WO2015192343A1 - Petites molécules à activateur de p53 - Google Patents

Petites molécules à activateur de p53 Download PDF

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Publication number
WO2015192343A1
WO2015192343A1 PCT/CN2014/080212 CN2014080212W WO2015192343A1 WO 2015192343 A1 WO2015192343 A1 WO 2015192343A1 CN 2014080212 W CN2014080212 W CN 2014080212W WO 2015192343 A1 WO2015192343 A1 WO 2015192343A1
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WO
WIPO (PCT)
Prior art keywords
indol
methanol
methyl
compound
cell
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PCT/CN2014/080212
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English (en)
Inventor
Baishan JIANG
Langxi HU
Yan Cui
Sheng Ding
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Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences
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Priority to PCT/CN2014/080212 priority Critical patent/WO2015192343A1/fr
Publication of WO2015192343A1 publication Critical patent/WO2015192343A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to field of medicine, specially relates to a P53 activator small molecules, its preparation method and its use in therapeutic applications.
  • p53 is best known as a tumor suppressor that transcriptionally regulates, in response to cellular stresses such as DNA damage or oncogene activation, the expression of various target genes that mediate cell-cycle arrest, DNA repair, senescence or apoptosis. Loss of p53 activity - either by somatic mutation of the TP53 gene or by functional inhibition of the p53 protein - is a common feature of human tumors.
  • TP53 is the most frequently mutated gene in human cancer with mutation frequencies ranging from 38%-50% in some reports to as high as 75% and 96% in pancreatic adenocarcinoma and high-grade serous ovarian carcinomas, respectively (Hingorani et al., 2005; Cancer Genome Atlas Research Network, 201 1 ; Petitjean et al., 2007).
  • the majority of mutations are mis-sense mutations that occur most frequently in six "hotspot" codons within the DNA binding domain (Olivier et al., 2010).
  • mutant proteins are classified as either DNA contact mutants (e.g., p53R273H) when the mutation occurs in a DNA binding residue or conformational mutants (e.g., p53R175H) when a conformational change causes a loss of WT p53 DNA binding.
  • Mutant p53 proteins are found at high concentrations in tumor cells relative to WT p53, mostly because of a loss of WT p53 transcription of the MDM2 gene that negatively regulates p53, as well as other rumor-specific alterations, such as loss of pl6INK4a (Haupt et al, 1997; Midgley and Lane, 1997; Terzian et al.,2008).
  • mutant p53 gain-of-function (GOF) phenotype The concept that these mutant proteins are functional and regulate important processes relevant to tumor biology is referred to as the mutant p53 gain-of-function (GOF) phenotype (Sigal and Rotter, 2000).
  • Properties attributed to mutant p53 GOF include enhanced tumorigenesis, invasion, and metastasis (Adorno et al., 2009; Dittmer et al., 1993; Liu et al., 2000; Muller et al., 2009). Taken together, these properties make mutant p53 an attractive target for drug development.
  • anticancer drugs will be defined by compounds that selectively kill cancer cells while leaving normal cells undisturbed.
  • Small molecule compounds that selectively kill cancer cells with a p53R175 or p53R273Hmutation without toxicity in normal cells will be an ideal drug for development. Those small molecules restore WT structure and function to the p53R175 o ⁇ 53R273FIprotein, may allow to be developed as new anti-cancer drug.
  • the present invention is to restore WT structure and function to the p53R175 or p53R273H protein by small molecules and to apply in therapeutic applications. Therefore, one aspect of the present invention is to provide p53 activators which can be used therapeutically, for example, a compound having the general structural formulae (I):
  • group R can be selected from the group consisting of
  • the compound of formula I can be selected from the group consisting of:
  • Ri , R 2 , R 3 and R4 are independently hydrogen, halogen, C 1-6 alkoxy, -S(0) 2 R 5 , -C(0)OR 5 , -C(0)R 5 , -C(0)NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl, cyclopropyl, or C 2- 6 alkynyl, each of which can be optionally substituted with halogen, amino, hydroxyl, alkoxy or cyano, morpholinyl, piperazinyl, quinolinyl, aryl, C 1-6 heterocycle, 5 or 6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S;
  • R 5, R 6 , R 7 is independently hydrogen, halogen, alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which can be optionally substituted with halogen, amino, hydroxyl, alkoxy or cyano.
  • R 1; R 2 , R 3 and R4 are independently hydrogen, halogen, methyl, ethyl, aryl, cyano, ethyloxyl, -C(0)NH 2 , -C(0)NHC 1-6 alkyl, C 1-6 heterocycle; R 5 , R 6 , R 7 are independently methyl.
  • Said halogen is preferred F or CI.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Alkyl when used as a substituent or part of a substituent, refers to a linear or branched aliphatic hydrocarbon substituent. Most preferable one is Q-C 6 alkyl, unless otherwise indicated. Examples of linear or branched Ci-C 6 alkyl include but not limited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl and the like.
  • Alkoxy refers to a substituent of (alkyl-O-), in which the alkyl is as defined herein. Preferably, it is Q-Qalkoxy. Examples include but not limited to methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • alkenyl when used as a substituent or part of a substituent, refers to an aliphatic hydrocarbon substituent with at least one carbon carbon double bond, and may be linear or branched. Most preferable one is C 2 -C 6 alkenyl. The said substituent may contain multiple double bonds in its backbone which may independently be E configuration or Z configuration. Examples of said alkenyl include but not limited to vinyl, propenyl, allyl, butylene and the like.
  • Alkynyl refers to an aliphatic hydrocarbon substituent with at least one carbon carbon triple bond, and may be linear or branched. Most preferable one is C 2 - C 6 alkynyl.Examples of said alkynyl include but not limited to all isomers of hexynyl, pentynyl, butynyl, propynyl and ethynyl.
  • Aryl refers to aromatic carbon-ring system with one or two rings, including such as phenyl, naphthyl and tetrahydronaphthyl. Preferred aryl is phenyl.
  • an H atom in any substituent groups encompasses all suitable
  • isotopic variations e.g., H, H and H.
  • other atoms in any substituent groups encompasses all suitable isotopic variations, including but not limited to n C, 13 C, 14 C , 15 N, 17 0, 18 0, 35 S, 18 F, 36 I and/or 123 I.
  • the preferred compounds of formula I of the present invention comprise the following compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and at least one pharmaceutically acceptable earner or diluent, wherein said compound is in free form or in a pharmaceutically acceptable salt form.
  • Such composition may be an oral composition, injectable composition or suppository.
  • the composition may be manufactured in a conventional manner in the art, for example, by mixing, granulating or coating methods.
  • the composition is an oral composition and it may be a tablet or gelatin capsule.
  • the oral composition comprises the present compound together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets, together with c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragamayth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; and if desired, d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) additives, e.g., absorbents, colorants, flavors, e.g.,
  • the composition is an injectable composition, and may be an aqueous isotonic solution or suspension.
  • the composition is a suppository and may be prepared from fatty emulsion or suspension.
  • the composition is sterilized and/or contains adjuvant.
  • adjuvant can be selected from preserving, stabilizing, wetting or emulsifying agent, solution promoter, salt for regulating the osmotic pressure, buffer and/or any combination thereof.
  • composition may further contain other therapeutically valuable substances for different applications, like solubilizers, stabilizers, tonicity enhancing agents, buffers and/ or preservatives.
  • the composition may be a formulation suitable for transdermal application.
  • Such formulation includes an effective amount of the compound of the present invention and a carrier.
  • the earner may include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • a transdermal device contain the formulation may also be used.
  • the transdermal device may be in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with earners, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • a matrix transdermal formulation may also be used.
  • the composition may be a formulation suitable for topical application, such as to the skin and eyes, and may be aqueous solution, ointment, cream or gel well known in the art.
  • the present invention provides a method of inhibiting WNT secretion from a cell.
  • the present invention provides a method of restoring mutant P53 function in a cell with an effective amount of the present compound.
  • the cell is contained within a mammal, and the administered amount is a therapeutically effective amount.
  • the restoring mutant P53 function further results in the inhibition of the growth of the cell.
  • the cell is a cancer cell.
  • the cell is a fibrogenic cell.
  • Cell proliferation is measured by using methods known to those skilled in the art.
  • a convenient assay for measuring cell proliferation is the CellTiter-GloTM Assay commercially available from Promega (Madison, WI).
  • the assay procedure involves adding the CellTiter-Glo® reagent to cells cultured on multi-well dishes.
  • the luminescent signal measured by a luminometer or an imaging device, is proportional to the amount of ATP present, which is directly proportional to the number of viable cells present in culture.
  • cell proliferation may also be measured using colony formation assays known in the art.
  • the present invention also provides a method for treating cancers related to the P53 mutation with an effective amount of the present compound.
  • Those skilled in the art would readily be able to determine whether a cancer is related to the P53 mutation by analyzing cancer cells using one of several techniques known in the art. For example, one could examine cancer cells for aberrations in the levels of proteins or mRNAs involved in P53 mutation using immune and nucleic acid detection methods.
  • the invention provides a method for treating P53 disorder in a subject suffering from the disorder by administering to the subject a therapeutically effective amount of a mutant P53 activator.
  • the disorder is a cell proliferative disorder associated with aberrant, e.g., decreased, activity of P53 signaling.
  • the cell proliferative disorder is cancer, include but are not limited to: lung (small cell and non-small cell), breast, prostate, carcinoid, bladder, gastric, pancreatic, liver (hepatocellular), hepatoblastoma, colorectal, head cancer and neck squamous cell carcinoma, esophageal, ovarian, cervical, endometrial, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid, desmoids, acute myelocytic leukemia (AML), and chronic myelocytic leukemia (CML).
  • lung small cell and non-small cell
  • breast breast
  • prostate carcinoid
  • bladder gastric
  • pancreatic liver
  • hepatoblastoma colorectal
  • head cancer and neck squamous cell carcinoma esophageal
  • ovarian cervical
  • endometrial mesothelioma
  • the compound of the present invention could be administered in a therapeutically effective amount via any acceptable way known in the art singly.
  • the therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the satisfactoiy result is indicated to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg/kg per body weight of the subject.
  • the indicated daily dosage for larger mammal as human is in the range from about 0.5mg to about lOOmg.
  • the compound is administered in divided doses up to four times a day or in retard form.
  • suitable unit dosage forms for oral admimstration comprise from ca. 1 to 100 mg active ingredient.
  • the compound of the present invention may be administered in a therapeutically effective amount as the active ingredient in combination with one or more therapeutic agents, such as pharmaceutical combinations.
  • therapeutic agents such as pharmaceutical combinations.
  • the dosage of the co-administered compounds could vaiy depending on the type of co-drug employed, the specific drug employed, the condition being treated and so forth.
  • the compound of the present invention or the composition thereof may be administered by any conventional route.
  • it is administered enterally, such as orally, and in the form of tablets or capsules.
  • it is administered parenterally and in the form of injectable solutions or suspensions.
  • it is administered topically and in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • the invention also provides a pharmaceutical combination, preferably, a kit, comprising a) a first agent which is the compound of the present invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent, selected from the group consisting of an aurora kinase inhibitor, a tyrosine kinase inhibitor and a histone deacetylase inhibitor.
  • the kit may comprise instructions for its administration.
  • the combination of the present invention may be used in vitro or in vivo.
  • the desired therapeutic benefit of the administration may be achieved by contacting cell, tissue or organism with a single composition or pharmacological formulation that includes the compound of the present invention and one or more agents, or by contacting the cell with two or more distinct compositions or formulations, wherein one composition includes one agent and the other includes another.
  • the agents of the combination may be administered at the same time or separately within a period of time.
  • the separate administration can result in a desired therapeutic benefit.
  • the present compound may precede, be co-current with and /or follow the other agents by intervals ranging from minutes to weeks.
  • a person skilled in the art could generally ensure the interval of the time of each delivery, wherein the agents administered separately could still be able to exert an advantageously combined effect on the cell, tissue or organism.
  • one may contact the cell, tissue or organism with two, three, four or more modalities substantially simultaneously as the candidate substance, i.e., with less than about one minute.
  • one or more agents may be administered about between lmintue to 14 days.
  • the present invention provides a process for preparing the compound of the present invention or the salts or derivatives thereof.
  • the compound having Formula (I), preferably Formula (II), (III),(IV), (V)(VI) and (Vll) may be prepared following any one of the synthetic methodologies described in Examples below.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, may be protected to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice (see e.g., T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991).
  • Suitable leaving groups for use in the synthetic methodologies described include halogen leaving groups and other conventional leaving groups known in the art.
  • the leaving group is chloro or bromo.
  • the compound of the invention or the salts thereof may also be obtainable in the form of hydrates, or their crystals may include for example the solvent used for crystallization (present as solvates).
  • Salts can usually be converted to compounds in free form by treating with suitable basic agents, preferably with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, more preferably with potassium carbonate or sodium hydroxide.
  • suitable basic agents preferably with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, more preferably with potassium carbonate or sodium hydroxide.
  • a compound of the invention in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid, such as hydrochloric acid.
  • any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate.
  • Salts of the present compound with a salt-forming group may be prepared in a manner known in the art.
  • Acid addition salts of compound of Formula (I),preferably Formula(II), (III),(rV),(V), (VI) and (VH) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • Pharmaceutically acceptable salts of the compound of the invention may be formed as acid addition salts from compound of Formula (I), preferably Formula(II), ( ⁇ ),( ⁇ ), (V), (VI) and (VII) with a basic nitrogen atom with organic or inorganic acids.
  • suitable inorganic acids include, but are not limited to, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • suitable organic acids include, but are not limited to, carboxylic, phosphoric, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,-malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethan
  • compound of the presentinvention in unoxidized form may be prepared from N-oxides of compound of the invention by treating with a reducing agent in a suitable inert organic solvent at 0 to 80°C.
  • the reducing agent is sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like.
  • the invert organic solvent is acetonitrile, ethanol, aqueous dioxane, or the like.
  • prodrug derivatives of the compound of the present invention may be prepared by methods known in the art (for further details see Saulnier et al, (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • an appropriate prodrug may be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent such as 1,1- acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • protected derivatives of the compound of the present invention may be made by means known in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal may be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.
  • compound of the present invention may be prepared as their individual stereoisomers.
  • the process includes steps: reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • Resolution of enantiomers may be earned out using covalent diastereomeric derivatives of the compound of the present invention, or by using dissociable complexes such as crystalline diastereomeric salts.
  • Diastereomers have distinct physical properties presented by melting points, boiling points, solubilities, reactivity, etc., and may be readily separated by taking advantage of these dissimilarities.
  • the diastereomers may be separated by fractionated crystallization, chromatography, or by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture may be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • a pharmaceutically acceptable salt may be converted from the compound of the present invention.
  • a pharmaceutically acceptable N-oxide may be converted from an unoxidized form of the compound the present invention
  • an individual isomer of the compound of the present invention is resolved from a mixture of isomers
  • a pharmaceutically acceptable prodrug derivative may be converted from a non-derivatized compound of the present invention.
  • Figure la shows mRNA levels of p53 targets p21, DR5, GADD45, PUMA and Noxa in SW620 (having p53 R273H mutation) cells upon treatment of compound 1.
  • Figure lb shows mRNA levels of p53 targets p21, DR5, GADD45, PUMA and Noxa in Saos2(without p53 R273H mutation) cells upon treatment of compound 1.
  • the compounds of the present invention may be prepared by methods such as those illustrated in the following scheme I .
  • lH-indole-3-carbox aldehyde is reacted with substituted chloromethylpyridine or chloromethylqumolone in the presence of a base, such as cesium carbonate, preferably at elevated temperatures (50°C ⁇ 100°C) to afford lH-indole-3-carboxaldehyde derivatives of compound of formula ( ⁇ ) of scheme I.
  • a base such as cesium carbonate
  • lH-indole-3-carboxaldehyde derivatives of compound of formula ( ⁇ ) of scheme I can be reduced with a reducing agent, such as sodium borohydride to obtain alcohol derivatives of compound of formula (I) of scheme I.
  • a reducing agent such as sodium borohydride
  • compound 16 ( 1 -((6-(piperidin- 1 -yl)pyridin-2-yl)methyl)- 1 H-indol-3 -yl)methanol;
  • compound 18 ( 1 -((6-(pyrrolidin- 1 -yl)pyridin-2-yl)methyl)- 1 H-indol-3-yl)methanol; compound 19: ( 1 -((6-(cyclopropylamino)pyridin-2-yl)methyl)- 1 H-indol-3 -yl)methanol; compound 20: (l-(quinolin-2-ylmethyl)-lH-indol-3-yl)methanol;
  • RNA is extracted from the cells SW620 (having p53 R273H mutation) and Saos2 (without p53 R273H mutation) using a QiagenRNeasy Kit, and the gene expression level is measured by quantitative RT-PCR using TaqMan gene expression assays (Applied Biosciences, Carlsbad, CA, USA). The gene expression level is normalized with b-actin, and the average is presented with standard deviation from duplicates or triplicates of repeated experiments. To compare the mRNA levels of p53 targets p21, DR5, GADD45, PUMA and Noxa in SW620 and Saos2 cells, upon treatment of compound 1, all 5 target genes expression were increased in SW620 cells but no change in Saos2 cells. The data showed the restoration of p53 transactivational gunction through the "WT-like" conformational change induced by compound 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne de petites molécules de formule (I) aptes à inhiber la sécrétion de WNT d'une cellule ou à restaurer la fonction P53 mutante d'une cellule, des compositions pharmaceutiques et leur utilisation dans le traitement d'états anormaux, tels que des tumeurs malignes.
PCT/CN2014/080212 2014-06-18 2014-06-18 Petites molécules à activateur de p53 WO2015192343A1 (fr)

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Cited By (1)

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JP2020509044A (ja) * 2017-03-01 2020-03-26 グラクソスミスクライン、インテレクチュアル、プロパティー、（ナンバー２）、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ （Ｎｏ．２） Ｌｉｍｉｔｅｄ ブロモドメイン阻害薬としてのピリジル誘導体

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WO2007062399A2 (fr) * 2005-11-23 2007-05-31 The Board Of Regents Of The University Of Texas System Compose cytotoxique speficique du ras oncogene et ses procedes d’utilisation
WO2008144263A1 (fr) * 2007-05-18 2008-11-27 The Ohio State University Research Foundation Agents antitumoraux efficaces dérivés de l'indole-3-carbinole
JP2009091326A (ja) * 2007-10-11 2009-04-30 Nippon Kayaku Co Ltd １−ベンジルインドール誘導体、並びにそれらの用途
CN102603717A (zh) * 2012-01-09 2012-07-25 中国人民解放军第二军医大学 吡咯酮类化合物及其作为药物的用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020509044A (ja) * 2017-03-01 2020-03-26 グラクソスミスクライン、インテレクチュアル、プロパティー、（ナンバー２）、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ （Ｎｏ．２） Ｌｉｍｉｔｅｄ ブロモドメイン阻害薬としてのピリジル誘導体

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