WO2012047017A2 - 2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물 - Google Patents

2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물 Download PDF

Info

Publication number
WO2012047017A2
WO2012047017A2 PCT/KR2011/007370 KR2011007370W WO2012047017A2 WO 2012047017 A2 WO2012047017 A2 WO 2012047017A2 KR 2011007370 W KR2011007370 W KR 2011007370W WO 2012047017 A2 WO2012047017 A2 WO 2012047017A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
fluoro
phenyl
dihydro
nmr
Prior art date
Application number
PCT/KR2011/007370
Other languages
English (en)
French (fr)
Other versions
WO2012047017A3 (ko
Inventor
홍용래
이미정
김정미
홍장원
장호진
박수봉
이휘성
최종류
노성구
조중명
Original Assignee
크리스탈지노믹스(주)
한국보건산업진흥원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 크리스탈지노믹스(주), 한국보건산업진흥원 filed Critical 크리스탈지노믹스(주)
Publication of WO2012047017A2 publication Critical patent/WO2012047017A2/ko
Publication of WO2012047017A3 publication Critical patent/WO2012047017A3/ko

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a 2,3-dihydro-isoindol-1-one derivative and a composition comprising the same, wherein the compounds and compositions of the present invention are for treating diseases or conditions associated with abnormal or deregulated kinase activity. It can be useful for mitigation or prevention.
  • Protein kinases have been important therapeutic targets because they phosphorylate specific amino acids of proteins and are closely associated with various signal transduction and disease mechanisms in cells. These protein kinases represent a large group of proteins that play a pivotal role in regulating various cellular processes in maintaining cellular function and are classified according to their phosphorylation substrate. The kinases are classified into the following groups: protein-tyrosine, protein-serine / threonine, protein-histidine, and the like.
  • Protein-tyrosine kinases include Abl, Irk, IGFR-1, Zap-70, BLK, Bmx, Btk, Csk homologous kinase (CHK), C-terminal Skin kinase (CSK), Itk-1, Src (c-Src, Lyn, yn, Lck, Syk, Hck, Yes, Blk, Fgr, Frk), Tec, Txk / Rlk, Abl, EGFR (EGFR-1 / ErbB-2, ErbB-2 / NEU / HER-2, ErbB-3 , ErbB-4), FAK, FGF1R (FGFR1 or FGR-1), FGF2R (FGR-2), MET (Met-1 or c-Met), PDGFR- ⁇ , PDGFR- ⁇ , Tie-1, Tie-2 (Tek-1 or Tek-2), VEGFR1 (FLT-1), VEGFR2 (KDR), FLT-3, FLT-4,
  • Protein serine / threonine kinases include Aurora, Ark, AMT (1--1). 3), CamK (I ⁇ IV), CamKK, Chk1 and 2, CKI, CK2, IKK-I, IKK-2, IlK, Jnk91-3), LimK (1 and 2), MLK3Raf (AC), CDK (1 -10), PKC, Plk (1-3), NIK, Pak (1-3), PDK1, PKR, RhoK, RIP, RIP-2, GSK3 (A and B), PKA, P38, Erk (1-3) ), PKB, IRAK1, FRK, SGK, TAK1, Tpl-2 (COT), and the like.
  • protein kinases involved in this process include Abl, Aurora, CDK, EGFR, EMT, Erk, FGF, FAK, Flk-1, Flt, JAK, KDR, HER-2, IGF-1R, IR, LCK, MAP, MEK, c-MET, PDGFR, PI3, RAF, Src. And m-Tor et al. (Traxler, P.M. protein Tyrosine Kinase Inhibitors in Cancer Treatment.Exp. Opin. Ther. Patents (1997) 7: 571-588).
  • non-selective kinase inhibitors such as Pfizer, Sprycel (BMS) and the like have been released and used.
  • BMS Sprycel
  • these drugs appear to be more effective than selective kinase inhibitors in some solid cancers, their range of use is quite limited due to off-target toxicity due to lack of selectivity.
  • the present invention provides a compound represented by the following formula (1).
  • R0 to R3 are as defined below.
  • the present invention is a pharmaceutical for the treatment, alleviation or prevention of diseases associated with abnormal or deregulated kinase activity, including the compound represented by Formula 1 and a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof To provide a composition.
  • the present invention provides a compound represented by the following formula (1).
  • R0 is or ego
  • R1 to R3 are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, cycloalkoxy, thioester, amide, amino , Substituted amino, aminoacyl, acyl, acyloxy, aryl, aryloxy, substituted aryl, urea, substituted urea, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle,
  • R 4 is selected from the group consisting of hydrogen, hydroxy, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle,
  • R 10 and R 11 are each independently hydrogen, alkyl, substituted alkyl, ethylhydroxy, amino, substituted amino, aryl, substituted aryl, urea, substituted urea, heteroaryl, substituted heteroaryl, heterocyclic or substituted Selected from the group consisting of heterocycles, when Y is N, R 10 and R 11 are not introduced, and
  • X and Y are each independently selected from elements consisting of C, N, O and S.
  • R0 is Phosphorus provides a compound represented by the following formula (2):
  • R1 to R4 are as defined in the formula (1).
  • specific examples of the compound wherein R1 is aryl or substituted aryl include a compound represented by the following formula (3).
  • R2 to R4 are as defined in Formula 1
  • R5 to R9 are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkoxy, substituted alkoxy, cycloalkoxy, thioester, amide, amino, substituted amino, aminoacyl, acyl, acyloxy, aryl, aryloxy, substituted aryl, urea, substituted urea, heteroaryl, substituted heteroaryl , Heterocyclic ring or substituted heterocyclic ring.
  • R9 is preferably selected from the following functional groups.
  • R12 may be selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero ring or substituted hetero ring, but is not limited thereto. no.
  • R0 is Phosphorus provides a compound represented by the following formula (4):
  • R1 to R3, R10, R11, X and Y are as defined in the formula (1).
  • specific examples of the compound wherein R1 is aryl or substituted aryl include a compound represented by the following formula (5).
  • R2, R3, R10, R11, X and Y are as defined in Formula 1
  • R5 to R9 is as defined in Formula 3.
  • R9 is preferably selected from the following functional groups.
  • R12 is as defined in formula (3).
  • the compounds of the present invention may contain one or more chiral centers.
  • such compounds may be prepared or separated as pure stereoisomers, ie as individual enantiomers or diastereomers, or as stereoisomer-diastereomers. All such stereoisomers (and diastereomers) are also included within the scope of the compounds of the present invention.
  • the present invention is a pharmaceutical for the treatment, alleviation or prevention of diseases associated with abnormal or deregulated kinase activity, including the compound represented by Formula 1 and a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof To provide a composition.
  • Diseases associated with abnormal or deregulated kinase activity subject to the application of the pharmaceutical composition of the present invention include cancer, asthma, allergies, atopic dermatitis, psoriasis, rheumatoid arthritis, etc.
  • the disease is preferably cancer.
  • the cancer may include gastric cancer, thyroid cancer, colon cancer, liver cancer, kidney cancer, brain cancer, uterine cancer, menstrual cancer, non-small cell lung cancer, pancreatic cancer, breast cancer, blood cancer, bladder cancer, colorectal cancer, glioblastoma, and the like.
  • composition of the present invention may further include at least one or more of an agent such as an antibiotic, an alkylating agent, an anti-metabolic agent, a hormonal agent, an immunological agent, an interferon agent or another anticancer agent.
  • an agent such as an antibiotic, an alkylating agent, an anti-metabolic agent, a hormonal agent, an immunological agent, an interferon agent or another anticancer agent.
  • the composition of the present invention is ultimately aimed at inhibiting the growth of cancer cells and inhibiting metastasis or necrosis of cancer cells.
  • Compounds represented by Formula 1 of the present invention act as selective combinations of single or multiple targets against protein kinases, in particular kinases that play an important role in the differentiation, growth, invasion and / or metastasis of cancer cells, thereby enhancing their activity. By regulating, the effect which is superior to a conventional anticancer agent and a protein kinase modulator can be exhibited.
  • protein kinases include Abl, Aurora, AXL, BLK, BMX, Aurora, c-KIT, c-MET, CDK, FER, FGFR, FGR, FLT, FRK, FYN, HCK, IRR, ITK, JAK, KDR , KIT, LCK, LYN, MAPK, MER, MEK, MUSK, PDGFR, PLK, RET, RON, SRC, SRM, TIE2, TNK1, TRKA, TNIK, VEGFR and the like, but are not limited thereto.
  • the types of representative kinases that play important roles in the differentiation, growth, invasion and / or metastasis of cancer cells and their roles are summarized as follows:
  • c-Met is a receptor tyrosine kinase (RTK) that has a high affinity for hepatocyte growth factor (HGF) / scatter factor (SF) .
  • RTK receptor tyrosine kinase
  • HGF hepatocyte growth factor
  • SF scatter factor
  • the signal activation process involves trans phosphorylation when HGF binds to form a dimer. The tyrosine residues are then phosphorylated to form docking sites. Subsequently, signal molecules in the down stream are induced to transmit signals into the cell.
  • HGF / c-Met signaling pathways also correlate with pathways related to cell proliferation and differentiation through MAPK activation, cell survival via PI3K-Akt signaling pathways, apoptosis, and PKC réelle pathways. It is also known to be involved in transformation and tubulogenesis through signaling pathways. It is known that dysregulation between HGF and c-Met and overexpression of c-Met play an important role in the progression of metastatic cancer, and thus c-Met is an important target for chemotherapy. Livio T., Andrea B. , Paolo M .; MET signaling: principles and function in development, organ regeneration and cancer, Nat. Rev. Mol. Cell Biol. 11 (12), (2010), 834-848).
  • the c-Met inhibitors are particularly angiogenesis-dependent, including diabetic retinopathy, macular degeneration and inflammatory diseases such as rheumatoid arthritis. It can also be effective in disease.
  • Aurora is a type of conserved serine / threonine kinase, which is divided into three types of aurora kinases (A, B and C), and these aurora families perform essential functions in cell differentiation.
  • the three mammalian paralogues have very similar sequences, but their positions, functions, substrates and regulatory partners are very different from each other.
  • Aurora A is primarily associated with spindles during mitosis, which is required for centrosome separation and maturation (Sausville EA. Nat. Med., 10, (2004), 234-235). Aurora A also performs its function in the meiosis process by promoting oocyte maturation, polar release, spindle localization and termination of mid-term I.
  • Aurora B is a chromosome-passenger protein with multiple functions in mitosis. This is necessary for phosphorylation of histone H3, target condensation and compaction of normal chromosomes. It has also recently been shown to be essential for chromosome biorientation, isotope-microtubule interactions and spindle-assembly checkpoints, and plays an essential role in the completion of cytoplasmic division.
  • aurora C kinase Little is known about aurora C kinase except that it appears to be preferentially expressed in meiotic cells, and aurora c kinase appears to provide additional levels of adjustment that may be essential for the construction of meiosis.
  • Aurora kinases are overexpressed in certain types of cancers, including colorectal cancer, breast cancer, pancreatic cancer, ovarian cancer and other solid cancers. Genes encoding Aurora A and B kinases tend to be amplified in certain types of cancers, while genes encoding Aurora C kinases are present in regions of the chromosome that are rearranged and deleted. Aurora A is associated with various malignancies including primary colon cancer, colon cancer, breast cancer, gastric cancer, ovarian cancer, prostate cancer and cervical cancer, neuroblastoma, and other solid-tumor cancers (Warner et al .; Molecular Cancer Therapeutics 2 , (2003), 589-595).
  • Aurora A and B kinases are frequently increased or overexpressed in human cancers, they may be interesting targets for effective cancer treatment (Mountzios et al., Cancer Treatment Reviews, 34, (2008), 175-182; Gautschi et al. , Clin., Cancer Res. 14 (6), (2008), 1639-1648; Mortlock et al., Current Topics in Medicinal Chemistry, 5, (2005), 807-821).
  • VEGF Vascular endothelial growth factor
  • VEGF Vascular endothelial growth factor
  • PDGF platelet-derived growth factor
  • VEGF is a dimeric glycoprotein associated with platelet-derived growth factor (PDGF), produced by normal and tumor cell lines, and exhibits angiogenic activity in in vivo test systems (e.g. rabbit cornea) Induces plasminogen activators associated with proteolysis of extracellular matrix during capillary formation in cells.
  • Many isoforms [VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3], which show comparable biological activity to VEGF but differ in cell morphology and heparin-binding capacity.
  • VEGFR-1 Flt-1
  • VEGFR-2 KDR
  • VEGFR-3 VEGFR-3
  • VEGF vascular endothelial growth
  • VEGF vascular endothelial growth
  • VEGF vascular endothelial growth factor
  • the compound represented by the formula (I) of the present invention is further understood by reference to the following embodiments for the purpose of pure illustration, but the present invention is not limited by the illustrated embodiment, and the compound of the present invention is any functionally equivalent method. It can be prepared by.
  • the introduction of a protecting group for any functional group is not limited to the illustrated embodiment, and may be extended to a method of introducing a protecting group or a deprotecting group generally known.
  • Reagent supply sources include, but are not limited to, companies such as Aldrich, Sigma, TCI, Wako, Kanto, Fluorchem, Acros, Abocado, Alfa, Fluka, and the like.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and / or deprotecting specific functional groups are well known in the art. For example, numerous protectors can be found in T.W. Greene and G.M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991, and references cited therein.
  • the compounds of the present invention may contain one or more chiral centers.
  • such compounds may be prepared or separated as pure stereoisomers, ie as individual enantiomers or diastereomers, or as stereoisomer-diastereomers.
  • Pure stereoisomers (and diastereomers) can be prepared, for example, using optically active starting materials or stereoselective reagents known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral degradants and the like.
  • the compound represented by the formula (2) of the present invention can be synthesized by the reaction according to Scheme 1, but is not limited thereto.
  • the compound represented by Chemical Formula 3 of the present invention may be synthesized by a reaction according to Scheme 2, but is not limited thereto.
  • the compound represented by Formula 4 of the present invention may be synthesized by the reaction according to the following Scheme 3 or Scheme 4, but is not limited thereto.
  • the compound represented by Chemical Formula 5 of the present invention may be synthesized by a reaction according to Scheme 5 or Scheme 6, but is not limited thereto.
  • Z 1 , Z 2 , Z 3 and Z 4 are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, alkyl, substituted alkyl, cycloalkyl, Substituted cycloalkyl, alkoxy, substituted alkoxy, cycloalkoxy, thioester, amide, amino, substituted amino, aminoacyl, acyl, acyloxy, aryl, aryloxy, substituted aryl, urea, substituted urea, heteroaryl , Substituted heteroaryl, hetero ring or substituted hetero ring can be selected from the group consisting of.
  • compositions of the present invention can be delivered in a pharmaceutical composition either directly or with a suitable carrier or excipient well known in the art.
  • the pharmaceutical compositions of the invention may be administered in an amount effective to a subject having or at risk of anemia due to, for example, chronic renal failure, diabetes, cancer, AIDS, radiation therapy, chemotherapy, kidney dialysis, or surgery.
  • the subject is a mammalian subject, more preferably a human subject.
  • the effective amount of the composition of the present invention can be easily determined by routine experimentation to be the most effective and convenient route and the most suitable formulation.
  • Suitable routes of administration of the compositions of the invention include intramuscular, subcutaneous, intramedullary injections as well as intradural, direct intraventricular, intravenous, intraperitoneal, nasal, or intraocular injections, eg, oral, rectal And, via mucosal, nasal or intestinal administration and parenteral delivery.
  • the agent or composition thereof may be administered topically rather than systemically.
  • suitable agents can be delivered via injection or into a targeted drug delivery system such as a storage or sustained release formulation.
  • compositions of the present invention may be prepared without limitation by any of the well known methods, such as conventional mixing, dissolving, granulating, dragee-making, flouring, emulsifying, encapsulating, encapsulating, or lyophilizing processes.
  • the compositions of the present invention may include one or more physiologically acceptable carriers such as excipients and adjuvants.
  • compositions of the present invention may be formulated with physiologically compatible buffers such as aqueous solutions, preferably Hanks' solutions, Ringer's solutions, or saline buffers.
  • physiologically compatible buffers such as aqueous solutions, preferably Hanks' solutions, Ringer's solutions, or saline buffers.
  • penetrants suitable for penetration into the barrier are used in the formulation. Such penetrants are generally well known in the art.
  • the compounds of the invention are prepared in a formulation for oral administration.
  • the compounds of the present invention can be readily formulated by combining with pharmaceutically acceptable carriers known in the art.
  • Such carriers allow the compounds of the invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject.
  • the compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas containing, for example, conventional suppository bases such as cocoa butter or other glycerides.
  • Formulations for oral use can be obtained as solid excipients by adding suitable auxiliaries to obtain tablets or dragee cores as needed, followed by optionally grinding the resulting mixture and processing the particulate mixture.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth rubber, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP) to be.
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth rubber, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidon
  • disintegrants such as cross-linked polyvinyl pyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate can be added.
  • wetting agents such as sodium dodecyl sulfate, may be included.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions can be used, which optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. It may contain.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize other combinations of active compound doses.
  • Formulations for oral administration include soft, sealed capsules made of gelatin and push-fit capsules made of gelatin as well as plasticizers such as glycerol or sorbitol.
  • Push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate, and optionally stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compounds of the present invention can be administered transdermally, or topically, such as through a skin patch.
  • transdermal or topical formulations of the invention may additionally include one or multiple infiltration enhancers or other effectors comprising agents that enhance the transport of the delivered compound. Transdermal or topical administration may be preferred, for example, in situations where location specific delivery is desired.
  • the compounds for use according to the invention may be formulated with a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or any other suitable gas.
  • a suitable propellant for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or any other suitable gas.
  • a suitable dosage unit can be determined by providing a valve for delivering a metered amount.
  • capsules and cartridges of gelatin for use in an inhaler or blower can be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions prepared for parenteral administration by injection may be presented in unit dose form, eg, in ampoules or in multi-dose containers, with an added preservative.
  • the composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain chemicals such as suspending, stabilizing and / or dispersing agents.
  • Formulations for parenteral administration include aqueous solutions or other compositions in water-soluble form.
  • suspensions of the active compounds can be prepared as appropriate oily injection suspensions.
  • suitable lipophilic solvents or vehicles include fatty oils such as sesame oil and synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may contain suitable stabilizers or agents that increase the solubility of the compounds to enable the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, for example sterile water free of pyrogen.
  • compositions of the present invention may also be formulated as a storage formulation.
  • Such long acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be suitable polymers or hydrophobic materials (e.g. as emulsions in acceptable oils) or ion exchange resins, or as very soluble derivatives, for example very soluble salts. It can be prepared as.
  • the effective dose for treatment can be estimated initially using various techniques well known in the art.
  • dosages can be formulated to achieve a circulating concentration range comprising an IC 50 as determined in cell culture in an animal model.
  • Dosage ranges suitable for human subjects can be determined, for example, using data obtained from cell culture assays and other animal studies.
  • An effective dosage for the treatment of a medicament means an amount of a medicament that results in alleviation of symptoms or prolongation of survival in the subject.
  • the toxicity and therapeutic efficacy of such molecules can be determined in standard pharmaceutical procedures by determining, for example, LD 50 (fatal dose up to 50% of the subject) and ED 50 (dose effective at 50% of the subject) in cell culture or experimental animals. Can be determined by.
  • the dose ratio of toxicity to treatment is the therapeutic index, which can be expressed as the ratio of LD 50 / ED 50 . Agents that exhibit high therapeutic indices are preferred.
  • the dose is preferably in the range of circulating concentrations comprising ED 50 which is little or no toxic.
  • the dosage may vary within this range depending upon the type of dosage employed and the route of administration utilized.
  • the exact formulation, route of administration, and dose should be selected according to methods known in the art in view of the nature of the subject's condition.
  • the dosage of the medicament or composition can vary depending on various factors, including the sex, age, weight, severity of pain, mode of administration, and the judgment of the prescribing physician of the subject being treated.
  • Compounds of the present invention or pharmaceutical compositions containing the same can be usefully used for the treatment, alleviation or prevention of diseases associated with abnormal or deregulated kinase activity by inhibiting the activity of various kinds of protein kinases.
  • Flask Compound A-6 (5 g, 21.1 mmol) and 3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)
  • phenylamide (8.1 g, 42.2 mmol)
  • Pd (PPh 3 ) 4 (1.6 g, 1.69 mmol)
  • LiCl (2 g, 59.1 mmol)
  • 100 ml of ethanol 100 ml of toluene and 1 N Na 2 CO 3 (40 mL) was added and stirred at 90 ° C. for 10 hours. Termination of the reaction was confirmed by TLC.
  • Flask Compound A-13 (2.56 g, 8.53 mmol), 1- (4-fluoro-phenylcarbamoyl) -cyclopropanecarboxylic acid (2.44 g, 11.09 mmol), EDC (2.45 g, 12.80 mol), HOBT (1.5 g, 11.09 mmol) was added and dissolved in 1 L of DMF, followed by stirring at room temperature for 3 hours.
  • c-Met, Aurora and KDR were expressed in insect cells in the following manner, and then purified by chromatography.
  • the eluate was received fractionally while eluting the protein using buffer A containing 500 mM imidazole. Samples were collected from these fractions, and the fractions for the next step were collected after confirming the location of the target protein through SDS-PAGE.
  • the next step was performed gel filtration chromatography (GE healthcare, HiLoad 16/600 Superdex 200 pg) using buffer B (25mM Tris-HCl, 200mM NaCl, 5% glycerol, 2mM DTT, 10mM EDTA, pH 7.5). Samples were collected from each fraction and the fractions were collected after confirming the location of the target protein through SDS-PAGE.
  • buffer B 25mM Tris-HCl, 200mM NaCl, 5% glycerol, 2mM DTT, 10mM EDTA, pH 7.5.
  • Next step was performed ion chromatography (GE healthcare, Resource Q) using buffer C (25mM Tris-HCl, 5% glycerol, 2mM DTT, 1mM EDTA, pH 7.5). At this time, the target protein was eluted without adhering to the ionic resin, and thus the flowthrough was collected. The solution was concentrated to 10 mg / ml and stored at -70 ° C.
  • the buffer was used 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 2 mM DTT. Samples were collected from each fraction to confirm the location of the target protein through SDS-PAGE, and the fractions were collected to complete purification. After purification, 4 mM ATP and 26 mM MgCl 2 were added at 4 ° C. for autophosphorylation. After the reaction, dialysis was performed with 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, and 2 mM DTT buffer. The solution was concentrated to 1 mg / ml and stored at -70 ° C.
  • the eluate was received fractionally while eluting the protein using buffer A containing 500 mM imidazole. Samples were collected from these fractions, and the fractions for the next step were collected after confirming the location of the target protein through SDS-PAGE.
  • the next step was performed gel filtration chromatography (GE healthcare, HiLoad 26/600 Superdex 200 pg) using buffer B (50mM Tris-HCl, 25mM NaCl, 5% glycerol, 1mM DTT, pH 8.0). Samples were collected from each fraction and the fractions were collected after confirming the location of the target protein through SDS-PAGE. The final 4 mM ATP, 26 mM MgCl 2 was added to this fraction and the autophosphorylation reaction proceeded at 4 ° C. overnight.
  • buffer B 50mM Tris-HCl, 25mM NaCl, 5% glycerol, 1mM DTT, pH 8.0.
  • Phosphorylated samples were dialyzed for 2 to 3 hours using 2 L of buffer C (10 mM HEPES, 10 mM NaCl, 10 mM DTT, pH7.5). This was repeated three times, concentrated to 6.0 mg / ml and stored at -70 ° C.
  • the c-Met protein was overexpressed by gene recombination, followed by enzymatic reaction using purified c-Met enzyme. Specifically, 250 nM biotin-Axl substrate peptide serving as a substrate with 20 nM c-Met enzyme was added to the reaction buffer (15 mM Tris-HCl (pH 7.5), 10 mM MgCl 2 , 5 mM MnCl 2 , 0.01% Tween-). 20, 2 mM DTT) enzyme reaction was carried out. Compounds of the concentration to be tested were treated and reacted at 30 ° C. for 1 hour.
  • the activity was measured using the ELISA method.
  • the absorbance value of the sample that was not treated with the compound was a 100% control group, and the activity of the c-Met inhibitor was evaluated as% of the residual activity of the c-Met enzyme in the sample treated with the compound of the concentration to be tested.
  • the concentration of the compound at which 50% c-Met enzyme activity inhibition occurs compared to the control group was determined as the IC 50 value of the c-Met inhibitor.
  • Aurora A purified after overexpression by gene recombination was used.
  • the compound was used dissolved in 100% DMSO.
  • kinase-glo mix Promega
  • Luminescence was measured using a Fusion-FP (Packard) device.
  • Enzyme inhibitory activity was expressed as a percentage of the measured value in the presence of the sample compound to the measured value in the absence of the test compound, the concentration of the compound inhibiting 50% of the enzyme activity was determined as IC 50 ( ⁇ M) value.
  • E4Y peptide acts as a substrate for the 2.5 nM KDR enzyme in reaction buffer (50 mM Tris-HCl, pH 7.5), 15 mM MgCl 2 , 1 mM MnCl 2 , 0.01% Tween-20, 2 mM DTT Enzymatic reaction was carried out. Compounds of the concentration to be tested were treated and reacted at 30 ° C. for 1 hour. After the enzymatic reaction, the kinase glo mix was added and reacted for 10 minutes at room temperature, and then the luminescence was measured using a Fusion-FP (Packard) instrument. The data was analyzed with the measured RLU values to verify the activity of the KDR inhibitors.
  • reaction buffer 50 mM Tris-HCl, pH 7.5
  • 15 mM MgCl 2 15 mM MgCl 2
  • 1 mM MnCl 2 0.01% Tween-20
  • 2 mM DTT Enzymatic reaction was carried out. Compounds of
  • the RLU value of the sample that was not treated with the compound was a 100% control, and the activity of the KDR inhibitor was evaluated as the percentage of the residual activity of the KDR enzyme in the sample that was treated with the concentration of the compound to be tested. After measuring the KDR enzyme activity remaining at various concentrations of compound treatment, the concentration of the compound at which 50% KDR enzyme activity inhibition occurs compared to the control group was determined as the IC 50 value of the KDR inhibitor.
  • MTS analysis was performed to determine whether the compound prepared above had cancer cell proliferation inhibitory effect through inhibition of extracellular signal-regulated kinase activity (Barltrop, JA et al., (1991) 5- (3-carboxymethoxyphenyl) -2- (4,5-dimethylthiazoly) -3- (4-sulfophenyl) tetrazolium, inner salt (MTS) and related analog of 3- (4,5-dimethylthiazolyl) -2,5, -diphenyltetrazolium bromide (MTT) reducing to purple water soluble formazans as cell-viability indicators.Bioorg.Med.Chem.Lett. 1, 611-4; Cory, AH et al (1991) Use of an aqueous soluble tertrazolium / formazan assay for cell growth assays in culture. Comm. 3, 207-12.).
  • MKN45 cell line and colon cancer cell line HCT-116 cell line were dispensed at concentrations of 5,000 cells / well in 96-well plates containing RPMI-1640 medium (GIBCO, Invitrogen) containing 10% FBS, respectively, at 5% CO 2 and 37 ° C. Incubated for 24 hours at. Thereafter, each well was treated with the compounds prepared in Example 3 at concentrations of 0.2, 1, 5, 25 and 100 ⁇ M, respectively, and 0.08% by weight of the same dimethylsulfoxide (DMSO) as the control group. Treated at a concentration of Each cell was then incubated for 48 hours.
  • DMSO dimethylsulfoxide
  • A ⁇ 50 nM
  • B 50 nM to 200 nM
  • C 200 nM to 1 ⁇ M
  • D > 1 ⁇ M
  • E ⁇ 0.5 ⁇ M
  • F 0.5 ⁇ M to 1 ⁇ M
  • G 1 ⁇ M to 5 ⁇
  • H > 5 ⁇ .
  • the compounds of the present invention exhibit excellent kinase inhibitory activity not only against kinase enzymes such as c-Met, VEGFR-2 and Aurora A, but also against gastric and colorectal cancer cell lines. It has been found that it can be usefully used for the treatment, alleviation or prevention of diseases or symptoms associated with modulated kinase activity, such as various types of cancer.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

본 발명은 화학식 1로 표시되는 화합물 및 약학적으로 허용가능한 그의 염, 수화물, 프로드러그 또는 용매화물을 포함하는, 이상 또는 탈조절된 키나제 활성과 관련된 질병의 치료, 완화 또는 예방용 약학적 조성물에 관한 것으로서, 본 발명의 화합물 및 조성물은 다양한 종류의 단백질 키나제의 활성을 저해함으로써, 이상 또는 탈조절된 키나제 활성과 관련된 질병의 치료, 완화 또는 예방용 유용하게 사용될 수 있다.

Description

2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물
본 발명은 2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물에 관한 것으로서, 본 발명의 화합물 및 조성물은 이상 또는 탈조절된 키나제(kinase) 활성과 관련된 질병 또는 증상의 치료, 완화 또는 예방에 유용하게 사용될 수 있다.
단백질 키나제는 단백질의 특정 아미노산을 인산화시켜 세포내의 다양한 신호 전달 및 질병 메커니즘과 밀접하게 연관되어 있으므로 상기 키나제의 저해는 중요한 치료학적 목표가 되어 왔다. 이러한 단백질 키나제는 세포 기능을 유지하는데 있어서 다양한 세포 과정을 조절하는 중추적인 역할을 하는 단백질 거대 군을 나타내며 그 인산화 기질에 따라 분류된다. 상기 키나제는 단백질-티로신, 단백질-세린/스레오닌, 단백질-히스티딘, 등의 군들로 분류되며 그 예로는 다음과 같은 것들이 있다:
단백질-티로신 키나제로는 Abl, Irk, IGFR-1, Zap-70, BLK, Bmx, Btk, CHK(Csk homologous kinase), CSK(C-terminal Src kinase), Itk-1, Src(c-Src, Lyn, yn, Lck, Syk, Hck, Yes, Blk, Fgr, Frk), Tec, Txk/Rlk, Abl, EGFR(EGFR-1/ErbB-2, ErbB-2/NEU/HER-2, ErbB-3, ErbB-4), FAK, FGF1R(FGFR1 또는 FGR-1), FGF2R(FGR-2), MET(Met-1 또는 c-Met), PDGFR-α, PDGFR-β, Tie-1, Tie-2(Tek-1 또는 Tek-2), VEGFR1(FLT-1), VEGFR2(KDR), FLT-3, FLT-4, c-KIT, JAK1, JAK2, JAK3, TYK2, LOK, RET, TRKA, PYK2, ALK, EPHA(1-8), EPHB(1-6), RON, Fes, Fer, EPHB4(EPHB4-1) 등이 포함되어 있고, 단백질 세린/스레오닌 키나제로는 Aurora, Ark, AMT(1-3), CamK(Ⅰ∼Ⅳ), CamKK, Chk1과 2, CKI, CK2, IKK-Ⅰ, IKK-2, IlK, Jnk91-3), LimK(1과2), MLK3Raf(A-C), CDK(1-10), PKC, Plk(1-3), NIK, Pak(1-3), PDK1, PKR, RhoK, RIP, RIP-2, GSK3(A와 B), PKA, P38, Erk(1-3), PKB, IRAK1, FRK, SGK, TAK1, Tpl-2(COT) 등이 포함되어 있다.
이러한 단백질 키나제는 세포증식, 발암, 아폽토시스 및 세포 분화를 포함하는 다양한 세포 작용을 위한 신호 전달에서 중요한 작용을 하므로 이들 효소의 저해제는 이들 효소에 의존적인 암과 같은 증식성 질환의 치료 및 예방에 유효하다(Plowman, G.D.; Ullrich, A.; Shawver, L. K.: Receptor Tyrosine Knases As Targets for Drug Intervention. SN amp; P (1994) 7: 334-339). 확실한 역학적 증거는 이러한 신호 전달에 관여하는 단백질 키나제의 과다발현 및 활성화가 다수의 인간 암종에서 중요한 인자로서 밝혀져 있다. 특히, 이러한 과정에 관여되는 단백질 키나제로서 Abl, Aurora, CDK, EGFR, EMT, Erk, FGF, FAK, Flk-1, Flt, JAK, KDR, HER-2, IGF-1R, IR, LCK, MAP, MEK, c-MET, PDGFR, PI3, RAF, Src. 및 m-Tor 등이 알려져 있다(Traxler, P.M. protein Tyrosine Kinase Inhibitors in Cancer Treatment. Exp. Opin. Ther. Patents (1997) 7: 571-588).
이러한 원리로 개발되어 최초로 출시된 글리벡의 성공적인 시장 진입 이후에, 많은 분자 생물학적 증거를 토대로 다른 암종에 대한 주요 키나제의 동정 및 이를 표적으로 하는 표적 저해제들의 개발이 활발히 진행되고 있다. 이러한 표적 치료제의 경우 단일 표적 치료제와 다중 표적 치료제로 크게 분류할 수 있는데, 단일 표적 치료제의 대부분은 작용시 키나제의 변이, 회피, 보상기전의 발생, 네거티브 피드백 효과 등의 내성으로 말미암아 저조한 치료율을 보이고 있다. 이 같은 단일 표적 치료제의 문제점을 극복하기 위하여, 조합 치료 이외에 다중 표적 신호전달 저해제의 필요성이 대두되고 있으며, 암과 관련된 신호기전들에 대한 복합적인 저해제를 개발하기 위해 많은 회사들이 연구개발 중에 있고 Sutent(Pfizer), Sprycel(BMS) 등과 같은 광범위한 비선택적 키나제 저해제들이 출시되어 사용되고 있다. 그러나 이들 약물은 일부 고형 암에 사용되어 선택적인 키나제 저해제보다 효과가 좋은 것으로 보이지만, 선택성의 결여로 인한 off-target 독성으로 인해 사용 범위가 상당히 제한되어 있다.
이를 극복하기 위해서는 정상세포에는 영향을 덜 미치면서 암세포의 증식, 성장, 전이 및 분화에 큰 영향들을 주는 다중표적들의 선택적 기전차단 및 세포 분열 주기 회로의 차단 효과를 갖는 신규 화합물의 연구가 지속적으로 요구되고 있다(Zachary A. Knight, Henry Lin and Kevan M. shokat; Targeting the cancer kinome through polypharmacology; Nature reviews/Cancer, 10, (2010), 130-136).
본 발명은 하기 화학식 1로 표시되는 화합물을 제공한다.
[화학식 1]
Figure PCTKR2011007370-appb-I000001
상기에서, R0 내지 R3은 하기에서 정의한 바와 같다.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 및 약학적으로 허용가능한 그의 염, 수화물, 프로드러그 또는 용매화물을 포함하는, 이상 또는 탈조절된 키나제 활성과 관련된 질병의 치료, 완화 또는 예방용 약학적 조성물을 제공한다.
본 발명은 하기 화학식 1로 표시되는 화합물을 제공한다.
[화학식 1]
Figure PCTKR2011007370-appb-I000002
상기에서,
R0은
Figure PCTKR2011007370-appb-I000003
또는
Figure PCTKR2011007370-appb-I000004
이고,
R1 내지 R3은 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로 선택되며,
R4는 수소, 히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되고,
R10 및 R11은 각각 독립적으로 수소, 알킬, 치환된 알킬, 에틸히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되지만, Y가 N일 경우에는 R10과 R11은 도입되지 않으며, 및
X 및 Y는 각각 독립적으로 C, N, O 및 S로 이루어진 원소로부터 선택된다.
또한, 본 발명의 한 구현예에 따르면, 본 발명은 상기 화학식 1의 화합물에 있어서 R0이
Figure PCTKR2011007370-appb-I000005
인 하기 화학식 2로 표시되는 화합물을 제공한다:
[화학식 2]
Figure PCTKR2011007370-appb-I000006
상기에서, R1 내지 R4는 상기 화학식 1에서 정의한 바와 같다. 특히, 본 발명의 바람직한 구현예에 따르면, 상기 R1이 아릴 또는 치환된 아릴인 화합물의 구체적인 예로는 하기 화학식 3으로 표시되는 화합물을 들 수 있다.
[화학식 3]
Figure PCTKR2011007370-appb-I000007
상기에서, R2 내지 R4는 상기 화학식 1에서 정의한 바와 같고, R5 내지 R9는 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택된다. 특히, R9는 하기 작용기들 중에서 선택되는 것이 바람직하다.
Figure PCTKR2011007370-appb-I000008
상기에서, R12는 수소, 히드록시, 알킬, 치환된알킬, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택될 수 있으나, 이에 한정되는 것은 아니다.
또한, 본 발명의 다른 구현예에 따르면, 본 발명은 상기 화학식 1의 화합물에 있어서 R0이
Figure PCTKR2011007370-appb-I000009
인 하기 화학식 4로 표시되는 화합물을 제공한다:
[화학식 4]
Figure PCTKR2011007370-appb-I000010
상기에서, R1 내지 R3, R10, R11, X 및 Y는 상기 화학식 1에서 정의한 바와 같다. 특히, 본 발명의 바람직한 구현예에 따르면, 상기 R1이 아릴 또는 치환된 아릴인 화합물의 구체적인 예로는 하기 화학식 5로 표시되는 화합물을 들 수 있다.
[화학식 5]
Figure PCTKR2011007370-appb-I000011
상기에서, R2, R3, R10, R11, X 및 Y는 상기 화학식 1에서 정의한 바와 같고, R5 내지 R9는 상기 화학식 3에서 정의한 바와 같다. 특히, R9는 하기 작용기들 중에서 선택되는 것이 바람직하다.
Figure PCTKR2011007370-appb-I000012
상기에서, R12는 상기 화학식 3에서 정의한 바와 같다.
본 발명에 있어서, 화학식 1로 표시되는 화합물 내에 광학 이성질체가 있을 경우에는 각각의 거울상 이성질체(enantiomers), 부분입체 이성질체(diastereomer) 또는 라세믹 혼합물(racemic mixture) 등도 모두 본 발명의 화합물의 범주에 포함한다. 본 발명에 개시된 화합물에 대한 다양한 변형은 본 발명에 개시된 내용으로부터 본 기술분야의 숙련자에게 자명할 것이다.
또한, 본 발명의 화합물은 하나 이상의 키랄 중심을 함유할 수도 있다. 따라서, 만일 원한다면, 그러한 화합물은 순수한 입체이성질체, 즉 개별적인 거울상 이성질체 또는 부분입체 이성질체로서, 또는 입체이성질체-부분입체 이성질체로서 제조되거나 분리될 수 있다. 이러한 모든 입체이성질체(및 다이아스테레오머)도 본 발명의 화합물의 범위 내에 포함된다.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 및 약학적으로 허용가능한 그의 염, 수화물, 프로드러그 또는 용매화물을 포함하는, 이상 또는 탈조절된 키나제 활성과 관련된 질병의 치료, 완화 또는 예방용 약학적 조성물을 제공한다.
본 발명의 약학적 조성물의 적용 대상이 되는 이상 또는 탈조절된 키나제 활성과 관련된 질병에는 암, 천식, 알러지, 아토피 피부염, 건선, 류마티스성 관절염 등이 있으며, 이 중에서도 상기 질병은 암인 것이 바람직하다. 상기 암은 위암, 갑상선암, 대장암, 간암, 신장암, 뇌암, 자궁암, 남소암, 비-소세포 폐암, 췌장암, 유방암, 혈액암, 방광암, 결장직장암, 교모세포종 등이 제한없이 포함될 수 있다.
또한, 본 발명의 약학적 조성물은 항생제, 알킬화제, 항대사제, 호르몬제, 면역학적 제제, 인터페론 제제 또는 다른 항암제와 같은 제제 중 적어도 1종 이상을 추가로 포함할 수 있다. 본 발명의 조성물은 궁극적으로는 암세포의 성장을 저해하고 전이를 억제하거나 암세포를 괴사시키는데 그 목적이 있다.
본 발명의 화학식 1로 표시되는 화합물은 단백질 키나제, 특히 암세포의 분화, 성장, 침윤 및/또는 전이에 있어서 중요한 역할을 담당하는 키나제에 대해 단일 또는 다중 표적의 선택적인 조합으로 작용하여 이들의 활성을 조절함으로써, 종래의 항암제나 단백질 키나제 조절제보다 우월한 효과를 나타낼 수 있다. 상기에서, 단백질 키나제로는 Abl, Aurora, AXL, BLK, BMX, Aurora, c-KIT, c-MET, CDK, FER, FGFR, FGR, FLT, FRK, FYN, HCK, IRR, ITK, JAK, KDR, KIT, LCK, LYN, MAPK, MER, MEK, MUSK, PDGFR, PLK, RET, RON, SRC, SRM, TIE2, TNK1, TRKA, TNIK, VEGFR 등을 예시할 수 있으나, 이에 한정되는 것은 아니다. 암세포의 분화, 성장, 침윤 및/또는 전이에 있어서 중요한 역할을 하는 대표적인 키나제들의 종류와 그의 역할을 요약하면 다음과 같다:
c-Met은 hepatocyte growth factor(HGF) / scatter factor(SF)에 높은 친화력을 갖는 수용체 티로신 키나제(RTK, receptor tyrosine kinase)로서, 신호 활성화 과정은 HGF가 결합하면 트랜스 인산화를 과정을 거쳐 다이머가 형성되고 다시 티로신 잔기가 인산화되면서 도킹 사이트를 형성하게 된다. 이후 down stream의 시그널 분자들이 유도되면서 세포 내로 신호를 전달하게 된다.
이러한 HGF/c-Met의 신호 전달 경로로는 MAPK 활성화를 통한 세포의 증식 및 분화와 관련된 경로, PI3K-Akt 신호 전달 경로를 경유하는 세포 생존, 아폽토시스, PKCа의 경로와도 관계가 있으며, STAT3의 신호전달 경로를 통해 transformation과 tubulogenesis에도 관여하는 것으로 알려져 있다. HGF와 c-Met간의 dysregulation 및 c-Met의 과발현은 전이암의 진행에 중요한 역할을 한다고 알려져 있으므로, c-Met은 항암 치료의 중요한 표적으로서 이에 대한 인식이 커지고 있다(Livio T., Andrea B., Paolo M.; MET signaling: principles and function in development, organ regeneration and cancer, Nat. Rev. Mol. Cell Biol. 11(12), (2010), 834-848).
또한, 다수의 실험 데이터가 종양의 침윤, 성장, 생존 및 전이에 이르는 진행에 있어서 HGF 및 c-Met의 역할을 뒷받침해 주고 있으며, 이들을 표적으로 하는 생물학적 제제, 예컨대 리보자임, 항체 및 안티센스 RNA는 종양의 발생을 억제하는 것으로 나타났다(Stabile et al., Gene therapy, 11, 2004, 325-335; Jiang et al., Clin. Cancer Res.,9, (2003), 4274-4281). 따라서, c-Met을 표적으로 하는 저분자 키나제 저해제가 c-Met 수용체 활성화가 원발성 종양 및 속발성 전이의 발생 및 진행에 있어서 중요한 역할을 하는 암의 치료에 대해 아주 효과적일 것으로 기대된다.
또한, HGF는 종양성장 및 전염에 중요한 과정인 혈관 형성을 조절하는 것으로 공지되어 있으므로, 상기 c-Met의 저해제는 특히 당뇨 망막병증, 황반변성 및 염증성 질환, 예컨대 류마티스 관절염을 포함하는 혈관형성-의존성 질환에도 효과를 보일 수 있다.
다음으로, Aurora는 보존된 세린/트레오닌 키나제의 일종으로서, 3 가지 타입의 오로라 키나제(A, B 및 C)로 구분되며, 이러한 오로라 패밀리는 세포 분화 과정에서 필수적인 기능을 수행한다. 3종의 포유동물 파라로고스(paralogues)는 매우 유사한 서열을 갖지만, 그들의 위치, 기능, 기질 및 조절 파트너(regulatory partner)는 서로 매우 다르다.
오로라 A는 주로 유사분열 동안 방추극과 연관되며, 여기서 중심체 분리 및 성숙에 필요하다(Sausville EA. Nat. Med., 10, (2004), 234-235). 또한, 오로라 A는 난모세포 성숙, 극체 방출, 방추 위치화 및 중기 I 의 종료를 촉진함으로써 감수분열 과정에서 그 기능을 수행한다.
오로라 B는 유사분열에서 다수의 기능을 갖는 염색체-패신저 단백질이다. 이것은 히스톤 H3의 인산화, 정상 염색체의 표적 응축 및 압축에 필요하다. 또한 최근에는 염색체 바이오리엔테이션(chromosome biorientation), 동원체-미세소관 상호작용 및 방추-조립 체크포인트에 필수적인 것으로 나타났으며, 세포질분열의 완료에 필수적인 역할을 한다.
오로라 C 키나제에 대해서는 감수분열 세포에서 우선적으로 발현되는 것으로 보인다는 것을 제외하고 거의 알려지지 않으며, 오로라 C 키나제는 감수분열의 구성에 필수적일 수 있는 추가적 조정 수준을 제공하는 것으로 보인다.
오로라 키나제는 대장암, 유방암, 췌장암, 난소암 및 다른 고형 암을 포함하는 특정 종류의 암에서 과발현된다. 오로라 A 및 B 키나제를 암호화하는 유전자는 특정 종류의 암에서 증폭되는 경향이 있는 반면, 오로라 C 키나제를 암호화하는 유전자는 재배열 및 결실되는 염색체의 영역에 존재한다. 오로라 A는 원발성 대장암, 결장암, 유방암, 위암, 난소암, 전립선암 및 자궁경부암, 신경모세포종, 및 다른 고체-종양 암을 포함하는 다양한 악성종양과 연관된다(Warner et al.; Molecular Cancer Therapeutics 2,(2003),589-595). 오로라 A 및 B 키나제는 사람의 암에서 빈번히 증가하거나 과발현되므로, 이들은 효과적인 암 치료에 흥미로운 표적이 될 수 있다(Mountzios et al., Cancer Treatment Reviews, 34, (2008), 175-182; Gautschi et al., Clin., Cancer Res. 14(6), (2008), 1639-1648; Mortlock et al., Current Topics in Medicinal Chemistry, 5,(2005), 807-821).
다음으로, 혈관계 및 이에 대한 성분의 성장 및 분화를 조절하는 네트워크 중심에 있는 혈관성 내피 성장 인자인 VEGF(Vascular endothelial growth factor)를 들 수 있다. VEGF는 혈소판-유래성 성장인자(PDGF)와 관련있는 이량체성 당단백질로서, 정상세포 및 종양 세포 주에 의해서 생성되며, 생체내 시험 시스템(예: 토끼의 각막)에서 혈관 형성 활성을 나타내고, 내피세포에서 모세혈관 형성 중에 세포외 기질의 단백질 분해와 관련된 플라스미노겐 활성인자를 유도한다. VEGF와 대등한 생물학적 활성을 보이지만 이를 분비하는 세포 형태 및 헤파린-결합능력에 있어서 차이를 보이는 다수의 이소폼들[VEGFR-1(Flt-1), VEGFR-2(KDR), VEGFR-3]이 공지되어 있다.
다수의 인체 종양, 특히 신경교종 및 암종은 높은 수준의 VEGF 및 이의 수용체가 발현되며, 종양 세포에서 발현된 VEGF가 신생혈관의 성장 및 종양 내피의 증식을 자극하고 혈액 공급의 개선을 통해 종양 성장을 가속화시킨다고 알려져 있다.
직경이 1-2 ㎜ 이하인 종양에서는 확산에 의해 산소 및 영양분이 공급이 가능하지만, 그 이상의 크기로 도달한 이후에는 종양의 기원 및 원인에 상관없이 신생혈관 형성이 절대적인 필수 요건이 되며, 이후의 종양 성장이 크게 좌우된다. 그러므로, VEGF의 저해 활성은 종양의 치료에 효과적인 수단이 될 수 있다(R. Connell, J. Beebe, Exp. Opin. Ther. Patents, 11, (2001), 77-114).
본 발명의 화합물의 합성
본 발명의 화학식 1로 표시되는 화합물은 순수한 예증이 목적인 하기 구현예를 참고하여 더욱 이해되지만, 본 발명은 예증된 구현예에 의해 한정되는 것은 아니며, 본 발명의 화합물은 기능적으로 등가인 임의의 방법에 의해 제조될 수 있다. 또한, 어떤 작용기에 대한 보호기 도입에 있어서도 예증된 구현예에 국한되지 않으며, 일반적으로 알려진 보호기 도입이나 탈 보호기의 방법까지 확장될 수 있다.
본 발명의 화합물을 합성하기 위한 출발 물질의 경우 다양한 합성법이 알려져 있으며, 상기 출발 물질이 시판되고 있는 경우는 공급처로부터 구매하여 사용할 수 있다. 시약 공급처로는 Aldrich, Sigma, TCI, Wako, Kanto, Fluorchem, Acros, Abocado, Alfa, Fluka 등의 회사가 있으나, 이에 한정되는 것은 아니다.
본 발명의 화합물은 하기의 일반적인 방법 및 과정을 사용하여 쉽게 이용 가능한 출발 물질로부터 제조될 수 있다. 전형적인 또는 바람직한 공정 조건(즉, 반응 온도, 시간, 반응물의 몰 비, 용매, 압력) 등은, 달리 언급한지 않는 한, 다른 공정 조건도 사용될 수 있다. 최적의 반응 상태는 사용된 특정 반응물 또는 용매에 따라 변할 수 있지만, 그러한 상태는 통상적인 최적화 과정에 의해 본 기술분야의 숙련자에 의해 결정될 수 있다.
아울러, 본 기술분야의 숙련자에게 있어서 자명한 바와 같이, 특정 기능적 기가 원하지 않는 반응을 겪지 않도록 방지하기 위하여 통상의 보호기가 필요할 수 있다. 특정한 기능적 기를 보호 및/또는 탈보호하기 위해 적합한 조건뿐만 아니라 다양한 기능적 기에 대해 적합한 보호기는 본 기술분야에 잘 알려져 있다. 예를 들어, 수많은 보호기는 T.W. Greene 및 G.M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991, 및 상기 문헌에 인용된 참고문헌에 기술되어 있다.
아울러, 본 발명의 화합물은 하나 이상의 키랄 중심을 함유할 수도 있다. 따라서, 만일 원한다면, 그러한 화합물은 순수한 입체이성질체, 즉 개별적인 거울상 이성질체 또는 부분입체 이성질체로서, 또는 입체이성질체-부분입체 이성질체로서 제조되거나 분리될 수 있다. 순수한 입체이성질체(및 부분입체 이성질체)는, 예를 들어, 본 기술분야에 공지된 광학적으로 활성인 출발 물질 또는 입체선택성 시약을 사용하여 제조될 수 있다. 다른 한편으로, 이러한 화합물의 라세믹 혼합물은, 예를 들어, 키랄 칼럼 크로마토그래피, 키랄 분해제 등을 사용하여 분리될 수 있다.
본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 2로 표시되는 화합물은 하기 반응식 1에 따른 반응에 의해 합성될 수 있으나, 이에 한정되는 것은 아니다.
[반응식 1]
Figure PCTKR2011007370-appb-I000013
또한, 본 발명의 화학식 3으로 표시되는 화합물은 하기 반응식 2에 따른 반응에 의해 합성될 수 있으나, 이에 한정되는 것은 아니다.
[반응식 2]
Figure PCTKR2011007370-appb-I000014
또한, 본 발명의 다른 바람직한 구현예에 따르면, 본 발명의 화학식 4로 표시되는 화합물은 하기 반응식 3 또는 반응식 4에 따른 반응에 의해 합성될 수 있으나, 이에 한정되는 것은 아니다.
[반응식 3]
Figure PCTKR2011007370-appb-I000015
[반응식 4]
Figure PCTKR2011007370-appb-I000016
또한, 본 발명의 화학식 5로 표시되는 화합물은 하기 반응식 5 또는 반응식 6에 따른 반응에 의해 합성될 수 있으나, 이에 한정되는 것은 아니다.
[반응식 5]
Figure PCTKR2011007370-appb-I000017
[반응식 6]
Figure PCTKR2011007370-appb-I000018
상기 반응식 1 내지 반응식 6에 개시된 화합물에 있어서, Z1, Z2, Z3 및 Z4는 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로 알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군에서 선택될 수 있다.
제약 제제 및 투여 경로
본 발명의 조성물은 직접적으로 또는 당업계에 잘 알려진 적합한 담체 또는 부형제와 함께 약학적 조성물로 송달될 수 있다. 본 발명의 약학적 조성물은, 예를 들어, 만성 신부전, 당뇨병, 암, AIDS, 방사선 요법, 화학요법, 신장 투석, 또는 수술로 인한 빈혈증이 있거나 위험에 있는 대상에게 효과적인 양으로 투여될 수 있다. 바람직한 구현예에서, 피험자는 포유동물 대상이고, 보다 바람직하게는 사람 대상이다.
본 발명의 조성물의 효과량은 가장 효과적이고 편리한 경로 및 가장 적당한 제법이 될 수 있도록 일상적인 실험에 의해 쉽게 결정될 수 있다. 다양한 제제와 약물 송달 시스템은 당업계에서 이용가능하다(예를 들면, Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences, 참조). 본 발명의 조성물의 적합한 투여 경로는 경막내, 직접 심실내, 정맥내, 복막내, 코안, 또는 눈속 주사는 물론이고, 근육내, 피하, 골수내 주사를 포함하여, 예를 들어, 경구, 직장, 점막을 통해, 코, 또는 창자 투여 및 비경구 송달을 포함할 수 있다. 작용제 또는 그것의 조성물은 전신 방식보다는 국소로 투여될 수 있다. 예를 들어, 적합한 작용제는 주사를 통해 또는 저장 또는 지속 방출제제과 같은 표적화 약물 송달 시스템으로 송달될 수 있다.
본 발명의 약학적 조성물은 잘 알려진 방법 중 종래의 혼합, 용해, 과립화, 당의정-제조, 가루화, 유화, 캡슐화, 포착화, 또는 동결건조 공정과 같은 어떤 것에 의해서도 제한없이 제조될 수 있다. 전술한 바와 같이, 본 발명의 조성물은 부형제 및 보조제와 같은 하나 이상의 생리적으로 허용가능한 담체를 포함할 수 있다.
본 발명의 약학적 조성물의 적절한 제형는 선택된 투여 경로에 의존한다. 주사를 위해, 예를 들어, 본 발명의 조성물은 수성 용액, 바람직하게는 Hanks 용액, Ringer 용액, 또는 생리식염수 완충액과 같이 생리학적으로 호환가능한 완충액으로 조제화될 수 있다. 점막을 통한 투여 또는 코 투여를 위하여, 장벽으로 침투하기에 적당한 침투제가 제제에 사용된다. 그러한 침투제는 일반적으로 당업계에 잘 알려져 있다. 본 발명의 바람직한 구현예에서, 본 발명의 화합물은 경구 투여를 위한 제제로 제조된다. 경구 투여를 위하여, 본 발명의 화합물은 당업계에 공지된 약학적으로 허용가능한 담체와 조합시킴으로써 용이하게 제제화될 수 있다. 그러한 담체는 본 발명의 화합물이 대상에 의한 경구 섭취를 위해 정제, 알약, 당의정, 캡슐, 액체, 겔, 시럽, 슬러리, 현탁액 등으로 제제화되도록 한다. 본 발명의 화합물은, 예를 들면, 코코아 버터 또는 다른 글리세라이드와 같은 종래의 좌약 베이스를 함유하는 좌약 또는 정체 관장액과 같은 직장 조성물로도 조제될 수 있다.
경구 용도를 위한 제제는, 필요시 정제 또는 당의정 코어를 얻기 위해 적합한 보조제를 첨가한 후에, 선택적으로 결과물인 혼합물을 그라인딩하고, 미립의 혼합물을 가공함으로써 고체 부형제로서 얻을 수 있다. 적합한 부형제는 특히, 유당, 수크로스, 만니톨, 또는 솔비톨을 포함하는 당과 같은 충전재; 셀룰로오스 제제, 예를 들어, 옥수수 전분, 밀 전분, 쌀 전분, 감자 전분, 젤라틴, 트래거캔스 고무, 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 나트륨 카르복시메틸셀룰로오스 및/또는 폴리비닐피롤리돈(PVP)이다. 필요시, 예를 들면, 가교-결합된 폴리비닐 피롤리돈, 한천, 또는 알긴산 또는 나트륨 알기네이트와 같은 그것의 염과 같은 붕괴제가 첨가될 수 있다. 또한, 나트륨 도데실설페이트와 같은 습윤제가 포함될 수 있다.
당의정 코어는 적합한 코팅이 제공된다. 이러한 목적을 위하여, 농축 당 용액이 사용될 수 있고, 이것은 선택적으로 아라비아 고무, 활석, 폴리비닐 피롤리돈, 카르보폴 겔, 폴리에틸렌글리콜 및/또는 티타늄 다이옥사이드, 래커 용액, 및 적합한 유기 용매 또는 용매 혼합물을 함유할 수 있다. 염료 또는 안료는 동정을 위해 또는 다른 조합의 활성 화합물 복용량을 특징짓기 위해 정제 또는 당의정 코팅에 첨가될 수 있다.
경구 투여를 위한 제형은 젤라틴으로 만들어진 부드러운, 밀봉의 캡슐 및 글리세롤 또는 솔비톨과 같은 가소제는 물론이고 젤라틴으로 만들어진 푸시-핏(밀어맞추기) 캡슐을 포함한다. 푸시-핏 캡슐은 유당과 같은 충전재, 전분과 같은 결합제 및/또는 활석 또는 마그네슘 스테아레이트와 같은 윤활제, 및 선택적으로는 안정화제와 혼합하여 활성 성분을 함유할 수 있다. 연질 캡슐에서, 활성 화합물은 지방 오일, 액체 파라핀 또는 액체 폴리에틸렌글리콜과 같은 적합한 액체에 용해되거나, 현탁될 수 있다. 아울러, 안정화제가 첨가될 수 있다. 경구 투여를 위한 모든 제제는 이러한 투여에 적합한 용량이 되어야 한다.
한 구현예에서, 본 발명의 화합물은 피부 패치를 통해서와 같이 경피로, 또는 국소로 투여될 수 있다. 한 양태에서, 본 발명의 경피 또는 국소 제제는 추가적으로 하나 또는 다중 침투 인핸서 또는 송달된 화합물의 이동을 강화하는 작용제를 포함하는 다른 작동체를 포함할 수 있다. 경피 또는 국소 투여는 예를 들면, 위치 특이적 송달이 바람직한 상황에서 바람직할 수 있다.
흡입에 의한 투여를 위하여, 본 발명에 따른 용도를 위한 화합물은 적합한 분사제, 예를 들면, 디클로로디플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소, 또는 어떠한 다른 적합한 가스의 사용과 함께, 가압 팩 또는 분무기로부터 에어로졸 스프레이의 형태로 편리하게 전달된다. 가압 에어로졸의 경우에, 적당한 용량 유닛은 계량된 양을 전달하기 위한 밸브를 제공함으로써 결정될 수 있다. 예를 들면, 흡입기 또는 취입기에서 사용하기 위한 젤라틴의 캡슐과 카트리지가 조제화될 수 있다. 이들은 전형적으로 화합물과 유당 또는 전분과 같은 적합한 분말 베이스의 분막 믹스를 함유한다. 주사에 의한, 예를 들면, 약덩이주사 또는 연속 주입에 의한 비경구 투여를 위해 조제된 조성물은, 첨가된 보존제와 함께 예를 들어, 앰풀 또는 다중-복용량 용기에 단위 용량 형태로 제시될 수 있다. 조성물은 유성 또는 수성 매개체 중의 현탁액, 용액, 또는 에멀전과 같은 형태를 취할 수 있고, 현탁제, 안정화제 및/또는 분산제와 같은 화학제를 함유할 수 있다. 비경구 투여를 위한 제제는 수성 용액 또는 수용성 형태의 다른 조성물을 포함한다.
또한, 활성 화합물의 현탁액은 적당한 유성 주사 현탁액으로 제조될 수 있다. 적합한 친유성 용매 또는 매개체는 참깨 오일과 같은 지방 오일 및 에틸 올레에이트 또는 트라이글리세리드, 또는 리포좀과 같은 합성 지방산 에스테르를 포함한다. 수성 주사 현탁액은 나트륨 카르복시메틸 셀룰로오스, 솔비톨 또는 덱스트란과 같이 현탁액의 점도를 증가시키는 물질을 함유할 수 있다. 선택적으로, 현탁액은 고농축 용액의 제조를 가능하게 하기 위해 적합한 안정화제 또는 화합물의 용해도를 증가시키는 작용제를 함유할 수 있다. 다른 한편으로, 활성 성분은 적합한 매개체, 예를 들면, 발열원이 없는 무균수와 함께 구성하기 위해 분말 형태가 될 수 있다.
전술한 바와 같이, 본 발명의 조성물은 또한 저장 제제로서 조제될 수 있다. 그러한 장기 작용 제제는 이식(예를 들면, 피하로 또는 근육내로)에 의해 또는 근육내 주사에 의해 투여될 수 있다. 따라서, 예를 들면, 본 발명 화합물은 적합한 폴리머 또는 소수성 물질(예를 들면, 허용가능한 오일 중의 에멀전으로서) 또는 이온 교환 수지로, 또는 아주 조금 가용성인 유도체로서, 예를 들면, 아주 조금 가용성인 염으로서 조제될 수 있다.
본 발명의 치료 방법에 사용된 어떠한 조성물에 있어서, 치료에 효과적인 복용량은 초기에 본 기술분야에 잘 알려진 다양한 기술을 사용하여 추정될 수 있다. 예를 들면, 세포 배양 분석법에서, 복용량은 동물 모델에서 세포 배양에서 결정된 바와 같은 IC50을 포함하는 순환하는 농도 범위를 달성하기 위하여 공식화될 수 있다. 사람 대상에 적당한 용량 범위는, 예를 들면, 세포 배양 분석법 및 다른 동물 연구로부터 얻어진 데이터를 사용하여 결정될 수 있다.
약제의 치료에 효과적인 복용량은 대상에서 증상의 완화 또는 생존의 연장을 가져오는 약제의 양을 의미한다. 그러한 분자의 독성 및 치료 효능은 세포 배양 또는 실험 동물에서, 예를 들면, LD50(개체의 50%까지 치사 복용) 및 ED50(개체의 50%에서 치료에 효과적인 복용량)을 결정함으로써 표준 제약 과정에 의해 결정될 수 있다. 치료에 대한 독성의 복용량 비는 치료 지수이고, 이것은 LD50/ED50의 비로서 표현될 수 있다. 높은 치료 지수를 나타내는 약제가 바람직하다.
용량은 바람직하게는 거의 또는 전혀 독성이 없는 ED50을 포함하는 순환하는 농도의 범위 내에 있다. 용량은 채택된 용량의 형태와 이용된 투여 경로에 따라 상기 범위 내에서 변할 수 있다. 정확한 조제물, 투여 경로 및 용량은 대상의 상태의 특징의 관점에서 본 기술분야에 공지된 방법에 따라 선택되어야 한다.
약제 또는 조성물의 투여량은 치료되는 대상의 성별, 연령, 체중, 고통의 심각성, 투여 방식 및 처방하는 의사의 판단을 포함하는 다양한 인자에 따라 변할 수 있다.
본 발명의 화합물 또는 이를 포함하는 약학적 조성물은 다양한 종류의 단백질 키나제의 활성을 저해함으로써, 이상 또는 탈조절된 키나제 활성과 관련된 질병의 치료, 완화 또는 예방용 유용하게 사용될 수 있다.
이하, 본 발명을 실시예에 의해 상세히 설명한다.
단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.
실시예 1. 화학식 2의 화합물의 합성
전술한 반응식 1 및 반응식 2에 개시된 '화합물 A-15'를 하기 단계에 따라 합성하였다.
(1) 화합물 A-1의 합성
메틸렌클로라이드(2.5 ℓ) 와 메탄올(2.5 ℓ)의 혼합용액에 3-니트로 프탈이미드(250 g, 1.3 ㏖)를 넣고 분산시켰다. 실온에서 NaBH4(50 g, 1.3 ㏖)를 천천히 나누어 첨가하고 2시간 동안 교반하였다. TLC로 반응을 확인한 후, 감압하에서 용매를 제거한 후 물(800 ㎖)을 가하였다. 생성된 고체를 여과하고 감압하에서 건조하여 목적 화합물 A-1을 노란색 고체로 얻었다(198 g; 수율: 78.5%).
(2) 화합물 A-2의 합성
화합물 A-1(198 g, 1.02 ㏖)을 메틸렌클로라이드(3 ℓ)에 녹인 후, Et3SiH(242 ㎖, 1.53 ㏖)와 TFA(707 ㎖, 9.18 ㏖)의 혼합 용액을 실온에서 천천히 적가하였다. 실온에서 3시간 교반한 후 반응이 종결되면 감압하에서 용매를 제거한 후, 물(1,000 ㎖)을 첨가하였다. 생성된 고체를 여과한 후 메탄올로 세척하여 목적 화합물 A-2를 노란색 고체로 얻었다(147 g; 수율: 80.9%).
(3) 화합물 A-3의 합성
화합물 A-2(147 g, 0.826 ㏖)와 Pd/C(10%, 14.7 g)룰 메탄올(2.8 ℓ)에 가한 후, 수소 가스 하, 실온에서 6시간 동안 교반하였다. 반응이 종결되면 반응액을 celite로 여과하고, 여과액을 감압 하에서 농축하였다. 농축액에 에틸아세테이트 100 ㎖를 첨가하여 고체화한 후 여과하고 건조하여 목적 화합물 A-3을 노란색 고체로 얻었다(98.6 g; 수율: 80.7%).
(4) 화합물 A-4의 합성
화합물 A-3(98.6 g, 0.666 ㏖)을 메탄올 1,500 ㎖와 THF 1600 ㎖에 녹이고 -65℃로 냉각한 후 NBS(118.5 g, 0.666 ㏖)을 소분하여 천천히 첨가하였다. 반응액을 이 온도에서 20분간 교반한 후, 물 800 ㎖로 Quenching 하였다. 감압 하에서 유기용매를 제거한 후, 생성된 고체를 여과하고 물로 세척하였다. 얻어진 고체를 감압 하에서 건조하여 목적 화합물 A-4를 얻었다(122 g; 수율: 80.7 %).
(5) 화합물 A-5의 합성
화합물 A-4(107.5 g, 470 m㏖), CuCN(50.9 g, 570 m㏖)을 DMF 537 ㎖에 녹이고 혼합물을 가열하여 환류 하에서 3시간 동안 교반하였다. 반응 종결 후 감압 하에서 DMF를 제거하고 THF/에틸아세테이트(500 ㎖/500 ㎖)의 혼합용매를 첨가한 후 30분 동안 환류한 후 여과하였다. THF/에틸아세테이트(500 ㎖/500 ㎖)의 혼합 용매로 9번 세척한 후, 여액을 농축하여 약간 불순한 목적 화합물 A-5를 얻었다(수율 약 50%).
(6) 화합물 A-6의 합성
화합물 A-5(49.4 g, 285 m㏖)를 THF(400 ㎖)와 HBr(40% aq, 490 ㎖)에 녹이고 0℃로 냉각하였다. 나트륨 나이트레이트(21.7 g, 313.7 m㏖) 수용액(200 ㎖ water)을 이 온도에서 천천히 적가하고 30분간 교반시켰다. 이후, 동일한 온도에서 CuBr(40.9 g, 285 m㏖)을 천천히 첨가한 후 1.5시간 더 교반시켰다. 반응 종결 후 반응액을 물(2,000 ㎖)에 부어 넣고, 생성된 고체를 여과하여 제거하였다. 여과액을 NaHCO3로 알카리화시키고, 다시 생성된 고체를 여과하여 제거하였다. 여과액을 에틸아세테이트로 추출하고 물로 씻은 후 무수 MgSO4로 건조하였다. 반응액을 여과하고 감압 하에서 농축하여 다소 불순한 목적 화합물 A-6을 얻었다. 이 다소 불순한 화합물을 에탄올로 재결정하여 순수한 목적 화합물 A-6을 얻었다(수율 약 60%).
(7) 화합물 A-11의 합성
플라스크에 화합물 A-6(5 g, 21.1 m㏖)과 3-플루오로-4-(4,4,5,5-테트라메틸-[1,3,2]디옥사보롤란-2-일)-페닐아미드(8.1 g, 42.2 m㏖), Pd(PPh3)4(1.6 g, 1.69 m㏖), LiCl(2 g, 59.1 m㏖)을 넣고, 에탄올 100 ㎖과 톨루엔 100 ㎖ 및 1 N Na2CO3(40 ㎖)을 넣고 90℃에서 10시간 동안 교반하였다. 반응의 종결을 TLC로 확인하였으며, 반응이 완료되면 실온으로 냉각한 후 여과하고 에틸아세테이트로 세척하였다. 여액을 NaHCO3 수용액으로 세척하고, 유기층을 무수 MgSO4로 건조하였다. 감압하에서 농축한 후, 잔사를 실리카겔 컬럼에서 메틸렌 클로라이드 : 메탄올 = 20 : 1로 전개하여 목적 화합물 A-11을 순수하게 얻었다(3.5 g, 수율 76%).
(8) 화합물 A-12의 합성
플라스크에 화합물 A-11(7.65 g, 28.6 m㏖)과 진한 염산(300 ㎖)을 넣고, 10시간 동안 환류 교반하였다. 반응 확인 후, 감압 증류하여 다소 불순한 상태의 목적 화합물 A-12를 얻었고, 추가 정제 없이 다음 반응에 사용하였다(10 g, 수율 122%).
(9) 화합물 A-13의 합성
다소 불순한 화합물 A-12(10 g, 34.9 m㏖)에 MeOH(300 ㎖)을 넣고, 실온에서 SOCl2(5 ㎖, 69.8 m㏖)를 적가한 후 2시간 30분 동안 환류, 교반하였다. 반응 완료 후 용매는 감압 증류하여 제거하였고, 메틸렌 클로라이드를 넣어 희석시킨 후, NaHCO3 수용액으로 세척하였다. 유기층은 무수 MgSO4로 건조하고 감압 증류 한 후, 실리카겔 컬럼에서 메틸렌 클로라이드 : 메탄올 = 20 : 1로 전개하여 목적 화합물 A-13을 순수하게 얻었다(5.6 g, 수율 64%).
(10) 화합물 A-14의 합성 {Z2= -C(시클로프로필)CONH(4-플루오로페닐)}
플라스크에 화합물 A-13(2.56 g, 8.53 m㏖), 1-(4-플루오로-페닐카바모일)-시클로프로판카르복시산(2.44 g, 11.09 m㏖), EDC(2.45 g, 12.80 ㏖), HOBT(1.5 g, 11.09 m㏖)를 넣고 DMF 1 ℓ에 녹인 후 실온에서 3시간 동안 교반하였다. 다시 1-(4-플루오로-페닐카바모일)-시클로프로판카르복시산(2.44 g, 11.09 m㏖), EDC(2.45 g, 12.8 m㏖), HOBT(1.5 g, 11.09 m㏖)를 넣고, 실온에서 12시간 이상 교반하였다. 반응 완료 후 에틸아세테이트로 희석시킨 후, NaHCO3 수용액으로 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압 증류한 후, 실리카겔 컬럼에서 메틸렌 클로라이드 : 메탄올 = 25 : 1로 전개하여 목적 화합물 A-14를 순수하게 얻었다(3.5 g, 수율 81%).
(11) 화합물 A-15의 합성 (하기 표 1의 112번 화합물)
{Z2= -C(시클로프로필)CONH(4-플루오로페닐), Z3= -CH2CH2N(CH3)2}
밀봉된 튜브에 화합물 A-14(3 g, 5.93 m㏖), N,N-디메틸에탄-1,2-디아민(30 ㎖) 및 디옥산(100 ㎖)을 넣고, 실온에서 14시간 동안 교반하였다. 용매를 감압 증류하여 제거한 후, 실리카겔 컬럼에서 메틸렌 클로라이드 : 메탄올 = 20 : 1로 전개하여 목적 화합물 A-15를 순수하게 얻었다(1.5 g, 수율 45%).
실시예 2. 화학식 4의 화합물의 합성
전술한 반응식 3 및 반응식 5에 개시된 '화합물 B-10'을 하기 단계에 따라 합성하였다.
(1) 화합물 B-1의 합성
화합물 A-6(40 g, 168 m㏖)을 아세트산(400 ㎖)에 분산시킨 후, 물(400 ㎖), 피리딘(800 ㎖)을 넣고 10℃로 냉각시켰다. Sodium phosphate monobasic monohydrate(101 g, 2.86 ㏖)를 첨가하고 Raney nickel(101 g)을 물(70 ㎖)을 이용해 첨가하였다. 반응액의 온도를 50℃로 올리고, 2시간 동안 반응시킨 후 냉각하고 여과하였다. 에틸아세테이트로 세척하고 여과액에 물을 가해 분액한 후 분리된 유기층을 감압 하에서 농축하였다. 여기에 냉각된 물(800 ㎖)을 넣고 생성된 고체를 여과한 후 냉각수로 세척한 후 건조하여 목적 화합물 B-1을 얻었다(26.7 g, 수율 66%).
(2) 화합물 B-2의 합성
화합물 B-1(25.6 g, 107 m㏖)을 에탄올(800 ㎖)에 분산시킨 후 메틸 글리옥살 48% 수용액(66 ㎖)과 암모니아 28% 수용액(72 ㎖)을 첨가하였다. 반응액의 온도를 90℃로 올리고 3시간 동안 교반하였다. 반응이 완료되면 감압 하에서 농축하여 반응액의 부피를 200 ㎖ 정도로 줄이고 생성된 고체를 여과하였다. 에탄올로 세척한 후 여과된 고체를 건조하여 목적 화합물 B-2를 얻었다(16.5 g, 수율 53%).
(3) 화합물 B-8의 합성
화합물 B-2(22.4 g, 76.7 m㏖)와 3-플루오로-4-(4,4,5,5-테트라메틸-[1,3,2]디옥사보롤란-2-일)-페닐아민(21.8 g, 107.4 m㏖), LiCl(9.1 g, 214.8 m㏖), Pd(Ph3)4(8.9 g, 7.7 m㏖)를 톨루엔(670 ㎖)과 에탄올(670 ㎖)에 분산시킨 후, 1 N Na2CO3 수용액(192 ㎖)을 첨가하고 85℃에서 12시간 동안 반응시켰다. 반응이 완결되면 반응액을 감압 하에서 완전히 농축시켰다. 여기에 아세톤(1.57 ℓ)과 아세토니트릴(1.57 ℓ)의 혼합 용액을 넣은 후 80℃에서 2시간 동안 교반시킨 후 냉각하여 여과하였다. 여과된 고체를 아세토니트릴과 n-헥산으로 세척하고 감압 하에서 건조하여 목적 화합물 B-8을 얻었다(14.3 g, 수율 70%).
(4) 화합물 B-10의 합성 (하기 표 1의 157번 화합물, Z4= 4-플루오로페닐)
화합물 B-8(10.7 g, 33.2 m㏖)과 4-플루오로페닐 이소시아네이트(9.1 g, 66.4 m㏖)를 THF(330 ㎖)에 용해시킨 후 90℃에서 6시간 교반 시켰다. 반응이 완결되면 감압 농축하여 반응액의 부피를 1/3로 줄이고 생성된 고체를 여과하였다. 여과된 고체를 THF와 n-헥산으로 세척하고 건조하여 목적 화합물 B-10을 얻었다. (9.5 g, 수율 65%).
실시예 3. 화학식 1의 화합물의 합성
전술한 반응식 1 내지 반응식 6에 개시된 합성 방법을 기초로 하여, 상기 시예 1 및 실시예 2에 개시된 방법에 따라 하기 표 1에 나타낸 것과 같은 총 268 종의 본 발명의 2,3-디히드로-이소인돌-1-온 유도체를 합성하였다.
표 1
화합물No. 화합물명
1 5-Methyl-2-(3-oxo-2,3-dihydro-1H-isoindol-4-yl)-1H-imidazole-4-carboxylic acid ethyl ester
2 2-[7-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester
3 2-(7-{2-Fluoro-4-[3-(3-trifluoromethyl-phenyl)-ureido]-phenyl}-3-oxo-2,3-dihydro-1H-isoindol-4-yl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester
4 1-{4-[7-(4,5-Dichloro-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-3-(3-trifluoromethyl-phenyl)-urea
5 Cyclopropane-1,1-dicarboxylic acid {4-[7-(4,5-dichloro-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
6 2-(1-Ethoxy-3-oxo-2,3-dihydro-1H-isoindol-4-yl)-5-methyl-1H-imidazole-4-carboxylic acid
7 2-[7-(2-Chloro-phenylmethanesulfonylamino)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester
8 2-[7-(2-Chloro-phenylmethanesulfonylamino)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid
9 2-[7-(2-Chloro-phenylmethanesulfonylamino)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid(2-piperidin-1-yl-ethyl)-amide
10 2-[7-(4-Amino-2-fluoro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carboxylic acid
11 2-[7-(2-Fluoro-4-{3-[2-(4-fluoro-phenyl)-acetyl]-ureido}-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carboxylic acid
12 Cyclopropane-1,1-dicarboxylic acid{3-fluoro-4-[7-(5-methyl-4-methylcarbamoyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
13 2-[7-(2-Fluoro-4-{3-[2-(4-fluoro-phenyl)-acetyl]-ureido}-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid methylamide
14 Cyclopropane-1,1-dicarboxylic acid {4-[7-(4-ethylcarbamoyl-5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
15 Cyclopropane-1,1-dicarboxylic acid(3-fluoro-4-{7-[5-methyl-4-(2-piperidin-1-yl-ethylcarbamoyl)-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-amide(4-fluoro-phenyl)-amide
16 2-[7-(2-Fluoro-4-{3-[2-(4-fluoro-phenyl)-acetyl]-ureido}-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid(2-piperidin-1-yl-ethyl)-amide
17 [(2-{7-[2-Fluoro-4-(2,2,2-trifluoro-acetylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carbonyl)-amino]-acetic acid
18 Cyclopropane-1,1-dicarboxylic acid(4-{7-[5-(2-diethylamino-ethylcarbamoyl)-4-methyl-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-3-fluoro-phenyl)-amide(4-fluoro-phenyl)-amide
19 2-[7-(2-Fluoro-4-{3-[2-(4-fluoro-phenyl)-acetyl]-ureido}-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carboxylic acid(2-diethylamino-ethyl)-amide
20 ({2-[7-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carbonyl}-amino)-acetic acid
21 Cyclopropane-1,1-dicarboxylic acid(3-fluoro-4-{7-[4-methyl-5-(2-pyrrolidin-1-yl-ethylcarbamoyl)-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-amide(4-fluoro-phenyl)-amide
22 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(5-hydroxymethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
23 Cyclopropane-1,1-dicarboxylic acid(3-fluoro-4-{7-[4-methyl-5-(2-pyrrolidin-1-yl-ethylcarbamoyl)-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-amide(4-fluoro-phenyl)-methyl-amide
24 Cyclopropane-1,1-dicarboxylic acid(3-fluoro-4-{7-[4-methyl-5-(2-morpholin-4-yl-ethylcarbamoyl)-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-amide(4-fluoro-phenyl)-amide
25 Cyclobutane-1,1-dicarboxylic acid(4-{7-[5-(2-diethylamino-ethylcarbamoyl)-4-methyl-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-3-fluoro-phenyl)-amide(4-fluoro-phenyl)-amide
26 2-{7-[2-Fluoro-4-(2,2,2-trifluoro-acetylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid(2-diethylamino-ethyl)-amide
27 Cyclopropane-1,1-dicarboxylic acid(3-fluoro-4-{7-[5-(2-hydroxy-ethylcarbamoyl)-4-methyl-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-amide(4-fluoro-phenyl)-amide
28 2-{7-[2-Fluoro-4-(3-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid(2-hydroxy-ethyl)-amide
29 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-{4-methyl-5-[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
30 2-[7-(4-Amino-2-fluoro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
31 N-(3-Fluoro-4-{7-[4-methyl-5-(2-pyrrolidin-1-yl-ethylcarbamoyl)-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-N'-(4-fluoro-phenyl)-malonamide
32 N-(3-Fluoro-4-{7-[4-methyl-5-(2-pyrrolidin-1-yl-ethylcarbamoyl)-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-N'-(4-fluoro-phenyl)-N'-methyl-malonamide
33 2-{7-[4-(Cyclopropanecarbonyl-amino)-2-fluoro-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
34 2-{7-[2-Fluoro-4-(3-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
35 2-[7-(4-Amino-2-fluoro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide
36 2-[7-(4-Hydroxy-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
37 N-(3-Fluoro-4-{7-[4-methyl-5-(3-pyrrolidin-1-yl-propylcarbamoyl)-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-N'-(4-fluoro-phenyl)-N'-methyl-malonamide
38 N-{3-Fluoro-4-[7-(4-methyl-5-methylcarbamoyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-N'-(4-fluoro-phenyl)-N'-methyl-malonamide
39 2-{7-[2-Fluoro-4-(4-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
40 2-{7-[2-Fluoro-4-(2-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
41 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-{4-methyl-5-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
42 2-[7-(4-Hydroxy-3-methoxy-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
43 2-[7-(4-Carbamoyl-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
44 2-[7-(4-Amino-2-fluoro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid methylamide
45 2-[7-(4-Amino-2-fluoro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid dimethylamide
46 2-[7-(2-Fluoro-4-{[3-(4-fluoro-phenyl)-2-oxo-imidazolidine-1-carbonyl]-amino}-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
47 2-[7-(4-Cyano-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-5-methyl-1H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
48 2-{7-[2-Fluoro-4-(4-fluoro-benzenesulfonylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid methylamide
49 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-{5-methyl-4-[(E)-methyliminomethyl]-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
50 3-(4-Fluoro-phenyl)-2-oxo-imidazolidine-1-carboxylic acid {3-fluoro-4-[7-(5-methyl-4-methylaminomethyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide
51 2-{7-[2-Fluoro-4-(4-fluoro-benzenesulfonylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide
52 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(4-methyl-5-methylaminomethyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
53 Cyclopropane-1,1-dicarboxylic acid {4-[7-(5-dimethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
54 2-(6-Isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-4-yl)-5-methyl-3H-imidazole-4-carboxylic acid(2-piperidin-1-yl-ethyl)-amide
55 2-(6-Isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-4-yl)-5-methyl-3H-imidazole-4-carboxylic acid [3-(2-methyl-piperidin-1-yl)-propyl]-amide
56 N-{4-[7-(5-Dimethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-N'-(4-fluoro-phenyl)-N'-methyl-malonamide
57 2-(7-{2-Fluoro-4-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-3-oxo-2,3-dihydro-1H-isoindol-4-yl)-5-methyl-3H-imidazole-4-carboxylic acid dimethylamide
58 2-Fluoro-N-{3-fluoro-4-[7-(4-methyl-5-methylaminomethyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-benzamide
59 N-{4-[7-(5-Dimethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-2-fluoro-benzamide
60 N-{3-Fluoro-4-[7-(4-methyl-5-methylaminomethyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-N'-(4-fluoro-phenyl)-N'-methyl-malonamide
61 2-{7-[2-(4-Chloro-phenyl)-2-oxo-ethylamino]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid methylamide
62 N-[3-Fluoro-4-(7-{5-[(2-hydroxy-ethylamino)-methyl]-4-methyl-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-N'-(4-fluoro-phenyl)-N'-methyl-malonamide
63 2-Fluoro-N-[3-fluoro-4-(7-{5-[(2-hydroxy-ethylamino)-methyl]-4-methyl-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-benzamide
64 4-Fluoro-N-{3-fluoro-4-[7-(4-methyl-5-methylaminomethyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-benzamide
65 4-Fluoro-N-[3-fluoro-4-(7-{5-[(2-hydroxy-ethylamino)-methyl]-4-methyl-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-benzamide
66 N-{4-[7-(5-Dimethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-4-fluoro-benzamide
67 Cyclopropane-1,1-dicarboxylic acid {4-[7-(5-ethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
68 N-{4-[7-(5-Ethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-2-fluoro-benzamide
69 Cyclopropane-1,1-dicarboxylic acid cyclopropylamide {4-[7-(5-diethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide
70 Cyclopropane-1,1-dicarboxylic acid(3-fluoro-4-{7-[5-(isopropylamino-methyl)-4-methyl-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-amide(4-fluoro-phenyl)-amide
71 2-Fluoro-N-(3-fluoro-4-{7-[5-(isopropylamino-methyl)-4-methyl-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-benzamide
72 Cyclopropane-1,1-dicarboxylic acid {4-[7-(5-diethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
73 N-{4-[7-(5-Diethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-2-fluoro-benzamide
74 N-{4-[7-(5-Cyclopropylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-2-fluoro-benzamide
75 Cyclopropane-1,1-dicarboxylic acid [4-(7-{5-[(ethyl-methyl-amino)-methyl]-4-methyl-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
76 Pyridine-2-carboxylic acid {4-[7-(5-ethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide
77 N-[4-(7-{5-[(Cyclopropylmethyl-amino)-methyl]-4-methyl-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide
78 Cyclopropane-1,1-dicarboxylic acid {4-[7-(5-cyclopropylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
79 Piperidine-4-carboxylic acid {3-fluoro-4-[7-(4-methyl-5-methylcarbamoyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide
80 2-{7-[2-Fluoro-4-(2-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-5-methyl-3H-imidazole-4-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide
81 Cyclopropane-1,1-dicarboxylic acid [4-(7-{5-[(cyclopropylmethyl-amino)-methyl]-4-methyl-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
82 4-Fluoro-N-(3-fluoro-4-{7-[5-(isopropylamino-methyl)-4-methyl-1H-imidazol-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-phenyl)-benzamide
83 N-[4-(7-{5-[(Cyclopropylmethyl-amino)-methyl]-4-methyl-1H-imidazol-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-4-fluoro-benzamide
84 6-Chloro-pyridine-2-carboxylic acid {4-[7-(5-ethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide
85 N-{4-[7-(5-Ethylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-4-fluoro-benzamide
86 N-{4-[7-(5-Cyclopropylaminomethyl-4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-4-fluoro-benzamide
87 4-Fluoro-N-{3-fluoro-4-[7-(4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-benzamide
88 N-{4-[7-(4-Ethylaminomethyl-5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-nicotinamide
89 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
90 3,5-Difluoro-N-{3-fluoro-4-[7-(4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-benzamide
91 7-[2-Fluoro-4-(2-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid methylamide
92 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-methylcarbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
93 7-[2-Fluoro-4-(2-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid(2-morpholin-4-yl-ethyl)-amide
94 3-Fluoro-N-{3-fluoro-4-[7-(4-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-5-morpholin-4-yl-benzamide
95 7-[2-Fluoro-4-(2-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid
96 7-[2-Fluoro-4-(3-fluoro-5-morpholin-4-yl-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid methylamide
97 7-{2-Fluoro-4-[(pyridine-3-carbonyl)-amino]-phenyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid methylamide
98 7-[2-Fluoro-4-(4-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid methylamide
99 7-[2-Fluoro-4-(2-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
100 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(3-morpholin-4-yl-propylcarbamoyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
101 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[1-oxo-7-(3-pyrrolidin-1-yl-propylcarbamoyl)-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
102 7-[2-Fluoro-4-(2-fluoro-benzoylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid(3-morpholin-4-yl-propyl)-amide
103 7-{2-Fluoro-4-[(pyridine-2-carbonyl)-amino]-phenyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid methylamide
104 Cyclopropane-1,1-dicarboxylic acid [4-(7-carbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
105 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(2-morpholin-4-yl-ethylcarbamoyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
106 7-{4-[3-(2-Dimethylamino-ethylamino)-5-fluoro-benzoylamino]-2-fluoro-phenyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid methylamide
107 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[1-oxo-7-(2-pyrrolidin-1-yl-ethylcarbamoyl)-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
108 7-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid
109 {[7-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carbonyl]-amino}-acetic acid
110 4-[2-Fluoro-4-(2-fluoro-benzylamino)-phenyl]-7-(4-methyl-1H-imidazol-2-yl)-2,3-dihydro-isoindol-1-one
111 7-[2-Fluoro-4-(2-fluoro-benzylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid methylamide
112 Cyclopropane-1,1-dicarboxylic acid {4-[7-(2-dimethylamino-ethylcarbamoyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
113 Cyclopropane-1,1-dicarboxylic acid {4-[7-(3-dimethylamino-propylcarbamoyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
114 4-[2-Fluoro-4-(2-fluoro-benzylamino)-phenyl]-7-(4-methyl-5-methylaminomethyl-1H-imidazol-2-yl)-2,3-dihydro-isoindol-1-one
115 7-(2-Fluoro-4-{[3-(4-fluoro-phenyl)-2-oxo-imidazolidine-1-carbonyl]-amino}-phenyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
116 4-(2-Fluoro-4-hydroxy-phenyl)-7-[5-(isopropylamino-methyl)-4-methyl-1H-imidazol-2-yl]-2,3-dihydro-isoindol-1-one
117 Cyclopropane-1,1-dicarboxylic acid [4-(7-ethylcarbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
118 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-isopropylcarbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
119 7-(2-Fluoro-4-{3-[2-(4-fluoro-phenyl)-acetyl]-ureido}-phenyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
120 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(2-hydroxy-ethylcarbamoyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
121 7-[2-Fluoro-4-(2-fluoro-benzylamino)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
122 Cyclopropane-1,1-dicarboxylic acid [4-(7-cyclopropylcarbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
123 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-methoxycarbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
124 Cyclopropane-1,1-dicarboxylic acid [4-(7-cyano-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
125 Cyclopropane-1,1-dicarboxylic acid [4-(7-carbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
126 Cyclopropane-1,1-dicarboxylic acid [4-(7-carbamoyl-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
127 6-(2-Fluoro-4-{[3-(4-fluoro-phenyl) -2-oxo-imidazolidine-1-carbonyl]-amino}-phenoxy)-3-oxo-2,3-dihydro-1H- isoindole-4-carboxylic acid amide
128 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(4-methyl-5-methylcarbamoyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide
129 Cyclobutane-1,1-dicarboxylic acid [4-(7-carbamoyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide
130 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(5-methyl-4H-[1,2,4]triazol-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
131 7-[4-(4-Chloro-phthalazin-1-ylamino)-2-fluoro-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
132 3-Fluoro-N-{3-fluoro-4-[7-(5-methyl-4H-[1,2,4]triazol-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-5-morpholin-4-yl-benzamide
133 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(5-methyl-[1,3,4]oxadiazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
134 7-(2-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-phenyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
135 1-{3-Fluoro-4-[7-(5-methyl-4H-[1,2,4]triazol-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea
136 N-(4-(7-carbamoyl-1-oxoisoindolin-4-yl)-3-methylphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
137 1-{3-Fluoro-4-[7-(5-methyl-4H-[1,2,4]triazol-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea
138 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[1-oxo-7-(4H-[1,2,4]triazol-3-yl)-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
139 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
140 3-Fluoro-N-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-5-(4-methyl-piperazin-1-yl)-benzamide
141 3-Fluoro-N-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-5-(2-morpholin-4-yl-ethylamino)-benzamide
142 4-(4-Hydroxy-phenyl)-7-(5-methyl-1H-imidazol-2-yl)-2,3-dihydro-isoindol-1-one
143 7-(4-Hydroxy-phenyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxilic acid amide
144 N-(4-(7-carbamoyl-1-oxoisoindolin-4-yl)-3-fluorophenyl)-N-(2-methoxyphenyl)cyclopropane-1,1-dicarboxamide
145 7-(5-Methyl-4H-[1,2,4]triazol-3-yl)-4-(3-nitro-phenyl)-2,3-dihydro-isoindol-1-one
146 N-(5-(7-carbamoyl-1-oxoisoindolin-4-yl)pyridin-2-yl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
147 Cyclopropane-1,1-dicarboxylic acid {4-[7-(4,5-dihydro-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-fluoro-phenyl}-amide(4-fluoro-phenyl)-amide
148 3-Fluoro-N-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-5-morpholin-4-yl-benzamide
149 methyl 1-(4-(7-carbamoyl-1-oxoisoindolin-4-yl)-3-fluorophenylcarbamoyl)cyclopropanecarboxylate
150 3-(2-Dimethylamino-ethylamino)-5-fluoro-N-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-benzamide
151 3-Fluoro-N-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-benzamide
152 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[1-oxo-7-(5-trifluoromethyl-1H-imidazol-2-yl)-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(4-fluoro-phenyl)-amide
153 3-Fluoro-N-{3-fluoro-4-[1-oxo-7-(5-trifluoromethyl-1H-imidazol-2-yl)-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-5-morpholin-4-yl-benzamide
154 7-{2-Fluoro-4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
155 7-{2-Fluoro-4-[3-(3-trifluoromethyl-phenyl)-ureido]-phenyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
156 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(4-fluoro-phenyl)-urea
157 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(4-fluoro-phenyl)-urea
158 Ethanesulfonic acid {3-[7-(5-methyl-4H-[1,2,4]triazol-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide
159 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxymethyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
160 7-[2-Fluoro-4-(3-m-tolyl-ureido)-phenyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide
161 Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-oxazol-2-yl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-amide(4-fluoro-phenyl)-amide
162 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea
163 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea
164 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-m-tolyl-urea
165 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide(2-fluoro-phenyl)-amide
166 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-m-tolyl-urea
167 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(3-fluoro-phenyl)-urea
168 N-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-morpholin-4-yl-isonicotinamide
169 Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide phenylamide
170 6-Morpholin-4-yl-pyridine-2-carboxylic acid {3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide
171 N-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-morpholin-4-yl-isonicotinamide
172 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(3-fluoro-phenyl)-urea
173 Cyclopropane-1,1-dicarboxylic acid(4-fluoro-phenyl)-amide {4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-3-methyl-phenyl}-amide
174 6-Morpholin-4-yl-pyridine-2-carboxylic acid {3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide
175 1-[3-Fluoro-4-(7-oxazol-2-yl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-3-(3-fluoro-phenyl)-urea
176 3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl-4'-carboxylic acid {3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide
177 1-(4-Chloro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
178 1-(2-Chloro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
179 1-(2,5-Difluoro-phenyl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
180 1-Cyclohexyl-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
181 1-[3-Fluoro-4-(7-oxazol-2-yl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-3-m-tolyl-urea
182 1-Benzyl-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
183 N-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-N'-(4-fluoro-phenyl)-N'-methyl-malonamide
184 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-oxazol-4-yl-urea
185 1-(5-tert-Butyl-isoxazol-3-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
186 1-(5-tert-Butyl-isoxazol-3-yl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
187 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(3-methoxy-phenyl)-urea
188 1-(3-Ethyl-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
189 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-thiazol-4-yl-urea
190 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-thiazol-4-yl-urea
191 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyridin-3-yl-urea
192 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyridin-3-yl-urea
193 1-(3-Chloro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
194 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyridin-2-yl-urea
195 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyridin-2-yl-urea
196 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyridin-4-yl-urea
197 1-Cyclopropyl-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
198 1-Cyclopropyl-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
199 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyridin-4-yl-urea
200 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-furan-2-yl-urea
201 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-furan-2-yl-urea
202 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(5-methyl-1H-imidazol-4-yl)-urea
203 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(1H-imidazol-4-yl)-urea
204 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(1H-imidazol-4-yl)-urea
205 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(1H-imidazol-2-yl)-urea
206 1-tert-Butyl-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
207 1-(4-Cyano-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
208 1-(3-Cyano-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
209 1-(3-Dimethylamino-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
210 1-(3-Dimethylamino-phenyl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
211 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(5-methyl-1H-imidazol-4-yl)-urea
212 1-(4-Dimethylamino-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
213 1-(4-Dimethylamino-phenyl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
214 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-piperidin-4-yl-urea
215 4-(3-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-ureido)-benzoic acid
216 1-(4-Benzyloxy-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
217 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-piperidin-4-yl-urea
218 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(4-hydroxy-phenyl)-urea
219 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2-methoxy-phenyl)-urea
220 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(3-methyl-furan-2-yl)-urea
221 3-(3-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-ureido)-benzoic acid
222 1-Ethyl-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
223 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2-piperidin-1-yl-ethyl)-urea
224 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2-pyrrolidin-1-yl-ethyl)-urea
225 1-(p-toulene sulfonyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
226 3-(3-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-ureido)-propionic acid
227 1-(2-Bromo-4-methyl-thiazol-5-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
228 1-(3-Amino-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
229 1-(2-Amino-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
230 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2-phenyl-thiazol-4-yl)-urea
231 1-(4-Chloro-pyridin-2-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
232 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(6-methyl-pyridin-2-yl)-urea
233 1-(4-Ethyl-pyridin-2-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
234 1-(6-Chloro-pyridin-2-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
235 1-(2,4-Dimethyl-thiazol-5-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
236 1-(6-Chloro-pyridin-2-yl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
237 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-quinolin-2-yl-urea
238 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(6-methyl-pyridin-2-yl)-urea
239 1-(4-Chloro-pyridin-2-yl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
240 1-(2-Dimethylamino-4-methyl-thiazol-5-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
241 1-(4-Ethyl-pyridin-2-yl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
242 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(4-methyl-pyridin-2-yl)-urea
243 1-{3-Fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(4-methyl-pyridin-2-yl)-urea
244 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(4-methoxy-pyridin-2-yl)-urea
245 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(6-hydroxy-pyridin-2-yl)-urea
246 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(6-methoxy-pyridin-2-yl)-urea
247 1-(6-Ethyl-pyridin-2-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
248 1-(6-Ethyl-pyridin-2-yl)-3-{3-fluoro-4-[7-(1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
249 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyrimidin-2-yl-urea
250 4-tert-Butyl-N-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-benzamide
251 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(6-fluoro-pyridin-2-yl)-urea
252 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-phenyl-thiourea
253 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pyridin-2-yl-thiourea
254 1-(3-Ethyl-phenyl)-3-[3-fluoro-4-(1-oxo-7-thiazol-2-yl-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-urea
255 1-[3-Fluoro-4-(1-oxo-7-thiazol-2-yl-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-3-pyridin-2-yl-urea
256 Propane-2-sulfonic acid {3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-amide
257 N-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-phenyl-acetamide
258 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-isopropyl-urea
259 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(4-nitro-pyridin-2-yl)-urea
260 1-(4-Amino-pyridin-2-yl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea
261 2-(4-Chloro-phenyl)-N-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-methyl-butyramide
262 N-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-(4-methoxy-phenyl)-acetamide
263 N-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-pyridin-2-yl-acetamide
264 1-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2-methyl-thiazol-4-yl)-urea
265 N-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-(4-fluoro-phenyl)-acetamide
266 N-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-(4-trifluoromethyl-phenyl)-acetamide
267 2-(3,5-Difluoro-phenyl)-N-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-acetamide
268 N-{3-Fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-2-(3-methoxy-phenyl)-acetamide
상기 화합물들의 NMR 및 LCMS 데이터를 하기 표 2에 나타내었다.
표 2
화합물No. NMR 자료 LCMS 자료E/Z;[M+1]
1 1H NMR(300 MHz, CDCl3) δ 8.73(brs, 1H), 7.69(brs, 1H), 7.48(brs, 1H), 6.48(brs, 1H), 4.57(s, 2H), 4.41(q, J = 6.9 Hz, 2H), 2.67(s, 3H), 1.43(t, J = 6.9 Hz, 3H) 286
2 1H NMR(300 MHz, DMSO-d6) δ 10.41(s, 1H), 9.98(s, 1H), 9.53(s, 1H), 8.49-8.43(m, 1H), 7.79(d, J = 12.9 Hz, 1H), 7.69-7.59(m, 3H), 7.54-7.48(m, 2H), 7.16-7.10(m, 2H), 4.44(s, 2H), 4.31-4.21(m, 2H), 2.45(s, 3H), 1.45(s, 4H), 1.32(t, J = 6.9 Hz, 3H) 600
3 1H NMR(300 MHz, DMSO-d6) δ 15.01(br s, 1H), 9.52(s, 1H), 9.43(s, 1H), 9.22(s, 1H), 8.49∼8.35(m, 1H), 8.01(s, 1H), 7.67∼7.52(m, 5H), 7.34∼7.30(m, 2H), 4.52∼4.46(m, 2H), 4.27∼4.26(m, 2H), 2.48(s, 3H), 1.32∼1.21(m, 3H) 582
4 1H NMR(300 MHz, DMSO-d6) δ 9.71(br s, 1H), 9.23∼9.22(m, 2H), 8.28(d, J = 7.8 Hz, 1H), 8.00(s, 1H), 7.71∼7.47(m, 5H), 7.34∼7.27(m, 2H), 4.48(s, 2H) 565
5 1H NMR(300 MHz, DMSO-d6) δ 10.41(s, 1H), 9.97(s, 1H), 9.73(s, 1H), 8.29(d, J = 8.1 Hz, 1H), 7.81∼7.50(m, 6H), 7.16∼7.10(s, 2H), 4.47(s, 2H), 1.49∼1.45(m, 4H) 583
6 1H NMR(300 MHz, CD3OD) δ 8.46(d, J = 7.5 Hz, 1H), 7.76(t, J = 7.5 Hz, 1H), 7.63(d, J = 7.5 Hz, 1H), 5.94(s, 1H), 3.70-3.52(m, 2H), 2.57(s, 3H), 1.23(t, J = 6.9 Hz, 3H) 302
7 1H NMR(300 MHz, CDCl3) δ 8.24(d, J= 11Hz, 1H), 7.62(d, J= 11Hz, 1H), 7.57(m, 1H), 7.28(m, 3H), 4.45(s, 2H), 4.40(s, 4H), 1.40(m, 3H). 489
8 1H NMR(300 MHz, DMSO-d6) δ 10.15(s, 1H), 9.46(s, 1H), 8.24(m,1H), 7.65(d, J = 9.0 Hz, 1H), 7.58∼7.30(m, 3H), 4.73(s, 2H), 4.41(s, 2H), 2.43(s, 3H). 461
9 1H NMR(300 MHz, DMSO-d6) δ 10.08(s, 1H), 9.45(s, 1H), 9.00(brd. S, 1H), 8.32(d, J=8.4Hz, 1H), 8.24(m, 1H), 7.62(d, J= 8.4Hz, 1H), 7.50-7.32(m, 4H), 4.75(s, 2H), 4.42(s, 2H), 3.60(m, 4H), 3.23(m, 2H), 2.88(m, 2H), 2.55(s, 3H), 1.82-1.26(m, 6H). 572
10 1H NMR(300 MHz, DMSO-d6) δ 9.43(s, 1H), 8.41(d, J = 8.1 Hz, 1H), 7.59(d, J = 8.1 Hz, 1H), 7.19(t, J = 8.4 Hz, 1H), 6.48-6.41(m, 2H), 6.75-5.50(brs, 2H), 4.41(s, 2H), 2.48(s, 3H) 367
11 1H NMR(300 MHz, DMSO-d6) δ 11.03(s, 1H), 10.63(s, 1H), 9.47(s, 1H), 8.47(d, J = 7.5 Hz, 1H), 7.72-7.66(m, 1H), 7.53(t, J = 8.1 Hz, 1H), 7.41-7.33(m, 2H), 7.30-7.23(m, 1H), 7.18-7.09(m, 3H), 4.43(s, 2H), 3.74(s, 2H), 2.48(s, 3H) 566
12 1H NMR(300 MHz, CDCl3) δ 14.28(s, 1H), 10.18(s, 1H), 9.34(s, 1H), 8.65(s, 1H), 8.61(d, J = 8.1 Hz, 1H), 8.16(s, 1H), 7.74∼7.69(m, 2H), 7.60∼7.43(m, 3H), 7.10∼7.03(m, 2H), 6.58∼6.53(m, 1H), 4.43(s, 2H), 3.00(d, J = 4.8 Hz, 3H), 2.69(s, 3H), 1.67∼1.60(m, 4H) 585
13 1H NMR(300 MHz, CDCl3) δ 8.56-8.51(m, 1H), 7.61-7.53(m, 2H), 7.36-7.17(m, 5H), 7.08-7.02(m, 1H), 4.40(s, 2H), 3.62(s, 2H), 3.00(d, J = 5.1 Hz, 3H), 2.71(s, 3H) 559
14 1H NMR(300 MHz, DMSO-d6) δ 11.21(s, 1H), 10.78(s, 1H), 10.28(s, 1H), 9.33(s, 1H), 8.74(s, 1H), 8.61∼8.57(m, 1H), 8.42∼8.31(m, 6H), 7.95∼7.93(m, 2H), 5.23(s, 2H), 4.16∼4.14(m, 2H), 3.36(s, 3H), 2.28∼2.26(m, 3H), 1.92∼1.90(m, 4H) 599
15 : 1H NMR(300 MHz, CD3OD) δ 8.58(d, J = 8.1 Hz, 1H), 7.76(d, J = 12.0 Hz, 1H), 7.65(d, J = 8.1 Hz, 1H), 7.58-7.53(m, 2H), 7.44-7.42(m, 2H), 7.09-7.03(m, 2H), 4.43(s, 2H), 3.55(t, J = 7.2 Hz, 2H), 2.65-2.51(m, 9H), 1.69-1.60(m, 8H), 1.54-1.45(m, 2H) 682
16 : 1H NMR(300 MHz, CD3OD) δ 8.57(d, J = 8.1 Hz, 1H), 7.69(d, J = 12.3 Hz, 1H), 7.63(d, J = 7.8 Hz, 1H), 7.45 -7.29(m, 4H), 7.10-7.04(m, 2H), 4.42(s, 2H), 3.72(s, 2H), 3.56(t, J = 6.6 Hz, 2H), 2.64-2.51(m, 9H), 1.68-1.61(m, 4H), 1.55-1.45(m, 2H) 656
17 1H NMR(300 MHz, CD3OD) δ 8.52(d, J = 7.8 Hz, 1H), 7.79-7.79(m, 2H), 7.62-7.50(m, 2H), 4.47(s, 2H), 4.14(s, 2H), 2.64(s, 3H) 520
18 1H NMR(300 MHz, CD3OD) δ 8.55(d, J = 8.1 Hz, 1H), 7.74(d, J = 13.2 Hz, 1H), 7.62(d, J = 8.1 Hz, 1H), 7.57-7.53(m, 2H), 7.44-7.38(m, 2H), 7.06(t, J = 9.0 Hz, 2H) 4.41(s, 2H), 3.49(t, J = 6.9 Hz, 2H), 2.75-2.61(m, 6H), 2.24(s, 3H), 1.64(s, 4H), 1.11(t, J = 6.9 Hz, 6H) 670
19 1H NMR(300 MHz, CDCl3) δ 14.78(s, 1H), 10.64(s, 1H), 9.49(s, 1H), 8.46(d, J=8.1Hz, 1H), 7.92(m, 1H), 7.67∼7.56(m, 5H), 7.40∼7.31(m, 5H), 4.43(s, 3H), 3.73(s, 2H), 3.25(m, 2H), 2.55(s, 3H), 2.48(m, 4H), 1.05(m, 6H) 644
20 1H NMR(300 MHz, DMSO-d6) δ 10.42(s, 1H), 9.97(s, 1H), 9.55(s, 1H), 8.50(d, J = 8.1 Hz, 1H), 8.22(br s, 1H), 7.81∼7.70(m, 2H), 7.64∼7.51(m, 5H), 7.13(t, J = 8.7 Hz, 2H), 4.44(s, 2H), 3.93(d, J = 5.7 Hz, 2H), 2.56(s, 3H), 1.47∼1.39(m, 4H) 629
21 1H NMR(300 MHz, CD3OD) δ 8.53(d, J = 7.8 Hz, 1H), 7.73(d, J = 13.2 Hz, 1H), 7.61-7.52(m, 3H), 7.44-7.38(m, 2H), 7.05(t, J = 8.7 Hz, 2H)4.39(s, 2H), 3.55(t, J = 6.6 Hz, 2H), 2.74(t, J = 6.6 Hz, 2H), 2.68-2.59(m, 7H), 1.84-1.81(m, 4H), 1.68-1.60(m, 4H) 668
22 1H NMR(300 MHz, CD3OD) δ 8.40(d, J = 8.1 Hz, 1H), 7.76(d, J = 12.0 Hz, 1H), 7.65(d, J = 8.1 Hz, 1H), 7.58-7.53(m, 2H), 7.45-7.40(m, 2H), 7.11-7.03(m, 2H) 4.63(s, 2H), 4.43(s, 2H), 2.36(s, 3H), 1.64(s, 4H) 558
23 1H NMR(300 MHz, CD3OD) δ 8.58(d, J = 8.1 Hz, 1H), 7.64(d, J = 8.4 Hz, 1H), 7.40-7.18(m, 5H), 7.04(t, J = 8.4 Hz, 2H), 4.43(s, 2H), 3.64(t, J = 7.8 Hz, 2H), 3.05-2.92(m, 9H), 2.63(s, 3H), 1.98-1.90(m, 4H), 1.53-1.48(m, 2H), 1.35-1.28(m, 2H) 682
24 : 1H NMR(300 MHz, CD3OD) δ 8.55(d, J = 8.1 Hz, 1H), 7.75(d, J = 13.2 Hz, 1H), 7.64(d, J = 8.1 Hz, 1H), 7.57-7.53(m, 2H), 7.45-7.40(m, 2H), 7.07(t, J = 8.7 Hz, 2H), 4.42(s, 2H), 3.74-3.67(m, 4H), 3.54(t, J = 6.6 Hz, 2H), 2.64-2.43(m, 9H), 1.64(s, 4H) 684
25 1H NMR(300 MHz, CD3OD) δ 8.55(d, J = 8.1 Hz, 1H), 7.77(d, J = 12.9 Hz, 1H), 7.63-7.56(m, 3H), 7.50-7.38(m, 2H), 7.05(d, J = 8.7 Hz, 2H), 4.41(s, 2H), 3.53(t, J = 6.9 Hz, 2H), 2.85-2.74(m, 10 H), 2.61(s, 3H), 2.05-1.94(m, 2H), 1.15(t, J = 7.2 Hz, 6H) 684
26 1H NMR(300 MHz, DMSO-d6) δ 14.79(s, 1H), 9.50(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 7.90(s, 1H), 7.78-7.60(m, 4H), 4.44(s, 2H), 3.38-3.23(m, 2H), 2.60-2.51(m, 9H), 0.99(t, J = 6.9 Hz, 6H) 561
27 1H NMR, 300 MHz, DMSO-d6) δ 14.81(s, 1H), 10.40(s, 1H), 9.97(s, 1H), 9.49(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 7.90-7.80(m, 2H), 7.70-7.60(m, 3H), 7.58-7.50(m, 2H), 7.14(t, J = 8.7 Hz, 2H), 4.78(t, J = 5.7 Hz, 1H), 4.42(s, 2H), 3.51(q, J = 5.7 Hz, 2H), 3.38(t, J = 5.7 Hz, 2H), 2.56(s, 3H), 1.45(s, 4H) 615
28 1H NMR(300 MHz, DMSO-d6) δ 14.82(s, 1H), 10.62(s, 1H), 9.51(s, 1H), 8.51(d, J = 8.1 Hz, 1H), 7.89-7.81(m, 4H), 7.69-7.59(m, 5H), 4.78(t, J = 5.4 Hz, 1H), 4.46(s, 2H), 3.51(q, J = 5.4 Hz, 2H), 3.34(t, J = 5.4 Hz, 2H), 2.56(s, 3H) 532
29 1H NMR(300 MHz, CD3OD) δ 8.54(d, J = 8.1 Hz, 1H), 7.76∼7.72(m, 1H), 7.63∼7.61(m, 1H), 7.57∼7.52(m, 2H), 7.43∼7.41(m, 2H), 7.10∼7.04(m, 2H), 4.41(s, 2H), 3.56∼3.53(m, 2H), 2.66∼2.55(m, 9H), 2.29(s, 3H), 1.64(s, 4H) 697
30 1H NMR(300 MHz, DMSO-d6) δ 10.53(s, 1H), 9.47(s, 1H), 8.47(d, J = 8.1 Hz, 1H), 7.84∼7.18(m, 6H), 6.40(brd. S, 2H), 4.26(s, 1H), 3.36(m, 4H), 3.23(m, 2H), 2.56(m, 5H), 1.68(m, 4H) 463
31 1H NMR(300 MHz, DMSO-d6) δ 9.50(br s, 1H), 8.48(d, J = 8.1 Hz, 1H), 7.88∼7.86(m, 1H), 7.80∼7.75(m, 1H), 7.68∼7.44(m, 5H), 7.18∼7.10(m, 2H), 4.42(s, 2H), 3.50∼3.28(m, 4H), 2.55∼2.48(m, 9H), 1.95∼1.92(m, 4H) 642
32 1H NMR(300 MHz, DMSO-d6) δ 14.79(s, 1H), 10.25(s, 1H), 9.49(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 7.85-7.80(m, 1H), 7.70-7.61(m, 2H), 7.57-7.40(m, 3H), 7.39-7.21(m, 3H), 4.42(s, 2H), 3.39-3.32(m, 2H), 3.22-3.15(m, 5H), 2.59-2.48(m, 9H), 1.67(s, 4H) 656
33 1H NMR(300 MHz, DMSO-d6) δ 10.53(s, 1H), 9.47(s, 1H), 8.47(d, J = 8.1 Hz, 1H), 7.84∼7.18(m, 6H), 4.26(s, 1H), 3.36(m, 4H), 3.23(m, 2H), 2.56(m, 5H), 1.78,(m, 1H), 1.68(m, 4H), 0.83(m, 4H). 531
34 1H NMR(300 MHz, CD3OD) δ 8.59(d, J = 8.1 Hz, 1H), 7.89∼7.85(m, 1H), 7.84∼7.79(m, 1H), 7.72∼7.45(m, 5H), 7.39∼7.34(m, 1H), 4.46(s, 2H), 3.58∼3.56(m, 2H), 2.83∼2.81(m, 2H), 2.74∼2.72(m, 4H), 2.63(s, 3H), 2.03∼2.01(m, 4H) 585
35 1H NMR(300 MHz, CDCl3) δ 14.27(br s, 1H), 8.59(d, J = 8.1 Hz, 1H), 7.61∼7.54(m, 2H), 7.11(t, J = 8.1 Hz, 1H), 6.57∼6.47(m, 3H), 4.44(s, 2H), 3.94(s, 2H), 3.58∼3.56(m, 2H), 2.68∼2.51(m, 11H), 2.31(s, 3H) 492
36 1H NMR(300 MHz, DMSO-d6) δ 14.80(s, 1H), 9.70(brs, 1H), 9.49(s, 1H), 8.46(d, J = 8.4 Hz, 1H), 7.85(t, J = 6.6 Hz, 1H), 7.63(d, J = 8.4 Hz, 1H), 7.45(d, J = 8.4 Hz, 2H), 6.87(d, J = 8.4 Hz, 2H), 4.59(s, 2H), 3.39-3.32(m, 2H), 2.59-2.48(m, 9H), 1.68(s, 4H) 446
37 1H NMR(300 MHz, CD3OD) δ 8.68(d, J = 7.8 Hz, 1H), 7.62(m, 2H), 7.44∼7.18(m, 5H), 4.41(s, 2H), 3.40(m, 2H), 2.66∼2.61(m, 9H), 1.86∼1.83(m, 7H), 1.28(m, 2H), 1.12(m, 2H). 670
38 1H NMR(300 MHz, DMSO-d6) δ 14.76(s, 1H), 10.27(s, 1H), 9.48(s, 1H), 8.50(d, J = 7.8 Hz, 1H), 7.92∼7.90(m, 1H), 7.68∼7.65(m, 2H), 7.54∼7.26(m, 6H), 4.41(s, 2H), 3.30(s, 2H), 3.17(s, 3H), 2.75(d, J = 4.8 Hz, 3H), 2.55(s, 3H) 573
39 1H NMR(300 MHz, DMSO-d6) δ 14.81(s, 1H), 10.58(s, 1H), 9.50(s, 1H), 8.50(d, J = 8.4 Hz, 1H), 8.05∼8.03(m, 2H), 7.90∼7.88(m, 2H), 7.72∼7.66(m, 2H), 7.59∼7.57(m, 1H), 7.40∼7.38(m, 2H), 4.45(s, 2H), 3.42∼3.36(m, 2H), 2.56∼2.49(m, 9H), 1.70∼1.68(m, 4H) 585
40 1H NMR(300 MHz, DMSO-d6) δ 14.80(s, 1H), 10.78(s, 1H), 9.50(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 7.89∼7.87(m, 2H), 7.69∼7.59(m, 5H), 7.39∼7.36(m, 2H), 4.45(s, 2H), 3.42∼3.36(m, 2H), 2.56∼2.48(m, 9H), 1.69∼1.66(m, 4H) 585
41 1H NMR(300 MHz, DMSO-d6) δ 10.42(br s, 1H), 10.00(s, 1H), 9.39(s, 1H), 8.42∼8.27(m, 3H), 7.78(d, J = 12.6 Hz, 1H), 7.64∼7.49(m, 5H), 7.13(t, J = 9.0 Hz, 2H), 4.40(s, 2H), 3.86(s, 2H), 3.49∼3.30(m, 2H), 2.69∼2.48(m, 9H), 1.70∼1.64(m, 4H), 1.46∼1.44(m, 4H) 654
42 1H NMR(300 MHz, CD3OD) δ 8.56-8.48(m, 2H), 7.69-7.62(m, 2H), 7.12-6.86(m, 3H) 4.60(s, 2H), 3.91(s, 3H), 3.76-3.70(m, 2H), 3.51-3.38(m, 6H), 2.63(s, 3H), 2.11(s, 4H) 476
43 1H NMR( 300 MHz, DMSO-d6) δ 14.81(s, 1H), 9.55(s, 1H), 8.52(d, J = 8.1 Hz, 1H), 8.05(s, 1H), 7.99(d, J = 8.4 Hz, 2H), 7.95(t, J = 6.6 Hz, 1H), 7.80(d, J = 8.1 Hz, 1H), 7.72(d, J = 8.4 Hz, 2H), 7.42(s, 1H), 4.65(s, 2H), 3.41(q, J = 6.9 Hz, 2H), 2.63(t, J = 6.9 Hz, 2H), 2.57-2.45(m, 7H), 1.70(s, 4H) 473
44 1H NMR(300 MHz, CDCl3) δ 8.62(d, J = 8.1 Hz, 1H), 8.03(m, 3H), 7.62(d, J = 8.1 Hz, 1H), 7.26(m, 2H), 6.96(d, J= 9.2Hz, 2H), 6.52(brs. S, 2H), 4.49(s, 2H), 3.00(s, 3H), 2.71(s, 3H). 380
45 1H NMR(300 MHz, CDCl3) δ 8.64(d, J = 8.1 Hz, 1H), 8.05(m, 3H), 7.64(d, J = 8.1 Hz, 1H), 7.28(m, 2H), 6.95(d, J= 9.2Hz, 2H), 4.45(s, 2H), 2.98(s, 3H), 2.74(s, 6H). 394
46 1H NMR(300 MHz, DMSO-d6) δ 14.80(s, 1H), 10.57(s, 1H), 9.48(s, 1H), 8.49(d, J = 7.8 Hz, 1H), 8.25∼8.22(m, 1H), 7.95∼7.88(m, 1H), 7.75∼7.52(m, 4H), 7.42∼7.32(m, 1H), 7.30∼7.24(m, 2H), 4.43(s, 2H), 3.94(s, 4H), 3.48∼3.42(m, 2H), 2.56∼2.49(m, 9H), 1.70∼1.68(m, 4H) 669
47 1H NMR( 300 MHz, CD3OD) δ 8.62(d, J = 8.1 Hz, 1H), 8.39(brs, 1H), 7.88(d, J = 8.1 Hz, 1H), 7.77-7.73(m, 2H), 7.65-7.62(m, 2H) 4.61(s, 2H), 3.75(t, J = 7.5 Hz, 2H), 3.54-3.41(m, 6H), 2.64(s, 3H), 2.15-2.08(m, 4H) 455
48 1H NMR(300 MHz, CDCl3) δ 8.62(d, J = 8.1 Hz, 1H), 8.03(m, 3H), 7.62(d, J = 8.1 Hz, 1H), 7.26(m, 6H), 6.96(d, J= 9.2Hz, 2H), 6.52(brs. S, 2H), 4.49(s, 2H), 3.00(s, 3H), 2.71(s, 3H). 538
49 1H NMR(300 MHz, CDCl3) δ 10.12(m, 1H), 8.62(m, 1H), 8.42(m, 1H), 7.74∼7.06(m, 6H), 6.42(s, 1H), 4.40(s, 2H), 3.66(s, 3H), 2.45(s, 3H).1.25(m, 6H). 569
50 1H NMR(300 MHz, CDCl3) δ 10.57(s, 1H), 8.62(d, J = 8.1 Hz, 1H), 7.82∼7.16(m, 8H), 4.42(s, 2H), 4.10(m, 2H), 3.97(m, 2H), 3.78(m, 2H), 2.51(s, 3H), 2.34(s, 3H). 572
51 1H NMR(300 MHz, CD3OD) δ 8.55(d, J = 8.1 Hz, 1H), 7.95∼7.89(m, 2H), 7.59(d, J = 8.1 Hz, 1H), 7.38∼7.26(m, 3H), 7.13∼7.03(m, 2H), 4.38(s, 2H), 3.75∼3.72(m, 2H), 3.40∼3.37(m, 6H), 2.63(s, 3H), 2.09∼2.07(m, 4H) 621
52 1H NMR(300 MHz, CD3OD) δ 8.40∼8.36(m, 1H), 7.76∼7.71(m, 1H), 7.61∼7.51(m, 3H), 7.41∼7.38(m, 2H), 7.09∼7.01(m, 2H), 4.39(s, 2H), 3.72(s, 2H), 2.49(s, 3H), 2.33(s, 3H), 1.64∼1.62(m, 4H) 571
53 1H NMR(300 MHz, CD3OD) δ 8.43(d, J= 7.5 Hz, 1H), 7.75(d, J = 12.0 Hz, 1H), 7.61(d, J = 8.1 Hz, 1H), 7.58∼7.53(m, 2H), 7.43∼7.41(m, 2H), 7.10∼7.03(m, 2H), 4.01(s, 2H), 3.55(br s, 2H), 2.31(s, 9H), 1.65∼1.63(m, 4H) 585
54 1H NMR(300 MHz, CD3OD) δ 8.48(s, 1H), 7.94(s, 1H), 7.09(s, 1H) 4.90-4.77(m, 1H), 4.47(s, 2H), 3.75-3.72(m, 2H), 3.30-3.24(m, 6H), 2.60(s, 3H), 1.91-1.73(m, 4H), 1.72-1.62(m, 2H), 1.38-1.35(m, 6H) 426
55 1H NMR(300 MHz, CD3OD) δ 8.52(s, 1H), 7.96(d, J = 1.8 Hz, 1H), 7.10(s, 1H) 4.90-4.77(m, 1H), 4.48(s, 2H), 3.52-3.48(m, 4H), 3.12-2.95(m, 2H), 2.61(s, 3H), 2.08-1.95(m, 4H), 1.94-1.75(m, 3H), 1.68-1.57(m, 2H), 1.38-1.34(m, 9H) 454
56 1H NMR(300 MHz, CD3OD) δ 8.42(d, J = 8.1 Hz, 1H), 7.67-7.59(m, 2H), 7.44-7.36(m, 3H), 7.29(d, J = 8.1 Hz, 1H), 7.21(t, J = 8.1 Hz, 2H), 4.40(s, 2H), 3.55(s, 2H), 3.33-3.29(m, 5H), 2.32(s, 9H) 573
57 1H NMR(300 MHz, CD3OD) δ 8.43(d, J = 8.4 Hz, 1H), 7.93∼7.90(m, 2H), 7.87∼7.82(m, 1H), 7.63∼7.58(m, 2H), 7.50∼7.41(m, 3H), 4.42(s, 2H), 3.60(s, 2H), 3.37∼3.34(m, 4H), 3.12∼3.10(m, 4H), 2.51(s, 6H), 2.47(s, 3H), 2.28(s, 3H) 610
58 1H NMR(300 MHz, CD3OD) δ 8.49∼8.48(m, 2H), 7.88∼7.84(m, 1H), 7.78∼7.74(m, 1H), 7.68(d, J = 8.1 Hz, 1H), 7.60∼7.56(m, 2H), 7.47(t, J = 8.1 Hz, 1H), 7.36∼7.24(m, 2H), 4.46(s, 2H), 4.18(s, 2H), 2.76(s, 3H), 2.41(s, 3H) 488
59 1H NMR(300 MHz, CD3OD) δ 8.53(br s, 1H), 8.48(d, J = 8.1 Hz, 1H), 7.87∼7.83(m, 1H), 7.78∼7.73(m, 1H), 7.67(d, J = 8.1 Hz, 1H), 7.60∼7.55(m, 2H), 7.46(d, J = 8.1 Hz, 1H), 7.36∼7.24(m, 2H), 4.46(s, 2H), 4.13(s, 2H), 2.79(s, 6H), 2.41(s, 3H) 502
60 1H NMR(300 MHz, CD3OD) δ 8.43-8.39(m, 1H), 7.70-7.59(m, 2H), 7.46-7.36(m, 3H), 7.34-7.18(m, 3H), 4.41(d, J = 3.3Hz, 2H), 3.75(s, 2H), 3.34-3.29(m, 5H), 2.44(d, J = 3.6 Hz, 3H), 2.35(s, 3H) 559
61 1H NMR(300 MHz, DMSO-d6) 14.32(s, 1H), 9.27(s, 1H), 8.17(d, J = 8.4 Hz, 1H), 8.09(d, J = 8.4 Hz, 2H), 7.71(q, J = 4.8 Hz, 1H), 7.64(d, J = 8.4 Hz, 2H), 6.86(d, J = 8.4 Hz, 1H), 6.04(t, J = 5.4 Hz, 1H), 4.86(d, J = 5.4 hz, 2H), 4.36(s, 2H), 2.73(d, J = 4.8 Hz, 3H), 2.49-2.48(s, 3H) 438
62 1H NMR(300 MHz, CD3OD) 8.40(d, J = 8.4 Hz, 1H), 7.67-7.59(m, 2H), 7.43-7.36(m, 3H), 7.31-7.17(m, 3H), 4.40(s, 2H), 3.79(s, 2H), 3.68-3.58(m, 2H), 3.34-3.25(m, 5H), 2.80-2.69(m, 2H), 2.34(s, 3H) 589
63 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.1 Hz, 1H), 7.86∼7.82(m, 1H), 7.78∼7.73(m, 1H), 7.64(d, J = 8.1 Hz, 1H), 7.60∼7.54(m, 2H), 7.45(d, J = 8.1 Hz, 1H), 7.36∼7.24(m, 2H), 4.43(s, 2H), 3.81(s, 2H), 3.70(t, J=5.4Hz, 2H), 2.80(t, J = 5.4 Hz, 2H), 2.34(s, 3H) 518
64 1H NMR(300 MHz, CD3OD) δ 8.48(d, J=8.1Hz, 1H), 8.05∼8.00(m, 2H), 7.88∼7.83(m, 1H), 7.67(d, J = 7.8 Hz, 1H), 7.63∼7.59(m, 1H), 7.46(t, J=8.4Hz, 1H), 7.29∼7.23(m, 2H), 4.46(s, 2H), 4.19(s, 2H), 2.77(s, 3H), 2.41(s, 3H) 488
65 1H NMR(300 MHz, CD3OD) δ 8.42(d, J = 8.1 Hz, 1H), 8.05-8.00(m, 2H), 7.85(d, J = 12.9 Hz, 1H), 7.64(d, J = 8.1 Hz, 1H), 7.60(d, J = 8.4 Hz, 1H), 7.46(t, J = 8.4 Hz, 1H), 7.26(t, J = 8.4 Hz, 2H) 4.44(s, 2H), 3.79(s, 2H), 3.71-3.65(m, 2H), 2.78(t, J = 5.7 Hz, 2H), 2.34(s, 3H) 518
66 1H NMR(300 MHz, CD3OD) δ 8.45(d, J = 7.8 Hz, 1H), 8.05-8.00(m, 2H), 7.85(d, J = 12.3 Hz, 1H), 7.65(d, J = 7.8 Hz, 1H), 7.60(d, J = 8.4 Hz, 1H), 7.46(t, J = 8.4 Hz, 1H), 7.26(t, J = 8.4 Hz, 2H), 4.45(s, 2H), 3.57(s, 2H), 2.33(s, 9H) 502
67 1H NMR(300 MHz, CD3OD) δ 8.47(s, 1H), 7.77-7.74(m, 1H), 7.65(brs, 1H), 7.55(brs, 2H), 7.43(brs, 2H), 7.06(brs, 2H), 4.43(s, 2H), 4.19(s, 2H), 3.18-3.12(s, 2H), 2.41(s, 3H), 1.64(s, 4H), 1.39-1.30(m, 3H) 585
68 1H NMR(300 MHz, CD3OD) δ 8.45(d, J= 7.8 Hz, 1H), 7.85(d, J = 12.6 Hz, 1H), 7.76(t, J = 7.8 Hz, 1H), 7.66(d, J = 7.8 Hz, 1H), 7.60-7.54(m, 2H), 7.47(t, J = 8.4 Hz, 1H), 7.35-7.24(m, 2H), 4.45(s, 2H), 3.93(s, 2H), 2.93-2.80(m, 2H), 2.37(s, 3H), 1.24(t, J = 6.9 Hz, 3H) 502
69 1H NMR(300 MHz, CD3OD) δ 8.48(d, J = 8.1 Hz, 1H), 7.74(d, J = 12.9 Hz, 1H), 7.65(d, J = 8.1 Hz, 1H), 7.46-7.37(m, 2H), 4.44(s, 2H), 4.31(s, 2H), 2.72-2.65(m, 1H), 2.43(s, 3H), 1.57-1.53(m, 2H), 1.49-1.38(m, 8H), 0.75-0.71(m, 2H), 0.56-0.53(m, 2H) 559
70 1H NMR(300 MHz, CD3OD) δ 8.40(d, J = 8.4 Hz, 1H), 7.76-7.72(m, 1H), 7.63-7.51(m, 3H), 7.42-7.41(m, 2H), 7.09-7.02(m, 2H), 4.41(s, 2H), 3.75(brs, 2H), 2.92-2.85(m, 1H), 2.33(s, 3H), 1.65-1.60(s, 4H), 1.14-1.11(m, 6H) 599
71 1H NMR(300 MHz, CD3OD) δ 8.42(d, J = 8.1 Hz, 1H), 7.85(d, J = 12.6 Hz, 1H), 7.76(t, J = 7.2 Hz, 1H), 7.66-7.54(m, 3H), 7.46(t, J = 8.4 Hz, 1H), 7.35-7.23(m, 2H), 4.44(s, 2H), 3.77(s, 2H), 2.94-2.89(m, 1H), 2.34(s, 3H), 1.14(d, J = 6.6 Hz, 6H) 516
72 1H NMR(300 MHz, CD3OD) δ 8.50∼8.47(m, 2H), 7.78∼7.74(m, 1H), 7.65(d, J = 8.4Hz, 1H), 7.57∼7.53(m, 2H), 7.44∼7.42(m, 2H), 7.10∼7.04(m, 2H), 4.44(s, 2H), 4.28(s, 2H), 3.29∼3.26(m, 4H), 2.42(s, 3H), 1.65(s, 4H), 1.40(t, J = 7.2 Hz, 6H) 613
73 1H NMR(300 MHz, CD3OD) δ 8.45(d, J = 8.1 Hz, 1H), 7.85(d, J = 12.3 Hz, 1H), 7.76(t, J = 7.2 Hz, 1H), 7.65(d, J = 8.1 Hz, 1H), 7.60-7.54(m, 2H), 7.46(t, J = 8.1 Hz, 1H), 7.35-7.24(m, 2H), 4.46(s, 2H), 3.74(s, 2H), 2.70-2.62(m, 4H), 2.33(s, 3H), 1.17(t, J = 6.9 Hz, 6H) 530
74 1H NMR(300 MHz, CD3OD) δ 8.42(d, J = 8.4 Hz, 1H), 7.87∼7.83(m, 1H), 7.78∼7.73(m, 1H), 7.64(d, J = 8.1 Hz, 1H), 7.60∼7.54(m, 2H), 7.49∼7.43(m, 1H), 7.36∼7.24(m, 2H), 4.44(s, 2H), 3.82(s, 2H), 2.34(s, 3H), 2.12∼2.09(m, 1H), 0.53∼0.50(m, 2H), 0.44∼0.42(m, 2H) 514
75 1H NMR(300 MHz, CD3OD) δ 8.43(d, J = 7.8 Hz, 1H), 7.75(d, J = 12.0 Hz, 1H), 7.62-7.52(m, 3H), 7.46-7.40(m, 2H), 7.06(t, J = 8.4 Hz, 2H), 4.41(s, 2H), 3.65(s, 2H), 2.62-2.55(m, 2H), 2.32(s, 6H), 1.64(s, 4H), 1.18(t, J = 7.5 Hz, 3H) 599
76 1H NMR(300 MHz, CD3OD) δ 8.73(d, J = 3.6 Hz, 1H), 8.42(d, J = 8.1 Hz, 1H), 8.24(d, J = 8.1 Hz, 1H), 8.06-7.96(m, 2H), 7.70-7.60(m, 3H), 7.48(t, J = 8.1 Hz, 1H), 4.45(s, 2H), 3.81(s, 2H), 2.76(q, J = 7.2 Hz, 2H), 2.34(s, 3H), 1.18(t, J = 7.5 Hz, 3H) 485
77 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.4 Hz, 1H), 7.87∼7.82(m, 1H), 7.78∼7.73(m, 1H), 7.64(d, J = 8.4 Hz, 1H), 7.61∼7,54(m, 2H), 7.48∼7.42(m, 1H), 7.36∼7.24(m, 2H), 4.43(s, 2H), 3.79(s, 2H), 2.52(d, J = 6.9 Hz, 2H), 2.33(s, 3H), 1.02∼0.98(m, 1H), 0.54∼0.51(m, 2H), 0.21∼0.17(m, 2H) 528
78 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.4 Hz, 1H), 7.77∼7.73(m, 1H), 7.62(d, J = 8.4 Hz, 1H), 7.58∼7.53(m, 2H), 7.43∼7.41(m, 2H), 7.10∼7.04(m, 2H), 4.41(s, 2H), 3.82(s, 2H), 2.34(s, 3H), 1.64(s, 4H), 0.89∼0.87(m, 1H), 0.52∼0.50(m, 2H), 0.46∼0.42(m, 2H) 597
79 1H NMR(300 MHz, CD3OD) δ 8.53(d, J = 8.1 Hz, 1H), 7.74(d, J = 13.5 Hz, 1H), 7.61(d, J = 7.8 Hz, 1H), 7.46-7.39(m, 2H), 4.40(s, 2H), 3.56-3.46(m, 2H), 3.12-3.04(m, 2H), 2.93(s, 3H), 2.58-2.50(m, 1H), 2.60(s, 3H), 2.15-1.92(m, 4H) 491
80 1H NMR(300 MHz, DMSO-d6) δ 10.79(s, 1H), 9.58(s, 1H), 8.54(d, J = 8.0 Hz, 1H), 8.28(brd. S, 1H), 7.86∼7.26(m, 8H), 5.74(s, 2H), 4.47(s, 2H), 3.59(m, 4H), 3.13(s, 3H), 2.58(s, 3H). 614
81 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.1 Hz, 1H), 7.75(d, J = 13.2 Hz, 1H), 7.62(d, J = 8.1 Hz, 1H), 7.58∼7.53(m, 2H), 7.43∼7.41(m, 2H), 7.10∼7.04(m, 2H), 4.42(s, 2H), 3.82(s, 2H), 2.56(d, J = 6.9 Hz, 2H), 2.34(s, 3H), 1.64(s, 4H), 1.02∼0.98(m, 1H), 0.55∼0.52(m, 2H), 0.21∼0.19(m, 2H) 611
82 1H NMR(300 MHz, CD3OD) δ 8.49(d, J = 8.4 Hz, 1H), 8.05∼8.01(m, 2H), 7.86(dd, J = 12.6 Hz, 1.8 Hz, 1H), 7.68(d, J = 8.4 Hz, 1H), 7.61(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.47(t, J = 8.4 Hz, 1H), 7.30∼7.24(m, 2H), 4.47(s, 2H), 4.18(s, 2H), 3.49∼3.36(m, 1H), 2.42(s, 3H), 1.41(d, J = 6.0 Hz, 4H) 516
83 1H NMR(300 MHz, CD3OD) δ 8.46(d, J = 8.4 Hz, 1H), 8.05∼8.00(m, 2H), 7.88∼7.83(m, 1H), 7.67(d, J = 8.4 Hz, 1H), 7.63∼7.59(m, 1H), 7.47(t, J = 8.4 Hz, 1H), 7.27(t, J = 9.0 Hz, 2H), 4.46(s, 2H), 4.09(s, 2H), 2.87(d, J = 7.5 Hz, 2H), 2.39(s, 3H), 1.05∼1.02(m, 1H), 0.69∼0.66(m, 2H), 0.37∼0.35(m, 2H) 528
84 1H NMR(300 MHz, CD3OD) δ 8.42(d, J = 8.1 Hz, 1H), 8.19(d, J = 7.5 Hz, 1H), 8.04(t, J = 7.5 Hz, 1H), 7.96(d, J = 12.9 Hz, 1H), 7.71-7.63(m, 3H), 7.47(t, J = 8.4 Hz, 1H), 4.44(s, 2H), 3.84(s, 2H), 2.80(q, J = 6.9 Hz, 2H), 2.35(s, 3H), 1.20(t, J = 7.2 Hz, 3H) 519
85 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.4 Hz, 1H), 8.05-7.99(m, 2H), 7.84(d, J = 12.9 Hz, 1H), 7.65-7.58(m, 2H), 7.46(t, J = 8.7 Hz, 1H), 7.26(t, J = 8.7 Hz, 2H), 4.44(s, 2H), 3.79(s, 2H), 2.73(q, J = 7.2 Hz, 2H), 2.34(s, 3H), 1.73(t, J = 7.2 Hz, 3H) 502
86 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.1 Hz, 1H), 8.05-7.99(m, 2H), 7.86-7.82(m, 1H), 7.64(d, J = 7.8 Hz, 1 H), 7.61-7.57(m, 1H), 7.45(t, J = 8.4 Hz, 1H), 7.26(t, J = 8.4 Hz, 2H), 4.43(s, 2H), 3.83(s, 2H), 2.34(s, 3H), 2.23-2.20(m, 1H), 0.53-0.43(m, 4H) 514
87 1H NMR(300 MHz, CD3OD) δ 8.30(d, J = 8.4 Hz, 1H), 8.04∼7.99(m, 2H), 7.86(dd, J = 12.6 Hz, 1.5 Hz, 1H), 7.72(d, J = 8.4 Hz, 1H), 7.61(dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.47(t, J = 8.4 Hz, 1H), 7.28∼7.22(m, 2H), 7.14(s, 1H), 4.48(s, 2H), 2.39(s, 3H) 445
88 1H NMR(300 MHz, CD3OD) δ 8.76(d, J = 3.6 Hz, 1H), 8.44(d, J = 8.1 Hz, 1H), 8.23(d, J = 8.1 Hz, 1H), 8.06-7.96(m, 2H), 7.70-7.60(m, 3H), 7.48(t, J = 8.1 Hz, 1H), 4.45(s, 2H), 3.81(s, 2H), 2.76(q, J = 7.2 Hz, 2H), 2.32(s, 3H), 1.20(t, J = 7.5 Hz, 3H) 485
89 1H NMR(300 MHz, CD3OD) δ 8.38(d, J = 8.4 Hz, 1H), 7.76∼7.71(m, 1H), 7.59(d, J = 8.4 Hz, 1H), 7.57∼7.52(m, 2H), 7.43∼7.39(m, 2H), 7.09∼7.03(m, 2H), 6.92(s, 1H), 4.39(s, 2H), 2.32(s, 3H), 1.64(s, 4H) 528
90 1H NMR(300 MHz, CD3OD) δ 8.38(d, J = 8.4 Hz, 1H), 7.80(dd, J = 12.6 Hz, 2.1 Hz, 1H), 7.65∼7.57(m, 2H), 7.45∼7.40(m, 1H), 7.31(s, 1H), 7.12∼7.09(m, 1H), 6.90∼6.85(m, 2H), 4.45(s, 2H), 2.36(s, 3H) 463
91 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 10.77(s, 1H), 9.39(s, 1H), 8.28(d, J = 8.1 Hz, 1H), 7.85(d, J = 12.3 Hz, 1H), 7.71-7.66(m, 2H), 7.61-7.55(m, 3H), 7.40-7.32(m, 2H), 4.37(s, 2H), 2.87(d, J = 4.5 Hz, 3H) 422
92 1H NMR(300 MHz, DMSO-d6) δ 11.22(q, J = 4.8 Hz, 1H), 10.40(s, 1H), 9.96(s, 1H), 9.37(s, 1H), 8.27(d, J = 7.5 Hz, 1H), 7.78(d, J = 13.2 Hz, 1H), 7.68-7.59(m, 3H), 7.50-7.48(m, 2H), 7.13(t, J = 8.7 Hz, 2H), 4.35(s, 2H), 2.87(d, J = 4.2 Hz, 3H), 1.46(d, J = 3.3 Hz, 4H) 505
93 1H NMR(300 MHz, CDCl3) δ 11.28(bs, 1H), 8.62(d, J = 8.0Hz, 1H), 8.58(m, 1H), 8.20(m, 1H), 7.87(dd, J = 1.5, 10.5Hz, 1H), 7.65(d, J = 8.0Hz, 1H), 7.59(m, 1H), 7.40(m, 3H), 6.47(s, 1H), 4.41(s, 2H), 3.75-3.65(m, 6H), 2.68(t, J = 6.6Hz, 2H), 2.58-2.48(m, 4H) 521
94 1H NMR(300 MHz, CD3OD) δ 8.42(d, J = 8.4 Hz, 1H), 7.85(dd, J = 12.3 Hz, 2.1 Hz, 1H), 7.66∼7.59(m, 2H), 7.49∼7.43(m, 1H), 7.34(s, 1H), 7.14∼7.11(m, 1H), 6.94∼6.89(m, 2H), 4.44(s, 2H), 3.87∼3.83(m, 4H), 2.32(s, 3H) 530
95 1H NMR(300 MHz, DMSO-d6) δ 10.78(s, 1H), 9.36(s, 1H), 8.28(d, J = 8.1 Hz, 1H), 7.85(d, J = 13.2 Hz, 1H), 7.71-7.66(m, 2H), 7.64-7.52(m, 3H), 7.40-7.32(m, 2H), 4.36(s, 2H) 409
96 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.8 Hz, 1H), 10.52(s, 1H), 9.39(s, 1H), 8.28(d, J = 8.1 Hz, 1H), 7.89(d, J = 12.9 Hz, 1H), 7.72-7.65(m, 2H), 7.56(t, J = 8.7 Hz, 1H), 7.29(s, 1H), 7.14(d, J = 8.7 Hz, 1H), 7.01(d, J = 12.3 Hz, 1H), 4.38(s, 2H), 3.76-3.72(m, 4H), 3.24-3.20(m, 4H), 2.87(d, J = 4.5 Hz, 3H) 507
97 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 10.75(s, 1H), 9.39(s, 1H), 9.11(d, J = 2.1 Hz, 1H), 8.78(d, J = 8.1 Hz, 1H), 8.32-8.27(m, 2H), 7.91(d, J = 12.6 Hz, 1H), 7.72-7.65(m, 2H), 7.60-7.55(m, 2H), 4.38(s, 2H), 2.87(d, J = 4.5 Hz, 3H) 405
98 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 10.62(s, 1H), 9.39(s, 1H), 8.28(d, J = 8.1 Hz, 1H), 8.08-8.04(m, 2H), 7.92(d, J = 12.9 Hz, 1H), 7.71-7.67(m, 2H), 7.59-7.53(m, 1H), 7.42-7.35(m, 2H), 4.38(s, 2H), 2.87(d, J = 4.5 Hz, 3H) 422
99 1H NMR(300 MHz, DMSO-d6) δ 10.79(br s, 1H), 10.77(s, 1H), 9.36(s, 1H), 8.28(d, J = 8.1 Hz, 1H), 7.88∼7.84(m, 2H), 7.71∼7.64(m, 3H), 7.61∼7.56(m, 2H), 7.40∼7.33(m, 2H), 4.36(s, 2H) 408
100 1H NMR(300 MHz, CD3OD) δ 8.26(d, J = 8.1 Hz, 1H), 7.79∼7.74(m, 1H), 7.69(d, J = 8.1 Hz, 1H), 7.58∼7.53(m, 2H), 7.45∼7.37(m, 2H), 7.10∼7.04(m, 2H), 4.40(s, 2H), 3.88∼3.85(m, 4H), 3.57(t, J = 6.6 Hz, 2H), 3.22(t, J = 6.6 Hz, 2H), 2.09∼2.01(m, 4H), 1.91∼1.85(m, 2H), 1.65(s, 4H) 618
101 1H NMR(300 MHz, CD3OD) δ 8.32(d, J = 8.1 Hz, 1H), 7.79∼7.74(m, 1H), 7.69(d, J = 8.1 Hz, 1H), 7.59∼7.53(m, 2H), 7.46∼7.41(m, 2H), 7.11∼7.04(m, 2H), 4.40(s, 2H), 3.55(d, J = 6.6 Hz, 2H), 2.94∼2.86(m, 6H), 2.01∼1.89(m, 6H), 1.64(s, 4H) 602
102 1H NMR(300 MHz, CD3OD) δ 8.37(d, J = 8.1 Hz, 1H), 7.86(dd, J = 13.5 Hz, 1.8 Hz, 1H), 7.78∼7.76(m, 1H), 7.72(d, J = 8.1Hz, 1H), 7.62∼7.55(m, 2H), 7.46(t, J = 8.1 Hz, 1H), 7.36∼7.24(m, 2H), 4.43(s, 2H), 3.71∼3.68(m, 4H), 3.53(t, J = 6.6 Hz, 2H), 3.41∼3.29(m, 2H), 2.58∼2.53(m, 6H) 535
103 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 11.03(s, 1H), 9.39(s, 1H), 8.82(d, J = 5.4 Hz, 1H), 8.28(d, J = 6.9 Hz, 1H), 8.18(d, J = 7.5 Hz, 1H), 8.10-8.03(m, 2H), 7.89(d, J = 8.4 Hz, 1H), 7.72-7.67(m, 2H), 7.57(t, J = 8.7 Hz, 1H), 4.39(s, 2H), 2.87(d, J = 4.5 Hz, 3H) 405
104 1H NMR(300 MHz, DMSO-d6) δ 10.78(s, 1H), 10.41(s, 1H), 9.97(s, 1H), 9.34(s, 1H), 8.27(d, J = 8.1 Hz, 1H), 7.79(d, J = 12.6 Hz, 1H), 7.68-7.59(m, 4H), 7.55-7.47(m, 2H), 7.13(t, J = 9.0 Hz, 2H), 4.34(s, 2H), 1.50-1.44(m, 4H) 491
105 1H NMR(300 MHz, DMSO-d6) δ 11.38(t, J = 5.4 Hz, 1H), 10.42(br s, 1H), 9.98(br s, 1H), 9.36(s, 1H), 8.27(d, J = 8.1 Hz, 1H), 7.81∼7.76(m, 1H), 7.69∼7.59(m, 3H), 7.49∼7.47(m, 2H), 7.16∼7.10(m, 2H), 4.35(s, 2H), 3.57∼3.44(m, 6H), 2.55∼2.40(m, 6H), 1.44(s, 4H) 604
106 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 10.43(s, 1H), 9.39(s, 1H), 8.28(d, J = 8.1 Hz, 1H), 7.88(d, J = 13.2 Hz, 1H), 7.71-7.65(m, 2H), 7.55(t, J = 8.4 Hz, 1H), 6.97(s, 1H), 6.85(d, J = 8.4 Hz, 1H), 6.59(d, J = 8.4 Hz, 1H), 6.07(t, J = 5.1 Hz, 1H), 4.38(s, 2H), 3.17-3.11(m, H), 2.88(d, J = 4.5 Hz, 3H), 2.44(t, J = 6 Hz, 2H), 2.18(s, 6H) 508
107 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 10.42(s, 1H), 9.98(s, 1H), 9.36(s, 1H), 8.27(d, J = 7.8 Hz, 1H), 7.79(d, J = 12.3 H, 1H), 7.68-7.59(m, 3H), 7.50-7.48(m, 2H), 7.16-7.09(m, 2H), 4.34(s, 2H), 2.62(t, J = 6.9 Hz, 2H), 2.48-2.46(m, 4H), 1.68-1.65(m, 4H), 1.48-1.43(m, 4H) 588
108 1H NMR(300 MHz, DMSO-d6) δ 10.42(brs, 1H), 9.99(brs, 1H), 8.15(d, J = 7.8 Hz, 1H), 7.82-7.73(m, 2H), 7.64-7.58(m, 2H), 7.53-7.49(m, 2H), 7.15-7.10(m, 2H), 4.52(s, 2H), 1.45(d, J = 3.6 Hz, 4H) 492
109 1H NMR(300 MHz, DMSO-d6) δ 11.69(brs, 1H), 10.42(s, 1H), 9.98(s, 1H), 9.41(s, 1H), 8.30(d, J= 8.1Hz,1H), 7.78-7.44(m, 6H), 7.13(t, J= 7.8Hz 2H), 4.37(s, 2H), 4.02(d, J = 3.6 Hz, 2H). 549
110 1H NMR(300 MHz, CD3OD) δ 8.33(d, J = 8.4 Hz, 1H), 7.55∼7.52(m, 1H), 7.42(t, J = 7.5 Hz, 1H), 7.31∼7.24(m, 1H), 7.17∼7.06(m, 3H), 6.55(dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.43(dd, J = 13.2 Hz, 2.1 Hz, 1H), 4.41(s, 2H), 4.38(s, 2H), 2.31(s, 3H) 431
111 1H NMR(300 MHz, CD3OD) δ 8.31(d, J = 7.8 Hz, 1H), 7.61∼7.58(m, 1H), 7.44∼7.39(m, 1H), 7.29∼7.24(m, 1H), 7.17∼7.06(m, 3H), 6.55(dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.44(dd, 13.5 Hz, 2.1 Hz, 1H), 4.41(s, 2H), 4.37(s, 2H), 2.99(s, 3H) 408
112 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 10.42(s, 1H), 9.98(s, 1H), 9.39(s, 1H), 8.20(d, J = 8.1 Hz, 1H), 7.79(d, J = 13.5 Hz, 1H), 7.69-7.60(m, 3H), 7.53-7.47(m, 2H), 7.13(t, J = 8.7 Hz, 2H), 4.36(s, 2H), 3.60-3.53(m, 2H), 2.54-2.42(m, 8H), 1.46(d, J = 4.2 Hz, 4H) 562
113 1H NMR(300 MHz, DMSO-d6) δ 11.23(q, J = 4.5 Hz, 1H), 10.40(s, 1H), 9.96(s, 1H), 9.36(s, 1H), 8.27(d, J = 8.1 Hz, 1H), 7.78(d, J = 12.9 Hz, 1H), 7.68-7.59(m, 3H), 7.50-7.48(m, 2H), 7.13(t, J = 8.7 Hz, 2H), 4.35(s, 2H), 3.39-3.34(m, 2H), 2.29(t, J = 7.5 Hz, 2H), 2.11(s, 6H), 1.71-1.62(m, 2H), 1.48-1.43(m, 4H) 576
114 1H NMR(300 MHz, CD3OD) δ 8.33(d, J = 8.1 Hz, 1H), 7.56∼7.54(m, 1H), 7.44∼7.39(m, 1H), 7.31∼7.24(m, 1H), 7.17∼7.06(m, 3H), 6.55(dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.44(dd, J = 13.5 Hz, 2.1 Hz, 1H), 4.41(s, 2H), 4.39(s, 2H), 3.99(dd, J = 14.4 Hz, 3.6 Hz, 1H), 3.62(dd, J = 14.4 Hz, 8.4 Hz, 1H), 2.40(d, J = 5.7 Hz, 3H), 2.33(s, 3H) 474
115 1H NMR(300 MHz, DMSO-d6) δ 10.79(s, 1H), 10.58(s, 1H), 9.35(s, 1H), 8.27(d, J = 8.1 Hz, 1H), 7.75-7.61(m, 5H), 7.53(t, J = 8.4 Hz, 1H), 7.41(d, J = 8.4 Hz, 1H), 7.27(t, J = 8.4 Hz, 1H), 4.35(s, 2H), 3.94(s, 4H) 492
116 1H NMR(300 MHz, DMSO-d6) δ 9.36(s, 1H), 8.39(d, J = 8.4 Hz, 1H), 8.29(s, 1H), 7.57(d, J = 7.8 Hz, 1H), 7.34(t, J = 8.4 Hz, 1H), 6.72-6.67(m, 2H), 4.37(s, 2H), 3.87(s, 2H), 3.47-3.41(m, 1H), 2.29(s, 3H), 1.16(s, 6H) 395
117 1H NMR(300 MHz, DMSO-d6) δ 11.35(t, J = 3.5 Hz, 1H), 10.41(s, 1H), 9.97(s, 1H), 9.35(s, 1H), 8.27(d, J = 8.1 Hz, 1H), 7.96-7.42(m, 7H), 7.13(t, J= 7.8Hz, 2H), 4.35(s, 2H), 3.41(m, 2H), 1.19(m, 3H). 519
118 1H NMR(300 MHz, DMSO-d6) δ 11.38(d, J = 7.8 Hz, 1H), 10.20(s, 1H), 9.98(s, 1H), 9.28(s, 1H), 8.24(d, J = 8.1 Hz, 1H), 7.96-7.42(m, 7H), 7.08(t, J= 7.8Hz, 2H), 4.28(s, 2H), 1.12(m, 6H). 533
119 1H NMR(300 MHz, DMSO-d6) δ 11.05(s, 1H), 10.78(s, 1H), 10.69(s, 1H), 9.34(s, 1H), 8.26(d, J = 8.1 Hz, 1H), 7.72-7.65(m, 3H), 7.50(t, J = 8.4 Hz,1H), 7.41-7.32(m, 3H), 7.15(t, J = 8.4 Hz, 2H), 4.34(s, 2H), 3.74(s, 2H) 465
120 1H NMR(300 MHz, DMSO-d6) δ 11.20(t, J = 5.1 Hz, 1H), 10.41(s, 1H), 9.96(s, 1H), 9.31(s, 1H), 8.23(d, J = 8.1 Hz, 1H), 7.79(d, J = 13.2 Hz, 1H), 7.68-7.59(m, 3H), 7.51-7.49(m, 2H), 7.13(t, J = 8.7 Hz, 2H), 4.71(t, J = 5.4 Hz, 1H), 4.35(s, 2H), 3.56-3.51(m, 2H), 3.43-3.40(m, 2H), 1.45(s, 4H) 535
121 1H NMR(300 MHz, CD3OD) δ 8.33(d, J = 7.8 Hz, 1H), 7.62∼7.59(m, 1H), 7.41(t, J = 7.8 Hz, 1H), 7.31∼7.24(m, 1H), 7.18∼7.06(m, 3H), 6.57∼6.54(m, 1H), 6.47∼6.42(m, 1H), 4.42(s, 2H), 4.37(s, 2H) 374
122 1H NMR(300 MHz, DMSO-d6) δ 11.43(d, J = 4.5 Hz, 1H), 10.39(s, 1H), 9.96(s, 1H), 9.34(s, 1H), 8.25(d, J = 8.1 Hz, 1H), 7.78(d, J = 13.5 Hz, 1H), 7.67-7.59(m, 3H), 7.51-7.47(m, 2H), 7.13(t, J = 9.0 Hz, 2H), 4.34(s, 2H), 1.44(s, 4H), 0.76-0.73(m, 2H), 0.53-0.50(m, 2H) 531
123 1H NMR(300 MHz, DMSO-d6) δ 14.04(s, 1H), 10.41(s, 1H), 9.96(s, 1H), 9.52(s, 1H), 8.19(d, J = 8.1 Hz, 1H), 7.79(d, J = 12.6 Hz, 1H), 7.71(d, J = 8.1 Hz, 1H), 7.64-7.59(m, 2H), 7.50-7.47(m, 2H), 7.13(t, J = 8.7 Hz, 2H), 4.37(s, 2H), 3.75(s, 3H), 1.45(s, 4H) 521
124 1H NMR(300 MHz, DMSO-d6) δ 10.44(s, 1H), 9.96(s, 1H), 9.04(s, 1H), 8.03(d, J = 8.1 Hz, 1H), 7.83∼7.73(m, 2H), 7.64∼7.52(m, 4H), 7.16∼7.10(m, 2H), 4.37(s, 2H), 1.46∼1.45(m, 4H) 473
125 1H NMR(300 MHz, DMSO-d6) δ 10.80(s, 1H), 10.42(s, 1H), 9.97(s, 1H), 9.35(s, 1H), 8.28(d, J = 8.1 Hz, 1H), 7.80(d, J = 12.6 Hz, 1H), 7.68-7.56(m, 4H), 7.52-7.45(m, 2H), 7.14(t, J = 9.0 Hz, 2H), 4.34(s, 2H), 1.50-1.45(m, 4H) 471
126 1H NMR(300 MHz, CD3OD) δ 7.85∼7.75(m, 2H), 7.57∼7.53(m, 2H), 7.38∼7.35(m, 1H), 7.26∼7.23(m, 2H), 7.09∼7.03(m, 2H), 4.44(s, 2H), 1.62(s, 4H) 507
127 1H NMR(300 MHz, DMSO-d6) δ 10.93(s, 1H), 10.49(s, 1H), 9.17(s, 1H), 7.81∼7.75(m, 2H), 7.68∼7.61(m, 3H), 7.41∼7.23(m, 5H), 4.40(s, 2H), 3.94(s, 4H) 508
128 1H NMR(300 MHz, DMSO-d6) δ 10.31(s, 1H), 9.96(s, 1H), 9.25(s, 1H), 8.04(s, 1H), 7.90-7.81(m, 2H), 7.65-7.58(m, 2H), 7.41-7.47(m, 1H), 7.28(t, J = 9.3 Hz, 1H), 7.13(t, J = 9.3 Hz, 2H), 6.96(s, 1H), 4.41(s, 2H), 2.72(t, J = 4.8 Hz, 3H), 2.53(s, 3H), 1.48-1.42(m, 4H) 601
129 1H NMR(300 MHz, CD3OD) δ 8.39(d, J = 8.1 Hz, 1H), 7.79(dd, J = 12.9 Hz, 1.8 Hz, 1H), 7.69(d, J = 8.1 Hz, 1H), 7.60∼7.55(m, 2H), 7.49(dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.41(t, J = 8.1 Hz, 1H), 7.08∼7.03(m, 2H), 4.38(s, 2H), 2.77(t, J = 8.1 Hz, 4H), 2.01∼1.97(m, 2H) 505
130 1H NMR(300 MHz, DMSO-d6) δ 10.43(s, 1H), 9.98(s, 1H), 9.60(s, 1H), 8.40(d, J = 8.1 Hz, 1H), 7.80(d, J = 12 Hz, 1H), 7.64-7.60(m, 2H), 7.54-7.48(m, 2H), 7.13(t, J = 9 Hz, 2H), 4,46(s, 2H), 2.35(s, 2H), 1.45(d, J = 3 Hz, 4H) 529
131 1H NMR(300 MHz, CD3OD) δ 8.57∼8.53(m, 1H), 8.35∼8.32(m, 1H), 8.13∼8.08(m, 3H), 7.99∼7.96(m, 1H), 7.81∼7.76(m, 2H), 7.51(t, J = 8.4 Hz, 1H), 4.99(s, 2H) 448
132 1H NMR(300 MHz, DMSO-d6) δ 10.53(s, 1H), 9.61(s, 1H), 8.41(d, J = 7.2 Hz, 1H), 7.90(d, J = 13.2 Hz, 1H), 7.77(d, J = 7.8 Hz, 1H), 7.69-7.58(m, 2H), 7.29(s, 1H), 7.14(d, J = 8.7 Hz, 1H), 7.02(d, J = 12.6 Hz, 1H), 4.48(s, 2H), 3.75-3.72(m, 4H), 3.25-3.21(m, 4H), 2.35(s, 3H) 531
133 1H NMR(300 MHz, DMSO-d6) δ 10.43(s, 1H), 9.97(s, 1H), 8.83(s, 1H), 7.83-7.79(m, 2H), 7.72(d, J = 7.8 Hz, 1H), 7.64-7.49(m, 4H), 7.16-7.10(m, 2H), 4.36(s, 2H), 2.56(s, 3H), 1.45(d, J = 2.4 Hz, 4H) 530
134 1H NMR(300 MHz, DMSO-d6) δ 12.16(s, 1H), 10.80(s, 1H), 9.36(s, 1H), 8.58(d, J = 7.2 Hz, 1H), 8.26(d, J = 8.1 Hz, 1H), 8.12(d, J = 7.2 Hz, 1H), 7.94(d, J = 12.3 Hz, 1H), 7.71∼7.38(m, 8H), 7.20(t, J = 7.2 Hz, 1H), 4.36(s, 2H) 501
135 1H NMR(300 MHz, DMSO-d6) δ 11.04,(s, 1H), 10.64(s, 1H), 9.59(s, 1H), 8.40(d, J = 8.1 Hz, 1H), 7.75-7.69(m, 2H), 7.54(t, J = 8.4 Hz, 1H), 7.42-7.33(m, 2H), 7.16(t, J = 9.0 Hz, 2H), 4.45(s, 2H), 3.74(s, 2H), 2.35(s, 3H) 503
136 1H NMR(300 MHz, DMSO-d6) δ 10.84(s, 1H), 10.15(s, 1H), 9.99(s, 1H), 9.31(s,1H),8.27(d, J = 8.1 Hz, 1H), 7.68-7.51(m, 6H), 7.21-7.10(m,3H), 4.13(s, 2H), 2.03(s,3H), 1.45(s, 4H) 487
137 1H NMR(300 MHz, DMSO-d6) δ 9.60(s, 1H), 9.25(s, 1H), 9.24(s, 1H), 8.39(d, J = 8.1 Hz, 1H), 8.01(s, 1H), 7.75(d, J = 8.1 Hz, 1H), 7.67-7.49(m, 4H), 7.31(t, J = 9.0 Hz, 2H), 4.48(s, 2H), 2.37(s, 3H) 511
138 1H NMR(300 MHz, DMSO-d6) δ 10.53(s, 1H), 9.99(s, 1H), 9.33(s, H), 8.80(s, 1H), 7.85-7.80(m, 2H), 7.74(d, J = 7.5 Hz, 1H), 7.62-7.47(m, 4H), 7.15-7.10(m, 2H), 4.34(s, 2H), 1.44(d, J = 2.4 Hz, 4H) 515
139 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 10.40(s, 1H), 9.99(s, 1H), 9.41(s, 1H), 8.48(d, J = 8.4 Hz, 1H), 7.78(d, J = 13.5 Hz, 1H), 7.64∼7.60(m, 3H), 7.54∼7.49(m, 2H), 7.38(s, 1H), 7.16∼7.10(m, 3H), 4.41(s, 2H), 1.45(s, 4H) 514
140 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.1 Hz, 1H), 7.85(dd, J = 12.6 Hz, 1.8 Hz, 1H), 7.66∼7.59(m, 2H), 7.46(t, J = 8.4 Hz, 1H), 7.35(s, 1H), 7.12∼7.10(m, 1H), 6.94∼6.90(m, 2H), 4.44(s, 2H), 3.36∼3.29(m, 4H), 2.65∼2.62(m, 4H), 2.37(s, 3H), 2.33(s, 3H) 543
141 1H NMR(300 MHz, CD3OD) δ 8.38(d, J = 7.8 Hz, 1H), 7.82(d, J = 12.3 Hz, 1H), 7.62∼7.56(m, 2H), 7.42(t, J = 7.8 Hz, 1H), 6.98∼6.85(m, 3H), 6.56∼6.53(m, 1H), 4.41(s, 2H), 3.73∼3.70(m, 4H), 3.28(t, J = 6.6 Hz, 2H), 2.62(t, J = 6.6 Hz, 2H), 2.53∼2.46(m, 4H), 2.32(s, 3H) 573
142 1H NMR(300 MHz, DMSO-d6) δ 14.31(d, J = 29.4 Hz, 1H), 9.68(s, 1H), 9.37(s, 1H), 8.39(d, J = 8.4 Hz, 1H), 7.60(d, J = 8.4 Hz, 1H), 7.42(d, J = 8.4 Hz, 2H), 6.92(d, J = 7.4 Hz, 1H), 6.86(d, J =8.4 Hz, 2H), 4.56(s, 2H), 2.23(d, J = 29.7 Hz, 3H) 306
143 1H NMR(300 MHz, DMSO-d6) δ 10.88(s, 1H), 9.75(s, 1H), 9.36(s, 1H), 8.25(d, J = 7.8 Hz, 1H), 7.67-7.64(m, 2H), 7.43(d, J = 8.7 Hz, 2H), 6.87(d, J = 8.7 Hz, 2H), 4.52(s, 2H) 269
144 1H NMR(300 MHz, DMSO-d6) δ 10.79(s, 1H), 10.23(s, 1H), 10.15(s, 1H), 9.36(s,1H),8.29(d, J = 8.1 Hz, 1H), 8.03(d,J=8.1 Hz,1H), 7.76-7.66(m, 3H), 7.58-7.51(m,2H), 7.07-7.03(m,2H),6.93-6.87(m,1H),4.35(s, 2H), 3.86(s,3H), 1.59(d, 4H) 503
145 1H NMR(300 MHz, DMSO-d6) δ 9.64(s, 1H), 8.43(d, J = 9.0Hz, 1H), 8.30(dd, J = 7.2Hz, 1H), 8.12(d, J = 7.5Hz, 1H), 7.92(d, J = 7.8Hz, 1H), 7.84(t,1H), 7.49(m, 2H), 4.66(s, 2H), 2.37(s, 3H) 336
146 1H NMR(300 MHz, DMSO-d6) δ 10.79(s, 1H), 10.15(s, 1H), 9.99(s, 1H), 9.31(s,1H),8.27(d, J = 8.1 Hz, 1H), 7.68-7.51(m, 6H), 7.21-7.10(m,3H), 4.13(s, 2H), 1.45(s, 4H) 474
147 1H NMR(300 MHz, DMSO-d6) δ 11.36(brs, 1H), 10.48(s, 1H), 9.95(s, 1H), 9.70(s, 1H), 8.16(d, J = 8.1 Hz, 1H), 7.90∼7.79(m, 2H), 7.64∼7.51(m, 4H), 7.14(t, J = 8.7 Hz, 2H), 4.48(s, 2H), 4.04(s, 4H), 1.46(d, J = 8.1 Hz, 4H) 516
148 1H NMR(300 MHz, CD3OD) δ 8.46(d, J = 7.8 Hz, 1H), 7.86(d, J = 12.9 Hz, 1H), 7.69∼7.60(m, 2H), 7.51∼7.45(m, 1H), 7.35(s, 1H), 7.21∼7.15(m, 2H), 6.95∼6.91(m, 2H), 4.46(s, 2H), 3.85∼3.84(m, 4H), 3.32∼3.28(m, 4H) 516
149 1H NMR(300 MHz, DMSO-d6) δ 10.84(s, 1H), 10.79(s, 1H), 10.64(s, 1H), 9.36(s,1H),8.28(d, J = 8.1 Hz, 1H), 7.77-7.65(m, 3H), 7.54-7.43(m,2H), 4.34(s, 2H),3.68(s,3H), 1.44-1.39(m, 4H) 412
150 1H NMR(300 MHz, CD3OD) δ 8.41(d, J = 8.1 Hz, 1H), 7.84(dd, J = 12.6 Hz, 2.1 Hz, 1H), 7.66∼7.58(m, 2H), 7.45(t, J = 8.4 Hz, 1H), 7.00∼6.95(m, 2H), 6.90∼6.87(m, 1H), 6.58∼6.54(m, 1H), 4.44(s, 2H), 3.29(t, J = 6.6 Hz, 2H), 2.64(t, J = 6.6 Hz, 2H), 2.35(s, 6H), 2.34(s, 3H) 531
151 1H NMR(300 MHz, CD3OD) δ 8.42(d, J = 8.4 Hz, 1H), 7.84(dd, J = 12.6 Hz, 1.8 Hz, 1H), 7.66∼7.58(m, 2H), 7.46(t, J = 8.4 Hz, 1H), 7.02∼6.90(m, 3H), 6.57∼6.53(m, 1H), 4.44(s, 2H), 3.95∼3.93(m, 1H), 3.48∼3.46(m, 1H), 3.38∼3.36(m, 1H), 2.75∼2.50(m, 6H), 2.33(s, 3H), 2.17∼2.07(m, 4H), 1.88∼1.85(m, 4H) 597
152 1H NMR(300 MHz, DMSO-d6) δ 9.59(s, 1H), 8.46(d, J = 8.4 Hz, 1H), 7.97(s, 1H), 7.81-7.77(m, 2H), 7.72-7.68(m, 1H), 7.64-7.59(m, 3H), 7.55-7.49(m, 2H), 7.13(t, J = 9.0 Hz, 2H), 4.45(s, 2H), 1.44(s, 4H) 582
153 1H NMR(300 MHz, DMSO-d6) δ 10.51(s, 1H), 9.60(s, 1H), 8.47(d, J = 8.1 Hz, 1H), 7.97(s, 1H), 7.90(d, J = 12.9 Hz, 1H), 7.73(d, J = 7.8 Hz, 1H), 7.69-7.65(m, 1H), 7.59(t, J = 9.0 Hz, 1H), 7.30(s, 1H), 7.14(d, J = 8.7 Hz, 1H), 7.01(d, J = 12.0 Hz, 1H), 4.48(s, 2H), 3.76 -3.72(m, 4H), 3.25-3.21(m, 4H) 584
154 1H NMR(300 MHz, DMSO-d6) δ 10.80(s, 1H), 9.35(s, 1H), 9.22(s, 1H), 8.99(s, 1H), 8.27(d, J = 8.1 Hz, 1H), 7.68-7.60(m, 3H), 7.49-7.43(m, 3H), 7.26(d, J = 8.1 Hz, 1H), 7.12(t, J = 9.0 Hz, 2H), 4.35(s, 2H) 423
155 1H NMR(300 MHz, DMSO-d6) δ 10.81(s, 1H), 9.35(s, 1H), 9.27(d, J = 4.8Hz, 2H), 8.27(d, J = 7.8Hz, 1H), 8.01(s, 1H), 7.69-7.31(m, 8H), 4.36(s, 2H) 473
156 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 9.39(s, 1H), 9.19(s, 1H), 8.97(s, 1H), 8.48(d, J = 7.8 Hz, 1H), 7.95(d, J = 12.0 Hz, 1H), 7.65(s, 1H), 7.62(t, J = 6.6 Hz, 1H), 7.50-7.45(m, 2H), 7.37(s, 1H), 7.26(d, J = 12.0 Hz, 1H), 7.15-7.09(m, 3H), 4.40(s, 2H) 446
157 1H NMR(300 MHz, DMSO-d6) δ 14. 40(d, J = 30 Hz, 1H), 9.48(s, 1H), 9.35(s, 1H), 9.25(s, 1H), 8.41(d, J = 8.1 Hz, 1H), 7.64-7.58(m, 2H), 7.51-7.41(m, 3H), 7.28(d, J = 8.4 Hz, 1H), 7.08(d, J = 8.7 Hz, 2H), 6.97(d, J = 92 Hz, 1H), 4.40(s, 2H) 460
158 1H NMR(300 MHz, CD3OD) δ 8.45(d, J = 7.5 Hz, 1H), 7.79(d, J = 8.1 Hz, 1H), 7.51∼7.46(m, 2H), 7.35∼7.30(m, 2H), 4.62(s, 2H), 3.16(q, J = 7.2 Hz, 2H), 2.45(s, 3H), 1.33(t, J = 7.2 Hz, 3H) 398
159 1H NMR(300 MHz, CDCl3) δ 10.07(s, 1H), 8.36(s, 1H), 7.66(d, J = 12.9 Hz, 1H), 7.47∼7.41(m, 3H), 7.38∼7.35(m, 1H), 7.32∼7.22(m, 2H), 7.08∼7.02(m, 2H), 6.82∼6.80(m, 1H), 5.76∼5.72(m, 1H), 4.94(d, J = 6.9 Hz, 2H), 4.40(s, 2H), 1.63∼1.61(m, 4H) 478
160 1H NMR(300 MHz, DMSO-d6) δ 10.83(s, 1H), 9.40(s, 1H), 9.25(s, 1H), 8.28(d, J = 8.0 Hz, 1H), 7.62∼7.38(m, 8H), 4.40(s, 2H), 2.25(s, 3H) 419
161 1H NMR(300 MHz, DMSO-d6) δ 10.41(s, 1H), 9.97(s, 1H), 8.71(s, 1H), 7.82-7.77(m, 2H), 7.67-7.52(m, 3H), 7.53(d, J = 7.2 Hz, 2H), 7.39(s, 1H), 7.13(t, J = 8.7 Hz, 2H), 4.32(s, 2H), 1.45(d, J = 2.1 Hz, 4H) 515
162 1H NMR(300 MHz, DMSO-d6) δ 14.61(s, 1H), 9.47(s, 2H), 9.40(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 8.01(s, 1H), 7.66-7.60(m, 3H), 7.54-7.46(m, 2H), 7.37(s, 1H), 7.33-7.27(m, 2H), 7.12(s, 1H), 4.42(s, 2H) 496
163 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 29.4 Hz, 1H), 9.36(s, 1H), 9.27(s, 2H), 8.42(dd, J = 8.1 Hz, 1.8 Hz, 1H), 8.01(s, 1H), 7.66-7.59(m, 3H), 7.54-7.46(m, 2H), 7.33-7.26(m, 2H), 6.95(d, J = 75 Hz, 1H), 4.41(s, 1H), 2.24(d, J = 30 Hz, 3H) 510
164 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 9.40(s, 1H), 9.09(s, 1H), 8.78(s, 1H), 8.48(d, J = 8.4 Hz, 1H), 7.66∼7.61(m, 2H), 7.48(t, J = 8.4 Hz, 1H), 7.38∼7.37(m, 1H), 7.30(s, 1H), 7.26∼7.22(m, 2H), 7.18∼7.12(m, 2H), 6.80(d, J = 7.2 Hz, 1H), 4.42(s, 2H), 2.27(s, 3H) 442
165 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 10.29(brs, 2H), 9.41(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 7.82∼7.73(m, 2H), 7.64(dd, J = 8.1 Hz, 1.5 Hz, 1H), 7.57∼7.48(m, 2H), 7.38∼7.37(m, 1H), 7.29∼7.12(m, 4H), 4.41(s, 2H), 1.58∼1.56(m, 4H) 514
166 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 29.4 Hz, 1H), 9.36(s, 1H), 9.03(s, 1H), 8.72(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.65-7.58(m, 2H), 7.47(t, J = 8.7 Hz, 1H), 7.30-7.07(m, 5H), 6.80(d, J = 7.5 Hz, 1H), 4.41(s, 2H), 2.27(s, 3H), 2.24(d, J = 30 Hz, 3H) 456
167 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 29.1 Hz, 1H), 9.36(s, 1H), 9.13(s, 1H), 9.05(s, 1H), 8.42(d, J = 8.4 Hz, 1H), 7.64-7.58(m, 2H), 7.51-7.45(m, 2H), 7.35-7.24(m, 2H), 7.16-6.76(m, 3H), 4.41(s, 2H), 2.24(d, J = 29.4 Hz, 3H) 460
168 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 27.3 Hz, 1H), 10.63(s, 1H), 9.37(s, 1H), 8.44(dd, J = 8.1 Hz, 1.8 Hz, 1H), 8.30(d, J = 5.1 Hz, 1H), 7.89∼7.85(m, 1H), 7.67∼7.56(m, 3H), 7.24(s, 1H), 7.11(d, J = 5.1 Hz, 1H), 6.95(d, J = 75.3 Hz, 1H), 4.42(s, 2H), 3.73∼3.70(m, 4H), 3.54∼3.51(m, 4H), 2.25(d, J = 29.7 Hz, 3H) 513
169 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 10.37(s, 1H), 9.96(s, 1H), 9.40(s, 1H), 8.48(d, J = 8.1 Hz, 1H), 7.80∼7.76(m, 1H), 7.65∼7.59(m, 3H), 7.51∼7.49(m, 2H), 7.38(s, 1H), 7.29(t, J = 8.1 Hz, 2H), 7.12∼7.03(m, 2H), 4.41(s, 2H), 1.46(s, 4H) 496
170 1H NMR(300 MHz, DMSO-d6) δ 14.65(s, 1H), 10.37(s, 1H), 9.36(s, 1H), 8.42(d, J = 8.5 Hz, 1H), 7.94(d, J = 12.0 Hz, 1H), 7.78∼7.43(m, 6H), 7.10(d, J = 8.5 Hz, 1H), 4.42(s, 2H), 3.74∼3.72(m, 4H), 3.61∼3.57(m, 4H), 2.20(s, 3H) 513
171 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 10.63(s, 1H), 9.39(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 8.29(d, J = 5.1 Hz, 1H), 7.82(d, J=12.0Hz, 1H), 7.68∼7.38(m, 3H), 7.23(s, 1H), 7.11(d, J = 5.7 Hz, 1H), 4.43(s, 2H), 3.78∼3.73(m, 4H), 3.70∼3.60(m, 4H) 499
172 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 9.40(s, 1H), 9.21(s, 1H), 9.13(s, 1H), 8.48(d, J = 8.4 Hz, 1H), 7.65-7.60(m, 2H), 7.51-7.46(m, 2H), 7.37(s, 1H), 7.35 -7.25(m, 2H), 7.16-7.12(m, 2H), 6.80(t, J = 8.4 Hz, 1H), 4.42(s, 2H) 446
173 1H NMR(300 MHz, DMSO-d6) δ 14.61(s, 1H), 10.13(s, 1H), 10.00(s, 1H), 9.34(s, 1H), 8.45(d, J = 8.1 Hz, 1H), 7.64∼7.47(m, 5H), 7.37(s, 1H), 7.23∼7.10(m, 4H), 4.20(s, 2H), 2.07(s, 3H), 1.46(s, 4H) 510
174 1H NMR(300 MHz, DMSO-d6) δ 14.65(s, 1H), 10.38(s, 1H), 9.42(s, 1H), 8.50(d, J = 8.1 Hz, 1H), 7.99(d, J = 12.3 Hz, 1H), 7.81∼7.76(m, 2H), 7.68(d, J = 8.1 Hz, 1H), 7.60(t, J = 8.4 Hz, 1H), 7.46∼7.39(m, 2H), 7.13∼7.10(m, 2H), 4.44(s, 2H), 3.75∼3.73(m, 4H), 3.63∼3.60(m, 4H) 499
175 1H NMR(300 MHz, CD3OD) δ 8.08(s, 1H), 7.87(d, J = 7.8 Hz, 1H), 7.71(d, J = 7.8 Hz, 1H), 7.65(dd, J = 12.9 Hz, 2.1 Hz, 1H), 7.47∼7.38(m, 3H), 7.33∼7.25(m, 2H), 7.13∼7.10(m, 1H), 6.79∼6.72(m, 1H), 4.43(s, 2H) 447
176 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 27.6 Hz, 1H), 10.60(s, 1H), 9.38(s, 1H), 8.43(dd, J = 8.1 Hz, 1.8 Hz, 1H), 8.24(d, J = 5.4 Hz, 1H), 7.90∼7.85(m, 1H), 7.68∼7.55(m, 3H), 7.20(s, 1H), 7.01∼6.99(m, 1H), 6.96(d, J = 75.6 Hz, 1H), 4.42(s, 2H), 3.61∼3.59(m, 4H), 2.25(d, J = 29.7 Hz, 3H), 1.58∼1.55(m, 6H) 511
177 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 28.5 Hz, 1H), 9.36(s, 1H), 9.17(s, 1H), 9.03(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.63∼7.45(m, 5H), 7.35∼7.24(m, 3H), 6.95(d, J = 75 Hz, 1H), 4.40(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 476
178 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 27 Hz, 1H), 9.78(s, 1H), 9.36(s, 1H), 8.45∼8.40(m, 2H), 8.13(dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.68∼7.62(m, 2H), 7.60∼7.45(m, 2H), 7.34∼7.21(m, 2H), 7.05∼7.02(m, 1H), 6.95(d, J = 75.3 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 476
179 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 9.56(s, 1H), 9.41(s, 1H), 8.94(s, 1H), 8.49(d, J = 8.4 Hz, 1H), 8.04-7.97(m, 1H), 7.66-7.61(m, 2H), 7.51(t, J = 9.0 Hz, 1H), 7.38(s, 1H), 7.34-7.23(m, 2H), 7.12(s, 1H), 6.88-6.81(m, 1H), 4.42(s, 2H) 464
180 1H NMR(300 MHz, DMSO-d6) δ 14.39(s, 1H), 9.94(s, 1H), 8.68(s, 1H), 8.42(d, J = 8.0 Hz, 1H), 7.58(d, J = 9.6 Hz, 2H), 7.42(t, 1H), 7.24(m, 2H), 6.22(d, J = 8.0 Hz, 1H), 4.39(s, 2H), 1.98-1.42(m, 5H), 1.34-1.16(m, 6H) 448
181 1H NMR(300 MHz, DMSO-d6) δ 9.14(s, 1H), 8.81(s, 1H), 8.71(s, 1H), 8.26(s, 1H), 7.78(d, J = 8.1 Hz, 1H), 7.68-7.62(m, 2H), 7.50(t, J = 8.4 Hz, 1H), 7.39(s, 1H), 7.30-7.13(m, 4H), 6.80(d, J = 7.5 Hz, 1H), 4.34(s, 2H), 2.27(s, 3H) 443
182 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.9 Hz, 1H), 9.34(s, 1H), 9.00(s, 1H), 8.41(dd, J = 8.4 Hz, 2.1 Hz, 1H), 7.62∼7.57(m, 2H), 7.44∼7.16(m, 7H), 6.94(d, J = 74.1 Hz, 1H), 6.80∼6.78(m, 1H), 4.39(s, 2H), 4.31(d, J = 5.7 Hz, 2H), 2.24(d, J = 29.7 Hz, 3H) 456
183 1H NMR(300 MHz, DMSO-d6) δ 14.61(s, 1H), 10.25(s, 1H), 9.40(s, 1H), 8.48(d, J = 8.1 Hz, 1H), 7.68-7.62(m, 2H), 7.53-7.26(m, 7H), 7.12(s, 1H), 4.40(s, 2H), 3.21(s, 2H), 3.17(s, 3H) 502
184 1H NMR(300 MHz, DMSO-d6) δ 9.35(s, 1H), 9.13(s, 1H), 9.07(s, 1H), 8.42(d, J = 7.8 Hz, 1H), 8.23(s, 1H), 7.93(s, 1H), 7.64-7.59(m, 2H), 7.48(t, J = 8.4 Hz, 1H), 7.22(d, J = 8.4 Hz, 1H), 6.97(s, 1H), 4.40(s, 2H), 2.24(s, 3H) 433
185 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 27.3 Hz, 1H), 9.69(s, 1H), 9.36(s, 1H), 9.20(s, 1H), 8.42(d, J = 8.4 Hz, 1H), 7.64∼7.47(m, 3H), 7.25(dd, J = 8.4 Hz, 1.8 Hz, 1H), 6.95(d, J = 75.6 Hz, 1H), 6.51(s, 1H), 4.40(s, 2H), 2.24(d, J = 29.7 Hz, 3H), 1.28(s. 9H) 489
186 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 9.73(brs, 1H), 9.40(s, 1H), 9.25(s, 1H), 8.48(d, J = 8.1 Hz, 1H), 7.65∼7.47(m, 3H), 7.38(s, 1H), 7.27∼7.25(m, 1H), 7.12(s, 1H), 6.51(s, 1H), 4.42(s, 2H), 1.28(s, 9H) 475
187 1H NMR(300 MHz, DMSO-d6) δ 9.37(s, 1H), 9.03(s, 1H), 8.81(s, 1H), 8.42(d, J = 8.4 Hz, 1H), 7.59(m, 2H), 7.48(t, 1H), 7.23-7.16(m, 3H), 6.94(d, J = 7.8 Hz, 1H), 6.49(d, J= 6.8Hz, 1H), 4.41(s, 2H), 3.72(s, 3H), 2.25(s, 3H) 472
188 1H NMR(300 MHz, DMSO-d6) δ 9.37(s, 1H), 9.06(s, 1H), 8.76(s, 1H), 8.41(d, J = 8.2 Hz, 1H), 7.62(t, 1H), 7.43(t, 1H), 7.33-7.06(m, 6H), 6.82(d, J = 8.2 Hz, 1H), 4.41(s, 2H), 2.57(m, 2H), 2.20(s, 3H), 1.17(t, 3H) 470
189 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 9.63(s, 1H), 9.41(s, 1H), 9.21(s, 1H), 8.94(d, J = 2.4 Hz, 1H), 8.48(d, J = 8.1 Hz, 1H), 7.68∼7.63(m, 2H), 7.50(t, J = 8.1 Hz, 1H), 7.38∼7.35(m, 2H), 7.25∼7.22(m, 2H), 7.12(s, 1H), 4.42(s, 3H) 435
190 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.9 Hz, 1H), 9.64(s, 1H), 9.36(s, 1H), 9.21(s, 1H), 8.94(d, J = 2.4 Hz, 1H), 8.42(dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.67∼7.59(m, 2H), 7.49(t, J = 8.7 Hz, 1H), 7.35(d, J = 2.1 Hz, 1H), 7.23(dd, J = 8.7 Hz, 2.1 Hz, 1H), 6.95(d, J = 74.7 Hz, 1H), 4.40(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 449
191 1H NMR(300 MHz, DMSO-d6) δ 14.4(d, J = 32 Hz, 1H), 9.36(s, 1H), 9.31(s, 1H), 9.10(s, 1H), 8.62(d, J = 2.4 Hz, 1 H), 8.42(d, J = 8.1 Hz, 1H), 8.20(dd, J = 4.5 Hz, 1.2 Hz, 1H), 7.96-7.92(m, 1H), 7.65-7.59(m, 2H), 7.49(t, J = 8.7 Hz, 1H), 7.34-7.26(m, 2H), 6.95(d, J = 75.9 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 443
192 1H NMR(300 MHz, DMSO-d6) δ 14.0(s,1H), 9.41(s, 1H), 9.32(s, 1H), 9.11(s, 1H), 8.62(d, J = 2.4 Hz, 1 H), 8.48(d, J = 8.1 Hz, 1H), 8.20(d, J = 4.8 Hz, 1H), 7.94(d, J = 8.4 Hz, 1H), 7.65(s, 1H), 7.62(d, J = 6.9 Hz, 1H), 7.49(t, J = 8.4 Hz, 1H), 7.38(s, 1H), 7.34-7.27(m, 2H), 7.12(s, 1H), 4.40(s, 2H) 429
193 1H NMR(300 MHz, DMSO-d6) δ 9.36(s, 1H), 9.19(s, 1H), 9.08(s, 1H), 8.42(d, J = 7.8 Hz, 1H), 7.70(s, 1H), 7.63(d, J = 6.6 Hz, 1H), 7.59(s, 1H), 7.48(t, J = 8.4 Hz, 1H), 7.31-7.24(m, 3H), 7.05-7.01(m, 1H), 6.95(d, J = 75.6 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 476
194 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 30 Hz, 1H), 10.90(s, 1H), 9.61(s, 1H), 9.37(s, 1H), 8.43(d, J = 8.4 Hz, 1H), 8.29(d, J = 5.4 Hz, 1H), 7.79-7.69(m, 2H), 7.62(d, J = 8.1 Hz, 1H), 7.54-7.49(m, 2H), 7.34(d, J = 8.4 Hz, 1H), 7.05-7.01(m, 1H), 6.95(d, J = 75 Hz, 1H), 4.41(s, 2H), 2.25(d, J = 29.7 Hz, 3H) 443
195 1H NMR(300 MHz, DMSO-d6) δ 14.41(s,1H), 10.88(s, 1H), 9.59(s, 1H), 9.42(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 8.30(d, J = 4.2 Hz, 1H), 7.79-7.64(m, 3H), 7.55-7.48(m, 2H), 7.38(s, 1H), 7.34(d, J = 8.4 Hz, 1H), 7.12(s, 1H), 7.03(t, J = 6.0 Hz, 1H), 4.43(s, 2H) 429
196 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 30 Hz, 1H), 9.37(s, 1H), 9.32(s, 2H), 8.43(d, J = 8.4 Hz, 1H), 8.36(d, J = 6.0 Hz, 2H), 7.65-7.60(m, 2H), 7.50(t, J = 8.4 Hz, 1H), 7.46-7.42(m, 2H), 7.28(dd, J = 8.4 Hz, , 1.8 Hz, 1H), 6.95(d, J = 75 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 30 Hz, 3H) 443
197 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.2 Hz, 1H), 9.34(s, 1H), 8.72(s, 1H), 8.40(dd, J = 8.7 Hz, 1.8 Hz, 1H), 7.61∼7.56(m, 2H), 7.41(t, J = 8.7 Hz, 1H), 7.19∼7.16(m, 1H), 6.94(d, J = 75 Hz, 1H), 6.57(s, 1H), 4.38(s, 2H), 2.57∼2.52(m, 1H), 2.24(d, J = 29.7 Hz, 3H), 0.67∼0.60(m, 2H), 0.43∼0.38(m, 2H) 406
198 1H NMR(300 MHz, DMSO-d6) δ 14.63(s, 1H), 9.38(s, 1H), 8.71(s, 1H), 8.46(d, J = 8.1 Hz, 1H), 7.63∼7.56(m, 2H), 7.44∼7.37(m, 2H), 7.20∼7.11(m, 2H), 6.59(s, 1H), 4.40(s, 2H), 2.55∼2.49(m, 1H), 0.66∼0.62(m, 2H), 0.43∼0.40(m, 2H) 392
199 1H NMR(300 MHz, DMSO-d6) δ 14.61(s, 1H), 9.41-9.34(m, 3H), 8.49(d, J = 8.4 Hz, 1H), 8.36(d, J = 5.7 Hz, 2H), 7.65-7.60(m, 2H), 7.51(t, J = 8.4 Hz, 1H), 7.46 -7.42(m, 2H), 7.38(s, 1H), 7.29(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.12(s, 1H), 4.41(s, 2H) 429
200 1H NMR(300 MHz, DMSO-d6) δ 14.39(d, J = 30 Hz, 1H), 9.35(s, 1H), 9.31(s, 1H), 9.20(s, 1H), 8.42(d, J = 8.4 Hz, 1H), 7.63-7.58(m, 2H), 7.47(t, J = 8.4 Hz, 1H), 7.30-7.25(m, 2H), 6.95(d, J = 75 Hz, 1H), 6.41(t, J = 3.0 Hz, 1H), 6.04(d, J = 3.0 Hz, 1H), 4.40(s, 2H), 2.24(d, J = 30 Hz, 1H) 432
201 1H NMR(300 MHz, DMSO-d6) δ 14.60(s, 1H), 9.40(s, 1H), 9.21(s, 1H), 9.10(s, 1H), 8.48(d, J = 8.1 Hz, 1H), 7.65-7.58(m, 2H), 7.48(t, J = 8.7 Hz, 1H), 7.37(s, 1H), 7.31(s, 1H), 7.26(d, J = 8.4 Hz, 1H), 7.12(s, 1H), 6.42(t, J = 3.3 Hz, 1H), 6.05(d, J = 3.3 Hz, 1H), 4.42(s, 2H) 418
202 1H NMR(300 MHz, DMSO-d6) δ 14.61(s, 1H), 11.86(s, 1H), 9.89(s, 1H), 9.40(s, 1H), 8.48(d, J = 8.4 Hz, 1H), 8.33(s, 1H), 7.67-7.62(m, 2H), 7.48-7.37(m, 3H), 7.22(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.12(s, 1H), 4.41(s, 2H), 2.10(s, 3H) 432
203 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.9 Hz, 1H), 11.83(s, 1H), 9.35(s, 1H), 8.78(s, 1H), 8.41(dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.66∼7.58(m, 3H), 7.48∼7.42(m, 2H), 7.18(dd, J = 8.4 Hz, 1.8 Hz, 1H), 6.94(d, J = 75 Hz, 1H), 6.92(s, 1H), 4.40(s, 2H), 2.24(d, J = 29.4 Hz, 3H) 432
204 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 11.85(brs, 1H), 9.40(s, 1H), 8.83(s, 1H), 8.48(d, J = 8.4 Hz, 1H), 7.76∼7.62(m, 3H), 7.49∼7.37(m, 3H), 7.20∼7.12(m, 2H), 6.92(s, 1H), 4.41(s, 2H) 418
205 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.2 Hz, 1H), 11.80(s, 1H), 9.35(s, 1H), 8.75(s, 1H), 8.41(d, J = 8.4 Hz, 1H), 7.73∼7.69(m, 1H), 7.60(d, J = 7.5 Hz, 1H), 7.46(t, J = 8.4 Hz, 1H), 7.29(dd, J = 6.6 Hz, 1.2 Hz, 1H), 6.93(d, J = 75.6 Hz, 1H), 6.80(s, 1H), 6.70(s, 2H), 4.40(s, 2H), 2.24(d, J = 30 Hz, 3H) 432
206 1H NMR(300 MHz, DMSO-d6) δ 9.34(s, 1H), 8.61(s, 1H), 8.41(d, J = 8.2 Hz, 1H), 7.60∼7.32(m, 3H), 7.01(m, 2H), 6.11(s, 1H), 4.38(s, 2H), 2.19(s, 3H), 1.29(s, 9H) 422
207 1H NMR(300 MHz, DMSO-d6) δ 9.37(s, 1H), 9.34(s, 1H), 9.24(s, 1H), 8.41(d, J = 8.2 Hz, 1H), 7.77∼7.22(m, 9H), 4.40(s, 2H), 2.20(s, 3H) 467
208 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 28.2 Hz, 1H), 9.36(s, 1H), 9.31(brs, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.97(s, 1H), 7.71∼7.59(m, 4H), 7.52∼7.42(m, 3H), 7.29∼7.26(m, 1H), 6.95(d, J = 74.7 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 467
209 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 26.7 Hz, 1H), 9.35(s, 1H), 9.00(s, 1H), 8.66(s, 1H), 8.41(d, J = 8.1 Hz, 1H), 7.64∼7.59(m, 2H), 7.46(t, J = 8.4 Hz, 1H), 7.22(d, J = 8.4 Hz, 1H), 7.09∼6.82(m, 3H), 6.72(d, J = 7.5 Hz, 1H), 6.37(d, J = 7.5 Hz, 1H), 4.40(s, 2H), 2.86(s, 6H), 2.24(d, J = 29.1Hz, 3H) 485
210 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 9.40(s, 1H), 9.24(s, 1H), 8.88(s, 1H), 8.48(d, J = 8.4 Hz, 1H), 7.65∼7.61(m, 2H), 7.46(t, J = 8.7 Hz, 1H), 7.37∼7.35(m, 1H), 7.24(dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.12∼7.03(m, 2H), 6.93∼6.92(m, 1H), 6.75∼6.72(m, 1H), 6.38∼6.35(m, 1H), 4.42(s, 2H), 2.87(s, 6H) 471
211 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 30 Hz, 1H), 11.86(s, 1H), 9.91(s, 1H), 9.35(s, 1H), 8.41(d, J = 8.1 Hz, 1H), 8.36(s, 1H), 7.67-7.58(m, 2H), 7.44(t, J = 9.0 Hz, 1H), 7.40(s, 1H), 7.22(d, J = 9.3 Hz, 1H), 6.94(d, J = 74.7 Hz, 1H), 4.40(s, 2H), 2.24(d, J = 29.7 Hz, 3H), 2.10(s, 3H) 446
212 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 29.1 Hz, 1H), 9.36(s, 1H), 8.97(s, 1H), 8.48(s, 1H), 8.42(d, J = 7.8 Hz, 1H), 7.64-7.58(m, 2H), 7.45(t, J = 8.7 Hz, 1H), 7.26(d, J = 9.0 Hz, 2H), 7.21(dd, J = 9.0 Hz, 2.1 Hz, 1H), 6.94(d, J = 75Hz, 1H), 6.69(d, J = 9.0 Hz, 2H), 4.40(s, 2H), 2.82(s, 6H), 2.24(d, J = 30 Hz, 3H) 485
213 1H NMR(300 MHz, DMSO-d6) δ 14.60(s, 1H), 9.40(s, 1H), 9.01(s, 1H), 8.53(s, 1H), 8.48(d, J = 8.4 Hz, 1H), 7.65-7.59(m, 2H), 7.45(t, J = 8.4 Hz, 1H), 7.37(s, 1H), 7.26(d, J = 9.0 Hz, 2H), 7.22(d, J = 8.4 Hz, 2.1 Hz, 1H), 7.12(s, 1H), 6.69(d, J = 9.0 Hz, 2H), 4.42(s, 2H), 2.82(s, 6H) 471
214 1H NMR(300 MHz, DMSO-d6) δ 14.38(d, J = 29.4 Hz, 1H), 9.33(s, 1H), 8.69(s, 1H), 8.41(d, J = 7.8 Hz, 1H), 7.59-7.54(m, 2H), 7.40(t, J = 9.0 Hz, 1H), 7.12(d, J = 8.4 Hz, 1H), 6.94(d, J = 74.7 Hz, 1H), 6.28(d, J = 7.5 Hz, 1H), 4.38(s, 2H), 3.57-3.43(m, 1H), 2.90-2.86(m, 2H), 2.57-2.41(m, 2H), 2.24(d, J = 29.7 Hz, 3H), 1.76-1.72(m, 2H), 1.27-1.15(m, 2H) 449
215 1H NMR(300 MHz, DMSO-d6) δ 9.67(s, 1H), 9.20(s, 1H), 9.10(s, 1H), 8.33(d, J = 8.4 Hz, 1H), 7.84-7.06(m, 12H), 4.50(s, 2H), 2.34(s, 6H) 486
216 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 29.4 Hz, 1H), 9.36(s, 1H), 9.04(s, 1H), 8.67(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.63-7.59(m, 2H), 7.49-7.30(m, 8H), 7.22(d, J = 8.7 Hz, 1H), 6.95(d, J = 9.0 Hz, 2H), 6.94(d, J = 75Hz, 1H), 5.05(s, 2H), 4.40(s, 2H), 2.24(d, J = 30 Hz, 3H) 548
217 1H NMR(300 MHz, DMSO-d6) δ 14.61(s, 1H), 9.40(s, 1H), 8.72(s, 1H), 8.47(d, J = 8.1 Hz, 1H), 7.62-7.55(m, 2H), 7.44-7.36(m, 2H), 7.14-7.11(m, 2H), 6.31(d, J = 8.1 Hz, 1H), 4.40(s, 2H), 3.58 -3.45(m, 2H), 2.93-2.88(m, 2H), 2.55-2.45(m, 2H), 1.79-1.70(m, 2H), 1.31-1.19(m, 2H) 435
218 1H NMR(300 MHz, DMSO-d6) δ 14.39(d, J = 29.7 Hz, 1H), 9.36(s, 1H), 9.08(s, 1H), 8.94(s, 1H), 8.48(s, 1H), 8.41(d, J = 8.1 Hz, 1H), 7.63-7.58(m, 2H), 7.45(t, J = 9.0 Hz, 1H), 7.23-7.20(m, 3H), 6.94(d, J = 75 Hz, 1H), 6.68(d, J = 8.7 Hz, 2 H), 4.40(s, 2H), 2.24(d, J = 30 Hz, 3H) 458
219 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 30 Hz, 1H), 9.69(s, 1H), 9.37(s, 1H), 8.42(d, J = 8.7 Hz, 1H), 8.32(s, 1H), 8.12(dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.67-7.58(m, 2H), 7.48(t, J = 8.7 Hz, 1H), 7.19(dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.07-6.82(m, 4H), 4.41(s, 2H), 3.88(s, 3H), 2.24(d, J = 30 Hz, 3H) 472
220 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 30 Hz, 1H), 9.36(s, 1H), 9.29(s, 1H), 9.20(s, 1H), 8.42(d, J = 8.4 Hz, 1H), 7.63-7.58(m, 2H), 7.47(t, J = 8.4 Hz, 1H), 7.30-7.25(m, 2H), 6.95(d, J = 75 Hz, 1H), 6.04(d, J = 3.0 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 30 Hz, 1H), 1.95(s, 3H) 446
221 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.2 Hz, 1H), 9.37(s, 1H), 9.18(s, 1H), 9.02(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.91(s, 2H), 7.66∼7.25(m, 6H), 6.95(d, J = 75 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 486
222 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 30 Hz, 1H), 9.35(s, 1H) 8.86(s, 1H), 8.31(d, J = 8.4 Hz, 1H), 7.61-7.56(m, 2H), 7.40(t, J = 8.7 Hz, 1H), 7.14(dd, J = 8.7 Hz, 2.1 Hz, 1H), 6.94(d, J = 75 Hz, 1H), 6.29(t, J = 5.4 Hz, 1H), 4.39(s, 2H), 3.15 -3.06(m, 2H), 2.24(d, J = 29.7 Hz, 3H), 1.05(t, J = 7.2 Hz, 3H) 394
223 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 9.40(s, 1H), 9.18(s, 1H), 8.47(d, J = 8.1 Hz, 1H), 7.63-7.56(m, 2H), 7.44-7.35(m, 2H), 7.16-7.11(m, 2H), 6.31(t, J = 5.1 Hz, 1H), 4.40(s, 2H), 3.22-3.15(m, 2H), 2.58-2.42(m, 2H), 2.34(t, J = 6.0 Hz, 4H), 1.55-1.32(m, 6H) 463
224 1H NMR(300 MHz, DMSO-d6) δ 14.61(s, 1H), 9.40(s, 1H), 9.07(s, 1H), 8.47(d, J = 8.1 Hz, 1H), 7.63-7.56(m, 2H), 7.43-7.36(m, 2H), 7.14-7.11(m, 2H), 6.29(t, J = 5.1 Hz, 1H), 4.40(s, 2H), 3.22-3.15(m, 2H), 2.58-2.41(m, 6H), 1.69(s, 4H) 449
225 1H NMR(300 MHz, DMSO-d6) δ 9.18(s, 1H), 8.28(d, J = 7.8 Hz, 1H), 7.85∼7.62(m, 5H), 7.58-7.38(m, 4H), 7.26-7.08(m, 3H), 4.64(s, 2H), 2.32(s, 3H), 2.28(s, 3H) 520
226 1H NMR(300 MHz, DMSO-d6) δ 9.43(s, 1H), 9.01(s, 1H), 8.45(d, J = 7.5 Hz, 1H), 7.64-7.04(m, 5H), 6.85(s, 1H), 6.61(s, 1H), 6.39(t, 1H), 4.41(s, 2H), 2.48-2.40(m, 4H), 2.15(s, 2H) 425
227 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.9 Hz, 1H), 9.59(brs, 1H), 9.36(s, 1H), 9.28(s, 1H), 8.42(d, J = 1H), 7.61∼7.47(m, 3H), 7.27(dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.95(d, J = 73.8Hz, 1H), 4.40(s, 2H), 2.29(s, 3H), 2.24(d, J = 29.7 Hz, 3H) 542
228 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.2 Hz, 1H), 9.36(s, 1H), 9.03(s, 1H), 8.59(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.65∼7.58(m, 2H), 7.46(t, J = 8.4 Hz, 1H), 7.22∼7.19(m, 1H), 7.07∼6.77(m, 3H), 6.57∼6.54(m, 1H), 6.19(d, J = 7.5 Hz, 1H), 5.02(s, 2H), 4.40(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 457
229 1H NMR(300 MHz, DMSO-d6) δ 14.38(d, J = 30 Hz, 1H), 9.36(s, 1H), 9.19(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.88(s, 1H), 7.65-7.58(m, 2H), 7.46(t, J = 8.7 Hz, 1H), 7.32(d, J = 8.1 Hz, 1H), 7.22(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.07(s, 1H), 6.88-6.82(m, 1H), 6.74(d, J = 7.8 Hz, 1H), 6.57(t, J = 7.5 Hz, 1H), 4.8(s, 2H), 4.40(s, 2H), 2.24(d, J = 30 Hz, 3H) 457
230 1H NMR(300 MHz, DMSO-d6) δ 10.99(s, 1H), 9.42(s, 1H), 9.28(s, 1H), 8.42(d, J = 7.8 Hz, 1H), 7.84(d, J = 7.5Hz, 2H), 7.86∼7.24(m, 7H), 6.85(s, 1H), 4.42(s, 2H), 2.24(s, 3H) 525
231 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 27.6 Hz, 1H), 10.37(s, 1H), 9.74(s, 1H), 9.37(s, 1H), 8.43(dd, J = 8.1 Hz, 1.8 Hz, 1H), 8.28(d, J = 5.4 Hz, 1H), 7.74∼7.49(m, 4H), 7.32(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.16(dd, J = 5.4 Hz, 1.8 Hz, 1H), 6.95(d, J = 75 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 30.6 Hz, 3H) 477
232 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.2 Hz, 1H), 11.21(s, 1H), 9.64(s, 1H), 9.37(s, 1H), 8.43(dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.74∼7.49(m, 4H), 7.31∼7.21(m, 2H), 6.95(d, J = 74.4 Hz, 1H), 6.89(d, J = 7.5 Hz, 1H), 4.41(s, 2H), 2.47(s, 3H), 2.25(d, J = 30 Hz, 3H) 457
233 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.9 Hz, 1H), 11.10(s, 1H), 9.63(s, 1H), 9.37(s, 1H), 8.42(d, J = 8.4 Hz, 1H), 8.17(d, J = 5.1 Hz, 1H), 7.75∼7.71(m, 1H), 7.61(d, J = 8.4 Hz, 1H), 7.51(t, J = 8.4 Hz, 1H), 7.35∼7.32(m, 2H), 6.95(d, J = 74.7 Hz, 1H), 6.91(d, J = 5.4 Hz, 1H), 4.41(s, 2H), 2.59(q, J = 7.5 Hz, 2H), 2.24(d, J = 29.7 Hz, 3H), 1.17(t, J = 7.5 Hz, 3H) 471
234 1H NMR(300 MHz, DMSO-d6) δ 14.38(d, J = 29.7 Hz, 1H), 9.79(s, 2H), 9.37(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.81-7.77(m, 2H), 7.66-7.59(m, 2H), 7.52(t, J = 9.0 Hz, 1H), 7.26(d, J = 8.4 Hz, 1H), 7.12(dd, J = 6.6 Hz, 1.8 Hz, 1H), 6.95(d, J = 74.7 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 30 Hz, 3H) 477
235 1H NMR(300 MHz, DMSO-d6) δ 9.37(s, 1H), 9.28(s, 1H), 9.08(s, 1H), 8.42(d, J = 8.7 Hz, 1H), 7.62-7.58(m, 2H), 7.48(t, J = 8.7 Hz, 1H), 7.26(dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.95(d, J = 75.3 Hz, 1H), 4.40(s, 2H), 2.24(d, J = 29.7 Hz, 3H), 2.22(s, 6H) 477
236 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 9.77(s, 2H), 9.42(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 7.84-7.76(m, 2H), 7.68-7.64(m, 2H), 7.53(t, J = 8.7 Hz, 1H), 7.38(s, 1H), 7.31(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.13-7.10(m, 2H), 4.42(s, 2H) 463
237 1H NMR(300 MHz, DMSO-d6) δ 14.42(d, J = 27.6 Hz, 1H), 12.28(s, 1H), 10.25(s, 1H), 9.38(s, 1H), 8.44(d, J = 8.1 Hz, 1H), 8.31(d, J = 9.0 Hz, 1 H), 8.00(d, J = 8.1 Hz, 1H), 7.89-7.83(m, 2H), 7.72(t, J = 6.9 Hz, 1H), 7.66-7.39(m, 5H), 6.96(d, J = 74.7 Hz, 1H), 4.43(s, 1H), 2.25(d, J = 29.4 Hz, 3H) 493
238 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 11.20(s, 1H), 9.62(s, 1H), 9.42(s, 1H), 8.49(d, J = 8.4 Hz, 1H), 7.74∼7.61(m, 3H), 7.52(t, J = 8.4 Hz, 1H), 7.38(s, 1H), 7.29(d, J = 8.4 Hz, 1H), 7.22(d, J = 8.4 Hz, 1H), 7.12(s, 1H), 6.90∼6.87(m, 1H), 4.42(s, 2H), 2.46(s, 3H) 443
239 1H NMR(300 MHz, DMSO-d6) δ 14.64(s, 1H), 10.33(s, 1H), 9.70(s, 1H), 9.41(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 8.27(d, J = 5.4 Hz, 1H), 7.73∼7.63(m, 3H), 7.52(t, J = 8.1 Hz, 1H), 7.38∼7.31(m, 2H), 7.17∼7.12(m, 2H), 4.42(s, 2H) 463
240 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.2 Hz, 1H), 9.35(s, 1H), 9.08(s, 1H), 8.41(d, J = 8.4 Hz, 1H), 8.32(s, 1H), 7.62∼7.57(m, 2H), 7.45(t, J = 8.4 Hz, 1H), 7.25(dd, J = 8.7 Hz, 1.8 Hz, 1H), 6.94(d, J = 75 Hz, 1H), 4.39(s, 2H), 2.94(s, 6H), 2.24(d, J = 29.7 Hz, 3H), 2.03(s, 3H) 506
241 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 11.05(s, 1H), 9.56(s, 1H), 9.42(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 8.18(d, J = 5.4 Hz, 1H), 7.73(d, J = 12.6 Hz, 1H), 7.65(d, J = 8.4 Hz, 1H), 7.52(t, J = 8.4 Hz, 1H), 7.38-7.33(m, 3H), 7.12(s, 1H), 6.91(d, J = 5.1 Hz, 1H), 4.43(s, 2H), 2.59(q, 7.5 Hz, 2H), 1.17(t, J = 7.5 Hz, 3H) 457
242 1H NMR(300 MHz, DMSO-d6) δ 14.39(d, J = 30 Hz, 1H), 11.02(s, 1H), 9.52(s, 1H), 9.36(s, 1H), 8.43(d, J = 8.1 Hz, 1H), 8.16(d, J = 5.7 Hz, 1H), 7.72(d, J = 13.2 Hz, 1H), 7.62(d, J = 8.1 Hz, 1H), 7.51(t, J = 8.7 Hz, 1H), 7.35-7.28(m, 2H), 6.95(d, J = 75.6 Hz, 1H), 6.88(d, J = 5.4 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 28.2 Hz, 6H) 457
243 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 11.04(s, 1H), 9.54(s, 1H), 9.42(s, 1H), 8.49(d, J = 8.1 Hz, 1H), 8.16(d, J = 5.1 Hz, 1H), 7.73(dd, J = 12.9 Hz, 2.1 Hz, 1H), 7.65(d, J = 8.1 Hz, 1H), 7.52(t, J = 8.4 Hz, 1H), 7.38-7.29(m, 3H), 7.12(s, 1H), 6.88(d, J = 4.2 Hz, 1H), 4.43(s, 2H), 2.29(s, 3H) 443
244 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 27.9 Hz, 1H), 11.07(s, 1H), 9.53(s, 1H), 9.37(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 8.11(d, J = 6.0 Hz, 1H), 7.73∼7.48(m, 3H), 7.34∼7.30(m, 1H), 7.03(d, J = 1.8 Hz, 1H), 6.95(d, J = 75.3 Hz, 1H), 6.65(dd, J = 6.0 Hz, 1.8 Hz, 1H), 4.41(s, 2H), 3.80(s, 3H), 2.24(d, J = 30 Hz, 3H) 473
245 1H NMR(300 MHz, DMSO-d6) δ 14.38(brs, 1H), 10.93(brs, 1H), 10.85(s, 1H), 9.47(s, 1H), 9.38(s, 1H), 8.43(d, J = 8.1 Hz, 1H), 7.81∼7.51(m, 4H), 7.17(d, J = 7.8 Hz, 1H), 7.07(d, J = 8.1 Hz, 1H), 6.75∼6.73(m, 1H), 6.24(d, J = 7.8 Hz, 1H), 4.42(s, 2H), 2.24(brs, 3H) 459
246 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 26.7 Hz, 1H), 10.07(s, 1H), 9.37(s, 1H), 9.32(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.70∼7.51(m, 4H), 7.26∼7.20(m, 2H), 6.95(d, J = 75 Hz, 1H), 6.44(d, J = 7.8 Hz, 1H), 4.41(s, 2H), 3.88(s, 3H), 2.24(d, J = 29.7 Hz, 3H) 473
247 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 29.7 Hz, 1H), 9.67(s, 1H), 9.37(s, 1H), 8.43(d, J = 7.8 Hz, 1H), 7.74-7.60(m, 3H), 7.53(t, J = 8.7 Hz, 1H), 7.27(d, J = 8.4 Hz, 1H), 7.21(d, J = 8.4 Hz, 1H), 6.95(d, J = 75.9 Hz, 1H), 6.90(d, J = 6.9 Hz, 1H), 4.42(s, 2H), 2.75(q, J = 7.5 Hz, 2H), 2.25(d, J = 29.4 Hz, 3H), 1.26(t, J = 7.5 Hz, 3H) 471
248 1H NMR(300 MHz, DMSO-d6) δ 14.62(s, 1H), 11.28(s, 1H), 9.67(s, 1H), 9.42(s, 1H), 8.49(d, J = 8.4 Hz, 1H), 7.74-7.64(m, 3H), 7.53(t, J = 8.4 Hz, 1H), 7.38(s, 1H), 7.29-7.20(m, 2H), 7.12(s, 1H), 6.90(d, J = 7.8 Hz 1H), 4.43(s, 2H), 2.75(q, J = 7.8 Hz, 2H), 1.26(t, J = 7.8 Hz, 3H) 457
249 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 29.7 Hz, 1H), 11.07(s, 1H), 9.65(s, 1H), 9.39(s, 1H), 8.74(d, J = 8.4 Hz, 2 H), 8.29(d, J = 5.4 Hz, 1H), 7.80-7.72(m, 2H), 7.64(d, J = 8.1 Hz, 1H), 7.54-7.49(m, 1H), 7.32(d, J = 8.4 Hz, 1H), 6.95(d, J = 75 Hz, 1H), 4.41(s, 2H), 2.24(d, J =29.7 Hz, 3H) 444
250 1H NMR(300 MHz, DMSO-d6) δ 14.38(s, 1H), 10.48(s, 1H), 9.28(s, 1H), 8.42(d, J = 7.8 Hz, 1 H), 7.90(m, 3H), 7.74-7.45(m, 5H), 7.04-6.82(m, 1H), 4.43(s, 2H), 2.20(d, J =25 Hz, 3H), 1.32(s, 9H) 483
251 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 28.2 Hz, 1H), 9.54(s, 2H), 9.37(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.94∼7.88(m, 1H), 7.77∼7.74(m, 1H), 7.66∼7.48(m, 3H), 7.24(d, J = 8.4 Hz, 1H), 6.95(d, J = 75.6 Hz, 1H), 6.74(d, J = 1.8 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 461
252 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 29.4 Hz, 1H), 10.09(s, 2H), 9.38(s, 1H), 8.44(d, J = 8.1 Hz, 1H), 7.74(d, J = 12.3 Hz, 1H), 7.61(d, J = 8.4 Hz, 1H), 7.54-7.46(m, 3H), 7.41-7.30(m, 3H), 7.13(t, J = 6.9 Hz, 1H), 6.95(d, J = 75.3 Hz, 1H), 4.42(s, 2H), 2.24(d, J = 30 Hz, 3H) 458
253 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 30 Hz, 1H), 14.25(s, 1H), 11.05(s, 1H), 9.39(s, 1H), 8.44(d, J = 8.1 Hz, 1H), 8.35(s, 1H), 8.13(d, J = 13.2 Hz, 1H), 7.85(t, J = 6.9 Hz, 1H), 7.66-7.59(m, 3H), 7.27(d, J = 8.1 Hz, 1H), 7.13(s, 1H), 6.96(d, J = 75 Hz, 1H), 4.42(s, 2H), 2.25(d, J = 29.4 Hz, 3H) 459
254 1H NMR(300 MHz, DMSO-d6) δ 9.12(s, 1H), 8.82(s, 1H), 8.79(s, 1H), 8.19(d, J = 8.1 Hz, 1H), 7.96(d, J = 3.3 Hz, 1H), 7.89(d, J = 3.3 Hz, 1H), 7.68-7.63(m, 2H), 7.49(t, J = 8.4 Hz, 1H), 7.33(s, 1H), 7.27(s, 1H), 7.24(s, 1H), 7.18(t, J = 8.1 Hz, 1H), 6.84(d, J = 7.2 Hz, 1H), 4.34(s, 2H), 2.57(q, J = 7.5 Hz, 2H), 1.17(t, J = 7.5 Hz, 3H) 473
255 1H NMR(300 MHz, DMSO-d6) δ 10.89(s, 1H), 9.59(s, 1H), 8.79(s, 1H), 8.30(d, J = 5.1 Hz, 1H), 8.20(d, J = 8.1 Hz, 1H), 7.96(d, J = 3.3 Hz, 1H), 7.89(d, J = 3.3 Hz, 1H), 7.79-7.65(m, 3H), 7.57-7.49(m, 2H), 7.37(d, J = 8.4 Hz, 1H), 7.05-7.01(m, 1H), 4.34(s, 2H) 446
256 1H NMR(300 MHz, DMSO-d6) δ 8.41(d, J = 5.1 Hz, 1H), 7.61(d, J = 7.8 Hz, 1H), 7.43(s, 1H), 7.44-6.95(m, 4H), 4.34(s, 2H), 2.37(s, 2H), 1.92(m, 1H), 1.86(m, 6H) 429
257 1H NMR(300 MHz, DMSO-d6) δ 10.51(s, 1H), 9.36(s, 1H), 8.41(d, J = 8.1 Hz, 1H), 7.68(d, J = 12.0 Hz, 1H), 7.58-6.94(m, 12H), 4.39(s, 2H), 3.67(s, 2H), 2.23(s, 3H) 441
258 1H NMR(300 MHz, DMSO-d6) δ 14.39(d, J = 27 Hz, 1H), 9.33(s, 1H), 8.66(s, 1H), 8.40(d, J = 8.1 Hz, 1H), 7.58∼7.56(m, 2H, 7.39(t, J = 8.4 Hz, 1H), 7.11(dd, J = 8.4 Hz, 1.8 Hz, 1H), 6.95(d, J = 75 Hz, 1H), 6.12(d, J = 1.8 Hz, 1H), 4.38(s, 2H). 3.81∼3.70(m, 1 H), 2.23(d, J = 27.3 Hz, 3H), 1.10(s, 6H) 408
259 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 27.9 Hz, 1H), 10.04(s, 1H), 9.37(s, 1H), 8.62(d, J = 5.4 Hz, 1H), 8.49(s, 1H), 8.43(d, J = 7.8 Hz, 1H), 7.74∼7.51(m, 5H), 7.33(d, J = 8.4 Hz, 1H), 6.95(d, J = 75.3 Hz, 1H), 4.41(s, 2H), 2.24(d, J = 30 Hz, 3H) 488
260 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 30 Hz, 1H), 11.02(s, 1H), 9.54(s, 1H), 9.35(s, 1H), 8.40(d, J = 8.1 Hz, 1H), 8.11(d, J = 6.0 Hz, 1H), 7.73∼7.48(m, 3H), 7.34∼7.30(m, 1H), 6.95(d, J = 75 Hz, 1H), 6.64(d, J = 1.8 Hz, 1H), 6.48(dd, J = 6.3 Hz, 1.8 Hz, 1H), 5.80(s, 2H), 4.41(s, 2H), 2.24(d, J = 29.7 Hz, 3H) 458
261 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.9 Hz, 1H), 10.47(s, 1H), 9.35(s, 1H), 8.41(d, J = 8.4 Hz, 1H), 7.73(d, J = 12.6 Hz, 1H), 7.59∼7.37(m, 7H), 6.95(d, J = 75.6 Hz, 1H), 4.37(s, 2H), 2.34∼2.32(m, 1H), 2.24(d, J = 29.7 Hz, 3H), 1.02(d, J = 6.3 Hz, 3H), 0.68(d, J = 6.6 Hz, 3H) 517
262 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.2 Hz, 1H), 10.45(s, 1H), 9.36(s, 1H), 8.42(d, J = 8.1 Hz, 1H), 7.74(dd, J = 12.9 Hz, 1.8 Hz, 1H), 7.60(dd, J = 9.6 Hz, 1.2 Hz, 1H), 7.51(d, J = 8.4 Hz, 1H), 7.41(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.25(d, J = 8.7 Hz, 2H), 6.95(d, J = 74.7 Hz, 1H), 6.89(d, J = 8.7 Hz, 2H), 4.39(s, 2H), 3.72(s, 3H), 3.59(s, 2H), 2.25(d, J = 30 Hz, 2H) 471
263 1H NMR(300 MHz, DMSO-d6) δ 10.81(s, 1H), 9.84(s, 1H), 8.50(m, 2H), 7.84(m, 3H), 7.52(m, 5H), 6.10(m, 1H), 6.00(m, 1H), 4.52(s, 2H), 3.93(s, 2H), 2.39(s, 3H) 442
264 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 28.5 Hz, 1H), 9.45(s, 1H), 9.36(s, 1H), 9.16(s, 1H), 8.43(d, J = 7.8 Hz, 1H), 7.67∼7.60(m, 2H), 7.49(t, J = 8.7 Hz, 1H), 7.24∼7.21(m, 2H), 6.95(d, J = 75.6 Hz, 1H), 4.41(s, 2H), 2.60(s, 3H), 2.25(d, J = 29.7 Hz, 3H) 463
265 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 28.5 Hz, 1H), 10.52(s, 1H), 9.36(s, 1H), 8.42(dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.73(d, J = 12.9 Hz, 1H), 7.60(d, J = 8.4 Hz, 1H), 7.51(d, J = 8.4 Hz, 1H), 7.42∼7.34(m, 3H), 7.18∼7.12(m, 2H), 6.95(d, J = 75.6 Hz, 1H), 4.39(s, 2H), 3.68(s, 2H), 2.25(d, J = 29.4 Hz, 3H) 459
266 1H NMR(300 MHz, DMSO-d6) δ 14.41(d, J = 28.5 Hz, 1H), 10.54(s, 1H), 9.36(s, 1H), 8.42(dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.72∼7.60(m, 2H), 7.53∼7.50(m, 1H), 7.45∼7.39(m, 3H), 7.17∼7.08(m, 2H), 6.95(d, J = 75 Hz, 1H), 4.40(s, 2H), 3.70(s, 2H), 2.25(d, J = 29.7 Hz, 3H) 509
267 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.6 Hz, 1H), 10.54(s, 1H), 9.35(s, 1H), 8.42(dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.73(dd, J = 13.2 Hz, 1.5 Hz, 1H). 7.60(dd, J = 7.8 Hz, 1.5 Hz, 1H), 7.52(t, J = 8.4 Hz, 1H), 7.41(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.17∼7.08(m, 3H), 6.94(d, J = 69.3 Hz, 1H), 4.39(s, 2H), 3.77(s, 2H), 2.25(d, J = 29.7 Hz, 3H) 477
268 1H NMR(300 MHz, DMSO-d6) δ 14.40(d, J = 27.6 Hz, 1H), 10.50(s, 1H), 9.35(s, 1H), 8.42(d, J = 9.0 Hz, 1H) 7.74(d, J = 12.6 Hz, 1H), 7.60(d, J = 7.8 Hz, 1H), 7.51(t, J = 9.0 Hz, 1H), 7.43∼7.40(m, 1H), 7.27∼6.81(m, 5H), 4.38(s, 2H), 3.72(s, 3H), 3.63(s, 2H), 3.63(s, 2H), 2.25(d, J = 30 Hz, 1H) 471
상기 합성된 268개 화합물 중 c-Met, Aurora 및 KDR(VEGFR-2)에서 활성이 상대적으로 좋은 화합물들에 대해서, 대표적으로 그들 및 그들의 합성 마지막 단계에 대한 수율을 하기 표 3 및 표 4에 나타내었다.
[규칙 제26조에 의한 보정 12.12.2011]　
표 3
Figure WO-DOC-TABLE-3
[규칙 제26조에 의한 보정 12.12.2011]　
표 4
Figure WO-DOC-TABLE-4
Figure WO-DOC-4
실시예 4. 효소 활성 억제 검정법
c-Met, Aurora 및 KDR(VEGFR-2)을 각각 곤충 세포에서 다음과 같은 방법으로 발현시킨 후, 크로마토그래피 방법으로 정제하였다
c-Met 발현 및 정제
수확한 High Five cell(Trichopulsia ni cell line)을 1% 트리톤 X-100을 함유한 버퍼 A(50 mM Tris-HCl, 100 mM NaCl, 5% glycerol, 5 mM B-mercaptoethanol, pH 8.0)에 현탁하였다. Sonicator를 이용하여 세포 현탁액을 파쇄한 후 원심분리(35,000×g, 1시간, 4℃)하여 상등액을 취하였다. 이 상등액을 membrane filter(0.45 ㎛)를 이용하여 거른 후, 버퍼 A로 평형화시킨 금속 친화성 크로마토그래피 컬럼(GE healthcare, HistrapTM HP)에 로딩하였다. 로딩이 끝나면 버퍼 A를 UV 값이 기준선(baseline)에 도달할 때 까지 흘려주었다. 500 mM 이미다졸을 함유한 버퍼 A를 이용하여 단백질을 용출시키면서 분획별로 용출액을 받았다. 이 분획에서 시료를 채취하여 SDS-PAGE를 통해 목적 단백질의 위치를 확인한 후 다음 단계를 진행할 분획을 모았다.
다음 단계는 버퍼 B(25mM Tris-HCl, 200mM NaCl, 5% glycerol, 2mM DTT, 10mM EDTA, pH 7.5)를 이용하여 겔 여과 크로마토그래피(GE healthcare, HiLoad 16/600 Superdex 200 pg)를 수행하였다. 각 분획에서 시료를 채취하여 SDS-PAGE를 통해 목적 단백질의 위치를 확인한 후 분획을 모았다.
다음 단계는 버퍼 C(25mM Tris-HCl, 5% glycerol, 2mM DTT, 1mM EDTA, pH 7.5)를 이용하여 이온 크로마토그래피(GE healthcare, Resource Q)를 수행하였다. 이때 목적 단백질은 이온 수지에 붙지 않고 용출되므로 flowthrough를 받아 모았다. 이 용액을 10 ㎎/㎖로 농축한 후 -70℃에 보관하였다.
Aurora 발현 및 정제
Aurora를 대장균 세포(E. coli)에서 발현시킨 후, 수확된 세포를 1 mM PMSF가 포함된 버퍼 A (50 mM Tris-HCl (pH 7.5), 200 mM NaCl, 10 % glycerol, 2 mM DTT)에 현탁하여 파쇄하고 18,000 rpm 에서 1시간 동안 원심분리하여 상등액을 취하였다. 분리된 상등액을 금속 친화성 크로마토그래피를 통해 1차 정제하였다. 구체적으로, 완충액 A로 평형화 시킨 금속 친화성 컬럼(GE healthcare, HistrapTM HP)에 로딩하여 목적 단백질을 결합시킨 후, 500 mM 이미다졸을 함유한 완충액 A를 이용하여 단백질을 용출시키면서 분획별로 용출액을 받았다. SDS-PAGE를 통해 목적 단백질의 위치를 확인한 후 다음 단계를 진행할 분획을 모았다.
이후, 겔 여과 크로마토그래피(GE healthcare, HiLoad 26/600 Superdex 200 pg)를 통해 최종 정제하였으며, 버퍼는 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 2 mM DTT를 이용하였다. 각 분획에서 시료를 채취하여 SDS-PAGE를 통해 목적 단백질의 위치를 확인한 후 분획을 모아 정제를 완료하였다. 정제를 마친 후 Autophosphorylation을 위해 4℃에서 4 mM ATP와 26 mM MgCl2를 첨가하여 하루 동안 반응하였다. 반응이 끝난 후, 50 mM Tris-HCl (pH7.5), 100 mM NaCl, 2 mM DTT 버퍼로 투석하였다. 이 용액을 1 ㎎/㎖로 농축한 후 -70℃에 보관하였다.
KDR 발현 및 정제
수확한 High Five cell(Trichopulsia ni cell line)을 1 mM PMSF를 함유한 버퍼 A(50 mM Tris-HCl, 100 mM NaCl, 5% glycerol, 5 mM B-mercaptoethanol, pH 8.0)에 현탁하였다. Sonicator를 이용하여 세포 현탁액을 파쇄한 후 원심분리(35,000×g, 1시간, 4℃)하여 상등액을 취하였다. 이 상등액을 membrane filter(0.45 ㎛)를 이용하여 거른 후 버퍼 A로 평형화시킨 금속 친화성 크로마토그래피 컬럼(GE healthcare, HistrapTM HP)에 로딩하였다. 로딩이 끝나면 버퍼 A를 UV 값이 기준선에 도달할 때까지 흘려주었다. 500 mM 이미다졸을 함유한 버퍼 A를 이용하여 단백질을 용출시키면서 분획별로 용출액을 받았다. 이 분획에서 시료를 채취하여 SDS-PAGE를 통해 목적 단백질의 위치를 확인한 후 다음 단계를 진행할 분획을 모았다.
다음 단계는 버퍼 B(50mM Tris-HCl, 25mM NaCl, 5% glycerol, 1mM DTT, pH 8.0)를 이용하여 겔 여과 크로마토그래피(GE healthcare, HiLoad 26/600 Superdex 200 pg)를 수행하였다. 각 분획에서 시료를 채취하여 SDS-PAGE를 통해 목적 단백질의 위치를 확인한 후 분획을 모았다. 이 분획에 최종 4 mM ATP, 26 mM MgCl2를 첨가하여 autophosphorylation 반응을 4℃에서 밤새 진행시켰다.
Phosphorylation을 시킨 시료를 버퍼 C(10 mM HEPES, 10 mM NaCl, 10 mM DTT, pH7.5) 2 ℓ를 이용하여 2∼3시간 정도 투석하였다. 이를 3회 반복하고, 6.0 ㎎/㎖로 농축한 후, -70℃에 보관하였다.
<4-1> c-Met 활성 억제 분석(ELISA method)
본 발명의 화합물의 c-Met 억제제로서의 활성을 평가하기 위하여, c-Met 단백질을 유전자 재조합에 의해 과량 발현시킨 후, 정제한 c-Met 효소를 사용하여 효소 반응을 시켰다. 구체적으로, 20 nM의 c-Met 효소와 기질로 작용하는 250 nM biotin-Axl 기질 펩티드를 반응 버퍼(15 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 5 mM MnCl2, 0.01% Tween-20, 2 mM DTT) 내에서 효소 반응을 수행하였다. 시험하고자 하는 농도의 화합물을 처리하여 30℃에서 1시간 동안 반응시켰다. 반응이 끝난 후, ELISA 방법을 이용하여 활성 여부를 측정하였다. 화합물을 처리하지 않은 시료의 흡광도값을 100% 대조군으로 하고, 시험하고자 하는 농도의 화합물을 처리한 시료에서 c-Met 효소의 잔류 활성의 %로서 c-Met 억제제의 활성을 평가하였다. 다양한 농도의 화합물 처리시 남아 있는 c-Met 효소 활성을 측정한 후, 대조군 대비 50% c-Met 효소 활성 억제가 일어나는 화합물의 농도를 c-Met 억제제의 IC50 값으로 결정하였다.
<4-2> Aurora 활성 억제 분석(kinase-glo method)
본 발명의 화합물의 Aurora A 억제제로서의 활성을 평가하기 위하여, 유전자 재조합에 의하여 과량 발현시킨 후 정제된 Aurora A를 사용하였다. 화합물은 100% DMSO에 용해하여 사용하였다. 기질인 100 μM Kemptide, 1 μM ATP, 반응 버퍼[20 mM HEPES(pH 7.4), 5 mM MgCl2, 0.5 mM EGTA, 200 mM KCl, 0.2 mM DTT, 0.25% Triton X-100]와 화합물에 7 nM Aurora A를 첨가하고, 30℃에서 1시간 동안 반응시켰다. 반응이 끝난 후, kinase-glo mix(Promega)를 첨가하고 상온에서 10분 동안 방치한 후, Fusion-FP(Packard) 기기를 사용하여 Luminescence를 측정하였다. 효소 저해능은 시험 화합물이 없는 상태에서의 측정값에 대한 시료 화합물 존재 시의 측정값을 백분율로 표시하였으며, 50%의 효소활성을 저해하는화합물의 농도를 IC50(μM) 값으로 판정하였다.
<4-3> KDR(VEGFR-2) 활성 억제 분석(kinase-glo method)
2.5 nM KDR 효소의 기질로 작용하는 250 μM E4Y 펩티드, 1 μM ATP를 반응 버퍼(50 mM Tris- HCl (pH 7.5), 15 mM MgCl2, 1 mM MnCl2, 0.01% Tween-20, 2 mM DTT) 내에서 효소 반응을 수행하였다. 시험하고자 하는 농도의 화합물을 처리하여 30℃에서 1시간 동안 반응시켰다. 효소 반응이 끝난 후, kinase glo mix를 첨가하고 실온에서 10분을 반응시킨 후, Fusion-FP(Packard) 기기를 사용하여 Luminescence를 측정하였다. 측정한 RLU 값으로 데이터를 분석하여 KDR 억제제의 활성을 검증하였다. 화합물을 처리하지 않은 시료의 RLU 값을 100% 대조군으로 하고, 시험하고자 하는 농도의 화합물을 처리한 시료에서 KDR 효소의 잔류 활성의 %로서 KDR 억제제의 활성을 평가하였다. 다양한 농도의 화합물 처리시 남아 있는 KDR 효소 활성을 측정한 후, 대조군 대비 50% KDR 효소 활성 억제가 일어나는 화합물의 농도를 KDR 억제제의 IC50 값으로 결정하였다.
<4-4> 세포기반 항-증식성 분석에 의한 검정법(MTS assay)
상기에서 제조된 화합물이 세포외 신호조절 키나제 활성 억제를 통하여 암세포 증식 억제 효과를 가지는지 여부를 확인하기 위하여 MTS 분석을 수행하였다(Barltrop, J.A. et al., (1991) 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazoly)-3-(4-sulfophenyl) tetrazolium, inner salt(MTS) and related analog of 3-(4,5-dimethylthiazolyl)-2,5,-diphenyltetrazolium bromide(MTT) reducing to purple water soluble formazans as cell-viability indicators. Bioorg. Med. Chem. Lett. 1, 611-4; Cory, A.H. et al(1991) Use of an aqueous soluble tertrazolium/formazan assay for cell growth assays in culture. Cancer Comm. 3, 207-12.).
인간의 위암 세포주인 MKN45 세포주 및 대장암 세포주인 HCT-116 세포주(ATCC, http://www.atcc.org)를 대상으로 하기와 같은 분석을 수행하였다. MKN45 및 HCT-116 세포주는 10% FBS를 포함하는 RPMI-1640 배지(GIBCO, Invitrogen)가 들어있는 96-웰 플레이트에 각각 5,000 세포/웰의 농도로 분주한 후, 5% CO2 및 37℃ 조건에서 24시간 동안 배양하였다. 그 후, 각 웰에 상기 실시예 3에서 제조한 화합물들을 각각 0.2, 1, 5, 25 및 100 μM 농도로 처리하였고, 대조군으로는 디메틸설폭사이드(DMSO)를 화합물 처리시 사용한 것과 동일한 0.08 중량%의 농도로 처리하였다. 그 후, 각 세포를 48시간 동안 배양하였다.
세포의 생존 능력을 확인하기 위하여, 상기 각 배양된 세포의 배지에 CellTiter 96® AQuous Non-Radioactive Cell Proliferation Assay Kit(Promega)에서 제공되는 MTS와 PMS(phenazine methosulfate)의 혼합물 20 ㎕를 첨가하고, 37℃ 조건에서 2시간 동안 추가로 배양하였다. 그 후, 490 ㎚에서 흡광도를 측정하였다. 화합물을 처리하지 않은 대조군 세포의 흡광도를 기준으로 각 화합물들의 처리 농도에 따른 세포 증식 저해 정도를 산출하였으며, 이때 암세포의 증식을 50% 억제하는 각 화합물의 농도를 EC50(μM) 값으로 결정하였다. 그 결과를 표 5에 나타내었다.
표 5
화합물No. Enzymatic assay IC50(uM) Cellular assay EC50(uM)
c-Met VEGFR-2 Aurora A MKN45 HCT-116
1 D D D - -
2 A A C F -
3 B A D F -
4 D B D - -
5 B B D H -
6 D D D - -
7 D C D - -
8 D D D - -
9 D C D - -
10 D A C - -
11 A B B H -
12 A A A E G
13 A A A E G
14 A A A - -
15 A A B F -
16 A A C F -
17 C A A H -
18 A A A E -
19 A B B E -
20 A A A H -
21 A A B E -
22 A A C F -
23 D A C G -
24 A - - - -
25 B A B - -
26 C A C H -
27 A A B E -
28 A A A E -
29 A A B F -
30 D A B E -
31 A A A G -
32 A A B G -
33 C A B G -
34 B A B G -
35 D A C - -
36 D A C H -
37 A A - G -
38 A A - G -
39 C A - G -
40 C A - - -
41 A A - G -
42 D A - - -
43 D D - H -
44 D A C - -
45 D B - H -
46 A A - H -
47 D D - H -
48 D - D H -
49 A - - - -
50 A B - H -
51 D A - - -
52 A A - G -
53 A A - F -
54 - C - - -
55 D B - - -
56 C A - G -
57 D B D G -
58 B A - F -
59 B A - F -
60 A A - H -
61 D B - - -
62 A A - H -
63 B A - E -
64 B A - G -
65 A A - G -
66 C A - G -
67 A A - F -
68 B A - F -
69 D C - H -
70 A A - F -
71 B A - F -
72 A A - F -
73 C B - E -
74 B A - E -
75 A A - F -
76 B A - F -
77 A C - E -
78 A A - F -
79 D C - H -
80 C A - F -
81 A A - F -
82 - A - G -
83 - A - G -
84 - B - G -
85 C A - - -
86 B A - - -
87 B A - H -
88 C A - G -
89 A A B E -
90 D A - - -
91 C C - G -
92 A A - G -
93 D D - - -
94 B A A E F
95 C C - H -
96 D D B - -
97 D C - H -
98 C C - H -
99 C C - H -
100 B C - H -
101 A C - G -
102 D D - H -
103 D C - G -
104 A A - G -
105 A C - G -
106 C C D H -
107 B D - H -
108 D - - - -
109 C D - H -
110 C A - G -
111 D A - H -
112 C D - H -
113 B C - G -
114 D A - H -
115 D B - H -
116 D A - G -
117 A B - G -
118 C D - H -
119 C B - H -
120 C B - G -
121 D B - H -
122 B B - G -
123 B A - G -
124 D D - - -
125 D A - H -
126 D C - H -
127 C D - H -
128 D A - H -
129 D B - - -
130 A A - G -
131 C B - - -
132 B A A H -
133 A B D H -
134 B A - H -
135 C B - H -
136 A B B G -
137 D A D F -
138 A A - G -
139 A A B E -
140 B A A H G
141 B A B G -
142 - A B H -
143 - D - - -
144 C B - H -
145 - D - - -
146 - B - H -
147 C C - H -
148 D A A H -
149 D C - - -
150 B A A H G
151 B A A H G
152 C A D G -
153 D C C G -
154 C C A G -
155 C A A G -
156 B B A E E
157 B B A E E
158 D D D - -
159 A C D - -
160 D D D G -
161 B D C H -
162 B A A E E
163 A A A G -
164 B A A G E
165 A A A F -
166 B A A G E
167 A A A G -
168 B A A H -
169 A A A F -
170 A C B - -
171 B B A H -
172 A A A E -
173 A B C F -
174 B D B - -
175 C C - - -
176 B A A E -
177 B A A H -
178 B A A H -
179 B A A H -
180 A A A E -
181 D C D G -
182 A A A E -
183 A A A H -
184 A A A H -
185 B A A E -
186 B A A E -
187 A A A E -
188 B A A E -
189 A A A E -
190 A A A E -
191 A A A H -
192 A A A G -
193 A A A E -
194 B A A E E
195 D A A G -
196 A A A H -
197 A A A G -
198 A A A G -
199 A B - - -
200 A A A G -
201 A A A G -
202 B A C H -
203 B A B G -
204 B A - - -
205 B A - H -
206 A B A E -
207 A A A H -
208 B A A H -
209 B A A E -
210 A A A E -
211 B A C - -
212 A A A E -
213 A A A H -
214 B C - - -
215 A A A H -
216 B B - - -
217 C C - - -
218 A A A F -
219 A A - E -
220 A A A E -
221 A A A H -
222 A A - H -
223 C A A H -
224 B B A - -
225 C D C - -
226 C D C - -
227 A A A H -
228 A A A G -
229 A A A - -
230 B B A G -
231 B D A - -
232 B A A F H
233 A A B E E
234 A A A H -
235 A A A H -
236 A B A H -
237 C D B - -
238 D A A F F
239 C A A H -
240 B A B - -
241 B A A H -
242 B A A H F
243 D A A H H
244 B A B H H
245 A A A - -
246 B A A H -
247 C A A G -
248 D C B G -
249 C C C H -
250 B D A - -
251 A A A G -
252 A A A G -
253 C B - G -
254 C B C - -
255 D D D - -
256 - - - H -
257 - - - G -
258 - - - F -
259 - - - G -
260 - - - H -
261 - - - G -
262 - - - G -
263 - - - H -
264 - - - G -
265 - - - H -
266 - - - H -
267 - - - H -
268 - - - H -
상기에서, A: < 50 nM, B: 50 nM ∼ 200 nM, C: 200 nM ∼ 1 μM, D: > 1 μM, E: < 0.5 μM, F: 0.5 μM ∼ 1 μM, G: 1 μM ∼ 5 μM 및 H: > 5 μM을 나타낸다.
상기에서 알 수 있는 바와 같이, 본 발명의 화합물은 c-Met, VEGFR-2 및 Aurora A와 같은 키나제 효소에 대해서 뿐만 아니라, 위암 및 대장암 세포주에 대해서도 뛰어난 키나제 억제 활성을 나타내므로, 이상 또는 탈조절된 키나제 활성과 관련된 질병 또는 증상, 예컨대 다양한 종류의 암의 치료, 완화 또는 예방에 유용하게 사용될 수 있음을 확인하였다.

Claims (14)

  1. 하기 화학식 1로 표시되는 화합물:
    [화학식 Ⅰ]
    Figure PCTKR2011007370-appb-I000019
    상기에서,
    R0은
    Figure PCTKR2011007370-appb-I000020
    또는
    Figure PCTKR2011007370-appb-I000021
    이고,
    R1 내지 R3은 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로 선택되며,
    R4는 수소, 히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되고,
    R10 및 R11은 각각 독립적으로 수소, 알킬, 치환된 알킬, 에틸히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되지만, Y가 N일 경우에는 R10과 R11은 도입되지 않으며, 및
    X 및 Y는 각각 독립적으로 C, N, O 및 S로 이루어진 원소로부터 선택된다.
  2. 청구항 1에 있어서,
    하기 화학식 2로 표시되는 화합물:
    [화학식 2]
    Figure PCTKR2011007370-appb-I000022
    상기에서,
    R1 내지 R3은 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로 선택되고,
    R4는 수소, 히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택된다.
  3. 청구항 2에 있어서,
    하기 화학식 3으로 표시되는 화합물:
    [화학식 3]
    Figure PCTKR2011007370-appb-I000023
    상기에서,
    R2 및 R3은 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로 선택되고,
    R4는 수소, 히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되며, 및
    R5 내지 R9는 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택된다.
  4. 청구항 3에 있어서,
    상기 R9는 하기 작용기로 이루어진 군으로부터 선택되는 화합물:
    Figure PCTKR2011007370-appb-I000024
    상기에서, R12는 수소, 히드록시, 알킬, 치환된알킬, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택된다.
  5. 청구항 1에 있어서,
    화학식 4로 표시되는 화합물:
    [화학식 4]
    Figure PCTKR2011007370-appb-I000025
    상기에서,
    R1 내지 R3은 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로 선택되고,
    R10 및 R11은 각각 독립적으로 수소, 알킬, 치환된 알킬, 에틸히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되지만, Y가 N일 경우에는 R10과 R11은 도입되지 않으며, 및
    X 및 Y는 각각 독립적으로 C, N, O 및 S로 이루어진 원소로부터 선택된다.
  6. 청구항 5에 있어서,
    화학식 5로 표시되는 화합물:
    [화학식 5]
    Figure PCTKR2011007370-appb-I000026
    상기에서,
    R2 및 R3은 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로 선택되고,
    R5 내지 R9는 각각 독립적으로 수소, 할로겐, 히드록시, 카르복시, 시아노, 니트로, 알킬, 치환된 알킬, 사이클로알킬, 치환된 사이클로알킬, 알콕시, 치환된 알콕시, 사이클로알콕시, 티오에스테르, 아마이드, 아미노, 치환된 아미노, 아미노아실, 아실, 아실옥시, 아릴, 아릴옥시, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되며,
    R10 및 R11은 각각 독립적으로 수소, 알킬, 치환된 알킬, 에틸히드록시, 아미노, 치환된 아미노, 아릴, 치환된 아릴, 우레아, 치환된 우레아, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택되지만, Y가 N일 경우에는 R10과 R11은 도입되지 않고, 및
    X 및 Y는 각각 독립적으로 C, N, O 및 S로 이루어진 원소로부터 선택된다.
  7. 청구항 6에 있어서,
    상기 R9는 하기 작용기로 이루어진 군으로부터 선택되는 화합물:
    Figure PCTKR2011007370-appb-I000027
    상기에서, R12는 수소, 히드록시, 알킬, 치환된알킬, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로환 또는 치환된 헤테로환으로 이루어진 군으로부터 선택된다.
  8. 청구항 1에 있어서,
    표 1에 개시된 화합물로 이루어진 군으로부터 선택되는 화합물.
  9. 청구항 1에 있어서,
    화학식 1의 화합물의 거울상 이성질체, 부분입체 이성질체 및 라세믹 혼합물로 이루어진 군으로부터 선택되는 화합물.
  10. 청구항 1 내지 청구항 9 중 어느 한 항에 개시된 화합물 및 약학적으로 허용가능한 그의 염, 수화물, 프로드러그 또는 용매화물을 포함하는, 이상 또는 탈조절된 키나제 활성과 관련된 질병의 치료, 완화 또는 예방용 약학적 조성물.
  11. 청구항 10에 있어서,
    상기 키나제는 Abl, Aurora, AXL, BLK, BMX, Aurora, c-KIT, c-MET, CDK, FER, FGFR, FGR, FLT, FRK, FYN, HCK, IRR, ITK, JAK, KDR, KIT, LCK, LYN, MAPK, MER, MEK, MUSK, PDGFR, PLK, RET, RON, SRC, SRM, TIE2, TNK1, TRKA, TNIK 및 VEGFR로 이루어진 군으로부터 선택되는 약학적 조성물.
  12. 청구항 10에 있어서,
    상기 질병은 암, 천식, 알러지, 아토피 피부염, 건선 및 류마티스성 관절염으로 이루어진 군으로부터 선택되는 약학적 조성물.
  13. 청구항 12에 있어서,
    상기 암은 위암, 갑상선암, 대장암, 간암, 신장암, 뇌암, 자궁암, 남소암, 비-소세포 폐암, 췌장암, 유방암, 혈액암, 방광암, 결장직장암 및 교모세포종으로 이루어진 군으로부터 선택되는 약학적 조성물.
  14. 청구항 10 내지 청구항 13 중 어느 한 항에 있어서,
    항생제, 알킬화제, 항대사제, 호르몬제, 면역학적 제제, 인터페론 제제 및 항암제로 이루어진 군으로부터 선택되는 1종 이상의 제제를 추가로 포함하는 약학적 조성물.
PCT/KR2011/007370 2010-10-05 2011-10-05 2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물 WO2012047017A2 (ko)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US38995010P 2010-10-05 2010-10-05
US61/389,950 2010-10-05

Publications (2)

Publication Number Publication Date
WO2012047017A2 true WO2012047017A2 (ko) 2012-04-12
WO2012047017A3 WO2012047017A3 (ko) 2012-05-31

Family

ID=45928221

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2011/007370 WO2012047017A2 (ko) 2010-10-05 2011-10-05 2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물

Country Status (1)

Country Link
WO (1) WO2012047017A2 (ko)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014104757A1 (ko) * 2012-12-28 2014-07-03 크리스탈지노믹스(주) Btk 키나아제 억제제로서의 2,3-디하이드로-이소인돌-1-온 유도체 및 이를 함유하는 약학적 조성물
CN105859638A (zh) * 2016-04-28 2016-08-17 西安交通大学 一种具有抗肿瘤活性的环丁二酰胺化合物及其制备方法和应用
CN105906568A (zh) * 2016-04-28 2016-08-31 西安交通大学 一种具有抗肿瘤活性的环丙二酰胺化合物及其制备方法和应用
CN105924403A (zh) * 2016-04-28 2016-09-07 西安交通大学 一种具有抗肿瘤活性的环丙二酰胺类化合物及其制备方法和应用
CN105924387A (zh) * 2016-04-28 2016-09-07 西安交通大学 一种具有抗肿瘤活性的双芳基脲化合物及其制备方法和应用
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T CRYSTALLINE FORMS
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds FORMULATIONS COMPRISING 6- (2-HYDROXY-2-METHYLPROPOXY) -4- (6- (6 - ((6-METHOXYPYRIDIN-3-YL) METHYL) -3,6-DIAZABICYCLO [3.1.1] HEPTAN-3- YL) PYRIDIN-3-YL) PYRAZOLO [1,5-A] pYRIDINE-3-carbonitrile
JP2019516673A (ja) * 2016-04-26 2019-06-20 コリア ユニバーシティ リサーチ アンド ビジネス ファウンデーションＫｏｒｅａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｂｕｓｉｎｅｓｓ Ｆｏｕｎｄａｔｉｏｎ 新規ｎ‐アシル尿素誘導体およびそれを含有する心血管疾患の予防または治療用組成物
WO2019134662A1 (zh) * 2018-01-03 2019-07-11 南京明德新药研发股份有限公司 作为csf-1r抑制剂的杂环化合物及其应用
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
CN110234645A (zh) * 2017-01-25 2019-09-13 巴斯夫欧洲公司 制备卞型酰胺的方法
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
JP2020508313A (ja) * 2017-02-21 2020-03-19 アプトース バイオサイエンシーズ， インコーポレイテッド 血液悪性腫瘍患者の治療方法
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
CN113365622A (zh) * 2018-11-30 2021-09-07 艾普托斯生物科学公司 使用2，3-二氢异吲哚-1-酮化合物的组合疗法及用于治疗具有各种突变的患者的方法
WO2022212893A1 (en) 2021-04-02 2022-10-06 Biogen Ma Inc. Combination treatment methods of multiple sclerosis
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
JP2023508772A (ja) * 2019-12-30 2023-03-03 路良 Ｊａｋ阻害剤化合物及びその使用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070161648A1 (en) * 2005-10-14 2007-07-12 Hughes Terry V Substituted dihydro-isoindolones useful in treating kinase disorders
US20090054407A1 (en) * 2005-04-19 2009-02-26 Kyowa Hakko Kogyo Co., Ltd. Nitrogen-containing heterocyclic compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090054407A1 (en) * 2005-04-19 2009-02-26 Kyowa Hakko Kogyo Co., Ltd. Nitrogen-containing heterocyclic compound
US20070161648A1 (en) * 2005-10-14 2007-07-12 Hughes Terry V Substituted dihydro-isoindolones useful in treating kinase disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HUGHES, T. V. ET AL.: '7-[1H-Indol-2-yl]-2,3-dihydro-isoindol-1-o nes as dual Aurora-A/ VEGF-R2 kinase inhibitors: Design, synthesis, and biological activity' BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 18, no. 18, 2008, ISSN 0960-894X pages 5130 - 5133 *

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US9758508B2 (en) 2012-12-28 2017-09-12 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-on derivative as BTK kinase suppressant, and pharmaceutical composition including same
RU2671847C2 (ru) * 2012-12-28 2018-11-07 Кристалдженомикс, Инк. Производные 2,3-дигидро-изоиндол-1-она и способы их применения в качестве ингибиторов тирозинкиназы брутона
AU2018214134B2 (en) * 2012-12-28 2020-03-12 Crystalgenomics, Inc. 2,3-dihydro-isoindol-1-on derivative as BTK kinase suppressant, and pharmaceutical composition including same
KR20160058720A (ko) * 2012-12-28 2016-05-25 크리스탈지노믹스(주) Btk 키나아제 억제제로서의 2,3-디하이드로-이소인돌-1-온 유도체 및 이를 함유하는 약학적 조성물
EP2940014A4 (en) * 2012-12-28 2016-06-22 Crystalgenomics Inc 2,3-DIHYDRO-ISOINDOL-1-ON DERIVATIVE AS BTK-KINASE INHIBITOR AND PHARMACEUTICAL COMPOSITION THEREWITH
KR102009163B1 (ko) * 2012-12-28 2019-08-09 크리스탈지노믹스(주) Btk 키나아제 억제제로서의 2,3-디하이드로-이소인돌-1-온 유도체 및 이를 함유하는 약학적 조성물
AU2013371146C1 (en) * 2012-12-28 2019-01-17 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-on derivative as BTK kinase suppressant, and pharmaceutical composition including same
EP3428161A1 (en) * 2012-12-28 2019-01-16 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-on derivative as btk kinase suppressant, and pharmaceutical composition including same
JP2016504351A (ja) * 2012-12-28 2016-02-12 クリスタルジェノミクス・インコーポレイテッドＣｒｙｓｔａｌｇｅｎｏｍｉｃｓ， Ｉｎｃ． Ｂｔｋキナーゼ抑制剤としての２，３−ジヒドロ−イソインドール−１−オン誘導体及びこれを含む薬学的組成物
US20150336934A1 (en) * 2012-12-28 2015-11-26 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-on derivative as btk kinase suppressant, and pharmaceutical composition including same
CN104995184B (zh) * 2012-12-28 2018-01-02 晶体基因技术株式会社 作为btk激酶抑制剂的2,3‑二氢异吲哚‑1‑酮诱导体与含此类的药学组合物
US20170362205A1 (en) * 2012-12-28 2017-12-21 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-one derivative as btk kinase suppressant, and pharmaceutical composition including same
AU2013371146B2 (en) * 2012-12-28 2018-05-10 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-on derivative as BTK kinase suppressant, and pharmaceutical composition including same
JP2018109069A (ja) * 2012-12-28 2018-07-12 クリスタルジェノミクス・インコーポレイテッドＣｒｙｓｔａｌｇｅｎｏｍｉｃｓ， Ｉｎｃ． Ｂｔｋキナーゼ抑制剤としての２，３−ジヒドロ−イソインドール−１−オン誘導体及びこれを含む薬学的組成物
AU2020201431B2 (en) * 2012-12-28 2021-07-22 Crystalgenomics, Inc. 2,3-dihydro-isoindol-1-on derivative as BTK kinase suppressant, and pharmaceutical composition including same
WO2014104757A1 (ko) * 2012-12-28 2014-07-03 크리스탈지노믹스(주) Btk 키나아제 억제제로서의 2,3-디하이드로-이소인돌-1-온 유도체 및 이를 함유하는 약학적 조성물
US11230539B2 (en) 2012-12-28 2022-01-25 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-one derivative as BTK kinase suppressant, and pharmaceutical composition including same
CN104995184A (zh) * 2012-12-28 2015-10-21 晶体基因技术株式会社 作为btk激酶抑制剂的2,3-二氢异吲哚-1-酮诱导体与含此类的药学组合物
US10604508B2 (en) 2012-12-28 2020-03-31 Crystalgenomics, Inc. 2,3-dihydro-isoindole-1-one derivative as BTK kinase suppressant, and pharmaceutical composition including same
US10138243B2 (en) 2015-07-16 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10174027B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10174028B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
JP2019516673A (ja) * 2016-04-26 2019-06-20 コリア ユニバーシティ リサーチ アンド ビジネス ファウンデーションＫｏｒｅａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｂｕｓｉｎｅｓｓ Ｆｏｕｎｄａｔｉｏｎ 新規ｎ‐アシル尿素誘導体およびそれを含有する心血管疾患の予防または治療用組成物
US11306073B2 (en) 2016-04-26 2022-04-19 Korea University Research And Business Foundation N-acylurea derivative and composition comprising same for prevention or treatment of cardiovascular disease
CN105924387A (zh) * 2016-04-28 2016-09-07 西安交通大学 一种具有抗肿瘤活性的双芳基脲化合物及其制备方法和应用
CN105924403A (zh) * 2016-04-28 2016-09-07 西安交通大学 一种具有抗肿瘤活性的环丙二酰胺类化合物及其制备方法和应用
CN105906568A (zh) * 2016-04-28 2016-08-31 西安交通大学 一种具有抗肿瘤活性的环丙二酰胺化合物及其制备方法和应用
CN105859638A (zh) * 2016-04-28 2016-08-17 西安交通大学 一种具有抗肿瘤活性的环丁二酰胺化合物及其制备方法和应用
US10172851B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10172845B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10953005B1 (en) 2016-10-10 2021-03-23 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US11648243B2 (en) 2016-10-10 2023-05-16 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10881652B2 (en) 2016-10-10 2021-01-05 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11998545B2 (en) 2016-10-10 2024-06-04 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10441581B2 (en) 2016-10-10 2019-10-15 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10555944B2 (en) 2016-10-10 2020-02-11 Eli Lilly And Company Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10137124B2 (en) 2016-10-10 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
US11851434B2 (en) 2017-01-18 2023-12-26 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyrazine compounds as ret kinase inhibitors
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
US11168090B2 (en) 2017-01-18 2021-11-09 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrazines as RET kinase inhibitors
CN110234645A (zh) * 2017-01-25 2019-09-13 巴斯夫欧洲公司 制备卞型酰胺的方法
JP2020508313A (ja) * 2017-02-21 2020-03-19 アプトース バイオサイエンシーズ， インコーポレイテッド 血液悪性腫瘍患者の治療方法
JP7431309B2 (ja) 2017-02-21 2024-02-14 アプトース バイオサイエンシーズ， インコーポレイテッド 血液悪性腫瘍患者の治療方法
JP7227913B2 (ja) 2017-02-21 2023-02-22 アプトース バイオサイエンシーズ， インコーポレイテッド 血液悪性腫瘍患者の治療方法
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds FORMULATIONS COMPRISING 6- (2-HYDROXY-2-METHYLPROPOXY) -4- (6- (6 - ((6-METHOXYPYRIDIN-3-YL) METHYL) -3,6-DIAZABICYCLO [3.1.1] HEPTAN-3- YL) PYRIDIN-3-YL) PYRAZOLO [1,5-A] pYRIDINE-3-carbonitrile
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T CRYSTALLINE FORMS
WO2019134662A1 (zh) * 2018-01-03 2019-07-11 南京明德新药研发股份有限公司 作为csf-1r抑制剂的杂环化合物及其应用
CN111556869A (zh) * 2018-01-03 2020-08-18 南京明德新药研发有限公司 作为csf-1r抑制剂的杂环化合物及其应用
US11384065B2 (en) 2018-01-03 2022-07-12 Medshine Discovery Inc. Heterocyclic compound as CSF-1R inhibitor and use thereof
JP2021509897A (ja) * 2018-01-03 2021-04-08 メッドシャイン ディスカバリー インコーポレイテッド Ｃｓｆ−１ｒ阻害剤としての複素環式化合物及びその使用
US11472802B2 (en) 2018-01-18 2022-10-18 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
US11603374B2 (en) 2018-01-18 2023-03-14 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
US11964988B2 (en) 2018-09-10 2024-04-23 Array Biopharma Inc. Fused heterocyclic compounds as RET kinase inhibitors
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
CN113365622A (zh) * 2018-11-30 2021-09-07 艾普托斯生物科学公司 使用2，3-二氢异吲哚-1-酮化合物的组合疗法及用于治疗具有各种突变的患者的方法
JP2023508772A (ja) * 2019-12-30 2023-03-03 路良 Ｊａｋ阻害剤化合物及びその使用
WO2022212893A1 (en) 2021-04-02 2022-10-06 Biogen Ma Inc. Combination treatment methods of multiple sclerosis

Also Published As

Publication number Publication date
WO2012047017A3 (ko) 2012-05-31

Similar Documents

Publication Publication Date Title
WO2012047017A2 (ko) 2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물
CN107295799B (zh) Parg抑制化合物
CA2906008C (en) Pyridazinone compounds and methods for the treatment of cystic fibrosis
EP1397364B1 (en) Novel pyrrole derivatives as pharmaceutical agents
DE60126997T2 (de) Stickstoff-enthaltende aromatische ringverbindungen zur behandlung von tumorerkrankungen
KR101804588B1 (ko) 조혈 성장 인자 모방체 소분자 화합물 및 이의 용도
JP5770281B2 (ja) ｃ−ＭＥＴチロシンキナーゼ阻害薬として有用な新規な縮合複素環式誘導体
KR101675984B1 (ko) 티에노디아제핀 유도체 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 포함하는 약학적 조성물
JP4828421B2 (ja) 受容体チロシンキナーゼ阻害剤としてのキナゾリン誘導体
CA2982588A1 (en) Bromodomain inhibitors
KR20210022655A (ko) 화합물
CA2922230A1 (en) Biaryl acetamide compounds and methods of use thereof
WO2014074661A1 (en) AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHα RESPONSES
BRPI0610568A2 (pt) fenilacetamidas adequadas como inibidores de proteìna cinase
AU2010214095A1 (en) Novel amino azaheterocyclic carboxamides
EP2044065A2 (en) Compounds and compositions as hedgehog pathway modulators
KR20180061316A (ko) 암의 치료 및 후성유전학을 위한 화합물
WO2012044090A2 (ko) 단백질 키나제 억제 활성을 갖는 신규한 아미노퀴나졸린 화합물
KR20180094880A (ko) 5원 헤테로시클릭 아미드계 wnt 경로 억제제
WO2018139876A1 (ko) 신규한 [1, 2, 4] 트리아졸로 [4, 3-a]퀴녹살린 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 bet 단백질 관련 질환의 예방 또는 치료용 약학적 조성물
KR20220066258A (ko) 단백질 키나아제 억제제로서의 퀴놀린 유도체
WO2020224607A1 (zh) Ezh2抑制剂及其用途
EP2079702A1 (en) 3-amino-pyrazole-4-carboxamide derivatives useful as inhibitors of protein kinases
JPH10291988A (ja) 複素環式化合物
EP4067354A1 (en) Novel triazolopyridine derivative and pharmaceutical composition comprising same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11830902

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11830902

Country of ref document: EP

Kind code of ref document: A2