Composition for the treatment of angiolipoma

Abstract

The present invention provides carbazole derivatives for treating angiolipomas and related symptoms and conditions in tissues and organs.

Description

[Technical Field]

[0001] cross reference This invention claims the benefit of U.S. Provisional Patent Application No. 62 / 966,577, filed on 28 January 2020, which is incorporated herein by reference. [Background technology]

[0002] Angiolipomas, subcutaneous tumors of the limbs and torso, account for approximately 10% of all lipomas. They are often multiple, with the first tumor appearing shortly after puberty. A familial history is observed in about 10% of cases, but no genetic pattern has been proposed. In rare cases, a history of past trauma to the site or a history of therapeutic use of protease inhibitors has been associated with the condition. In one case, multiple angiolipomas appeared in a young adult male with familial angiolipomatosis at the same time as the initiation of anabolic steroid use. Mild pain or discomfort is often observed upon compression or movement of the lesion, and this pain appears to be related to the vascularity of the lesion.

[0003] Subcutaneous angiolipomas have a normal karyotype and are distinguished from most other fatty tumors, including lipomas. For this reason, subcutaneous angiolipomas have been viewed not as true fatty tumors, but as hamartomas of blood vessels and fat. Macroscopically, they are yellowish, hard, localized tumors ranging in diameter from 1 to 4 cm. The cross-section may appear yellow to red, reflecting the degree of vascular distribution. Subcutaneous angiolipomas must be distinguished from invasive angiolipomas, which are isolated lesions in deep soft tissue.

[0004] In contrast to lipomas, which contain only adipose tissue, angiolipomas have a thin fibrous capsule with incomplete fibrous septa extending into the lesion, and are divided into lobules of varying sizes. These are composed of varying proportions of adipose tissue and blood vessels. The adipocytes are mature and have one vacuole and an eccentric nucleus. The vascular component, which accounts for 5-50% or more of the tumor, consists of capillaries and occasionally large-diameter vessels. In lesions reported as cellular angiolipomas, adipocytes are sparsely present and consist mostly of small vessels. Often, angiolipomas show prominent pericytes around the vessels. Red blood cells are present in the lumen, and scattered fibrin thrombi are readily found. In one report, hemorrhagic infarction of fat was present with numerous fibrin thrombi and disseminated intravascular coagulation. Thus, because angiolipomas contain fibrous tissue, they appear to be less responsive to lipid-reducing agents. While fat-reducing agents can remove fat from angiolipomas, they are not expected to reduce the size of the angiolipoma because they cannot interact with the fibrous capsule that forms the boundary of the angiolipoma.

[0005] Angiolipomas can cause significant pain by compressing adjacent nerves. Treatment for angiolipomas typically involves surgery, or in some cases, injections of corticosteroids into the cell mass. Therefore, there remains a need for the development of further drugs for the treatment of angiolipomas. [Overview of the project]

[0006] In one embodiment, formula (I) is used for the treatment of hemangiolipoma and any associated symptoms or diseases:

[0007] [ka] Pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof are provided herein. During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R6 、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, and C 2-5 alkynyl, whereby alkyl, alkenyl, and alkynyl are each independently 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 is optionally substituted with one or more substituents selected from -N(=O), and -ON(=O), R 9 is, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, and 3 - to 10 - member heterocycloalkyl, where R 9 is substituted with at least one quaternary amino group or phosphonium group, R 10 is each 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 cycloalkyl, R 11 and R 12 are each independently H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 heteroalkyl, C 1-5 haloalkyl, C 3-6 cycloalkyl, or one R 12 and one R 13 may together with the nitrogen atom to which they are attached form a 3 - to 10 - member heterocycloalkyl, and R 13 is each independently H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 heteroalkyl, C 1-5 haloalkyl, and C 3-6It is selected from cycloalkyl.

[0008] In some embodiments, R 9 is C1-C9 alkyl substituted with at least one quaternary amino group.

[0009] In some embodiments, at least one ammonium group is of the formula (V):

[0010]

Chemical formula

[0011] In some embodiments, at least one of R 1 , R 2 , R 3 , and R 4 is halogen. In some embodiments, at least one of R 5 , R 6 , R 7 , and R 8 is halogen. In some embodiments, at least one of R 1 , R 2 , R 3 , and R 4 is halogen, and at least one of R 5 , R 6 , R 7 , and R 8 is halogen. In some embodiments, the halogen is bromo.​​​​​​2 , R 3 , and R 4 At least one of them is OH. In some embodiments, R 5 , R 6 , R 7 , and R 8 At least one of them is OH.

[0013] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of them is nitro, and R 5 , R 6 , R 7 , and R 8 At least one of them is nitro.

[0014] In certain embodiments, the compound of formula (I) is 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropane-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-trimethylpentane-1-aminium Selected from.

[0015] In some embodiments, the pharmaceutical composition contains less than about 50% by weight of water. In some embodiments, the pharmaceutical composition contains less than about 30% by weight of water. In some embodiments, the pharmaceutical composition contains less than about 10% by weight of water. In some embodiments, the pharmaceutical composition contains about 0% to about 30% by weight of water.

[0016] In some embodiments, the pharmaceutical composition contains at least about 0.1% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.1% to about 10% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 1% to about 5% by weight of the compound of formula (I).

[0017] In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0018] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into an angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of about 0.05 to about 0.1 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of about 0.1 to about 0.4 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of about 0.4 to about 1 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of about 1 to about 2 mL per angiolipoma for direct subcutaneous injection into angiolipoma.

[0019] In other embodiments, a kit is provided herein, comprising a pharmaceutical composition provided herein, means for administering the pharmaceutical composition, and instructions for use thereof.

[0020] In some embodiments, the kit further includes at least one additional therapeutic agent.

[0021] In another embodiment, a method for treating a target angiolipoma is provided herein, the method comprising formula (I):

[0022] [ka] The process includes administering a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof to a subject. During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 These are H, halogen, -CN, -NO2, and -OR, respectively, independently. 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 and C 2-5 Selected from alkynyl, where alkyl, alkenyl, and alkynyl are independently halogen, -CN, -NO2, and -OR, respectively. 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 R12 -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 It is optionally substituted with one or more substituents selected from N(=O) and -ON(=O), R 9 C 1-9 Alkyl, C 2-9 Alkenil, C 2-9 Selected from alkynyls and 3- to 10-membered heterocycloalkyls, where R 9 It is substituted with at least one quaternary amino group or phosphonium group, R 10 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 Selected from cycloalkyl groups, or one R group 12 and one R 13 These may, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocycloalkyl group, and further, R 13 These are H and C, which are independent of each other. 1-5Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups.

[0023] 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 administered subcutaneously directly to the angiolipoma at a dose of approximately 0.05 to approximately 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of approximately 0.1 to approximately 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of approximately 0.4 to approximately 1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of approximately 1 to approximately 2 mL per angiolipoma.

[0024] Embedding by citation All publications, patents, and patent applications referenced herein are incorporated herein by reference in whole to the same extent that each publication, patent, or patent application is intended to be incorporated by specific and individual reference. [Modes for carrying out the invention]

[0025] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art in which this disclosure pertains.

[0026] As used herein, the singular forms "a," "an," and "the" include multiple items unless the context explicitly specifies otherwise.

[0027] "C x-yThe term "C" means a group containing x to y carbon atoms in a chain, when used in combination with chemical moieties such as alkyl, alkynyl, or alkenyl. For example, "C 1-6 The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups containing 1 to 6 carbon atoms. -C x-y The term "alkylene-" refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms. For example, -C 1-6 The alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, and one of these may be optionally substituted.

[0028] "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups. Alkyl groups consist of 1 to 8 carbon atoms (C 1-8 Alkyl) or 1 to 6 carbon atoms (C 1-6 Alkyl) and other elements with 1 to 12 carbon atoms (for example, C 1-12 The molecule may contain alkyl groups. 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. The alkyl group is attached to the rest of the molecule by a single bond. Unless otherwise specifically provided herein, the alkyl group may be optionally substituted with one or more substituents, such as those described herein.

[0029] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0030] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group containing a linear or branched alkenyl group having at least one double bond. The alkenyl group may contain 2 to 12 carbon atoms (for example, C 2-12 Alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, buto-1-enyl, penta-1-enyl, and penta-1,4-dienyl. Unless otherwise specified herein, alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0031] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group containing a linear or branched alkynyl group having at least one triple bond. The alkynyl group may contain 2 to 12 carbon atoms (for example, C 2-12 Alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless otherwise specified herein, the alkynyl group may be optionally substituted with one or more substituents, such as those described herein.

[0032] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, respectively, having one or more skeletal chain atoms selected from atoms other than carbon. Exemplary skeletal chain atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof. Nitrogen, phosphorus, and sulfur atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. If given, the range of numbers refers to the total chain length. For example, 3- to 8-membered heteroalkyls have a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be via a heteroatom or carbon in the heteroalkyl chain, heteroalkenyl chain, or heteroalkynyl chain. Unless otherwise specifically provided herein, heteroalkyl, heteroalkenyl, or heteroalkynyl groups are optionally substituted with one or more substituents, such as substituents described herein.

[0033] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl groups are optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, the aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless otherwise specifically defined herein, the term "aryl" or the prefix "ar-" (as in "aralkyl") means that it includes optionally substituted aryl radicals.

[0034] A "heteroaryl" refers to a 3- to 12-membered aromatic ring containing at least one heteroatom, each of which can be independently selected from N, O, and S. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Heteroatoms in heteroaryls may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryls may also be bonded to the rest of the molecule via any valence-acceptable atom of the heteroaryl, such as the carbon or nitrogen atoms of the heteroaryl. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imi Dazo[1,2-a]pyridinyl], carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridadinyl, 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]pyrimidinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthilidinyl, 1,6-naphthilidinolyl, oxadiazolyl, 2-o Xoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl Dinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, 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-cyclo Examples include hepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyrimidinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically provided herein, heteroaryls are optionally substituted with one or more substituents, such as those described herein.

[0035] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, where each of the ring-forming atoms (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or crosslinked compounds. In some embodiments, cycloalkyls may be condensed at an aromatic ring (in which case the cycloalkyl is bonded via non-aromatic ring carbon atoms). Cycloalkyl groups include those having 3 to 10 cyclic atoms. Representative cycloalkyls, but not limited to, include those having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic radicals include adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, dekalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl. Unless otherwise specified herein, cycloalkyl groups may be optionally substituted.

[0036] The term "heterocycloalkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically provided herein, heterocycloalkyl radicals may be monocyclic or bicyclic ring systems, which may include condensed (when condensed with an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atom in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. Heterocycloalkyls may be partially or completely saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, 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, trithianil, tetrahydropyranil, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl further includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 12 carbon atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, note that the number of carbon atoms in a 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 specifically specified herein, heterocycloalkyls may be optionally substituted.

[0037] The term “substituted” refers to a portion of a structure having a substituent that replaces a hydrogen atom on one or more carbon or heteroatoms. “Substituted” or “substituted with” implies the implicit condition that such substitution conforms to the acceptable valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo deformation, such as reconfiguration, cyclization, or removal. As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In a wide range of embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carboxycyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. There may be one or more acceptable substituents for a given organic compound, and they may be the same or different. For the purposes of this disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and / or any acceptable substituent of an organic compound described herein that satisfies the valency of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyls, carbonyls (carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (such as thioesters, thioacetates, or thioformates), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, carbocyclics, heterocyclics, cycloalkyls, heterocycloalkyls, aromatic moieties, and heteroaromatic moieties.

[0038] It will be understood by those skilled in the art that substituents can be substituted by themselves where appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein should be understood to include substituted variants. For example, references to “heteroaryl” groups or moieties implicitly include both substituted and unsubstituted variants.

[0039] When substituents are identified by their conventional formulas and written from left to right, these equally encompass chemically identical substituents resulting from writing the structure from right to left; for example, -CH2O- is equal to -OCH2-.

[0040] "Optional" or "optionally" means that the event or situation described below may or may not occur, and that this description includes examples of when the event or situation occurs and examples of when it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that this description includes both substituted and unsubstituted aryl groups.

[0041] The compounds of this disclosure include these compounds, pharmaceutically acceptable salts of the above compounds having the same type of activity, and crystalline and amorphous forms of active metabolites, and include, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous), stereopolymorphs, and amorphous forms of the above compounds, as well as mixtures thereof.

[0042] The compounds disclosed herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure. For example, hydrogen, 1 H (protium), 2 H (deuterium), and 3 It has three naturally occurring isotopes, denoted as H(tritium). Protium is the most abundant hydrogen isotope in nature. Deuterium enrichment may result in certain therapeutic benefits, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating in vivo pathways of drug excretion and metabolism. Isotope-enriched compounds can be prepared by prior art well known to those skilled in the art.

[0043] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to represent a racemic mixture when appropriate. "Diastereoisomers" are stereoisomers that have at least two chiral atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Divided compounds whose absolute configuration is unknown can be specified as (+) or (-) by the direction in which they rotate the plane-polarized light at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein contain one or more chiral centers, and thus can give rise to enantiomers, diastereomers, and other stereoisomers, the chiral centers of which may be defined as (R)- or (S)- with respect to absolute stereochemistry. The chemical entities, pharmaceutical compositions, and methods described herein 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 can be separated using conventional techniques. The optical activity of a compound can be analyzed by appropriate methods, including, but not limited to, chiral chromatography and polarimetric analysis, to determine the degree of dominance of one stereoisomer over the other isomers.

[0044] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond may exist in Z-form or E-form (or cis-form or trans-form). Furthermore, some chemical entities may exist in various tautomers. Unless otherwise specified, the chemical entities described herein are intended to include all Z-, E-, and tautomer forms.

[0045] The isolation and purification of the chemical entities and intermediates described herein can be carried out by any suitable separation or purification procedure, as necessary, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination thereof. Specific examples of suitable separation and isolation procedures can be obtained by referring to the following examples herein. However, other equivalent separation or isolation procedures may also be used.

[0046] Where stereochemistry is not specified, the specific small molecules described herein, without limitation, include isomers, e.g., enantiomers and diastereomers, mixtures of enantiomers including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent that they can be prepared by those skilled in the art through routine experimentation. In these situations, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by the resolution of a racemate or mixture of diastereomers. The resolution of a racemate or mixture of diastereomers can be achieved, if possible, by conventional methods, e.g., crystallization in the presence of a resolving agent, or by chromatography, e.g., using a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture enriched in one of the two enantiomers can be purified and recrystallized and / or tritulated to provide a further optically enriched form of the major enantiomer. Furthermore, such specific small molecules include Z and E forms (or cis and trans forms) of a small molecule having a carbon-carbon double bond or a carbon-nitrogen double bond. When a small molecule described herein exists in various tautomers, the term “a small molecule” is intended to include all tautomers of that small molecule.

[0047] The terms "salt" or "pharmaceutically acceptable salt" refer to salts derived from various organic and inorganic counterions known in the art. Pharmacopoecitable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmacopoecitable salt addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts may be derived include, for example, primary amines, secondary amines, and tertiary amines, spontaneously occurring substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from salts of ammonium, potassium, sodium, calcium, and magnesium.

[0048] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation and is not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, and corn oil. (10) Oils such as sorghum oil and soybean oil, (11) Glycols such as propylene glycol, (12) Polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (13) Esters such as ethyl oleate and ethyl laurate, (14) Agar, (15) Buffers such as magnesium hydroxide and aluminum hydroxide, (16) Alginic acid, (17) Water free of pyrogens, (18) Isotonic saline, (19) Ringer's solution, (10) Ethyl alcohol, (11) Phosphate buffer, and (12) Other non-toxic suitable substances used in pharmaceutical formulations.

[0049] The terms “effective dose” or “therapeutic effective dose” refer to the amount of a compound described herein that is sufficient to produce an effect for the intended use, including, but not limited to, the treatment of diseases as defined below. The therapeutic effective dose may vary depending on the intended treatment use (in vivo) or the condition of the subject and the disease being treated, e.g., the subject’s weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that induce a specific response in target cells, e.g., a decrease in platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compound selected, the subsequent drug regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system through which it is carried.

[0050] As used herein, “treatment” or “treating” refers to a method for obtaining a beneficial or desired outcome with respect to a disease, disorder, or medical condition, including, but not limited to, therapeutic and / or preventive benefits. Therapeutic benefits may include, for example, the eradication or remission of the underlying disorder being treated. Similarly, therapeutic benefits may include, for example, the eradication or remission of one or more physiological symptoms associated with the underlying disorder, such that improvement in the subject is observed, even though the subject may still be affected by the underlying disorder. In certain embodiments, with respect to preventive benefits, the composition is administered to a subject at risk of progression of a particular disease, or to a subject reporting one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0051] "Therapeutic effect" encompasses the therapeutic and / or preventive benefits described above, as the term is used herein. Preventive effects include delaying or eliminating the onset of disease or illness, delaying or eliminating the onset of symptoms of disease or illness, slowing, halting, or reversing the progression of disease or illness, or any combination thereof.

[0052] The terms "co-administration," "administered in combination with," and their grammatical equivalents encompass the administration of two or more drugs to an animal, including humans, where both the drugs and / or their metabolites are present in the target simultaneously. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which both drugs are present.

[0053] compound In one aspect, equation (I):

[0054] [ka] Compounds of or pharmaceutically acceptable salts thereof are provided herein. During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 These are H, halogen, -CN, -NO2, and -OR, respectively, independently. 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 and C 2-5 Selected from alkynyl, where alkyl, alkenyl, and alkynyl are independently halogen, -CN, -NO2, and -OR, respectively. 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 It is optionally substituted with one or more substituents selected from N(=O) and -ON(=O), R 9 C 1-9 Alkyl, C 2-9 Alkenil, C 2-9 Selected from alkynyls and 3- to 10-membered heterocycloalkyls, where R 9 It is substituted with at least one quaternary amino group or phosphonium group, R 10 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C3-6 Selected from cycloalkyl groups, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 Selected from cycloalkyl groups, or one R group 12 and one R 13 These may, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocycloalkyl group, and further, R 13 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups.

[0055] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 These are H, halogen, -CN, -NO2, and -OR, respectively, independently. 10 , -SR 10 -S(=O)R 10 -S(=O)2R 10 , -NR 11 R 12 -C(=O)NR 11 R 12 -S(=O)NR 11 R 12 -S(=O)2NR 11 R 12 -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)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 and C 2-5 Selected from alkynyl, where alkyl, alkenyl, and alkynyl are independently halogen, -CN, -NO2, and -OR, respectively. 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 It is optionally substituted with one or more substituents selected from N(=O) and -ON(=O). In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 These are H, halogen, -CN, -NO2, and -OR, respectively, independently. 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 Selected from alkynyl, where alkyl, alkenyl, and alkynyl are halogen, -CN, -NO2, and -OR, respectively. 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 It is optionally replaced with one or more substituents selected from. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8These are H, halogen, -CN, -NO2, and -OR, respectively, independently. 10 , -NR 11 R 12 -C(=O)R 10 , -C(=O)OR 10 , and C 1-5 Selected from alkyl groups, where each alkyl group is independently halogen, -CN, -NO2, and -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 It is optionally replaced with one or more substituents selected from. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 These are H, halogen, -CN, -NO2, and -OR, respectively, independently. 10 , and -NR 11 R 12 Selected from.

[0056] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of them is a halogen. In some embodiments, R 1 is a halogen. In some embodiments, R 2 is a halogen. In some embodiments, R3 is a halogen. In some embodiments, R 4 is a halogen. In some embodiments, R 5 , R 6 , R 7 , and R 8 At least one of them is a halogen. In some embodiments, R 5 is a halogen. In some embodiments, R 6 is a halogen. In some embodiments, R 7 is a halogen. In some embodiments, R 8 is a halogen. In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of them is a halogen, and R 5 , R 6 , R 7 , and R 8 At least one of them is a halogen. In some embodiments, R 1 is a halogen, and R 5 is a halogen. In some embodiments, R 1 is a halogen, and R 6 is a halogen. In some embodiments, R 1 is a halogen, and R 7 is a halogen. In some embodiments, R 1 is a halogen, and R 8 is a halogen. In some embodiments, R 2 is a halogen, and R 5 is a halogen. In some embodiments, R 2 is a halogen, and R 6 is a halogen. In some embodiments, R 2 is a halogen, and R 7 is a halogen. In some embodiments, R 2 is a halogen, and R 8 is a halogen. In some embodiments, R 3 is a halogen, and R 5 is a halogen. In some embodiments, R3 is a halogen, and R 6 is a halogen. In some embodiments, R 3 is a halogen, and R 7 is a halogen. In some embodiments, R 3 is a halogen, and R 8 is a halogen. In some embodiments, R 4 is a halogen, and R 5 is a halogen. In some embodiments, R 4 is a halogen, and R 6 is a halogen. In some embodiments, R 4 is a halogen, and R 7 is a halogen. In some embodiments, R 4 is a halogen, and R 8 is a halogen. In some embodiments, the halogen is bromo. In some embodiments, the halogen is chloro. In some embodiments, the halogen is fluoro.

[0057] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of them 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 them is OH. In some embodiments, R 5 is OH. In some embodiments, R 6 is OH. In some embodiments, R 7 is OH. In some embodiments, R 8 It is OH.

[0058] In some embodiments, R1 , R 2 , R 3 , and R 4 At least one of them is nitro, and R 5 , R 6 , R 7 , and R 8 At least one of them is nitro. In some embodiments, R 1 It is nitro, R 5 is nitro. In some embodiments, R 1 It is nitro, R 6 is nitro. In some embodiments, R 1 It is nitro, R 7 is nitro. In some embodiments, R 1 It is nitro, R 8 is nitro. In some embodiments, R 2 is a halogen, and R 5 is nitro. In some embodiments, R 2 It is nitro, R 6 is nitro. In some embodiments, R 2 is a halogen, and R 7 is nitro. In some embodiments, R 2 It is nitro, R 8 is nitro. In some embodiments, R 3 is a halogen, and R 5 is nitro. In some embodiments, R 3 It is nitro, R 6 is nitro. In some embodiments, R 3 is a halogen, and R 7 is nitro. In some embodiments, R 3 It is nitro, R 8 is nitro. In some embodiments, R 4 is a halogen, and R 5 is nitro. In some embodiments, R 4 It is nitro, R 6 is nitro. In some embodiments, R 4 is a halogen, and R 7is nitro. In some embodiments, R 4 It is nitro, R 8 It is nitro.

[0059] In some embodiments, R 9 C 1-9 Alkyl, C 2-9 Alkenil, C 2-9 Selected from alkynyls and 3- to 10-membered heterocycloalkyls, where R 9 is substituted with at least one quaternary amino group or phosphonium group. In some embodiments, R 9 is a C substituted with at least one phosphonium group. 2-9 It is an alkenyl. In some embodiments, R 9 is a C substituted with at least one quaternary amino group. 2-9 It is an alkenyl. In some embodiments, R 9 is a C substituted with at least one phosphonium group. 2-9 In some embodiments, R 9 is a C substituted with at least one quaternary amino group. 2-9 In some embodiments, R 9 R is a 3-membered to 10-membered heterocycloalkyl. In some embodiments, R 9 is piperazinyl. In some embodiments, R 9 is pyridinyl. In some embodiments, R 9 is piperidinyl. In some embodiments, R 9 is morpholinyl. In some embodiments, R 9 is thiomorpholinyl. In some embodiments, R 9 is a C substituted with at least one phosphonium group. 1-9 It is alkyl. In some embodiments, R 9 is a C substituted with at least one quaternary amino group. 1-9 It is alkyl. In some embodiments, R 9 is a propyl substituted with at least one quaternary amino group. In some embodiments, R9 It is a pentyl compound substituted with at least one quaternary amino group.

[0060] In some embodiments, at least one quaternary amino group is of formula (V):

[0061] [ka] In the formula, R 14 , R 15 , and R 16 Each is independent of C 1-9 Alkyl, C 2-9 Alkenyl and C 2-9 - Selected from alkynnyl. In some embodiments, R 14 , R 15 , and R 16 Each is independent of C 2-9 It is an alkenyl. In some embodiments, R 14 , R 15 , and R 16 Each is independent of C 2-9 In some embodiments, R 14 , R 15 , and R 16 Each is independent of C 1-9 It is alkyl. In some embodiments, R 14 , R 15 , and R 16 Each of these is methyl.

[0062] In some embodiments, at least one phosphonium group is of formula (VI):

[0063] [ka] In the formula, R 17 , R 18 , and R 19 Each is independent of C 1-9 Alkyl, C 2-9 Alkenyl and C 2-9- Selected from alkynnyl. In some embodiments, R 17 , R 18 , and R 19 Each is independent of C 2-9 It is an alkenyl. In some embodiments, R 17 , R 18 , and R 19 Each is independent of C 2-9 In some embodiments, R 17 , R 18 , and R 19 Each is independent of C 1-9 It is alkyl. In some embodiments, R 17 , R 18 , and R 19 Each of these is methyl.

[0064] In some embodiments, R 10 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 10 These are H and C, which are independent of each other. 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 10 These are H and C, which are independent of each other. 1-5 Alkyl, and C 3-6 Selected from cycloalkyl. In some embodiments, R 10 Each of these is H. In some embodiments, R 10 Each is independently C 1-5 It is alkyl. In some embodiments, R 10 Each is independently C 2-5 It is an alkenyl. In some embodiments, R 10 Each is independently C 2-5In some embodiments, R 10 Each is independently C 1-5 It is heteroalkyl. In some embodiments, R 10 Each is independently C 1-5 In some embodiments, R 10 Each is independently C 3-6 It is a cycloalkyl group.

[0065] In some embodiments, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 -Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups, or one R group 12 and one R 13 These may combine with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycloalkyl group. In some embodiments, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, and C 3-6 Selected from cycloalkyl. In some embodiments, R 11 and R 12Each of these is H. In some embodiments, R 11 and R 12 Each is independently C 1-5 It is alkyl. In some embodiments, R 11 and R 12 Each is independently C 2-5 It is an alkenyl. In some embodiments, R 11 and R 12 Each is independently C 2-5 In some embodiments, R 11 and R 12 Each is independently C 1-5 It is heteroalkyl. In some embodiments, R 11 and R 12 Each is independently C 1-5 In some embodiments, R 11 and R 12 Each is independently C 3-6 It is cycloalkyl. In some embodiments, one R 12 and one R 13 These atoms, together with the nitrogen atom to which they are bonded, form 3- to 10-membered heterocycloalkyl groups.

[0066] In some embodiments, R 13 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 13 These are H and C, which are independent of each other. 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 13 These are H and C, which are independent of each other. 1-5 Alkyl, and C 3-6Selected from cycloalkyl. In some embodiments, R 13 Each of these is H. In some embodiments, R 13 Each is independently C 1-5 It is alkyl. In some embodiments, R 13 Each is independently C 2-5 It is an alkenyl. In some embodiments, R 13 Each is independently C 2-5 In some embodiments, R 13 Each is independently C 1-5 It is heteroalkyl. In some embodiments, R 13 Each is independently C 1-5 In some embodiments, R 13 Each is independently C 3-6 It is a cycloalkyl group.

[0067] In some embodiments, the compound of formula (I) is 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropane-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-trimethylpentane-1-aminium Selected from.

[0068] In some embodiments, the compound of formula (I) is 3-(3,6-dibromo-9H-carbazole-9-yl)-N,N,N-trimethylpropane-1-aminium. In some embodiments, the compound of formula (I) is 5-(9H-carbazole-9-yl)-N,N,N-trimethylpentane-1-aminium. In some embodiments, the compound of formula (I) is 5-(2-hydroxy-9H-carbazole-9-yl)-N,N,N-trimethylpentane-1-aminium. In some embodiments, the compound of formula (I) is 5-(3,6-dibromo-9H-carbazole-9-yl)-N,N,N-trimethylpentane-1-aminium.

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

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

[0071] [ka] In some embodiments, the compound of formula (I) is represented by the following structure.

[0072] [ka] In some embodiments, the compound of formula (I) is represented by the following structure.

[0073] [ka]

[0074] Pharmaceutical composition The compositions of this disclosure may be formulated in any suitable pharmaceutical formulation. The pharmaceutical compositions of this disclosure typically contain an active ingredient (e.g., a compound of formula (I), or a pharmaceutically acceptable salt and / or coordination complex thereof), as well as one or more pharmaceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. The compositions of this disclosure may be formulated in any suitable pharmaceutical formulation.

[0075] The pharmaceutical composition may be provided in any suitable form that may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein may be formulated in dosage forms for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, transdermal, buccal, sublingual, subcutaneous, intramuscular, intravenous, intracavitary, and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition is formulated as a unit dose.

[0076] The amount of each compound administered will depend on the mammal being treated, the severity of the disorder or disease, the administration rate, the pharmacokinetics of the compound, and the discretion of the prescribing physician. However, the effective dose may be in the range of approximately 0.001 to approximately 100 mg per kg of body weight per day, either as a single dose or in divided doses. In some cases, dose levels below the lower limit of the aforementioned range may be more than sufficient, but in other cases, such a large dose may be employed without causing any adverse side effects by dividing the large dose into several small doses per day. In some embodiments, the effective dose may be provided by pulse administration (i.e., administering the compound for several consecutive days, followed by several consecutive days of rest).

[0077] In some embodiments, the composition is provided in one or more unit doses. For example, the composition may be administered in doses of 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more. Such amounts may be administered daily, for example, in individual doses administered once, twice, or three or more times a day. However, the daily doses described herein should not be construed as requiring the daily dose to be administered every day. For example, if one of the drugs is appropriately provided in a sustained-release form, two or more daily doses may be administered at a lower frequency, for example, as a depot injection administered every other day, once a month, or even longer. Most typically and subjectively, a pharmaceutical composition containing a compound of formula (I) may be administered once a day, for example, in the morning, evening, or during the day.

[0078] The unit dose can be administered simultaneously or sequentially. This composition can be administered over an extended treatment period. Exemplary, the treatment period may be at least about one month, for example, at least about three months, at least about six months, or at least about one year. In some cases, administration may continue for substantially the remainder of the subject's life.

[0079] In some embodiments, a pharmaceutical composition comprising the compound of formula (I) may be administered as part of a treatment regimen comprising administering one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents) simultaneously with or sequentially with the pharmaceutical composition comprising the compound of formula (I). When administered sequentially, the pharmaceutical composition comprising the compound of formula (I) may be administered before or after the one or more second agents. When administered simultaneously, the pharmaceutical composition comprising the compound of formula (I) and the one or more second agents may be administered as part of the same route (e.g., injection at the same site), different routes (e.g., tablets taken orally while being administered intravenously), or the same combination (e.g., a solution comprising the pharmaceutical composition comprising the compound of formula (I) and one or more second agents).

[0080] The combination therapy according to the present invention may be effective over a wide dose range. For example, in the treatment of adult humans, doses of 0.01–1000 mg, 0.5–100 mg, 1–50 mg, and 5–40 mg per day are examples of doses that may be used. The exact dose will depend on the selected drug, route of administration, the form in which the compound is administered, the patient being treated, the patient's weight, and the attending physician's priorities and experience.

[0081] In some embodiments, the pharmaceutical composition comprises one or more surfactants. Surfactants that may be used to form the pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0082] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while a suitable lipophilic surfactant may generally have an HLB value of about 10 or less. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with high HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than about 10, as are anionic, cationic, or amphoteric compounds to which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough criterion commonly used to enable the formulation of emulsions for industrial, pharmaceutical, and cosmetic purposes.

[0083] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidicates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecitin and hydrogenated lysolecitin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; sodium doxate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citrate esters of monoglycerides and diglycerides; and mixtures thereof.

[0084] Within the aforementioned group, ionic surfactants include, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; sodium doxate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citrate esters of monoglycerides and diglycerides; and mixtures thereof.

[0085] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, and lactyl esters of fatty acids (lactylic These include esters, stearoyl-2-lactylate, stearoyl lactylate, succinyl monoglycerides, monoacetylated / diacetylated tartaric acid esters of monoglycerides / diglycerides, citrate esters of monoglycerides / diglycerides, cholylsarcosine, caproate esters, caprylic acid esters, capric acid esters, laurate esters, myristic acid esters, palmitate esters, oleate esters, ricinoleate esters, linoleate esters, linolenic acid esters, stearate esters, lauryl sulfate, teracecyl sulfate, doxate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and ionized forms of salts and mixtures thereof.

[0086] 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 alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerin 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 having at least one member from the group of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols having at least one member from the group of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerin, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0087] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100, PEG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil Oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 capric acid / caprylate glyceride, PEG-8 capric acid / caprylate glyceride, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleic acid, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether This includes 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, Tween40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0088] Suitable lipophilic surfactants include, as an example, aliphatic alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides and diglycerides; hydrophobic transesterification products of polyols having at least one member from the group of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; lipid-soluble vitamins / vitamin derivatives; and mixtures thereof. Among this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols having at least one member from the group of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0089] In one embodiment, the composition may contain a solubilizer to ensure good solubilization and / or dissolution of the compounds of the Disclosure and to minimize precipitation of the compounds of the Disclosure. This may be particularly important for injection. The solubilizer may further be added to increase the solubility of hydrophilic drugs and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0090] Examples of suitable solubilizers, but not limited to, include: alcohols and polyols, e.g., ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transktol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose, and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycoflor) or methoxyPEG; amides and other nitrogen-containing compounds, e.g., 2-pyrrolidone, 2-p The solubilizers include peridone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0091] Mixtures of solubilizers can also be used. Examples, but not limited to, include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycoflor, transktol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycoflor, and propylene glycol.

[0092] The amount of solubilizer that can be included is not particularly limited. A given amount of solubilizer may be limited to a bioacceptable amount that can be readily determined by those skilled 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 far exceeding the bioacceptable amount, and the excess solubilizer may be removed before providing the composition to the patient using conventional techniques such as distillation or evaporation. If present, the solubilizer may be present in a weight ratio of 10% by weight, 25% by weight, 50% by weight, 100% by weight, or up to about 200% by weight, based on the total weight of the drug and other excipients. If necessary, very small amounts of solubilizer may also be used, for example, 5%, 2%, 1%, or even less. Typically, the solubilizer may be present in amounts of about 1% by weight to about 100% by weight, more typically about 5% by weight to about 25% by weight.

[0093] The composition may further contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifiers, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, isotonic agents, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0094] In addition, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, aluminum magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, and tris(hydroxymethyl)aminomethane (TRIS). Furthermore, suitable bases are pharmaceutically acceptable acids, such as salts of 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, and uric acid. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, or alkaline earth metals. Examples, but not limited to, include sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0095] A suitable acid is a pharmaceutically acceptable organic or inorganic acid. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, 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, and uric acid.

[0096] In one aspect, equation (I):

[0097] [ka] Pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof are provided herein. During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 These are H, halogen, -CN, -NO2, and -OR, respectively, independently. 10 , -SR 10 -S(=O)R 10 -S(=O)2R 10 , -NR 11 R 12 -C(=O)NR 11 R 12 -S(=O)NR 11 R 12 -S(=O)2NR 11 R 12 -C(=O)R 10 , -C(=O)OR 10 , -NR 13 C(=O)R 10 , -NR 13 C(=O)NR11 R 12 , -NR 13 S(=O)2R 10 , -NR 13 S(=O)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 and C 2-5 Selected from alkynyl, where alkyl, alkenyl, and alkynyl are independently halogen, -CN, -NO2, and -OR, respectively. 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 It is optionally substituted with one or more substituents selected from N(=O) and -ON(=O), R 9 C 1-9 Alkyl, C 2-9 Alkenil, C 2-9 Selected from alkynyls and 3- to 10-membered heterocycloalkyls, where R 9 It is substituted with at least one quaternary amino group or phosphonium group, R 10 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 Selected from cycloalkyl groups, or one R group 12 and one R 13 These may, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocycloalkyl group, and further, R 13 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups.

[0098] In some embodiments, the pharmaceutical composition contains less than about 50% by weight of water. In some embodiments, the pharmaceutical composition contains less than about 30% by weight of water. In some embodiments, the pharmaceutical composition contains less than about 10% by weight of water. In some embodiments, the pharmaceutical composition contains about 0% to about 30% by weight of water. In some embodiments, the pharmaceutical composition contains about 10% to about 30% by weight of water. In some embodiments, the pharmaceutical composition contains about 15% to about 30% by weight of water. In some embodiments, the pharmaceutical composition contains about 15% to about 25% by weight of water. In some embodiments, the pharmaceutical composition contains about 20% to about 30% by weight of water. In some embodiments, the pharmaceutical composition contains about 23% to about 27% by weight of water. In some embodiments, the pharmaceutical composition contains about 24% to about 26% by weight of water. In some embodiments, the pharmaceutical composition contains about 0% by weight of water. In some embodiments, the pharmaceutical composition contains about 1% by weight of water. In some embodiments, the pharmaceutical composition contains about 2% by weight of water. In some embodiments, the pharmaceutical composition contains about 3% by weight of water. In some embodiments, the pharmaceutical composition contains about 4% by weight of water. In some embodiments, the pharmaceutical composition contains about 5% by weight of water. In some embodiments, the pharmaceutical composition contains about 6% by weight of water. In some embodiments, the pharmaceutical composition contains about 7% by weight of water. In some embodiments, the pharmaceutical composition contains about 8% by weight of water. In some embodiments, the pharmaceutical composition contains about 9% by weight of water. In some embodiments, the pharmaceutical composition contains about 10% by weight of water. In some embodiments, the pharmaceutical composition contains about 11% by weight of water. In some embodiments, the pharmaceutical composition contains about 12% by weight of water. In some embodiments, the pharmaceutical composition contains about 13% by weight of water. In some embodiments, the pharmaceutical composition contains about 14% by weight of water. In some embodiments, the pharmaceutical composition contains about 15% by weight of water. In some embodiments, the pharmaceutical composition contains about 16% by weight of water. In some embodiments, the pharmaceutical composition contains about 17% by weight of water. In some embodiments, the pharmaceutical composition contains about 18% by weight of water. In some embodiments, the pharmaceutical composition contains about 19% by weight of water.In some embodiments, the pharmaceutical composition contains about 20% by weight of water. In some embodiments, the pharmaceutical composition contains about 21% by weight of water. In some embodiments, the pharmaceutical composition contains about 22% by weight of water. In some embodiments, the pharmaceutical composition contains about 23% by weight of water. In some embodiments, the pharmaceutical composition contains about 24% by weight of water. In some embodiments, the pharmaceutical composition contains about 25% by weight of water. In some embodiments, the pharmaceutical composition contains about 26% by weight of water. In some embodiments, the pharmaceutical composition contains about 27% by weight of water. In some embodiments, the pharmaceutical composition contains about 28% by weight of water. In some embodiments, the pharmaceutical composition contains about 29% by weight of water. In some embodiments, the pharmaceutical composition contains about 30% by weight of water.

[0099] In some embodiments, the pharmaceutical composition contains at least about 0.1% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.1% to about 10% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 1% to about 5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.1% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.2% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.3% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.4% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.6% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.7% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.8% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 0.9% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 1% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 1.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 2% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 2.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 3% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 3.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 4% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 4.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 5.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 6% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 6.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 7% by weight of the compound of formula (I).In some embodiments, the pharmaceutical composition contains about 7.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 8% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 8.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 9% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 9.5% by weight of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 10% by weight of the compound of formula (I).

[0100] In some embodiments, the pharmaceutical composition further comprises at least one additional active agent. In some embodiments, the additional active agent is a cytotoxic agent.

[0101] In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, transdermal, buccal, sublingual, subcutaneous, intramuscular, intravenous, intracavitary, 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.

[0102] Pharmaceutical compositions for injection In some embodiments, this disclosure provides injectable pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutical excipient suitable for injection. The components and amounts of the drug in the composition are as described herein.

[0103] Forms in which the novel compositions of this disclosure may be incorporated for administration by injection include aqueous or oily suspensions or emulsions having sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0104] Aqueous solutions in physiological saline have also been conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Adequate fluidity can be maintained, for example, by using coatings such as lecithin to maintain the particle size required in the case of dispersion, and by using surfactants. Prevention of microbial action may be induced by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0105] Sterile injectable solutions are prepared by incorporating the required amount of the compounds of this disclosure in a suitable solvent with various other components, such as those listed above, and then sterilizing by filtration as necessary. Generally, dispersants are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. In the case of sterile powders for preparing sterile injectable solutions, particular preferred preparation methods are vacuum drying and lyophilization techniques, which yield a powder of the active ingredient in addition to any additional desired components from a previously sterile filtered solution.

[0106] The present invention also provides kits. A kit may contain a pharmaceutical composition comprising the compound of formula (I) and one or more additional agents, in appropriate packaging, along with documentation that may include instructions for use, discussions of clinical trials, lists of side effects, etc. Such a kit may further include information such as references to scientific literature, package inserts, clinical trial results, and / or summaries thereof, which indicate or establish the activity and / or benefits of the composition and / or describe dosing, administration, side effects, pharmacological interactions, or other information useful to healthcare professionals. Such information may be obtained from the results of various studies, e.g., studies using experimental animals, including in vivo models, and studies based on human clinical trials. The kit may further contain another agent. In some embodiments, the compound and agent of the present invention are provided as separate compositions in separate containers within the kit. In some embodiments, the compound and agent of the present invention are provided as a single composition in a container within the kit. Appropriate packaging and additional articles used (e.g., measuring cups for liquid preparations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein may be provided to, sold to, and / or advertised to healthcare providers, including physicians, nurses, pharmacists, and pharmacy staff (formulary officials). Depending on the embodiment, the kits may also be sold directly to consumers.

[0107] How to use Removing or reducing an angiolipoma differs significantly from treating a typical lipoma. This is because the former contains fibrous tissue. This fibrous capsule can firmly hold the angiolipoma in place, even when lipolytic agents are injected. Although angiolipomas are expected to be resistant to lipolytic agents, what is provided herein are lipolytic compounds for the treatment of angiolipomas. A single injection of compound 1 into a lipoma containing a fibrous capsule can significantly reduce its height and alleviate pain associated with the angiolipoma.

[0108] In one aspect, a pharmaceutical composition for use in treating angiolipoma and any associated symptoms or diseases, of formula (I):

[0109]

Chemical formula

[0110] In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0111] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.05 to approximately 0.1 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.1 to approximately 0.4 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.4 to approximately 1 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1 to approximately 2 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of less than approximately 0.05 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.05 mL per angiolipoma for direct subcutaneous injection into angiolipoma. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.1 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.2 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.3 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.4 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.5 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.6 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.7 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.8 mL per angiolipoma for direct subcutaneous injection into the angiolipoma.In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 0.9 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.0 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.1 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.2 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.3 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.4 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.5 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.6 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.7 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.8 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 1.9 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose of approximately 2.0 mL per angiolipoma for direct subcutaneous injection. In some embodiments, the pharmaceutical composition is formulated in a dose greater than approximately 2.0 mL per angiolipoma for direct subcutaneous injection.

[0112] In another embodiment, a method for treating a target angiolipoma is provided herein, the method comprising formula (I):

[0113] [ka] administering to a subject a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, wherein 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, and C 2-5 alkynyl, each independently selected from 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 11R 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 It is optionally substituted with one or more substituents selected from N(=O) and -ON(=O), R 9 C 1-9 Alkyl, C 2-9 Alkenil, C 2-9 Selected from alkynyls and 3- to 10-membered heterocycloalkyls, where R 9 It is substituted with at least one quaternary amino group or phosphonium group, R 10 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups, R 11 and R 12 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl, C 3-6 Selected from cycloalkyl groups, or one R group 12 and one R 13 These may, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered heterocycloalkyl group, and further, R13 These are H and C, which are independent of each other. 1-5 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 Selected from cycloalkyl groups.

[0114] 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 administered subcutaneously directly to the angiolipoma at a dose of approximately 0.05 to approximately 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of approximately 0.1 to approximately 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of approximately 0.4 to approximately 1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of approximately 1 to approximately 2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of less than approximately 0.05 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously directly to the angiolipoma at a dose of approximately 0.05 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.3 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.5 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.6 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.7 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.8 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 0.9 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.0 mL per angiolipoma.In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.3 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.5 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.6 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.7 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.8 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 1.9 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose of approximately 2.0 mL per angiolipoma. In some embodiments, the pharmaceutical composition is administered subcutaneously to the angiolipoma at a dose greater than approximately 2.0 mL per angiolipoma. [Examples]

[0115] Example 1: Clinical Trial

[0116] The clinical trial described herein was an open-label, Phase 2a clinical trial to evaluate the safety and efficacy of Compound 1 for the treatment of women and men with Darkum's disease nodosa (DD). Six women or men with DD received one treatment session in which Compound 1 was injected into multiple lipomas in each patient. Prior to injection, angiolipomas (i.e., lipomas with fibrous capsules, a total of 11 lipomas) were defined, and the height of each lipoma was assessed by ultrasound (US). Pain scores for individual lipomas were also determined prior to injection using a comparative pain scale.

[0117] DD patients were followed up on days 28 and 56 after injection to determine lipoma height and lipoma pain. Tables 1 and 2 show the evaluation of lipoma height and lipoma pain before and after administration of compound 1. Angiolipoma size and height were evaluated in the United States. Injection of compound 1 into angiolipomas significantly reduced their height and relieved pain.

[0118] [Table 1]

[0119] [Table 2]

[0120] While several embodiments have been shown and described, various modifications and substitutions can be made thereto without departing from the spirit and scope of the invention. For example, for the purposes of the claims, the claims described below are not intended to be interpreted in any way narrower than their literal language, and therefore, exemplary embodiments from the specification are not intended to be incorporated into the claims. Thus, it will be understood that the invention is described for illustrative purposes only and is not intended to limit the scope of the claims.

Claims

1. For use in the treatment of angiolipomas, 5-(3,6-dibromo-9H-carbazole-9-yl)-N,N,N-trimethylpentan-1-aminium A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains less than about 50% by weight of water.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition contains less than about 30% by weight of water.

4. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition contains less than about 10% by weight of water.

5. The pharmaceutical composition according to claim 1 or 2, comprising about 0% to about 30% by weight of water.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition comprises at least about 0.1% by weight of the compound.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition contains about 0.1% to about 10% by weight of the compound.

8. The pharmaceutical composition according to any one of claims 1 to 7, comprising about 1% to about 5% by weight of the compound.

9. The pharmaceutical composition according to any one of claims 1 to 8, further comprising at least one additional active agent.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is formulated for parenteral administration.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated for direct subcutaneous injection into an angiolipoma.

12. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated in a dose of about 0.05 to about 0.1 mL per angiolipoma for direct subcutaneous injection into the angiolipoma.

13. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated in a dose of about 0.1 to about 0.4 mL per angiolipoma for direct subcutaneous injection into the angiolipoma.

14. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated in a dose of about 0.4 to about 1 mL per angiolipoma for direct subcutaneous injection into the angiolipoma.

15. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated in a dose of about 1 to about 2 mL per angiolipoma for direct subcutaneous injection into an angiolipoma.

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