WO2013082150A1 - Inhibiteurs à petite molécule de nicotinamide phosphoribosyltransférase (nampt) - Google Patents

Inhibiteurs à petite molécule de nicotinamide phosphoribosyltransférase (nampt) Download PDF

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Publication number
WO2013082150A1
WO2013082150A1 PCT/US2012/066849 US2012066849W WO2013082150A1 WO 2013082150 A1 WO2013082150 A1 WO 2013082150A1 US 2012066849 W US2012066849 W US 2012066849W WO 2013082150 A1 WO2013082150 A1 WO 2013082150A1
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formula
compound
integer ranging
saturated
unsaturated
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PCT/US2012/066849
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English (en)
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Jr. Mark Wayne LEE
Yulia SEVRYUGINA
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The Curators Of The University Of Missouri
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Priority to US14/361,857 priority Critical patent/US9382267B2/en
Publication of WO2013082150A1 publication Critical patent/WO2013082150A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B35/00—Boron; Compounds thereof
    • C01B35/08—Compounds containing boron and nitrogen, phosphorus, oxygen, sulfur, selenium or tellurium

Definitions

  • the present invention relates to novel compounds, their synthesis, and their use as anti cancer compounds.
  • the compounds contain cluster boron moieties and act as inhibitors for the enzyme Nicotinamide Phosphoribosyltranferase (Nampt).
  • cluster boron compounds which are icosahedral clusters comprised of boron, carbon, and hydrogen, demonstrate high chemical stability and may be incorporated into small molecules as analogs of aromatic hydrocarbons. Because each of the vertices of a cluster boron compound may be derivatized through substitution chemistry, these clusters may serve as rigid scaffolds upon which to build molecules with well-defined, three-dimensional conformations. In addition to hydrophobic interactions, it has been elucidated that carboranes bind strongly with biomolecules through a unique form of hydrogen bonding.
  • Nicotinamide Phosphoribosyltranferase is the first and rate limiting enzyme in the mammalian NAD + recycling pathway, converting nicotinamide to nicotinamide mononucleotide (NMN). Owing to the many disparate physiological roles and the cellular compartmentalization of NAD + , this vital enzyme has been given different names (visfatin, pre-B cell colony enhancing factor (PBEF), NAmPRTase and Nampt). It has recently been shown that Nampt activity plays a central role in
  • the present disclosure provides a compound comprising Formula (I):
  • B is a cluster boron
  • X is an aromatic moiety having one or more nitrogen atoms
  • n is an integer ranging from 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • n is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated.
  • the present invention provides a method of producing a compound comprising Formula (I), the method comprising: (a) contacting a deprotonated cluster boron with an alkyl dihalide, to produce an alkyl halide substituted cluster boron compound; (b) contacting the alkyl halide substituted cluster boron with a nitrogen containing compound to produce the compound comprising Formula (II),
  • R is chosen from OH and CI; and X, n, m and B are as described above for Formula (I) in the presence of a coupling agent or base to form the compound comprising Formula (I).
  • the present invention provides a process for producing the compound comprising Formula (I), wherein the compound comprising Formula (II) is contacted with the compound comprising Formula (III) in the presence of a coupling agent or base.
  • the invention provides a method of inhibiting Nampt in a subject, the method comprising administering a compound comprising Formula (I).
  • FIG. 1 shows the concentration dependent cell viability exhibited by (1)-(4), (6), (7) against the A549 human lung cancer cell line.
  • FIG. 2 shows the concentration-dependent cell rescue.
  • A549 cells were treated with 10nM (1), (5), (6), or (7). Error bars represent the mean ⁇ SD. Cell viability was measured using the MTT assay. Each measurement was repeated 4 times. A nearly complete rescue of the cells was afforded with increasing concentration-dependent cell rescue.
  • FIG. 3 shows recombinant Nampt inhibition for FK866 against compound (6).
  • FIG. 4 shows a synthetic route to compound (4).
  • Reagents and conditions a) AIBr 3 , CH 2 CHBr, 4h at -65°C; b) KO f Bu, THF, 4-5 d rt; c) "BuLi, THF, 2h at -65°C; d) AIMes, (CH 2 ) 2 O, THF, 2d rt; e) Et 3 N, MsCI, Et 2 O, 4h rt; f) NaN 3 , DMF, 3h refluxing; g) LiAIH 4 ; THF, 3h, rt; h) DMF, BOP, Et 3 N, C 5 NH 4 (CH) 2 COOH, overnight rt.
  • FIG. 5 shows a synthetic route to compound (6).
  • Reagents and conditions a) "BuLi, THF, 4h, rt; b) CI(CH 2 ) 4 I, overnight rt; c) KN(CO) 2 C 6 H 4 , DMF, reflux overnight; d) N 2 H 4 , EtOH, 4.5h reflux, e) DMF, BOP, Et 3 N, C 5 NH 4 (CH 2 )COOH, overnight rt.
  • FIG. 6 shows a synthetic route to compound (7).
  • Reagents and conditions a) "BuLi, THF, 5h rt; b) Br(CH 2 ) 4 N(CO) 2 C 6 H 4 , overnight rt; c) 10 N 2 H 4 , EtOH, 4h reflux; d) DMF, BOP, Et 3 N, C 5 NH 4 (CH) 2 COOH, overnight rt.
  • FIG. 7 shows two synthetic routes to compound (5).
  • Reagents and conditions a) "BuLi, -78°C, 4h; b) f-BuMe 2 SiCI, -78°C, 1 h, rt; d) CI(CH 2 ) 4 Br, rt, 12h; d) 5% Lil, Cs 2 CO 3 , NHBoc 2 , 2-butanone, 2 days, reflux; e) 4M HCI in dioxane, rt, 3.5h; f) Et 2 S, toluene, 4h reflux; g) HC 2 (CH 2 ) 4 N(CO) 2 C 6 H 4 , 12h reflux; h) NaBH 4 , 6:1 2- propanol/H 2 O, rt, 12h; i) HC c, reflux, 12h, j) DMF, BOP, Et 3 N, C 5 H 4 (CH 2 )COOH, rt,
  • FIG. 8 shows an alternate synthetic route. Reagents and conditions: a) "BuLi, THF, 4h rt; b) CI(CH 2 ) 4 I, overnight rt; c) KN(CO) 2 C 6 H 4 , DMF, reflux, overnight; d) N 2 H 4 , EtOH, 4.5h reflux; e) DMF, BOP, Et 3 N, C 5 NH 4 (CH) 2 COOH, overnight rt.
  • FIG. 9 shows the results of scratch test assays against DLD1 at Oh and at 24h.
  • FIG. 10 shows the results of scratch test assays against A549 at Oh and at 24h.
  • FIG. 11 show results for MTT assays.
  • A shows results of a PC3 MTT assay;
  • B shows results of a T47D MTT assay;
  • C shows results of a U87 MTT assay; and
  • D shows a D1 D1 MTT assay.
  • FIG. 12 shows results of a A549 MTT assay.
  • FIG. 13 shows the results of scratch test assays against DLD1 at Oh and at 24h.
  • FIG. 14 shows the results of scratch test assays against PC3 at Oh and at 24h.
  • the present invention relates to novel cluster boron compounds.
  • the novel cluster boron compounds may be inhibitors of Nampt.
  • the novel compounds contain a cluster boron group.
  • the biological properties are greater than other small molecule inhibitors of Nampt.
  • B is a cluster boron
  • X is an aromatic moiety having one or more nitrogen atoms
  • n is an integer ranging from 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • B in the compound comprising Formula (I) represents a cluster boron compound.
  • Cluster boron may be either an icosahedral boron (closo), or it may be a nido boron compound.
  • the compound contains twelve vertexes which may be boron or carbon atoms. In some aspects, all vertices are boron atoms.
  • the valence of boron is such that the boron atoms making up the icosahedral structure may be bonded to a further substituent.
  • the boron atoms may be bonded to one or more substituents, by way of non- limiting example, selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amino, amido, azo, esters, ethers, halogens, hydroxy, nitro, mercapto, phosphino, silyl, or sulfonated groups.
  • the icosahedral boron compound comprises one or more carbons in the icosahedral structure.
  • the carbon atoms comprising the icosahedral structure may be bonded to one or more additional substituents, these may be chosen from, for example, hydrogen, hydrocarbyl, substituted hydrocarbyl, amino, amido, azo, esters, ethers, halogens, hydroxy, nitro, mercapto, phosphino, silyl or sulfonated groups.
  • the nido compound has 11 vertexes.
  • the nido compound may be substituted, by way of non-limiting example, with hydrogen, hydrocarbyl, substituted hydrocarbyl, amino, amido, azo, esters, ethers, halogens, hydroxy, nitro, mercapto, phosphino, or sulfonated groups similarly to the icosahedral compounds.
  • Exemplary nido compounds include 7,8-, 7,9- and 2,9-C2B 9 Hi 2 " .
  • the incorporation of carbon into the cluster boron structure may occur at any vertex.
  • the cluster boron may contain 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms in a twelve vertex compound, and 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 borons in an eleven vertex compound. Due to the three dimensional nature of the cluster boron compound, addition of more than one carbon in the cluster boron structure may create different structural isomers. For example, where two carbon atoms are present in the icosahedral structure the two carbon atoms may produce configurations described as ortho, meta, and para.
  • the cluster boron is a carborane having two carbon atoms, wherein the carbon atoms are configured ortho to each other ([1 ,2-C 2 Bi 0 ]), meta to each other ([1 ,7-C 2 Bi 0 ]), or para ([1 ,12-C 2 Bi 0 ]) to each other.
  • the carbon atoms are configured ortho to each other ([1 ,2-C 2 Bi 0 ]), meta to each other ([1 ,7-C 2 Bi 0 ]), or para ([1 ,12-C 2 Bi 0 ]) to each other.
  • they can similarly be set in the cluster at any position without limitation.
  • the cluster boron is bound to the remainder of the compound comprising Formula (I) by a carbon-carbon bond or by a boron-carbon bond.
  • This linkage can occur at any point on the icosahedral structure. In preferred embodiments, the linkage occurs through carbon atom vertexes.
  • the variable n is an integer ranging from 1 and 10, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated. In some embodiments, the variable n is an integer ranging from 1 and 6. In various embodiments, n is equal to 1 , 2, 3, 4, 5, or 6. In preferred embodiments, n is equal to 4 or 6. In some embodiments, the hydrocarbyl may contain one or more unsaturations along the chain. Where a double bond unsaturation occurs, the configuration of the double bond may be E or Z. In a preferred embodiment, the resulting hydrocarbyl chain is saturated.
  • the variable m is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated. In some embodiments, m is zero and the amide functionality is connected directly to X. In other embodiments, m is greater than 1 . In one embodiment, m is an integer ranging from 0 and 4. In other embodiments, m is 0, 1 , 2, or 3. Where m is greater than 1 , the hydrocarbyl may contain one or more unsaturations along the chain. Where a double bond unsaturation occurs, the configuration of the double bond may be E or Z. In a preferred embodiment, the resulting hydrocarbon chain is unsaturated with a E double bond.
  • the variable X is an aromatic moiety having one or more nitrogens. In preferred embodiments, there are 1 , 2, or 3 nitrogens in the aromatic moiety. In some embodiments, the aromatic moiety is a 1 -pyridyl, a 2-pyridyl, or a 3-pyridyl. In other embodiments, the aromatic moiety has two or more nitrogens which may be oriented in any position on the aromatic ring. In a preferred embodiment, the aromatic moiety is a 3-pyridyl moiety.
  • the disclosure provides a compound comprising Formula (l)(a):
  • B is a cluster boron
  • n is an integer ranging from 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • n is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated.
  • the disclosure provides a compound comprising Formula (l)(b):
  • B is a cluster boron
  • n is an integer ranging from 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • the dashed line represents a single or double bond
  • X is an aromatic moiety having one or more nitrogen atoms.
  • the compound comprising Formula (I) may be isolated in free form as salts.
  • the salt will be a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include, without limitation, hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, acetate, formate, tartaric acid, bitartrate, stearate, phthalate, hydroiodide, lactate, monohydrate, mucate, nitrate, phosphate, salicylate, phenylpriopionate, isobutyrate, hypophosphite, maleic, malic, citrate, isocitrate, succinate, lactate, gluconate, glucuronate, pyruvate, oxalate, fumarate, propionate, aspartate, glutamate, benzoate, terephthalate, and the like.
  • compositions of the invention are shown and numbered in
  • the disclosure provides a pharmaceutical
  • composition comprising the compound comprising Formula (I) and at least one pharmaceutically acceptable excipient.
  • one or more of the compounds described in section (l)(a) may be combined with at least one
  • a pharmaceutical compositions of the disclosure comprises at least one pharmaceutically acceptable excipient.
  • suitable excipients may include diluents, binders, fillers, buffering agents, pH modifying agents,
  • disintegrants dispersing agents, stabilizers, preservatives, and coloring agents.
  • the amount and types of excipients may be selected according to known principles of pharmaceutical science.
  • the excipient may include at least one diluent.
  • suitable diluents may include microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, and trehalose.
  • MCC microcrystalline cellulose
  • cellulose derivatives i.e., acetate and butyrate
  • the excipient may comprise a binder.
  • Suitable binders may include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the excipient may include a filler.
  • Suitable fillers include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone.
  • the filler may be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.
  • the excipient may comprise a buffering agent.
  • suitable buffering agents may include, but are not limited to, MOPS, HEPES, TAPS, Bicine, Tricine, TES, PIPES, MES, Tris buffers or buffered saline salts (e.g., Tris buffered saline or phosphate buffered saline).
  • the excipient may include a pH modifier.
  • the pH modifying agent may be sodium carbonate or sodium bicarbonate.
  • the excipient may also include a preservative.
  • suitable preservatives may include antioxidants, such as alpha-tocopherol or ascorbate.
  • the excipient may include a disintegrant.
  • Suitable disintegrants may include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
  • the excipient may include a dispersion enhancer.
  • Suitable dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose.
  • the excipient may include a lubricant.
  • suitable lubricants may include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate or stearic acid.
  • Suitable color additives may include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).
  • the weight fraction of the excipient(s) in the composition may be about 98% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1 % or less of the total weight of the composition.
  • the pharmaceutical composition may be mixed with one or more excipients to form a solid, liquid or cream dosage form.
  • excipients for example, a pharmaceutically acceptable sulfate, alumilicate, alumilicate, alumilicate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate
  • the compound comprising Formula (I) may be combined with other compounds comprising Formula (I) or may be combined with one or more than one additional active pharmaceutical ingredients.
  • the disclosure provides a method of making the compound comprising Formula (I):
  • B is a cluster boron
  • X is an aromatic moiety having one or more nitrogen atoms; n is an integer between 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • n is an integer between 0 and 4, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • B is a cluster boron
  • n is an integer ranging from 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • n is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • R is chosen from OH and CI
  • X is an aromatic moiety having one or more nitrogen atoms; and m is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated
  • step (a) involves contacting a deprotonated cluster boron with an alkyl dihalide, to produce an alkyl halide substituted cluster boron compound.
  • the cluster boron may be a cluster boron as described in section (I) which has been deprotonated in at least one position. Deprotonation can occur prior to contacting the deprotonated cluster boron with an alkyl dihalide for example by reaction with n-butyl lithium (n-BuLi) or another suitable base.
  • the deprotonated cluster boron compound may be protected at one or more sites.
  • the cluster boron is a carborane with more than one carbon atom
  • protecting groups can be used to provide selectivity to formation of the alkyl halide substituted cluster boron at one site or away from one site.
  • the protecting group may be a silyl protecting group. The protection reaction may occur prior to contacting with the alkyl dihalide. The protecting group may later be removed as is understood by one of skill in the art.
  • the alkyl dihalide is generally a hydrocarbyl moiety having two halide substitutents, typically on the terminal ends of a straight chain hydrocarbyl.
  • the halides are chosen form CI, Br, and I.
  • the alkyl dihalide may have from 1 to 6 carbon atoms, and the resulting hydrocarbyl may be saturated or unsaturated.
  • the alkyl dihalide may be a 1 -bromo-2-chloroethane, 1 -bromo-3- chloropropane, 1 -bromo-4-chlorobutatne, 1 -bromo-5-chloropentane, or 1 -bromo-6- chlorohexane.
  • the alkyl substituted cluster boron formed in step (a) may be reacted to give the compound comprising Formula (II).
  • the variables for the compound comprising Formula (II) are as described for Formula (I) in section (I).
  • the compound comprising Formula (II) is protonated at the terminal amine position to form an -NH 3 cation or salt.
  • Step (b) involves reaction of the alkyl halide substituted cluster boron with a nitrogen containing compound to facilitate introduction of the nitrogen in place of the halide.
  • the nitrogen atom may be substituted in a variety of ways.
  • the alkyl halide substituted cluster boron is reacted with a compound chosen from a phthalimide, an azide or is a protecting ammonia compound such as B0C 2 NH to give an intermediate nitrogen containing compound which is then reduced to give the compound comprising Formula (II).
  • reduction may be accomplished by a variety of agents.
  • Suitable reducing agents include borohydride reagents (such as sodium borohydride) and aluminum hydrides, hydrazines, and hydrogenation regents.
  • Hydrogenation reagents may be chosen from transition metals, for example, ruthenium, iridium, palladium, platinum, or rhodium.
  • the reduction may occur from a hydrazine reduction.
  • the nitrogen containing compound is an azide
  • the reduction may be accomplished by a Palladium(O) source such as palladium on carbon.
  • the compound comprising Formula (II) may be contacted with a compound comprising Formula (III) to form the compound comprising Formula (I).
  • the reaction in general, is facilitated by a coupling agent or a base.
  • the compound comprising Formula (III) may be referred to as a carboxylic acid or acyl chloride depending on the identity of R which is chosen from OH and CI.
  • X is as described in section (I).
  • the compound comprising Formula (III) is generally a short chain carboxylic acid or acyl chloride.
  • Exemplary, but non limiting, examples of compounds comprising Formula (III) are shown in TABLE 2, and in each case R is chosen from OH and CI.
  • the compound comprising Formula (III) are (E)-3- (3'-pyridyl)acrylic acid or (E)-3-(pyridine-3-yl)acryloyl chloride.
  • the mole to mole ratio of the compound comprising Formula (II) to the compound comprising Formula (III) can range over different embodiments of the invention. In one embodiment, the ratio of the compound comprising Formula (II) to the compound comprising Formula (III) varies from about 0.9:1 to about 1 :10. In some embodiments, the mole to mole ratio of the compound comprising Formula (II) to the compound comprising Formula (III) is about 1 :1 to about 1 :1 .5. In various
  • the mole to mole ratio of the compound comprising Formula (II) to the compound comprising Formula (III) is about 1 :1 , about 1 :1 .1 , about 1 :1 .2, about 1 :1 .3, about 1 :1 .4, or about 1 :1 .5.
  • the mole to mole ratio of the compound comprising Formula (II) to the compound comprising Formula (III) is 1 :1 .
  • the reaction is preferably carried out in a solvent and is more preferably carried out in an organic solvent.
  • the solvent may be chosen without limitation from including alkane and substituted alkane solvents (including cycloalkanes) alcohol solvents, halogenated solvents, aromatic hydrocarbons, esters, ethers, ketones, and combinations thereof.
  • Non-limiting examples of suitable organic solvents are acetonitrile, acetone, allyl alcohol, benzene, butyl acetate, chlorobenzene, chloroform, chloromethane, cyclohexane, cyclopentane, dichloromethane (DCM), dichloroethane, diethyl ether, dimethoxyethane (DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dioxane, ethanol, ethyl acetate, ethylene dichloride, ethylene bromide, formic acid, fluorobenzene, heptane, hexane, isobutylmethyl ketone, isopropanol, isopropyl acetate, N-methylpyrrolidone, methanol, methylene bromide, methylene chloride, methyl iodide, methylethyl ketone, methyltetrahydrofuran,
  • An additional proton acceptor may be added to facilitate the reaction.
  • the proton acceptor generally has a pKa greater than about 7, or from about 7 to about 13, or more preferably from about 8 to about 10.
  • Representative proton acceptors include, but are not limited to, borate salts (such as, for example, NaBOs), di- and tri- basic phosphate salts, (such as, for example, Na 2 HPO 4 and NaPO 4 ), bicarbonate salts, carbonate salts, hydroxides, alkoxides, (including methoxide, ethoxide, propoxide, butoxide, and pentoxide, including straight chain and branched), and organic proton acceptors, (such as, for example, pyridine, triethylamine, N-methylmorpholine, and N,N- dimethylaminopyridine), and mixtures thereof.
  • the proton acceptor may be stabilized by a suitable counterion such as lithium, potassium, sodium, calcium, magnesium, and the like.
  • the amount of the proton acceptor which is added may vary.
  • the proton acceptor is added in excess to the compound comprising Formula (II).
  • Formula (II) to the proton acceptor can range from about 1 :1 .1 to about 1 :20.
  • the mole to mole ratio of the compound comprising Formula (II) to the proton acceptor is about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, or about 1 :10.
  • the mole to mole ratio of the compound comprising Formula (II) to the proton acceptor is 1 :3.
  • a coupling agent may facilitate the reaction.
  • Suitable coupling agents may be chosen from benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, N,N -Dicyclohexylcarbodiimide, 0-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate, benzotriazol-1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate, and 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimide.
  • the coupling agent is benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate.
  • a proton acceptor facilitates the reaction. Suitable proton acceptors include, but are not limited to organic bases such as alkyl amines, for example triethylamine, trimethylamine, or ⁇ , ⁇ -diisopropylethylamine, or N-heterocyclic
  • the base is N,N-diisopropylethylamine.
  • the amount of time over which the reaction is conducted may also vary within various embodiments.
  • the reaction may be conducted over a period of 8 hours to 1 day.
  • the reaction is carried out for about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, or about 18 hours.
  • the reaction is conducted for about 12 hours.
  • the temperature may vary over different embodiments, in some embodiments the temperature may range from about 15°C to about 40°C. In particular embodiments the temperature may range from about 15°C to about 25°C, from about 20°C to about 30°C, from about 25°C to about 30°C. In preferred embodiments the temperature may be about 20°C, about 21 °C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C.
  • the reaction may be carried out in an inert atmosphere such as argon, nitrogen, or a similar inert atmosphere.
  • Suitable apparatus for maintaining an inert atmosphere may be used to facilitate performing the reaction under an inert atmosphere.
  • Steps (a)-(c) may have an overall yield of at least about 40%.
  • the yield of the compound comprising Formula (I) may be greater than about 45%, about 50% or about 55%.
  • the compositions may be purified by methods known in the art including crystallization, chromatography, filtration and the like.
  • the compound comprising Formula (I) is isolated by a biphasic extraction and the solvent is removed by evaporation.
  • the purified isolated yield may similarly be greater than about 45%, about 50% or about 55%.
  • the present disclosure provides method a for making a compound comprising Formula (I),
  • B is a cluster boron
  • X is an aromatic moiety having one or more nitrogen atoms
  • B is a cluster boron
  • n is an integer ranging from 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • n is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated,
  • R is chosen from OH and CI
  • X is an aromatic moiety having one or more nitrogen atoms
  • n is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated
  • the yield may be at least about 80%. In still another embodiment, the yield of the compound comprising
  • Formula (I) may be greater than about 85%, about 90% or about 95%. In still another embodiment, the yield may be about 95%.
  • the compositions may be purified by methods known in the art including crystallization, chromatography, filtration and the like. In preferred embodiments, the compound comprising Formula (I) is isolated by a biphasic extraction and the solvent is removed by evaporation. The purified isolated yield may similarly be greater than about 85%, about 90% or about 95%.
  • the disclosure provides a method of inhibiting Nampt in a subject, the method comprising administering a subject a compound comprising Formula (I),
  • B is a cluster boron
  • X is an aromatic moiety having one or more nitrogen atoms
  • n is an integer ranging from 1 and 6, and where n is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated;
  • n is an integer ranging from 0 and 4, and where m is greater than 1 , the resulting hydrocarbyl chain may be saturated or unsaturated.
  • Administration of a compound comprising Formula (I) may act to inhibit the enzyme Nampt.
  • the variety of conditions that the compounds may be useful in treating are those associated with, or which may be alleviated by, modification of Nampt function.
  • the compositions may be used to treat a conditions including cancer (including, but not limited to, colorectal, breast, prostate, brain, pancreatic, lung, gastric, fibrosarcoma, lymphoma, leukemia, and liver), arthritis, diabetes, Huntington's disease, Alzheimer's, inflammation, neurodegeneration, spinal cord injury, and the like.
  • the compounds described in section (I) may show enhanced inhibition over FK866.
  • inhibition is 50X greater than that by FK866.
  • inhibition is 100X greater, 200X greater, or 500X greater than that by FK866.
  • the compounds may be administered to the subject by a variety of routes.
  • a compound comprising Formula (I) may be administered orally (via a solid or liquid dosage form), parenterally (i.e., subcutaneously, intradermally, intravenously, intramuscularly, intracranially, or intraperitoneally), or topically (i.e., transdermal ⁇ or transmucosally).
  • Suitable subjects include, without limit, humans, as well as companion animals such as cats, dogs, rodents, and horses; research animals such as rabbits, sheep, pigs, dogs, primates, mice, rats and other rodents; agricultural animals such as cows, cattle, pigs, goats, sheep, horses, deer, chickens and other fowl; zoo animals; and primates such as chimpanzees, monkeys, and gorillas.
  • the subject may be a human.
  • the compounds may be administered in saline or with a
  • the amount of the compound which is administered to the subject may depend on the subject and the route of administration and may be determined by a person of ordinary skill in the art.
  • IC 5 0 values are the half maximal inhibitory concentration, which measures the effectiveness of a compound in biological inhibition.
  • the IC 50 values for the compounds described in section (I) are 30% to 90% decreased when compared to FK866.
  • the compounds of the invention are 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decreased when compared to FK866.
  • Administration of the compounds described in section (I) coincides with a high cancer cell antiproliferative effect when compared to FK866. In some
  • the antiproliferative effect of the compound comprising Formula (I) is 5X greater than that of FK866. In other embodiments, the antiproliferative effect of the compound comprising Formula (I) is 10X greater than that of FK866, and in still other embodiments, the antiproliferative effect of the compound comprising Formula (I) is 25X greater than that of FK866.
  • A549 (Ademnocarcinomic human alveolar basal epithelial cells (lung)
  • acyl denotes the moiety formed by removal of the hydroxyl group from the group COOH of an organic carboxylic acid, e.g., RC(O)-, wherein R is R 1 , R 1 O-, R 1 R 2 N-, or R 1 S-, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R 2 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
  • acyloxy denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(O)O- wherein R is as defined in connection with the term "acyl.”
  • O oxygen linkage
  • alkyl as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
  • alkenyl as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • alkoxide or "alkoxy” as used herein is the conjugate base of an alcohol.
  • the alcohol may be straight chain, branched, cyclic, and includes aryloxy compounds.
  • alkynyl as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
  • aromatic as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic conjugated planar ring or ring system comprising delocalized electrons. These aromatic groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups containing from 5 to 14 atoms in the ring portion.
  • aromatic encompasses "aryl” groups defined below.
  • aryl or “Ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.
  • BOC or Boc as used herein refers to the t-butyloxycarbonyl protecting group.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thio.
  • DLD1 refers to Human Colon Carcinoma Cells.
  • halide or halo as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
  • heteroatom refers to atoms other than carbon and hydrogen.
  • heteroaromatic as used herein alone or as part of another group denotes optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heteroaromatic group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon.
  • Exemplary groups include furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and the like.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thiol.
  • heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom.
  • Exemplary heterocyclo groups include heteroaromatics as described above.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thio.
  • hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
  • PANC1 refers to Human Pancreatic Carcinoma.
  • PC3 refers to Human Prostate Cancer Cells.
  • U87 refers to Human g/Zoi /asfoma-astroncytonria (brain).
  • T47D refers to Human Ductal Breast Epithelial Tumor Cells.
  • hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or a halogen atom, and moieties in which the carbon chain comprises additional substituents.
  • substituents include alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thio.
  • Te/f-butyldimethylsilyl-o-carborane, o-[ C 2 Bi 0 Hn]SiMe 2 f-Bu was prepared using the method described previously as in F. A. Gomez, M.F. Hawthorne, J. Org. Chem. 1992, 57, 1384-1390.
  • A549, DLD1 , T47D and PC3 were purchased from ATCC (Manassas, VA). MTT assay kit was purchased from Promega (Madison, Wl). FK866 and NMN were purchased from Enzo Life Sciences (Farmingdale, NY) and Sigma (St Louis, MO) respectively.
  • MTT assay provides a direct measure of mitochondrial activity which can be compared directly with previously reported numbers of (1) by Hasmann
  • FIG. 1 shows the concentration-response curves against A549 cell line. For clarity (5) was omitted from the graph but displayed results between 1 and 7. Additional MTT assays are show in FIG. 11(A)-(D) and FIG. 12 for compounds (33)-(37).
  • NAD neurodeficiency kinase
  • Busso et al. (Busso, N.; Karababa, M.; Nobile, M.; Rolaz, A.; Van Gool, F.; Galli, M.; Leo, O.; So, A.; De Smedt, T.
  • Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.
  • PLoS One 2008, 21 , e2267. Briefly, A549 and DLD1 cells were plated at a density of 10,000 cells per well in 96 well plates for overnight. Cells were then treated with 10nM concentrations of agents (1), (5)-(7).
  • concentrations of 1 , 10 or 100 ⁇ NMN were added to the cultures. Cultures were then continued for 72 h. MTT reagent was added to the cells after 72 h for a period of 3 h and then MTT crystals were solubilized using solubilization buffer. Readings were taken at 570 nm wavelength. Control cells were considered as 100% survival to plot the inhibition and rescue graph. The experiments were repeated four times. Results are shown in FIG. 2.
  • the assay was performed according to the manufacturers protocol (CycLex NAMPT Colorimetric Assay Kit, MBL International Corp., Woburn, MA).
  • the NAMPT assay was performed according manufacturers protocol. Briefly we used the "1 - Step Assay Method" for which following reagents were mixed to make assay buffer and kept at ice before starting the assay: 10 ⁇ _ each of 10X Nampt assay buffer,
  • the Nampt inhibition assay was performed by mixing 2 ⁇ of various concentrations (to make 1 pM-100 nM) of FK866 or (6) (or 2 ⁇ _ DMSO as vehicle control) with the following: 2 ⁇ _ recombinant Nampt and 36 ⁇ _ D 2 O.
  • the reaction was initiated by adding 60 ⁇ _ of 1 - Step Assay Buffer to each well and mixed thoroughly followed by incubation at 30°C for 20 mins. After this period, the absorbance at 450 nm was measured and compared with the positive control.
  • TABLE 4 lists measured Half-Maximal Inhibitory Concentrations (IC 50 ) against Human Tumor Cell Lines A549 (Lung), DLD1 (Colon), and T47D (Breast).
  • Compound 2 was prepared and isolated by reacting butylamine (0.3 mL, 3.04 mmol) with frans-3-(3'-pyridyl)acrylic acid (302 mg, 2.02 mmol), and BOP (893 mg, 2.02 mmol) in dimethylfonnamide (14 mL). The reaction was allowed to stir overnight to yield yellow oil (70 mg, 18%).
  • Compound (3) was prepared and isolated by reacting 4- phenylbutylamine (1 mL, 6.21 mmol) with frans-3-(3'-pyridypacrylic acid (617 mg, 4.14 mmol), and BOP (1829 mg, 4.14 mmol) in dimethylformamide (12 mL). The reaction was allowed to stir overnight to yield a pale yellow oil (630 mg, 60%).
  • Methanesulfonylchlonde (0.11 mL, 1 .47 mmol) was added dropwise to a stirred solution of (10) (250 mg, 1 .23 mmol) and triethylamine (0.2 mL, 1 .47 mmol) in anhydrous diethyl ether (3 mL) at -15°C under an argon atmosphere. After 3.5h water (10 mL) and diethyl ether (10 mL) were added to the reaction mixture. The organic layer was separated, washed three times each with 20 mL of water and brine, then dried over anhydrous Na 2 SO 4 and evaporated to yield (11) (300 mg, 87%) as a pale yellow oil.
  • tetrahydrofuran (10 mL) was added slowly a 2 M solution of lithium aluminum hydride in THF (0.89 mL 2.2 mmol) at 5°C. The mixture was slowly warmed to room temperature and stirred overnight. Upon completion, water was added dropwise to quench the excess LAH. The mixture was filtered through a pad of Celite and sodium sulfate, and the filtrate vacuum-dried to afford the yellow oil as a pure product (380 mg, 88%).
  • Example 5 1 -(4'-(Trans-3"-(3"'pyridyl)acrylamido)butyl)-1 , 7-dicarba-closo- dodecaborane (6).
  • the biphasic mixture was transferred to a separatory funnel; the organic layer was removed and the aqueous layer was extracted with twice with 20 mL of ethyl acetate. The organic fractions were combined and washed with 20 mL of water and 3 mL of brine, dried over anhydrous Na 2 SO 4 and the solvent removed under vacuum. The residue was purified by silica gel chromatography (dichloromethane/methanol) to afford a yellow oil (40 mg, 36%).
  • Example 6 1 -(4'-(Trans-3"-(3"'-pyridyl)acrylamido)butyl)-1 , 12-dicarba-closo- dodecaborane (7).
  • the biphasic mixture was transferred to a separatory funnel; the organic layer was removed and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The organic fractions were combined and washed with 20 mL of water and 3 mL of brine and then dried over anhydrous Na 2 SO . The solvent was removed under vacuum and the residue was purified by silica gel chromatography using dichloromethane/methanol to afford a yellow oil (30 mg, 19%).
  • Two overall synthetic routes can be used to produce compound (5) .
  • Derivatives of o-carborane were produced by direct substitution of a carbon atom on o- carborane or by inserting an alkyne into decaborane to form the closo icosahedron.
  • a strong base such as n-butyllithium can extract a weakly acidic proton of one (or both) carbon atoms in a carborane.
  • the resulting anion reacts with electrophile, and was reacted with 1 -bromo-4-chlorobutane.
  • the resulting chloride was converted to a protected amine using di-terf-butyl dicarbonate.
  • phthalimide was reduced using sodium borohydride, followed by refluxing in aqueous HCI.
  • the vessel was evacuated under reduced pressure to remove solvent and any gaseous byproducts.
  • the crude product was redissolved in anhydrous THF (15 mL) and cooled to 0 °C. 1 -(4- Aminobutyl)-1 ,7-dicarbadodecaborane. (0.670 g, 3.11 mmol) was dissolved in anhydrous THF (5 mL) and Hunig's Base (1 .860 g, 2.50 mL, 14.36 mmol) and added drop wise to the reaction vessel. The resulting solution was allowed to stir overnight while slowly reaching ambient temperature.
  • the crude product was redissolved in DCM (10 mL) and washed with saturated solution of sodium bicarbonate (20 mL).
  • the antimigratory effects of compounds (5)-(7) were compared with FK866 by employing a wound healing or scratch test analysis using various cell cancer lines.
  • the assay measures the ability of a drug to inhibit cancer cell migration across a gap "scratched" in a confluent layer of cells.
  • the cells were imaged immediately after the formation of the wound and then incubated with 1 nM concentrations of each test agent. After 24 h, the wounds were imaged again and compared with a control group of untreated cells. The results are shown in FIG. 9. The control cells repopulated the wound area, whereas treatment with FK866 partially inhibited cell migration.

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Abstract

La présente invention concerne de nouveaux composés, leur utilisation en tant qu'agents antinéoplasiques et leur synthèse. En particulier, les composés contiennent des fractions groupées du bore telles que carborane ou un borohydrure, et agissent en tant qu'inhibiteurs pour l'enzyme Nampt. Les propriétés biologiques des composés groupés du bore de l'invention, en termes d'inhibition biologique et d'effet antiprolifératif, sont supérieures à celles d'autres inhibiteurs à petite molécule de Nampt.
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WO2016012958A1 (fr) 2014-07-23 2016-01-28 Aurigene Discovery Technologies Limited Dérivés de 4,5-dihydroisoxazole comme inhibiteurs de nampt
US9856241B2 (en) 2013-07-03 2018-01-02 Karyopharm Therapeutics Inc. Substituted benzofuranyl and benzoxazolyl compounds and uses thereof
US9938258B2 (en) 2012-11-29 2018-04-10 Karyopharm Therapeutics Inc. Substituted 2,3-dihydrobenzofuranyl compounds and uses thereof
US9994558B2 (en) 2013-09-20 2018-06-12 Karyopharm Therapeutics Inc. Multicyclic compounds and methods of using same
US10144742B2 (en) 2014-04-18 2018-12-04 Millennium Pharmaceuticals, Inc. Quinoxaline compounds and uses thereof
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741250B2 (en) 2011-08-05 2014-06-03 The Curators Of The University Of Missouri Hydroxylation of icosahedral boron compounds
US9938258B2 (en) 2012-11-29 2018-04-10 Karyopharm Therapeutics Inc. Substituted 2,3-dihydrobenzofuranyl compounds and uses thereof
US10399963B2 (en) 2013-07-03 2019-09-03 Karyopharm Therapeutics Inc. Substituted benzofuranyl and benzoxazolyl compounds and uses thereof
US9856241B2 (en) 2013-07-03 2018-01-02 Karyopharm Therapeutics Inc. Substituted benzofuranyl and benzoxazolyl compounds and uses thereof
US11008309B2 (en) 2013-07-03 2021-05-18 Karyopharm Therapeutics Inc. Substituted benzofuranyl and benzoxazolyl compounds and uses thereof
US9994558B2 (en) 2013-09-20 2018-06-12 Karyopharm Therapeutics Inc. Multicyclic compounds and methods of using same
US10144742B2 (en) 2014-04-18 2018-12-04 Millennium Pharmaceuticals, Inc. Quinoxaline compounds and uses thereof
WO2016012958A1 (fr) 2014-07-23 2016-01-28 Aurigene Discovery Technologies Limited Dérivés de 4,5-dihydroisoxazole comme inhibiteurs de nampt
US10323018B2 (en) 2015-01-20 2019-06-18 Millennium Pharmaceuticals, Inc. Quinazoline and quinoline compounds and uses thereof
US10363247B2 (en) 2015-08-18 2019-07-30 Karyopharm Therapeutics Inc. (S,E)-3-(6-aminopyridin-3-yl)-N-((5-(4-(3-fluoro-3-methylpyrrolidine-1-carbonyl)phenyl-7-(4-fluorophenyl)benzofuran-2-yl)methyl)acrylamide for the treatment of cancer
US10858347B2 (en) 2015-12-31 2020-12-08 Karyopharm Therapeutics Inc. Multicyclic compounds and uses thereof
US11638762B2 (en) 2016-10-18 2023-05-02 Seagen Inc. Targeted delivery of nicotinamide adenine dinucleotide salvage pathway inhibitors
US11931414B2 (en) 2017-04-27 2024-03-19 Seagen Inc. Quaternized nicotinamide adenine dinucleotide salvage pathway inhibitor conjugates
CN110627841A (zh) * 2019-09-28 2019-12-31 上海应用技术大学 一种含间位碳硼烷三唑配体的铁配合物及其制备与应用

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