Compositions and methods for treating lipoma pain - Patents.com

Abstract

The present invention provides carbazole derivatives for the treatment of lipoma pain in tissues and organs, in particular for the treatment of lipoma pain in patients with Dercum's Disease (DD).

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 226,441, filed July 28, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] Dercum's disease is a rare disorder characterized by multiple painful growths of adipose tissue (lipomas). Lipomas occur primarily on the trunk, upper arms, and upper thighs and are found just under the skin (subcutaneous), but may also be found deeper within the body, attached by connective tissue to muscles, tendons, ligaments, or bones. The pain associated with Dercum's disease is often debilitating and can be resistant to typical pain relief treatments. The pain can be caused by lipomas compressing nearby nerves, or inflamed connective tissue, also called fascia, which is commonly associated with lipomas. In addition, there are numerous associated symptoms, such as easy bruising, sleep disorders, memory problems, depression, difficulty concentrating, anxiety, rapid heartbeat, shortness of breath, diabetes, abdominal bloating, constipation, fatigue, joint pain, weight gain, lethargy, and / or confusion.

[0003] Dercum's disease occurs primarily in adults, affecting more women than men, and there is no approved treatment. Summary of the Invention

[0004] The present disclosure provides carbazole derivatives useful for treating pain associated with lipomas. In some embodiments, the carbazole derivatives are useful for treating pain associated with lipomas in tissues and organs, particularly in patients with Dercum's disease (DD).

[0005] In one aspect, provided herein is a method of reducing lipoma pain, the method comprising administering to a subject in need of pain reduction a therapeutically effective amount of a pharmaceutical composition in a unit dosage form, the pharmaceutical composition comprising a compound of Formula (I), or a pharma- ceutical acceptable salt thereof.

[0006] In one aspect, provided herein is a pharmaceutical composition in unit dosage form comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in treating lipoma pain.

[0007] The compound of formula (I) is represented by the following structure:

[0008] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently 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)2NR11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 N(=O), -ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl, or C 2-5 alkynyl, where each alkyl, alkenyl, or alkynyl is independently optionally 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)2NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 Substituted with one or more substituents selected from the group consisting of N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, or 3 to 10 membered heterocycloalkyl; R 9 is substituted with at least one quaternary ammonium or phosphonium group; Each R 10 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 is cycloalkyl, Each R 11 and R 12 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl or C 3-6 cycloalkyl or R 11 and R 12 together with the nitrogen atom to which they are attached, are optionally substituted 3- to 10-membered heterocycloalkyl; and Each R 13 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 It is cycloalkyl.

[0009] In some embodiments, treating lipoma pain includes reducing or alleviating pain associated with the lipoma. In some embodiments, the pain is reduced by at least 30% compared to before treatment. In some embodiments, the pain is reduced by at least 50% compared to before treatment. In some embodiments, the lipoma is not angiolipoma.

[0010] In some embodiments, the subject has Dercum's disease.

[0011] In some embodiments, pain is relieved for at least about 1 month after a single administration of Compound (I). In some embodiments, pain is relieved for at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or more than 6 months after a single administration of Compound (I).

[0012] In some embodiments, R 9 is a C1-C9 alkyl substituted with at least one quaternary ammonium group. In some embodiments, the at least one ammonium group is a group according to formula (V):

[0013] [ka] In the formula, R 14 , R 15 , and R 16 are each independently 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 It is an alkyl.

[0014] In some embodiments, at least one ammonium group is a group according to formula (V'):

[0015] [ka] wherein X is a negatively charged ion, in some embodiments, X is a halogen, e.g., Cl.

[0016] In some embodiments, R 14 , R 15 , and R 16 are each independently methyl. 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 is a halogen.

[0017] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of is halogen, and R 5, R 6 , R 7 , and R 8 At least one of is a halogen. In some embodiments, the halogen is bromo.

[0018] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of is OH. In some embodiments, R 5 , R 6 , R 7 , and R 8 At least one of is OH. 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 the is nitro.

[0019] 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, or 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium.

[0020] In some embodiments, the compound of formula (I) is represented by the structure set forth in formula (1) below.

[0021] [ka]

[0022] In some embodiments, the compound of formula (I) is 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride.

[0023] In some embodiments, the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient. In some embodiments, the excipient is a surfactant. In some embodiments, the surfactant is Tween-80. In some embodiments, the excipient is a solubilizing agent. In some embodiments, the solubilizing agent is benzyl alcohol. In some embodiments, the excipient is a solvent. In some embodiments, the solvent is propylene glycol.

[0024] In some embodiments, the solvent is water. 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 about 10% to about 30% water by weight.

[0025] In some embodiments, the pharmaceutical composition comprises at least 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).

[0026] In some embodiments, the pharmaceutical composition comprises 1 mg to 100 mg of the compound of formula (I) per mL. In some embodiments, the pharmaceutical composition comprises 50 mg of the compound of formula (I) per mL.

[0027] In some embodiments, the pharmaceutical compositions are formulated in a liquid dosage form.

[0028] In some embodiments, the pharmaceutical composition is administered in a single injection. In some embodiments, the pharmaceutical composition is administered in multiple injections.

[0029] In some embodiments, the pharmaceutical composition is administered parenterally, hi some embodiments, the pharmaceutical composition is administered subcutaneously.

[0030] In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the lipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the lipoma at a dosage of about 1 mg to about 10 mg per cm of lipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the lipoma at a dosage of about 5 mg to about 10 mg per cm of lipoma.

[0031] In some embodiments, the pharmaceutical composition further comprises at least one additional active agent.

[0032] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0033] [Figure 1] Figure 1 shows the percentage reduction in pain per lipoma after 84 days of treatment of Dercum's disease patients with Compound 1 or placebo. A statistically significant mean reduction in pain of 59.06% was seen in the treatment group compared to 37.50% in the placebo group (p=0.0004, t-test). [Diagram 2] Figure 2 shows the percent pain reduction per patient after 84 days of treatment of Dercum's disease patients with Compound 1 or placebo. A mean pain reduction of 56.37% was seen in the treatment group compared to 36.82% for placebo.

[0034] Detailed Description of the Invention 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.

[0035] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0036] 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 a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl 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 carbons 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.

[0037] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups. An alkyl group is a group having 1 to 9 carbon atoms (C 1-9 alkyl), 1 to 8 carbon atoms (C 1-8 alkyl), 1 to 6 carbon atoms (C 1-6 alkyl), 1 to 5 carbon atoms (C 1-5 alkyl) and the like, with 1 to 12 carbon atoms (e.g., C 1-12The alkyl group may contain a substituted or unsubstituted alkyl group (alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl, and the like. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise stated herein, the alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0038] "Haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0039] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group, including straight or branched chain alkenyl groups containing at least one double bond. Alkenyl groups are groups having 2 to 9 carbon atoms (C 2-9 alkenyl), 2 to 8 carbon atoms (C 2-8 alkenyl), 2 to 6 carbon atoms (C 2-6 alkenyl), 2 to 5 carbon atoms (C 2-5 alkenyl) and the like (e.g., C 2-12 Alkenyl). Exemplary alkenyl groups include ethynyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0040] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group, including straight or branched chain alkynyl groups containing at least one triple bond. Alkynyl groups are alkynyl groups having 2 to 9 carbon atoms (C 2-9 alkynyl), 2 to 8 carbon atoms (C2-8 alkynyl), 2 to 6 carbon atoms (C 2-6 alkynyl), 2 to 5 carbon atoms (C 2-5 alkynyl) and the like (e.g., C 2-12 Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted by one or more substituents, such as those described herein.

[0041] "Heteroalkyl", "heteroalkenyl", and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups having one or more skeletal atoms selected from atoms other than carbon, respectively. Exemplary skeletal atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, where the nitrogen (N), phosphorus (P), or sulfur (S) atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized (i.e., to form a quaternary ammonium ion). In given cases, the numerical ranges refer to the total chain length. For example, a 3-8 membered heteroalkyl has a chain length of 3-8 atoms. Attachment to the remainder of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless otherwise stated herein, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted with one or more substituents, such as those described herein.

[0042] "Aryl" refers to an aromatic ring in which the atoms forming the ring are each carbon atoms. As used herein, an aryl ring may be selected from a monocyclic, bicyclic, tricyclic, or polycyclic ring system, in which at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Huckel theory. An aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl naphthyl, fluorenyl, indanyl, indenyl, and tetralinyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless otherwise stated in the specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include aryl radicals that are optionally substituted with one or more substituents, such as those described herein.

[0043] "Heteroaryl" refers to a 3-12 membered aromatic ring containing at least one heteroatom, each heteroatom may be independently selected from N, O, and S. As used herein, a heteroaryl ring 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., it contains a cyclic delocalized (4n+2) π-electron system according to Huckel theory. The 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 where valence allows, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 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, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imido, and the like. Dazo[l,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[l,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, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxazolyl, Xoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl pyridyl, 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-cycloheptyl Examples of heteroaryl include thiazolyl, thiadiazolyl, triazolyl, tetraazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl is optionally substituted with one or more substituents, such as those described herein.

[0044] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, where each of the atoms forming the ring (i.e., skeletal atoms) are carbon atoms. In some embodiments, a cycloalkyl is saturated or partially unsaturated. In some embodiments, a cycloalkyl is a spirocyclic or bridged compound. In some embodiments, a cycloalkyl is fused to an aromatic ring (where the cycloalkyl is attached via a non-aromatic ring carbon atom). A cycloalkyl group is a ring having from 3 to 9 carbon atoms (C 3-9 Cycloalkyl), 3 to 8 carbon atoms (C 3-8 Cycloalkyl), 3 to 6 carbon atoms (C 3-6 Cycloalkyl), 3 to 5 carbon atoms (C 3-5 Cycloalkyl) and the like, with 3 to 10 ring atoms (e.g., C 3-10 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 groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraynyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. Unless otherwise specified herein, cycloalkyl groups may be optionally substituted with one or more substituents, such as those described herein.

[0045] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated in the specification, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially or fully saturated. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, 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, and the like. The term "heterocycloalkyl" also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2-12 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood 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 herein, a heterocycloalkyl group may be optionally substituted with one or more substituents, such as those described herein.

[0046] The term "substituted" refers to a moiety having one or more substituents replacing hydrogen on one or more carbon or heteroatoms of the structure. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, as well as the implicit proviso that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In some embodiments, examples of substituents include, but are not limited to, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds, and the like. Permissible substituents can be one or more per appropriate organic compound and can be the same or different. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Substituents can include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., a 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 and heteroaromatic moieties, and the like.

[0047] Those skilled in the art will understand that the substituents themselves can be substituted, where appropriate.Unless specifically stated as "unsubstituted", references to chemical moieties herein are understood to include substituted variants.For example, references to "heteroaryl" groups or moieties implicitly include both substituted and unsubstituted variants.

[0048] Where substituents are specified by their conventional chemical formula written from left to right, they equally encompass the chemically identical substituents resulting from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0049] "Optional" or "optionally" means that the event described following the circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups that have no substitution.

[0050] The compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharma- ceutically acceptable salts, zwitterions, prodrugs, and active metabolites of these compounds, having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0051] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number 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 natural isotopes, designated H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment of deuterium may provide certain therapeutic benefits, such as increased in vivo half-life and / or exposure, or provide a compound useful for investigating in vivo pathways of drug elimination and metabolism. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0052] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of an enantiomer pair is a "racemic" mixture. The term "(±)" is used to indicate 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 configuration at each chiral carbon can be specified by either R or S, where the absolute configuration is unknown. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute configuration as (R)- or (S)-. The chemical compounds, pharmaceutical compositions, and methods of the present invention 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 by any suitable method, including, but not limited to, chiral chromatography and polarimetry, to determine the degree to which one stereoisomer predominates over the other.

[0053] Chemical substances having carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E-forms (or cis- or trans-forms). Additionally, some chemical substances can exist in various tautomeric forms. Unless otherwise specified, chemical substances described herein are intended to include all of the Z-, E-, and tautomeric forms as well.

[0054] Isolation and purification of the chemicals and intermediates described herein, if desired, can be carried out by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin or thick layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[0055] When no configuration is specified, the specific small molecules described herein include, but are not limited to, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, etc., to the extent that they can be made by one of ordinary skill in the art through routine experimentation, if possible. In these circumstances, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of racemic or diastereomeric mixtures. Resolution of racemic or diastereomeric mixtures, if possible, can be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two enantiomers can be purified to provide further optically enriched forms of the major enantiomer by recrystallization and / or trituration. Furthermore, such specific small molecules include Z- and E-forms (or cis- and trans-forms) of specific small molecules having carbon-carbon or carbon-nitrogen double bonds. Where a particular small molecule described herein exists in various tautomeric forms, the term "particular small molecule" is intended to encompass all tautomeric forms of the particular small molecule.

[0056] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect the intended use, including but not limited to disease treatment (including alleviation of symptoms), as defined below. Therapeutically effective amounts may vary depending on the intended treatment use (in vivo), or the subject and disease state to be treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., and can be easily determined by those skilled in the art. The term also applies to a dose that induces a particular response in target cells, such as a reduction in platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compound selected, the administration regimen to be followed, 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 to which it is delivered.

[0057] As used herein, "treat" or "treating" refers to an approach to obtain a beneficial or desired result with respect to a disease, disorder, or condition, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can include, for example, eradication or amelioration of the underlying disease being treated. A therapeutic benefit can also include, for example, eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such that an improvement is observed in the subject, even though the subject may still be afflicted with the underlying disease. In certain embodiments, for prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject who reports one or more of the physiological symptoms of the disease, even if the disease has not been diagnosed.

[0058] A "therapeutic benefit," as that term is used herein, encompasses the therapeutic benefits described above and / or prophylactic benefits. 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.

[0059] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, include administration of two or more agents to an animal, including a human, such that both agents and / or their metabolic products are present in the subject at the same time. Co-administration includes administration at the same time in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0060] compound In one embodiment, a compound according to formula (I):

[0061] [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently 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)2NR 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, or C 2-5 alkynyl, where each alkyl, alkenyl, or alkynyl is independently optionally 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)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)2NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 Substituted with one or more substituents selected from the group consisting of N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, or 3- to 10-membered heterocycloalkyl; R 9 is substituted with at least one quaternary ammonium or phosphonium group; Each R 10 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 is cycloalkyl, Each R 11 and R 12 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl or C 3-6 cycloalkyl or R 11 and R 12 together with the nitrogen atom to which they are attached, are an optionally substituted 3- to 10-membered heterocycloalkyl; and Each R13 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 It is cycloalkyl.

[0062] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently 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)2NR 11 R 12 , C 1-5 Alkyl, C 2-5 Alkenyl, and C 2-5 alkynyl, where each alkyl, alkenyl, and alkynyl is independently optionally selected from the group consisting of 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 , and -NR 13 S(=O)2NR 11 R 12 is substituted with one or more substituents selected from:

[0063] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, halogen, -CN, -NO2, -OR 10 , -NR 11 R 12 , -C(=O)R 10 , -C(=O)OR 10 , and C 1-5 alkyl, where each alkyl is independently optionally selected from the group consisting of 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 , and -NR 13 S(=O)2NR 11 R 12 is substituted with one or more substituents selected from:

[0064] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, halogen, -CN, -NO2, -OR 10 , and -NR 11 R 12 is selected from the group consisting of:

[0065] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each hydrogen.

[0066] 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 R4 At least one of is halogen, and R 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 is a halogen, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 The remainder of R are hydrogen. 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 6 is 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 3is 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.

[0067] In some embodiments, the halogen is bromo. In some embodiments, the halogen is chloro. In some embodiments, the halogen is fluoro. In some embodiments, the halogen is iodo.

[0068] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of is OH. In some embodiments, 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 8 At least one of is OH. In some embodiments, R 5 is OH. In some embodiments, R 6 is OH. In some embodiments, R 7is OH. In some embodiments, R 8 is OH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 At least one of is OH, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 The remainder is hydrogen.

[0069] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of R is nitro, and R 5 , R 6 , R 7 , and R 8 At least one of R is nitro. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 At least one of R is nitro, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 The remainder of R are hydrogen. 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 7is 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 3 is 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.

[0070] In some embodiments, R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 In some embodiments, R is selected from the group consisting of alkynyl, and 3- to 10-membered heterocycloalkyl. 9 is optionally replaced by C 1-9 In some embodiments, R9 is a C substituted with at least one quaternary ammonium group 1-9 In some embodiments, R 9 is a C substituted with at least one phosphonium group 1-9 In some embodiments, R 9 is a C substituted with at least one phosphonium group 2-9 In some embodiments, R is alkenyl. 9 is a C substituted with at least one quaternary ammonium group 2-9 In some embodiments, R is alkenyl. 9 is a C substituted with at least one phosphonium group 2-9 In some embodiments, R is alkynyl. 9 is a C substituted with at least one quaternary ammonium group 2-9 In some embodiments, R is alkynyl. 9 is 3-10 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 9 is thiomorpholinyl. In some embodiments, R 9 is a C substituted with at least one phosphonium group 1-9 In some embodiments, R 9 is a C substituted with at least one quaternary ammonium group 1-9 In some embodiments, R 9 is propyl substituted with at least one quaternary ammonium group. In some embodiments, R 9 is butyl substituted with at least one quaternary ammonium group. In some embodiments, R 9 is pentyl substituted with at least one quaternary ammonium group.

[0071] In some embodiments, the compound comprises a positively charged moiety (e.g., ammonium, phosphonium). In some embodiments, the compound comprising a positively charged moiety can be in the form of a salt that further comprises a negatively charged counterion. For example, if the compound comprises a quaternary ammonium or phosphonium salt, the compound can be in the form of a salt with a negatively charged counterion, such as a halide (e.g., chloride).

[0072] In some embodiments, the compound comprises a negatively charged moiety, hi some embodiments, the compound comprising a negatively charged moiety may be in the form of a salt that further comprises a positively charged counterion.

[0073] In some embodiments, the at least one quaternary ammonium group is represented by a structure according to formula (V):

[0074] [ka] In the formula, R 14 , R 15 , and R 16 are each independently 1-9 Alkyl, C 2-9 Alkenyl, and C 2-9 In some embodiments, R is selected from the group consisting of alkynyl. 14 , R 15 , and R 16 are each independently 2-9 In some embodiments, R is alkenyl. 14 , R 15 , and R 16 are each independently 2-9 In some embodiments, R is alkynyl. 14 , R 15 , and R 16 are each independently 1-9 In some embodiments, R 14 , R 15 , and R 16In some embodiments, formula (V) further comprises a counter ion, as represented by the structure set forth in formula (V'):

[0075] [ka] During the ceremony,

[0076] [ka] is a negatively charged counterion as defined herein. In some embodiments, X is a halogen, e.g., Cl, Br, F, I. In some embodiments, X is a halide, e.g., Cl.

[0077] In some embodiments, at least one phosphonium group is according to formula (VI):

[0078] [ka] In the formula, R 17 , R 18 , and R 19 are each independently 1-9 Alkyl, C 2-9 Alkenyl, and C 2-9 In some embodiments, R is selected from the group consisting of alkynyl. 17 , R 18 , and R 19 are each independently 2-9 In some embodiments, R is alkenyl. 17 , R 18 , and R 19 are each independently 2-9 In some embodiments, R is alkynyl. 17 , R 18 , and R 19 are each independently 1-9 In some embodiments, R 17 , R 18 , and R19 is independently methyl. In some embodiments, formula (VI) further comprises a counter ion, as represented by the structure set forth in formula (VI'):

[0079] [ka] During the ceremony,

[0080] [ka] is a negatively charged counterion as defined herein. In some embodiments, X is a halogen, e.g., Cl, Br, F, I. In some embodiments, X is a halide, e.g., Cl.

[0081] In some embodiments, R 10 are independent of each other, H, C 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 independent of each other, H, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 10 are independent of each other, H, C 1-5 Alkyl, and C 3-6 In some embodiments, R 10 is H. In some embodiments, R 10 is independent, C 1-5 In some embodiments, R 10 is independent, C 2-5 In some embodiments, R is alkenyl. 10 is independent, C 2-5In some embodiments, R is alkynyl. 10 is independent, C 1-5 In some embodiments, R 10 is independent, C 1-5 In some embodiments, R 10 is independent, C 3-6 It is cycloalkyl.

[0082] In some embodiments, R 11 and R 12 are independent of each other, H, C 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 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-10 membered heterocycloalkyl. In some embodiments, R 11 and R 12 are independently H, C 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 independently H, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 11 and R 12 are independently H, C 1-5 Alkyl, and C 3-6 In some embodiments, R 11 and R 12are both H. In some embodiments, R 11 and R 12 are each independently 1-5 In some embodiments, R 11 and R 12 are each independently 2-5 In some embodiments, R is alkenyl. 11 and R 12 are each independently 2-5 In some embodiments, R is alkynyl. 11 and R 12 are each independently 1-5 heteroalkyl, and in some embodiments, R 11 and R 12 are each independently 1-5 haloalkyl, and in some embodiments, R 11 and R 12 are each independently 3-6 In some embodiments, R 11 and R 12 can be combined with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycloalkyl.

[0083] In some embodiments, R 13 are independent of each other, H, C 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 13 are independent of each other, H, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, and C 3-6 In some embodiments, R 13 are independent of each other, H, C 1-5 Alkyl, and C 3-6In some embodiments, R 13 is H. In some embodiments, R 13 is independent, C 1-5 In some embodiments, R 13 is independent, C 2-5 In some embodiments, R is alkenyl. 13 is independent, C 2-5 In some embodiments, R is alkynyl. 13 is independent, C 1-5 In some embodiments, R 13 is independent, C 1-5 In some embodiments, R 13 is independent, C 3-6 It is cycloalkyl.

[0084] In some embodiments, the compound of formula (I) is selected from the group consisting of 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.

[0085] 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-(carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium 9H-. 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.

[0086] In some embodiments, the compound of formula (I) is in a pharmaceutically acceptable salt form.The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions.When the compound of formula (I) contains one or more positive charges, the counterion has one or more corresponding negative charges to produce a neutral molecule.When the compound of formula (I) contains one or more negative charges, the counterion has one or more corresponding positive charges to produce a neutral molecule.

[0087] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids and their corresponding counterions. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. For example, salts can include counter anions that are halogen counter anions, such as chloride and bromide anions. Organic acids from which salts can be obtained 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 and their corresponding counter ions. Inorganic bases from which salts can be obtained include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and the like. In some embodiments, the pharma-ceutically acceptable base addition salts are selected from ammonium, phosphonium, potassium, sodium, calcium, and magnesium salts.

[0088] In some embodiments, Compound (I) is in the form of a salt with an inorganic acid. In some embodiments, Compound (I) is in the form of a salt with hydrochloric acid (i.e., the counter ion is chloride (Cl)).

[0089] In some embodiments, the compound of formula (I) is 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, represented by the structure set forth in Formula 1 below.

[0090] [ka]

[0091] In some embodiments, the compound of formula (I) is 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, represented by the structure set forth in Formula 1A below.

[0092] [ka]

[0093] In some embodiments, the compound of formula (I) is represented by the structure set forth in formula (2) below.

[0094] [ka]

[0095] In some embodiments, the compound of formula (I) is represented by the structure set forth in formula (3) below.

[0096] [ka]

[0097] In some embodiments, the compound of formula (I) is represented by the structure set forth in formula (IV) below.

[0098]

change

[0099] Any compound herein can be purified. The compound herein can be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure. At least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure. at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure.It may be at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

[0100] How to use In some embodiments, the compounds and compositions described herein are useful for treating pain. In some embodiments, the compounds and compositions described herein are useful for treating pain associated with lipoma (i.e., lipoma pain). In some embodiments, the compounds and compositions described herein are useful for treating pain associated with lipoma in subjects with skin disease. As shown herein, injection of a single dose of Compound 1 into lipoma (either by single injection or multiple injections) significantly reduces lipoma-associated pain.

[0101] In some embodiments, the subject to be treated has Dercum's disease. In some embodiments, the subject has lipomas associated with Dercum's disease. The skin disease is a rare adipose disorder (RAD) and is typically characterized by obesity and chronic pain (>3 months) in the subcutaneous adipose tissue (SAT). The pain associated with DD is often debilitating and resistant to typical analgesic treatments.

[0102] The etiology of Dercum's disease is currently unknown. Several hypotheses have been proposed, including nervous system dysfunction, adipose tissue dysfunction, lymphatic vasculopathy, endocrine dysfunction, mechanical pressure on the nerves, and the result of trauma. Some reports suggest that Dercum's disease may be an inherited autosomal dominant disorder with variable expression, but the majority of cases occur sporadically without any specific genetic mutation.

[0103] Dercum's disease can be classified into four types: generalized diffuse type, generalized nodular type, localized nodular type, and juxta-articular form. The diffuse type is characterized by widespread pain from the SAT located anywhere from the head to the sole of the foot without obvious lipoma. Generalized nodular typically occurs in widespread and painful adipose tissue with more pain in the vicinity of the lipoma, whereas in localized nodular type, pain is limited to the area in and around the lipoma. Finally, the carbazole derivatives of the present disclosure (e.g., compounds I, 1, 2, 3, or 4) are useful for treating any one or more of the types of skin disease, including generalized diffuse type, generalized nodular type, localized nodular type, and juxta-articular form.

[0104] There are subjects with Dercum's disease who have mixed lipomas, i.e., small and large lipomas. Lipomas can range from less than 1 cm in diameter to more than 10 cm in diameter. In some embodiments, lipomas treatable by the compounds of the present disclosure range from 1-2 cm, 2-3 cm, 3-4 cm, 4-5 cm, 5-6 cm, 6-7 cm, 7-8 cm, 8-9 cm, 9-10 cm, 1-3 cm, 2-4 cm, 3-5 cm, 4-6 cm, 5-7 cm, 6-8 cm, 7-9 cm, 8-10 cm, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 cm in diameter, or shorter or longer. As described herein, the dose of the carbazole derivative of the present disclosure (e.g., compound I, 1, 2, 3, or 4) can be adjusted based on the size of the lipoma to be treated and / or the degree of pain experienced by the subject to be treated.

[0105] In some embodiments, a method of treating lipoma pain, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition in unit dosage form, the pharmaceutical composition comprising a compound according to formula (I):

[0106] [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently 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)2NR 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, or C 2-5alkynyl, where each alkyl, alkenyl, or alkynyl is independently optionally 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)2NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 Substituted with one or more substituents selected from the group consisting of N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, or 3- to 10-membered heterocycloalkyl; R 9 is substituted with at least one quaternary ammonium or phosphonium group; Each R 10 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 is cycloalkyl, Each R 11 and R 12 are independent of each other, H, C 1-5 Alkyl, C2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl or C 3-6 cycloalkyl or R 11 and R 12 together with the nitrogen atom to which they are attached, are an optionally substituted 3- to 10-membered heterocycloalkyl; and Each R 13 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 is cycloalkyl, Methods are provided herein.

[0107] In some embodiments, provided herein is a method of treating lipoma pain, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition in unit dosage form, the pharmaceutical composition comprising a compound of formula 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating lipoma pain, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition in unit dosage form, the pharmaceutical composition comprising a compound of formula 2, or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating lipoma pain, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition in unit dosage form, the pharmaceutical composition comprising a compound of formula 3, or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating lipoma pain, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition in unit dosage form, the pharmaceutical composition comprising a compound of formula 4, or a pharma- ceutically acceptable salt thereof.

[0108] Provided herein is a pharmaceutical composition in unit dosage form comprising a compound of formula (I) for use in treating lipoma pain, for example, pain associated with Dercum's lipoma. Provided herein is a pharmaceutical composition in unit dosage form comprising a compound of formula 1 for use in treating lipoma pain, for example, pain associated with Dercum's lipoma. Provided herein is a pharmaceutical composition in unit dosage form comprising a compound of formula 2 for use in treating lipoma pain, for example, pain associated with Dercum's lipoma. Provided herein is a pharmaceutical composition in unit dosage form comprising a compound of formula 3 for use in treating lipoma pain, for example, pain associated with Dercum's lipoma. Provided herein is a pharmaceutical composition in unit dosage form comprising a compound of formula 4 for use in treating lipoma pain, for example, pain associated with Dercum's lipoma.

[0109] The compounds of the present disclosure reduce or eliminate the pain associated with lipoma. In some embodiments, the pain is reduced by at least 10% compared to before treatment, for example, by about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to before treatment. In some embodiments, the pain is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to before treatment after a single administration of a compound of formula (I), where the single administration may be given as a single injection or multiple injections as described herein.

[0110] In some embodiments, the reduction in pain is measured by a comparative pain scale that ranks pain on a score of 0 to 10. For example, a score of 0 may indicate no pain, a score of 1-3 may indicate mild pain, a score of 4-6 may indicate moderate pain, and a score of 7-10 may indicate severe pain. In some embodiments, the reduction in pain is assessed per subject as described herein. In some embodiments, the reduction in pain is assessed per subject as compared to pre-treatment. In some embodiments, the reduction in pain is assessed per subject as compared to a placebo control. In some embodiments, the reduction in pain is measured / analyzed per lipoma as described herein. In some embodiments, the reduction in pain is measured / analyzed per lipoma as compared to pre-treatment. In some embodiments, the reduction in pain is measured / analyzed per lipoma as compared to a placebo control.

[0111] In some embodiments, the lipoma is not an angiolipoma. Angiolipomas are subcutaneous tumors of the extremities and trunk. Subcutaneous angiolipomas have a normal karyotype, which distinguishes them from most other adipose tumors, including lipomas. For this reason, they have been considered vascular and adipose hamartomas, rather than true adipose tumors. In contrast to lipomas that contain only adipose tissue, angiolipomas have a thin fibrous capsule with incomplete fibrous septa that extend throughout the lesion, dividing it into lobules of different sizes. They are composed of various proportions of adipose tissue and blood vessels.

[0112] In some embodiments, the compounds of the present disclosure reduce lipoma pain for an extended period of time after a single administration of compound (I). For example, the duration of pain can be reduced for at least about 1 month after a single administration of compound (I). In some embodiments, the pain can be reduced for at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or more after a single administration of compound (I). For example, the duration of pain can be reduced for at least about 30 days after a single administration of compound (I). In some embodiments, pain may be relieved for at least about 60 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 120 days, 150 days, 180 days, 200 days, 220 days, 240 days, 260 days, 280 days, 300 days, 320 days, 340 days, 360 days or 365 days or more following a single administration of Compound (I). It is understood that a single administration of Compound (I) may be provided in a single injection or multiple injections of a dose of Compound (I).

[0113] Administration and Dosing Regimen In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into the lipoma. In some embodiments, the injections can be randomly spread on the surface of the lipoma with a distance between injections of at least 1 cm, for example, 1.1 cm, 1.2 cm, 1.3 cm, 1.4 cm, 1.5 cm, 1.6 cm, 1.7 cm, 1.8 cm, 1.9 cm, 2.0 cm, or more than 2.0 cm. In some embodiments, the injections can be made at 90° to the surface of the skin being injected, or at any other angle as needed, for example, 5°, 10°, 15°, 20°, 25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, or 85°. In some embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 lipomas / nodules may be injected per subject.

[0114] In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1 mg to about 10 mg / cm of Compound (I) (e.g., Compounds 1, 2, 3, 4) per lipoma (based on the diameter of the lipoma). In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1 mg to about 50 mg / cm of Compound (I) (e.g., Compounds 1, 2, 3, 4) per lipoma (based on the diameter of the lipoma), e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg , 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, or 50 mg / cm / cm of Compound (I) (e.g., Compounds 1, 2, 3, 4).

[0115] In some embodiments, the pharmaceutical composition is administered parenterally. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the lipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the lipoma at a dosage of about 0.05 mL to about 0.1 mL per lipoma. In some embodiments, the pharmaceutical composition is formulated at a dosage of about 0.05 mL to about 0.2 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated at a dosage of about 0.1 mL to about 0.2 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated at a dosage of about 0.1 mL to about 0.4 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated at a dosage of about 0.4 mL to about 1 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated at a dosage of about 1 mL to about 2 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of less than about 0.05 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.05 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.1 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.2 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.3 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.4 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.5 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.6 mL per lipoma for direct subcutaneous injection into the lipoma.In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.7 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.8 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 0.9 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.0 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.1 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.2 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.3 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.4 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.5 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.6 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.7 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.8 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 1.9 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of about 2.0 mL per lipoma for direct subcutaneous injection into the lipoma. In some embodiments, the pharmaceutical composition is formulated in a dosage of more than about 2.0 mL per lipoma for direct subcutaneous injection into the lipoma.

[0116] In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the lipoma at a dosage of about 0.05 mL to about 0.1 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into the lipoma at a dosage of about 0.05 mL to about 0.2 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into the lipoma at a dosage of about 0.1 mL to about 0.2 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into the lipoma at a dosage of about 0.1 mL to about 0.4 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into the lipoma at a dosage of about 0.4 mL to about 1 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into the lipoma at a dosage of about 1 mL to about 2 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of less than about 0.05 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.05 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.1 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.2 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.3 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.4 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.5 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.6 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.7 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.8 mL / cm / lipoma.In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 0.9 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.0 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.1 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.2 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.3 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.4 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.5 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.6 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.7 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.8 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 1.9 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of about 2.0 mL / cm / lipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into a lipoma at a dosage of greater than about 2.0 mL / cm / lipoma.

[0117] The total amount of each compound administered will depend on the mammal being treated, the severity of the disorder or disease, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. However, an effective dosage may range from about 0.001 mg to about 100 mg / kg / body weight / day, in single or divided doses. In some embodiments, the compound is administered in an amount ranging from about 0.01 mg / kg to about 100 mg / kg, 0.1 mg / kg to about 100 mg / kg, about 10 mg / kg to about 80 mg / kg, about 20 mg / kg to about 50 mg / kg, etc. In some instances, dosage levels below the lower end of the aforementioned ranges may be fully appropriate, while in other cases even larger doses may be used without causing any adverse side effects, for example, by dividing such larger doses into several smaller doses for administration throughout the day. In some embodiments, an effective dosage may be provided by pulsed dosing (i.e., daily administration of the compound followed by daily rests from administration).

[0118] In some embodiments, the compound of formula (I) is administered at about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about The compound may be administered in an amount of about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0119] In some embodiments, the pharmaceutical composition is administered in a single dose. In some embodiments, the pharmaceutical composition is administered by a single injection. In some embodiments, the pharmaceutical composition is administered in a single dose by a single injection. In some embodiments, the pharmaceutical composition is administered in a single dose by multiple injections. In some embodiments, the pharmaceutical composition is administered in multiple doses, the pharmaceutical composition is administered in multiple doses by multiple injections.

[0120] In some embodiments, the pharmaceutical composition is administered by multiple injections, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 injections per lipoma. In some embodiments, the pharmaceutical composition is administered by multiple injections, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 injections per subject. In some embodiments, the pharmaceutical composition is administered in a single dose by multiple injections, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 injections per lipoma. In some embodiments, the pharmaceutical composition is administered in a single dose by multiple injections, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 injections per subject.

[0121] Combination therapy In some embodiments, the carbazole derivatives of the present disclosure can be used in combination with one or more additional therapies.In some embodiments, the carbazole derivatives of the present disclosure can be used in combination with the medicines that are used as standard treatment for treating pain, for example, lipoma pain, for example, lipoma pain associated with Dercum's disease.

[0122] There is no specific treatment for Dercum's disease. Treatment is primarily symptomatic and supportive, focusing primarily on relieving the characteristic painful episodes. Various painkillers are used (i.e., lidocaine). Surgical removal of lipomas may temporarily relieve symptoms, but recurrence often occurs. Liposuction has been used as a supportive treatment for some individuals with Dercum's disease and may provide an initial reduction in pain and improvement in quality of life. Psychotherapy and consultation with pain management specialists may be useful in enabling affected individuals to cope with prolonged severe pain.

[0123] In some embodiments, the disclosed compounds or pharmaceutical compositions may be used in conjunction with any one or more of the aforementioned therapies. Thus, in some embodiments, the disclosed pharmaceutical compositions further comprise at least one additional active agent. In some embodiments, the additional active agent is a cytotoxic agent. In some embodiments, the additional active agent is an analgesic agent. An "analgesic agent" may be any one of a group of drugs used to achieve pain reduction or relief in a mammal. Non-limiting examples include acetaminophen / paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, opioids, and the like.

[0124] Thus, in some embodiments, the pharmaceutical composition comprising the compound of formula (I) can be administered as part of a treatment regimen that includes administering one or more second agents (e.g., one, two, three, four, five, or more than five second agents useful for treating pain, e.g., pain associated with Dercum lipoma) simultaneously or sequentially with the pharmaceutical composition comprising the compound of formula (I). When administered sequentially, the pharmaceutical composition comprising the compound of formula (I) can be administered before or after the one or more second agents. When administered simultaneously, the pharmaceutical composition comprising the compound of formula (I) and one or more second agents can be administered by the same route (e.g., injection into the same place), by different routes (e.g., tablets taken orally while receiving intravenous infusion), or as part of the same combination (e.g., a solution containing the pharmaceutical composition comprising the compound of formula (I) and one or more second agents).

[0125] The combination treatments described in the present disclosure may be effective over a wide dosage range. For example, in treating adults, dosages of 0.01 mg to 1000 mg per day, 0.5 mg to 100 mg, 1 mg to 50 mg, and 5 mg to 40 mg per day are examples of dosages that may be used. The exact dosage depends on the agent selected, the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, and the preferences and experience of the attending physician.

[0126] Pharmaceutical Compositions The composition of the present disclosure can be formulated into any suitable pharmaceutical preparation.The pharmaceutical composition of the present disclosure typically contains active ingredient (e.g., compound of formula (I), or its pharma- ceutically acceptable salt and / or coordination complex) and one or more pharma- ceutically acceptable excipients or carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants.The composition of the present disclosure can be formulated into any suitable pharmaceutical preparation.

[0127] 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 dosage form.

[0128] In some embodiments, the composition is provided in one or more unit doses. For example, the composition can be administered in one, two, three, four, five, six, seven, fourteen, thirty, sixty, or more than sixty doses. Such amounts can be administered in individual doses administered daily, for example, once, twice, or three or more times a day. However, the dosages described herein per day should not be interpreted as requiring daily administration of the daily dose. For example, if one of the agents is provided in a suitable slow-release form, two or more daily doses can be administered as a depot injection administered less frequently, for example, from every other day to once a month or more frequently. Most typically and conveniently for a subject, the pharmaceutical composition comprising the compound of formula (I) can be administered once a day, for example, in the morning, evening, or during the day.

[0129] The unit dose can be administered simultaneously or sequentially. The composition can be administered over a long-term 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 remaining life of the subject.

[0130] The pharmaceutical compositions described herein may contain one or more pharma- ceutically acceptable excipients.As used herein, the phrase "pharma-ceutically acceptable excipient" or "pharma-ceutically acceptable carrier" refers to a pharma-ceutically acceptable material, composition, or vehicle, such as liquid or solid filler, diluent, excipient, solvent, or sealing material.Each carrier must be "acceptable" in the sense that it is compatible with other ingredients of the formulation and is not harmful to the patient. Some examples of materials that can serve as pharma- ceutically acceptable carriers include: (1) surfactants, such as hydrophilic surfactants, lipophilic surfactants, nonionic surfactants, cationic surfactants, and anionic surfactants; (2) solubilizing agents, such as alcohols; (3) solvents, such as water, alcohols, and glycols; (4) sugars, such as lactose, glucose, and sucrose; (5) starches, such as corn starch and potato starch; (6) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (7) powdered tragacanth; (8) malt; (9) gelatin; (10) talc; (11) cocoa butter and suppository waxes. (12) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (13) glycols, such as propylene glycol; (14) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (15) esters, such as ethyl oleate and ethyl laurate; (16) agar; (17) buffers, such as magnesium hydroxide and aluminum hydroxide; (18) alginic acid; (19) pyrogen-free water; (20) isotonic saline; (21) Ringer's solution; (22) ethyl alcohol; (23) phosphate buffer; (24) other non-toxic and compatible substances used in pharmaceutical formulations. The composition may further include one or more pharma- ceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifiers, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicity agents, flavors, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0131] In some embodiments, the pharmaceutical composition comprises one or more surfactants.Surfactants that can be used to form the pharmaceutical composition and dosage form of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, nonionic surfactants, cationic surfactants, anionic 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.

[0132] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. 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 higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with HLB values ​​greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​equal to or less than about 10. However, the HLB value of a surfactant is merely a rough guide that is commonly used to enable the formulation of emulsions for industrial, pharmaceutical, and cosmetic applications.

[0133] Hydrophilic surfactants can be either ionic or nonionic.Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidic acid 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 their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; docusate sodium; acyl acrylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0134] Within the aforementioned group, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids, and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; docusate sodium; acyl acrylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0135] The ionic surfactants can be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic acid esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters, citrate esters of mono / diglycerides, cholyl, caprylic acid. It may be caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearic acid, lauryl sulfate, teraceyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0136] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one of the groups of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyethylene glycol sorbitan fatty acid esters and polyols with at least one of the groups of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0137] Other hydrophilic non-ionic 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 stearate, PEG-32 distearate, PEG-40 stearate, PEG-10 stearate 0, 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, PEG- 40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60com Oil, PEG-6 Caprylic / Capric Glycerides, PEG-8 Caprylic / Capric 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, Tween 80, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer. In some embodiments, the surfactant is a Tween. In some embodiments, the surfactant is a Tween 80.

[0138] 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, monoglyceride and diglyceride lactic acid derivatives, hydrophobic transesterification products of polyols with at least one of the following groups: glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-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 are hydrophobic transesterification products of polyols with at least one of the following groups: vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0139] In one embodiment, the composition may contain a solvent / solubilizer 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.Solubilizers may 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. Examples of suitable solvents / solubilizers include, but are not limited to, alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and their isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidinone, 2-pyrroli ... The solubilizing agent may be selected from the group consisting of 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, beta-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. In some embodiments, the solubilizing agent is benzyl alcohol.

[0140] Mixtures of solubilizers may 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.

[0141] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biologically acceptable amount, which can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer that far exceeds the biologically acceptable amount, and the excess solubilizer is removed before providing the composition to the patient using conventional techniques such as distillation or evaporation. When present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or less, can also 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.

[0142] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharma-ceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, carbonates, 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), and the like. Also suitable are bases that are salts of pharma- ceutically 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, hydroquinosulfonic 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, etc. Salts of polyprotic 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, pharma-ceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0143] The acid suitable for use in the composition of the present disclosure is a pharma- ceutically acceptable organic or inorganic acid.Suitable examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc.Suitable examples of organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic 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.

[0144] In one embodiment, a pharmaceutical composition comprising a compound according to formula (I):

[0145] [ka] or a pharma- ceutically acceptable salt thereof is provided herein: During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently 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 13C(=O)NR 11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)2NR 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, or C 2-5 alkynyl, where each alkyl, alkenyl, or alkynyl is independently optionally 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)2NR 11 R 12 , -C(=S)R 10 , -N(=O), -SN(=O), -NR 13 Substituted with one or more substituents selected from the group consisting of N(=O), and -ON(=O); R 9 is C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 alkynyl, or 3 to 10 membered heterocycloalkyl; R 9 is substituted with at least one quaternary ammonium or phosphonium group; Each R 10 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 is cycloalkyl, Each R 11 and R 12 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl or C 3-6 cycloalkyl or R 11 and R 12 together with the nitrogen atom to which they are attached, are optionally substituted 3- to 10-membered heterocycloalkyl; and Each R 13 are independent of each other, H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, or C 3-6 It is cycloalkyl.

[0146] 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 about 0% to about 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 10% to about 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 15% to about 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 15% to about 25% water by weight. In some embodiments, the pharmaceutical composition comprises about 20% to 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 23% to about 27% water by weight. In some embodiments, the pharmaceutical composition comprises about 24% to 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.

[0147] In some embodiments, the pharmaceutical composition comprises at least 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). 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 0.2% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.3% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.4% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.6% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.7% by weight of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.8% by weight of the 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).

[0148] In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 10 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 20 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 25 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 50 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 75 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 100 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 150 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 200 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 250 mg / mL. In some embodiments, the compound of formula (I) may be present in the composition in an amount of about 400 mg / mL.

[0149] In some embodiments, the compound of formula (I) is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 20 ... 0mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg , about 900mg, about 950mg, about 1000mg, about 1050mg, about 1100mg, about 1150mg, about 1200mg, about 1250mg, about 1300mg, about 1350mg, about 1400mg, about 1450mg. It may be present in the composition in an amount of about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0150] Injectable pharmaceutical composition In some embodiments, the present disclosure provides an injectable pharmaceutical composition comprising a compound of formula (I) and a pharmaceutical excipient suitable for injection. The amounts of ingredients and drugs in the composition are as described herein.

[0151] Forms in which the compositions of the present disclosure may be incorporated for administration by injection include aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. In some embodiments, the compositions include solvents (e.g., water, alcohol, glycol), solubilizers, solvents, and surfactants.

[0152] Aqueous solutions in physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (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 dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0153] Sterile injectable solution is prepared by incorporating the compound of the present disclosure in the required amount in a suitable solvent together with various other components as listed above as necessary, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active components into a sterile vehicle that contains a basic dispersion medium and other components as listed above.For the preparation of sterile powder for the preparation of sterile injectable solution, the specific desired preparation method is vacuum drying and freeze-drying technology, which produces powder of active component and any additional desired component from its previously sterile filtered solution.

[0154] 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.

[0155] kit The present invention also provides kits. The kits may include pharmaceutical compositions containing a compound of formula (I) and one or more additional agents in suitable packaging, along with written materials that may include instructions for use, clinical trial discussions, lists of side effects, and the like. Such kits may also include information such as references to scientific literature, package insert materials, clinical trial results, and / or summaries thereof, that show or establish the activity and / or benefits of the composition, and / or describe dosing, administration, side effects, drug interactions, or other information useful to medical practitioners. Such information may be based on the results of various studies, for example, studies using laboratory animals, including in vivo models, and studies based on human clinical trials. The kits may further include another agent. In some embodiments, the compounds and agents of the present invention are provided as separate compositions in separate containers in the kit. In some embodiments, the compounds and agents of the present invention are provided as a single composition in a container in the kit. Suitable packaging and additional items for use (e.g., measuring cups for liquid preparations, foil wrapping to minimize exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein can be provided, sold and / or promoted to health care providers, including physicians, nurses, pharmacists, prescribers, etc. The kits may also, in some embodiments, be sold directly to consumers. EXAMPLES

[0156] Example 1: Clinical Trials The clinical trial described herein was a double-blind, randomized, placebo-controlled Phase 2b clinical trial to evaluate the safety and efficacy of Compound 1 (5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, provided as the chloride salt, also referred to as Compound 1A) in subjects with Dercum's disease (DD) lipomas.

[0157] Study Objectives: The primary objective was to assess the mean reduction in lipoma height at 84 days post-injection and at baseline in the treatment group compared with the placebo group. Efficacy was determined by ultrasound assessment of lipoma / nodule dimensions post-treatment and at baseline. A key secondary objective was assessment of pain associated with the lipoma / nodule using a comparative pain scale. Safety was assessed by frequency of adverse events and by changes from baseline in vital signs, clinical laboratory values, and ECG. Study design. The study was a double-blind, multicenter, randomized, placebo-controlled clinical trial in DD subjects with lipomas. A total of 38 DD patients were enrolled in the study. Patients were randomly assigned in approximately a 1:1 ratio to either the intervention or placebo group. Twenty subjects with a total of 125 lipomas were treated with Compound 1. Eighteen subjects with a total of 110 lipomas were treated with placebo. After 84 days of dosing, the code was opened upon completion of the study.

[0158] Controls received the test treatments in multiple injections at one time, and dosing was calculated according to the size (diameter) of the lipomas as determined by ultrasound.

[0159] Subjects were dosed according to Table 1. Injections were perpendicular (90°) to the surface of the skin being injected and randomly spread at least 1 cm apart.

[0160] [Table 1]

[0161] At least 4, preferably 6, and no more than 8 lipomas / nodules were injected per subject. The dose of Compound 1 per injection site was 5 mg, and a distance of 1 cm to 3 cm was maintained between injection points to allow good dispersion of Compound 1 within the fat of the lipoma. A maximum dose of up to 240 mg per subject (a total of 48 injections of 5 mg each) was allowed in the study, with the actual maximum tested dose being 200 mg per subject (40 injections into 4 to 8 lipomas). A total of 20 patients were treated with Compound 1, and a total of 18 patients were treated with placebo.

[0162] The primary endpoint was the mean percent reduction in lipoma / nodule height at 84 days post-injection and at baseline, as assessed by ultrasound, for Compound 1-treated versus placebo groups. A key secondary endpoint was the reduction in local pain scores per lipoma / nodule at 84 days post-injection and at baseline, as measured by a comparative pain scale. Pain was ranked on a scale of 0 to 10, with a score of 0 indicating no pain, a score of 1-3 indicating mild pain, a score of 4-6 indicating moderate pain, and a score of 7-10 indicating severe pain. Pain was compared between the intervention (Compound 1) and placebo groups at two levels: (1) at the patient level, and (2) by lipoma, i.e., comparison between all injected lipomas before and after injection.

[0163] Investigational Medications. Compound 1 was administered as a ready-to-use liquid for subcutaneous fat injection, supplied in a 1-vial kit. Each vial contains Compound 1, a solution of 250 mg of Compound 1 per 5 mL (50 mg / mL) in a vehicle composed of water, propylene glycol, and surfactant. The formulation is described in Table 2.

[0164] [Table 2]

[0165] The placebo was a solution consisting of vehicle only. Compound 1 and placebo injections were 0.1 ml each. The vehicle was a ready-to-use liquid for subcutaneous fat injections, supplied in a 1-vial kit. Each vial contained 5 mL and had a similar composition to the Compound 1 formulation, but without the active substance. The ingredients were Tween-80, propylene glycol, benzyl alcohol, and water. The vehicle was manufactured and packaged by Nextar (Israel) and was in accordance with cGMP standards.

[0166] Statistical methods. All measured variables and derived parameters are listed separately and tabulated with descriptive statistics where appropriate. For categorical variables, summary tables are provided giving the sample size, absolute and relative frequencies, and 95%CI (confidence intervals) for the proportions by study group. For continuous variables, summary tables are provided giving the sample size, arithmetic mean, standard deviation, coefficient of variation (CV%), median, minimum and maximum, and 95%CI (confidence intervals) for the mean of the variables by study group. All tests were two-sided and a p-value of 5% or less will be considered statistically significant. Data were analyzed using SAS® version 9.4 (SAS Institute, Cary, NC).

[0167] Per-patient analysis (based on 4-8 lipomas / nodules per patient). Two-sample T-test for independent samples or non-parametric Wilcoxon signed rank test (as appropriate) was applied to test for statistically significant differences between study groups in the percentage reduction in lipoma / nodules height at 84 days post-injection and at baseline. Analysis of covariance (ANCOVA) models were applied to identify covariance parameters suspected to be associated with lipoma / nodules height reduction and to test for differences in the percentage reduction in lipoma / nodules height between treatment groups adjusted for the covariates mentioned above.

[0168] Analysis by lipoma / nodule (based on 4–8 lipomas / nodule per patient). MMRM models (mixed-effects models for repeated measures) were applied to analyze between-group differences in the percentage reduction in lipoma / nodule height from baseline to day 84, adjusting appropriately for the covariates listed above.

[0169] result The effect of Compound 1 on Dercum's lipomas was assessed by: (1) change in lipoma height and other dimensions based on ultrasound measurements of each injected lipoma at the baseline visit and at post-treatment follow-up visits 28, 56, and 84 days after injection; and (2) change in lipoma pain based on the Comparative Pain Scale for each injected lipoma at the baseline visit and at post-treatment follow-up visits 28, 56, and 84 days after injection.

[0170] Lipoma pain changes Pain in each injected lipoma was assessed by a blinded physician at the baseline visit before injection and at each follow-up visit using the comparative pain scale described herein.

[0171] (i) Changes in lipoma pain by lipoma A total of 125 lipomas were evaluated for pain at baseline in the Compound 1 treatment group, and 108 lipomas were evaluated in the placebo group. Table 3 summarizes the mean total lipoma pain by treatment group and study visit. The change in lipoma pain (percentage) from baseline by analysis of all lipomas is shown in Table 4. Figure 1 shows the percentage reduction in pain by lipoma 84 days after treatment.

[0172] The results show a significant reduction in pain per lipoma in the Compound 1 treatment group versus the placebo group. Total lipoma analysis showed a mean pain reduction of 59.06% ± 40.41 in the Compound 1 treatment group versus 37.50% ± 49.69 in the placebo group. Statistical significance tested by a mixed model with repeated measures yielded a p-value of 0.079. Calculation of statistical difference using a t-test yielded a p-value of 0.0004.

[0173] [Table 3]

[0174] [Table 4]

[0175] (ii) Changes in lipoma pain by patient Table 5 shows the mean pain by patient by treatment group and study visit. The change in lipoma pain (percentage) from baseline by patient analysis is shown in Table 6. The patient analysis showed a mean pain reduction of 56.37% ± 35.72 in treated subjects compared with a mean pain reduction of 36.82% ± 37.20 in placebo-treated subjects (P = 0.98). Figure 2 shows the percent pain reduction by patient at 84 days after treatment.

[0176] [Table 5]

[0177] [Table 6]

[0178] conclusion Although the reduction in lipoma height was not significant, Compound 1 showed a statistically significant reduction in pain in lipoma-specific analysis and a trend toward pain reduction in patient-specific analysis compared to the placebo group.Without wishing to be bound by any theory or mechanism of action, the effectiveness of Compound 1 treatment for pain reduction may be related to the fact that adipose tissue is dissolved in the injected lipoma, which can reduce the density of the lipoma and result in a reduction in the pressure on the nerve caused by the lipoma after treatment.

[0179] The compound was generally well tolerated. No serious adverse events were reported and there were no clinically significant changes in hematological parameters. Adverse events consisted mostly of injection site edema, pain and pruritus.

[0180] Although several embodiments have been shown and described, various modifications and substitutions can be made without departing from the spirit and scope of the present invention. For example, for the purpose of claim construction, the claims set forth below are not intended to be interpreted narrower than their literal meaning, and thus, the exemplary embodiments from this specification are not intended to be read into the claims. Therefore, it should be understood that the present invention has been described by way of example, and not by way of limiting the scope of the claims.

Claims

1. A pharmaceutical composition in unit dosage form for use in treating the pain of lipoma in a subject, said pharmaceutical composition comprising a compound of formula (I) below, 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R6, R7, and R8 are each independently H, halogen, -CN, -NO2, -OR10, -SR10, -S(=O)R10, -S(=O)2R10, -NR11R12, -C(=O)NR11R12, -S(=O)NR11R12, -S(=O)2NR11R12, -C(=O)R10, -C(=O)OR10, -NR13C(=O)R10, -NR13C(=O)NR11R12, -NR13S(=O)2R10, -NR13S(=O)2NR11R12, -C(=S)R10, -N(=O), -SN(=O), -NR13N(=O), -ON(=O), C1-5 alkyl, C2-5 alkenyl, or C2-5 alkynyl, where each alkyl, alkenyl, or alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO2, -OR10, -SR10, -S(=O)R10, -S(=O)2R10, -NR11R12, -C(=O)NR11R12, -S(=O)NR11R12, -S(=O)2NR11R12, -C(=O)R10, -C(=O)OR10, -NR13C(=O)R10, -NR13C(=O)NR11R12, -NR13S(=O)2R10, -NR13S(=O)2NR11R12, -C(=S)R10, -N(=O), -SN(=O), -NR13N(=O), and -ON(=O), R9 is C1-9 alkyl substituted with at least one quaternary ammonium group, each R10 is independently H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-5 heteroalkyl, C1-5 haloalkyl, or C3-6 cycloalkyl, Each R11 and R12 is independently H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-5 heteroalkyl, C1-5 haloalkyl, or C3-6 cycloalkyl, or R11 and R12, together with the nitrogen atom to which they are attached, are an optionally substituted 3- to 10-membered heterocycloalkyl, and each R13 is independently H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-5 heteroalkyl, C1-5 haloalkyl, or C3-6 cycloalkyl, Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the subject has Duchenne disease.

3. The at least one quaternary ammonium group is a group described by the following formula (V'), [Chemical Formula 2] wherein, X is a negatively charged ion, optionally, X is Cl, R14, R15, and R16 are each independently methyl, the pharmaceutical composition according to claim 1 or 2.

4. At least one of R1, R2, R3, and R4 is halogen, at least one of R5, R6, R7, and R8 is halogen, the pharmaceutical composition according to claim 1.

5. The halogen is bromo, the pharmaceutical composition according to claim 4.

6. At least one of R1, R2, R3, and R4 is OH, or at least one of R5, R6, R7, and R8 is OH, the pharmaceutical composition according to claim 1.

7. The compound described by the 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, or 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium, the pharmaceutical composition according to claim 1.

8. The compound described by the formula (I) is The pharmaceutical composition according to claim 1, which is 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride.

9. The pharmaceutical composition according to claim 1, further comprising at least one pharmaceutically acceptable excipient.

10. The excipient is a surfactant, and the surfactant is Tween-80, the excipient is a solubilizer, and the solubilizer is benzyl alcohol, and / or the excipient is a solvent, and the solvent is propylene glycol or water, the pharmaceutical composition according to claim 9.

11. The pharmaceutical composition according to claim 1, comprising about 10% to about 30% by weight of water.

12. The pharmaceutical composition according to claim 1, comprising about 0.1% to about 10% by weight of the compound described in formula (I).

13. The pharmaceutical composition according to claim 1, comprising 1 mg to 100 mg of the compound described in formula (I) per 1 mL.

14. The pharmaceutical composition is formulated in a liquid dosage form, the pharmaceutical composition is formulated for single or multiple injections, the pharmaceutical composition is directly subcutaneously injected into the lipoma, the pharmaceutical composition according to claim 1.

15. The pharmaceutical composition according to claim 14, which is directly subcutaneously injected into the lipoma at a dosage of about 1 mg to about 10 mg per 1 cm of the lipoma.

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