publications and patents cited herein are incorporated by reference in their entirety.

[0167] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0168] Scheme 1 shows the preparation of compound 1. [ka] Phenothiazine-5-ium tetraiodide hydrate (101) [ka]

[0169] A solution of phenothiazine (100) (4.98 g, 25 mmol) in anhydrous chloroform (50 mL) was stirred at 5 °C, and a solution of iodine (12.7 g, 50 mmol) in CHCl (250 mL) was added dropwise over 4 h. The resulting dark solution was stirred at 5 °C for an additional 3 h and monitored by TLC. After the disappearance of the starting material, the resulting precipitate was filtered, washed with copious amounts of chloroform, and dried under vacuum overnight to give a dark solid (101) (13.9 g, 74%).

[0170] Example 1: 3,7-di(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-N-yl)phenothiazinium iodide (1) [ka] A solution of phenothiazin-5-ium tetraiodide hydrate (101) (3.0 g, 4.0 mmol) in a mixture of acetonitrile / methanol (50 mL) and 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (1.11 g, 10 mmol) was stirred at room temperature for 1 h. The resulting mixture was concentrated to dryness and purified by reverse-phase flash chromatography using an acetonitrile / water gradient to give 3,7-di(6,6-dimethyl-3-azabicyclo[3.1.0]hexane-N-yl)phenothiazinium iodide (1) (1.2 g, 53%).

[0171] Scheme 2 shows the preparation of compound 30. [ka] 3-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-N-yl)phenothiazinium iodide (102) [ka]

[0172] A solution of phenothiazine-5-ium tetraiodide hydrate (1) (220 mg, 0.3 mmol), prepared as described above, in chloroform (5 mL) and 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (33 mg, 0.3 mmol) was stirred at room temperature for 1 h. The resulting mixture was concentrated to dryness to give compound 102, which was used without further purification.

[0173] Example 2: 3-[6,6-dimethyl-3-azabicyclo[3.1.0]hexan-N-yl]-7-(azepan-1-yl)phenothiazinium iodide (30) [ka] A solution of 3-[6,6-dimethyl-3-azabicyclo[3.1.0]hexan-N-yl]phenothiazin-5-ium triiodide (102) in methanol (5 mL) and azepane (100 mg, 1.0 mmol) was stirred at room temperature for 1 h. The resulting mixture was concentrated to dryness and purified by reverse-phase flash chromatography to give compound 30 (47 mg, 30%).

[0174] Scheme 3 shows an alternative preparation of compound 1. [ka] 3,7-Dibromo-10H-phenothiazine (103) [ka]

[0175] Phenothiazine (100) (1.23 g, 6.2 mmol) was dissolved in acetic acid (10 mL) and stirred at room temperature while a solution of bromine (2.96 g, 0.95 mL, 18.5 mmol) in acetic acid (50 mL) was added. The mixture was stirred overnight, and then NaSO (1.56 g, 12.4 mmol) and water (2 mL) were added. The mixture was stirred at room temperature for 3 hours and then poured into 100 mL of ice water containing NaOH (1.0 g, 25 mmol). The mixture was stirred overnight and then filtered to give compound 103 (1.62 g, 73%) as a light green solid. 3,7-Dibromo-10-Boc-phenothiazine (104) [ka]

[0176] 3,7-Dibromo-10H-phenothiazine (103) (1.6 g, 4.5 mmol) was suspended in AcN (20 mL), and BocO (2.94 g, 13.5 mmol) and DMAP (0.55 g, 4.5 mmol) were added. The mixture was heated to 50 °C. After 5 min, the starting material was dissolved in the solvent, and CO was removed to form a solid. After 1 h, the reaction mixture was cooled to room temperature, and the solid was filtered and dried in air to give compound 104 (1.65 g, 80%). 3,7-Di(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-N-yl)-10-Boc-phenothiazine (105) [ka]

[0177] To a stirred solution of 3,7-dibromo-10-Boc-phenothiazine (104) (1.7 g, 3.74 mmol) in xylene was added 20 mL of Pd(dba)2 (80 mg, 0.14 mmol), BINAP (70 mg, 0.11 mmol), sodium t-butoxide (1.8 g, 18.7 mmol), and 6,6-dimethyl-3-azabicyclo[3,1,0]hexane (2.1 g, 18.7 mmol). The mixture was refluxed for 24 h, then cooled, filtered, and the solvent removed. The residue was purified by flash chromatography (hexane-ethyl acetate) to give compound 105 (1.2 g, 63%).

[0178] Example 3: 3,7-di(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-N-yl)phenothiazin-5-ium trifluoroacetate (1) [ka] To a solution of 3,7-di(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-N-yl)-10-Boc-phenothiazine (1.2 g, 2.3 mmol) in dichloromethane (10 mL) was added TFA (4 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed, and the residue was purified by reverse-phase flash chromatography to give compound 1 (900 mg, 75%).

[0179] MS and HPLC data for compounds 1–150

[0180] The MS and HPLC data for compounds 1 to 150 are shown in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0181] Example 4: In vitro antibacterial activity (MIC assay) The minimum inhibitory concentrations (MICs) against susceptible Gram-positive bacteria, such as Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Acinetobacter baumannii ATCC 19606, Enterococcus faecalis ATCC 29212, Enterococcus faecium ATCC 700221, Staphylococcus epidermidis ATCC 14990, Group A Streptococcus ATCC 49399, Streptococcus pneumoniae ATCC 49619, and Clostridium difficile ATCC BAA18770, were determined by serial dilution in broth (Clinical Laboratory Standards Institute, Document M7-A73. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—7th Edition, Wayne, Pa. Clinical Laboratory Standards Institute, 2006).

[0182] In this method, aliquots of 10 mM stock test compound taken from an eight-step series of two-fold serial dilutions in 100% DMSO were added to wells of a microdilution plate. Test organisms were measured by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after addition to the wells was approximately 5 x 10, with or without compound. 5The concentrations of test compounds were adjusted to CFU / mL. After inoculation into microdilution plates, the plates were incubated at 37°C for 16–24 hours and bacterial growth was assessed. The MIC was defined as the lowest concentration of test compound that completely inhibited visible growth of the test organism or the reduction of the redox fluorescent dye resazurin. Bacterial growth in the wells converts resazurin to resorufin. Growth in wells containing test compounds was compared with growth in growth control wells (no test compound added) and wells containing a control drug (e.g., ciprofloxacin) on each plate. The results for Compound 1 are shown in Table 1 below. In vitro susceptibility testing of Compound 1 demonstrated potent activity against various Gram-positive bacteria with MICs ranging from 0.25–0.5 μg / mL, except for E. faecalis, where MIC was 2 μg / mL (Table 3).

[0183] [Table 3-1] [Table 3-2]

[0184] Example 5: Minimum Bactericidal Concentration Assay The minimal bactericidal activity of compounds against susceptible Gram-positive bacteria, including Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Enterococcus faecium ATCC 700221, Staphylococcus epidermidis ATCC 14990, Group A Streptococcus ATCC 49399, and Streptococcus pneumoniae ATCC 49619, was determined by determining bacterial viability on MIC plates. This test was performed in accordance with CLSI document M26-A, Wayne, PA: Clinical and Laboratory Standards Institute: 1999.

[0185] After MIC determination in broth culture systems under standard conditions, a measured aliquot of the growth medium can be quantitatively subcultured onto solid media to assess bactericidal activity. To calculate the degree of killing at each antibiotic concentration, plates are incubated under appropriate conditions, colonies are counted, and the results are compared to those of growth control wells. The minimum bactericidal concentration (MBC) is generally defined as the lowest concentration of test compound at which a 99.9% (3 log) or greater reduction in growth is observed compared to the initial inoculum. The minimum bactericidal concentration of compound 1 against all Gram-positive bacterial species did not exceed >2×MIC, indicating bactericidal activity (Table 4).

[0186] [Table 4]

[0187] The results as EC50 for selected compounds against E. coli are shown in Table 5 below.

[0188] [Table 5-1] [Table 5-2] [Table 5-3]

[0189] Example 6: Cross-resistance test The MICs of the compound were tested against resistant strains, including MRSA ATCC43300, macrolide-resistant S. aureus, vancomycin-resistant E. faecium, ciprofloxacin-resistant E. faecium, tetracycline-resistant S. aureus, MDR S. aureus, ampicillin-resistant strains, chloramphenicol-resistant strains, and kanamycin-resistant strains, using the methods described previously. Compound 1 demonstrated potent in vitro activity against bacteria resistant to different classes of antibiotics and MDR S. aureus, with MICs ranging from 0.25 to 0.5 μg / mL, confirming the absence of cross-resistance (Table 6).

[0190] [Table 6]

[0191] Example 7: One-stage resistance frequency The one-stage resistance frequency (FOR) was determined by Graham Bell and Craig MacLean, 2018, Trends Microbiol. 471-483. Staphylococcus aureus ATCC25923, MRSA ATCC43300, MDR Staphylococcus aureus ATCC BAA44, vancomycin-resistant E. faecium (VRE), macrolide-resistant Staphylococcus aureus ATCC BAA976, and ciprofloxacin-resistant E. faecium were cultured in medium containing 4x and 8x the test compounds. The resistance frequency was calculated from the colony formation rate on the medium relative to the number of inoculated bacteria. The frequency of resistance due to spontaneous mutation to one of the compounds 1 was determined in duplicate experiments. Bacterial suspensions (10 9 ~10 10 cfu / mL) were inoculated (100 μL) onto MH2 agar plates containing 4× and 8× the MIC of the test compound. Plates were incubated at 37°C in ambient air for 48 hours, after which colonies were counted. MIC determination using broth microdilution confirmed that isolated colonies represented resistant bacteria. Resistance was defined as an MIC equal to or greater than 4× the MIC of the parent strain. The frequency of one-step resistance to a given compound was calculated as the ratio of the number of confirmed resistant colonies to the total number of colonies obtained in the drug-free control group. The in vitro one-step resistance frequency of compound 1 against susceptible and resistant Gram-positive bacteria was 10 at 4× and 8× the MIC concentrations. -9 was less than (Table 7).

[0192] [Table 7]

[0193] Compound 1 showed potent activity against 17 S. aureus / MRSA isolates with an MIC50 value of 0.125 μg / mL (Table 6).

[0194] [Table 8]

[0195] Example 8: Time-kill kinetics In vitro time-kill kinetics testing of compound 1 against Staphylococcus aureus ATCCC25923, MRSA ATCC43300, and MDR Staphylococcus aureus BAA44 was performed according to CLSI M26-A procedure. Overnight cultures of the test strains were prepared and 5 × 10 5 The primary inoculum was obtained in cfu / mL. The primary inoculum was divided into 5 mL aliquots in 50 Falcon tubes. One was a no-antibiotic control (containing 4% DMSO), and the others were spiked with compound 1 (in DMSO) at 2x and 4x the MIC against the test strain, respectively. The cultures were incubated at 37°C for 24 hours. After shaking, 100–200 μL aliquots were taken from each culture at 0, 2, 4, 8, and 24 hours. Each aliquot was then serially diluted 10-fold with 1x PBS, and 50 μL was plated onto tryptic soy agar plates. After 24 hours of incubation at 37°C in ambient air, CFU were counted. At all incubation times, a ≥3 log reduction in the primary inoculum was observed, corresponding to a significant bactericidal effect. Time-kill kinetics data for compound 1 demonstrate that the compound is a bactericidal antimicrobial agent, killing both susceptible and resistant bacteria within 6 hours of treatment (Figures 1, 2, and 3).

[0196] Example 9: Sustained antibacterial effect The antibacterial effect was calculated using the formula PAE = TC (where T is the time (h) required for the number of viable bacteria to increase by at least 10-fold from the number of bacteria after washing in the presence of antibiotics, and C is the time required for the number of viable bacteria to increase by at least 10-fold from the number of bacteria after washing in the absence of antibiotics). The standard viable plate count method described in Craig and Gudmundsson, Antibiotics in Laboratory Medicine, Lorian, V. ed., was used.

[0197] The initial cell concentration in PAE was 1 × 10 5 ~5×10 5The MIC values ​​are expressed as cfu / mL. Liquid medium alone or with drug (1x or 2x MIC; tubes from step 8) was exposed to the medium at 37°C with 140 rpm shaking for 1 hour. After incubation, the drug was removed by centrifugation at 5000 rpm for 10 minutes at room temperature. The supernatant was discarded, and the microorganisms were resuspended in fresh drug-free medium at 37°C. 200 μL samples were taken immediately after washing (T=0), then at T=2, 4, 6, 8, and 24 hours. The samples were diluted 10-fold in sterile 1x PBS. A 10 μL aliquot of each dilution was plated on a separate TSA agar plate. The plates were incubated at 37°C for 24 hours. After incubation, colonies were counted and the results recorded. Data were plotted with time (h) on the x-axis and colony-forming units per mL (CFU / mL) on the y-axis. The antibacterial effect of Compound 1 after 2 hours of exposure was confirmed to be ≧8rs against MRSA and MDR (FIGS. 3 and 4).

[0198] Example 10: Minimal biofilm inhibition assay Biofilm susceptibility assays and antibiotic reduction calculations were performed as previously described (Pettit et al., Antimicrob Agents Chem 2005, 49:2612-17). Biofilm formation was induced by growing MRSA on 2% glucose-containing TSA at 37°C for 24 hours. After incubation, cell numbers were determined using the culture medium at 1–5 × 10 5 The CFU / mL was adjusted. In parallel, the test drugs / antibiotics were diluted 2-fold with DMSO / solvent and separately prepared in PCR dilution plates. 100 μL of the CFU-adjusted culture medium was added to a 96-well plate, leaving a control well containing medium alone. After adding the culture medium, 2-fold diluted compounds in 100% DMSO were added to the 96-well plate, and the plate was incubated at 37°C for an additional 16–20 hours to confirm the susceptibility of biofilm-forming MRSA to the test drugs / antibiotics. After the susceptibility incubation, resazurin was added to confirm the inhibition of biofilm-forming cells. Compound 1 can inhibit biofilm-forming MRSA at a concentration equivalent to 1× the MIC (Table 9).

[0199] [Table 9]

[0200] Example 11: Minimal Biofilm Removal Assay Biofilms were cultured in TSB with 2% glucose for 24 hours. Mature biofilms were treated with test compounds diluted in cation-adjusted Mueller-Hinton broth for 24 hours. Compound / antibiotic potency was determined by checking viability of compound / antibiotic-treated cultures in 96-well plates as described by Christensen et al., J Clin Microbiol 1985;22:996-1006.

[0201] Biofilms were formed in 96-well plates as described above, and the plates were washed with 1x PBS to remove nonbiofilm-forming / non-adherent cells. Fresh CAMHb was added to the biofilm plates, and aliquots of test compounds from an eight-step series of two-fold serial dilutions in 100% DMSO were added to the wells of the plates. The biofilm-containing plates were then incubated at 37°C for 24 hours to measure the compound's disinfection activity. After incubation, bacterial viability in the drug / antibiotic-treated biofilm plates was assessed by adding resazurin or counting CFUs. The lowest drug concentration at which no bacterial survival was observed was considered the MBEC concentration. Compound 1 demonstrated the ability to invade and kill S. aureus cells within biofilms under in vitro conditions, albeit at high concentrations. Its biofilm-dissolving activity was comparable to that of linezolid and superior to that of vancomycin (Figure 3).

[0202] Example 12: Activity against NorA efflux pump Overexpression of the NorA efflux pump was induced by continuous exposure of bacteria to sublethal concentrations of EtBr, as per the protocol of Isabel Couto et al. (J. Antimicrob. Chemother. 2008, 504-513). The MICs of compound 1 and ciprofloxacin were measured to test whether efflux pump overexpression affected the MICs. Overexpression of the NorA efflux pump did not affect the MIC of compound 1, but did affect the MIC of ciprofloxacin (Table 10).

[0203] [Table 10]

[0204] Example 13: Effect of serum on the antibacterial activity of Compound 1 The MICs in the presence of 20% and 40% FBS were determined by the broth microdilution method described above. The MICs in the presence of 20% and 40% serum were also determined to assess the effect of serum on compound activity. The results showed that the activity of compound 1 was reduced in the presence of serum. This is likely due to protein binding of compound 1 (Table 11).

[0205] [Table 11]

[0206] Example 14: Pharmacokinetics and Organ Exposure For mouse plasma pharmacokinetic analysis, a single intravenous dose of 3 mg / kg was administered to BALB / c mice. Blood samples were collected at 10 time points per dose (0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours post-dose). Four mice were sampled at each time point from the retro-orbital venous plexus. Peripheral blood sampling was used for all PK studies. Plasma concentrations of Compound 1 were measured using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) method. PK parameters were estimated using non-compartmental analysis. Organ exposure of Compound 1 was assessed by collecting various organs from mice after intravenous administration of 3 mg / kg. The plasma concentration-time curves of Compound 1 in mice after a single 3 mg / kg dose are shown in Figure 7. The pharmacokinetic parameters, AUC and C max is greater than 10×MIC, and T max The elimination time was 0.08 hours. The half-life of Compound 1 was 10 hours, the plasma clearance was 17 mL / min / kg, and the volume of distribution was 7 L / kg (Table 10). Distribution to the lungs and liver was particularly high. Meanwhile, distribution to the kidney and heart exceeded the MIC and was sufficient to achieve efficacy (Table 12).

[0207] [Table 12]

[0208] Dose: mg / kg, AUC: ng.h / mL, C max :ng / mL, T max :h, Kel:1 / h, Half-life:h, MRT:h, Clearance:mL / min / kg, V d : L / kg, Bioavailability: %. IV: Intravenous, IP: Intraperitoneal, PO: Oral.

[0209] [Table 13]

[0210] Example 15: Oncology Screening All compounds listed as active were tested by the Hennes method. Hits selected from the Hennes screening were subjected to additional anti-cancer testing.

[0211] Hennes To screen compounds for antitumor 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 screening is that an intrinsically toxic compound should kill cells, including Hennes-20 cells, regardless of density. However, compounds that selectively induce proliferation arrest will suppress cell growth and thereby exhibit cytotoxicity when seeded at low density, but will be nontoxic to cells seeded at high density, where cells approach confluence and cell viability assays are already near their maximum.

[0212] To perform the Hennes-20 screen, two 96-well plates were seeded simultaneously with Hennes-20 cells at 500 cells / well in one and 15,000 cells / well in the other. 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 following day, 10 μL of medium containing compound diluted in DMSO was added to each plate. 10 μL of medium containing DMSO alone was added to six wells of each plate. 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 AlamarBlue was added to each well. The wells were mixed five times and incubated at 37°C for 72 hours. The plates were then measured at 530 / 590°C.

[0213] The rationale for this screening is as follows: Hennes-20 cells do not undergo intrinsic apoptosis. Cells seeded at low density proliferate and approach confluence by 72 hours. Drugs that inhibit growth may mask their growth-inhibitory effects by inducing intrinsic apoptosis. However, in Hennes cell lines lacking intrinsic apoptosis, dose-dependence is maintained at low cell densities, making growth inhibition apparent. Because high-density cells are seeded near confluence, the difference between AlamarBlue cell viability measurements after 72 hours reflects the drug's ability to inhibit growth in low-density seeded cells. In high-density seeded cells, the decrease in AlamarBlue measurements relative to the vehicle control is due to intrinsic toxicity rather than growth inhibition, as the cells are already confluent. Therefore, compound-specific toxicity should be observed at both low and high cell densities, rather than preferentially in low-density plates, so a compound that appears toxic in low-density plates (low AlamarBlue readings after 72 hours) but not toxic in high-density plates (high AlamarBlue readings after 72 hours) must be inhibiting growth.

[0214] Results for selected compounds are shown in Table 15.

[0215] [Table 14-1] [Table 14-2] [Table 14-3]

[0216] Oncopanel A panel of human tumor cell lines (A172, BFTC-905, COR-L105, DB, FaDu, H9, Hs294T, MCF7, MDA MB436, MeWo, MHH-PREB-1, SJSA1-OSA, SW1353, and U2OS) was cultured in RPMI 1640, 10% FBS, 2 mM L-alanyl-L-glutamine, and 1 mM sodium pyruvate. Cells were seeded into 384-well plates and cultured at 37°C in a humidified atmosphere with 5% CO2. After 24 hours of culture, DMSO or compounds were added, and the plates were incubated for 3 days. Cells were then lysed using CellTiter-Glo (Promega), which generates a bioluminescent signal relative to ATP levels and is used to measure viable cells. Bioluminescence was measured 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 formula POC = (Ix / I0) * 100, where Ix is the signal intensity of all wells for a given treatment and I0 is the average intensity of untreated vehicle wells.

[0217] Lung cancer xenograft model A549 cells grown in RPMI-1640 medium were suspended in Matrigel in PBS. 0.1 mL of the cell suspension containing 1 × 10 cells was injected subcutaneously into the left flank of 6- to 8-week-old female nude mice (CrTac:Ncr-Foxn1nu). Thirty days after tumor formation, mice were randomly assigned to treatment groups. For the Compound 68 study, six mice received vehicle alone (10% DMSO, 10% propylene glycol, 80% sterile water) intraperitoneally once daily for 28 days, six mice received gemcitabine hydrochloride at 100 mg / kg intraperitoneally twice weekly, and six mice received Compound 68 at 10 mg / kg intraperitoneally once daily. Mice were weighed, and tumors were measured using digital calipers. Tumor volume was calculated using the formula: (L × W 2 ) / 2 (where L is the maximum diameter of the tumor and W is the minimum diameter). Statistical analysis was performed using Graph Pad Prism (Ver. 5.03). Statistical analysis of tumor growth inhibition between the control and treatment groups was performed using one-way analysis of variance followed by Dunnett's test. The results are shown in Figure 8.

[0218] Example 16: HIV screening MT-2 cells were preseeded in 100 μL of complete RPMI in a 96-well plate. PAV-951 was serially diluted in DMSO at multiple concentrations and then further diluted into infection medium prepared by diluting NL4-3 Rluc virus stock in complete RPMI to 400 IU / 100 μL. This was transferred to MT-2 cells at a final MOI of 0.02 and a final DMSO concentration of 1% at the infection site. For normalization and background measurements, DMSO alone was added instead of PAV-951 to one well, and medium alone was added to one well. The cells were cultured 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 the plates were cultured at 37°C for 1.5 hours. The plates were then read using a luminescence plate reader. Bioluminescence intensity was measured using a Synergy H1 BioTek plate reader. The mean and standard deviation of the virus titers observed under various treatment conditions were calculated using Microsoft Excel and graphed as percent inhibition in PAV-951-treated cells compared to untreated cells. Results for selected compounds are shown in Table 16.

[0219] [Table 15]

[0220] Example 17: Pox Screening All compounds that showed activity were tested against chickenpox, and selected hits were also screened against monkeypox.

[0221] chickenpox HeLa cells were infected with VACV-LUC virus at an MOI of 3 in the presence or absence of compound. After 2 hours, cells were lysed and luciferase activity was measured as a proxy for early gene expression. Values ​​for each treatment were plotted as a percentage of relative light units (RLU) compared to cells infected with virus alone. Results for selected compounds are shown in Table 17.

[0222] [Table 16]

[0223] monkeypox BSC-40 cells at 95% confluence in 24-well plates were infected with 100 pfu of MPXV Zaire-79 diluted in Eagle's minimum essential medium containing 2% fetal bovine serum and incubated at 37°C and 5% CO2 for 1 hour. The virus inoculum was removed and replaced with test compound at six half-log dilutions (0.1 mL / well). Cells were overlaid with growth medium containing 1% methylcellulose (1 mL / well). Culture and virus control cells received growth medium containing 1% methylcellulose. Three days after infection, when plaques appeared, cells were stained with crystal violet for 1 hour, washed with water, and allowed to dry overnight. The following day, plaques were counted and protection rates were determined by comparing wells containing virus alone with wells containing compound. Infected cells were stained with crystal violet, and viral plaques were counted.

[0224] Example 18: Rabies Screening BSR cells (a clone of baby hamster kidney (BHK) cells) were cultured in DMEM supplemented with 10% FBS (Atlanta Biologicals) at 37°C in a 5% CO2 incubator. The RABV ERA strain was obtained from the American Type Culture Collection and stored at the Centers for Disease Control and Prevention (CDC) in Atlanta. For virus titer determination and antiviral compound treatment, confluent BSR cells in a T75 flask were split and seeded into 24-well plates (Fisher Scientific). After 24 h of culture, confluent BSR cells in the plate were infected with RABV ERA at 1 MOI before or after antiviral compound treatment for the indicated time course. Virus titers in the treated cell supernatant were calculated as focus-forming units (ffu) per mL. Briefly, 20 μL of cell supernatant was mixed with 180 μL of freshly prepared BSR cell suspension and seeded onto Lab-Tek chamber slides (Fisher Scientific). Virus-containing cell supernatants were serially diluted 10-fold using the same BSR cell suspension on the same slide. After culturing the cells for 24 hours in a 37°C, 5% CO2 incubator, titration was performed using direct fluorescent antibody assay (DFA). To assess the effect of antiviral compound treatment on primary cells grown in 24-well plates, virus titers were measured according to the standard DFA protocol (www.cdc.gov / rabies / pdf / rabiesdfaspv2.pdf). Results for selected compounds are shown in Table 18.

[0225] [Table 17]

[0226] Example 19: Alzheimer's Disease Screening For viability analysis, 4 × 104 Vero cells or 8 × 104 SH-SY5Y-tau P301S cells were seeded into a 96-well plate and cultured overnight at 37°C and 5% CO2. Compounds diluted in DMSO were then added to the cells. The final DMSO concentration was 1%. The cells were then cultured for 24 hours (Vero) or 48 hours (SH-SY5Y). Subsequently, 20 μL of thiazolyl blue tetrazolium bromide (MTT) solution (5 mg / mL in PBS) was added to the cells and cultured for 4 hours to allow viable cells to reduce the yellow MTT to its blue formazan metabolite. After aspirating the medium, the formazan was resuspended in 200 μL isopropanol / 40 mM HCl and incubated for 30 minutes at room temperature. The diluted formazan was analyzed spectrophotometrically at 560 nm, with background subtraction at 670 nm. The results for selected compounds are shown in Table 19.

[0227] [Table 18]

[0228] Example 20: Antifungal assay The test strain Candida albicans ATCC24433 was obtained from the American Type Culture Collection and stored at -80°C. MIC assays followed the procedures of the American Clinical Laboratory Standards Council. Aliquots of 10 mM stock test compound, taken from eight 2-fold serial dilutions in 100% DMSO, were added to wells of microdilution plates. Candida inoculations were prepared according to the CLSI method. Colonies were picked from streak plates, suspended in RPMI, and diluted to the cell concentration specified in the CLSI method. After inoculation of the microdilution plates, the plates were incubated at 37°C for 16–20 hours, and fungal growth was assessed. The MIC was defined as the lowest concentration of test compound that completely inhibited visible growth of the test strain or, after incubation, completely inhibited the conversion of the redox fluorescent dye resazurin to resorufin by fungal growth in the wells. The amount of growth in wells containing test compound was compared to the amount of growth in growth control wells (no test compound added) on each plate and to the amount of growth in wells containing a control drug (e.g., fluconazole). The results are shown in Table 20.

[0229] [Table 19]

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (In the formula, R １ is H, -NR ７ R ８ , -OR ９ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; R ２ -H, -NR １０ R １１ ,or 【Chemistry 2】 and R ３ -H, halo, -OR １２ , alkyl, or substituted alkyl; R ４ -H, -NR １３ R １４ ,or 【Transformation 3】 and R ５ -H, halo, -OR １５ , alkyl, or substituted alkyl; R ６ -H, -NR １６ R １７ , -OR １８ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or halo; R ７ and R ８ are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R １０ and R １１ are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R １６ and R １７ are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, or together with the atom to which they are attached form a cycloheteroalkyl ring, substituted cycloheteroalkyl ring, cycloheteroalkenyl ring, substituted cycloheteroalkenyl ring, bicycloheteroalkyl ring, substituted bicycloheteroalkyl ring, spirocycloheteroalkyl ring, or substituted spirocycloheteroalkyl ring; R ９ , R １２ , R １５ , and R １８ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted aryl, heteroalkyl, or substituted heteroalkyl; X- is a pharmaceutically acceptable salt; As a condition, R ２ and R ４ Both are C ５ ~C ７ cycloheteroalkyl ring or C ５ ~C ７ When forming a substituted cycloheteroalkyl ring, R ６ When is t-butyl, R １ is not H, but R ６ is H, provided that R ５ Ga-CH ２ Except for Boc or -OMe, R １ is not H or methyl, and R ６ is ethyl, R １ is not methyl or ethyl; with the proviso that R １０ and R １１ or R １３ and R １４ Either of these is C ５ ~C ７ cycloheteroalkyl ring or C ５ ~C ７ When forming a substituted cycloheteroalkyl ring, R １ and R ６ are independently —H, alkyl, alkenyl, or haloalkyl, then R １０ , R １１ , R １３ , or R １４ wherein none of the groups is alkyl or substituted alkyl.

2. R ２ Ha-NR ９ R １０ and R ４ Ha-NR １１ R １２ That is, The compound of claim 1.

3. R ９ and R １０ together with the atoms to which they are attached form a bicycloheteroalkyl ring or a substituted bicycloheteroalkyl ring, and R １１ and R １２ together with the atoms to which they are attached form a bicycloheteroalkyl ring or a substituted bicycloheteroalkyl ring; The compound of claim 2.

4. R １ , R ３ , R ５ , and R ６ is -H, The compound of claim 3.

5. R ３ , R ５ , and R ６ is -H, The compound of claim 3.

6. R １ , R ３ , and R ６ is -H, The compound of claim 3.

7. R ３ and R ５ is -H, The compound of claim 3.

8. R ５ is -H, The compound of claim 3.

9. R １ , R ３ , and R ６ is -H, The compound of claim 3.

10. R ９ and R １０ together with the atoms to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring, and R １１ and R １２ together with the atom to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring; The compound of claim 2.

11. R ９ and R １０ together with the atoms to which they are attached form a bicycloheteroalkyl ring or a substituted bicycloheteroalkyl ring, and R １１ and R １２ are alkyl or together with the atom to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring; The compound of claim 2.

12. R ９ and R １０ together with the atoms to which they are attached form a cycloheteroalkyl ring, a substituted cycloheteroalkyl ring, a cycloheteroalkenyl ring, or a substituted cycloheteroalkenyl ring, and R １１ and R １２ is -H, The compound of claim 2.

13. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

14. 10. A method for preventing or treating a bacterial infection, cancer, Alzheimer's disease, or pox in a patient, comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of claim 1.

15. 15. A method for preventing or treating a bacterial infection, cancer, Alzheimer's disease, or pox in a patient, comprising administering to a patient in need thereof a therapeutically acceptable amount of the pharmaceutical composition of claim 14.

16. A compound having the following structure: 【Chemistry 4】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

17. 17. A pharmaceutical composition comprising a compound of claim 16 and a pharmaceutically acceptable excipient.

18. A compound having the following structure: 【Transformation 5】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

19. 20. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable excipient.

20. 17. A method for preventing or treating a bacterial infection, cancer, Alzheimer's disease, or pox in a patient, comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of claim 16.

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