WO2020055164A1 - 7-hydroxy-4h-thieno[3,2-b]pyridin-5-on derivative and use thereof - Google Patents

7-hydroxy-4h-thieno[3,2-b]pyridin-5-on derivative and use thereof Download PDF

Info

Publication number
WO2020055164A1
WO2020055164A1 PCT/KR2019/011832 KR2019011832W WO2020055164A1 WO 2020055164 A1 WO2020055164 A1 WO 2020055164A1 KR 2019011832 W KR2019011832 W KR 2019011832W WO 2020055164 A1 WO2020055164 A1 WO 2020055164A1
Authority
WO
WIPO (PCT)
Prior art keywords
trideca
thia
hydroxy
oxo
pentaen
Prior art date
Application number
PCT/KR2019/011832
Other languages
French (fr)
Korean (ko)
Inventor
홍용래
조중명
Original Assignee
크리스탈지노믹스(주)
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
Priority claimed from KR1020190112154A external-priority patent/KR20200030466A/en
Application filed by 크리스탈지노믹스(주) filed Critical 크리스탈지노믹스(주)
Publication of WO2020055164A1 publication Critical patent/WO2020055164A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that inhibit HIF prolyl hydroxylase (hypoxia-inducible factor prolyl hydroxylase) and uses thereof.
  • Hypoxia refers to a variety of disease states caused by insufficient supply of oxygen to cells.
  • Hypoxia inducible factor plays a key role in the treatment of hypoxia.
  • HIF is divided into ⁇ -subunit (HIF- ⁇ ), which is regulated according to oxygen concentration, and ⁇ -subunit (HIF- ⁇ ), which is structurally expressed. After binding as heterogeneous gene transcription, it enters the salivary nucleus and expresses various genes to express various genes. Combined with, it compensates for hypoxia.
  • HIF- ⁇ serves as an important sensor that recognizes hypoxia in the human body.
  • the HIF-PH enzyme introduces a hydroxyl group into HIF- ⁇ through oxygen.
  • VHL Volt Hippel-Lindau
  • HIF- ⁇ which is continuously produced in the human body, disappears as soon as it is generated through a fast half-life of about 5 minutes through the above process in a normal oxygen state to recognize the oxygen concentration.
  • HIF- ⁇ is not decomposed by HIF- ⁇ hydroxylation by the oxygen-mediated HIF-PH enzyme, so HIF- ⁇ is not decomposed and HIF- ⁇ stabilizes, binds to HIF- ⁇ , enters the cell nucleus, and oxygen Expression of genes (EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT-1, etc.) involved in various physiological processes that can be supplemented with insufficient oxygen or energy to save cells in emergency due to lack do.
  • EPO oxygen expression of genes (EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT-1, etc.) involved in various physiological processes that can be supplemented with insufficient oxygen or energy to save cells in emergency due to lack do.
  • HIF- ⁇ may be beneficial for myocardial acute ischemia and initial infarction, pulmonary arterial hypertension and inflammation.
  • the hypoxic condition in which the target organ is subjected to a short period of hypoxia, has been shown to protect both the myocardium and brain against hypoxia-ischemia damage.
  • HIF- ⁇ stabilization is closely related to ischemia and is induced by hypoxic conditions (Wang and Semenza, (1993) Proc. Natl. Acad. Sci. USA, 90: 4304-4308; Stroka, et al.
  • Hypoxia a condition that causes the production of HIF- ⁇ , is a condition of reduced oxygen that can occur when the lungs are damaged or blood flow is reduced.
  • Ischemia due to a decrease in blood flow can be caused by disorders in the arteries or veins, by blood clotting (thrombosis) or by any external circulating material (embolism), or by vascular disorders such as atherosclerosis.
  • a decrease in blood flow can have a sudden onset and a short duration (acute ischemia), or a slow onset with a long duration or frequent relapse (chronic ischemia).
  • HIF- ⁇ Stabilization of HIF- ⁇ involves not only hematopoietic action but also a role in regulating the production of proteins necessary for cells to survive in a hypoxic crisis, and is also effective in the treatment of various diseases including inflammatory bowel disease.
  • HIF- ⁇ By effectively inhibiting HIF-PH enzyme in normal oxygen state using this principle, HIF- ⁇ can be stabilized and tissue regeneration, anemia, and ischemia deeply related to the genes expressed accordingly (ischemia), neuro-protection, stroke, infection, inflammation, fibrosis, atopic dermatitis, inflammatory bowel disease (IBD) ).
  • ischemia ischemia
  • IBD inflammatory bowel disease
  • HIF prolyl hydroxylase inhibitor activating HIF- ⁇ acts on the intestinal surface through inhibition of HIF-prolyl hydroxylase (HIF-PH) enzyme
  • IBD inflammatory bowel disease
  • HIF-PH HIF-prolyl hydroxylase
  • the causes of IBD are diverse and complex, so it is difficult to treat the symptoms with one target, so many developmental drugs are showing limitations, while overall homeostasis is maintained in the intestines of normal people, whereas antigens in the intestines of IBD patients Incorrect recognition of dendritic cells causes inflammation from T-cell attack, thereby releasing various inflammatory cytokines and destroying the barrier's barrier function, causing microorganisms including various bacteria in the gut As it enters the tissue, the T-cells and leukocytes are induced to cause repeated symptoms of inflammation.
  • Inflammatory lesions of the intestinal epithelial cells often become severely hypoxic, and as a factor inducing tissue hypoxia during inflammation, cells significantly infected by the increase in oxygen consumption of Neutrophil, a type of white blood cell, and proliferation of pathogens within the cell Oxygen consumption from is mentioned. Therefore, by activating HIF- ⁇ , it is possible to treat inflammatory bowel disease by improving diseases caused by hypoxia (Sean P. Colgan and Cormac T. Tailor, (2010) Nature Review, Volume 7, 281-287. Louise E. Glover and Sean P. Colgan, (2011) NIH Public Access, 140 (6), 1748-1755. Holger K. Eltizsching et al. (20101) NIH Public Access, 364 (7), 656-665).
  • HIF-PH inhibitors are expected to be a new alternative in the field of IBD treatment, which requires the development of effective therapeutic agents for new mechanisms of action, and the results of research and HIF that hypoxia or HIF- ⁇ are related to IBD treatment Results have recently been reported that have been shown to be effective in animals with -PH inhibitors.
  • the compounds according to the present invention regulate HIF, HIF-PH to stabilize HIF- ⁇ , thereby treating hypoxia-related disorders including inflammatory bowel disease (IBD), atopy and pulmonary fibrosis. It is an object to provide a compound that can be used for prevention.
  • IBD inflammatory bowel disease
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • R6 is hydrogen, halogen, C 1 ⁇ 3 alkyl, C 3 ⁇ 6 Im croissant alkyl, C 6- 12 aryl, or C 3- 12 heteroaryl,
  • R5 is hydrogen or C 1-3 alkyl
  • R1 is hydrogen, C 1 ⁇ 10 alkyl, C 1 ⁇ 10 alkyl, aryl C 1 alkyl sayikeu 1-5 alkyl, C 1 ⁇ 5 alkyl, aryl, C 1 to 5 alkyl heteroaryl allyl, C 2 - 5 Al kaennil, C 2 1-5 alkynyl, C 2 - 5 alkynyl, aryl, C 3 - 8 Cy croissant alkyl, acyl, carbonyl acid, carbonyl, C 1 ⁇ 10-carbonyl ester, C 6 - 12 aryl, and C 3 ⁇ 12 heteroaryl Is selected from the group consisting of,
  • R2 is represented by formulas V-1 and V-2,
  • E is -N (R7)-
  • R7 is H or C 1 ⁇ 5 alkyl
  • R7 is a C 1 to 5 in the case of R7 through to R8 or R9 and the carbon and to achieve a C 3 ⁇ 7 Im croissant alkyl
  • R8 and R9 are each independently H, C 1- 5 alkyl, C 1 ⁇ 5 alkyl alcohol, or C 1 ⁇ 5 alkyl, CO 2 H, R8 and R9 is a C 1- 5 alkyl, if R8 and R9 with the carbon are connected and can achieve an alkyl to C 3 ⁇ 5 sayikeu,
  • R10 is H or C 1-5 alkyl
  • n 1 or 2.
  • W of Chemical Formula I may be N.
  • R1 is ethylbenzyl
  • R2 is 2-formamidoacetic acid (2-formamidoacetic acid)
  • hypoxia inducible factor comprising the compound as described above.
  • Another aspect of the present invention provides a method for inhibiting an active hydroxylase that modifies the alpha subunit of hypoxia-inducible factor, and includes the compound as described above, for inhibiting HIF-PH (Hypoxia Inducible Factor-Prolyl Hydroxylase) Compositions can be provided.
  • HIF-PH Hydrophilic Factor-Prolyl Hydroxylase
  • composition for inhibiting inflammatory cytokines comprising the compound as described above.
  • the present invention provides a method of modulating HIF by inhibiting HIF- ⁇ hydroxylation, thereby stabilizing HIF and activating HIF-regulated gene expression.
  • the method can be applied to the prevention, precautions, or treatment of conditions associated with HIF, including ischemic and hypoxic conditions.
  • Ischemic and hypoxia as treatment targets for HIF-associated conditions are two conditions associated with HIF, including but not limited to myocardial infarction, liver ischemia, kidney ischemia, kidney disease, diabetic kidney disease and seizures, peripheral vascular disorders, Ulcers, burns and chronic damage; Pulmonary embolism; And ischemia-reperfusion injury, fibrosis, atopic dermatitis, Inflamatory Bowel Disease (IBD) associated with surgery and organ transplantation, for example.
  • IBD Inflamatory Bowel Disease
  • the present invention can be usefully used for the treatment, improvement or prevention of Inflammatory Bowel Disease (IBD).
  • composition for improving a long surface barrier function and repairing a barrier junction comprising the compound as described above.
  • the inflammatory growth disease may include one or more selected from the group consisting of Crohn's disease, ulcerative colitis, Behcet's disease (Intestinal Behets disease).
  • the present invention provides a method of treating a condition associated with hypoxia, including IBD, the method comprising combining an effective amount of a compound or a pharmaceutically acceptable salt thereof for treatment, alone or in combination with a pharmaceutically acceptable excipient. , Including administration to a subject.
  • the compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that given typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise stated. The optimum reaction conditions may vary depending on the particular reactant or solvent used, but such conditions can be determined by those skilled in the art by conventional optimization procedures.
  • protecting groups may be needed to prevent certain functional groups from undergoing unwanted reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, numerous protecting groups are described 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 can 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 present invention, unless otherwise indicated.
  • Pure stereoisomers (and diastereomers) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the compounds according to the invention are effective in modulating HIF and treating and preventing HIF-related disorders including conditions involving ischemia and hypoxia. In particular, it is effective for the prevention and treatment of inflammatory bowel disease (IBD: Inflamatory Bowel Disease).
  • IBD Inflamatory Bowel Disease
  • 3 is a graph measuring changes in body weight in the colitis model.
  • the compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that given typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise stated. The optimum reaction conditions may vary depending on the particular reactant or solvent used, but such conditions can be determined by those skilled in the art by conventional optimization procedures.
  • protecting groups may be needed to prevent certain functional groups from undergoing unwanted reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991, and references cited therein.
  • a protecting group for any functional group is not limited to the exemplified embodiments, but can be extended to generally known methods of introducing a protecting group or deprotecting groups, and if there are optical isomers in the compound, each enantiomer, diastereomer Both isomer and racemic mixtures are included.
  • Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the description related to the above specification herein. Such variations are within the scope of the appended claims.
  • the compounds of the present invention may contain one or more chiral centers.
  • such compounds can be prepared or isolated 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 present invention, unless otherwise indicated.
  • Pure stereoisomers (and dia stereomers) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the present invention is represented by the following formula (I), and relates to prodrugs, salts, hydrates, solvates and isomers thereof, pharmaceutical compositions containing them, and methods for their preparation.
  • the compounds according to the present invention inhibit the HIF-PH (Hypoxia inducible factor-Prolyl Hydroxylase) enzyme to inhibit the hydroxylation reaction of HIF- ⁇ (Hypoxia inducible factor- ⁇ ), and HIF- ⁇ is not ubiquitinated by It can be used to treat Inflammatory Bowel Disease (IBD) and other diseases using expression of various genes regulated by HIF by stabilizing HIF- ⁇ according to a mechanism that does not degrade.
  • IBD Inflammatory Bowel Disease
  • the intestinal barrier function is improved to treat and repair the barrier, and at the same time, it can be usefully used to treat the disease with various actions such as anti-inflammatory action. have.
  • ITF Intestinal Trefoil Factor-1
  • CD73 ecto-5'-nucleotide genes among various genes expressed by the stabilized HIF- ⁇ complex into HIF- ⁇ and into the nucleus.
  • This intestinal barrier function intestinal barrier function
  • HIF- ⁇ can treat IBD through the improvement of hypoxia (hypoxia) in the inflamed area of the intestine and anti-inflammatory effect.
  • the present invention stabilizes HIF- ⁇ by inhibiting the HIF-PH enzyme through a novel HIF-PH inhibitor, thereby expressing various genes expressed by HIF- ⁇ (EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT- 1st) to provide treatment methods such as tissue regeneration, anemia, ischemia, neuro-protection, stroke, infection, inflammation, fibrosis, atopic dermartitis, and Inflammatory Bowel Disease (IBD).
  • EPO VEGF
  • GLUT-1 GLUT-1
  • ITF CD73
  • TGFb TGFb
  • DMT- 1st DMT- 1st
  • One aspect of the present invention includes a compound represented by the following formula (I) and pharmaceutically acceptable salts, esters and prodrugs thereof:
  • R6 is hydrogen, halogen, C 1 ⁇ 3 alkyl, C 3 ⁇ 6 Im croissant alkyl, C 6- 12 aryl, or C 3 ⁇ 12 heteroaryl,
  • R5 is hydrogen or C 1-3 alkyl
  • R1 is hydrogen, C 1 ⁇ 10 alkyl, C 1 ⁇ 10 alkyl, aryl C 1 alkyl sayikeu 1-5 alkyl, C 1 ⁇ 5 alkyl, aryl, C 1 to 5 alkyl heteroaryl allyl, C 2 - 5 Al kaennil, C 2 1-5 alkynyl, C 2 - 5 alkynyl, aryl, C 3 - 8 Cy croissant alkyl, acyl, carbonyl acid, carbonyl, C 1 ⁇ 10-carbonyl ester, C 6 - 12 aryl, and C 3 ⁇ 12 heteroaryl Is selected from the group consisting of,
  • R2 is represented by formulas V-1 and V-2,
  • E is -N (R7)-
  • R7 is H or C 1 ⁇ 5 alkyl
  • R7 is a C 1 to 5 in the case of R7 through to R8 or R9 and the carbon and to achieve a C 3 ⁇ 7 Im croissant alkyl
  • R8 and R9 are each independently H, C 1- 5 alkyl, C 1 ⁇ 5 alkyl alcohol, or C 1 ⁇ 5 alkyl, CO 2 H, R8 and R9 is a C 1- 5 alkyl, if R8 and R9 with the carbon are connected and can achieve an alkyl to C 3 ⁇ 5 sayikeu,
  • R10 is H or C 1- 5 alkyl
  • n 1 or 2.
  • aryl as used herein can include organic radicals derived by removing one hydrogen from an aromatic hydrocarbon, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl.
  • Aryl also includes fused rings in which one or more rings are aromatic.
  • heteroaryl is an aryl ring system having 1 to 4 heteroatoms, such as N, O or S, as ring atoms in a heteroaromatic ring system, wherein the rest of the atoms are It is a carbon atom. Heteroaryl may be monocyclic or bicyclic.
  • heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl, Tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, cynolinyl, indazolyl, indololi Genyl, phthalazinyl, triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl, purinyl, benzofuranyl, oxadiazolyl, thiadia Zolyl,
  • the compound of formula I can be synthesized by the method of scheme 1.
  • I-01 can be prepared by adding a base to the starting material (SM) and methyl thioglycolate to cause a cyclization reaction.
  • Various R1s can be introduced to the obtained amine of I-01 by the method of Scheme 2 to introduce the I-02 compound.
  • I-03 can be synthesized by introducing ethylmalonylchloride into I-02 to synthesize I-03 and then using a base to make a ring of hydroxypyridinone.
  • the compound of formula I (I-07) can be synthesized by introducing an amine to the thus-formed compound of I-04 to form an amide bond and then removing the protective group.
  • R1s can be introduced using the method of Scheme 2.
  • the substituent R1 can be introduced into the amine in the presence of a base using R1-L having a leaving group.
  • the reduction reaction is performed by NaBH (OAc) 2 and the RaCH2- group I as in I-02. It can be variously introduced into -01 amine.
  • W of Chemical Formula I may be N.
  • R 1 in Formula I is ethylbenzyl
  • R2 is 2-formamidoacetic acid
  • the compound according to the present invention may be used as a composition for stabilizing hypoxia inducible factor (HIF), suppressing HIF-PH (Hypoxia Inducible Factor-Prolyl Hydroxylase) and inhibiting inflammatory cytokines.
  • HIF hypoxia inducible factor
  • HIF-PH Hapoxia Inducible Factor-Prolyl Hydroxylase
  • the inflammatory growth disease may include one or more selected from the group consisting of Crohn's disease, ulcerative colitis, and Intestinal Behets disease.
  • the present invention may also be provided as a composition comprising a mixture with Formula I in combination with at least one additional therapeutic agent.
  • the biological activity of the compounds according to the invention can be assessed using any method known in the art. Suitable assay methods are well known in the art. The following assays are presented as examples only and are not intended to be limiting. The compounds of the present invention exhibit activity in at least one of the following assays.
  • Example 109 As Compound A used below, the compound of Example 109 was used.
  • HIF-PH2 (EGLN1) was expressed from E. coli cells and partially purified through two processes: a nickel-affinity chromatography column and a size separation chromatography column.
  • HIF-PH2 (PHD2) analysis Homogeneous Time Resolved Fluorescence method
  • HIF-PH2 enzyme 500 nM peptide substrate (Biotin-DLDLEMLAPYIPMDDDFQL), and 0.2 uM ⁇ -ketoglutarate ( ⁇ -ketoglutarate) reaction buffer (reaction buffer, 50 mM Tris-HCl (pH7.4) ), 0.01% Tween20, 0.1 mg / ml BSA, 20 ug / ml Catalase).
  • the TR-FRET value of the sample not treated with the HIF-PH2 inhibitor was set to 100% control, and the percentage of HIF-PH2 enzyme activity remained in the sample treated with the HIF-PH2 inhibitor at the concentration to be tested. Activity was evaluated.
  • the concentration of the inhibitor that inhibits 50% HIF-PH2 enzyme activity compared to the control is determined by IC50 Did.
  • HeLa cells were inoculated in 12 well plates and grown in DMEM (Gibco), 10% FBS at 37 ° C, 5% CO 2 .
  • the compound or DMSO was treated and incubated in DMEM (Gibco), 10% FBS, 37 ° C., 5% CO 2 for 24 hours.
  • HIF-1a (BD) and HIF-2a (Novus) were analyzed by western blotting, and the results are shown in FIG. 1.
  • ITF gene expression known as a factor that enhances intestinal barrier function
  • DNBS Stembet-Aldrich, Cat.no. 556971-25G
  • Vehicles vehicle, negative control (Nor.), 1% CMC
  • drugs were repeatedly administered orally to mice in each experimental group for 7 days from the day before the day before DNBS administration.
  • the mice were euthanized and autopsied to collect colon tissue.
  • the collected colon tissue removes feces, physiological saline and DEPC (Diethyl Pyrocarbonate) treated water, Invitrogen, Cat.no. 46-2224), followed by rapid freezing by liquid nitrogen treatment and storage at -70 ° C until further processing.
  • DEPC Diethyl Pyrocarbonate
  • TriZol Invitorgen TRIzol reagent, Cat.no.15596-018
  • TriZol Invitorgen TRIzol reagent
  • 0.7 ml of TriZol is additionally added.
  • 200 ul of chloroform was added to vortex. It was confirmed that it was standing at room temperature and separated into two layers. After centrifugation at 14,000 rpm for 15 minutes, about 400 ul of the upper layer was well mixed with the same amount of isopropanol.
  • the total mRNA obtained in each experimental group was measured using Nanodrop of Thermo fisher scientific, and 2.5 ug of total RNA was used to reverse-transcribe enzyme (reverse transcriptase, Thermo fisher scientific, Superscript III First strand synthesis system, # 18080051). CDNA synthesis was performed. 1 ul of cDNA from each control group and the experimental group was used as a template, and a reaction mixture solution was prepared according to Takara's TB green (# RR420A) manual. The completed reaction mixture solution was used to compare and analyze real time PCR (Takara, Cycler Dice Real Time System III) mRNA relative expression values. The relative expression value of ITF used in this experiment was compared and analyzed based on the beta-actin expression value. The results are shown in FIG. 2.
  • Example 109 compound In a DNBS mouse model inducing colitis with 3% DNBS, Compound A (Example 109 compound) of the present invention was treated at 15 mg / kg and 50 mg / kg, respectively, from Day -1, and then the weight was changed for 5 days. Observation was shown in Figure 3 the results. In addition, after 5 days, the colon was collected from each model and the length was observed, and the results are shown in FIG. 4.
  • compositions of the present invention can be delivered in pharmaceutical compositions either directly or in combination with suitable carriers or excipients well known in the art.
  • This method of treatment may include administering an effective amount of a compound of the invention to an IBD patient or subject at risk.
  • the subject is a mammalian subject, and in the most preferred embodiment, the subject is a human subject.
  • suitable routes of administration include intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, as well as intramuscular, subcutaneous, and intramedullary injections. Including, for example, oral, rectal, 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 agent.
  • compositions of the present invention can be prepared by any of the well-known methods, such as conventional mixing, dissolving, granulating, dragee-making, powdering, 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, that facilitate the processing of the active molecule into manufacture for pharmaceutical use.
  • the composition may be formulated in an aqueous solution, preferably with a physiologically compatible buffer, such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants suitable for penetration into the barrier are used in the formulation. Such penetrants are generally known in the art.
  • the compounds of the invention are prepared in preparations for oral administration.
  • the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art.
  • Such carriers allow the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a subject.
  • the compounds can also be formulated with rectal compositions, such as suppositories or retention enemas, containing conventional suppository bases, for example cocoa butter or other glycerides.
  • compositions for oral use can be obtained as solid excipients, if desired, after adding suitable auxiliaries to obtain tablets or dragee cores, optionally grinding the resulting mixture and processing the particulate mixture.
  • suitable excipients are, inter alia, fillers such as lactose, sucrose, mannitol, or sugars comprising sorbitol; Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth rubber, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone ( PVP).
  • 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 may be used, which may optionally be 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 can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound dosages.
  • compositions for oral administration include soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol, as well as push-fit capsules made of gelatin.
  • 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 compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compounds of the 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 penetration enhancers or other effectors, including agents that enhance the transport of the delivered compound.
  • Transdermal or topical administration may be suitable, for example, in situations where location specific delivery is desired.
  • the compounds for use according to the invention are suitable propellants, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or Along with the use of any other suitable gas, it is conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer.
  • a suitable dosage unit can be determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of gelatin for use in an inhaler or insufflator can be formulated. They typically contain a powder mix of a compound and a suitable powder base such as lactose or starch.
  • compositions prepared for parenteral administration by injection can be presented in unit dose form, for example in ampoules or multi-dose containers, with added preservatives.
  • the composition may take the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain chemicals such as suspending agents, stabilizers and / or dispersing agents.
  • Formulations for parenteral administration include aqueous solutions or other compositions in aqueous form.
  • Suspensions of the active compounds can also be prepared as suitable oily injection suspensions.
  • suitable lipophilic solvents or mediators 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 that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also 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 medium, for example, sterile pyrogen-free water.
  • compositions of the present invention can also be formulated as a storage agent.
  • long acting agents can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the present invention are suitable polymers or hydrophobic substances (eg as emulsions in acceptable oils) or ion exchange resins, or as very soluble derivatives, for example as very soluble salts Can be dispensed.
  • hydrophobic molecules can be employed.
  • Liposomes and emulsions are well known examples of delivery mediators or carriers for hydrophobic drugs.
  • Liposomal delivery systems are discussed above in the context of gene-delivery systems.
  • Certain organic solvents, such as dimethylsulfoxide, can also be employed, although usually at the cost of greater toxicity.
  • the compound can be delivered using a sustained-release system, such as a semi-permeable matrix of solid hydrophobic polymers containing an effective amount of the composition to be permeated.
  • sustained-release materials are established and available to those skilled in the art. Sustained-release capsules can release the compound for several weeks over 100 days or less, depending on their chemical properties. Depending on the chemical properties and biological stability of the therapeutic reagents, additional strategies for protein stabilization can be employed.
  • composition of the present invention can be presented in a pack or dispenser device containing one or more unit dose forms containing the active ingredient, if desired.
  • packs or devices can include metal or plastic foils, for example, foam packs.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • compositions comprising the compounds of the invention formulated with compatible pharmaceutical carriers can also be prepared, placed in suitable containers, and labeled for treatment of the indicated condition.
  • Suitable conditions indicated on the label may include treatment of a condition, disorder, or disease in which inflammatory growth disease (IBD) is the primary indication.
  • IBD inflammatory growth disease

Abstract

Provided in the present invention is the following compound effective in treating and preventing HIF-associated diseases including ischemia and hypoxia by regulating HIF and stabilizing HIF-α. In particular, the compound is effective in preventing and treating inflammatory bowel disease (IBD). The compound of the present invention is represented by chemical formula I, and in addition, provided are: a prodrug, a salt, and a solvate of the compound, and isomers thereof; a pharmaceutical composition comprising the same; and a preparation method thereof. [Chemical Formula 1] (In the formula, U, V, W, X, Y, R1, R2, and R5 are as defined in the description)

Description

7-하이드록시-4H-티에노[3,2-B]피리딘-5-온 유도체 및 그의 용도7-hydroxy-4H-thieno [3,2-B] pyridin-5-one derivatives and uses thereof
본 발명은 HIF 프롤릴 하이드록실레이즈(hypoxia-inducible factor prolyl hydroxylase)를 저해하는 화합물 및 그의 용도에 관한 것이다.The present invention relates to compounds that inhibit HIF prolyl hydroxylase (hypoxia-inducible factor prolyl hydroxylase) and uses thereof.
저산소증(hypoxia)이란 세포들에게 산소의 공급이 부족하여 나타나는 여러 가지 질환 상태를 말한다. 저산소증의 치료에 핵심적인 역할을 하는 것이 HIF (hypoxia inducible factor, 저산소증 유도 인자)이다. HIF는 산소농도에 따라 조절되는 α-subunit(HIF-α)와 구조적으로 발현되는 β-subunit(HIF-β)으로 나뉘며, 이종의 유전자 전사로써 결합한 후 새포핵 안으로 들어가 다양한 유전자를 발현시켜 다양한 유전자에 결합하여 저산소증에 대한 보상작용을 한다.Hypoxia refers to a variety of disease states caused by insufficient supply of oxygen to cells. Hypoxia inducible factor (HIF) plays a key role in the treatment of hypoxia. HIF is divided into α-subunit (HIF-α), which is regulated according to oxygen concentration, and β-subunit (HIF-β), which is structurally expressed. After binding as heterogeneous gene transcription, it enters the salivary nucleus and expresses various genes to express various genes. Combined with, it compensates for hypoxia.
HIF-α는 인체에서 산소 부족(hypoxia)을 인지하는 중요한 센서(sensor)의 역할을 하는데, 산소가 존재하는 정상상태(normoxia)에서는 HIF-PH 효소가 산소를 매개로 HIF-α에 수산화기를 도입시키고 여기에 VHL(Von Hippel-Lindau)이 붙은 후 유비퀴틴화(ubiquitination) 과정을 거쳐 프로테아좀(proteasome)에 의해 즉시 분해가 일어나게 된다. 그러므로 인체 내에서 지속적으로 생성되는 HIF-α는 정상산소 상태에서 상기 과정을 거쳐 5분 정도의 빠른 반감기로 생성되자마자 소멸됨으로써 산소 농도를 인지하게 한다. HIF-α serves as an important sensor that recognizes hypoxia in the human body. In the normal state (normoxia) where oxygen is present, the HIF-PH enzyme introduces a hydroxyl group into HIF-α through oxygen. After VHL (Von Hippel-Lindau) is attached to it, it undergoes ubiquitination and immediately decomposes by proteasome. Therefore, HIF-α, which is continuously produced in the human body, disappears as soon as it is generated through a fast half-life of about 5 minutes through the above process in a normal oxygen state to recognize the oxygen concentration.
그러나 산소 부족 상태가 오면 산소를 매개로 하는 HIF-PH 효소에 의한 HIF-α의 수산화 반응이 일어나지 못하여 HIF-α의 분해도 일어나지 않으므로 HIF-α는 안정화되어 HIF-β와 결합한 후, 세포핵 안으로 들어가 산소부족으로 인한 위급상황의 세포들을 살리기 위해, 부족한 산소나 에너지가 보충될 수 있는 여러 생리학적 과정에 관여하는 gene(EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT-1등)들이 발현된다.However, when oxygen deficiency occurs, HIF-α is not decomposed by HIF-α hydroxylation by the oxygen-mediated HIF-PH enzyme, so HIF-α is not decomposed and HIF-α stabilizes, binds to HIF-β, enters the cell nucleus, and oxygen Expression of genes (EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT-1, etc.) involved in various physiological processes that can be supplemented with insufficient oxygen or energy to save cells in emergency due to lack do.
HIF-α의 유도는 심근 급성 허혈 및 초기 경색, 폐동맥 고혈압 및 염증 등에 유익할 수 있다. 표적 장기가 짧은 기간의 저 산소증에 놓이는, 저 산소 조건은, 저 산소-허혈 손상에 대해 심근과 뇌 모두를 보호하는 것으로 나타났다. HIF-α 안정화는 허혈과 밀접한 연관이 있고 저산소 조건에 의해 유도된다(Wang 및 Semenza, (1993) Proc.Natl. Acad. Sci. USA, 90: 4304-4308; Stroka, et al. (2001) FASEB. J., 15: 2445-2453; Semenza, et al., (1997) Kidney Int., 51: 553-555; Carmeliet, et al., (1998), Nature 394: 485-490; Zhong, et al., (1999) Cancer Res., 59:5830-5835; Lee, et al., (2000)n. Engl. J. Med. , 343: 148-149; Sharp, et al., (2000) J. Cereb. Blood Flow Metab.,20: 1011-1032; Semenza, et al., (2000) Adv. Exp. Med. Biol., 475: 123-130; Thornton, et al., (2000) Biochem. J. 350: 307-312; Deindl 및 Schaper, (1998) Mol. Cell. Biochem. , 186: 43-51; Bergeron, et al., (2000) Ann. Neurol. 48: 285-296).Induction of HIF-α may be beneficial for myocardial acute ischemia and initial infarction, pulmonary arterial hypertension and inflammation. The hypoxic condition, in which the target organ is subjected to a short period of hypoxia, has been shown to protect both the myocardium and brain against hypoxia-ischemia damage. HIF-α stabilization is closely related to ischemia and is induced by hypoxic conditions (Wang and Semenza, (1993) Proc. Natl. Acad. Sci. USA, 90: 4304-4308; Stroka, et al. (2001) FASEB J., 15: 2445-2453; Semenza, et al., (1997) Kidney Int., 51: 553-555; Carmeliet, et al., (1998), Nature 394: 485-490; Zhong, et al ., (1999) Cancer Res., 59: 5830-5835; Lee, et al., (2000) n. Engl. J. Med., 343: 148-149; Sharp, et al., (2000) J. Cereb.Blood Flow Metab., 20: 1011-1032; Semenza, et al., (2000) Adv.Exp.Med. Biol., 475: 123-130; Thornton, et al., (2000) Biochem. J. 350: 307-312; Deindl and Schaper, (1998) Mol. Cell. Biochem., 186: 43-51; Bergeron, et al., (2000) Ann. Neurol. 48: 285-296).
HIF-α의 생산을 유발하는 상태인 저산소증은 폐가 손상되거나 혈류가 감소될 때 일어날 수 있는 감소된 산소의 상태이다. 혈류의 감소로 인한 허혈은 동맥 또는 정맥의 장애에 의해, 혈액 응고(혈전)에 의해 또는 어떠한 외부 순환 물질(색전)에 의해, 또는 죽상 경화증과 같은 혈관 장애에 의해 유발될 수 있다. 혈류 감소는 갑작스런 발병과 짧은 지속기간(급성 허혈)을 가지거나, 또는 긴 지속기간 또는 잦은 재발을 갖는(만성 허혈) 느린 발병을 가질 수 있다.Hypoxia, a condition that causes the production of HIF-α, is a condition of reduced oxygen that can occur when the lungs are damaged or blood flow is reduced. Ischemia due to a decrease in blood flow can be caused by disorders in the arteries or veins, by blood clotting (thrombosis) or by any external circulating material (embolism), or by vascular disorders such as atherosclerosis. A decrease in blood flow can have a sudden onset and a short duration (acute ischemia), or a slow onset with a long duration or frequent relapse (chronic ischemia).
HIF-α의 안정화는 조혈작용뿐만 아니라 저산소 상태의 위기상황에서 세포가 살아가는데 필요한 단백질의 생성을 조절하는 역할을 수반하고, 아울러 염증성 장 질환을 포함한 다양한 질환의 치료에도 효과적이다.Stabilization of HIF-α involves not only hematopoietic action but also a role in regulating the production of proteins necessary for cells to survive in a hypoxic crisis, and is also effective in the treatment of various diseases including inflammatory bowel disease.
이러한 원리를 이용하여 정상산소 상태에서도 HIF-PH 효소를 효과적으로 저해하면, HIF-α를 안정화시킬 수 있고 그에 따라 발현되는 유전자들과 관련이 깊은 조직재생(tissue regeneration), 빈혈(anemia), 국소빈혈(ischemia), 신경세포보호(neuro-protection), 뇌졸중(stroke), 감염(infection), 염증(inflammation), 섬유화증(fibrosis), 아토피 피부염(atopic dermatitis), 염증성 장질환(Inflammatory Bowel Disease, IBD) 등의 치료에 이용할 수 있다.By effectively inhibiting HIF-PH enzyme in normal oxygen state using this principle, HIF-α can be stabilized and tissue regeneration, anemia, and ischemia deeply related to the genes expressed accordingly (ischemia), neuro-protection, stroke, infection, inflammation, fibrosis, atopic dermatitis, inflammatory bowel disease (IBD) ).
특히, HIF-프롤릴 하이드록실레이즈(HIF-PH) 효소의 억제를 통하여 HIF-α를 활성화시키는 HIF 프롤릴 하이드록실레이즈 억제제가 장 표면에서 작용하면 염증성 장 질환(inflammatory bowel disease, IBD)의 치료를 위하여 사용될 수 있다.In particular, treatment of inflammatory bowel disease (IBD) when HIF prolyl hydroxylase inhibitor activating HIF-α acts on the intestinal surface through inhibition of HIF-prolyl hydroxylase (HIF-PH) enzyme Can be used for
IBD의 발병원인은 다양하고 복잡하여 한가지 표적으로 그 증상을 치료하기는 어려움이 있으므로 많은 개발 약제들이 한계를 보이고 있는 실정이며, 정상인의 장에서는 전체적인 항상성이 유지되고 있는데 반하여 IBD 환자의 장에서는 항원을 수지상세포가 잘못 인식함으로서 T-세포(T-cell)의 공격으로부터 염증이 유발되고 그로 인해 다양한 염증성 사이토카인이 방출되며 장벽의 장벽 기능(tight function)이 파괴되어, 장내 각종 세균을 포함한 미생물들이 내부조직으로 유입됨에 따라 T-세포와 백혈구의 결집이 유도되어 염증이 반복되는 증상이 발생한다.The causes of IBD are diverse and complex, so it is difficult to treat the symptoms with one target, so many developmental drugs are showing limitations, while overall homeostasis is maintained in the intestines of normal people, whereas antigens in the intestines of IBD patients Incorrect recognition of dendritic cells causes inflammation from T-cell attack, thereby releasing various inflammatory cytokines and destroying the barrier's barrier function, causing microorganisms including various bacteria in the gut As it enters the tissue, the T-cells and leukocytes are induced to cause repeated symptoms of inflammation.
장의 상피세포에 염증이 있는 병변은 종종 심하게 저산소 상태가 되는데, 염증 중 조직 저산소증을 유발하는 요인으로는 백혈구의 일종인 뉴트로필의 산소 소비를 크게 증가시키는 점과 세포 내 병원균의 증식에 의하여 감염된 세포로부터의 산소 소비를 들 수 있다. 그러므로, HIF-α를 활성화시킴으로써 저산소증에 따른 질환을 개선시킴으로써 염증성 장 질환을 치료할 수 있다(Sean P. Colgan and Cormac T. Tailor, (2010) Nature Review, Volume 7, 281-287. Louise E. Glover and Sean P. Colgan, (2011) NIH Public Access, 140(6), 1748-1755. Holger K. Eltizsching et al. (20101) NIH Public Access, 364(7), 656-665).Inflammatory lesions of the intestinal epithelial cells often become severely hypoxic, and as a factor inducing tissue hypoxia during inflammation, cells significantly infected by the increase in oxygen consumption of Neutrophil, a type of white blood cell, and proliferation of pathogens within the cell Oxygen consumption from is mentioned. Therefore, by activating HIF-α, it is possible to treat inflammatory bowel disease by improving diseases caused by hypoxia (Sean P. Colgan and Cormac T. Tailor, (2010) Nature Review, Volume 7, 281-287. Louise E. Glover and Sean P. Colgan, (2011) NIH Public Access, 140 (6), 1748-1755. Holger K. Eltizsching et al. (20101) NIH Public Access, 364 (7), 656-665).
IBD 질환 적용 면에서 보면, HIF-PH 효소 저해를 통한 HIF-α의 안정화는 질환환자의 장표면에서 일어나는 저산소 상태를 개선시킬 뿐 아니라, ITF(Intestinal Trefoil Factor-1)와 CD73(ecto-5'-nucleotide) 유전자들의 발현으로 장 표면 장벽 기능(intestinal barrier function)을 향상시켜 IBD에 치료효과를 나타낸다는 것이 최근 알려졌다. 즉, IBD 질환으로 인한 장벽의 무너진 표면장벽 기능(intestinal barrier function)을 복구하고 뮤신(mucin) 등의 발현을 증가시켜 밀착연접(tight junction)을 개선시킴으로써 미생물의 조직 침투를 근원적으로 차단시키고, 생체이물(xenobiotic)을 제거시킬 수 있다. 또한, 염증 수치를 나타내는 다양한 사이토카인(cytokine)의 수치(level)를 저하시킬 수 있고, HIF-α의 또 다른 역할로서 저산소 상태의 개선과 미생물(microbiome)들에 대한 항균 효과(antibiotic effect)가 서로 상호 보완적으로 작용하기 때문에 IBD 치료에서 시너지 효과를 낼 수 있는 최신 치료법이 될 수 있다(Recent Patents on Inflammation & Allergy Drug Discovery, 3, (2009), 1; Journal of Investigative Dermatology 131, (2011), 179; Clinical and Experimental Gastroenterology 7, (2014), 13; Nat. Rev. Gastroenterol Hepatol., 14(10), (2017), 596; Cellular and Molecular Gastroenterology and Hepatology, 3(3), (2017), 303 등).In terms of IBD disease application, stabilization of HIF-α through HIF-PH enzyme inhibition not only improves the hypoxic condition occurring in the intestinal surface of the patient, but also ITF (Intestinal Trefoil Factor-1) and CD73 (ecto-5 ') It has recently been reported that the expression of genes improves the intestinal barrier function, thereby showing a therapeutic effect on IBD. That is, by restoring the intestinal barrier function of the barrier due to IBD disease and increasing the expression of mucin, etc., thereby improving the tight junction, fundamentally blocking the tissue infiltration of microorganisms, and the biological Water (xenobiotic) can be removed. In addition, it is possible to lower the level of various cytokines that indicate the level of inflammation, and as another role of HIF-α, the improvement of hypoxia and the antibiotic effect on microbiome Because they work complementarily with each other, they can be the latest therapies that can have synergistic effects in IBD treatment (Recent Patents on Inflammation & Allergy Drug Discovery, 3, (2009), 1; Journal of Investigative Dermatology 131, (2011) , 179; Clinical and Experimental Gastroenterology 7, (2014), 13; Nat. Rev. Gastroenterol Hepatol., 14 (10), (2017), 596; Cellular and Molecular Gastroenterology and Hepatology, 3 (3), (2017), 303, etc.).
현재까지 IBD 치료에 오랫동안 사용되어 오고 있던 약제는 아미노살리실산염(aminosalicylate), 코르티코스테로이드류(corticosteroids), 면역조절제(immunomodulator) 등이 사용되어 왔으나 약효의 한계가 있고 부작용이 심해 새로운 생물학적(biologic) 약재들의 개발이 계속 시도되고 있는 실정이고 새로운 생물학적 약재들로는 Anti-TNF, Anti-integrin receptor biologics, Antibiotics 등이 개발되고 있으나 낮은 반응률(response rate), 면역원성(immunogenicity), 반감기 문제(half-life issue) 등 단점들을 가지고 있어 새로운 약의 요구는 계속되고 있다. 따라서 새로운 작용기작의 효과적인 치료제 개발이 절실히 요구되는 IBD 치료분야에서 HIF-PH 저해제는 새로운 대안이 될 수 있을 것으로 판단되며, 저산소증(hypoxia)이나 HIF-α가 IBD 치료와 관련되어 있다는 연구 결과와 HIF-PH 저해제로 동물에서 효과를 보였다는 결과들이 최근 보고되고 있다.Pharmaceuticals that have been used for a long time to treat IBD have been used for aminosalicylate, corticosteroids, immunomodulators, etc. Anti-TNF, Anti-integrin receptor biologics, and Antibiotics are being developed as new biological drugs, but low response rate, immunogenicity, and half-life issue As it has disadvantages, the demand for new drugs continues. Therefore, HIF-PH inhibitors are expected to be a new alternative in the field of IBD treatment, which requires the development of effective therapeutic agents for new mechanisms of action, and the results of research and HIF that hypoxia or HIF-α are related to IBD treatment Results have recently been reported that have been shown to be effective in animals with -PH inhibitors.
그러므로, HIF-PH 효소를 효과적으로 저해하고, HIF-α를 안정화시켜 IBD를 치료할 수 있는 화합물에 대한 연구가 필요하다.Therefore, there is a need for research on compounds capable of effectively inhibiting HIF-PH enzyme and stabilizing HIF-α to treat IBD.
본 발명에 따른 화합물은 HIF, HIF-PH를 조절하여 HIF-α를 안정화시킴으로써, 염증성 장질환(Inflammatory bowel disease, IBD), 아토피 및 폐섬유화증을 수반하는 상태를 포함하는 저산소증 관련 장애를 치료하고 예방하는데 사용할 수 있는 화합물을 제공하는 것을 목적으로 한다.The compounds according to the present invention regulate HIF, HIF-PH to stabilize HIF-α, thereby treating hypoxia-related disorders including inflammatory bowel disease (IBD), atopy and pulmonary fibrosis. It is an object to provide a compound that can be used for prevention.
본 발명은 화학식 Ⅰ의 화합물 또는 그의 약학적으로 허용 가능한 염, 에스테르 또는 프로드러그를 제공한다.The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof.
[화학식 Ⅰ][Formula Ⅰ]
Figure PCTKR2019011832-appb-img-000001
Figure PCTKR2019011832-appb-img-000001
상기 식에서,In the above formula,
W, X, Y, Z가 각각 위치에 따라 독립적으로 C(R6), N, C=O, 또는 N-옥사이드(N-oxide)이고, 이중 하나 이상은 반드시 N이거나 N-옥사이드이며,W, X, Y, and Z are each independently C (R6), N, C = O, or N-oxide, depending on the position, at least one of which is necessarily N or N-oxide,
R6이 수소, 할로겐, C 1~ 3알킬, C 3~ 6싸이크로 알킬, C 6- 12아릴 또는 C 3- 12헤테로아릴이고,R6 is hydrogen, halogen, C 1 ~ 3 alkyl, C 3 ~ 6 Im croissant alkyl, C 6- 12 aryl, or C 3- 12 heteroaryl,
R5가 수소 또는 C 1~3 알킬이고,R5 is hydrogen or C 1-3 alkyl,
R1이 수소, C 1~ 10알킬, C 1~ 10알킬 사이크로알킬, 아릴C 1 ~ 5알킬, C 1~ 5알킬아릴, C 1~ 5알킬헤테로알릴, C 2~ 5알캔닐, C 2~ 5알키닐, C 2~ 5알키닐아릴, C 3~ 8싸이크로 알킬, 아실, 카르보닐 산, 카르보닐, C 1~ 10카르보닐에스터, C 6~ 12아릴 및 C 3~ 12헤테로아릴로 이루어진 군으로부터 선택되고,R1 is hydrogen, C 1 ~ 10 alkyl, C 1 ~ 10 alkyl, aryl C 1 alkyl sayikeu 1-5 alkyl, C 1 ~ 5 alkyl, aryl, C 1 to 5 alkyl heteroaryl allyl, C 2 - 5 Al kaennil, C 2 1-5 alkynyl, C 2 - 5 alkynyl, aryl, C 3 - 8 Cy croissant alkyl, acyl, carbonyl acid, carbonyl, C 1 ~ 10-carbonyl ester, C 6 - 12 aryl, and C 3 ~ 12 heteroaryl Is selected from the group consisting of,
상기 W, X, Y, Z, R6, R5 및 R1이 각각 독립적으로 아민, 하이드록시, 나이트로겐, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~ 5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, C 6- 12아릴, C 3~ 12헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있으며,Wherein W, X, Y, Z, R6, R5 and R1 are each independently selected from amine, hydroxyl, nitrogen, halogen, acyl, C 1 ~ 5 alkyl, C 3 to 7 sayikeu alkyl, C 3-7 heteroaryl sayikeu roal Kiel, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl, C 2 ~ 3 alkynyl, aryl, CO 2 H, -C (= O) C 1 ~ 5 alkyl, -C (= O) NHC 1 ~ 5-alkyl, -C (= O) N ( C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, C 6- 12 aryl, C 3 ~ 12 heteroaryl, sulfonyl , the group consisting of C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl piperidine, piperazine, C 1- 3 alkyl piperazine, -N (C 1 ~ 4 alkyl) 2, and aniline It may be substituted with one or more substituents selected from,
상기 치환기가 아민, 하이드록시, 나이트로, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~ 5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, 아릴, 헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고,In which the substituents amine, hydroxy, nitro, halogen, acyl, C 1 ~ 5 alkyl, C 3 to 7 sayikeu alkyl, a C 3-7 heteroaryl sayikeu, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl Neil, C 2 ~ 3 alkynyl aryl, CO 2 H, -C (= O) C 1 ~ 5 alkyl, -C (= O) NHC 1 ~ 5 alkyl, -C (= O) N (C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, aryl, heteroaryl, sulfonyl, C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl-piperidine , piperazine, C 1- 3 piperazine, -N (C 1 ~ 4 alkyl) may be substituted with one or more substituents selected from the group consisting of 2 and aniline,
R2가 식 V-1 및 V-2로 대표되고,R2 is represented by formulas V-1 and V-2,
Figure PCTKR2019011832-appb-img-000002
Figure PCTKR2019011832-appb-img-000002
식 V-1 및 V-2에서,In formulas V-1 and V-2,
E가 -N(R7)-이고,E is -N (R7)-,
R7이 H 또는 C 1~ 5알킬이고, R7이 C 1~5인 경우 중 R7가 R8 또는 R9과 탄소로 연결되어 C 3~7싸이크로알킬을 이룰 수 있고,R7 is H or C 1 ~ 5 alkyl, R7 is a C 1 to 5 in the case of R7 through to R8 or R9 and the carbon and to achieve a C 3 ~ 7 Im croissant alkyl,
R8과 R9이 각각 독립적으로 H, C 1- 5알킬, C 1~ 5알킬알콜, 또는 C 1~ 5알킬CO 2H이고, R8과 R9이 C 1- 5알킬인 경우 R8과 R9이 탄소로 연결되어 C 3~ 5사이크로알킬을 이룰 수 있고,And R8 and R9 are each independently H, C 1- 5 alkyl, C 1 ~ 5 alkyl alcohol, or C 1 ~ 5 alkyl, CO 2 H, R8 and R9 is a C 1- 5 alkyl, if R8 and R9 with the carbon are connected and can achieve an alkyl to C 3 ~ 5 sayikeu,
R10이 H 또는 C 1-5알킬이고,R10 is H or C 1-5 alkyl,
식 V-2에서 n은 1 또는 2이다.In formula V-2, n is 1 or 2.
일구현예에 따르면, 상기 화학식 I의 W가 N일 수 있다.According to an embodiment, W of Chemical Formula I may be N.
일구현예에 따르면, 상기 화학식 I에서, R1이 에틸벤질이고, R2가 2-포름아미도아세트산(2-formamidoacetic acid)이고, 상기 R1 및 R2가 수소, 아민, 하이드록시, 나이트로, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~ 5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, 아릴, 헤테로 아릴, 설포닐, C 1~10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있다.According to one embodiment, in the formula (I), R1 is ethylbenzyl, R2 is 2-formamidoacetic acid (2-formamidoacetic acid), R1 and R2 are hydrogen, amine, hydroxy, nitro, halogen, acyl, C 1 ~ 5 alkyl, C 3 ~ alkyl, 7 sayikeu C 3 ~ 7 in heteroaryl sayikeu alkyl, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl, C 2 ~ 3 alkynyl, aryl, CO 2 H , -C (= O) C 1 ~ 5 alkyl, -C (= O) NHC 1 ~ 5 alkyl, -C (= O) N ( C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, aryl, heteroaryl, sulfonyl, C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl piperidine, piperazine, C 1- 3 alkyl piperazine, - N (C 1-4 alkyl) 2 and one or more substituents selected from the group consisting of aniline.
본 발명의 다른 구현예에 따르면, 상기와 같은 화합물을 포함하는, 저산소 상태 유발인자(HIF: Hypoxia Inducible Factor) 안정화용 조성물을 제공할 수 있다.According to another embodiment of the present invention, it is possible to provide a composition for stabilizing hypoxia inducible factor (HIF), comprising the compound as described above.
본 발명의 또 다른 양태에서는 저산소증 유발가능 인자의 알파 서브유닛을 변경하는 활성 수산화효소를 억제하는 방법을 제공하며, 상기와 같은 화합물을 포함하는, HIF-PH(Hypoxia Inducible Factor-Prolyl Hydroxylase) 억제용 조성물을 제공할 수 있다.Another aspect of the present invention provides a method for inhibiting an active hydroxylase that modifies the alpha subunit of hypoxia-inducible factor, and includes the compound as described above, for inhibiting HIF-PH (Hypoxia Inducible Factor-Prolyl Hydroxylase) Compositions can be provided.
일구현예에 따르면, 상기와 같은 화합물을 포함하는, 염증성 사이토카인 저해용 조성물을 제공할 수 있다.According to one embodiment, it is possible to provide a composition for inhibiting inflammatory cytokines comprising the compound as described above.
본 발명은 HIF-α 수산화를 저해하고, 그로 인해 HIF를 안정화하고 HIF-조절된 유전자 발현을 활성화함으로써 HIF를 조절하는 방법을 제공한다. 상기 방법은 허혈 및 저산소 상태를 포함하는 HIF와 연관된 상태의 예방, 예비조치, 또는 치료에 적용될 수 있다.The present invention provides a method of modulating HIF by inhibiting HIF-α hydroxylation, thereby stabilizing HIF and activating HIF-regulated gene expression. The method can be applied to the prevention, precautions, or treatment of conditions associated with HIF, including ischemic and hypoxic conditions.
HIF-연관된 상태의 치료 대상으로 허혈 및 저산소증은 HIF와 연관된 두 가지 상태이고, 이것으로 제한되지는 않지만, 심근 경색, 간 허혈, 신장 허혈, 신장질환, 당뇨성신장질환 및 발작, 말초 혈관 장애, 궤양, 화상 및 만성 손상; 폐 색전증; 및 예를 들어, 수술 및 장기 이식과 연관된 허혈-재관류 손상, 섬유화증(fibrosis), 아토피 피부염(atopic dermatitis), 염증성장질환(IBD: Inflamatory Bowel Disease)을 포함한다. 특히, 본 발명은 염증성장질환(IBD: Inflamatory Bowel Disease)의 치료, 개선 또는 예방에 유용하게 사용될 수 있다.Ischemic and hypoxia as treatment targets for HIF-associated conditions are two conditions associated with HIF, including but not limited to myocardial infarction, liver ischemia, kidney ischemia, kidney disease, diabetic kidney disease and seizures, peripheral vascular disorders, Ulcers, burns and chronic damage; Pulmonary embolism; And ischemia-reperfusion injury, fibrosis, atopic dermatitis, Inflamatory Bowel Disease (IBD) associated with surgery and organ transplantation, for example. In particular, the present invention can be usefully used for the treatment, improvement or prevention of Inflammatory Bowel Disease (IBD).
또한, 상기와 같은 화합물을 포함하는, 장표면 장벽 기능(barrier function) 개선 및 장벽 밀착연접(tight junction) 복구용 조성물을 제공할 수 있다.In addition, it is possible to provide a composition for improving a long surface barrier function and repairing a barrier junction, comprising the compound as described above.
일구현예에 따르면, 상기 염증성장질환은 크론병(Crohn's disease), 궤양성 대장염(Ulcerative colitis), 베체트 장염(Intestinal Behets disease)으로 이루어지는 군으로부터 선택되는 하나 이상을 포함할 수 있다.According to one embodiment, the inflammatory growth disease may include one or more selected from the group consisting of Crohn's disease, ulcerative colitis, Behcet's disease (Intestinal Behets disease).
본 발명은 IBD를 포함한 저산소증과 연관된 상태를 치료하는 방법을 제공하고, 상기 방법은 치료에 효과적인 양의 화합물 또는 약학적으로 허용가능한 그것의 염을, 단독으로 또는 약학적으로 허용가능한 부형제와 조합하여, 대상에 투여하는 것을 포함한다.The present invention provides a method of treating a condition associated with hypoxia, including IBD, the method comprising combining an effective amount of a compound or a pharmaceutically acceptable salt thereof for treatment, alone or in combination with a pharmaceutically acceptable excipient. , Including administration to a subject.
본 발명의 화합물은 하기의 일반적인 방법 및 과정을 사용하여 쉽게 이용 가능한 출발물질로부터 제조될 수 있다. 전형적인 또는 바람직한 프로세스 조건 (즉, 반응 온도, 시간, 반응물의 몰 비, 용매, 압력, 등)이 주어진다면, 달리 언급되지 않으면 다른 공정 조건도 사용될 수 있다는 것을 이해할 것이다. 최적 반응 상태는 사용된 특정 반응물 또는 용매에 따라 변할 수 있지만, 그러한 상태는 통상적인 최적화 과정에 의해 당업자들에 의해 결정될 수 있다.The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that given typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise stated. The optimum reaction conditions may vary depending on the particular reactant or solvent used, but such conditions can be determined by those skilled in the art by conventional optimization procedures.
추가적으로, 당업자들에게 명백한 바와 같이, 특정 기능적 기가 원하지 않는 반응을 겪지 않도록 방지하는데 통상의 보호기가 필요할 수 있다. 특정한 기능적 기를 보호하고 탈보호하기 위해 적합한 조건은 물론이고 다양한 기능적 기에 대해 적합한 보호기는 당업계에 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 여기에 인용된 참고문헌에 기술되어 있다.Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be needed to prevent certain functional groups from undergoing unwanted reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991 and references cited therein.
더 나아가, 본 발명의 화합물은 하나 이상의 키랄 중심을 함유할 수도 있다. 따라서, 만일 원한다면, 그러한 화합물은 순수한 입체이성체, 즉, 개별적인 거울상 이성질체(enantiomers) 또는 부분입체이성질체(diastereomer)로서, 또는 입체이성체-부분입체이성질체로서 제조되거나 분리될 수 있다. 모든 그러한 입체이성체 (및 부분입체이성질체)도 달리 지시되지 않더라도 본 발명의 범위 내에 포함된다. 순수한 입체이성체 (및 부분입체이성질체)는, 예를 들어, 당업계에 잘 공지된 광학적으로 활성 출발 물질 또는 입체선택성 시약을 사용하여 제조될 수 있다. 대안으로서는, 그러한 화합물의 라세미 혼합물(racemic mixture)은, 예를 들어, 키랄 칼럼 크로마토그래피, 키랄 분해제 등을 사용하여 분리될 수 있다.Furthermore, the compounds of the present invention may contain one or more chiral centers. Thus, if desired, such compounds can 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 present invention, unless otherwise indicated. Pure stereoisomers (and diastereomers) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
본 발명에 따른 화합물은 HIF를 조절하고, 허혈 및 저산소증을 수반하는 상태를 포함하는 HIF-관련 장애를 치료하고 예방하는데 효과적이다. 특히, 염증성 장질환(IBD: Inflamatory Bowel Disease)의 예방 및 치료에 유효하다.The compounds according to the invention are effective in modulating HIF and treating and preventing HIF-related disorders including conditions involving ischemia and hypoxia. In particular, it is effective for the prevention and treatment of inflammatory bowel disease (IBD: Inflamatory Bowel Disease).
도 1은 HIF-1a 및 HIF-2a를 분석한 웨스턴 블로팅 결과이다.1 is a result of Western blotting analyzing HIF-1a and HIF-2a.
도 2는 ITF 발현을 확인한 PCR 결과이다.2 is a PCR result confirming the ITF expression.
도 3은 colitis 모델에서 몸무게 변화를 측정한 그래프이다.3 is a graph measuring changes in body weight in the colitis model.
도 4는 colitis 모델에서 colon의 길이를 측정한 그래프이다.4 is a graph measuring colon length in a colitis model.
본 발명의 화합물은 하기의 일반적인 방법 및 과정을 사용하여 쉽게 이용가능한 출발물질로부터 제조될 수 있다. 전형적인 또는 바람직한 프로세스 조건 (즉, 반응 온도, 시간, 반응물의 몰 비, 용매, 압력, 등)이 주어진다면, 달리 언급되지 않으면 다른 공정 조건도 사용될 수 있다는 것을 이해할 것이다. 최적 반응 상태는 사용된 특정 반응물 또는 용매에 따라 변할 수 있지만, 그러한 상태는 통상적인 최적화 과정에 의해 당업자들에 의해 결정될 수 있다.The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that given typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise stated. The optimum reaction conditions may vary depending on the particular reactant or solvent used, but such conditions can be determined by those skilled in the art by conventional optimization procedures.
추가적으로, 당업자들에게 명백한 바와 같이, 특정 기능적 기가 원하지 않는 반응을 겪지 않도록 방지하는데 통상의 보호기가 필요할 수 있다. 특정한 기능적 기를 보호하고 탈보호하기 위해 적합한 조건은 물론이고 다양한 기능적 기에 대해 적합한 보호기는 당업계에 잘 알려져 있다. 예를 들어, 수많은 보호 기는 T. W. Greene 및 G. M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991 및 여기에 인용된 참고문헌에 기술되어 있다.Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be needed to prevent certain functional groups from undergoing unwanted reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991, and references cited therein.
예를 들어, 어떤 작용기에 대한 보호기 도입에 있어서도 예증된 구체예에 국한되지 않고 일반적으로 알려진 보호기 도입이나 탈 보호기의 방법까지 확장될 수 있으며 화합물 내에 광학 이성질체가 있을 경우는 각각의 거울상 이성질체, 부분입체이성질체, 라세미 혼합물을 모두 포함한다. 본원에 기술된 것들 이외에 본 발명의 다양한 변형은 전술된 본원 명세서와 관련된 설명으로부터 당업자들에게 명백할 것이다. 그러한 변형은 첨부된 청구항의 범위 내에 든다.For example, the introduction of a protecting group for any functional group is not limited to the exemplified embodiments, but can be extended to generally known methods of introducing a protecting group or deprotecting groups, and if there are optical isomers in the compound, each enantiomer, diastereomer Both isomer and racemic mixtures are included. Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the description related to the above specification herein. Such variations are within the scope of the appended claims.
더 나아가, 본 발명의 화합물은 하나 이상의 키랄 중심을 함유할 수도 있다. 따라서, 만일 원한다면, 그러한 화합물은 순수한 입체이성체, 즉, 개별적인 거울상 이성질체 또는 부분입체이성질체로서, 또는 입체이성체-다이아스테레오머로서 제조되거나 분리될 수 있다. 모든 그러한 입체이성체(및 다이아스테레오머)도 달리 지시되지 않더라도 본 발명의 범위 내에 포함된다. 순수한 입체이성체(및 다이아 스테레오머)는 예를 들어, 당업계에 잘 공지된 광학적 활성 출발 물질 또는 입체선택성 시약을 사용하여 제조될 수 있다. 대안으로서는, 그러한 화합물의 라세미 혼합물은 예를 들어, 키랄 칼럼 크로마토 그래피, 키랄 분해제 등을 사용하여 분리될 수 있다.Furthermore, the compounds of the present invention may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated 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 present invention, unless otherwise indicated. Pure stereoisomers (and dia stereomers) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
다음 기술하려는 출발물질인 경우, 다양한 합성법이 알려져 있으며 시판되고 있는 경우는 공급처로부터 구매하여 사용하였고 구매한 시약 공급처는 Aldrich, Sigma, TCI, Wako, Kanto, Fluorchem, Acros, Abocado, Alfa, Fluka 등이다.For the starting materials to be described, various synthetic methods are known, and commercially available reagents are purchased and used from suppliers, and purchased reagent sources are Aldrich, Sigma, TCI, Wako, Kanto, Fluorchem, Acros, Abocado, Alfa, Fluka, etc. .
본 발명은 하기 화학식 I로 대표되며, 그 프로드럭, 염, 수화물, 용매화물 및 이들의 이성체, 이들을 함유하는 약제학적 조성물 및 그의 제조방법에 관한 것이다. 본 발명에 따른 화합물은 HIF-PH(Hypoxia inducible factor-Prolyl Hydroxylase) 효소를 저해하여 HIF-α(Hypoxia inducible factor-α)의 수산화 반응을 저해하고, HIF-α가 유비퀴틴화(ubiquitination)되지 않음으로써 분해되지 않게 하는 기작에 따라 HIF-α안정화시킴으로써 HIF에 의하여 조절되는 다양한 유전자(gene)들의 발현을 이용하여 IBD(Inflammatory Bowel Disease)와 그 밖의 질환들을 치료하는데 활용할 수 있다. 특히, IBD 질환 치료에 도움이 되는 다양한 유전자를 발현시킴으로써 장표면 장벽 기능(intestinal barrier function)을 향상시켜 장벽을 치료, 복구 함과 동시에 항염증 작용 등의 다양한 작용으로 병증을 치료하는데 유용하게 사용될 수 있다.The present invention is represented by the following formula (I), and relates to prodrugs, salts, hydrates, solvates and isomers thereof, pharmaceutical compositions containing them, and methods for their preparation. The compounds according to the present invention inhibit the HIF-PH (Hypoxia inducible factor-Prolyl Hydroxylase) enzyme to inhibit the hydroxylation reaction of HIF-α (Hypoxia inducible factor-α), and HIF-α is not ubiquitinated by It can be used to treat Inflammatory Bowel Disease (IBD) and other diseases using expression of various genes regulated by HIF by stabilizing HIF-α according to a mechanism that does not degrade. In particular, by expressing various genes conducive to the treatment of IBD disease, the intestinal barrier function is improved to treat and repair the barrier, and at the same time, it can be usefully used to treat the disease with various actions such as anti-inflammatory action. have.
IBD 질환의 경우, 안정화된 HIF-α가 HIF-β와 복합체(complex)를 이루어 핵 안으로 들어가 발현되는 다양한 유전자 중 ITF(Intestinal Trefoil Factor-1)와 CD73(ecto-5'-nucleotide) 유전자들의 발현이 장표면 장벽 기능(intestinal barrier function)의 향상과 관련되어 치료 효과를 나타낼 수 있고, HIF-α는 장의 염증부위에 일어나는 저산소(hypoxia) 상태 개선과 항염증 효과를 통해 IBD를 치료할 수 있다.In the case of IBD disease, the expression of the ITF (Intestinal Trefoil Factor-1) and CD73 (ecto-5'-nucleotide) genes among various genes expressed by the stabilized HIF-α complex into HIF-β and into the nucleus. This intestinal barrier function (intestinal barrier function) can be associated with the improvement of the therapeutic effect, HIF-α can treat IBD through the improvement of hypoxia (hypoxia) in the inflamed area of the intestine and anti-inflammatory effect.
본 발명은 신규의 HIF-PH 저해제를 통해 HIF-PH 효소를 저해함으로써 HIF-α를 안정화시켜 HIF-α가 발현시키는 다양한 유전자 발현(EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT-1등)을 통해 tissue regeneration, anemia, ischemia, neuro-protection, stroke, infection, inflammation, fibrosis, atopic dermartitis, IBD(Inflammatory Bowel Disease) 등의 치료방법을 제공할 수 있다.The present invention stabilizes HIF-α by inhibiting the HIF-PH enzyme through a novel HIF-PH inhibitor, thereby expressing various genes expressed by HIF-α (EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT- 1st) to provide treatment methods such as tissue regeneration, anemia, ischemia, neuro-protection, stroke, infection, inflammation, fibrosis, atopic dermartitis, and Inflammatory Bowel Disease (IBD).
본 발명의 하나의 양태에는 하기 화학식 Ⅰ로 표시되는 화합물 및 그의 약학적으로 허용 가능한 염, 에스테르 및 프로드러그가 포함된다:One aspect of the present invention includes a compound represented by the following formula (I) and pharmaceutically acceptable salts, esters and prodrugs thereof:
[화학식 Ⅰ][Formula Ⅰ]
Figure PCTKR2019011832-appb-img-000003
Figure PCTKR2019011832-appb-img-000003
상기 식에서,In the above formula,
W, X, Y, Z가 각각 위치에 따라 독립적으로 C(R6), N, C=O, 또는 N-옥사이드(N-oxide)이고, 이중 하나 이상은 반드시 N이거나 N-옥사이드이며,W, X, Y, and Z are each independently C (R6), N, C = O, or N-oxide, depending on the position, at least one of which is necessarily N or N-oxide,
R6이 수소, 할로겐, C 1~ 3알킬, C 3~ 6싸이크로 알킬, C 6- 12아릴 또는 C 3~ 12헤테로아릴이고,R6 is hydrogen, halogen, C 1 ~ 3 alkyl, C 3 ~ 6 Im croissant alkyl, C 6- 12 aryl, or C 3 ~ 12 heteroaryl,
R5가 수소 또는 C 1~3 알킬이고,R5 is hydrogen or C 1-3 alkyl,
R1이 수소, C 1~ 10알킬, C 1~ 10알킬 사이크로알킬, 아릴C 1 ~ 5알킬, C 1~ 5알킬아릴, C 1~ 5알킬헤테로알릴, C 2~ 5알캔닐, C 2~ 5알키닐, C 2~ 5알키닐아릴, C 3~ 8싸이크로 알킬, 아실, 카르보닐 산, 카르보닐, C 1~ 10카르보닐에스터, C 6~ 12아릴 및 C 3~ 12헤테로아릴로 이루어진 군으로부터 선택되고,R1 is hydrogen, C 1 ~ 10 alkyl, C 1 ~ 10 alkyl, aryl C 1 alkyl sayikeu 1-5 alkyl, C 1 ~ 5 alkyl, aryl, C 1 to 5 alkyl heteroaryl allyl, C 2 - 5 Al kaennil, C 2 1-5 alkynyl, C 2 - 5 alkynyl, aryl, C 3 - 8 Cy croissant alkyl, acyl, carbonyl acid, carbonyl, C 1 ~ 10-carbonyl ester, C 6 - 12 aryl, and C 3 ~ 12 heteroaryl Is selected from the group consisting of,
상기 W, X, Y, Z, R6, R5 및 R1이 각각 독립적으로 아민, 하이드록시, 나이트로겐, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~ 5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, C 6- 12아릴, C 3~ 12헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있으며,Wherein W, X, Y, Z, R6, R5 and R1 are each independently selected from amine, hydroxyl, nitrogen, halogen, acyl, C 1 ~ 5 alkyl, C 3 to 7 sayikeu alkyl, C 3-7 heteroaryl sayikeu roal Kiel, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl, C 2 ~ 3 alkynyl, aryl, CO 2 H, -C (= O) C 1 ~ 5 alkyl, -C (= O) NHC 1 ~ 5-alkyl, -C (= O) N ( C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, C 6- 12 aryl, C 3 ~ 12 heteroaryl, sulfonyl , the group consisting of C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl piperidine, piperazine, C 1- 3 alkyl piperazine, -N (C 1 ~ 4 alkyl) 2, and aniline It may be substituted with one or more substituents selected from,
상기 치환기가 아민, 하이드록시, 나이트로, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~ 5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, 아릴, 헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고,In which the substituents amine, hydroxy, nitro, halogen, acyl, C 1 ~ 5 alkyl, C 3 to 7 sayikeu alkyl, a C 3-7 heteroaryl sayikeu, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl Neil, C 2 ~ 3 alkynyl aryl, CO 2 H, -C (= O) C 1 ~ 5 alkyl, -C (= O) NHC 1 ~ 5 alkyl, -C (= O) N (C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, aryl, heteroaryl, sulfonyl, C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl-piperidine , piperazine, C 1- 3 may be substituted with alkyl piperazine, -N (C 1 ~ 4 alkyl) one or more substituents selected from the group consisting of 2 and aniline,
R2가 식 V-1 및 V-2로 대표되고,R2 is represented by formulas V-1 and V-2,
Figure PCTKR2019011832-appb-img-000004
Figure PCTKR2019011832-appb-img-000004
식 V-1 및 V-2에서,In formulas V-1 and V-2,
E가 -N(R7)-이고,E is -N (R7)-,
R7이 H 또는 C 1~ 5알킬이고, R7이 C 1~5인 경우 중 R7가 R8 또는 R9과 탄소로 연결되어 C 3~ 7싸이크로알킬을 이룰 수 있고,R7 is H or C 1 ~ 5 alkyl, R7 is a C 1 to 5 in the case of R7 through to R8 or R9 and the carbon and to achieve a C 3 ~ 7 Im croissant alkyl,
R8과 R9이 각각 독립적으로 H, C 1- 5알킬, C 1~ 5알킬알콜, 또는 C 1~ 5알킬CO 2H이고, R8과 R9이 C 1- 5알킬인 경우 R8과 R9이 탄소로 연결되어 C 3~ 5사이크로알킬을 이룰 수 있고,And R8 and R9 are each independently H, C 1- 5 alkyl, C 1 ~ 5 alkyl alcohol, or C 1 ~ 5 alkyl, CO 2 H, R8 and R9 is a C 1- 5 alkyl, if R8 and R9 with the carbon are connected and can achieve an alkyl to C 3 ~ 5 sayikeu,
R10이 H 또는 C 1- 5알킬이고,And R10 is H or C 1- 5 alkyl,
식 V-2에서 n은 1 또는 2이다.In formula V-2, n is 1 or 2.
본 명세서에 사용된 용어 "아릴"은 방향족 탄화수소에서 1개의 수소를 제거함으로써 유도되는 유기 라디칼, 예를 들어 페닐 (Ph), 나프틸, 인데닐, 인다닐 및 플루오레닐을 포함할 수 있다. 또한 아릴은 하나 이상의 고리가 방향족인 융합된 고리를 포함한다.The term “aryl” as used herein can include organic radicals derived by removing one hydrogen from an aromatic hydrocarbon, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl. Aryl also includes fused rings in which one or more rings are aromatic.
또한, 본 명세서에 사용된 용어 "헤테로아릴"은 헤테로방향족 고리계 내에 고리 원자로서 1 내지 4개의 헤테로원자, 예를 들어 N, O 또는 S를 가지는 아릴 고리계이며, 여기에서 상기 원자들의 나머지는 탄소 원자이다. 헤테로아릴은 단일고리 또는 이중고리(bicyclic)일 수 있다. 헤테로아릴 기의 예에는 피리디닐, 피리다지닐, 이미다졸릴, 피리미디닐, 피라졸릴, 트리아졸릴, 피라지닐, 퀴놀릴, 이소퀴놀릴, 1,2,3,4-테트라히드로퀴놀릴, 테트라졸릴, 푸릴, 티에닐, 이소옥사졸릴, 티아졸릴, 옥사졸릴, 이소티아졸릴, 피롤릴, 인돌릴, 벤즈이미다졸릴, 벤조퓨라닐, 벤조티엔일, 신놀리닐, 인다졸릴, 인돌리지닐, 프탈라지닐, 트리아지닐, 1,2,4-트리아지닐, 1,3,5-트리아지닐, 이소인돌릴, 1-옥소이소인돌릴, 퓨리닐, 벤조퓨란일, 옥사디아졸릴, 티아디아졸릴, 벤조푸라자닐, 벤조티오페닐, 벤조트리아졸릴, 벤조티아졸릴, 벤조피라졸릴, 벤족사졸릴, 쿠마린일, 퀴나졸리닐, 퀴녹살리닐, 나프티리디닐, 디히드로퀴놀릴, 테트라히드로퀴놀릴, 디히드로이소퀴놀릴, 테트라히드로이소퀴놀릴, 벤조푸릴, 푸로피리디닐, 피롤로피리미디닐 및 아자인돌릴을 포함할 수 있다. 또한 예를 들어 C 1- 3알킬벤즈이미다졸릴, 벤조디옥솔 등을 포함할 수 있으나 이에 한정되지는 않는다.Also, as used herein, the term "heteroaryl" is an aryl ring system having 1 to 4 heteroatoms, such as N, O or S, as ring atoms in a heteroaromatic ring system, wherein the rest of the atoms are It is a carbon atom. Heteroaryl may be monocyclic or bicyclic. Examples of heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl, Tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, cynolinyl, indazolyl, indololi Genyl, phthalazinyl, triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl, purinyl, benzofuranyl, oxadiazolyl, thiadia Zolyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzopyrazolyl, benzoxazolyl, coumarinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl , Dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl and aza It may include a turn. In addition, for example, and the like C 1- 3 alkyl, benzimidazolyl, benzodioxol, but are not limited to.
화학식 I의 화합물은 scheme 1의 방법으로 합성할 수 있다. 출발물질(SM)과 메틸 티오글리콜레이트(methyl thioglycolate)에 염기(base)를 가하여 고리화 반응을 일으켜 I-01을 만들 수 있다. 얻어진 I-01의 아민(amine)에 Scheme 2의 방법으로 다양한 R1을 도입하여 I-02 화합물을 도입할 수 있다. 에틸말로닐 클로라이드(ethylmalonylchloride)를 I-02에 도입하여 I-03을 합성한 뒤 염기를 사용하여 하이드록시피리딘온(hydroxypyridinone)의 고리를 만들어 I-04를 합성할 수 있다. 이렇게 생성된 I-04의 화합물에 아민을 도입시켜 아마이드 결합(amide bond)을 형성한 뒤 보호 그룹(protective group)을 제거함으로써 화학식 I의 화합물(I-07)을 합성할 수 있다.The compound of formula I can be synthesized by the method of scheme 1. I-01 can be prepared by adding a base to the starting material (SM) and methyl thioglycolate to cause a cyclization reaction. Various R1s can be introduced to the obtained amine of I-01 by the method of Scheme 2 to introduce the I-02 compound. I-03 can be synthesized by introducing ethylmalonylchloride into I-02 to synthesize I-03 and then using a base to make a ring of hydroxypyridinone. The compound of formula I (I-07) can be synthesized by introducing an amine to the thus-formed compound of I-04 to form an amide bond and then removing the protective group.
Scheme 1. 화학식Ⅰ의 일반적인 합성법Scheme 1. General synthesis of formula I
Figure PCTKR2019011832-appb-img-000005
Figure PCTKR2019011832-appb-img-000005
Scheme 2. R1의 도입방법 Scheme 2. Introduction of R1
Figure PCTKR2019011832-appb-img-000006
Figure PCTKR2019011832-appb-img-000006
Scheme 2의 방법을 이용하여 다양한 R1을 도입할 수 있다. 이탈 그룹(leaving group)을 가지는 R1-L을 이용하여 염기(base) 존재 하에서 치환기 R1을 아민(amine)에 도입할 수 있다. 또한, Ra-COH의 다양한 알데하이드를 이용하여 I-01의 아민(amine)과 이민(imine)을 형성한 뒤, NaBH(OAc) 2에 의해서 환원반응을 진행하고 I-02와 같이 RaCH2-기를 I-01의 아민에 다양하게 도입할 수 있다.Various R1s can be introduced using the method of Scheme 2. The substituent R1 can be introduced into the amine in the presence of a base using R1-L having a leaving group. In addition, after forming the amine and imine of I-01 using various aldehydes of Ra-COH, the reduction reaction is performed by NaBH (OAc) 2 and the RaCH2- group I as in I-02. It can be variously introduced into -01 amine.
일구현예에 따르면, 화학식 I의 W는 N일 수 있다.According to an embodiment, W of Chemical Formula I may be N.
일구현예에 따르면, 화학식 I의 R1은 에틸벤질이고,According to one embodiment, R 1 in Formula I is ethylbenzyl,
R2는 2-포름아미도아세트산(2-formamidoacetic acid)이고,R2 is 2-formamidoacetic acid,
상기 R1 및 Ra는 수소, 아민, 하이드록시, 나이트로, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~ 5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~ 5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, 아릴, 헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있다.Wherein R1 and Ra is hydrogen, amine, hydroxy, nitro, halogen, acyl, C 1 ~ 5 alkyl, C 3 alkyl with 1-7 sayikeu, C 3 to 7 in heteroaryl sayikeu alkyl, C 2 - 3 Al kaennil, C 2 to 3 alkynyl, C 2 to 3 alkynyl aryl, CO 2 H, -C (= O) C 1 to 5 alkyl, -C (= O) NHC 1 to 5 alkyl, -C (= O) N ( C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, aryl, heteroaryl, sulfonyl, C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl piperidine, piperazine, C 1- 3 may be substituted with alkyl piperazine, -N (C 1 ~ 4 alkyl) one or more substituents selected from the group consisting of 2 and aniline.
일구현예에 따르면, 본 발명에 따른 화합물은 저산소 상태 유발인자(HIF: Hypoxia Inducible Factor) 안정화, HIF-PH(Hypoxia Inducible Factor-Prolyl Hydroxylase) 억제 및 염증성 사이토카인 저해용 조성물로 사용될 수 있다.According to one embodiment, the compound according to the present invention may be used as a composition for stabilizing hypoxia inducible factor (HIF), suppressing HIF-PH (Hypoxia Inducible Factor-Prolyl Hydroxylase) and inhibiting inflammatory cytokines.
또한, 장표면 장벽 기능(barrier function) 개선 및 장벽 밀착연접(tight junction) 복구용으로 사용될 수 있다. 예를 들어, 상기 염증성장질환은 크론병(Crohn's disease), 궤양성 대장염(Ulcerative colitis), 베체트 장염(Intestinal Behets disease)으로 이루어지는 군으로부터 선택되는 하나 이상을 포함할 수 있다.In addition, it can be used for improving the barrier function of the long surface and restoring the tight junction of the barrier. For example, the inflammatory growth disease may include one or more selected from the group consisting of Crohn's disease, ulcerative colitis, and Intestinal Behets disease.
일구현예에 따르면, 본 발명은 또한 적어도 하나의 추가의 치료제와 조합하여 화학식 Ⅰ과의 혼합물을 포함하는 조성물로 제공될 수 있다.According to one embodiment, the present invention may also be provided as a composition comprising a mixture with Formula I in combination with at least one additional therapeutic agent.
본 발명은 순수한 예증이 목적인 하기 실시예를 참고하여 더욱 이해된다. 본 발명은 예증된 구체예에 의해 제한되지 않는다. 기능적으로 등가인 어떠한 방법도 본 발명의 범위 내에 포함될 수 있다.The present invention is further understood by reference to the following examples, for which pure illustration is the purpose. The invention is not limited by the illustrated embodiments. Any functionally equivalent method can be included within the scope of the present invention.
본 발명의 화학식 I 범위 내에 포함되는 화합물은, 예를 들어, 하기의 것들을 포함한다:Compounds included within the scope of Formula I of the present invention include, for example:
Figure PCTKR2019011832-appb-img-000007
Figure PCTKR2019011832-appb-img-000007
Figure PCTKR2019011832-appb-img-000008
Figure PCTKR2019011832-appb-img-000008
Figure PCTKR2019011832-appb-img-000009
Figure PCTKR2019011832-appb-img-000009
Figure PCTKR2019011832-appb-img-000010
Figure PCTKR2019011832-appb-img-000010
Figure PCTKR2019011832-appb-img-000011
Figure PCTKR2019011832-appb-img-000011
Figure PCTKR2019011832-appb-img-000012
Figure PCTKR2019011832-appb-img-000012
Figure PCTKR2019011832-appb-img-000013
Figure PCTKR2019011832-appb-img-000013
Figure PCTKR2019011832-appb-img-000014
Figure PCTKR2019011832-appb-img-000014
Figure PCTKR2019011832-appb-img-000015
Figure PCTKR2019011832-appb-img-000015
Figure PCTKR2019011832-appb-img-000016
Figure PCTKR2019011832-appb-img-000016
Figure PCTKR2019011832-appb-img-000017
Figure PCTKR2019011832-appb-img-000017
Figure PCTKR2019011832-appb-img-000018
Figure PCTKR2019011832-appb-img-000018
Figure PCTKR2019011832-appb-img-000019
Figure PCTKR2019011832-appb-img-000019
Figure PCTKR2019011832-appb-img-000020
Figure PCTKR2019011832-appb-img-000020
Figure PCTKR2019011832-appb-img-000021
Figure PCTKR2019011832-appb-img-000021
Figure PCTKR2019011832-appb-img-000022
Figure PCTKR2019011832-appb-img-000022
Figure PCTKR2019011832-appb-img-000023
Figure PCTKR2019011832-appb-img-000023
Figure PCTKR2019011832-appb-img-000024
Figure PCTKR2019011832-appb-img-000024
Figure PCTKR2019011832-appb-img-000025
Figure PCTKR2019011832-appb-img-000025
Figure PCTKR2019011832-appb-img-000026
Figure PCTKR2019011832-appb-img-000026
Figure PCTKR2019011832-appb-img-000027
Figure PCTKR2019011832-appb-img-000027
Figure PCTKR2019011832-appb-img-000028
Figure PCTKR2019011832-appb-img-000028
Figure PCTKR2019011832-appb-img-000029
Figure PCTKR2019011832-appb-img-000029
Figure PCTKR2019011832-appb-img-000030
Figure PCTKR2019011832-appb-img-000030
Figure PCTKR2019011832-appb-img-000031
Figure PCTKR2019011832-appb-img-000031
Figure PCTKR2019011832-appb-img-000032
Figure PCTKR2019011832-appb-img-000032
Figure PCTKR2019011832-appb-img-000033
Figure PCTKR2019011832-appb-img-000033
Figure PCTKR2019011832-appb-img-000034
Figure PCTKR2019011832-appb-img-000034
Figure PCTKR2019011832-appb-img-000035
Figure PCTKR2019011832-appb-img-000035
Figure PCTKR2019011832-appb-img-000036
Figure PCTKR2019011832-appb-img-000036
Figure PCTKR2019011832-appb-img-000037
Figure PCTKR2019011832-appb-img-000037
Figure PCTKR2019011832-appb-img-000038
Figure PCTKR2019011832-appb-img-000038
Figure PCTKR2019011832-appb-img-000039
Figure PCTKR2019011832-appb-img-000039
Figure PCTKR2019011832-appb-img-000040
Figure PCTKR2019011832-appb-img-000040
Figure PCTKR2019011832-appb-img-000041
Figure PCTKR2019011832-appb-img-000041
Figure PCTKR2019011832-appb-img-000042
Figure PCTKR2019011832-appb-img-000042
Figure PCTKR2019011832-appb-img-000043
Figure PCTKR2019011832-appb-img-000043
Figure PCTKR2019011832-appb-img-000044
Figure PCTKR2019011832-appb-img-000044
Figure PCTKR2019011832-appb-img-000045
Figure PCTKR2019011832-appb-img-000045
Figure PCTKR2019011832-appb-img-000046
Figure PCTKR2019011832-appb-img-000046
Figure PCTKR2019011832-appb-img-000047
Figure PCTKR2019011832-appb-img-000047
Figure PCTKR2019011832-appb-img-000048
Figure PCTKR2019011832-appb-img-000048
Figure PCTKR2019011832-appb-img-000049
Figure PCTKR2019011832-appb-img-000049
Figure PCTKR2019011832-appb-img-000050
Figure PCTKR2019011832-appb-img-000050
Figure PCTKR2019011832-appb-img-000051
Figure PCTKR2019011832-appb-img-000051
Figure PCTKR2019011832-appb-img-000052
Figure PCTKR2019011832-appb-img-000052
Figure PCTKR2019011832-appb-img-000053
Figure PCTKR2019011832-appb-img-000053
Figure PCTKR2019011832-appb-img-000054
Figure PCTKR2019011832-appb-img-000054
Figure PCTKR2019011832-appb-img-000055
Figure PCTKR2019011832-appb-img-000055
Figure PCTKR2019011832-appb-img-000056
Figure PCTKR2019011832-appb-img-000056
Figure PCTKR2019011832-appb-img-000057
Figure PCTKR2019011832-appb-img-000057
Figure PCTKR2019011832-appb-img-000058
Figure PCTKR2019011832-appb-img-000058
Figure PCTKR2019011832-appb-img-000059
Figure PCTKR2019011832-appb-img-000059
Figure PCTKR2019011832-appb-img-000060
Figure PCTKR2019011832-appb-img-000060
Figure PCTKR2019011832-appb-img-000061
Figure PCTKR2019011832-appb-img-000061
Figure PCTKR2019011832-appb-img-000062
Figure PCTKR2019011832-appb-img-000062
Figure PCTKR2019011832-appb-img-000063
Figure PCTKR2019011832-appb-img-000063
Figure PCTKR2019011832-appb-img-000064
Figure PCTKR2019011832-appb-img-000064
Figure PCTKR2019011832-appb-img-000065
Figure PCTKR2019011832-appb-img-000065
Figure PCTKR2019011832-appb-img-000066
Figure PCTKR2019011832-appb-img-000066
Figure PCTKR2019011832-appb-img-000067
Figure PCTKR2019011832-appb-img-000067
Figure PCTKR2019011832-appb-img-000068
Figure PCTKR2019011832-appb-img-000068
Figure PCTKR2019011832-appb-img-000069
Figure PCTKR2019011832-appb-img-000069
Figure PCTKR2019011832-appb-img-000070
Figure PCTKR2019011832-appb-img-000070
Figure PCTKR2019011832-appb-img-000071
Figure PCTKR2019011832-appb-img-000071
Figure PCTKR2019011832-appb-img-000072
Figure PCTKR2019011832-appb-img-000072
Figure PCTKR2019011832-appb-img-000073
Figure PCTKR2019011832-appb-img-000073
Figure PCTKR2019011832-appb-img-000074
Figure PCTKR2019011832-appb-img-000074
Figure PCTKR2019011832-appb-img-000075
Figure PCTKR2019011832-appb-img-000075
Figure PCTKR2019011832-appb-img-000076
Figure PCTKR2019011832-appb-img-000076
Figure PCTKR2019011832-appb-img-000077
Figure PCTKR2019011832-appb-img-000077
Figure PCTKR2019011832-appb-img-000078
Figure PCTKR2019011832-appb-img-000078
Figure PCTKR2019011832-appb-img-000079
Figure PCTKR2019011832-appb-img-000079
Figure PCTKR2019011832-appb-img-000080
Figure PCTKR2019011832-appb-img-000080
Figure PCTKR2019011832-appb-img-000081
Figure PCTKR2019011832-appb-img-000081
Figure PCTKR2019011832-appb-img-000082
Figure PCTKR2019011832-appb-img-000082
Figure PCTKR2019011832-appb-img-000083
Figure PCTKR2019011832-appb-img-000083
Figure PCTKR2019011832-appb-img-000084
Figure PCTKR2019011832-appb-img-000084
테스트 및 투여Test and dosing
생물학적 테스트Biological testing
본 발명에 따른 화합물의 생물학적 활성은 종래에 공지된 어떤 방법을 사용하여 평가될 수 있다. 적합한 검정 방법은 당업계에 잘 공지되어 있다. 다음의 검정법은 오직 예로서 제시는 것이며 이를 제한하려는 의도가 아니다. 본 발명의 화합물은 하기 검정법 중 적어도 하나에서 활성을 나타낸다.The biological activity of the compounds according to the invention can be assessed using any method known in the art. Suitable assay methods are well known in the art. The following assays are presented as examples only and are not intended to be limiting. The compounds of the present invention exhibit activity in at least one of the following assays.
이하에 사용된 Compound A로는 실시예 109번 화합물을 사용하였다.As Compound A used below, the compound of Example 109 was used.
HIF-PH2(PHD2) 분석법 HIF-PH2 (PHD2) Assay
재료material
HIF-PH2(EGLN1)는 E.coli 세포로부터 발현되었고 니켈-친화 크로마토그래피 칼럼(Ni-affinity chromatography column)과 크기(size) 분리 크로마토그래피 칼럼의 두 과정을 통해 부분 정제되었다.HIF-PH2 (EGLN1) was expressed from E. coli cells and partially purified through two processes: a nickel-affinity chromatography column and a size separation chromatography column.
HIF-PH2 (PHD2) 분석 (Homogeneous Time Resolved Fluorescence 방법)HIF-PH2 (PHD2) analysis (Homogeneous Time Resolved Fluorescence method)
HIF-PH2 억제제의 활성을 평가하기 위하여 우선 유전자 재조합에 의하여 과량 발현시킨 후 정제한 HIF-PH2 효소를 사용하였다. HIF-PH2 효소와 500 nM 펩타이드 기질(peptide substrate, Biotin-DLDLEMLAPYIPMDDDFQL), 그리고 0.2 uM α-케토글루타르산염(α-ketoglutarate)을 반응용 완충용액(reaction buffer, 50 mM Tris-HCl(pH7.4), 0.01% Tween20, 0.1 mg/ml BSA, 20 ug/ml Catalase)에서 반응시켰다. 이때 1 mM 아스코르브산나트륨(sodium ascorbate), 10 uM FeSO 4를 반응 조효소로 함께 사용하였다. 시험하고자 하는 농도의 HIF-PH2 억제제를 처리하여 30℃에서 1시간 동안 반응시켰다.In order to evaluate the activity of the HIF-PH2 inhibitor, first, overexpressed by gene recombination, then purified HIF-PH2 enzyme was used. HIF-PH2 enzyme, 500 nM peptide substrate (Biotin-DLDLEMLAPYIPMDDDFQL), and 0.2 uM α-ketoglutarate (α-ketoglutarate) reaction buffer (reaction buffer, 50 mM Tris-HCl (pH7.4) ), 0.01% Tween20, 0.1 mg / ml BSA, 20 ug / ml Catalase). At this time, 1 mM sodium ascorbate (sodium ascorbate) and 10 uM FeSO 4 were used together as a reaction coenzyme. The HIF-PH2 inhibitor of the concentration to be tested was treated and reacted at 30 ° C for 1 hour.
프롤릴 수산화(prolyl hydroxylation)가 일어난 기질을 확인하기 위하여 2 ug GST-VBC(GST-VHL-Elongin B-Elongin C) 단백질, 1 mM 오르쏘-페난트롤린(ortho-phenanthroline), 0.1 mM EDTA, 0.5 nM anti-LANCE-GST, 100 nM AF647-labeled streptavidin을 반응완충용액(50 mM Tris-HCl(pH7.4), 0.01% Tween20, 0.01 mg/ml BSA)에 첨가하여 상온에서 30 분간 방치하였다. 반응이 끝난 후, SpectraMax i3X-TR-FRET LANCE(Molecular device) 기기를 사용하여 330 nm/665 nm(ex/em)에서 측정하였다.2 ug GST-VHL-Elongin B-Elongin C (GST-VBC) protein, 1 mM ortho-phenanthroline, 0.1 mM EDTA, to identify the substrate on which prolyl hydroxylation occurred 0.5 nM anti-LANCE-GST, 100 nM AF647-labeled streptavidin was added to the reaction buffer (50 mM Tris-HCl (pH7.4), 0.01% Tween20, 0.01 mg / ml BSA) and left at room temperature for 30 minutes. After the reaction was completed, it was measured at 330 nm / 665 nm (ex / em) using a SpectraMax i3X-TR-FRET LANCE (Molecular device) instrument.
HIF-PH2 억제제를 처리하지 않은 시료의 TR-FRET 값을 100 % control로 하고, 시험하고자 하는 농도의 HIF-PH2 억제제를 처리한 시료에서 HIF-PH2 효소 활성이 남아있는 %로 HIF-PH2 억제제의 활성을 평가하였다. HIF-PH2 억제제의 IC50를 구하기 위하여 다양한 농도의 HIF-PH2 억제제 처리 시 남아있는 HIF-PH2 효소 활성을 측정한 후, control 대비 50 %의 HIF-PH2 효소 활성 억제가 일어나는 억제제의 농도를 IC50로 결정하였다.The TR-FRET value of the sample not treated with the HIF-PH2 inhibitor was set to 100% control, and the percentage of HIF-PH2 enzyme activity remained in the sample treated with the HIF-PH2 inhibitor at the concentration to be tested. Activity was evaluated. In order to obtain the IC50 of the HIF-PH2 inhibitor, after measuring the remaining HIF-PH2 enzyme activity when treating various concentrations of the HIF-PH2 inhibitor, the concentration of the inhibitor that inhibits 50% HIF-PH2 enzyme activity compared to the control is determined by IC50 Did.
Figure PCTKR2019011832-appb-img-000085
Figure PCTKR2019011832-appb-img-000085
세포-기반 HIF-α 안정화 검정법Cell-based HIF-α stabilization assay
HeLa 세포를 12 well plate에 접종하여 DMEM (Gibco), 10% FBS에서 37℃, 5% CO 2에서 성장시켰다.HeLa cells were inoculated in 12 well plates and grown in DMEM (Gibco), 10% FBS at 37 ° C, 5% CO 2 .
화합물 또는 DMSO를 처리하고, 24 시간 동안 DMEM(Gibco), 10% FBS에서 37℃, 5% CO 2에 배양시켰다.The compound or DMSO was treated and incubated in DMEM (Gibco), 10% FBS, 37 ° C., 5% CO 2 for 24 hours.
배양 후에 배지를 제거하고 PBS(Welgene)로 세척한 후, 얼음 위에서 200 ul Protease inhibitor (Roche)와 Phosphatase inhibitor (A. G. Scientific, Inc)가 포함된 RIPA buffer (Sigma)를 넣고 1 분 후 scrapping을 시행하였다.After incubation, the medium was removed, washed with PBS (Welgene), and then RIPA buffer (Sigma) containing 200 ul Protease inhibitor (Roche) and Phosphatase inhibitor (AG Scientific, Inc) was added on ice and scraping was performed after 1 minute. .
정량 후에, 웨스턴 블로팅(western blotting)을 통해 HIF-1a (BD), HIF-2a (Novus)를 분석하였으며 그 결과는 도 1에 나타내었다.After quantification, HIF-1a (BD) and HIF-2a (Novus) were analyzed by western blotting, and the results are shown in FIG. 1.
장표면 장벽 기능(intestinal barrier function)을 향상시키는 인자로 알려진 ITF 유전자 발현 측정Measurement of ITF gene expression, known as a factor that enhances intestinal barrier function
3% DNBS로 대장염(colitis)를 유발한 DNBS 마우스 모델에서, HIF-PH 저해제인 화합물 A(compound A = 2-{[6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido)acetic acid, 실시예 109)를 6일 투약한 후 측정한 결과에서 전혀 투약하지 않은 군(Nor.)이나 3% DNBS만을 투약한 군(Veh.)에 비해 화합물 A를 투약한 군에서는 농도 의존적으로 ITF의 mRNA의 발현이 증가하였다. 이는 HIF-PH 저해제로 인해 HIF-α가 안정화됨에 따라 장내의 장벽 기능을 강화시킬 수 있는 유전자 발현이 증가된다는 증거로서 염증성장질환의 치료가능성을 보여준다고 할 수 있다. In a DNBS mouse model that caused colitis with 3% DNBS, compound A (compound A = 2-{[6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia), an HIF-PH inhibitor, -3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido) acetic acid, Example 109) for 6 days In the measurement result after administration, the expression of ITF mRNA increased in a concentration-dependent manner in the group administered with Compound A compared to the group not administered at all (Nor.) Or the group administered only with 3% DNBS (Veh.). This can be said to show the therapeutic potential of inflammatory growth diseases as evidence that the HIF-PH inhibitor stabilizes HIF-α, thereby increasing the expression of genes capable of enhancing the intestinal barrier function.
ITF mRNA level 측정 방법 ITF mRNA level measurement method
1주간의 순화를 거친 7주령의 C57BL/6 마우스(mouse)에게 에탄올(ethanol)에 3% 농도로 용해시켜 제조한 DNBS(Sigma-Aldrich, Cat.no. 556971-25G) 용액을 마우스 존대를 사용한 항문투여를 통하여 대장염을 유발시킨 모델을 형성하였다. DNBS 투여 하루 전일 시점으로부터 7일간 각 실험군의 마우스에 비히클(vehicle, 음성대조군(Nor.), 1% CMC)과 약물을 경구를 통해 각각 반복투여 하였다. 1주간의 투여 종료 후, mouse를 안락사 시킨 후 부검하여, colon 조직을 채취하였다. 채취된 콜론(colon) 조직은 대변을 제거하고, 생리식염수와 DEPC(Diethyl Pyrocarbonate) treated water, Invitrogen, Cat.no. 46-2224)로 순차적으로 세척한 후 액체질소 처리하여 급속 동결시킨 후 이후 과정 전까지 -70℃에 보관하였다.DNBS (Sigma-Aldrich, Cat.no. 556971-25G) solution prepared by dissolving in 3% concentration in ethanol to 7-week-old C57BL / 6 mice after 1 week of purification using mouse zone A model that induced colitis was formed through anal administration. Vehicles (vehicle, negative control (Nor.), 1% CMC) and drugs were repeatedly administered orally to mice in each experimental group for 7 days from the day before the day before DNBS administration. After one week of administration, the mice were euthanized and autopsied to collect colon tissue. The collected colon tissue removes feces, physiological saline and DEPC (Diethyl Pyrocarbonate) treated water, Invitrogen, Cat.no. 46-2224), followed by rapid freezing by liquid nitrogen treatment and storage at -70 ° C until further processing.
조직으로부터의 mRNA 분리를 위하여, 보관된 조직이 담긴 마이크로튜브(microtube)에 TriZol, Invitorgen TRIzol reagent, Cat.no.15596-018) 0.3 ml을 추가한 후 균질기(homogenizer)를 통해 파쇠하였다. 각 대조군과 실험군의 파쇠된 마우스 장 조직을 원심분리기 14,000rpm, 5 분 동안 침전 후 TriZol 0.7 ml을 추가 첨가한다. 조직이 완전히 녹은 것을 확인 한 뒤, 클로로포름(chloroform) 200 ul를 첨가하여 볼텍스(vortex) 하였다. 상온에 스탠딩하고 두 개의 층으로 분리되는 것을 확인하였다. 14,000 rpm 으로 15 분 원심분리 후 상층 약 400 ul를 동일 양의 아이소프로판올(isopropanol)과 잘 섞었다. 상온에서 10 분간 스탠딩 후 4℃, 14,000 rmp, 10 분 원심 분리하여 하얀색 침전 물질을 생성시키고, 상층액을 모두 제거하였다. 하얀색 침전 물질에 70 % 에탄올(ethanol) 700 ul을 넣고 가볍게 탭핑한 후 4℃, 14,000 rpm, 5 분간 원심분리 후 침전물만 남기고 에탄올을 제거하였다. 같은 방법으로 다시 침전물을 세정하였다. 세정 후 침전물만 남기고 에탄올을 완전히 제거하기 위해 37℃ 오븐에서 30분 건조 후, DEPC 처리된 물(DEPC treated water) 50 ul로 침전물을 녹였다. 이렇게 녹여 낸 침전물이 총 mRNA(total mRNA)로써 ITF의 mRNA 상대적 적량을 위한 전구체로 사용된다. 각 실험군에서 획득한 total mRNA는 Thermo fisher scientific 의 Nanodrop을 이용하여 농도를 측정하고 2.5 ug 의 total RNA를 사용하여 역전사 효소(reverse transcriptase, Thermo fisher scientific, Superscript III First strand synthesis system, #18080051)를 사용하여 cDNA합성을 수행하였다. 각 대조군과 실험군의 cDNA 1 ul 를 템플레이트(template)로 사용하고 Takara의 TB green (#RR420A)의 매뉴얼에 따라 반응 혼합 용액을 만들었다. 완성된 반응 혼합 용액은 real time PCR(Takara, Cycler Dice Real Time System III) mRNA 상대적 발현 값을 비교 분석하기 위해 사용하였다. 본 실험에 사용된 ITF의 상대적 발현 값은 베타-엑틴(beta-actin) 발현 값을 기준으로 하여 비교 분석 되었다. 그 결과는 도 2에 나타내었다.For mRNA separation from the tissue, 0.3 ml of TriZol, Invitorgen TRIzol reagent, Cat.no.15596-018) was added to the microtube containing the stored tissue, and then disrupted through a homogenizer. After separating the mouse intestinal tissue of each control group and the experimental group by centrifugation at 14,000 rpm for 5 minutes, 0.7 ml of TriZol is additionally added. After confirming that the tissue was completely dissolved, 200 ul of chloroform was added to vortex. It was confirmed that it was standing at room temperature and separated into two layers. After centrifugation at 14,000 rpm for 15 minutes, about 400 ul of the upper layer was well mixed with the same amount of isopropanol. After standing at room temperature for 10 minutes, 4 ℃, 14,000 rmp, centrifuged for 10 minutes to produce a white precipitate, and all the supernatant was removed. After adding 700 ul of 70% ethanol to the white precipitate, tapping lightly, centrifuged at 4 ° C, 14,000 rpm for 5 minutes, leaving only the precipitate and removing ethanol. The precipitate was washed again in the same manner. After washing, the precipitate was dissolved in 50 ul of DEPC treated water after drying for 30 minutes in a 37 ° C. oven to completely remove ethanol, leaving only the precipitate. The dissolved precipitate is used as a precursor for the relative amount of ITF mRNA as total mRNA. The total mRNA obtained in each experimental group was measured using Nanodrop of Thermo fisher scientific, and 2.5 ug of total RNA was used to reverse-transcribe enzyme (reverse transcriptase, Thermo fisher scientific, Superscript III First strand synthesis system, # 18080051). CDNA synthesis was performed. 1 ul of cDNA from each control group and the experimental group was used as a template, and a reaction mixture solution was prepared according to Takara's TB green (# RR420A) manual. The completed reaction mixture solution was used to compare and analyze real time PCR (Takara, Cycler Dice Real Time System III) mRNA relative expression values. The relative expression value of ITF used in this experiment was compared and analyzed based on the beta-actin expression value. The results are shown in FIG. 2.
DNBS로 유발시킨 Colitis 모델에서의 몸무게 및 colon 길이 변화 측정Measurement of changes in body weight and colon length in a DNBS-induced Colitis model
3% DNBS로 대장염(colitis)를 유발시키는 DNBS 마우스 모델에서, 본 발명의 화합물 A(실시예 109 화합물)를 -1일째부터 각각 15mg/kg 및 50mg/kg 처리한 후, 5일 동안 무게의 변화를 관찰하여 그 결과를 도 3에 나타내었다. 또한, 5일 후, 각각의 모델에서 결장(colon)을 체취한 뒤 그 길이를 관찰하였으며, 도 4에 결과를 나타내었다.In a DNBS mouse model inducing colitis with 3% DNBS, Compound A (Example 109 compound) of the present invention was treated at 15 mg / kg and 50 mg / kg, respectively, from Day -1, and then the weight was changed for 5 days. Observation was shown in Figure 3 the results. In addition, after 5 days, the colon was collected from each model and the length was observed, and the results are shown in FIG. 4.
도 3에 나타난 바와 같이, 대조군에 비하여 화합물 A를 처리한 모델에서 몸무게의 감소가 적은 것을 확인할 수 있고, 도 4에 나타난 바와 같이, 화합물 A를 처리한 모델에서 염증으로 인한 colon의 길이 축소를 방지하는 효과가 있음을 확인할 수 있다.As shown in Figure 3, it can be seen that the decrease in body weight is small in the model treated with Compound A compared to the control group, and as shown in Figure 4, the length reduction of colon due to inflammation is prevented in the model treated with Compound A. It can be confirmed that there is an effect.
제약 제제 및 투여의 경로Pharmaceutical formulations and routes of administration
본 발명의 조성물은 직접적으로 또는 당업계에 잘 알려진 적합한 담체 또는 부형제와 함께 제약 조성물로 송달될 수 있다. 치료의 본 방법은 IBD 환자나 위험에 있는 대상에게 효과적인 양의 본 발명의 화합물의 투여를 포함할 수 있다. 바람직한 구체예에서, 피험자는 포유동물 대상이고, 가장 바람직한 구체예에서, 피험자는 사람 대상이다.The compositions of the present invention can be delivered in pharmaceutical compositions either directly or in combination with suitable carriers or excipients well known in the art. This method of treatment may include administering an effective amount of a compound of the invention to an IBD patient or subject at risk. In a preferred embodiment, the subject is a mammalian subject, and in the most preferred embodiment, the subject is a human subject.
효과적인 양의 그러한 약제는 가장 효과적이고 편리한 경로 및 가장 적당한 제법이 될 수 있도록 일상적인 실험에 의해 쉽게 결정될 수 있다. 다양한 제제와 약물 송달 시스템은 당업계에서 이용 가능하다. 예를 들어, Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences를 참조할 수 있고, 적합한 투여의 경로는 경막 내, 직접 심실 내, 정맥 내, 복막 내, 코 안, 또는 눈 속 주사는 물론이고, 근육 내, 피하, 골수 내 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.Effective amounts of such agents can be readily determined by routine experimentation to be the most effective and convenient route and the most appropriate recipe. Various formulations and drug delivery systems are available in the art. For example, Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences, suitable routes of administration include intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, as well as intramuscular, subcutaneous, and intramedullary injections. Including, for example, oral, rectal, mucosal, nasal, or intestinal administration and parenteral delivery. The agent or composition thereof may be administered topically rather than systemically. For example, suitable agents can be delivered via injection or into a targeted drug delivery system, such as a storage or sustained release agent.
본 발명의 제약 조성물은 잘 알려진 방법 중 종래의 혼합, 용해, 과립화, 당의정-제조, 가루화, 유화, 캡슐화, 포착화, 또는 동결건조 프로세스와 같은 어떤 것에 의해 제조될 수 있다. 위에서 명시된 바와 같이, 본 발명의 조성물은 부형제 및 보조제와 같이, 활성 분자의 프로세싱을 제약 용도를 위한 제조로 촉진시키는 하나 이상의 생리적으로 허용 가능한 담체를 포함할 수 있다.The pharmaceutical compositions of the present invention can be prepared by any of the well-known methods, such as conventional mixing, dissolving, granulating, dragee-making, powdering, emulsifying, encapsulating, encapsulating, or lyophilizing processes. As indicated above, the compositions of the present invention may include one or more physiologically acceptable carriers, such as excipients and adjuvants, that facilitate the processing of the active molecule into manufacture for pharmaceutical use.
적절한 제제는 선택된 투여의 경로에 의존한다. 주사를 위해, 예를 들어, 조성물은 수성 용액에 바람직하게는 Hanks 용액, Ringer 용액, 또는 생리적 식염수 완충액과 같이 생리적으로 호환 가능한 완충액으로 조제화될 수 있다. 점막을 통한 또는 코 투여를 위해, 장벽으로 침투하기에 적당한 침투제는 제제에 사용된다. 그러한 침투제는 일반적으로 당업계에 알려져 있다. 본 발명의 바람직한 구체예에서, 본 발명의 화합물은 경구 투여를 위한 제제로 제조된다. 경구 투여를 위해, 화합물은 활성 화합물은 당업계에 공지된 약학적으로 허용 가능한 담체와 조합시킴으로써 쉽게 조제화될 수 있다. 그러한 담체는 본 발명의 화합물은 대상에 의한 경구 섭취를 위해 정제, 알약, 당의정, 캡슐, 액체, 겔, 시럽, 슬러리, 현탁액 등으로 조제화 되도록 한다. 화합물은 예를 들어, 코코아 버터 또는 다른 글리세리드와 같은 종래의 좌약 베이스를 함유하는 좌약 또는 정체 관장액과 같은 직장 조성물로 또한 조제될 수 있다.Proper formulation is dependent upon the route of administration chosen. For injection, for example, the composition may be formulated in an aqueous solution, preferably with a physiologically compatible buffer, such as Hanks' solution, Ringer's solution, or physiological saline buffer. For administration via the mucous membrane or for nasal administration, penetrants suitable for penetration into the barrier are used in the formulation. Such penetrants are generally known in the art. In a preferred embodiment of the invention, the compounds of the invention are prepared in preparations for oral administration. For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers allow the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a subject. The compounds can also be formulated with rectal compositions, such as suppositories or retention enemas, containing conventional suppository bases, for example cocoa butter or other glycerides.
경구 용도를 위한 제약 제제는 만일 원한다면, 정제 또는 당의정 코어를 얻기 위해 적합한 보조제를 첨가한 후에, 선택적으로 결과의 혼합물을 그라인딩하고, 미립의 혼합물을 가공하여, 고체 부형제로서 얻을 수 있다. 적합한 부형제는 특히, 유당, 수크로스, 만니톨, 또는 소르비톨을 포함하는 당과 같은 충전재; 셀룰로오스 제제, 예를 들어, 옥수수 전분, 밀 전분, 쌀 전분, 감자 전분, 젤라틴, 트래거캔스 고무, 메틸 셀룰로오스, 히드록시프로필메틸-셀룰로오스, 나트륨 카르복시메틸셀룰로오스, 및/또는 폴리비닐피롤리돈 (PVP)이다. 만일 원한다면, 이를테면 가교-결합된 폴리비닐 피롤리돈, 한천, 또는 알긴산 또는 나트륨 알기네이트와 같은 그것의 염과 같은 붕괴제가 첨가될 수 있다. 또한, 나트륨 도데실술페이트와 같은 습윤제가 포함될 수 있다.Pharmaceutical formulations for oral use can be obtained as solid excipients, if desired, after adding suitable auxiliaries to obtain tablets or dragee cores, optionally grinding the resulting mixture and processing the particulate mixture. Suitable excipients are, inter alia, fillers such as lactose, sucrose, mannitol, or sugars comprising sorbitol; Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth rubber, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone ( PVP). If desired, disintegrants such as cross-linked polyvinyl pyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate can be added. In addition, wetting agents such as sodium dodecyl sulfate may be included.
당의정 코어는 적합한 코팅이 제공된다. 이러한 목적을 위해서, 농축 당 용액이 사용될 수 있고, 이것은 선택적으로 아라비아 고무, 활석, 폴리비닐 피롤리돈, 카르보폴 겔, 폴리에틸렌 글리콜, 및/또는 타이타늄 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.Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally be 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 can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound dosages.
경구 투여를 위한 제약 제제는 젤라틴으로 만들어진 부드러운, 밀봉의 캡슐 및 글리세롤 또는 소르비톨과 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, 선택적으로, 안정화제와 혼합하여 활성 성분을 함유할 수 있다. 연질 캡슐에서, 활성 화합물은 지방오일, 액체 파라핀, 또는 액체 폴리에틸렌 글리콜과 같은 적합한 액체에 용해되거나 또는 현탁될 수 있다. 게다가, 안정화제가 첨가될 수 있다. 경구 투여를 위한 모든 제제는 그러한 투여에 적합한 용량이 되어야 한다.Pharmaceutical formulations for oral administration include soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol, as well as push-fit capsules made of gelatin. 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. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
하나의 구체예에서, 본 발명의 화합물은 피부 패치를 통해서와 같이 경피로, 또는 국소로 투여될 수 있다. 한가지 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 들어, 위치 특이적 송달이 바람직한 상황에 적합할 수 있다.In one embodiment, the compounds of the invention can be administered transdermally or topically, such as through a skin patch. In one aspect, transdermal or topical formulations of the invention may additionally include one or multiple penetration enhancers or other effectors, including agents that enhance the transport of the delivered compound. Transdermal or topical administration may be suitable, for example, in situations where location specific delivery is desired.
흡입에 의한 투여를 위해, 본 발명에 따르는 용도를 위한 화합물은 적합한 분사제, 예를 들어, 다이클로로다이플루오로메테인, 트라이클로로플루오로메테인, 다이클로로테트라플루오로에테인, 탄소 다이옥사이드, 또는 어떠한 다른 적합한 가스의 사용과 함께, 가압 팩 또는 분무기로부터 에어로졸 스프레이 제시의 형태로 편리하게 전달된다. 가압 에어로졸의 경우에, 적당한 용량 유닛은 계량된 양을 전달하기 위한 밸브를 제공함으로써 결정될 수 있다. 예를 들어, 흡입기 또는 취입기에서 사용하기 위한 젤라틴의 캡슐과 카트리지가 조제화될 수 있다. 이들은 전형적으로 화합물과 유당 또는 전분과 같은 적합한 분말 베이스의 분말 믹스를 함유한다. 주사에 의한 예를 들어, 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 매개체중의 현탁액, 용액, 또는 에멀젼과 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.For administration by inhalation, the compounds for use according to the invention are suitable propellants, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or Along with the use of any other suitable gas, it is conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer. In the case of pressurized aerosols, a suitable dosage unit can be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator can be formulated. They typically contain a powder mix of a compound and a suitable powder base such as lactose or starch. Compositions prepared for parenteral administration by injection, for example by injection or continuous infusion, can be presented in unit dose form, for example in ampoules or multi-dose containers, with added preservatives. The composition may take the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain chemicals such as suspending agents, stabilizers and / or dispersing agents. Formulations for parenteral administration include aqueous solutions or other compositions in aqueous form.
활성 화합물의 현탁액은 또한 적당한 유성 주사 현탁액으로 제조될 수 있다. 적합한 친유성 용매 또는 매개체는 참깨 오일과 같은 지방 오일 및 에틸 올레에이트 또는 트라이글리세리드, 또는 리포솜와 같은 합성 지방산 에스테르를 포함한다. 수성 주사 현탁액은 나트륨 카르복시메틸 셀룰로오스, 소르비톨, 또는 덱스트란과 같은 현탁액의 점도를 증가시키는 물질을 함유할 수 있다. 선택적으로, 현탁액은 또한 고 농축 용액의 제조를 가능하게 하기 위해 적합한 안정화제 또는 화합물의 용해도를 증가시키는 작용제를 함유할 수 있다. 대안으로서는, 활성 성분은 적합한 매개체, 예를 들어, 무균 발열원-없는 물과 함께 구성을 위해 분말 형태가 될 수 있다.Suspensions of the active compounds can also be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or mediators 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 that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to enable the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable medium, for example, sterile pyrogen-free water.
위에서 언급된 바와 같이, 본 발명의 조성물은 또한 저장 제제로서 조제될 수 있다. 그러한 장기 작용 제제는 이식(예를 들어, 피하로 또는 근육 내로)에 의해 또는 근육 내 주사에 의해 투여될 수 있다. 따라서, 예를 들어, 본 발명 화합물은 적합한 폴리머 또는 소수성 물질(예를 들어 허용 가능한 오일 중의 에멀젼으로서) 또는 이온 교환 수지로, 또는 아주 조금 가용성인 유도체로서, 예를 들어, 아주 조금 가용성인 염으로서 조제될 수 있다.As mentioned above, the compositions of the present invention can also be formulated as a storage agent. Such long acting agents can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention are suitable polymers or hydrophobic substances (eg as emulsions in acceptable oils) or ion exchange resins, or as very soluble derivatives, for example as very soluble salts Can be dispensed.
대안으로서는, 소수성 분자에 대한 다른 송달 시스템이 채택될 수 있다. 리포솜과 에멀젼은 소수성 약물에 대해 송달 매개체 또는 담체의 잘 알려진 예이다. 리포솜 송달 시스템은 유전자-송달 시스템의 문맥에서 위에서 논의된다. 다이메틸술폭사이드와 같은 특정 유기 용매는 또한 비록 보통 더 큰 독성의 대가이지만 채택될 수 있다. 추가적으로, 화합물은 투과될 효과적인 양의 조성물을 함유하는 고체 소수성 폴리머의 반-투과성 매트릭스와 같은 지속-방출 시스템을 사용하여 송달될 수 있다. 다양한 지속-방출 물질은 확립되어 있고 당업자들에게 이용 가능하다. 지속-방출 캡슐은 그들의 화학 성질에 의존하여, 100일 이하에 걸쳐 몇 주 동안 화합물을 방출할 수 있다. 치료 시약의 화학 성질 및 생물학적 안정성에 의존하여, 단백질 안정화에 대한 추가의 전략이 채택될 수 있다.Alternatively, other delivery systems for hydrophobic molecules can be employed. Liposomes and emulsions are well known examples of delivery mediators or carriers for hydrophobic drugs. Liposomal delivery systems are discussed above in the context of gene-delivery systems. Certain organic solvents, such as dimethylsulfoxide, can also be employed, although usually at the cost of greater toxicity. Additionally, the compound can be delivered using a sustained-release system, such as a semi-permeable matrix of solid hydrophobic polymers containing an effective amount of the composition to be permeated. Various sustained-release materials are established and available to those skilled in the art. Sustained-release capsules can release the compound for several weeks over 100 days or less, depending on their chemical properties. Depending on the chemical properties and biological stability of the therapeutic reagents, additional strategies for protein stabilization can be employed.
본 발명의 조성물은 만일 원한다면, 활성 성분을 함유하는 하나 이상의 단위 용량 형태를 함유하는 팩 또는 디스펜서 디바이스에 제시될 수 있다. 그러한 팩 또는 디바이스는 예를 들어, 발포 팩과 같은 금속 또는 플라스틱 호일을 포함할 수 있다.The composition of the present invention can be presented in a pack or dispenser device containing one or more unit dose forms containing the active ingredient, if desired. Such packs or devices can include metal or plastic foils, for example, foam packs.
팩 또는 디스펜서 디바이스는 투여를 위한 지시사항이 수반될 수 있다.The pack or dispenser device may be accompanied by instructions for administration.
호환 가능한 제약 담체로 조제된 본 발명의 화합물을 포함하는 조성물은 또한 제조되고, 적당한 용기에 넣고, 표시된 상태의 치료를 위해 라벨화될 수 있다. 라벨에 표시된 적합한 상태는 염증성장질환(IBD)이 주된 표시인 상태, 장애, 또는 질병의 치료를 포함할 수 있다.Compositions comprising the compounds of the invention formulated with compatible pharmaceutical carriers can also be prepared, placed in suitable containers, and labeled for treatment of the indicated condition. Suitable conditions indicated on the label may include treatment of a condition, disorder, or disease in which inflammatory growth disease (IBD) is the primary indication.
본 발명의 이들 및 다른 구체예는 본원의 개시 내용으로부터 당업자들에게 쉽게 수행될 수 있다.These and other embodiments of the invention can be readily carried out by those skilled in the art from the disclosure herein.

Claims (7)

  1. 화학식 Ⅰ의 화합물 또는 그의 약학적으로 허용 가능한 염, 에스테르 또는 프로드러그를 포함하는, 염증성 장질환(IBD: Inflamatory Bowel Disease)의 치료 또는 예방용 조성물:A composition for the treatment or prevention of inflammatory bowel disease (IBD) comprising a compound of formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:
    [화학식 Ⅰ][Formula Ⅰ]
    Figure PCTKR2019011832-appb-img-000086
    Figure PCTKR2019011832-appb-img-000086
    상기 식에서,In the above formula,
    W, X, Y, Z가 각각 위치에 따라 독립적으로 C(R6), N, C=O, 또는 N-옥사이드(N-oxide)이고, 이중 하나 이상은 반드시 N이거나 N-옥사이드이며,W, X, Y, and Z are each independently C (R6), N, C = O, or N-oxide, depending on the position, at least one of which is necessarily N or N-oxide,
    R6이 수소, 할로겐, C 1~ 3알킬, C 3~ 6싸이크로 알킬, C 6- 12아릴 또는 C 3- 12헤테로아릴이고,R6 is hydrogen, halogen, C 1 ~ 3 alkyl, C 3 ~ 6 Im croissant alkyl, C 6- 12 aryl, or C 3- 12 heteroaryl,
    R5가 수소 또는 C 1~3 알킬이고,R5 is hydrogen or C 1-3 alkyl,
    R1이 수소, C 1~ 10알킬, C 1~ 10알킬 사이크로알킬, 아릴C 1 ~ 5알킬, C 1~ 5알킬아릴, C 1~ 5알킬헤테로알릴, C 2~ 5알캔닐, C 2~ 5알키닐, C 2~ 5알키닐아릴, C 3~ 8싸이크로 알킬, 아실, 카르보닐 산, 카르보닐, C 1~ 10카르보닐에스터, C 6~ 12아릴 및 C 3- 12헤테로아릴로 이루어진 군으로부터 선택되고,R1 is hydrogen, C 1 ~ 10 alkyl, C 1 ~ 10 alkyl, aryl C 1 alkyl sayikeu 1-5 alkyl, C 1 ~ 5 alkyl, aryl, C 1 to 5 alkyl heteroaryl allyl, C 2 - 5 Al kaennil, C 2 1-5 alkynyl, C 2 - 5 alkynyl, aryl, C 3 - 8 Cy croissant alkyl, acyl, carbonyl acid, carbonyl, C 1 ~ 10-carbonyl ester, C 6 - 12 aryl, and C 3- 12 heteroaryl Is selected from the group consisting of,
    상기 W, X, Y, Z, R6, R5 및 R1이 각각 독립적으로 아민, 하이드록시, 나이트로겐, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~ 5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, C 6- 12아릴, C 3- 12헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있으며,Wherein W, X, Y, Z, R6, R5 and R1 are each independently selected from amine, hydroxyl, nitrogen, halogen, acyl, C 1 ~ 5 alkyl, C 3 to 7 sayikeu alkyl, C 3-7 heteroaryl sayikeu roal Kiel, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl, C 2 ~ 3 alkynyl, aryl, CO 2 H, -C (= O) C 1 ~ 5 alkyl, -C (= O) NHC 1 ~ 5-alkyl, -C (= O) N ( C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, C 6- 12 aryl, C 3- 12 heteroaryl, sulfonyl , the group consisting of C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl piperidine, piperazine, C 1- 3 alkyl piperazine, -N (C 1 ~ 4 alkyl) 2, and aniline It may be substituted with one or more substituents selected from,
    상기 치환기가 아민, 하이드록시, 나이트로, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~ 5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, 아릴, 헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고,In which the substituents amine, hydroxy, nitro, halogen, acyl, C 1 ~ 5 alkyl, C 3 to 7 sayikeu alkyl, a C 3-7 heteroaryl sayikeu, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl Neil, C 2 ~ 3 alkynyl aryl, CO 2 H, -C (= O) C 1 ~ 5 alkyl, -C (= O) NHC 1 ~ 5 alkyl, -C (= O) N (C 1 ~ 5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, aryl, heteroaryl, sulfonyl, C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl-piperidine , piperazine, C 1- 3 may be substituted with alkyl piperazine, -N (C 1 ~ 4 alkyl) one or more substituents selected from the group consisting of 2 and aniline,
    R2가 식 V-1 및 V-2로 대표되고,R2 is represented by formulas V-1 and V-2,
    Figure PCTKR2019011832-appb-img-000087
    Figure PCTKR2019011832-appb-img-000087
    식 V-1 및 V-2에서,In formulas V-1 and V-2,
    E가 -N(R7)-이고,E is -N (R7)-,
    R7이 H 또는 C 1~ 5알킬이고, R7이 C 1~5인 경우 중 R7가 R8 또는 R9과 탄소로 연결되어 C 3~7싸이크로알킬을 이룰 수 있고,R7 is H or C 1 ~ 5 alkyl, R7 is a C 1 to 5 in the case of R7 through to R8 or R9 and the carbon and to achieve a C 3 ~ 7 Im croissant alkyl,
    R8과 R9이 각각 독립적으로 H, C 1- 5알킬, C 1~ 5알킬알콜, 또는 C 1~ 5알킬CO 2H이고, R8과 R9이 C 1- 5알킬인 경우 R8과 R9이 탄소로 연결되어 C 3~ 5사이크로알킬을 이룰 수 있고,And R8 and R9 are each independently H, C 1- 5 alkyl, C 1 ~ 5 alkyl alcohol, or C 1 ~ 5 alkyl, CO 2 H, R8 and R9 is a C 1- 5 alkyl, if R8 and R9 with the carbon are connected and can achieve an alkyl to C 3 ~ 5 sayikeu,
    R10이 H 또는 C 1-5알킬이고,R10 is H or C 1-5 alkyl,
    식 V-2에서 n은 1 또는 2이다.In formula V-2, n is 1 or 2.
  2. 화학식 Ⅰ의 화합물 또는 그의 약학적으로 허용 가능한 염, 에스테르 또는 프로드러그를 포함하는, 염증성 사이토카인 저해용 조성물.A composition for inhibiting inflammatory cytokines comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof.
  3. 화학식 Ⅰ의 화합물 또는 그의 약학적으로 허용 가능한 염, 에스테르 또는 프로드러그를 포함하는, 장표면 장벽 기능(barrier function) 개선 및 장벽 밀착연접(tight junction) 복구용 조성물.A composition for improving long surface barrier function and restoring barrier tight junction, comprising a compound of Formula I or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  4. 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 화학식 I의 W가 N인 것인, 조성물.The composition according to any one of claims 1 to 3, wherein W in the formula (I) is N.
  5. 제1항 내지 제3항 중 어느 한 항에 있어서, R1이 페닐에틸이고,The compound according to any one of claims 1 to 3, wherein R1 is phenylethyl,
    R2가 2-포름아미도아세트산(2-formamidoacetic acid)이고,R2 is 2-formamidoacetic acid,
    상기 R1 및 R2가 아민, 하이드록시, 나이트로, 할로겐, 아실, C 1~ 5알킬, C 3~ 7사이크로알킬, C 3~ 7헤테로사이크로알킬, C 2~ 3알캔닐, C 2~ 3알키닐, C 2~ 3알키닐 아릴, CO 2H, -C(=O)C 1~ 5알킬, -C(=O)NHC 1 ~ 5알킬, -C(=O)N(C 1~ 5알킬) 2, -OC 1~ 5알킬, -O아릴, -O헤테로아릴, 아릴, 헤테로 아릴, 설포닐, C 1~ 10알킬아민, 모폴린, 피페리딘, C 1~ 3알킬피페리딘, 피페라진, C 1- 3알킬피페라진, -N(C 1~ 4알킬) 2 및 아닐린으로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환되는 것인, 조성물.Wherein R1 and R2 are amine, hydroxy, nitro, halogen, acyl, C 1 ~ 5 alkyl, C 3 to 7 sayikeu alkyl, a C 3-7 heteroaryl sayikeu, C 2 ~ 3 Al kaennil, C 2 ~ 3 alkynyl, C 2 to 3 alkynyl aryl, CO 2 H, -C (= O) C 1 to 5 alkyl, -C (= O) NHC 1 to 5 alkyl, -C (= O) N (C 1 1-5 alkyl) 2, -OC 1 ~ 5 alkyl, -O aryl, -O-heteroaryl, aryl, heteroaryl, sulfonyl, C 1 ~ 10 alkyl amine, morpholine, piperidine, C 1 ~ 3 alkyl blood the composition of piperidine, piperazine, to C 3 alkyl-piperazin-1-, -N (C 1 ~ 4 alkyl) substituted with one or more substituents selected from the group consisting of 2 and aniline.
  6. 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 화학식 I로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택되는 것인, 조성물:The composition according to any one of claims 1 to 3, wherein the compound represented by the formula (I) is selected from the group consisting of the following compounds:
    2-({6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5 -yl} formamido) acetic acid,
    2-({6-hydroxy-3-methyl-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3-methyl-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    4-{6-hydroxy-3-methyl-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}-4-oxobutanoic acid,4- {6-hydroxy-3-methyl-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12- pentaen-5-yl} -4-oxobutanoic acid,
    2-({6-hydroxy-3-methyl-4-oxo-8-thia-3,13-diazatricyclo[7.4.0.0 2,7] trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3-methyl-4-oxo-8-thia-3,13-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-methyl-4-oxo-8-thia-3,13-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3-methyl-4-oxo-8-thia-3,13-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-({3-ethyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-ethyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-3-(2-methylpropyl)-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-3- (2-methylpropyl) -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5 , 10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[12-chloro-6-hydroxy-3-(2-methylpropyl)-4-oxo-8-thia-3,11-diazatri-cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[12-chloro-6-hydroxy-3- (2-methylpropyl) -4-oxo-8-thia-3,11-diazatri-cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[12-chloro-6-hydroxy-3-(2-methylpropyl)-4-oxo-8-thia-3,10-diazatri-cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid, 2-{[12-chloro-6-hydroxy-3- (2-methylpropyl) -4-oxo-8-thia-3,10-diazatri-cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[3-(cyclopropylmethyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[3- (cyclopropylmethyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10 , 12-pentaen-5-yl] formamido} acetic acid,
    2-{[3-(2-cyclopropylethyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[3- (2-cyclopropylethyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5 , 10,12-pentaen-5-yl] formamido} acetic acid,
    2-({3-cyclopentyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7] trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-cyclopentyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-({3-cyclohexyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7] trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-cyclohexyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-({3-cycloheptyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7] trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-cycloheptyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-{[3-(cyclohexylmethyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7] trideca- 1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid2-{[3- (cyclohexylmethyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca- 1 (9), 2 (7), 5,10 , 12-pentaen-5-yl] formamido} acetic acid
    2-{[6-hydroxy-3-(oxan-4-ylmethyl)-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[6-hydroxy-3- (oxan-4-ylmethyl) -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[3-(2-cyclohexylethyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[3- (2-cyclohexylethyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5 , 10,12-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-3-[2-(oxan-4-yl)ethyl]-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3- [2- (oxan-4-yl) ethyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9) , 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-4-oxo-3-[2-(piperidin-1-yl)ethyl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-4-oxo-3- [2- (piperidin-1-yl) ethyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (13) , 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(morpholin-4-yl)ethyl]-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-3- [2- (morpholin-4-yl) ethyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (13) , 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-4-oxo-3-(3-phenylprop-2-yn-1-yl)-8-thia-3,10-diazatri-cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[6-hydroxy-4-oxo-3- (3-phenylprop-2-yn-1-yl) -8-thia-3,10-diazatri-cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-11-methyl-4-oxo-3-(3-phenylprop-2-yn-1-yl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl] formamido}acetic acid,2-{[6-hydroxy-11-methyl-4-oxo-3- (3-phenylprop-2-yn-1-yl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca -1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-({3-[3-(4-fluorophenyl)prop-2-yn-1-yl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido) acetic acid,2-({3- [3- (4-fluorophenyl) prop-2-yn-1-yl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[3-(4-fluorophenyl)prop-2-yn-1-yl]-6-hydroxy- 11-methyl-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido)acetic acid,2-({3- [3- (4-fluorophenyl) prop-2-yn-1-yl] -6-hydroxy- 11-methyl-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-4-oxo-3-(5-phenylpenta-2,4-diyn-1-yl)-8-thia-3,10- diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[6-hydroxy-4-oxo-3- (5-phenylpenta-2,4-diyn-1-yl) -8-thia-3,10- diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[3-(1-ethyl-1H-pyrazol-4-yl)-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[3- (1-ethyl-1H-pyrazol-4-yl) -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[3-(4-fluorophenyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0. 0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl]formamido}acetic acid,2-{[3- (4-fluorophenyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0. 0 2,7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-4-oxo-3-[4-(trifluoromethyl)phenyl]-8-thia-3,10-diazatri-cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-4-oxo-3- [4- (trifluoromethyl) phenyl] -8-thia-3,10-diazatri-cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-4-oxo-3-[4-(trifluoromethoxy)phenyl]-8-thia-3,10-diazatri- cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-4-oxo-3- [4- (trifluoromethoxy) phenyl] -8-thia-3,10-diazatri-cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-11-methyl-4-oxo-3-[4-(trifluoromethoxy)phenyl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido)acetic acid,2-({6-hydroxy-11-methyl-4-oxo-3- [4- (trifluoromethoxy) phenyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9) , 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-{[3-(4-cyclopropylphenyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[3- (4-cyclopropylphenyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5 , 10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[3-(4-acetamidophenyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[3- (4-acetamidophenyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5 , 10,12-pentaen-5-yl] formamido} acetic acid,
    2-({3-[4-(dimethylcarbamoyl)phenyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3- [4- (dimethylcarbamoyl) phenyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-3-(4-methanesulfonamidophenyl)-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl]formamido} acetic acid,2-{[6-hydroxy-3- (4-methanesulfonamidophenyl) -4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl] formamido} acetic acid,
    2-[(3-{4-[(2,2-dimethylpropoxy)methyl]phenyl}-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl) formamido]acetic acid,2-[(3- {4-[(2,2-dimethylpropoxy) methyl] phenyl} -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-({6-hydroxy-3-[4-(morpholin-4-yl)phenyl]-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3- [4- (morpholin-4-yl) phenyl] -4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[4-(4-methylpiperazin-1-yl)phenyl]-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl} formamido)acetic acid,2-({6-hydroxy-3- [4- (4-methylpiperazin-1-yl) phenyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 13), 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-{[3-(4-chloro-3-fluorophenyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[3- (4-chloro-3-fluorophenyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-3-(1-methyl-1H-indazol-5-yl)-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-3- (1-methyl-1H-indazol-5-yl) -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (13 ), 2 (7), 5,9,11-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-4-oxo-3-(3,4,5-trimethoxyphenyl)-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3- (3,4,5-trimethoxyphenyl) -8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-11-methyl-4-oxo-3-(3,4,5-trimethoxyphenyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl] formamido}acetic acid,2-{[6-hydroxy-11-methyl-4-oxo-3- (3,4,5-trimethoxyphenyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-({3-benzyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca -1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-benzyl-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca -1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-({3-benzyl-6-hydroxy-4-oxo-8-thia-3,13-diazatricyclo[7.4.0.0 2,7]trideca -1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-benzyl-6-hydroxy-4-oxo-8-thia-3,13-diazatricyclo [7.4.0.0 2,7 ] trideca -1 (9), 2 (7), 5,10,12 -pentaen-5-yl} formamido) acetic acid,
    2-({13-benzyl-10-hydroxy-12-oxo-8-thia-3,6,13-triazatricyclo[7.4.0.0 2,7] trideca-1(9),2(7),3,5,10-pentaen-11-yl}formamido)acetic acid,2-({13-benzyl-10-hydroxy-12-oxo-8-thia-3,6,13-triazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 3,5 , 10-pentaen-11-yl} formamido) acetic acid,
    (2S)-2-({13-benzyl-10-hydroxy-12-oxo-8-thia-3,6,13-triazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),3,5,10-pentaen-11-yl}formamido) propanoic acid.(2S) -2-({13-benzyl-10-hydroxy-12-oxo-8-thia-3,6,13-triazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 3,5,10-pentaen-11-yl} formamido) propanoic acid.
    2-{[6-hydroxy-4-oxo-3-(pyridin-4-ylmethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3- (pyridin-4-ylmethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-4-oxo-3-(pyridin-3-ylmethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3- (pyridin-3-ylmethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-4-oxo-3-(pyridin-2-ylmethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3- (pyridin-2-ylmethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-({3-[(4-fluorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-[(4-fluorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7 ), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(4-chlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(4-chlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    (2S)-2-({3-[(4-chlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) propanoic acid,(2S) -2-({3-[(4-chlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) propanoic acid,
    3-({3-[(4-chlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) propanoic acid,3-({3-[(4-chlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) propanoic acid,
    2-({3-[(3-chlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(3-chlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2-chlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,13-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(2-chlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,13-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    (2S)-2-({3-[(2-chlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,13-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) propanoic acid,(2S) -2-({3-[(2-chlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,13-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) propanoic acid,
    2-({3-[(2-chlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(2-chlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({13-[(2-chlorophenyl)methyl]-10-hydroxy-12-oxo-8-thia-3,6,13-triaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),3,5,10-pentaen-11-yl}formamido) acetic acid,2-({13-[(2-chlorophenyl) methyl] -10-hydroxy-12-oxo-8-thia-3,6,13-triaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 3,5,10-pentaen-11-yl} formamido) acetic acid,
    2-({3-[(5-chloropyridin-2-yl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-[(5-chloropyridin-2-yl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2,3-dichlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-[(2,3-dichlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2,5-dichlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-[(2,5-dichlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2,6-dichlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(2,6-dichlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2,4-dichlorophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(2,4-dichlorophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(4-chloro-3-fluorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3- [2- (4-chloro-3-fluorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-[(6-hydroxy-4-oxo-3-{[4-(trifluoromethyl)phenyl]methyl}-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido] acetic acid,2-[(6-hydroxy-4-oxo-3-{[4- (trifluoromethyl) phenyl] methyl} -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(6-hydroxy-4-oxo-3-{[2-(trifluoromethyl)phenyl]methyl}-8-thia-3,10- diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido] acetic acid,2-[(6-hydroxy-4-oxo-3-{[2- (trifluoromethyl) phenyl] methyl} -8-thia-3,10- diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-({6-hydroxy-3-[(4-hydroxyphenyl)methyl]-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3-[(4-hydroxyphenyl) methyl] -4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(4-bromophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(4-bromophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    (2S)-2-({3-[(4-bromophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) propanoic acid,(2S) -2-({3-[(4-bromophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) propanoic acid,
    3-({3-[(4-bromophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) propanoic acid,3-({3-[(4-bromophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) propanoic acid,
    1-{3-[(4-bromophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaene-5-amido} cyclopropane-1- carboxylic acid,1- {3-[(4-bromophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaene-5-amido} cyclopropane-1-carboxylic acid,
    2-({13-[(4-bromophenyl)methyl]-10-hydroxy-12-oxo-8-thia-3,6,13-triazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),3,5,10-pentaen-11-yl}formamido) acetic acid,2-({13-[(4-bromophenyl) methyl] -10-hydroxy-12-oxo-8-thia-3,6,13-triazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 3,5,10-pentaen-11-yl} formamido) acetic acid,
    2-({3-[(3-bromophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(3-bromophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2-bromophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(2-bromophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2-chloro-4-methoxyphenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-[(2-chloro-4-methoxyphenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9) , 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(4-ethynylphenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(4-ethynylphenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[(4-methoxyphenyl)methyl]-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid, 2-({6-hydroxy-3-[(4-methoxyphenyl) methyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7 ), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(4-cyanophenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3-[(4-cyanophenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7 ), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-[(6-hydroxy-4-oxo-3-{[4-(trifluoromethoxy)phenyl]methyl}-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido] acetic acid,2-[(6-hydroxy-4-oxo-3-{[4- (trifluoromethoxy) phenyl] methyl} -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(6-hydroxy-4-oxo-3-{[2-(trifluoromethoxy)phenyl]methyl}-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido] acetic acid,2-[(6-hydroxy-4-oxo-3-{[2- (trifluoromethoxy) phenyl] methyl} -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(6-hydroxy-4-oxo-3-{[4-(propan-2-yl)phenyl]methyl}-8-thia-3,10- diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido] acetic acid,2-[(6-hydroxy-4-oxo-3-{[4- (propan-2-yl) phenyl] methyl} -8-thia-3,10- diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(3-{[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]methyl}-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl) formamido]acetic acid,2-[(3-{[3-fluoro-4- (2,2,2-trifluoroethoxy) phenyl] methyl} -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2 , 7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(6-hydroxy-3-{[4-(2-methoxyethoxy)phenyl]methyl}-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl) formamido]acetic acid,2-[(6-hydroxy-3-{[4- (2-methoxyethoxy) phenyl] methyl} -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-({3-[(4-tert-butylphenyl)methyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3-[(4-tert-butylphenyl) methyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-{[3-(2H-1,3-benzodioxol-5-ylmethyl)-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[3- (2H-1,3-benzodioxol-5-ylmethyl) -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-[(3-{[4-(cyclopropylmethoxy)phenyl]methyl}-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido]acetic acid,2-[(3-{[4- (cyclopropylmethoxy) phenyl] methyl} -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(3-{[4-(2-cyclopropylethynyl)phenyl]methyl}-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl) formamido]acetic acid,2-[(3-{[4- (2-cyclopropylethynyl) phenyl] methyl} -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(3-{[4-(2-cyclopentylethynyl)phenyl]methyl}-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl) formamido]acetic acid,2-[(3-{[4- (2-cyclopentylethynyl) phenyl] methyl} -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-{[3-({4-[(2,2-dimethylpropoxy)methyl]phenyl}methyl)-6-hydroxy-4-oxo -8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[3-({4-[(2,2-dimethylpropoxy) methyl] phenyl} methyl) -6-hydroxy-4-oxo -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-4-oxo-3-[(3,4,5-trimethoxyphenyl)methyl]-8-thia-3,10- diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-4-oxo-3-[(3,4,5-trimethoxyphenyl) methyl] -8-thia-3,10- diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9) , 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-4-oxo-3-[(4-phenylphenyl)methyl]-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-4-oxo-3-[(4-phenylphenyl) methyl] -8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    tert-butyl 2-({6-hydroxy-4-oxo-3-[(4-phenylphenyl)methyl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetate,tert-butyl 2-({6-hydroxy-4-oxo-3-[(4-phenylphenyl) methyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetate,
    2-[(3-{[4-(4-fluorophenyl)phenyl]methyl}-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido] acetic acid,2-[(3-{[4- (4-fluorophenyl) phenyl] methyl} -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(6-hydroxy-3-{[4-(4-methylpiperazin-1-yl)phenyl]methyl}-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido]acetic acid,2-[(6-hydroxy-3-{[4- (4-methylpiperazin-1-yl) phenyl] methyl} -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca -1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-{[6-hydroxy-4-oxo-3-({4-[4-(trifluoromethyl)phenyl]phenyl}methyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3-({4- [4- (trifluoromethyl) phenyl] phenyl} methyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca- 1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-4-oxo-3-[(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)methyl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-4-oxo-3-[(4-{[5- (trifluoromethyl) pyridin-2-yl] oxy} phenyl) methyl] -8-thia-3,10-diazatricyclo [7.4. 0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-4-oxo-3-({6-[4-(trifluoromethyl)phenoxy]pyridin-3-yl} methyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3-({6- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} methyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2, 7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-3-({1-[(4-methoxyphenyl)methyl]piperidin-4-yl}methyl)-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen -5-yl]formamido}acetic acid,2-{[6-hydroxy-3-({1-[(4-methoxyphenyl) methyl] piperidin-4-yl} methyl) -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2, 7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-4-oxo-3-({6-[4-(propan-2-yl)phenoxy]pyridin-3-yl}methyl) -8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3-({6- [4- (propan-2-yl) phenoxy] pyridin-3-yl} methyl) -8-thia-3,10-diazatricyclo [7.4 .0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-[(6-hydroxy-4-oxo-3-{[6-(4-propylphenoxy)pyridin-3-yl]methyl}-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido]acetic acid, 2-[(6-hydroxy-4-oxo-3-{[6- (4-propylphenoxy) pyridin-3-yl] methyl} -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca -1 (9), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(3-{[4-(2-cyclohexylethynyl)phenyl]methyl}-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl) formamido]acetic acid,2-[(3-{[4- (2-cyclohexylethynyl) phenyl] methyl} -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-[(6-hydroxy-4-oxo-3-{[4-(2-phenylethynyl)phenyl]methyl}-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido] acetic acid,2-[(6-hydroxy-4-oxo-3-{[4- (2-phenylethynyl) phenyl] methyl} -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-{[6-hydroxy-4-oxo-3-({4-[2-(pyridin-3-yl)ethynyl]phenyl}methyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3-({4- [2- (pyridin-3-yl) ethynyl] phenyl} methyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2, 7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-4-oxo-3-[2-(thiophen-3-yl)ethyl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid, 2-({6-hydroxy-4-oxo-3- [2- (thiophen-3-yl) ethyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9) , 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(5-methylthiophen-2-yl)ethyl]-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-3- [2- (5-methylthiophen-2-yl) ethyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(1H-imidazol-1-yl)ethyl]-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-3- [2- (1H-imidazol-1-yl) ethyl] -4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-4-oxo-3-[2-(2H-1,2,3-triazol-2-yl)ethyl]-8-thia-3,10- diazatricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-4-oxo-3- [2- (2H-1,2,3-triazol-2-yl) ethyl] -8-thia-3,10- diazatricyclo [7.4.0.0 2, 7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-4-oxo-3-[2-(1H-1,2,3-triazol-1-yl)ethyl]-8-thia-3,10- diazatricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl} formamido)acetic acid,2-({6-hydroxy-4-oxo-3- [2- (1H-1,2,3-triazol-1-yl) ethyl] -8-thia-3,10- diazatricyclo [7.4.0.0 2, 7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5 , 10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[12-chloro-6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[12-chloro-6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[10-hydroxy-12-oxo-13-(2-phenylethyl)-8-thia-3,6,13-triazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),3,5,10-pentaen-11-yl]formamido}acetic acid,2-{[10-hydroxy-12-oxo-13- (2-phenylethyl) -8-thia-3,6,13-triazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 3,5,10-pentaen-11-yl] formamido} acetic acid,
    2-{[12-chloro-6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,11-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[12-chloro-6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,11-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-11-methyl-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetic acid,2-{[6-hydroxy-11-methyl-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-{[6-hydroxy-4,11-dioxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,12-tetraen-5-yl]formamido}acetic acid,2-{[6-hydroxy-4,11-dioxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,12-tetraen-5-yl] formamido} acetic acid,
    5-[(carboxymethyl)carbamoyl]-6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-10-ium-10-olate,5-[(carboxymethyl) carbamoyl] -6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-10-ium-10-olate,
    2-({6-hydroxy-4-oxo-3-[2-(pyridin-3-yl)ethyl]-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-4-oxo-3- [2- (pyridin-3-yl) ethyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9) , 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    (2S)-2-{[6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}propanoic acid,(2S) -2-{[6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl] formamido} propanoic acid,
    (2R)-2-{[6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl]formamido}propanoic acid,(2R) -2-{[6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (13), 2 ( 7), 5,9,11-pentaen-5-yl] formamido} propanoic acid,
    Methyl-2-{[6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetate,Methyl-2-{[6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaen-5-yl] formamido} acetate,
    2-{1-[6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]-N-methylformamido}acetic acid,2- {1- [6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaen-5-yl] -N-methylformamido} acetic acid,
    tert-butyl-2-{[6-hydroxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido}acetate,tert-butyl-2-{[6-hydroxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetate,
    (2S)-2-{[6-hydroxy-11-methyl-4-oxo-3-(2-phenylethyl)-8-thia-3,10- diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} propanoic acid,(2S) -2-{[6-hydroxy-11-methyl-4-oxo-3- (2-phenylethyl) -8-thia-3,10- diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl] formamido} propanoic acid,
    Methyl-2-{[6-methoxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetateMethyl-2-{[6-methoxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7) , 5,10,12-pentaen-5-yl] formamido} acetate
    2-{[6-ethoxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl]formamido}acetic acid,2-{[6-ethoxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (13), 2 (7), 5 , 9,11-pentaen-5-yl] formamido} acetic acid,
    2-{[6-methoxy-4-oxo-3-(2-phenylethyl)-8-thia-3,10-diazatricyclo[7.4.0. 0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl]formamido}acetic acid,2-{[6-methoxy-4-oxo-3- (2-phenylethyl) -8-thia-3,10-diazatricyclo [7.4.0. 0 2,7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-4-oxo-3-[(2S)-2-phenylpropyl]-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-4-oxo-3-[(2S) -2-phenylpropyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-4-oxo-3-[(2R)-2-phenylpropyl]-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid2-({6-hydroxy-4-oxo-3-[(2R) -2-phenylpropyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid
    2-{[6-hydroxy-4-oxo-3-(2-phenylpropyl)-8-thia-3,10-diazatricyclo[7.4.0. 0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[6-hydroxy-4-oxo-3- (2-phenylpropyl) -8-thia-3,10-diazatricyclo [7.4.0. 0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-4-oxo-3-[(1-phenylcyclopropyl)methyl]-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-4-oxo-3-[(1-phenylcyclopropyl) methyl] -8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-4-oxo-3-(1-phenylpropan-2-yl)-8-thia-3,10-diazatricyclo [7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[6-hydroxy-4-oxo-3- (1-phenylpropan-2-yl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 ( 7), 5,10,12-pentaen-5-yl] formamido} acetic acid,
    (2S)-2-{[6-hydroxy-4-oxo-3-(1-phenylpropan-2-yl)-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} propanoic acid,(2S) -2-{[6-hydroxy-4-oxo-3- (1-phenylpropan-2-yl) -8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl] formamido} propanoic acid,
    (2R)-2-{[6-hydroxy-4-oxo-3-(1-phenylpropan-2-yl)-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} propanoic acid,(2R) -2-{[6-hydroxy-4-oxo-3- (1-phenylpropan-2-yl) -8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl] formamido} propanoic acid,
    2-({3-[2-(4-fluorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3- [2- (4-fluorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(4-chlorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3- [2- (4-chlorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(2-methylphenyl)ethyl]-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3- [2- (2-methylphenyl) ethyl] -4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(2-chlorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3- [2- (2-chlorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(2,6-dichlorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3- [2- (2,6-dichlorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-3- [2- (4-methoxyphenyl) ethyl] -4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    (2S)-2-({6-hydroxy-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) propanoic acid,(2S) -2-({6-hydroxy-3- [2- (4-methoxyphenyl) ethyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) propanoic acid,
    2-({6-hydroxy-11-methyl-3-[2-(2-methylphenyl)ethyl]-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido)acetic acid,2-({6-hydroxy-11-methyl-3- [2- (2-methylphenyl) ethyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(4-fluorophenyl)ethyl]-6-hydroxy-11-methyl-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3- [2- (4-fluorophenyl) ethyl] -6-hydroxy-11-methyl-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-[(6-hydroxy-4-oxo-3-{2-[2-(trifluoromethyl)phenyl]ethyl}-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl)formamido]acetic acid,2-[(6-hydroxy-4-oxo-3- {2- [2- (trifluoromethyl) phenyl] ethyl} -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl) formamido] acetic acid,
    2-({3-[2-(3-chlorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3- [2- (3-chlorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(2-fluorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3- [2- (2-fluorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(4-methoxyphenyl)ethyl]-11-methyl-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({6-hydroxy-3- [2- (4-methoxyphenyl) ethyl] -11-methyl-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(4-cyanophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido)acetic acid,2-({3- [2- (4-cyanophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(4-nitrophenyl)ethyl]-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-3- [2- (4-nitrophenyl) ethyl] -4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(4-acetamidophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(13),2(7),5,9,11-pentaen-5-yl}formamido) acetic acid,2-({3- [2- (4-acetamidophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (13), 2 (7), 5,9,11-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-3-[2-(naphthalen-2-yl)ethyl]-4-oxo-8-thia-3,10-diazatri cyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({6-hydroxy-3- [2- (naphthalen-2-yl) ethyl] -4-oxo-8-thia-3,10-diazatri cyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(4-chloro-3-fluorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido) acetic acid,2-({3- [2- (4-chloro-3-fluorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[2-(3,4-difluorophenyl)ethyl]-6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl}formamido) acetic acid,2-({3- [2- (3,4-difluorophenyl) ethyl] -6-hydroxy-4-oxo-8-thia-3,10-diaza tricyclo [7.4.0.0 2,7 ] trideca-1 (9 ), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-4-oxo-3-[2-(3,4,5-trimethoxyphenyl)ethyl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido) acetic acid,2-({6-hydroxy-4-oxo-3- [2- (3,4,5-trimethoxyphenyl) ethyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 ( 9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({6-hydroxy-11-methyl-4-oxo-3-[2-(3,4,5-trimethoxyphenyl)ethyl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido)acetic acid,2-({6-hydroxy-11-methyl-4-oxo-3- [2- (3,4,5-trimethoxyphenyl) ethyl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-{[6-hydroxy-4-oxo-3-(3-phenylpropyl)-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl]formamido} acetic acid,2-{[6-hydroxy-4-oxo-3- (3-phenylpropyl) -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5 , 10,12-pentaen-5-yl] formamido} acetic acid,
    2-({6-hydroxy-4-oxo-3-[(2E)-3-phenylprop-2-en-1-yl]-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido) acetic acid,2-({6-hydroxy-4-oxo-3-[(2E) -3-phenylprop-2-en-1-yl] -8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca -1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid,
    2-({3-[(2E)-3-(4-chlorophenyl)prop-2-en-1-yl]-6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),5,10,12-pentaen-5-yl} formamido)acetic acid.2-({3-[(2E) -3- (4-chlorophenyl) prop-2-en-1-yl] -6-hydroxy-4-oxo-8-thia-3,10-diazatricyclo [7.4.0.0 2,7 ] trideca-1 (9), 2 (7), 5,10,12-pentaen-5-yl} formamido) acetic acid.
  7. 제1항에 있어서, 상기 염증성 장질환이 크론병(Crohn's disease), 궤양성 대장염(Ulcerative colitis), 베체트 장염(Intestinal Behets disease)으로 이루어지는 군으로부터 선택되는 것인, 조성물.The composition of claim 1, wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease, ulcerative colitis, and Intestinal Behets disease.
PCT/KR2019/011832 2018-09-12 2019-09-11 7-hydroxy-4h-thieno[3,2-b]pyridin-5-on derivative and use thereof WO2020055164A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20180108757 2018-09-12
KR10-2018-0108757 2018-09-12
KR1020190112154A KR20200030466A (en) 2018-09-12 2019-09-10 7-hydroxy-4h-thieno[3,2-b]pyridin-5-one derivatives and methods of use of thereof
KR10-2019-0112154 2019-09-10

Publications (1)

Publication Number Publication Date
WO2020055164A1 true WO2020055164A1 (en) 2020-03-19

Family

ID=69777999

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2019/011832 WO2020055164A1 (en) 2018-09-12 2019-09-11 7-hydroxy-4h-thieno[3,2-b]pyridin-5-on derivative and use thereof

Country Status (1)

Country Link
WO (1) WO2020055164A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022167445A1 (en) * 2021-02-02 2022-08-11 Liminal Biosciences Limited Gpr84 antagonists and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008137060A1 (en) * 2007-05-04 2008-11-13 Amgen Inc. Thienopyridine and thiazolopyridine derivatives that inhibit prolyl hydroxylase activity
WO2009053799A1 (en) * 2007-10-24 2009-04-30 Glenmark Pharmaceuticals, S.A. Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
KR20100045480A (en) * 2007-08-10 2010-05-03 크리스탈지노믹스(주) Pyridine derivatives and methods of use thereof
WO2011057892A1 (en) * 2009-10-27 2011-05-19 Elara Pharmaceuticals Gmbh 2,3-dihydrobenzoxazine and 2,3-dihydrobenzothiazine derivates as hif-inhibitors for the treatment of cancer and inflammatory diseases
WO2012130322A1 (en) * 2011-03-31 2012-10-04 Elara Pharmaceuticals Gmbh Imidazo [1,2-a]pyridine compounds for use in therapy

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008137060A1 (en) * 2007-05-04 2008-11-13 Amgen Inc. Thienopyridine and thiazolopyridine derivatives that inhibit prolyl hydroxylase activity
KR20100045480A (en) * 2007-08-10 2010-05-03 크리스탈지노믹스(주) Pyridine derivatives and methods of use thereof
WO2009053799A1 (en) * 2007-10-24 2009-04-30 Glenmark Pharmaceuticals, S.A. Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
WO2011057892A1 (en) * 2009-10-27 2011-05-19 Elara Pharmaceuticals Gmbh 2,3-dihydrobenzoxazine and 2,3-dihydrobenzothiazine derivates as hif-inhibitors for the treatment of cancer and inflammatory diseases
WO2012130322A1 (en) * 2011-03-31 2012-10-04 Elara Pharmaceuticals Gmbh Imidazo [1,2-a]pyridine compounds for use in therapy

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022167445A1 (en) * 2021-02-02 2022-08-11 Liminal Biosciences Limited Gpr84 antagonists and uses thereof

Similar Documents

Publication Publication Date Title
JP6219882B2 (en) IRE-1α inhibitor
JP2802547B2 (en) Isoxazoline compounds as anti-inflammatory agents
EP2325181B1 (en) Stat3 inhibitor containing quinolinecarboxamide derivative as active ingredient
US20030232860A1 (en) Medicine comprising dicyanopyridine derivative
WO2018196677A1 (en) Fluoroallylamine derivative and use thereof
RU2493154C2 (en) Azole compounds
EP2800748B1 (en) Cyclic amide derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase and uses thereof
KR20040023616A (en) Hiv protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for the synthesis
CA2437492A1 (en) Fused heterocyclic compounds
EA011719B1 (en) Inhibitor against release of inflammatory cytokines
EP1056725A1 (en) Inhibition of raf kinase using aryl and heteroaryl substituted heterocyclic ureas
JPH11513021A (en) Quinolones and their medical uses
KR20080046637A (en) Condensed imidazolo derivatives for the inhibition of aldosterone synthase and aromatase
JP2003518116A (en) 3-thiazol-4-ylpyrrolidine derivatives as AMP-specific phosphodiester inhibitors
WO2001052845A1 (en) Gyrase inhibitors and uses thereof
KR20100044251A (en) Certain chemical entities, compositions, and methods
TW201125865A (en) Oxadiazole derivative having inhibion activity on endothelial lipase
HRP940209A2 (en) Hiv protease inhibitors useful for the treatment of aids
TW202035412A (en) Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis b infections
KR20050044476A (en) Phenyl substituted triazoles and their use as selective inhibitors of alk5 kinase
KR20220141331A (en) P2X3 modifier
BR112014015298B1 (en) COMPOUND DERIVED FROM AZA-ADAMANTANE, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND
WO2020055164A1 (en) 7-hydroxy-4h-thieno[3,2-b]pyridin-5-on derivative and use thereof
WO2002053155A1 (en) Telomerase inhibitor
WO2023195669A1 (en) Novel benzothiophene derivative and use thereof as bet inhibitor

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: 19860131

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19860131

Country of ref document: EP

Kind code of ref document: A1