Compositions for the treatment of solid tumors

Abstract

The present invention provides carbazole derivatives for the treatment of liposarcoma and other solid tumors in tissues and organs, and related conditions and diseases thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 900,557, filed September 15, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Despite advances in treatment, cancer remains a leading cause of death worldwide. Systemic therapies such as chemotherapy are often toxic, resulting in negative side effects for patients. Surgical solutions often fail to completely remove tumor tissue, resulting in disease recurrence. Despite treatment options, solid tumors often do not respond to currently available therapies. There is a need to find pharmacological solutions for the treatment of solid tumors. Summary of the Invention

[0003] In one aspect, provided herein is a method of treating a solid tumor in a subject in need thereof, said method comprising administering to a subject a compound of formula (I):

[0004] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 N(=O), -ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl, and C 2-5 alkynyl, wherein alkyl, alkenyl, and alkynyl are independently selected from halogen, —CN, —NO, —OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 optionally substituted independently with one or more substituents selected from N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, and 3- to 10-membered heterocycloalkyl, wherein R 9 is substituted with at least one quaternary amino or phosphonium group, R 10 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl; R 11 and R 12 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 cycloalkyl, or R 12 and R 13 can be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycloalkyl, and R 13 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl.

[0005] In some embodiments, R is a C substituted with at least one quaternary amino group. 1-9 It is alkyl.

[0006] In some embodiments, at least one quaternary amino group is of formula (V):

[0007] [ka] In the formula, R 14 , R 15 , and R 16 is C 1-9 Alkyl, C 2-9 Alkenyl, and C 2-9 In some embodiments, R 14 , R 15 , and R 16 Each of the is independently C 1-9 is alkyl,

[0008] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of R is halogen. 5 , R 6 , R 7 , and R 8 At least one of R is halogen. 1 , R 2 , R 3 , and R 4 At least one of R is halogen; 5 , R 6 , R 7 , and R 8 At least one of is a halogen. In some embodiments, the halogen is bromo.

[0009] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of R is OH. 5 , R 6 , R 7 , and R 8 At least one of the is OH.

[0010] In some embodiments, R 1 , R 2 , R 3 , and R4 At least one of is nitro, and R 5 , R 6 , R 7 , and R 8 At least one of the is nitro.

[0011] In some embodiments, the compound of formula (I) is 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-1-aminium, 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, and 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium.

[0012] In some embodiments, the pharmaceutical composition comprises less than about 50% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 30% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 10% water by weight. In some embodiments, the pharmaceutical composition comprises between about 0% and about 30% water by weight.

[0013] In some embodiments, the pharmaceutical composition comprises about 0.1% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.1% to about 10% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1% to about 5% by weight of the compound of Formula (I).

[0014] In some embodiments, the pharmaceutical composition further comprises at least one additional active agent, hi some embodiments, the additional active agent is a cytotoxic agent.

[0015] In some embodiments, the solid tumor is a liposarcoma.

[0016] In some embodiments, the subject has been diagnosed with lung cancer, breast cancer, colon cancer, prostate cancer, melanoma, gastric cancer, bladder cancer, endometrial cancer, kidney cancer, leukemia, liver cancer, lymphoma, pancreatic cancer, or thyroid cancer.

[0017] In some embodiments, the pharmaceutical composition is administered parenterally. In some embodiments, the pharmaceutical composition is administered as an injection, patch, cream, gel, or ointment. In some embodiments, the pharmaceutical composition is administered as an injection. In some embodiments, the pharmaceutical composition is injected directly into the tumor.

[0018] In some embodiments, the method further comprises administering an additional pharmaceutical composition, hi some embodiments, the two pharmaceutical compositions are injected directly into the tumor at a predetermined distance from each other.

[0019] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0020] The novel features of the invention are set forth with particularity in the appended claims. For a better understanding of the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

[0021] [Figure 1] 1 shows the change in tumor volume over time for the different cohorts studied in Xenograft Study 1. [Figure 2] 1 shows the change in body weight over time for the various cohorts studied in Xenograft Study 1. [Figure 3] 1 shows the change in tumor volume over time for the different cohorts studied in Xenograft Study 2. [Figure 4]1 shows the change in body weight over time for the various cohorts studied in Xenograft Study 2. DETAILED DESCRIPTION OF THE INVENTION

[0022] 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 disclosure belongs.

[0023] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0024] The term “C x-y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups, containing 1 to 6 carbons. The term -C x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, -C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0025] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups. An alkyl group contains 1 to 8 carbon atoms (C 1-8 alkyl) or 1 to 6 carbon atoms (C 1-6 alkyl) and the like, 1 to 12 carbon atoms (e.g., C 1-12The alkyl group may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0026] "Haloalkyl" refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0027] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group, including straight or branched chain alkenyl groups containing at least one double bond. Alkenyl groups contain 2 to 12 carbon atoms (e.g., C 2-12 Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0028] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group, including straight or branched chain alkynyl groups containing at least one triple bond. Alkynyl groups contain 2 to 12 carbon atoms (e.g., C 2-12 Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0029] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, respectively, having one or more skeletal atoms selected from atoms other than carbon. Exemplary skeletal atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, where the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. When given, numerical ranges refer to the total length of the chain. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Attachment to the remainder of the molecule can be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless specifically stated otherwise in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted with one or more substituents, such as those described herein.

[0030] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise expressly stated in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0031] "Heteroaryl" refers to a 3- to 12-membered aromatic ring containing at least one heteroatom, where each heteroatom may be independently selected from N, O, and S. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic, and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroatoms in a heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, where valence allows. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranoyl. nyl), benzothienyl, benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl droquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl (phthalazinyl), pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7 ,8-Tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in the specification, heteroaryl is optionally substituted by one or more substituents, such as those described herein.

[0032] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl can be fused with an aromatic ring (in which case the cycloalkyl is attached through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. Unless stated otherwise specifically in the specification, cycloalkyl groups may be optionally substituted.

[0033] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated herein, a heterocycloalkyl radical can be a monocyclic or bicyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized. The nitrogen atom can be optionally quaternized. The heterocyclyl radical can be partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, and morpholinyl. , octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl.The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 12 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise specified in the specification, heterocycloalkyl groups may be optionally substituted.

[0034] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbon or heteroatoms of the structure. "Substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more for appropriate organic compounds and can be the same or different. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocycle, heterocycle, cycloalkyl, heterocycloalkyl, aromatic moiety, and heteroaromatic moiety.

[0035] It is understood by those skilled in the art that substituents, where appropriate, can themselves be substituted. Unless specifically specified as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0036] Where substituents are specified by their conventional chemical formula and written from left to right, they equally encompass the chemically identical substituents that result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0037] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples when the event or circumstance occurs and examples when it does not occur. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and that the description includes both substituted aryl groups and aryl groups with no substitution.

[0038] The compounds of the present disclosure include crystalline and amorphous forms of the compounds, pharmaceutically acceptable salts of these compounds having the same type of activity, and active metabolites, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), stereopolymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0039] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen is: 1 H (protium), 2 H (deuterium), and 3 It has three naturally occurring isotopes, designated H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium may provide certain therapeutic advantages, such as increased half-life and / or exposure in vivo, or may provide compounds useful for investigating in vivo pathways of drug excretion and metabolism. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0040] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture when appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each chiral carbon is specified as either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which asymmetric centers can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The subject chemical entities, pharmaceutical compositions, and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via appropriate methods, including, but not limited to, chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over another can be determined.

[0041] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E-forms (or cis- or trans-forms). Additionally, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E-, and tautomeric forms as well.

[0042] Isolation and purification of the chemical entities and intermediates described herein can be carried out, if desired, by any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, or thick layer chromatography, or a combination of such procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other comparable separation or isolation procedures can also be used.

[0043] Unless stereochemistry is specified, certain small molecules described herein include, but are not limited to, isomers such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, where possible, to the extent that one skilled in the art can prepare them through routine experimentation. In these cases, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of racemates or diastereomeric mixtures. Resolution of racemates or diastereomeric mixtures, where possible, can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, mixtures enriched in one of the two enantiomers can be purified to provide more optically enriched forms of the major enantiomer by recrystallization and / or trituration. In addition, certain such small molecules include Z- and E-forms (or cis- and trans-forms) of certain small molecules having carbon-carbon or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term "a small molecule" is intended to encompass all tautomeric forms of the small molecule.

[0044] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0045] The phrases "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and the like. (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic compatible substances utilized in pharmaceutical formulations.

[0046] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect its intended use, including, but not limited to, the treatment of diseases as defined below. A therapeutically effective amount will vary depending on the intended treatment use (in vivo), or the subject and disease state being treated, e.g., the subject's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dosage that induces a specific response in target cells, e.g., a decrease in platelet adhesion and / or cell migration. Specific dosage amounts will vary depending on the particular compound selected, the subsequent administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0047] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may include, for example, eradication or amelioration of the underlying disorder being treated. A therapeutic benefit may also include, for example, eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement in the subject is observed, even though the subject may still be affected by the underlying disorder. In certain embodiments, with respect to a prophylactic benefit, a composition is administered to a subject at risk of developing a particular disease or reporting one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0048] A "therapeutic benefit," as that term is used herein, encompasses therapeutic benefits and / or prophylactic benefits as described above. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0049] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass the administration of two or more agents to an animal, including a human, whereby both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0050] The term "solid tumor" refers to any abnormal mass of tissue that does not contain cysts or areas of fluid. Solid tumors can be benign or malignant. Different types of solid tumors are named according to the type of cells they are made up of. Examples of solid tumors include sarcomas (such as liposarcoma), carcinomas, and lymphomas.

[0051] compound In one aspect, provided herein is a compound of formula (I):

[0052] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 N(=O), -ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl, and C 2-5 alkynyl, wherein alkyl, alkenyl, and alkynyl are independently selected from halogen, —CN, —NO, —OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 optionally substituted independently with one or more substituents selected from N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, and 3- to 10-membered heterocycloalkyl, wherein R 9is substituted with at least one quaternary amino or phosphonium group, R 10 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl; R 11 and R 12 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 cycloalkyl, or R 12 and R 13 can be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycloalkyl, and R 13 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl.

[0053] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 N(=O), -ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl, and C 2-5 alkynyl, wherein alkyl, alkenyl, and alkynyl are independently selected from halogen, —CN, —NO, —OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13In some embodiments, R is optionally substituted with one or more substituents independently selected from N(=O), and -ON(=O). 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , C 1-5 Alkyl, C 2-5 Alkenyl, and C 2-5 alkynyl, wherein alkyl, alkenyl, and alkynyl are independently selected from halogen, —CN, —NO, —OR 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , and -NR13 S(=O)NR 11 R 12 In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , -NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , and C 1-5 alkyl, wherein each alkyl is selected from halogen, —CN, —NO, —OR 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , and -NR 13 S(=O)NR 11 R 12 In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , and -NR 11 R 12 are independently selected from

[0054] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of R is halogen. 1 is halogen. In some embodiments, R 2 is halogen. In some embodiments, R 3 is halogen. In some embodiments, R 4 is halogen. In some embodiments, R 5 , R 6 , R 7 , and R 8 At least one of R is halogen. 5 is halogen. In some embodiments, R 6 is halogen. In some embodiments, R 7 is halogen. In some embodiments, R 8 is halogen. In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of R is halogen; 5 , R 6 , R 7 , and R 8 At least one of R is halogen. 1 is a halogen and R 5 is halogen. In some embodiments, R 1 is a halogen and R 6 is halogen. In some embodiments, R 1 is a halogen and R 7 is halogen. In some embodiments, R 1 is a halogen and R 8 is halogen. In some embodiments, R 2 is a halogen and R 5 is halogen. In some embodiments, R 2 is a halogen and R 6is halogen. In some embodiments, R 2 is a halogen and R 7 is halogen. In some embodiments, R 2 is a halogen and R 8 is halogen. In some embodiments, R 3 is a halogen and R 5 is halogen. In some embodiments, R 3 is a halogen and R 6 is halogen. In some embodiments, R 3 is a halogen and R 7 is halogen. In some embodiments, R 3 is a halogen and R 8 is halogen. In some embodiments, R 4 is a halogen and R 5 is halogen. In some embodiments, R 4 is a halogen and R 6 is halogen. In some embodiments, R 4 is a halogen and R 7 is halogen. In some embodiments, R 4 is a halogen and R 8 is a halogen. In some embodiments, the halogen is bromo. In some embodiments, the halogen is chloro. In some embodiments, the halogen is fluoro.

[0055] In some embodiments, R 1 , R 2 , R 3 , and R 4 In some embodiments, at least one of R 1 is OH. In some embodiments, R 2 is OH. In some embodiments, R 3 is OH. In some embodiments, R 4 is OH. In some embodiments, R 5 , R 6 , R 7 , and R 8In some embodiments, at least one of R 5 is OH. In some embodiments, R 6 is OH. In some embodiments, R 7 is OH. In some embodiments, R 8 is OH.

[0056] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of is nitro, and R 5 , R 6 , R 7 , and R 8 At least one of R is nitro. 1 is nitro and R 5 is nitro. In some embodiments, R 1 is nitro and R 6 is nitro. In some embodiments, R 1 is nitro and R 7 is nitro. In some embodiments, R 1 is nitro and R 8 is nitro. In some embodiments, R 2 is a halogen and R 5 is nitro. In some embodiments, R 2 is nitro and R 6 is nitro. In some embodiments, R 2 is a halogen and R 7 is nitro. In some embodiments, R 2 is nitro and R 8 is nitro. In some embodiments, R 3 is a halogen and R 5 is nitro. In some embodiments, R 3 is nitro and R 6 is nitro. In some embodiments, R 3 is a halogen and R 7 is nitro. In some embodiments, R 3is nitro and R 8 is nitro. In some embodiments, R 4 is a halogen and R 5 is nitro. In some embodiments, R 4 is nitro and R 6 is nitro. In some embodiments, R 4 is a halogen and R 7 is nitro. In some embodiments, R 4 is nitro and R 8 is nitro.

[0057] In some embodiments, R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, and 3- to 10-membered heterocycloalkyl, wherein R 9 is substituted with at least one quaternary amino or phosphonium group. In some embodiments, R 9 is substituted with at least one phosphonium group 2-9 In some embodiments, R is alkenyl. 9 is substituted with at least one quaternary amino group 2-9 In some embodiments, R is alkenyl. 9 is substituted with at least one phosphonium group 2-9 In some embodiments, R is alkynyl. 9 is substituted with at least one quaternary amino group 2-9 In some embodiments, R is alkynyl. 9 is a 3- to 10-membered heterocycloalkyl. In some embodiments, R 9 is piperazinyl. In some embodiments, R 9 is pyridinyl. In some embodiments, R 9 is piperidinyl. In some embodiments, R 9 is morpholinyl. In some embodiments, R 9is thiomorpholinyl. In some embodiments, R 9 is substituted with at least one phosphonium group 1-9 In some embodiments, R 9 is substituted with at least one quaternary amino group 1-9 In some embodiments, R 9 is propyl substituted with at least one quaternary amino group. In some embodiments, R 9 is pentyl substituted with at least one quaternary amino group.

[0058] In some embodiments, at least one quaternary amino group is of formula (V):

[0059] [ka] In the formula, R 14 , R 15 , and R 16 Each of the 1-9 Alkyl, C 2-9 Alkenyl, and C 2-9 In some embodiments, R 14 , R 15 , and R 16 Each of the is independently C 2-9 In some embodiments, R is alkenyl. 14 , R 15 , and R 16 Each of the is independently C 2-9 In some embodiments, R is alkynyl. 14 , R 15 , and R 16 Each of the is independently C 1-9 In some embodiments, R 14 , R 15 , and R 16 Each of is methyl.

[0060] In some embodiments, at least one phosphonium group is of formula (VI):

[0061] [ka] In the formula, R 17 , R 18 , and R 19 Each of the 1-9 Alkyl, C 2-9 Alkenyl, and C 2-9 In some embodiments, R 17 , R 18 , and R 19 Each of the is independently C 2-9 In some embodiments, R is alkenyl. 17 , R 18 , and R 19 Each of the is independently C 2-9 In some embodiments, R is alkynyl. 17 , R 18 , and R 19 Each of the is independently C 1-9 In some embodiments, R 17 , R 18 , and R 19 Each of is methyl.

[0062] In some embodiments, R 10 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 10 are H and C, respectively. 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 10 are H and C, respectively. 1-5Alkyl, and C 3-6 In some embodiments, R 10 are each H. In some embodiments, R 10 are each independently C 1-5 In some embodiments, R 10 are each independently C 2-5 In some embodiments, R is alkenyl. 10 are each independently C 2-5 In some embodiments, R is alkynyl. 10 are each independently C 1-5 In some embodiments, R 10 are each independently C 1-5 In some embodiments, R 10 are each independently C 3-6 It is cycloalkyl.

[0063] In some embodiments, R 11 and R 12 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl, or R 12 and R 13 can be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycloalkyl. In some embodiments, R 11 and R 12 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 11 and R 12 are H and C, respectively. 1-5 Alkyl, C1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 11 and R 12 are H and C, respectively. 1-5 Alkyl, and C 3-6 In some embodiments, R 11 and R 12 are each H. In some embodiments, R 11 and R 12 are each independently C 1-5 In some embodiments, R 11 and R 12 are each independently C 2-5 In some embodiments, R is alkenyl. 11 and R 12 are each independently C 2-5 In some embodiments, R is alkynyl. 11 and R 12 are each independently C 1-5 In some embodiments, R 11 and R 12 are each independently C 1-5 In some embodiments, R 11 and R 12 are each independently C 3-6 In some embodiments, R 12 and R 13 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl.

[0064] In some embodiments, R 13 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6In some embodiments, R 13 are H and C, respectively. 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 13 are H and C, respectively. 1-5 Alkyl, and C 3-6 In some embodiments, R 13 are each H. In some embodiments, R 13 are each independently C 1-5 In some embodiments, R 13 are each independently C 2-5 In some embodiments, R is alkenyl. 13 are each independently C 2-5 In some embodiments, R is alkynyl. 13 are each independently C 1-5 In some embodiments, R 13 are each independently C 1-5 In some embodiments, R 13 are each independently C 3-6 It is cycloalkyl.

[0065] In some embodiments, the compound of Formula (I) is selected from 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-1-aminium, 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, and 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium.

[0066] In some embodiments, the compound of Formula (I) is 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-1-aminium. In some embodiments, the compound of Formula (I) is 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium. In some embodiments, the compound of Formula (I) is 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium. In some embodiments, the compound of Formula (I) is 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium.

[0067] In some embodiments, the compound of formula (I) has the structure

[0068] [ka] In some embodiments, the compound of formula (I) is represented by the structure

[0069] [ka] In some embodiments, the compound of formula (I) is represented by the structure

[0070] [ka] In some embodiments, the compound of formula (I) is represented by the structure

[0071] [ka] It is expressed by:

[0072] Pharmaceutical Composition The compositions of the present disclosure can be formulated in any suitable pharmaceutical formulation. Pharmaceutical compositions of the present disclosure typically contain an active ingredient (e.g., a compound of formula (I), or its pharmaceutically acceptable salt and / or coordination compound) and one or more pharmaceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. The compositions of the present disclosure can be formulated in any suitable pharmaceutical formulation.

[0073] The pharmaceutical composition may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein may be formulated into a dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, transdermal, buccal, sublingual, subcutaneous, intramuscular, intravenous, intratumoral, and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition may be formulated as a unit dose.

[0074] The amount of each compound administered will depend on the mammal being treated, the severity of the disorder or disease, the rate of administration, the predisposition of the compound, and the discretion of the prescribing physician. However, effective dosages may range from about 0.001 to about 100 mg per kg of body weight per day, in single or divided doses. In some instances, dosage levels below the lower end of the range may be more than sufficient, while in other cases, even larger dosages may be utilized without causing any adverse side effects, for example, by dividing such larger dosages into several smaller dosages for administration throughout the day. In some embodiments, an effective dosage may be provided in pulse doses (i.e., the compound is administered on consecutive days, followed by a cessation of administration on consecutive days).

[0075] In some embodiments, the composition is provided in one or more unit doses. For example, the composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60 or more doses. Such amounts can be administered daily, for example, in individual doses administered once, twice, three times, or more times per day. However, the daily doses described herein should not be interpreted as requiring daily administration. For example, if one of the agents is provided in a suitable sustained-release form, two or more doses per day can be administered less frequently, for example, as a depot injection administered every two days to once a month, or even more frequently. Most typically and conveniently for a subject, a pharmaceutical composition comprising a compound of Formula (I) can be administered once a day, for example, in the morning, evening, or during the day.

[0076] The unit doses can be administered simultaneously or sequentially. The composition can be administered for an extended treatment period. Illustratively, the treatment period can be at least about 1 month, for example, at least about 3 months, at least about 6 months, or at least about 1 year. In some cases, administration can continue for substantially the entire life of the subject.

[0077] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) may be administered as part of a treatment regimen that includes administering one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents) either simultaneously or sequentially with the pharmaceutical composition comprising a compound of Formula (I). When administered sequentially, the pharmaceutical composition comprising a compound of Formula (I) may be administered before or after the one or more second agents. When administered simultaneously, the pharmaceutical compositions comprising a compound of Formula (I) and one or more second agents may be administered by the same route (e.g., injection into the same location), by different routes (e.g., a tablet taken orally while receiving an intravenous injection), or as part of the same combination (e.g., a solution containing a pharmaceutical composition comprising a compound of Formula (I) and one or more second agents).

[0078] The combination treatments of the invention may be effective over a wide dosage range. For example, in adult human treatment, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the subject's weight, and the preferences and experience of the attending physician.

[0079] In some embodiments, the pharmaceutical composition comprises one or more surfactants.Surfactants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0080] Suitable hydrophilic surfactants generally have an HLB value of at least 10, while suitable lipophilic surfactants generally have an HLB value of less than 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value equal to or less than about 10. However, the HLB value of a surfactant is merely a rough guide commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0081] Hydrophilic surfactants can be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, sodium docusate, acylactylates, monoacetylated and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0082] Within this group, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, sodium docusate, acylactylates, monoacetylated and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0083] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate esters of fatty acids, stearoyl-2-lactate, stearoyl lactate, succinylated monoglycerides. , mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, stearic acid, lauryl sulfate, teracecyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0084] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogolglycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol glycerin fatty acid esters, polyglycerol fatty acid esters, polyethylene glycol sorbitan fatty acid esters, glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and hydrophilic transesterification products of polyols having at least one member of a sterol group, polyoxyethylene sterols, derivatives and analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols having at least one member of a triglyceride, vegetable oil, and hydrogenated vegetable oil group. The polyol is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0085] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearic acid, PEG-32 distearate, PEG-40 stearic acid, PEG-100 stearate. Phosphoric Acid, PEG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0086] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and diglycerides, glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and hydrophilic transesterification products of polyols having at least one member of a sterol group, fat-soluble vitamins / vitamin derivatives, and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophilic transesterification products of vegetable oils, hydrogenated vegetable oils, and polyols having at least one member of a triglyceride group.

[0087] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the disclosed compound and minimize precipitation of the disclosed compound. This may be particularly important for injection. Solubilizing agents may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0088] Examples of suitable solubilizing agents include, but are not limited to, alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PE. amides and other nitrogen-containing compounds, such as ethers of ethylene glycol, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0089] Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0090] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a bioacceptable amount, which can be easily determined by one skilled in the art. In some situations, it may be advantageous to remove excess solubilizer using conventional techniques, such as distillation or evaporation, before providing the composition to a patient, e.g., to maximize drug concentration, and to include an amount of solubilizer that far exceeds the bioacceptable amount. When present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the total weight of the drug and other excipients. If desired, even very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, can be used. Typically, the solubilizer can be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0091] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifiers, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavors, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0092] In addition, acids or bases can be incorporated into the composition for ease of processing, stability enhancement, or other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Further suitable bases are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0093] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0094] In one aspect, provided herein is a compound of formula (I)

[0095] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 N(=O), -ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl, and C 2-5 alkynyl, wherein alkyl, alkenyl, and alkynyl are independently selected from halogen, —CN, —NO, —OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 optionally substituted independently with one or more substituents selected from N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, and 3- to 10-membered heterocycloalkyl, wherein R 9 is substituted with at least one quaternary amino or phosphonium group, R 10 are H and C, respectively.1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl; R 11 and R 12 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 cycloalkyl, or R 12 and R 13 can be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycloalkyl, and R 13 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl.

[0096] In some embodiments, the pharmaceutical composition comprises less than about 50% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 30% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 10% water by weight. In some embodiments, the pharmaceutical composition comprises between about 0% and about 30% water by weight. In some embodiments, the pharmaceutical composition comprises between about 10% and about 30% water by weight. In some embodiments, the pharmaceutical composition comprises between about 15% and about 30% water by weight. In some embodiments, the pharmaceutical composition comprises between about 15% and about 25% water by weight. In some embodiments, the pharmaceutical composition comprises between about 20% and about 30% water by weight. In some embodiments, the pharmaceutical composition comprises between about 23% and about 27% water by weight. In some embodiments, the pharmaceutical composition comprises between about 24% and about 26% water by weight. In some embodiments, the pharmaceutical composition comprises about 0% water by weight. In some embodiments, the pharmaceutical composition comprises about 1% water by weight. In some embodiments, the pharmaceutical composition comprises about 2% water by weight. In some embodiments, the pharmaceutical composition comprises about 3% water by weight. In some embodiments, the pharmaceutical composition comprises about 4% water by weight. In some embodiments, the pharmaceutical composition comprises about 5% water by weight. In some embodiments, the pharmaceutical composition comprises about 6% water by weight. In some embodiments, the pharmaceutical composition comprises about 7% water by weight. In some embodiments, the pharmaceutical composition comprises about 8% water by weight. In some embodiments, the pharmaceutical composition comprises about 9% water by weight. In some embodiments, the pharmaceutical composition comprises about 10% water by weight. In some embodiments, the pharmaceutical composition comprises about 11% water by weight. In some embodiments, the pharmaceutical composition comprises about 12% water by weight. In some embodiments, the pharmaceutical composition comprises about 13% water by weight. In some embodiments, the pharmaceutical composition comprises about 14% water by weight. In some embodiments, the pharmaceutical composition comprises about 15% water by weight. In some embodiments, the pharmaceutical composition comprises about 16% water by weight. In some embodiments, the pharmaceutical composition comprises about 17% water by weight. In some embodiments, the pharmaceutical composition comprises about 18% water by weight. In some embodiments, the pharmaceutical composition comprises about 19% water by weight. In some embodiments, the pharmaceutical composition comprises about 20% water by weight.In some embodiments, the pharmaceutical composition comprises about 21% water by weight. In some embodiments, the pharmaceutical composition comprises about 22% water by weight. In some embodiments, the pharmaceutical composition comprises about 23% water by weight. In some embodiments, the pharmaceutical composition comprises about 24% water by weight. In some embodiments, the pharmaceutical composition comprises about 25% water by weight. In some embodiments, the pharmaceutical composition comprises about 26% water by weight. In some embodiments, the pharmaceutical composition comprises about 27% water by weight. In some embodiments, the pharmaceutical composition comprises about 28% water by weight. In some embodiments, the pharmaceutical composition comprises about 29% water by weight. In some embodiments, the pharmaceutical composition comprises about 30% water by weight.

[0097] In some embodiments, the pharmaceutical composition comprises at least about 0.1% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.1% to about 10% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1% to about 5% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.1% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.2% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.3% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.4% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.6% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.7% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.8% by weight of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.9% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 2% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 2.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 3% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 3.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 4% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 4.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 5.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 6% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 6.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 7% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 7.5% by weight of the compound of Formula (I).In some embodiments, the pharmaceutical composition comprises about 8% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 8.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 9% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 9.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 10% by weight of the compound of Formula (I).

[0098] In some embodiments, the pharmaceutical composition further comprises at least one additional active agent, hi some embodiments, the additional active agent is a cytotoxic agent.

[0099] In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, transdermal, buccal, sublingual, subcutaneous, intramuscular, intravenous, intratumoral, and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for injection. In some embodiments, the pharmaceutical composition is formulated for intratumoral injection. In some embodiments, the pharmaceutical composition is formulated as an injection, patch, cream, gel, or ointment.

[0100] Pharmaceutical compositions for injection In some embodiments, the present disclosure provides a pharmaceutical composition for injection containing a compound of Formula (I) and a pharmaceutical excipient suitable for injection. The components and amounts of the drugs in the composition are as described herein.

[0101] Forms into which the novel compositions of the present disclosure may be incorporated for administration by injection include sesame oil, corn oil, cottonseed oil, or peanut oil, as well as aqueous or oil suspensions, or emulsions or sterile solutions with elixirs, mannitol, glucose, and similar pharmaceutical vehicles.

[0102] Aqueous solutions in physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0103] Injectable aqueous solution is prepared by incorporating the compound of the present disclosure in the required amount in a suitable solvent with various other components as listed above, and then filter sterilization is carried out as needed.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and other necessary components as listed above.For sterile powder to prepare sterile injectable solution, a particular desired preparation method is vacuum drying and freeze-drying technology, which can obtain powder of active ingredient, in addition to any additional desired component from the solution that has been previously filter-sterilized.

[0104] The present invention also provides kits. The kits may contain a pharmaceutical composition comprising a compound of Formula (I) and one or more additional agents in suitable packaging along with materials that may include instructions for use, a discussion of clinical studies, a list of side effects, etc. Such kits may further include information such as scientific literature references, package insert materials, clinical trial results, and / or summaries thereof, which indicate or establish the activity and / or benefits of the composition and / or describe dosage, administration, side effects, pharmacological interactions, or other information useful to medical professionals. Such information may be based on the results of various studies, for example, studies using laboratory animals involving in vivo models, and studies based on human clinical trials. The kits may also include additional agents. In some embodiments, the compound and agent of the present invention are provided as separate compositions in separate containers within the kit. In some embodiments, the compound and agent of the present invention are provided as a single composition within a container within the kit. Suitable packaging and additional items for use (e.g., measuring cups for liquid formulations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein may be provided, sold, and / or promoted to healthcare providers, including doctors, nurses, pharmacists, formulary officials, etc. Kits may also be sold directly to consumers in some embodiments.

[0105] How to use In one aspect, provided herein is a method of treating a solid tumor in a subject in need thereof, said method comprising administering to a subject a compound of formula (I):

[0106] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , and R 8 Each of the following is H, halogen, -CN, -NO2, -OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 N(=O), -ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl, and C 2-5 alkynyl, wherein alkyl, alkenyl, and alkynyl are independently selected from halogen, —CN, —NO, —OR 10 , -SR 10 , -S(=O)R 10 , -S(=O)2R 10 , -NR 11 R 12 , -C(=O)NR 11 R 12 , -S(=O)NR 11 R 12 , -S(=O)2NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 optionally substituted independently with one or more substituents selected from N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, and 3- to 10-membered heterocycloalkyl, wherein R 9 is substituted with at least one quaternary amino or phosphonium group, R 10 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl; R 11 and R 12 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 cycloalkyl, or R 12 and R 13 can be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycloalkyl, and R 13 are H and C, respectively. 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl.

[0107] In some embodiments, compounds of Formula (I) exhibit cytotoxic activity against solid tumor cells. In some embodiments, compounds of Formula (I) exhibit cytotoxic activity against solid tumor cells by disrupting the integrity of the cell membrane of the tumor cells. In some embodiments, compounds of Formula (I) exhibit cytotoxic activity against solid tumor cells regardless of cell type.

[0108] In some embodiments, the solid tumor is a liposarcoma.

[0109] In some embodiments, the solid tumor is lung cancer, breast cancer, colon cancer, prostate cancer, melanoma, gastric cancer, bladder cancer, endometrial cancer, kidney cancer, liver cancer, pancreatic cancer, or thyroid cancer.

[0110] In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, transdermal, buccal, sublingual, subcutaneous, intramuscular, intravenous, intratumoral, and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition is administered via parenteral administration. In some embodiments, the pharmaceutical composition is administered as an injection, patch, cream, gel, or ointment. In some embodiments, the pharmaceutical composition is administered as an injection. In some embodiments, the pharmaceutical composition is injected directly into a tumor. In some embodiments, the pharmaceutical composition is administered by non-invasive ultrasound-directed injection.

[0111] In some embodiments, the volume of each injection is about 25 to about 250 microliters. In some embodiments, the volume of each injection is about 25 to about 150 microliters. In some embodiments, the volume of each injection is about 50 to about 100 microliters. In some embodiments, the volume of each injection is about 25 microliters. In some embodiments, the volume of each injection is about 50 microliters. In some embodiments, the volume of each injection is about 75 microliters. In some embodiments, the volume of each injection is about 100 microliters. In some embodiments, the volume of each injection is about 125 microliters. In some embodiments, the volume of each injection is about 150 microliters. In some embodiments, the volume of each injection is about 175 microliters. In some embodiments, the volume of each injection is about 200 microliters. In some embodiments, the volume of each injection is about 225 microliters. In some embodiments, the volume of each injection is about 250 microliters.

[0112] In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 20 to about 100 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 40 to about 70 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 10 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 20 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 30 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 40 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 50 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 60 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 70 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 80 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 90 milligrams per milliliter. In some embodiments, the concentration of the compound of Formula (I) in the pharmaceutical composition is about 100 milligrams per milliliter.

[0113] In some embodiments, each injection contains about 1 milligram to about 25 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 2.5 milligrams to about 15 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 5 milligrams to about 10 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 1 milligram of the compound of Formula (I). In some embodiments, each injection contains about 2.5 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 5 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 10 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 15 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 20 milligrams of the compound of Formula (I). In some embodiments, each injection contains about 25 milligrams of the compound of Formula (I).

[0114] In some embodiments, the method further comprises administering an additional pharmaceutical composition. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor a predetermined distance from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 1 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 2 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 3 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 4 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 5 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 6 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 7 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 8 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 9 cm from each other. In some embodiments, the two pharmaceutical compositions are injected directly into the tumor 10 cm from each other.

[0115] In some embodiments, the method further comprises at least one additional direct tumor treatment, such as ablation, radiation, surgical removal of the tumor and margins, and any combination thereof. [Example]

[0116] Example 1: Xenograft Study 1

[0117] A549 cells were injected subcutaneously into nude mice, resulting in an estimated tumor volume of approximately 500 mm, determined by caliper. 3 Mice were divided into four groups (N=10 per group) and administered two intratumoral injections of either vehicle (containing water for injection, benzyl alcohol, propylene glycol, and Tween 80) or 1 mg, 2.5 mg, or 5 mg of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride according to the experimental design shown in Table 1 below.

[0118] [Table 1]

[0119] Three weeks after injection, tumor size was determined by caliper and tumor volume was calculated. The average tumor volumes for the various cohorts are summarized in Table 2 below and graphically summarized in Figure 1 (arrows point to treatment days), while the variation in mouse weight is summarized in Figure 2. Treatment with 5 mg of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride significantly reduced tumor size and did not affect mouse weight.

[0120] [Table 2]

[0121] Example 2: Xenograft Study 2

[0122] A549 cells were injected subcutaneously into nude mice, resulting in an estimated tumor volume of approximately 300 mm, as determined by calipers. 3 The mice were divided into three groups (N=10 per group) and administered three doses of intratumoral injection of either vehicle (containing water for injection, benzyl alcohol, propylene glycol, and Tween 80), 5 mg of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or no injection, according to the experimental design shown in Table 3 below.

[0123] [Table 3]

[0124] Three weeks after injection, tumor size was determined by caliper and tumor volume was calculated. The median tumor volumes for the various cohorts are summarized in Table 4 below and graphically summarized in Figure 3 (arrows point to treatment days), while the variation in mouse weight is summarized in Figure 4. Treatment with 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride significantly reduced tumor size and did not affect mouse weight.

[0125] [Table 4]

[0126] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A pharmaceutical composition for use in the treatment of solid tumors, said pharmaceutical composition comprising the following compound: 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-1-aminium, 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, or A pharmaceutical composition comprising 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, or a pharmaceutically acceptable salt thereof.

2. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises less than about 50% water by weight.

3. 3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises less than about 30% water by weight.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition comprises less than about 10% by weight of water.

5. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition comprises from about 0% to about 30% by weight of water.

6. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition comprises about 10% to about 30% water by weight.

7. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition comprises about 20% to about 30% water by weight.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the pharmaceutical composition comprises at least about 0.1% by weight of the compound.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the pharmaceutical composition comprises from about 0.1% to about 10% by weight of the compound.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition comprises about 1% to about 5% by weight of the compound.

11. The pharmaceutical composition of any one of claims 1 to 10, further comprising at least one additional active agent.

12. The pharmaceutical composition of claim 11 , wherein the additional active agent is a cytotoxic agent.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the solid tumor is liposarcoma.

14. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the solid tumor is selected from the list consisting of lung cancer, breast cancer, colon cancer, prostate cancer, melanoma, gastric cancer, bladder cancer, endometrial cancer, kidney cancer, liver cancer, pancreatic cancer, and thyroid cancer.

15. The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition is administered via parenteral administration.

16. The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition is administered as an injection.

17. 17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is injected directly into the solid tumor.

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