Composition for treating angiolipoma

Abstract

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

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 966,577, filed January 28, 2020, which is incorporated herein by reference. Background Art

[0003] Angiolipomas, subcutaneous tumors of the limbs and trunk, account for approximately 10% of fatty tumors. They are often multiple, with the first tumor appearing just after puberty. A family history is found in approximately 10% of cases, but a pattern of inheritance has not yet been established. In rare cases, a history of previous trauma to the site or therapeutic use of protease inhibitors has been implicated. In one case, numerous angiolipomas developed in a young adult male with familial angiolipoma after initiation of anabolic steroid use. Mild pain or discomfort is often noted with application of pressure or movement of the lesion, and the pain appears to be related to the vascularity of the lesion.

[0004] Subcutaneous angiolipomas have a normal karyotype, which distinguishes them from most other fatty tumors, including lipomas. For this reason, they have been considered hamartomas of blood vessels and fat rather than true fatty tumors. Macroscopically, they are yellow, firm, circumscribed tumors ranging from 1 to 4 cm in diameter. They may have a yellow-red appearance on the cut surface, reflecting the degree of vascularity. Subcutaneous angiolipomas must be distinguished from infiltrating angiolipomas, which are solitary lesions of deep soft tissue.

[0005] Unlike lipomas, which contain only adipose tissue, angiolipomas have a thin fibrous capsule with incomplete fibrous septa extending into the lesion, dividing it into lobules of varying sizes. They are composed of variable proportions of adipose tissue and blood vessels. Adipocytes are mature, with single vacuoles and eccentric nuclei. The vascular component, which accounts for 5–50% or more of the tumor, consists of multiple groups of capillaries and occasional larger-caliber vessels. Only sparse adipocytes are present in lesions reported as cellular angiolipomas, which are composed almost entirely of small vessels. In most cases, angiolipomas show prominent pericytes surrounding 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 associated with numerous fibrin thrombi and disseminated intravascular coagulation. Therefore, due to the fibrotic tissue they contain, angiolipomas appear less amenable to treatment with fat-reducing agents. Although fat reducing agents can remove fat from angiolipomas, they cannot interact with the fibrous cap lining the borders of angiolipomas and therefore would be expected to be ineffective in reducing angiolipoma size.

[0006] Angiolipomas can cause significant pain by compressing adjacent nerves. Treatment of angiolipomas is typically performed surgically or, in some cases, by injecting corticosteroids into the cell mass. Therefore, there remains a need to develop other agents for the treatment of angiolipomas. Summary of the Invention

[0007] In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein

[0010] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from 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 2-5Alkynyl; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of 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) and –ON(=O);

[0011] R 9 Selected from C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl and 3 to 10 membered heterocycloalkyl; wherein R 9 is substituted with at least one quaternary amino group or phosphonium group;

[0012] Each R 10 Independently selected from 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;

[0013] Each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Halogenated alkyl, C3-6 Cycloalkyl; or R 12 and R 13 Together with the nitrogen atom to which they are attached, they may form a 3- to 10-membered heterocycloalkyl group; and

[0014] Each R 13 Independently selected from 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;

[0015] The pharmaceutical composition is used to treat angiolipoma and any symptoms or conditions associated therewith.

[0016] In some embodiments, R9 is a C1-C9 alkyl group substituted with at least one quaternary amino group.

[0017] In some embodiments, at least one ammonium group has formula (V):

[0018]

[0019] where R 14 、R 15 and R 16 Each of which is independently selected from C 1-9 Alkyl, C 2-9 Alkenyl and C 2-9 In some embodiments, R 14 、R 15 and R 16 Each of them is independently C 1-9 alkyl.

[0020] In some embodiments, R 1 、R 2 、R 3 and R 4 In some embodiments, at least one of R 5 、R 6 、R 7 and R 8 In some embodiments, at least one of R 1 、R 2 、R 3 and R 4 At least one of is a halogen, and R 5 、R 6 、R 7 and R 8 At least one of is a halogen. In some embodiments, the halogen is a bromo group.

[0021] In some embodiments, R 1 、R 2 、R 3 and R 4 In some embodiments, at least one of R 5 、R 6 、R 7 and R 8 At least one of them is OH.

[0022] In some embodiments, R 1 、R 2 、R 3 and R 4 At least one of them is a nitro group, and R 5 、R 6 、R 7 and R 8 At least one of them is nitro.

[0023] In some embodiments, the compound of formula (I) is selected from:

[0024] 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-1-amine,

[0025] 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine,

[0026] 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine, and

[0027] 5-(3,6-Dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium.

[0028] In some embodiments, the pharmaceutical composition comprises less than about 50% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 30% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 10% water by weight. In some embodiments, the pharmaceutical composition comprises from about 0% to about 30% water by weight.

[0029] In some embodiments, the pharmaceutical composition comprises at least about 0.1% by weight of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 0.1% to about 10% by weight of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 1% to about 5% by weight of a compound of formula (I).

[0030] In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0031] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dosage of about 0.05 to about 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dosage of about 0.1 to about 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dosage of about 0.4 to about 1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dosage of about 1 to about 2 mL per angiolipoma.

[0032] In another aspect, provided herein is a kit comprising a pharmaceutical composition provided herein, a device for administering the pharmaceutical composition, and instructions for use thereof.

[0033] In some embodiments, the kit further comprises at least one additional therapeutic agent.

[0034] In another aspect, provided herein is a method of treating angiolipoma in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I):

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein:

[0037] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from 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)OR10 ,–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; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of 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) and –ON(=O);

[0038] R 9 Selected from C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl and 3 to 10 membered heterocycloalkyl; wherein R 9 is substituted with at least one quaternary amino group or phosphonium group;

[0039] Each R 10 Independently selected from 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;

[0040] Each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Halogenated alkyl, C 3-6 Cycloalkyl; or R 12 and R 13 Together with the nitrogen atom to which they are attached, they may form a 3- to 10-membered heterocycloalkyl group; and

[0041] Each R 13 Independently selected from 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.

[0042] In some embodiments, the pharmaceutical composition is administered parenterally. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.05 to about 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.1 to about 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.4 to about 1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1 to about 2 mL per angiolipoma.

[0043] Incorporation by reference

[0044] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0045] definition

[0046] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0047] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0048] The term "C x-y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl is intended to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight-chain alkyl and branched-chain alkyl. The term -C x-y Alkylene - refers to a substituted or unsubstituted alkylene chain having from x to y carbons in the alkylene chain. For example, -C 1-6 Alkylene - may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which is optionally substituted.

[0049] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl. Alkyl groups can contain from one to twelve carbon atoms (e.g., C 1-12 Alkyl), such as one to eight carbon atoms (C 1-8 Alkyl) or one to six carbon atoms (C 1-6 Alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl group is attached to the rest of the molecule by a single bond. Unless specifically stated otherwise in the specification, the alkyl group is optionally substituted with one or more substituents such as those described herein.

[0050] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0051] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one double bond, including straight-chain or branched alkenyl groups. Alkenyl groups can contain two to twelve carbon atoms (e.g., C 2-12Exemplary alkenyl groups include ethylidene (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless specifically stated otherwise in the specification, an alkenyl group is optionally substituted with one or more substituents such as those described herein.

[0052] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one triple bond, including straight-chain or branched alkynyl groups. Alkynyl groups can contain two to twelve carbon atoms (e.g., C 2-12 Alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted with one or more substituents such as those described herein.

[0053] "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, having one or more backbone chain atoms selected from atoms other than carbon. Exemplary backbone chain atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or a combination thereof, wherein the nitrogen, phosphorus and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Numerical ranges, if given, refer to overall chain lengths. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through a heteroatom or carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain. Unless specifically stated otherwise in the specification, a heteroalkyl, heteroalkenyl or heteroalkynyl group is optionally substituted with one or more substituents such as those described herein.

[0054] "Aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, aryl is phenyl. Depending on the structure, an aryl group may be a monovalent group or a divalent group (i.e., an arylene group). Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (such as in the case of "aralkyl") is intended to include optionally substituted aryl groups.

[0055] "Heteroaryl" refers to a 3- to 12-membered aromatic ring containing at least one heteroatom, wherein each heteroatom can be independently selected from N, O and S. As used herein, the heteroaryl ring can be selected from a monocyclic or bicyclic and fused or bridged ring system, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2)π electron system that conforms to Hückel's theory. One or more heteroatoms in the heteroaryl group can be optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. Where valence permits, the heteroaryl group can be attached to the rest of the molecule through any atom of the heteroaryl group, such as a carbon or nitrogen atom of the heteroaryl group.Examples of heteroaryl groups include, but are not limited to, azacycloheptatrienyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepenyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazole, benzothiophene, benzothiazolyl ... oxazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6, 7] cycloheptatrienol[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyridazinyl, cyclooctatetraenol[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepine, oxazolyl, oxazolyl, Cyclopropane, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d ]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptatrienol[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted with one or more substituents such as those described herein.

[0056] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, wherein each atom (i.e., skeleton atom) forming the ring is a carbon atom. In some embodiments, cycloalkyl is saturated or partially unsaturated. In some embodiments, cycloalkyl is a spirocycle or a bridged compound. In some embodiments, cycloalkyl is fused to an aromatic ring (in the case of the condensed aromatic ring, cycloalkyl is bonded to a non-aromatic ring carbon atom). Cycloalkyl includes a group with 3 to 10 ring atoms. Representative cycloalkyl includes but is not limited to a cycloalkyl with three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrahydronaphthyl, decahydronaphthyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless specifically stated otherwise in the specification, a cycloalkyl group may be optionally substituted.

[0057] The term "heterocycloalkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in the specification, a heterocycloalkyl group may be a monocyclic or bicyclic ring system, which may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom) or bridged ring system. The nitrogen, carbon, or sulfur atoms in the heterocyclyl group may optionally be oxidized. The nitrogen atom may optionally be quaternized. The heterocycloalkyl group may be partially or fully saturated. Examples of heterocycloalkyl include, but are not limited to, dioxolane, thienyl[1,3]dithianyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, heterocycloalkyl groups have 2 to 12 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms (including heteroatoms) that constitute the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). Unless specifically stated otherwise in the specification, a heterocycloalkyl group may be optionally substituted.

[0058] The term "substituted" refers to a substituent of hydrogen on one or more carbons or heteroatoms that partially has a replacement structure. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., the substitution conforms to the permissible valences of the substituted atom and the substituent, and the substitution produces a stable compound, e.g., a stable compound that does not spontaneously undergo a transformation such as that achieved by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is considered to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of an organic compound described herein that conform to the valences of the heteroatoms. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocyclic, heterocyclic, cycloalkyl, heterocycloalkyl, aromatic, and heteroaromatic moieties.

[0059] Those skilled in the art will appreciate that substituents themselves may be substituted, if appropriate. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0060] When substituent groups are designated by their conventional chemical formula written left to right, they equally encompass chemically identical substituents that would result from writing the structure right to left, for example, -CH2O- is equivalent to -OCH2-.

[0061] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups without substitution.

[0062] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0063] The compounds described herein may have their natural isotopic abundances, or one or more atoms may be artificially enriched in a specific isotope having the same atomic number as the atom predominantly found in nature, but having a mass or mass number different from that of the atom predominantly found in nature. All isotopic variations of the disclosed compounds, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, represented as 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or can provide compounds useful for studying drug elimination and metabolic pathways in vivo. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0064] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" is used to designate a racemic mixture. "Diastereomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right-handed or left-handed) of rotation of plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over another can be determined.

[0065] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the chemical entities described herein are also intended to include all Z, E and tautomeric forms.

[0066] If desired, the chemical entities and intermediates described herein may be isolated and purified by any suitable isolation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be obtained by reference to the examples below. However, other equivalent separation or isolation procedures may also be used.

[0067] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, their isomers, such as enantiomers and diastereomers, when possible; mixtures of enantiomers, including racemates; mixtures of diastereomers; and other mixtures thereof, as long as they can be prepared by ordinary skill in the art by routine experiments. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by resolving a mixture of racemates or diastereomers. If possible, the separation of a mixture of a racemate or diastereomer can be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column. In addition, a mixture of two enantiomers enriched in one of the two enantiomers can be purified by recrystallization and / or wet grinding to provide a further optically enriched form of the major enantiomer. In addition, certain small molecules of this type include Z and E forms (or cis and trans forms) of certain small molecules having a carbon-carbon double bond or a carbon-nitrogen double bond. When certain small molecules described herein exist in various tautomeric forms, the term "certain small molecule" is intended to include all tautomeric forms of the certain small molecule.

[0068] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0069] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve 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 waxes; (9) oils such as peanut oil, cottonseed oil, , safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0070] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to achieve the intended application, including but not limited to the treatment of a disease, as defined below. The therapeutically effective amount may vary depending on the intended therapeutic application (in vivo); or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition; the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to doses that will induce a specific response in the target cells (e.g., a decrease in platelet adhesion and / or cell migration). The specific dose will vary depending on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0071] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may include, for example, the eradication or improvement of the underlying disorder being treated. Additionally, a therapeutic benefit may include, for example, the eradication or improvement of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be suffering from the underlying disorder. In certain embodiments, for prophylactic benefit, a composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not yet have been made.

[0072] A "therapeutic effect," as the term is used herein, encompasses therapeutic benefits and / or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0073] As used herein, the terms "co-administration," "administered in combination with," and their grammatical equivalents encompass the administration of two or more agents to animals, including humans, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0074] Compound

[0075] In one aspect, provided herein is a compound of formula (I):

[0076]

[0077] or a pharmaceutically acceptable salt thereof, wherein:

[0078] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from 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 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 N(=O), –ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of 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) and –ON(=O);

[0079] R 9 Selected from C 1-9 Alkyl, C2-9 Alkenyl, C 2-9 Alkynyl and 3 to 10 membered heterocycloalkyl; wherein R 9 is substituted with at least one quaternary amino group or phosphonium group;

[0080] Each R 10 Independently selected from 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;

[0081] Each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Halogenated alkyl, C 3-6 Cycloalkyl; or R 12 and R 13 Together with the nitrogen atom to which they are attached, they may form a 3- to 10-membered heterocycloalkyl group; and

[0082] Each R 13 Independently selected from 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.

[0083] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from 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 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 N(=O), –ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of 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) and -ON(=O). In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R7 and R 8 Each of which is independently selected from H, halogen, -CN, -NO2, -OR 10 、–S(=O)2R 10 ,–NR 11 R 12 、–C(=O)NR 11 R 12 、–S(=O)2NR 11 R 12 、–C(=O)R 10 、–C(=O)OR 10 ,–NR 13 C(=O)R 10 ,–NR 13 C(=O)NR 11 R 12 ,–NR 13 S(=O)2R 10 ,–NR 13 S(=O)2NR 11 R 12 、C 1-5 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO2, -OR 10 、–S(=O)2R 10 ,–NR 11 R 12 、–C(=O)NR 11 R 12 、–S(=O)2NR 11 R 12 、–C(=O)R 10 、–C(=O)OR 10 ,–NR 13 C(=O)R 10 ,–NR 13 C(=O)NR 11 R 12 ,–NR 13 S(=O)2R 10 and –NR 13 S(=O)2NR 11 R 12 In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8Each of which is independently selected from H, halogen, -CN, -NO2, -OR 10 ,–NR 11 R 12 、–C(=O)R 10 、–C(=O)OR 10 and C 1-5 Alkyl; wherein each alkyl group is independently optionally substituted by one or more substituents selected from the group consisting of halogen, -CN, -NO2, -OR 10 、–S(=O)2R 10 ,–NR 11 R 12 、–C(=O)NR 11 R 12 、–S(=O)2NR 11 R 12 、–C(=O)R 10 、–C(=O)OR 10 ,–NR 13 C(=O)R 10 ,–NR 13 C(=O)NR 11 R 12 ,–NR 13 S(=O)2R 10 and –NR 13 S(=O)2NR 11 R 12 In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from H, halogen, -CN, -NO2, -OR 10 and –NR 11 R 12 .

[0084] In some embodiments, R 1 、R 2 、R 3 and R 4 In some embodiments, at least one of R 1 In some embodiments, R 2 In some embodiments, R 3 In some embodiments, R 4 In some embodiments, R 5 、R 6 、R 7and R 8 In some embodiments, at least one of R 5 In some embodiments, R 6 In some embodiments, R 7 In some embodiments, R 8 In some embodiments, R 1 、R 2 、R 3 and R 4 At least one of is a halogen, and R 5 、R 6 、R 7 and R 8 In some embodiments, at least one of R 1 is a halogen, and R 5 In some embodiments, R 1 is a halogen, and R 6 In some embodiments, R 1 is a halogen, and R 7 In some embodiments, R 1 is a halogen, and R 8 In some embodiments, R 2 is a halogen, and R 5 In some embodiments, R 2 is a halogen, and R 6 In some embodiments, R 2 is a halogen, and R 7 In some embodiments, R 2 is a halogen, and R 8 In some embodiments, R 3 is a halogen, and R 5 In some embodiments, R 3 is a halogen, and R 6 In some embodiments, R 3 is a halogen, and R 7 In some embodiments, R 3 is a halogen, and R 8 In some embodiments, R 4 is a halogen, and R 5 In some embodiments, R 4 is a halogen, and R 6 In some embodiments, R 4 is a halogen, and R 7 In some embodiments, R4 is a halogen, and R 8 In some embodiments, the halogen is bromo. In some embodiments, the halogen is chloro. In some embodiments, the halogen is fluoro.

[0085] In some embodiments, R 1 、R 2 、R 3 and R 4 In some embodiments, at least one of R 1 In some embodiments, R 2 In some embodiments, R 3 In some embodiments, R 4 In some embodiments, R 5 、R 6 、R 7 and R 8 In some embodiments, at least one of R 5 In some embodiments, R 6 In some embodiments, R 7 In some embodiments, R 8 It's OH.

[0086] In some embodiments, R 1 、R 2 、R 3 and R 4 At least one of them is a nitro group, and R 5 、R 6 、R 7 and R 8 In some embodiments, at least one of R 1 is nitro, and R 5 In some embodiments, R 1 is nitro, and R 6 In some embodiments, R 1 is nitro, and R 7 In some embodiments, R 1 is nitro, and R 8 In some embodiments, R 2 is a halogen, and R 5 In some embodiments, R 2 is nitro, and R 6 In some embodiments, R 2 is a halogen, and R 7 In some embodiments, R2 is nitro, and R 8 In some embodiments, R 3 is a halogen, and R 5 In some embodiments, R 3 is nitro, and R 6 In some embodiments, R 3 is a halogen, and R 7 In some embodiments, R 3 is nitro, and R 8 In some embodiments, R 4 is a halogen, and R 5 In some embodiments, R 4 is nitro, and R 6 In some embodiments, R 4 is a halogen, and R 7 In some embodiments, R 4 is nitro, and R 8 It's nitro.

[0087] In some embodiments, R 9 Selected from C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl and 3 to 10 membered heterocycloalkyl; wherein R 9 is substituted with at least one quaternary amino group or phosphonium group. 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 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 is a 3- to 10-membered heterocycloalkyl. 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 is a C substituted with at least one phosphonium group 1-9In some embodiments, R 9 is a C substituted with at least one quaternary amino group 1-9 In some embodiments, R 9 is propyl substituted with at least one quaternary amino group. 9 is a pentyl group substituted with at least one quaternary amino group.

[0088] In some embodiments, at least one quaternary amino group has formula (V):

[0089]

[0090] where R 14 、R 15 and R 16 Each of which is independently selected from C 1-9 Alkyl, C 2-9 Alkenyl and C 2-9 In some embodiments, R 14 、R 15 and R 16 Each of them is independently C 2-9 In some embodiments, R 14 、R 15 and R 16 Each of them is independently C 2-9 In some embodiments, R 14 、R 15 and R 16 Each of them is independently C 1-9 In some embodiments, R 14 、R 15 and R 16 Each of them is a methyl group.

[0091] In some embodiments, at least one phosphonium group has formula (VI):

[0092]

[0093] where R 17 、R 18 and R 19 Each of which is independently selected from C 1-9 Alkyl, C 2-9 Alkenyl and C 2-9 In some embodiments, R 17 、R 18 and R 19 Each of them is independently C 2-9 In some embodiments, R 17 、R 18 and R19 Each of them is independently C 2-9 In some embodiments, R 17 、R 18 and R 19 Each of them is independently C 1-9 In some embodiments, R 17 、R 18 and R 19 Each of them is a methyl group.

[0094] In some embodiments, each R 10 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 In some embodiments, each R 10 Independently selected from H, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 In some embodiments, each R 10 Independently selected from H, C 1-5 Alkyl and C 3-6 In some embodiments, each R 10 is H. In some embodiments, each R 10 Independently C 1-5 In some embodiments, each R 10 Independently C 2-5 In some embodiments, each R 10 Independently C 2-5 In some embodiments, each R 10 Independently C 1-5 In some embodiments, each R 10 Independently C 1-5 In some embodiments, each R 10 Independently C 3-6 Cycloalkyl.

[0095] In some embodiments, each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6Cycloalkyl; or R 12 and R 13 Together with the nitrogen atom to which they are attached, they may form a 3- to 10-membered heterocycloalkyl group. 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 In some embodiments, each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 In some embodiments, each R 11 and R 12 Independently selected from H, C 1-5 Alkyl and C 3-6 In some embodiments, each R 11 and R 12 is H. In some embodiments, each R 11 and R 12 Independently C 1-5 In some embodiments, each R 11 and R 12 Independently C 2-5 In some embodiments, each R 11 and R 12 Independently C 2-5 In some embodiments, each R 11 and R 12 Independently C 1-5 In some embodiments, each R 11 and R 12 Independently C 1-5 In some embodiments, each R 11 and R 12 Independently C 3-6 In some embodiments, R 12 and R 13 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group.

[0096] In some embodiments, each R 13 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 In some embodiments, each R 13 Independently selected from H, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 1-5 Haloalkyl and C 3-6 In some embodiments, each R 13 Independently selected from H, C 1-5 Alkyl and C 3-6 In some embodiments, each R 13 is H. In some embodiments, each R 13 Independently C 1-5 In some embodiments, each R 13 Independently C 2-5 In some embodiments, each R 13 Independently C 2-5 In some embodiments, each R 13 Independently C 1-5 In some embodiments, each R 13 Independently C 1-5 In some embodiments, each R 13 Independently C 3-6 Cycloalkyl.

[0097] In some embodiments, the compound of formula (I) is selected from:

[0098] 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-1-amine,

[0099] 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine,

[0100] 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine, and

[0101] 5-(3,6-Dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium.

[0102] In some embodiments, the compound of formula (I) is 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-1-aminium. In some embodiments, the compound of formula (I) is 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium. In some embodiments, the compound of formula (I) is 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium. In some embodiments, the compound of formula (I) is 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium.

[0103] In some embodiments, the compound of formula (I) is represented by the following structure: In some embodiments, the compound of formula (I) is represented by the following structure: In some embodiments, the compound of formula (I) is represented by the following structure: In some embodiments, the compound of formula (I) is represented by the following structure:

[0104] Pharmaceutical composition

[0105] The compositions of the present disclosure can be formulated into any suitable pharmaceutical preparation. The pharmaceutical compositions of the present disclosure generally contain an active ingredient (e.g., a compound of formula (I) or a pharmaceutically acceptable salt and / or coordination complex thereof) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and excipients. The compositions of the present disclosure can be formulated into any suitable pharmaceutical preparation.

[0106] The pharmaceutical composition can be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated into a dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, transdermal, buccal, sublingual, subcutaneous, intramuscular, intravenous, intratumoral, and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition can be formulated into a unit dose.

[0107] The amount of each compound administered will depend on the severity of the mammal being treated, the disorder or condition, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. However, the effective dose can be in the range of about 0.001 to about 100 mg per kg body weight per day, administered in a single or divided dose. In some cases, the dosage level below the lower limit of the aforementioned range may be more than sufficient, while in other cases, even larger doses can be adopted without causing any harmful side effects, such as by dividing such larger doses into several small doses for all-day administration. In some embodiments, the effective dose can be provided with pulse administration (i.e., administering the compound for several consecutive days, followed by stopping administration, and discontinuing the drug for several consecutive days).

[0108] In some embodiments, the composition is provided in one or more unit doses. For example, the composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60 or more dosages. This amount can be administered daily, for example, in a single dose administered once a day, twice or three times or more. However, the dosage stated herein based on daily should not be interpreted as requiring daily administration of a daily dose. For example, if a type of agent is provided in a suitable slow-release form, then two or more daily dose quantities can be administered at a lower frequency, for example, in a reservoir injection form administered once every other day to a month or even longer. It is most common and convenient for an object that a pharmaceutical composition comprising a compound of formula (I) can be administered once a day, for example, in the morning, in the evening, or during the day.

[0109] The unit doses can be administered simultaneously or sequentially. The composition can be administered for an extended treatment period. As an illustration, the treatment period can be at least about one month, e.g., at least about three months, at least about six months, or at least about one year. In some cases, administration can be continued for substantially the remainder of the subject's life.

[0110] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) can be administered as part of a treatment regimen that includes administering one or more second doses (e.g., 1, 2, 3, 4, 5, or more second doses) simultaneously or sequentially with the pharmaceutical composition comprising the compound of Formula (I). When administered sequentially, the pharmaceutical composition comprising the compound of Formula (I) can be administered before or after the one or more second doses. When administered simultaneously, the pharmaceutical composition comprising the compound of Formula (I) and the one or more second doses can be administered by the same route (e.g., injection into the same location), by different routes (e.g., oral tablets administered simultaneously with intravenous infusion), or as part of the same combination (e.g., a solution comprising a pharmaceutical composition comprising a compound of Formula (I) and one or more second doses).

[0111] The combination therapy according to the present invention can be effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg, and 5 to 40 mg per day are examples of dosages that can be used. The exact dosage will depend on the selected agent, the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0112] In some embodiments, the pharmaceutical composition comprises one or more surfactants. Surfactants that can 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 can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0113] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0114] The hydrophilic surfactant may be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acylactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0115] Within the above-mentioned groups, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0116] The ionic surfactant can be an ionized form of lecithin, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactylates, stearoyl-2-lactyloyl lactylate, stearoyl lactyloyl lactylate, succinylated Monoglycerides, monoacetylated / diacetylated tartaric acid esters of monoglycerides / diglycerides, citrate esters of monoglycerides / diglycerides, choylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linolenate, linolenate, stearate, lauryl sulfate, myristyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0117] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glycosides; alkyl maltosides; alkyl thioglycosides; lauryl polyethylene glycol 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 glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols with at least one member of the group of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a sugar.

[0118] 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 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil. , PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Plant Sterols, PEG-30 Soybean Sterols, PEG-20 Trioleate, PEG-40 Sorbitan monooleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamer.

[0119] By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides and diglycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0120] In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This may be particularly important for injection. A solubilizing agent may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants, or to maintain the composition into a stable or homogeneous solution or dispersion.

[0121] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, diethylene glycol monoethyl ether (transcutol), 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 (tetrahydrofurfuryl alcohol polyethylene glycol ether) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactone, 2-octyl thiocyanate ... amines, N-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, glycerol triacetate, 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.

[0122] Mixtures of solubilizing agents can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-Methyl pyrrolidone, N-hydroxyethyl pyrrolidone, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, tetrahydrofurfuryl alcohol polyethylene glycol ether, diethylene glycol monoethyl ether, propylene glycol and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, tetrahydrofurfuryl alcohol polyethylene glycol ether and propylene glycol.

[0123] The amount of the solubilizing agent that can be included is not subject to specific restriction.The amount of given solubilizing agent can be limited to biologically acceptable amount, and it can be easily determined by those skilled in the art.In some cases, it can be advantageous to comprise that quantity far exceeds the solubilizing agent of biologically acceptable amount, for example so that drug concentration is maximized, wherein before providing compositions to the patient, conventional techniques such as distillation or evaporation are used to remove excessive solubilizing agent.If there is, so based on the combined weight of medicine and other excipients, solubilizing agent can be in 10%, 25%, 50%, 100% or until about 200% weight ratio by weight.If necessary, so also can use a small amount of solubilizing agent, such as 5%, 2%, 1% or even less.Usually, by weight, solubilizing agent can exist with about 1% to about 100%, more typically about 5% to about 25% amount.

[0124] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, defoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tension modifiers, flavoring agents, colorants, flavor enhancers, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0125] In addition, acids or bases can be incorporated into the composition to aid 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, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases as salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polyacids 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 suitable and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0126] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.

[0127] In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I):

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein:

[0130] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from 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; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of 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) and –ON(=O);

[0131] R 9 Selected from C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl and 3 to 10 membered heterocycloalkyl; wherein R 9 is substituted with at least one quaternary amino group or phosphonium group;

[0132] Each R 10 Independently selected from 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;

[0133] Each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Halogenated alkyl, C 3-6 Cycloalkyl; or R 12 and R 13 Together with the nitrogen atom to which they are attached, they may form a 3- to 10-membered heterocycloalkyl group; and

[0134] Each R 13 Independently selected from 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.

[0135] In some embodiments, the pharmaceutical composition comprises less than about 50% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 30% water by weight. In some embodiments, the pharmaceutical composition comprises less than about 10% water by weight. In some embodiments, the pharmaceutical composition comprises about 0% to about 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 10% to about 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 15% to about 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 15% to about 25% water by weight. In some embodiments, the pharmaceutical composition comprises about 20% to about 30% water by weight. In some embodiments, the pharmaceutical composition comprises about 23% to about 27% water by weight. In some embodiments, the pharmaceutical composition comprises about 24% to about 26% water by weight. In some embodiments, the pharmaceutical composition comprises about 0% water by weight. In some embodiments, the pharmaceutical composition comprises about 1% water by weight. In some embodiments, the pharmaceutical composition comprises about 2% water by weight. In some embodiments, the pharmaceutical composition comprises about 3% water by weight. In some embodiments, the pharmaceutical composition comprises about 4% water by weight. In some embodiments, the pharmaceutical composition comprises about 5% water by weight. In some embodiments, the pharmaceutical composition comprises about 6% water by weight. In some embodiments, the pharmaceutical composition comprises about 7% water by weight. In some embodiments, the pharmaceutical composition comprises about 8% water by weight. In some embodiments, the pharmaceutical composition comprises about 9% water by weight. In some embodiments, the pharmaceutical composition comprises about 10% water by weight. In some embodiments, the pharmaceutical composition comprises about 11% water by weight. In some embodiments, the pharmaceutical composition comprises about 12% water by weight. In some embodiments, the pharmaceutical composition comprises about 13% water by weight. In some embodiments, the pharmaceutical composition comprises about 14% water by weight. In some embodiments, the pharmaceutical composition comprises about 15% water by weight. In some embodiments, the pharmaceutical composition comprises about 16% water by weight. In some embodiments, the pharmaceutical composition comprises about 17% water by weight. In some embodiments, the pharmaceutical composition comprises about 18% water by weight. In some embodiments, the pharmaceutical composition comprises about 19% water by weight. In some embodiments, the pharmaceutical composition comprises about 20% water by weight. In some embodiments, the pharmaceutical composition comprises about 21% water by weight. In some embodiments, the pharmaceutical composition comprises about 22% water by weight. In some embodiments, the pharmaceutical composition comprises about 23% water by weight. In some embodiments, the pharmaceutical composition comprises about 24% water by weight.In some embodiments, the pharmaceutical composition comprises about 25% water by weight. In some embodiments, the pharmaceutical composition comprises about 26% water by weight. In some embodiments, the pharmaceutical composition comprises about 27% water by weight. In some embodiments, the pharmaceutical composition comprises about 28% water by weight. In some embodiments, the pharmaceutical composition comprises about 29% water by weight. In some embodiments, the pharmaceutical composition comprises about 30% water by weight.

[0136] In some embodiments, the pharmaceutical composition comprises at least about 0.1% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises between about 0.1% and about 10% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises between about 1% and about 5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.1% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.2% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.3% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.4% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.6% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.7% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.8% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 0.9% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 1% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 1.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 2% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 2.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 3% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 3.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 4% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 4.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 5.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 6% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 6.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 7% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 7.5% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 8% of a compound of formula (I) by weight. In some embodiments, the pharmaceutical composition comprises about 8.5% of a compound of formula (I) by weight.In some embodiments, the pharmaceutical composition comprises about 9% by weight of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 9.5% by weight of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 10% by weight of a compound of formula (I).

[0137] 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.

[0138] In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, transdermal, buccal, sublingual, subcutaneous, intramuscular, intravenous, intratumoral, and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for injection. In some embodiments, the pharmaceutical composition is formulated for intratumoral injection. In some embodiments, the pharmaceutical composition is formulated as an injection, patch, cream, gel, or ointment.

[0139] Pharmaceutical compositions for injection

[0140] In some embodiments, the present disclosure provides a pharmaceutical composition for injection containing a compound of formula (I) and a pharmaceutical excipient suitable for injection. The components and amounts of the composition are as described herein.

[0141] The forms into which the novel compositions of the present disclosure can be incorporated for administration by injection include aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0142] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Preventing the effects of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0143] Sterile injectable solutions are prepared by incorporating the disclosed compounds in the desired amount into an appropriate solvent along with various other ingredients as listed above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution thereof.

[0144] The present invention also provides a kit. The kit may include a pharmaceutical composition comprising a compound of formula (I) and one or more additional agents in suitable packaging, and written materials such as instructions for use, a discussion of clinical studies, a list of side effects, etc. Such kits may also include information indicating or determining the activity and / or advantages of the composition, and / or describing dosing, application, side effects, drug interactions, such as scientific references, package inserts, clinical trial results, and / or summaries of such information, or other information useful to health care providers. Such information may be based on the results of various studies, such as studies involving in vivo models using experimental animals and studies based on human clinical trials. The kit may also contain another agent. In some embodiments, the compound of the present invention and the agent are provided in separate containers within the kit as separate compositions. In some embodiments, the compound of the present invention and the agent are provided in a container within the kit as a single composition. Suitable packaging and additional supplies (e.g., measuring cups for liquid preparations, foil packaging materials to minimize air exposure, etc.) are known in the art and may be included in the kit. The kits described herein may be provided, sold, and / or marketed to health providers, including physicians, nurses, pharmacists, prescribing officials, etc. In some embodiments, the kits can also be sold directly to consumers.

[0145] How to use

[0146] Eliminating or alleviating angiolipoma is significantly different from treating common lipomas because the former contains fibrous tissue. Even when injected with a fat-reducing agent, this fibrous capsule can keep angiolipomas hard. Although it is expected that angiolipomas are resistant to fat-reducing agents, a fat-reducing compound for treating angiolipomas is provided herein. A single injection of Compound 1 into a lipoma containing a fibrous capsule can significantly reduce their height and alleviate angiolipoma-related pain.

[0147] In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I):

[0148]

[0149] or a pharmaceutically acceptable salt thereof, wherein

[0150] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from 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; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of 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 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 N(=O) and –ON(=O);

[0151] R 9 Selected from C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl and 3 to 10 membered heterocycloalkyl; wherein R 9 is substituted with at least one quaternary amino group or phosphonium group;

[0152] Each R 10 Independently selected from 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;

[0153] Each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Halogenated alkyl, C 3-6 Cycloalkyl; or R 12 and R 13 Together with the nitrogen atom to which they are attached, they may form a 3- to 10-membered heterocycloalkyl group; and

[0154] Each R 13 Independently selected from 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;

[0155] The pharmaceutical composition is used to treat angiolipoma and any symptoms or conditions associated therewith.

[0156] In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0157] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.05 to about 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.1 to about 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.4 to about 1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1 to about 2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of less than about 0.05 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.05 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.3 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.5 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.6 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.7 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.8 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 0.9 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.0 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.2 mL per angiolipoma.In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.3 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.5 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.6 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.7 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.8 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for direct subcutaneous injection into angiolipomas at a dose of about 1.9 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into angiolipoma at a dose of about 2.0 mL per angiolipoma. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection directly into angiolipoma at a dose of greater than about 2.0 mL per angiolipoma.

[0158] In another aspect, provided herein is a method of treating angiolipoma in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I):

[0159]

[0160] or a pharmaceutically acceptable salt thereof, wherein:

[0161] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of which is independently selected from 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 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 N(=O), –ON(=O), C 1-5 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl; wherein each alkyl, alkenyl and alkynyl is independently optionally substituted with one or more substituents selected from the group consisting of 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) and –ON(=O);

[0162] R 9 Selected from C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9Alkynyl and 3 to 10 membered heterocycloalkyl; wherein R 9 is substituted with at least one quaternary amino group or phosphonium group;

[0163] Each R 10 Independently selected from 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;

[0164] Each R 11 and R 12 Independently selected from H, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Heteroalkyl, C 1-5 Halogenated alkyl, C 3-6 Cycloalkyl; or R 12 and R 13 Together with the nitrogen atom to which they are attached, they may form a 3- to 10-membered heterocycloalkyl group; and

[0165] Each R 13 Independently selected from 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.

[0166] In some embodiments, the pharmaceutical composition is administered parenterally. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.05 to about 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.1 to about 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.4 to about 1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1 to about 2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of less than about 0.05 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.05 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.3 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.5 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.6 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.7 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 0.8 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of about 0.9 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of about 1.0 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of about 1.1 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of about 1.2 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of about 1.3 mL per angiolipoma.In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1.4 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1.5 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1.6 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1.7 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1.8 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 1.9 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of about 2.0 mL per angiolipoma. In some embodiments, the pharmaceutical composition is injected directly into the angiolipoma subcutaneously at a dose of greater than about 2.0 mL per angiolipoma.

[0167] Example

[0168] Example 1: Clinical trial

[0169] The clinical trial described herein is an open-label Phase 2a clinical trial for the safety and efficacy of Compound 1 in treating women and men with nodular Dercum's disease (DD). Six (6) women or men with DD were given a single treatment period in which Compound 1 was injected into several lipomas in each patient. Prior to injection, angiolipomas (i.e., lipomas containing fibrous capsules, a total of 11 lipomas) were identified and the height of each lipoma was assessed by ultrasound (US). Individual lipoma pain scores were also determined using a comparative pain scale prior to injection.

[0170] DD patients were followed up on days 28 and 56 after injection to determine lipoma height and lipoma pain. Tables 1 and 2 present the assessment of lipoma height and lipoma pain before and after administration of Compound 1. Angiolipoma size and height were assessed by US. Injection of Compound 1 into angiolipomas significantly reduced their height and alleviated pain.

[0171]

[0172] Table 1: Relative changes from baseline in angiolipoma height (*P < 0.05 relative to baseline)

[0173]

[0174] Table 2: Relative changes from baseline in pain associated with angiolipoma (*P < 0.05 relative to baseline)

[0175] Although certain embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the present invention. For example, for claim construction purposes, it is not intended that the claims set forth below be interpreted in any manner narrower than their literal wording, and thus it is not intended that the exemplary embodiments from the specification be read into the claims. Therefore, it should be understood that the present invention has been described by way of illustration and not by way of limitation of the scope of the claims.

Claims

1. Use of a pharmaceutical composition comprising 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating angiolipoma and any symptoms or conditions associated therewith.

2. The use according to claim 1, wherein the pharmaceutical composition comprises less than 50% water by weight.

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

4. The use of claim 1, wherein the pharmaceutical composition comprises less than 10% water by weight.

5. The use according to claim 1, wherein the pharmaceutical composition comprises 0% to 30% water by weight.

6. The use according to claim 1, wherein the pharmaceutical composition comprises at least 0.1% by weight of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine or a pharmaceutically acceptable salt thereof.

7. The use according to claim 1, wherein the pharmaceutical composition comprises 0.1% to 10% by weight of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine or a pharmaceutically acceptable salt thereof.

8. The use according to claim 1, wherein the pharmaceutical composition comprises 1% to 5% by weight of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-amine or a pharmaceutically acceptable salt thereof.

9. The use of claim 1, wherein the pharmaceutical composition further comprises at least one additional active agent.

10. The use of claim 1, wherein the pharmaceutical composition is formulated for parenteral administration.

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

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

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

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

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

16. Use of a pharmaceutical composition comprising 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating angiolipoma in a subject in need thereof.

17. The use according to claim 16, wherein the pharmaceutical composition is administered parenterally.

18. The use according to claim 16, wherein the pharmaceutical composition is administered subcutaneously.

19. The use according to claim 16, wherein the pharmaceutical composition is injected subcutaneously directly into the angiolipoma.

20. The use according to claim 16, wherein the pharmaceutical composition is directly injected subcutaneously into the angiolipoma at a dose of 0.05 to 0.1 mL per angiolipoma.

21. The use according to claim 16, wherein the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of 0.1 to 0.4 mL per angiolipoma.

22. The use according to claim 16, wherein the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of 0.4 to 1 mL per angiolipoma.

23. The use according to claim 16, wherein the pharmaceutical composition is injected subcutaneously directly into the angiolipoma at a dose of 1 to 2 mL per angiolipoma.

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