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WO2018182341A1 - Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof - Google Patents

Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof Download PDF

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Publication number
WO2018182341A1
WO2018182341A1 PCT/KR2018/003744 KR2018003744W WO2018182341A1 WO 2018182341 A1 WO2018182341 A1 WO 2018182341A1 KR 2018003744 W KR2018003744 W KR 2018003744W WO 2018182341 A1 WO2018182341 A1 WO 2018182341A1
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substituted
compound
unsubstituted
alkyl
mmol
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PCT/KR2018/003744
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French (fr)
Korean (ko)
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송호영
김성민
김형래
박경은
정철웅
박윤희
최효정
이수인
백주열
이현정
이주영
오지혜
채제욱
오영수
김용주
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주식회사 레고켐 바이오사이언스
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Priority to CN201880003365.6A priority Critical patent/CN109790171B/en
Priority to AU2018246806A priority patent/AU2018246806B2/en
Priority to BR112019020136A priority patent/BR112019020136A2/en
Priority to IL269535A priority patent/IL269535B2/en
Priority to EP18774896.7A priority patent/EP3604311A4/en
Priority to NZ757701A priority patent/NZ757701A/en
Priority to JP2019515212A priority patent/JP2020512270A/en
Priority to US16/328,256 priority patent/US11654197B2/en
Application filed by 주식회사 레고켐 바이오사이언스 filed Critical 주식회사 레고켐 바이오사이언스
Priority to MX2019011655A priority patent/MX2019011655A/en
Priority to CA3058360A priority patent/CA3058360A1/en
Priority claimed from KR1020180036895A external-priority patent/KR101938800B1/en
Publication of WO2018182341A1 publication Critical patent/WO2018182341A1/en
Priority to US18/113,948 priority patent/US20230270868A1/en
Priority to JP2023081396A priority patent/JP2023113699A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyrrolobenzodiazepine dimer precursors and their ligand-linker conjugate compounds, compositions containing them, and in particular for their therapeutic use as anticancer agents.
  • Pyrrolobenzodiazepine is known as a natural substance with antibiotic or anti-tumor activity, produced by various actinomycetes. Pyrrolobenzodiazepine is a sequence selective DNA alkylated anticancer agent that covalently binds to cellular DNA. Pyrrolobenzodiazepine, a DNA-crosslinking agent, is known to exhibit significantly stronger anticancer activity than systemic chemotherapeutic agents and can prevent the division of cancer cells without destroying DNA helix.
  • Pyrrolobenzodiazepine has the following general structure:
  • the pyrrolobenzodiazepines differ in the number, type and position of substituents on the aromatic rings A and pyrrolo C rings, and the saturation of the C rings.
  • Some pyrrolobenzodiazepine dimers are undergoing Phase I clinical trials with SGN-CD123A from Seattle Genetics for acute myelocytic leukemia (AML) as a dPBD conjugate for acute myeloid leukemia (AML) disease.
  • AML acute myelocytic leukemia
  • Koltan Pharmaceuticals and Genentech / Roche are known to develop antibody-drug conjugates using pyrrolobenzodiazepine as a cytotoxic drug.
  • Spirogen has developed a technology for treating acute myeloid leukemia based on pyrrolobenzodiazepine.
  • published patents (medyok limited, patent document 1) on pyrrolobenzodiazepine and conjugates thereof, published patents (medyzeb limited, patent document 2) on asymmetric pyrrolobenzodiazepine dimers for the treatment of proliferative diseases, blood Registered patent (medium shock, patent document 3) regarding rolobenzodiazepine, registered patent (medium shock, patent document 4) regarding pyrrolobenzodiazepine for the treatment of proliferative disease, and open patent (mediponate limited, Patent document 5) and the registered patent (spirogen limited, patent document 6) regarding a pyrrolobenzodiazepine exist.
  • the anti-tumor activity is enhanced by modifying the pyrrolobenzodiazepine compound structure, or the anti-cancer activity can be enhanced by administering the pyrrolobenzodiazepine compound having such a modified structure in the form of an antibody-drug conjugate. It only starts.
  • the antibody-drug conjugate having a form linked to carbamate with respect to the form of pyrrolobenzodiazepine dimer, and a cytosol having low cytotoxicity by making the pyrrolobenzodiazepine compound in monomer form into a precursor form There are papers on which it appears that there are research papers on the preparation and activity of N10- (4-nitrobenzyl) carbamate-protected pyrrolobenzodiazepine precursors (Non-Patent Documents 7, Non-Patent Documents 8 and 9). Reference).
  • ADCs antibody-drug conjugates
  • antibody-drug conjugates consist of "antibody-linker-small molecule drugs (toxins)".
  • the linker is not only a functional role that connects the antibody and the drug, but also reaches the target cell stably during the body circulation, and then the drug enters the cell and dissociates between the antibodies and the drug (eg, the result of hydrolysis by enzymes). By dropping the drug well to target cancer cells should be effective. That is, the linker plays a very important role in terms of safety, such as the efficacy of the antibody-drug conjugate and systemic toxicity, depending on the stability of the linker (Discovery Medicine 2010, 10 (53): 329-39).
  • the inventors of the present invention have developed a linker comprising an effective self-immolative group which is more stable in plasma, stable even in the body circulation, and which drug can be easily released in cancer cells to exhibit efficacy.
  • Patent has been secured (Korean Patent No. 1,628,872, etc.).
  • Patent Document 1 Korean Patent Publication No. 2013-0040835 (published April 24, 2013)
  • Patent Document 2 Korean Patent Publication No. 2011-0075542 (Published June 30, 2011)
  • Patent Document 3 Korean Registered Patent No. 1,700,460 (January 20, 2017 registration)
  • Patent Document 4 Korean Registered Patent No. 1,687,054 (registered Dec. 9, 2016)
  • Patent Document 5 Korean Patent Publication No. 2015-0016245 (published Feb. 11, 2015)
  • Patent Document 6 Korean Patent No. 1,059,183 (August 18, 2011)
  • Patent Document 7 PCT / US2016 / 063564
  • Patent Document 8 PCT / US2016 / 063595
  • Patent Document 9 Korean Patent Publication No. 2014-0035393 (published March 21, 2014)
  • Patent Document 10 WO 2017/160569 (Published Sept. 21, 2017)
  • Patent Document 11 US Patent 8,697,688 (April 15, 2014 registration)
  • Patent Document 12 US Patent 9,713,647 (July 25, 2017 registration)
  • Patent Document 13 United States Patent Publication 2015-0283258 (2015.10. 8. publication)
  • Non-Patent Document 1 Kemp Gary C et al., Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin, Bioorganic & Medicinal Chemistry Letters Vol. 27 No. 5, 1154-1158 (2017)
  • Non-Patent Document 2 Julia Mantaj et al., From Anthramycin to Pyrrolobenzodiazepine (PBD) -Containing Antibody-Drug Conjugates (ADCs), Angewandte Chemie International Edition Vol. 56 No. 2, 462-488 (2017)
  • Non-Patent Document 3 Giddens Anna C. et al., Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody-drug conjugates, Bioorganic & Medicinal Chemistry Vol. 24 No. 22, 6075-6081 (2016)
  • Non-Patent Document 4 Hartley, JA, The development of pyrrolobenzodiazepines as antitumour agents, EXPERT OPIN INV DRUG, 20 (6) 733-744 (2011)
  • Non-Patent Document 5 Kamal Ahmed et al., Synthesis, anticancer activity and mitochondrial mediated apoptosis inducing ability of 2,5-diaryloxadiazole-pyrrolobenzodiazepine conjugates, Bioorganic & Medicinal Chemistry Vol. 18 No. 18, 6666-6677 (2010)
  • Non-Patent Document 6 Guichard S.M et al., Influence of P-glycoprotein expression on in vitro cytotoxicity and in vivo antitumour activity of the novel pyrrolobenzodiazepine dimer SJG-136, European Journal of Cancer Vol. 41 No. 12, 1811-1818 (2005)
  • Non-Patent Document 7 Zhang, Donglu et al, Linker Immolation Determines Cell Killing Activity of Disulfide-Linked Pyrrolobenzodiazepine Antibody-Drug Conjugates, ACS Medicinal Chemistry Letters, 7 (11), 988-993 (2016)
  • Non-Patent Document 8 Masterson, Luke A. et al., Synthesis and biological evaluation of novel pyrrolo [2,1-c] [1,4] benzodiazepine prodrugs for use in antibody directed enzyme prodrug therapy, Bioorganic & Medicinal Chemistry Letters , 16 (2), 252-256 (2006)
  • Non-Patent Document 9 Sangnou, M. J. et al., Design and synthesis of novel pyrrolobenzodiazepine (PBD) prodrugs for ADEPT and GDEPT, Bioorganic & Medicinal Chemistry Letters, 10 (18), 2083-2086 (2000)
  • Non-Patent Document 10 Nature Rev. Cancer 2005, 5 (5), pp. 405-12; Nature Chemical Biology, 2010, 17, pp. 498-506; Lane KT, Bees LS, Structural Biology of Protein of Farnesyltransferase and Geranylgeranyltransferase Type I, Journal of Lipid Research, 47, pp. 681-699 (2006); Patrick J. Kasey, Miguel C. Seabra; Protein Prenyltransferases, The Journal of Biological Chemistry, Vol. 271, No. 10, Issue of March 8, pp. 5289-5292 (1996)
  • Non-Patent Document 11 Benjamin P. Duckworth et al, Chem Bio Chem 2007, 8, 98; Uyen T. T. Nguyen et al, Chem Bio Chem 2007, 8, 408; Guillermo R. Labadie et al, J. Org. Chem. 2007, 72 (24), 9291; James W. Wollack et al, Chem BioChem 2009, 10, 2934
  • Non-Patent Document 13 Berge, et al., J. Pharm. Sci., 66, 1-19 (1977)
  • a pyrrolobenzodiazepine dimer precursor of a novel structure that can increase the blood stability of the pyrrolobenzodiazepine having a low blood stability after administration.
  • the pyrrolobenzodiazepine dimer precursor is further stabilized in the plasma and stable in the body circulation, by incorporating a linker technology comprising a self-immolative group which can be easily released in cancer cells to maximize the efficacy.
  • the present invention aims to provide a drug precursor-linker-ligand system that can stably reach target cells to effectively exert its effect while significantly lowering toxicity.
  • the present invention relates to pyrrolobenzodiazepine dimer prodrugs, pharmaceutically acceptable salts or solvates thereof.
  • R, and R ' are each independently H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NHNH 2, halo, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 3- 8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3- 20 heteroaryl, substituted or unsubstituted and 1- or di -C 8 alkylamino, - C 20 aryl or 5- mono-
  • C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl is substituted, H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NNH 2, halo, C 1-6 alkyl, C 1- 6 alkoxy, C 6- 12 aryl is optionally substituted with substituents selected from the group consisting of,
  • a pyrrolobenzodiazepine dimer precursor is provided.
  • it is necessary to be converted into a valid drug by an additional reaction upon exposure to blood, thereby preventing the possibility of side effects that may occur during unexpected decomposition of the linker, Toxicity to normal cells is reduced, and the drug is more stable than conventional PBD drugs in that the drug is more stable.
  • the antibody-drug conjugate prepared by the conventional method in the production of the antibody-drug conjugate has a high impurity content and exposed imine groups may be attacked by nucleophiles, resulting in the formation of a drug having an unwanted structure.
  • the antibody-drug conjugate prepared by the method according to the present invention has an advantage of high purity and easy separation, and physical properties have been improved as compared with conventional PBD or PBD dimer.
  • the pyrrolobenzodiazepine dimer precursor has the structure of formula (Ia) or (Ia '),
  • Dashed lines indicate any presence of a double bond between C1 and C2, or C2 and C3,
  • R m ' is selected from the group consisting of R m , CO 2 R m , COR m , CHO, CO 2 H, and halo,
  • R m is a substituted or unsubstituted C 1- 12 alkyl, substituted or unsubstituted C 2- 12 alkenyl, substituted or unsubstituted C 2- 12 alkynyl, substituted or unsubstituted C 5- 20 aryl, substituted or unsubstituted C 5- 20 heteroaryl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted 3 to 7-membered heterocyclyl, substituted or unsubstituted 3 to 7-membered Heterocycloalkyl, and substituted or unsubstituted 5 to 7-membered heteroaryl;
  • C 1- 12 alkyl, C 1- 12 alkoxy, C 2- 12 alkenyl, C 2- 12 alkynyl, C 5- 20 aryl, C 5- 20 heteroaryl, C 3- 6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered-heterocycloalkyl, or 5 to 7 each of the hydrogen atoms of the member heteroaryl are each independently a C 1- 12 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, from 5- C 20 aryl, C 5- 20 heteroaryl, C 3- 6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7 membered heteroaryl group, consisting of Substituted with any one or more selected;
  • R 2, R 3 and R 5 are each independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m ' , NO 2 , Me 3 Sn And halo,
  • R m and R m ′ are as defined above;
  • R 4 is H, R m, OH, OR m, SH, SR m, NH 2, NHR m, NR m R m ', NO 2, Me 3 Sn, halo, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 1- 6 alkoxy, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2- 6-alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted hwandoen 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5- C 12 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -CN, -NO 2, -NCO, -OR n, - OC (O) R n , -OC (O) NR n R n ' , -OS (O
  • C 1- 6 alkyl, C 1- 6 alkoxy, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 12 aryl, 5 to 7 membered each hydrogen atom of the heteroaryl are each independently a C 1 - 6 alkyl, C 1- 6 alkoxy, C 2 - 6 alkenyl, C 2- 6 alkynyl , C 3- C 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5 - 10 aryl, 5- to 7-membered heteroaryl group, -OR p, -OC
  • R n, R o, R p, and R q is independently H, C 1 - 7 alkyl, C 2 - 7 alkenylene, C 2- 7 alkynyl, C 3- 13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10, selected from aryl, and a 5- to 7-membered group consisting of heteroaryl, and;
  • X and X ' are each independently -C (O) O *, -S (O) O *, -C (O) *, -C (O) NR *, -S (O) 2 NR *, -P Any one selected from the group consisting of (O) R'NR *, -S (O) NR *, and -PO 2 NR * is attached,
  • R, and R ' are each independently H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NHNH 2, halo, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 3- 8 cycloalkyl, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 1- 8 alkylthio, substituted or unsubstituted C 3- 20 heteroaryl, substituted or unsubstituted and 1- or di -C 8 alkylamino, - C 20 aryl or 5- mono-
  • Y and Y ' are each independently selected from the group consisting of O, S, and N (H);
  • R 6 is a substituted or unsubstituted saturated or unsaturated C 3-12 hydrocarbon chain
  • chain thereof may be interrupted by one or more heteroatoms, NMe or substituted or unsubstituted aromatic rings,
  • a chain or aromatic ring thereof has at least one position of hydrogen atom on its chain or aromatic ring, -NH, -NR m , -NHC (O) R m , -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or - May be unsubstituted or substituted with [CH 2 CH 2 O] n -R,
  • R m and R are the same as defined above for R m and R,
  • n is an integer from 1 to 12;
  • R 7 is H, substituted or unsubstituted C 1 - 6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl alkyl, substituted or unsubstituted 3 to 7-membered optionally substituted heterocycloalkyl, unsubstituted or unsubstituted C 6 - 10 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -OR r, -OC (O) r r , -OC (O) NR r R r ' , -OS (O) R r , -OS (O) 2 R r , -SR r , -S (O) R r , -S (O) 2 R r , -S (O) NR r R r '
  • C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5 to 7-membered each hydrogen atom of the heteroaryl are each independently a C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5-7 membered heteroaryl, -OR t, -OC (O) R t, -OC (O
  • R r, R r ', R s, R s', R t, R t ', R u and R u' are each independently H, C 1- 7 alkyl, C 2-7 alkenyl, C 1-7 alkynyl, C 3- 13 is selected from cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5- to 7-membered group consisting of-heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and X are as defined above in Formula Ia,
  • R 8 is H, halo, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3- 6 heteroalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted C 5- 10 arylalkyl, substituted or unsubstituted 5 to 7 membered heteroaryl, -CN, -NO 2, - NCO, -OH, OR m , -OC (O) R m , -OC (O) NR m R m ', -OS (O) R m , -OS (O) 2 R m , -SR m , -S (O) R m , -S (O) 2 R m , -S (O) NR m R m '
  • C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, or a 5- to 7-membered when a heteroaryl group optionally substituted C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, or 5 to 7 membered each hydrogen atom of the heteroaryl are each independently C 1-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl , 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR m, -OC (O) R m, -OC (O) NR m R m ', -OS (O) R m,
  • R m , R m ' , R n and R n ' are as defined in Formula Ia,
  • Z a and Z b are each independently O, N, or S,
  • R 12a, R 13a, and R 14a are each independently selected from H, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5- C 10 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -C (O) R 15a , -C (O) OR 15a and -C (O) NR 15a R 15a ' , wherein R 15a and R 15a' are as defined in R m ,
  • C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl when the aryl is substituted each is hydrogen C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR o, -OC (O) R o, -OC (O) NR o R o ', -OS (O) R o, - OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o '
  • R 13a and R 14a combine with the atoms to which they are attached to form a 3 to 7-membered heterocyclyl, or 3 to 7-membered heterocycloalkyl, or R 13a and R 14a to which they are attached Can be combined together to form a 3 to 7 membered heteroaryl,
  • 3 to each of the hydrogen atoms present in the 7-membered heterocycloalkyl or 3 to 7-membered heteroaryl are each independently a C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR o, -OC (o) R o, - OC (O) NR o R o ' , -OS (O) R o , -OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o ' , -S (O) 2 NR o R o ' , -OS (O) NR o R o R o , -OS (O) NR o
  • R n, R n ', R o, R o', R p, and R p ' are each independently H, C 1- 7 alkyl, 2- C 7 alkenyl, C 2- 7 alkynyl, C 3- 13 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, and a 5- to 7-membered heteroaryl is selected from the group consisting of;
  • R 1 ′ , R 2 ′ , R 3 ′ , R 4 ′ , R 5 ′ , R 7 ′, and R 8 ′ are R 1 , R 2 , R 3 , R 4, R 5 , It is as defined about R ⁇ 7> and R ⁇ 8> .
  • the dashed line indicates the presence of a double bond between C2 and C3.
  • R 1 is a substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 5-7 aryl, and substituted or unsubstituted C It is selected from the group consisting of 3-6 heteroaryl.
  • R 2 , R 3 and R 5 are each independently H or OH.
  • R 4 is C 1-6 alkoxy, more specifically methoxy, ethoxy or butoxy.
  • X and X ' are each independently selected from the group consisting of -C (O) O *, -C (O) * and -C (O) NR *,
  • R is each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, substituted or unsubstituted C 1-8 alkyl or substituted or unsubstituted C 1- 8 alkoxy, in the case where C 1- 8 alkyl, C 1- 8 alkoxy which is substituted, H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NNH is substituted by 2, or halo .
  • R 6 is a substituted or unsubstituted saturated or unsaturated C 3-8 hydrocarbon chain
  • Its chain may be interrupted by one or more heteroatoms or substituted or unsubstituted aromatic rings,
  • heteroatom is O, S or N (H)
  • aromatic ring is benzene, pyridine, imidazole or pyrazole,
  • At least one position of a hydrogen atom on the chain or aromatic ring is -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or -[CH 2 CH 2 O] n -R can be substituted,
  • n is an integer of 1-6.
  • pyrrolobenzodiazepine dimer precursor pharmaceutically acceptable salt or solvate thereof selected from:
  • R O and R ′ O are each an oxygen protecting group and may be the same as or different from each other.
  • the present invention also provides a conjugate having the structure of formula IIa or a pharmaceutically acceptable salt or solvate thereof:
  • Ligand is a ligand
  • L is a linker
  • D is a pyrrolobenzodiazepine dimer precursor as described above, wherein the linker is selected from the N10, N10 ', or N10 and N10' positions of D, or X, X 'or X and X' of D as described above.
  • n is an integer from 1 to 20.
  • the linker is bonded to D via the N10 and N10 'positions of D, or X and X' of D.
  • n is an integer from 1 to 10.
  • the present invention also provides a pyrrolobenzodiazepine dimer precursor-linker compound having the structure of Formula IIb or Formula IIb ', a pharmaceutically acceptable salt or solvate thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
  • each independently are Xa and Xa '(bond), or a substituted or unsubstituted C 1- 6 alkylene, and, if this is a C 1- 6 alkylene substituted with a hydrogen, C 1-8 alkyl or C 3 Substituted with -8 cycloalkyl,
  • G and G ' are glucuronide groups, galactoside groups or derivatives thereof,
  • Z is H, C 1- 8 alkyl, halo, NO 2, CN, , And-(CH 2 ) m -OCH 3 ,
  • R 8, R 9 and R 10 is selected from each independently H, C 1- 8 alkyl, C 2- 6 alkenyl, and the group consisting of C 1- 6 alkoxy, m is 0 to 12,
  • n is an integer of 1 to 3, when n is an integer of 2 or more, each Z may be the same or different from each other,
  • W is -C (O)-, -C (O) NR ''-, -C (O) O-, -S (O) 2 NR ''-, -P (O) R '''NR'' -, -S (O) NR '' -, or -PO 2 NR '' -, and wherein R '' and R '''are each independently H, C 1- 8 alkyl, C 3- 8 cycloalkyl, 1- C 8 alkoxy, C 1- 8 alkyl thio, mono- or di -C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl,
  • L is one or more units selected from the group consisting of a branching unit, a connection unit and a binding unit, or a combination of these units, wherein the connection unit is a combination of W, Connecting the W and the branching unit, the branching unit and the branching unit, or the branching unit and the coupling unit, wherein the branching unit connects the connection unit and the W, or the connection unit and another connection unit,
  • Branching unit 100 C 2- alkenyl (wherein the carbon atom of the alkenyl group is one or more N, O and may be substituted with a hetero atom selected from the group consisting of S, alkenyl has one or more C 1- 20 may be further substituted with alkyl), hydrophilic amino acid, -C (O)-, -C (O) NR '''-, -C (O) O-,-(CH 2 ) s- NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t- C (O)-,-(CH 2 ) u -C (O) NH- (CH 2 ) v -C (O)-,-S (O) 2 NR '''-, -P (O) R ''''NR'
  • the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, -O-, or S-,
  • L 1 is a single bond or a C 2- 30 alkenyl Al
  • R 11 is H or C 1-10 alkyl
  • L 2 is a C 2- 30 alkenyl group, and;
  • R v is -NH 2, N 3, substituted or unsubstituted C 1- 12 alkyl, C 1- 12 alkynylene, C 1- 3 alkoxy, substituted or unsubstituted C 3- 20 heteroaryl, C 3-20 ring Heterocyclyl or substituted or unsubstituted C 5-20 aryl,
  • Xa and Xa ' are each independently a bond or C 1-3 alkyl.
  • Z is H, , And-(CH 2 ) m -OCH 3 ,
  • W is -C (O)-, -C (O) NR '''-or -C (O) O-, wherein R''' is H or C 1-8 alkyl ,
  • L is one or more units selected from the group consisting of a branching unit, a connection unit and a binding unit, or a combination of these units, wherein the connection unit is a combination of W, Connecting the W and the branching unit, the branching unit and the branching unit, or the branching unit and the coupling unit, wherein the branching unit connects the connection unit and the W, or the connection unit and another connection unit,
  • Branching units C 2- 8 alkenyl (wherein the carbon atom of the alkenyl group is one or more N, O and may be substituted with a hetero atom selected from the group consisting of S, alkenyl has one or more C 1- 6 may be further substituted with alkyl), or a hydrophilic amino acid, -C (O)-, -C (O) NR '''-, -C (O) O-,-(CH 2 ) s -NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t -C (O) -, or - (CH 2) u -C ( O) NH- (CH 2) v -C (O) - , and (wherein, R ''' is H, C 1- 8 alkyl, C 3- 8
  • the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, or -O-,
  • L 1 is a single bond or a C 2- 8 alkenyl Al
  • R 11 is H or C 1- 6 alkyl
  • L 2 is C 2- 8 alkenyl
  • the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- ,
  • r is an integer from 0 to 8
  • p is an integer from 1 to 12
  • q is an integer from 1 to 10
  • V is a single bond or -O-.
  • G and G ' may each independently be a ⁇ -glucuronide group, galactoside group or derivative thereof.
  • pyrrolobenzodiazepine dimer precursor-linker compound of Formula IIc a pharmaceutically acceptable salt or solvate thereof:
  • Dashed lines indicate any presence of a double bond between C1 and C2, or C2 and C3,
  • R 1 is methyl, ethyl, methylene, methoxy and substituted or doedoe selected from the group consisting of unsubstituted phenyl, when phenyl is substituted with H, OH, halo, C 1- 6 alkyl, C 1- 6 alkoxy and C 6 - is substituted with substituents selected from the group consisting of 12-aryl,
  • n 1 to 10
  • n is an integer from 1 to 10.
  • R 1 is methyl, methylene; And substituted with H, OH, halo, C 1- 6 substituents selected from the group consisting of alkyl and C 1- 6 alkoxy or may be an unsubstituted phenyl.
  • m may be an integer of 2 to 8, specifically an integer of 3 to 7, more specifically an integer of 4 to 6.
  • n may be an integer of 2 to 8, specifically an integer of 3 to 7, more specifically an integer of 4 to 6.
  • the present invention also provides a pyrrolobenzodiazepine dimer precursor-linker compound, a pharmaceutically acceptable salt or solvate thereof, having the following chemical structure.
  • a pyrrolobenzodiazepine dimer precursor-linker compound having the following chemical structure.
  • the following pyrrolobenzodiazepine dimer precursor-linker compounds are illustrative, and one of ordinary skill in the art can make and use various pyrrolobenzodiazepine dimer-linker compounds within the scope described above:
  • the present invention also provides a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate having the structure of Formula IIIa or IIIb, a pharmaceutically acceptable salt or solvate thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
  • Xa, G, Z, W, L, Xa ', G', Z ' are the same as defined for the compound of formula IIb in claim 11, respectively;
  • Ligand is an antigen binding moiety.
  • Ligand is a protein
  • the protein is an oligopeptide, polypeptide, antibody, fragment of an antigenic polypeptide, or a phosphor.
  • the protein has one or more amino acid motifs that can be recognized by isoprenoid transferases. That is, the C-terminus (fragment, analog or derivative thereof) of a protein can be bound to an amino acid motif that can be recognized by an isoprenoid transferase.
  • the protein and the amino acid motif may further comprise a spacer unit consisting of an amino acid, oligopeptide or polypeptide.
  • the protein is covalently linked to the linker via an amino acid motif.
  • the amino acid motif may be covalently bonded to the C-terminus of the protein, or covalently bonded to at least one spacer unit covalently to the C-terminus of the protein.
  • a protein may be directly covalently linked to an amino acid motif or covalently linked to a spacer unit to be linked to an amino acid motif.
  • the amino acid spacer unit is composed of 1 to 20 amino acids, of which a glycine unit is preferable.
  • the C-terminus of the protein is that of the light or heavy chain of the antibody.
  • the protein is a monoclonal antibody.
  • the isoprenoid transferase comprises a farnesyl protein transferase (FTase) or a geranylgeranyl transferase (GGTase), which are the C-terminal cysteines of the target protein of the farnesyl or geranyl-geranyl residues, respectively. Involves transition to (s). GGTase can be classified into GGTase I and GGTase II. FTase and GGTase I can recognize CAAX motifs.
  • FTase and GGTase I can recognize CAAX motifs.
  • the amino acid motif is CYYX, XXCC, XCXC or CXX, wherein C is cysteine, Y is an aliphatic amino acid, and X is an amino acid that determines the substrate specificity of the isoprenoid transferase.
  • the protein having the amino acid motif is A-HC- (G) Z CVIM, A-HC- (G) zCVLL, A-LC- (G) Z CVIM and A-LC- (G ) Z CVLL, wherein A represents an antibody, HC represents a heavy chain, LC represents a light chain, G represents a glycine unit and z is an integer from 0 to 20.
  • Isoprenoid transferases can recognize substrates as well as isosubstrates.
  • Iso substrates refer to substrate analogs with modifications to the substrate.
  • Isoprenoid transferases alkylate specific amino acid motifs (eg, CAAX motifs) at the C-terminus of the protein (see Benjamin P. Duckworth et al, ChemBioChem 2007, 8, 98; Uyen TT Nguyen et al, ChemBioChem 2007, 8, 408; Guillermo R. Labadie et al, J. Org.Chem. 2007, 72 (24), 9291; James W. Wollack et al, Chem BioChem 2009, 10, 2934).
  • Functionalized proteins can be produced using isoprenoid transferases and iso substrates via alkylation in the C-terminal cysteine (s).
  • cysteine residues of the C-terminal CAAX motif can be reacted with iso substrates using isoprenoid transferases.
  • AAX can then be removed by proteases.
  • the obtained cysteine can then be methylated at the carboxy terminus by enzyme (Iran M. Bell, J. Med. Chem. 2004, 47 (8), 1869).
  • Proteins of the present invention can be prepared using any molecular or cellular biology well known in the art. For example, transient transfection may be used. Genetic sequences encoding specific amino acid motifs that can be recognized by isoprenoid transferases are known phrases using standard PCR techniques to express a protein (fragment or analog thereof) having a specific amino acid motif at its C-terminus. Can be inserted into the mid vector. As such, proteins having one or more amino acid motifs that can be recognized by isoprenoid transferases can be expressed.
  • the protein is a monoclonal antibody
  • at least one light chain of the monoclonal antibody, at least one heavy chain of the monoclonal antibody, or both has an amino acid site having an amino acid motif that can be recognized by an isoprenoid transferase It may include, and those skilled in the art can immediately select a protein (eg target cells of the subject) to selectively bind the target of interest.
  • it may comprise a fragment of an antibody or antigen that specifically binds to a target of interest.
  • the amino acid motif is CYYX, XXCC, XCXC or CXX (wherein C is cysteine, Y is aliphatic amino acid and X is amino acid that determines the substrate specificity of isoprenoid transferase), More preferably, the amino acid motif is CYYX.
  • the present invention also provides a pharmaceutical composition for preventing or treating a proliferative disease, comprising the pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, pharmaceutically acceptable salts or solvates thereof described above.
  • the present invention also relates to pyrrolobenzodiazepine dimer precursor-linker-ligand conjugates, pharmaceutically acceptable salts or solvates thereof; And it provides a pharmaceutical composition for the prevention or treatment of proliferative disease, comprising a pharmaceutically acceptable excipient.
  • the present invention also relates to pyrrolobenzodiazepine dimer precursor-linker-ligand conjugates, pharmaceutically acceptable salts or solvates thereof; One or more therapeutic co-agents; And it provides a pharmaceutical composition for the prevention or treatment of proliferative disease, comprising a pharmaceutically acceptable excipient.
  • the therapeutic co-agent is an agent that exhibits a prophylactic, ameliorating or therapeutic effect on a proliferative disease, or an agent that can reduce the onset of side effects that occur when administering a proliferative disease treatment, or enhances immunity.
  • Agents which may be effective, and the like, but are not limited thereto, and have a therapeutically useful effect when applied in the form of a combination with pyrrolobenzodiazepines, and / or further improve the stability of pyrrolobenzodiazepines, and / or This means that any agent that can reduce the side effects that may occur when benzodiazepines are administered and / or enhance the immunity to maximize the therapeutic effect may be applied in any combination.
  • the proliferative disease refers to a cell proliferation related disease in which undesirably excessive or abnormal cells, such as neoplasia or hyperplastic growth, are undesirably controlled in vitro or in vivo.
  • Proliferative diseases can be selected from the group consisting of neoplasms, tumors, cancers, leukemias, psoriasis, bone diseases, fibrotic disorders, and atherosclerosis. Examples of neoplasms and tumors include histiocytoma, glioma, astrocytoma, osteoma and the like.
  • the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma And melanoma may be selected from the group, but if the pyrolobenzodiazepine is a carcinoma that can exhibit a therapeutic effect is applicable to all.
  • the invention also has a proliferative disease, comprising administering to a subject an effective amount of a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, a pharmaceutically acceptable salt or solvate thereof, for treating a proliferative disease.
  • a proliferative disease comprising administering to a subject an effective amount of a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, a pharmaceutically acceptable salt or solvate thereof, for treating a proliferative disease.
  • a method of treating cancer comprising administering the pharmaceutical composition to a patient.
  • the present invention is suitable for use in providing a PBD compound at a target position in a subject.
  • the conjugate according to the invention releases an active PBD compound which has no linker moiety, and there is nothing that can affect the reactivity of the PBD compound.
  • conjugates refers to cell binders that are covalently bound to one or more molecules of a cytotoxic compound.
  • a “cell binding agent” is a molecule having affinity for a biological target, and may be, for example, a ligand, a protein, an antibody, specifically a monoclonal antibody, a protein or antibody fragment, peptide, oligonucleotide, oligosaccharide, The binder serves to induce the biologically active compound to the biological target.
  • the conjugate can be designed to target tumor cells via cell surface antigens.
  • the antigen may be a cell surface antigen that is overexpressed or expressed in an abnormal cell type.
  • the target antigen may be one expressed only on proliferative cells (eg tumor cells). Target antigens can usually be selected based on different expressions between proliferative and normal tissues.
  • the ligand is bound to the linker.
  • an “antibody” herein is an immunoglobulin molecule capable of specifically binding to a target such as carbohydrates, polynucleotides, lipids, polypeptides, and the like through at least one antigen recognition site located in the variable region of an immunoglobulin molecule.
  • antibody refers to an intact polyclonal or monoclonal antibody, as well as any antigen binding portion of an intact antibody that possesses the ability to specifically bind a given antigen (eg, "Antigen-binding fragment") or a single chain thereof, a fusion protein comprising an antibody, and any other modified arrangement of an immunoglobulin molecule comprising an antigen recognition site, such as, but not limited to, Fab; Fab '; F (ab ') 2 Fd fragments; Fv fragments; Single domain antibody (dAb) fragments; Isolated complementarity determining regions (CDRs); Encompasses single chain (scFv) and single domain antibodies (e.g., shark and camel antibodies), maxibody, minibody, intrabody, diabody, tribody, tetrabody, v-NAR and bis-scFv ( See, eg, Hollinger and Hudson, 2005, Nature Biotechnology 23 (9): 1126-1136).
  • Antibodies include any class of antibody, such as IgG, IgA or IgM (or a subclass thereof), and the antibody need not be in any particular class.
  • immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, some of which are additionally in subclasses (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. Can be classified.
  • the heavy chain (HC) constant domains corresponding to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma and mu, respectively.
  • Subunit structures and three-dimensional coordination of different classes of immunoglobulins are well known.
  • Antibodies of the invention can be prepared using techniques well known in the art, such as recombinant techniques, phage display techniques, synthetic techniques, or combinations of these techniques, or other techniques that are readily known in the art.
  • an “isolated antibody” refers to an antibody that is substantially free of other antibodies with different antigen specificity and may be substantially free of other cellular materials and / or chemicals.
  • biological target refers to an antigen located on the surface of a tumor, cancer cell, or extracellular matrix.
  • linker refers to a compound that covalently binds a cytotoxic compound to a ligand.
  • the linker disclosed in PCT / US2016 / 063564 and PCT / US2016 / 063595 can be used.
  • a “therapeutic agent” herein is an agent that exerts cytotoxic, cytostatic and / or immunomodulatory effects on proliferative diseases, such as cancer cells or activated immune cells.
  • therapeutic agents include cytotoxic agents, chemotherapeutic agents, cytostatic agents and immunomodulators.
  • chemotherapeutic agent is a chemical compound useful for the treatment of cancer.
  • a “subject” is intended to include humans and non-human animals, especially mammals.
  • subjects include human subjects, such as the concept comprising a human patient or a normal subject having a disorder described herein, more specifically cancer.
  • “Non-human animals” are useful for all vertebrates, eg, non-mammals (eg, chickens, amphibians, reptiles) and mammals, eg, non-human primates, livestock, and / or agriculture. Animals (eg, sheep, dogs, cats, cattle, pigs, etc.) and rodents (eg, mice, rats, hamsters, guinea pigs, etc.).
  • the subject is a human patient.
  • treatment refers to both therapeutic treatment and prophylactic or prophylactic measures.
  • Subjects in need of treatment include those already with the disease and subjects susceptible to the disease or subjects to which the disease is to be prevented.
  • the term when used with respect to a subject in need of a disease or treatment, the term includes, compared to untreated subjects, slowing or slowing disease progression, preventing symptoms, reducing disease and / or symptom severity, or reducing disease duration. It is not limited to one.
  • administering refers to providing and / or contacting and / or delivering a compound or compounds by any suitable route to achieve the desired effect.
  • Administration may be oral, sublingual, parenteral (eg, intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intravitreal, intrasternal, intrathecal, intralesional or intracranial injection), transdermal, topical, Buccal, rectal, vaginal, nasal, ophthalmic, inhalation and administration via implants may include, but is not limited to.
  • unsubstituted or substituted refers to a parent group which may be unsubstituted or substituted
  • substituted refers to a parent group having one or more substituents
  • substituted refers to a mosquito refers to a chemical moiety covalently bonded to a parent group or fused to a parent group.
  • Halo refers to fluorine, chlorine, bromine, iodine and the like.
  • alkyl is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or cycloaliphatic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound
  • saturated alkyl examples are methyl, ethyl, propyl, butyl
  • saturated linear alkyl examples include pentyl, hexyl, heptyl and the like, and examples of saturated branched alkyl such as methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-hexyl and n-heptyl Isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl and the like.
  • alkoxy means -OR [where R is an alkyl group], for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy etc. are mentioned.
  • aryl means a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.
  • alkenyl is an alkyl having at least one carbon-carbon double bond.
  • alkynyl is an alkyl group having at least one carbon-carbon triple bond, and examples of the unsaturated alkynyl group include ethynyl and 2-propynyl.
  • aryl relates to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound.
  • C 5- 7 aryl as a moiety having from 5 to 7 ring atoms, and 1 is obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound means a moiety
  • C 5 - 10 aryl means that the moiety has 5 to 10 ring atoms, and is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound.
  • C 5-7 , C 5-10, etc. refers to the range of the number of ring atoms or the number of ring atoms, whether they are carbon atoms or hetero atoms.
  • C 5- 6 aryl relates to an aryl group having 5 or 6 ring atoms.
  • the ring atoms may all be carbon atoms as in the "carboaryl group".
  • Examples of carboaryl groups include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene and pyrene.
  • aryl groups including fused rings wherein at least one is an aromatic ring include, but are not limited to, groups derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, penalene, acefenanthrene and aceanthrene It is not limited.
  • the ring atom may comprise one or more hetero atoms as in a "heteroaryl group".
  • heteroaryl is an aryl containing one or more hetero atoms, for example pyridine, pyrimidine, benzothiophene, furyl, dioxalanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidy More specifically, benzofuran, isobenzofuran, indole, isoindole, indolizine, indolin, isoindolin, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, C 9 , chrome, isochromen, chromman, isochrome, benzo with two fused rings derived from benzodioxol, benzofuran, benzotriazole, benzothiofuran, benzothiazole, benzothiadiazole Two fused rings derived from dioxane, quinoline
  • cycloalkyl is an alkyl group which is a cyclyl group and relates to a monovalent portion obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound.
  • cycloalkyl groups include, but are not limited to, those derived from:
  • Saturated monocyclic hydrocarbon compounds cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane and methylcyclohexane;
  • Unsaturated monocyclic hydrocarbon compounds cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene and methylcyclohexene;
  • Saturated heterocyclic hydrocarbon compounds norcaran, norpinan, norbornane.
  • heterocyclyl relates to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound.
  • Prefixes eg, C 1-12 , C 3-8, etc.
  • C 3- 6 heterocyclyl relates heterocyclyl groups having from 3 to 6 ring atoms.
  • monocyclic heterocyclyl groups include, but are not limited to, those derived from:
  • N 1 aziridine, azetidine, pyrrolidine, pyrroline, 2H- or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine;
  • N 2 imidazolidine, pyrazolidine, imidazoline, pyrazoline, piperazine;
  • O 1 oxirane, oxetane, oxolane, oxol, oxane, dihydropyran, pyran, oxepin;
  • O 2 dioxolane, dioxane and dioxepane
  • N 1 O 1 tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, oxazine
  • N 1 S 1 thiazolin, thiazolidine, thiomorpholine;
  • N 1 O 1 S 1 Oxathiazine.
  • a "prodrug” refers to pyrrolobenzodia by the action of an enzyme, gastric acid under in vivo physiological conditions (e.g., enzymatic oxidation, reduction and / or hydrolysis). It refers to a compound that can be converted directly or indirectly to zepin drugs.
  • an acid addition salt formed by a pharmaceutically acceptable free acid may be used, and an organic acid or an inorganic acid may be used as the free acid.
  • the organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid.
  • the inorganic acid also includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
  • the salt may be formed with a suitable cation.
  • suitable inorganic cations include alkali metal ions such as Na + and K +, alkaline earth cations such as Ca 2 + and Mg 2 +, and other cations such as Al + 3, but is not limited to this.
  • suitable organic cations include, but are not limited to, ammonium ions (ie, NH 4 + ) and substituted ammonium ions (eg, NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • substituted ammonium ions examples include those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine , Phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine.
  • An example of a typical quaternary ammonium ion is N (CH 3 ) 4 + .
  • a compound When a compound has functional groups which may be a cation or cations, or may form a salt (e.g., -NH 2 may be that one -NH 3 +), suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid, and the like.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-aceticoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethane Disulfonic acid, ethanesulfonic acid, fumaric acid, glutenic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalene carboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, Malic acid, methanesulfonic acid, slime acid, oleic acid, oxalic acid, palmitic acid, palmic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid,
  • solvate refers to a molecular complex between a compound according to the invention and a solvent molecule
  • examples of solvates are water, isopropanol, ethanol, methanol, dimethylsulfoxide (dimethylsulfoxide), ethyl acetate, acetic acid, ethanolamine, or a compound according to the present invention in combination with a solvent thereof, but is not limited thereto.
  • solvates may conveniently be referred to as hydrates such as monohydrate, dihydrate, trihydrate and the like.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can include macromolecules that are typically slowly metabolized, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, lipid aggregates, and the like. Acceptable carriers may be appropriately selected and used by those skilled in the art.
  • composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. Mix is prepared. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like can also be used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition is selected from the group consisting of injections, tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have any one formulation.
  • the active ingredient may be in the form of an acceptable aqueous solution for parenteral administration with pyrogen-free and suitable pH, isotonicity and stability.
  • suitable solutions using, for example, isotonic vehicles, such as aqueous sodium chloride solution, Ringer's solution, lactate Ringer's solution, and the like, and can be included as necessary as preservatives, stabilizers, buffers, antioxidants or other additives.
  • Solid forms suitable for injection can also be prepared as emulsions or in the form of polypeptides encapsulated in liposomes.
  • the phrase “effective amount” or “therapeutically effective amount” refers to the amount necessary (relative to dosage and administration period and means) to achieve the desired therapeutic result.
  • An effective amount is at least the minimum amount of active agent necessary to confer a therapeutic benefit to a subject and is below the toxic amount.
  • the dosage can be administered in the range of about 100 ng to about 100 mg / kg per patient, more typically in the range of about 1 ⁇ g / kg to about 10 mg / kg.
  • the active compound is a salt, ester, amide, prodrug, or the like, the dosage is calculated based on the parent compound, so the actual weight used is increased proportionally.
  • the pyrrolobenzodiazepine compound according to the present invention may be formulated to include, but is not limited to, 0.1 mg to 3000 mg, 1 mg to 2000 mg, 10 mg to 1000 mg of active ingredient per dosage form.
  • the active ingredient may be administered to obtain a peak plasma concentration of the active compound of about 0.05 ⁇ M to 100 ⁇ M, 1 ⁇ M to 50 ⁇ M, 5 ⁇ M to 30 ⁇ M.
  • a peak plasma concentration of the active compound of about 0.05 ⁇ M to 100 ⁇ M, 1 ⁇ M to 50 ⁇ M, 5 ⁇ M to 30 ⁇ M.
  • a peak plasma concentration of the active compound of about 0.05 ⁇ M to 100 ⁇ M, 1 ⁇ M to 50 ⁇ M, 5 ⁇ M to 30 ⁇ M.
  • the concentration of the active compound in the pharmaceutical composition can be determined by the rate of absorption, inactivation and excretion of the drug and other factors known to those skilled in the art. Dosage may vary depending on the severity of the condition / disease. In addition, the dosage and dosing regimen for a particular patient may be adjusted according to the occupational supervisor's professional judgment, taking into account the degree, necessity, age, responsiveness to the drug, etc. of the patient's symptoms / diseases. The scope is merely one example and is not intended to limit the embodiments of the claimed compositions thereto.
  • the active ingredient may also be administered once, or several smaller doses may be administered.
  • the precursor compounds, or precursor-linker compounds, precursor-linker-ligand conjugate compounds according to the invention can be used to treat proliferative diseases, in particular cancer diseases.
  • proliferative disease refers to unwanted or uncontrolled cell proliferation of undesirable excessive or abnormal cells, such as neoplasia or hyperplasia, in vitro or in vivo.
  • Proliferative diseases include, for example, neoplasia, tumors, cancer, leukemia, psoriasis, bone diseases, fibrotic disorders, atherosclerosis, and the like, and may include, but are not limited to, benign, premalignant or malignant cell proliferation. .
  • the cancer may be lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma or melanoma It is not limited.
  • the pyrrolobenzodiazepine precursor, pyrrolobenzodiazepine precursor-linker compound, and pyrrolobenzodiazepine-linker-ligand conjugate according to the invention can be synthesized according to the following procedure.
  • Pyrrolobenzodiazepine precursor-linker compounds, and pyrrolobenzodiazepine precursor-linker-ligand conjugates according to the present invention can be prepared using the knowledge of those skilled in the art using the techniques provided herein.
  • the pyrrolobenzodiazepine dimer precursor (prodrug), pyrrolobenzodiazepine dimer precursor (prodrug) -linker, or pyrrolobenzodiazepine dimer precursor (prodrug) -linker-ligand conjugate according to the present invention the stability of the compound itself and in the plasma It is excellent in stability and has an advantage in terms of toxic expression, and is industrially useful in that it is possible to target a proliferative disease such as cancer, specific treatment, maximization of drug efficacy and minimization of side effects.
  • Oxalyl chloride (3.1 mL, 36.2 mmol) was dissolved in dichloromethane (40 mL) and then dimethyl sulfoxide (4.7 mL, 66.4 mmol) was added at -78 ° C under nitrogen atmosphere. After 10 minutes, compound 1 (10 g, 30.2 mmol, Compound 1 J. Org. Chem., 2003, 68, was prepared by a method described in the 3923-3931) to a solution in dichloromethane (140 mL) Slowly added, the reaction solution was stirred for 1 hour, triethylamine (16.7 mL, 120.6 mmol) was added thereto, and the reaction temperature was slowly raised to 0 ° C. for 2 hours.
  • reaction solution was diluted with dichloromethane (200 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 2 (9.5 g, 95%).
  • reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography yielded compound 23 (2.5 g, 72%).
  • reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography yielded compound 25 (800 mg, 40%).
  • Compound 32 was prepared in a similar manner to the synthesis of Compound 22 from Compound 19 and Compound 31 (Compound 31 was prepared by the method described in PCT / US2016 / 063564).
  • EI-MS m / z: [M + H] + 731.5.
  • reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 56 (1.15 mg, 54%) was obtained.
  • reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 58 (650 mg, 64%) was obtained.
  • Compound 85 was prepared by a method analogous to the synthesis of compound 28 from compound 9, compound 84 (compound 84 was prepared by the method described in WO2011 / 130598 A1), and compound 32.
  • reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography gave compound 95 (130 mg, 43%).
  • reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure were followed by purification by column chromatography to give compound 97 (168 mg, 41%).
  • 1,3-Diaminopropane (0.93 mL, 11.1 mmol) was dissolved in dichloromethane (30 mL) and di- t -butyl dicarbonate (0.84 mL, 3.7 mmol) was added at 0 ° C. under nitrogen atmosphere. After stirring for 3 hours at room temperature, brine (50 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. After filtration the reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 101 (658 mg, based on 100% Boc 2 O).
  • reaction solution was diluted with ethyl acetate (30 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 132 (1.0 g, 83%) was obtained.
  • Compound 136 was prepared by a method analogous to the synthesis of compound 134 from compound 126 and compound 118. EI-MS m / z: [M + H] + 2032.98, 1/2 [M + H] + 1017.03.
  • Compound 138 was prepared by a method similar to the synthesis of compound 137 from compound 126 and compound 124. EI-MS m / z: [M + H] + 1647.60, 1/2 [M + H] + 824.31.
  • reaction solution was concentrated and diluted with ethyl acetate (100 mL), then saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the reaction solution, and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 ⁇ 100 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 140 (1.53 g, 72%) was obtained.
  • reaction solution was concentrated and diluted with dichloromethane (50 mL), washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 143 (340 mg, 71%) was obtained.
  • reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (2 x 50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 145 (250 mg, 43%) was obtained.
  • reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (2 x 50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 147 (170 mg, 42%) was obtained.
  • Oxalyl chloride (2.1 mL, 14.1 mmol) was dissolved in dichloromethane (20 mL) and then dimethyl sulfoxide (1.5 mL, 21.1 mmol) was added at ⁇ 78 ° C. under nitrogen atmosphere. After 1 h, a solution of compound 158 (2.7 g, 6.9 mmol) in dichloromethane (50 mL) was added slowly. The reaction solution was stirred for 2 hours and then triethylamine (3.4 mL, 42.3 mmol) was diluted in dichloromethane (30 mL) and added slowly. The reaction temperature was slowly raised to 0 ° C. for 2 hours.
  • reaction solution was diluted with dichloromethane (100 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 159 (2.7 g, 96%).

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Abstract

The present invention relates to a pyrrolobenzodiazepine precursor and a ligand-linker conjugate compound thereof, a composition containing the same, and, in particular, a therapeutic use thereof as an anti-cancer agent. The present invention is industrially useful in that it is possible to target proliferative diseases such as cancer, perform a specific treatment, maximize medicinal effects, and minimize the occurrence of side effects, since the compound itself is very stable, has excellent stability in plasma, and has advantages in terms of toxicity manifestation.

Description

피롤로벤조디아제핀 이량체 전구체 및 이의 리간드-링커 접합체 화합물Pyrrolobenzodiazepine dimer precursors and ligand-linker conjugate compounds thereof
본 발명은 피롤로벤조디아제핀 이량체 전구체 및 이의 리간드-링커 접합체 화합물, 이를 함유하는 조성물, 및 특히 항암제로서 이의 치료용도에 관한 것이다.The present invention relates to pyrrolobenzodiazepine dimer precursors and their ligand-linker conjugate compounds, compositions containing them, and in particular for their therapeutic use as anticancer agents.
피롤로벤조디아제핀(pyrrolobenzodiazepine, PBD)은 다양한 방선균(actinomycetes)에 의해 생산되는, 항생 또는 항종양 활성을 갖는 천연물질로 알려져 있다. 피롤로벤조디아제핀은 세포 DNA에 공유 결합하는, 서열 선택성 DNA 알킬화 항암제이다. 피롤로벤조디아제핀은 DNA-교차결합제(DNA-crosslinking agents)로서, 전신 화학요법제보다 현저히 강력한 항암 활성을 나타내는 것으로 알려져 있으며, DNA 힐릭스(helix)를 파괴하지 않고 암세포의 분열을 막을 수 있다.Pyrrolobenzodiazepine (PBD) is known as a natural substance with antibiotic or anti-tumor activity, produced by various actinomycetes. Pyrrolobenzodiazepine is a sequence selective DNA alkylated anticancer agent that covalently binds to cellular DNA. Pyrrolobenzodiazepine, a DNA-crosslinking agent, is known to exhibit significantly stronger anticancer activity than systemic chemotherapeutic agents and can prevent the division of cancer cells without destroying DNA helix.
피롤로벤조디아제핀은 하기의 일반적 구조를 갖는다:Pyrrolobenzodiazepine has the following general structure:
Figure PCTKR2018003744-appb-I000001
Figure PCTKR2018003744-appb-I000001
상기 피롤로벤조디아제핀은 방향족 고리 A 및 피롤로 C 고리에서의 치환기의 수, 유형 및 위치, 그리고 C 고리의 포화도에 있어 차이가 있다. B 고리에는 DNA의 알킬화를 담당하는 친전자성 중심인 N10-C11 위치에 이민(N=C), 카르비놀아민(NH-CH(OH)) 또는 카르비놀아민 메틸에테르(NH-CH(OMe))가 존재한다.The pyrrolobenzodiazepines differ in the number, type and position of substituents on the aromatic rings A and pyrrolo C rings, and the saturation of the C rings. The B ring contains an imine (N = C), carbinolamine (NH-CH (OH)) or carbinolamine methyl ether (NH-CH () at the N10-C11 position, the electrophilic center responsible for alkylation of DNA. OMe)) exists.
일부 피롤로벤조디아제핀 이량체는 급성 골수성 백혈병(acute myelocytic leukemia, AML) 환자 치료를 위해 씨애틀 제네틱스사의 SGN-CD123A가 급성 골수성 백혈병(AML) 질환에 대해 dPBD 접합체로 임상 1상을 진행 중에 있다.Some pyrrolobenzodiazepine dimers are undergoing Phase I clinical trials with SGN-CD123A from Seattle Genetics for acute myelocytic leukemia (AML) as a dPBD conjugate for acute myeloid leukemia (AML) disease.
콜탄 파마슈티칼스(Kolltan Pharmaceuticals)와 제넨텍/로슈(Genentech/Roche) 등에서는 피롤로벤조디아제핀을 세포독성 약물로 하는 항체-약물 접합체를 개발하고 있는 것으로 알려져 있다. 이밖에도 스피로젠(Spirogen)은 피롤로벤조디아제핀을 기반으로 하는 급성 골수성 백혈병 치료제 기술을 개발해오고 있다.Koltan Pharmaceuticals and Genentech / Roche are known to develop antibody-drug conjugates using pyrrolobenzodiazepine as a cytotoxic drug. In addition, Spirogen has developed a technology for treating acute myeloid leukemia based on pyrrolobenzodiazepine.
이와 관련하여 피롤로벤조디아제핀 및 그의 접합체에 관한 공개특허(메디뮨 리미티드, 특허문헌1), 증식 질환의 치료를 위한 비대칭 피롤로벤조디아제핀 이량체에 관한 공개특허(메디뮨 리미티드, 특허문헌 2), 피롤로벤조디아제핀에 관한 등록특허(메디뮨 리미티드, 특허문헌3), 증식성 질환 치료용 피롤로벤조디아제핀에 관한 등록특허(메디뮨 리미티드, 특허문헌 4), 피롤로벤조디아제핀에 관한 공개특허(메디뮨 리미티드, 특허문헌 5), 피롤로벤조디아제핀에 관한 등록특허(스피로젠 리미티드, 특허문헌 6) 등이 존재한다. 이들은 피롤로벤조디아제핀 화합물 구조를 변형하여 항종양 활성이 증진된다는 점 등을 개시하고 있거나, 이러한 변형된 구조를 갖는 피롤로벤조디아제핀 화합물을 항체-약물 접합체의 형태로 투여하여 항암 활성을 증진시킬 수 있다는 점을 개시하고 있을 뿐이다.In this regard, published patents (medyok limited, patent document 1) on pyrrolobenzodiazepine and conjugates thereof, published patents (medyzeb limited, patent document 2) on asymmetric pyrrolobenzodiazepine dimers for the treatment of proliferative diseases, blood Registered patent (medium shock, patent document 3) regarding rolobenzodiazepine, registered patent (medium shock, patent document 4) regarding pyrrolobenzodiazepine for the treatment of proliferative disease, and open patent (mediponate limited, Patent document 5) and the registered patent (spirogen limited, patent document 6) regarding a pyrrolobenzodiazepine exist. They disclose that the anti-tumor activity is enhanced by modifying the pyrrolobenzodiazepine compound structure, or the anti-cancer activity can be enhanced by administering the pyrrolobenzodiazepine compound having such a modified structure in the form of an antibody-drug conjugate. It only starts.
한편 피롤로벤조디아제핀 이량체(dimer)의 형태에 대해 카바메이트로 연결되는 형태를 갖는 항체-약물 접합체에 관한 기술, 단량체 형태의 피롤로벤조디아제핀 화합물을 전구체(prodrug) 형태로 함으로써 세포독성이 적고 안정한 것으로 나타났다는 점이 개시된 논문, N10-(4-니트로벤질)카바메이트-보호된 피롤로벤조디아제핀 전구체의 제법 및 활성에 대한 연구논문 등이 존재한다(비특허문헌 7, 비특허문헌 8 및 비특허문헌 9 참조).On the other hand, the antibody-drug conjugate having a form linked to carbamate with respect to the form of pyrrolobenzodiazepine dimer, and a cytosol having low cytotoxicity by making the pyrrolobenzodiazepine compound in monomer form into a precursor form There are papers on which it appears that there are research papers on the preparation and activity of N10- (4-nitrobenzyl) carbamate-protected pyrrolobenzodiazepine precursors (Non-Patent Documents 7, Non-Patent Documents 8 and 9). Reference).
그러나 상기 기술들의 경우, 피롤로벤조디아제핀 합성 시 낮은 수율로 인해 스케일 업이 쉽지 않은 문제가 있다는 점, 또한 투약 후 혈중에서의 안정성이 떨어지는 문제가 충분히 해결되기에는 부족하다는 점에서 한계가 있다. 따라서 피롤로벤조디아제핀의 수율을 높일 수 있는 제조방법의 개발, 및 투약 후 혈중 안정성을 높이고 독성을 낮추기 위한 전구체화 기술이 필요하다. However, in the above techniques, there is a problem in that scale up is not easy due to low yield in pyrrolobenzodiazepine synthesis, and that the problem of poor stability in blood after administration is insufficient to be sufficiently solved. Therefore, there is a need for the development of a manufacturing method that can increase the yield of pyrrolobenzodiazepine, and precursor technology for increasing the stability in the blood after administration and lowering the toxicity.
한편 항체-약물 접합체(ADCs, antibody-drug conjugates)는 항원과 결합하는 항체에 독소 또는 약물을 결합시킨 후 세포 내부에서 독성물질을 방출하면서 암세포 등을 사멸에 이르게 하는 표적지향성 신기술이다. 건강한 세포에는 최소한으로 영향을 주면서 약물을 타깃 암세포에 정확하게 전달하고, 특정한 조건하에서만 방출되도록 해주기 때문에 항체 치료제 자체보다 효능이 우수하고 기존의 항암제들에 비해 부작용의 위험성을 크게 낮출 수 있는 기술이다.On the other hand, antibody-drug conjugates (ADCs) are new target-oriented technologies that cause cancer cells to die while releasing toxins or drugs after binding to toxins or drugs to antibodies that bind antigens. Because it delivers drugs to target cancer cells accurately and releases them under specific conditions with minimal impact on healthy cells, it is more effective than antibody treatment itself and can significantly reduce the risk of side effects compared to conventional anticancer drugs.
이러한 항체-약물 접합체의 기본 구조는 "항체-링커-저분자 약물(독소)"로 구성되어 있다. 여기서 링커는 단순히 항체와 약물을 연결시켜주는 기능적인 역할뿐 아니라, 체내 순환시 안정하게 타깃 세포까지 도달 후 약물이 세포내로 들어가 항체-약물간 해리현상(예, 효소에 의한 가수분해에 의한 결과)에 의해 약물이 잘 떨어지면서 타깃 암세포에 약효를 나타내도록 해야 한다. 즉 링커의 안정성에 따라 항체-약물 접합체의 효능 및 전신독성(systemic toxicity) 등의 안전성 면에서 링커는 매우 중요한 역할을 한다 (Discovery Medicine 2010, 10(53): 329-39).The basic structure of such antibody-drug conjugates consists of "antibody-linker-small molecule drugs (toxins)". Here, the linker is not only a functional role that connects the antibody and the drug, but also reaches the target cell stably during the body circulation, and then the drug enters the cell and dissociates between the antibodies and the drug (eg, the result of hydrolysis by enzymes). By dropping the drug well to target cancer cells should be effective. That is, the linker plays a very important role in terms of safety, such as the efficacy of the antibody-drug conjugate and systemic toxicity, depending on the stability of the linker (Discovery Medicine 2010, 10 (53): 329-39).
본 발명의 발명자는 혈장 내에서 보다 안정하고 체내 순환시에도 안정적이며 약물이 암세포 내에서 쉽게 방출되어 약효를 나타낼 수 있는 효과적인 자가-희생 기(self-immolative group)을 포함하는 링커를 개발하여 이에 대해 특허를 확보한 바 있다(한국등록특허 제1,628,872호 등).The inventors of the present invention have developed a linker comprising an effective self-immolative group which is more stable in plasma, stable even in the body circulation, and which drug can be easily released in cancer cells to exhibit efficacy. Patent has been secured (Korean Patent No. 1,628,872, etc.).
[선행기술문헌][Preceding technical literature]
[특허문헌][Patent Documents]
(특허문헌 1) 한국공개특허 제2013-0040835호 (2013. 4. 24. 공개)(Patent Document 1) Korean Patent Publication No. 2013-0040835 (published April 24, 2013)
(특허문헌 2) 한국공개특허 제2011-0075542호 (2011. 6. 30. 공개)(Patent Document 2) Korean Patent Publication No. 2011-0075542 (Published June 30, 2011)
(특허문헌 3) 한국등록특허 제1,700,460호 (2017. 1. 20. 등록)(Patent Document 3) Korean Registered Patent No. 1,700,460 (January 20, 2017 registration)
(특허문헌 4) 한국등록특허 제1,687,054호 (2016. 12. 9. 등록)(Patent Document 4) Korean Registered Patent No. 1,687,054 (registered Dec. 9, 2016)
(특허문헌 5) 한국공개특허 제2015-0016245호 (2015. 2. 11. 공개)(Patent Document 5) Korean Patent Publication No. 2015-0016245 (published Feb. 11, 2015)
(특허문헌 6) 한국등록특허 제1,059,183호 (2011. 8. 18. 등록)(Patent Document 6) Korean Patent No. 1,059,183 (August 18, 2011)
(특허문헌 7) PCT/US2016/063564호(Patent Document 7) PCT / US2016 / 063564
(특허문헌 8) PCT/US2016/063595호(Patent Document 8) PCT / US2016 / 063595
(특허문헌 9) 한국공개특허 제2014-0035393호 (2014. 3. 21. 공개)(Patent Document 9) Korean Patent Publication No. 2014-0035393 (published March 21, 2014)
(특허문헌 10) WO 2017/160569 (2017. 9. 21. 공개)(Patent Document 10) WO 2017/160569 (Published Sept. 21, 2017)
(특허문헌 11) 미국특허 8,697,688호 (2014. 4. 15. 등록)(Patent Document 11) US Patent 8,697,688 (April 15, 2014 registration)
(특허문헌 12) 미국특허 9,713,647호 (2017. 7. 25. 등록)(Patent Document 12) US Patent 9,713,647 (July 25, 2017 registration)
(특허문헌 13) 미국공개특허 2015-0283258 (2015. 10. 8. 공개)(Patent Document 13) United States Patent Publication 2015-0283258 (2015.10. 8. publication)
[비특허문헌][Non-Patent Documents]
(비특허문헌 1)Kemp Gary C et al., Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin, Bioorganic & Medicinal Chemistry Letters Vol. 27 No. 5, 1154 - 1158 (2017)(Non-Patent Document 1) Kemp Gary C et al., Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin, Bioorganic & Medicinal Chemistry Letters Vol. 27 No. 5, 1154-1158 (2017)
(비특허문헌 2)Julia Mantaj et al., From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs), Angewandte Chemie International Edition Vol. 56 No. 2, 462 - 488 (2017)(Non-Patent Document 2) Julia Mantaj et al., From Anthramycin to Pyrrolobenzodiazepine (PBD) -Containing Antibody-Drug Conjugates (ADCs), Angewandte Chemie International Edition Vol. 56 No. 2, 462-488 (2017)
(비특허문헌 3)Giddens Anna C. et al., Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody-drug conjugates, Bioorganic & Medicinal Chemistry Vol. 24 No. 22, 6075 - 6081 (2016)(Non-Patent Document 3) Giddens Anna C. et al., Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody-drug conjugates, Bioorganic & Medicinal Chemistry Vol. 24 No. 22, 6075-6081 (2016)
(비특허문헌 4)Hartley, JA, The development of pyrrolobenzodiazepines as antitumour agents, EXPERT OPIN INV DRUG, 20(6) 733 - 744 (2011)(Non-Patent Document 4) Hartley, JA, The development of pyrrolobenzodiazepines as antitumour agents, EXPERT OPIN INV DRUG, 20 (6) 733-744 (2011)
(비특허문헌 5)Kamal Ahmed et al., Synthesis, anticancer activity and mitochondrial mediated apoptosis inducing ability of 2,5-diaryloxadiazole-pyrrolobenzodiazepine conjugates, Bioorganic & Medicinal Chemistry Vol. 18 No. 18, 6666 - 6677 (2010)(Non-Patent Document 5) Kamal Ahmed et al., Synthesis, anticancer activity and mitochondrial mediated apoptosis inducing ability of 2,5-diaryloxadiazole-pyrrolobenzodiazepine conjugates, Bioorganic & Medicinal Chemistry Vol. 18 No. 18, 6666-6677 (2010)
(비특허문헌 6)Guichard S.M et al., Influence of P-glycoprotein expression on in vitro cytotoxicity and in vivo antitumour activity of the novel pyrrolobenzodiazepine dimer SJG-136, European Journal of Cancer Vol. 41 No. 12, 1811 - 1818 (2005)(Non-Patent Document 6) Guichard S.M et al., Influence of P-glycoprotein expression on in vitro cytotoxicity and in vivo antitumour activity of the novel pyrrolobenzodiazepine dimer SJG-136, European Journal of Cancer Vol. 41 No. 12, 1811-1818 (2005)
(비특허문헌 7)Zhang, Donglu et al, Linker Immolation Determines Cell Killing Activity of Disulfide-Linked Pyrrolobenzodiazepine Antibody-Drug Conjugates, ACS Medicinal Chemistry Letters, 7(11), 988-993 (2016)(Non-Patent Document 7) Zhang, Donglu et al, Linker Immolation Determines Cell Killing Activity of Disulfide-Linked Pyrrolobenzodiazepine Antibody-Drug Conjugates, ACS Medicinal Chemistry Letters, 7 (11), 988-993 (2016)
(비특허문헌 8)Masterson, Luke A. et al., Synthesis and biological evaluation of novel pyrrolo[2,1-c][1,4]benzodiazepine prodrugs for use in antibody directed enzyme prodrug therapy, Bioorganic & Medicinal Chemistry Letters, 16(2), 252-256 (2006)(Non-Patent Document 8) Masterson, Luke A. et al., Synthesis and biological evaluation of novel pyrrolo [2,1-c] [1,4] benzodiazepine prodrugs for use in antibody directed enzyme prodrug therapy, Bioorganic & Medicinal Chemistry Letters , 16 (2), 252-256 (2006)
(비특허문헌 9)Sangnou, M. J. et al., Design and synthesis of novel pyrrolobenzodiazepine (PBD) prodrugs for ADEPT and GDEPT, Bioorganic & Medicinal Chemistry Letters, 10(18), 2083-2086 (2000)(Non-Patent Document 9) Sangnou, M. J. et al., Design and synthesis of novel pyrrolobenzodiazepine (PBD) prodrugs for ADEPT and GDEPT, Bioorganic & Medicinal Chemistry Letters, 10 (18), 2083-2086 (2000)
(비특허문헌 10) Nature Rev. Cancer 2005, 5(5), pp. 405-12; Nature ChemicalBiology, 2010, 17, pp. 498-506; Lane KT, Bees LS, Structural Biology of Protein of Farnesyltransferase and Geranylgeranyltransferase Type I, Journal of Lipid Research, 47, pp. 681-699 (2006); Patrick J. Kasey, Miguel C. Seabra; Protein Prenyltransferases, The Journal of Biological Chemistry, Vol. 271, No. 10, Issue of March 8, pp. 5289-5292 (1996)(Non-Patent Document 10) Nature Rev. Cancer 2005, 5 (5), pp. 405-12; Nature Chemical Biology, 2010, 17, pp. 498-506; Lane KT, Bees LS, Structural Biology of Protein of Farnesyltransferase and Geranylgeranyltransferase Type I, Journal of Lipid Research, 47, pp. 681-699 (2006); Patrick J. Kasey, Miguel C. Seabra; Protein Prenyltransferases, The Journal of Biological Chemistry, Vol. 271, No. 10, Issue of March 8, pp. 5289-5292 (1996)
(비특허문헌 11) Benjamin P. Duckworth et al, ChemBioChem 2007, 8, 98; Uyen T. T. Nguyen et al, ChemBioChem 2007, 8, 408; Guillermo R. Labadie et al, J. Org. Chem. 2007, 72(24), 9291; James W. Wollack et al, ChemBioChem 2009, 10, 2934(Non-Patent Document 11) Benjamin P. Duckworth et al, Chem Bio Chem 2007, 8, 98; Uyen T. T. Nguyen et al, Chem Bio Chem 2007, 8, 408; Guillermo R. Labadie et al, J. Org. Chem. 2007, 72 (24), 9291; James W. Wollack et al, Chem BioChem 2009, 10, 2934
(비특허문헌 12) Iran M. Bell, J. Med. Chem. 2004, 47(8), 1869(Non-Patent Document 12) Iran M. Bell, J. Med. Chem. 2004, 47 (8), 1869
(비특허문헌 13) Berge, et al., J. Pharm. Sci., 66, 1-19 (1977)(Non-Patent Document 13) Berge, et al., J. Pharm. Sci., 66, 1-19 (1977)
본 발명에서는, 투약 후 혈중 안정성이 떨어지는 피롤로벤조디아제핀의 혈중 안정성을 높일 수 있는 신규 구조의 피롤로벤조디아제핀 이량체 전구체를 제공하고자 한다.In the present invention, it is to provide a pyrrolobenzodiazepine dimer precursor of a novel structure that can increase the blood stability of the pyrrolobenzodiazepine having a low blood stability after administration.
본 발명에서는 또한 혈장 내에서 보다 안정하고 체내 순환시에도 안정적이며, 약물이 암세포 내에서 쉽게 방출되어 약효를 극대화할 수 있는 자가-희생기를 포함하는 링커 기술을 접목시켜, 상기 피롤로벤조디아제핀 이량체 전구체가 표적 세포에 안정적으로 도달하여 약효를 효과적으로 발휘하면서도 독성을 크게 낮출 수 있는, 약물 전구체-링커-리간드 시스템을 제공하고자 한다.In the present invention, the pyrrolobenzodiazepine dimer precursor is further stabilized in the plasma and stable in the body circulation, by incorporating a linker technology comprising a self-immolative group which can be easily released in cancer cells to maximize the efficacy. The present invention aims to provide a drug precursor-linker-ligand system that can stably reach target cells to effectively exert its effect while significantly lowering toxicity.
본 발명은 피롤로벤조디아제핀 이량체 전구체(pyrrolobenzodiazepine dimer prodrug), 이의 약학적으로 허용되는 염 또는 용매화물에 관한 것이다.The present invention relates to pyrrolobenzodiazepine dimer prodrugs, pharmaceutically acceptable salts or solvates thereof.
보다 구체적으로 본 발명에 따른 피롤로벤조디아제핀 이량체는, More specifically pyrrolobenzodiazepine dimer according to the present invention,
피롤로벤조디아제핀 이량체의 N10 및 N'10 위치에 각각 독립적으로 -C(O)O*, -S(O)O*, -C(O)*, -C(O)NR*, -S(O)2NR*, -P(O)R'NR*, -S(O)NR*, 및 -PO2NR*기로 이루어진 그룹으로부터 선택되는 어느 하나가 부착되며,Independently at the N10 and N'10 positions of the pyrrolobenzodiazepine dimer, -C (O) O *, -S (O) O *, -C (O) *, -C (O) NR *, -S ( O) any one selected from the group consisting of 2 NR *, -P (O) R'NR *, -S (O) NR *, and -PO 2 NR * is attached,
여기에서 *은 링커가 부착되는 부분이고,Where * is where the linker is attached,
여기에서, R, 및 R'은 각각 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, 치환되거나 비치환된 C1- 8알킬, 치환되거나 비치환된 C3- 8사이클로알킬, 치환되거나 비치환된 C1-8알콕시, 치환되거나 비치환된 C1-8알킬티오, 치환되거나 비치환된 C3- 20헤테로아릴, 치환되거나 비치환된 C5- 20아릴 또는 모노- 또는 다이-C1- 8알킬아미노이고, Here, R, and R 'are each independently H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NHNH 2, halo, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 3- 8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3- 20 heteroaryl, substituted or unsubstituted and 1- or di -C 8 alkylamino, - C 20 aryl or 5- mono-
여기에서 C1-8알킬, C3-8사이클로알킬, C1-8알콕시, C1-8알킬티오, C3-20헤테로아릴, C5-20아릴이 치환되는 경우, H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 할로, C1-6알킬, C1- 6알콕시 및 C6- 12아릴로 이루어진 그룹으로부터 선택되는 치환기로 치환되는,Where C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl is substituted, H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NNH 2, halo, C 1-6 alkyl, C 1- 6 alkoxy, C 6- 12 aryl is optionally substituted with substituents selected from the group consisting of,
피롤로벤조디아제핀 이량체 전구체(pyrrolobenzodiazepine dimer prodrug), 이의 약학적으로 허용되는 염 또는 용매화물을 제공한다.Pyrrolobenzodiazepine dimer prodrugs, pharmaceutically acceptable salts or solvates thereof.
본 발명의 일 양태에서, 피롤로벤조디아제핀 이량체 전구체가 제공된다. 본 발명에 따른 전구체 형태로 투여하는 경우, 혈중 노출 시 추가적인 반응에 의해 유효한 약물로 전환되어야 할 필요가 있기 때문에 예상치 못한 링커의 분해 시에 생길 수 있는 부작용의 발생가능성을 미연에 방지할 수 있고, 정상세포에 대한 독성이 감소하며, 약물이 보다 안정적이라는 점에서 기존 PBD 약물에 비해 유리한 점이 있다. In one aspect of the invention, a pyrrolobenzodiazepine dimer precursor is provided. When administered in the form of a precursor according to the present invention, it is necessary to be converted into a valid drug by an additional reaction upon exposure to blood, thereby preventing the possibility of side effects that may occur during unexpected decomposition of the linker, Toxicity to normal cells is reduced, and the drug is more stable than conventional PBD drugs in that the drug is more stable.
또한 항체-약물 접합체 제조 시, 기존 방법으로 제조한 항체-약물 접합체의 경우 불순물의 함량이 높고 노출된 이민 그룹이 뉴클레오필(nucleophile)의 공격을 받아 원치 않는 구조의 약물이 생성될 우려가 있는 반면, 본 발명에 따른 방법으로 제조된 항체-약물 접합체는 순도가 높아 분리가 용이하다는 장점이 있고, 기존 PBD 또는 PBD 이량체에 비하여 물성이 보다 향상되는 것으로 나타났다.In addition, the antibody-drug conjugate prepared by the conventional method in the production of the antibody-drug conjugate has a high impurity content and exposed imine groups may be attacked by nucleophiles, resulting in the formation of a drug having an unwanted structure. On the other hand, the antibody-drug conjugate prepared by the method according to the present invention has an advantage of high purity and easy separation, and physical properties have been improved as compared with conventional PBD or PBD dimer.
본 발명의 일 양태에서, 피롤로벤조디아제핀 이량체 전구체는 하기 화학식 Ia 또는 Ia'의 구조를 갖는 것을 특징으로 하는, In one embodiment of the present invention, the pyrrolobenzodiazepine dimer precursor has the structure of formula (Ia) or (Ia '),
피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물이다:Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof:
[화학식 Ia]Formula Ia
Figure PCTKR2018003744-appb-I000002
Figure PCTKR2018003744-appb-I000002
상기 식에서,Where
점선은 C1 및 C2, 또는 C2 및 C3 사이의 이중결합의 임의의 존재를 나타내고, Dashed lines indicate any presence of a double bond between C1 and C2, or C2 and C3,
R1은 H, OH, =O, =CH2, CN, Rm, ORm, =CH-Rm ' =C(Rm ')2, O-SO2-Rm, CO2Rm, CORm, 할로 및 디할로(dihalo)로 이루어진 그룹으로부터 선택되고,R 1 is H, OH, = O, = CH 2 , CN, R m , OR m , = CH-R m ' = C (R m ' ) 2 , O-SO 2 -R m , CO 2 R m , COR m , halo and dihalo, and
여기에서, Rm'는 Rm, CO2Rm, CORm, CHO, CO2H, 및 할로로 이루어진 그룹으로부터 선택되며,Wherein R m ' is selected from the group consisting of R m , CO 2 R m , COR m , CHO, CO 2 H, and halo,
여기에서, Rm은 치환되거나 비치환된 C1- 12알킬, 치환되거나 비치환된 C2- 12알케닐, 치환되거나 비치환된 C2- 12알키닐, 치환되거나 비치환된 C5- 20아릴, 치환되거나 비치환된 C5- 20헤테로아릴, 치환되거나 비치환된 C3- 6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클릴, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 및 치환되거나 비치환된 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되고, Here, R m is a substituted or unsubstituted C 1- 12 alkyl, substituted or unsubstituted C 2- 12 alkenyl, substituted or unsubstituted C 2- 12 alkynyl, substituted or unsubstituted C 5- 20 aryl, substituted or unsubstituted C 5- 20 heteroaryl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted 3 to 7-membered heterocyclyl, substituted or unsubstituted 3 to 7-membered Heterocycloalkyl, and substituted or unsubstituted 5 to 7-membered heteroaryl;
C1- 12알킬, C2- 12알케닐, C2- 12알키닐, C5- 20아릴, C5- 20헤테로아릴, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 또는 5 내지 7-원 헤테로아릴이 치환되는 경우, C 1- 12 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, C 5- 20 aryl, C 5- 20 heteroaryl, C 3- 6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 To 7-membered heterocycloalkyl, or 5 to 7-membered heteroaryl is substituted,
C1- 12알킬, C1- 12알콕시, C2- 12알케닐, C2- 12알키닐, C5- 20아릴, C5- 20헤테로아릴, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 또는 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로 C1- 12알킬, C2- 12알케닐, C2- 12알키닐, C5- 20아릴, C5- 20헤테로아릴, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되는 어느 하나 이상으로 치환되고;C 1- 12 alkyl, C 1- 12 alkoxy, C 2- 12 alkenyl, C 2- 12 alkynyl, C 5- 20 aryl, C 5- 20 heteroaryl, C 3- 6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered-heterocycloalkyl, or 5 to 7 each of the hydrogen atoms of the member heteroaryl are each independently a C 1- 12 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, from 5- C 20 aryl, C 5- 20 heteroaryl, C 3- 6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7 membered heteroaryl group, consisting of Substituted with any one or more selected;
R2, R3 및 R5는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRmRm ', NO2, Me3Sn 및 할로로 이루어진 그룹으로부터 선택되며,R 2, R 3 and R 5 are each independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m ' , NO 2 , Me 3 Sn And halo,
여기에서 Rm 및 Rm'은 상기에서 정의한 바와 같고;Wherein R m and R m ′ are as defined above;
R4는 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRmRm ', NO2, Me3Sn, 할로, 치환되거나 비치환된 C1- 6알킬, 치환되거나 비치환된 C1- 6알콕시, 치환되거나 비치환된 C2- 6알케닐, 치환되거나 비치환된 C2- 6알키닐, 치환되거나 비치환된 C3- 6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C5- 12아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -CN, -NO2, -NCO, -ORn, -OC(O)Rn, -OC(O)NRnRn', -OS(O)Rn, -OS(O)2Rn, -SRn, -S(O)Rn, -S(O)2Rn, -S(O)NRnRn ', -S(O)2NRnRn', -OS(O)NRnRn ', -OS(O)2NRnRn ', -NRnRn ', -NRnC(O)Ro, -NRnC(O)ORo, -NRnC(O)NRoRo', -NRnS(O)Ro, -NRnS(O)2Ro, -NRnS(O)NRoRo ', -NRnS(O)2NRoRo ', -C(O)Rn, -C(O)ORn 및 -C(O)NRnRn'로 이루어진 그룹으로부터 선택되고,R 4 is H, R m, OH, OR m, SH, SR m, NH 2, NHR m, NR m R m ', NO 2, Me 3 Sn, halo, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 1- 6 alkoxy, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2- 6-alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted hwandoen 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5- C 12 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -CN, -NO 2, -NCO, -OR n, - OC (O) R n , -OC (O) NR n R n ' , -OS (O) R n , -OS (O) 2 R n , -SR n , -S (O) R n , -S ( O) 2 R n , -S (O) NR n R n ' , -S (O) 2 NR n R n' , -OS (O) NR n R n ' , -OS (O) 2 NR n R n ' , -NR n R n ' , -NR n C (O) R o , -NR n C (O) OR o , -NR n C (O) NR o R o ' , -NR n S (O) R o , -NR n S (O) 2 R o , -NR n S (O) NR o R o ' , -NR n S (O) 2 NR o R o ' , -C (O) R n , -C (O) OR n and -C (O) NR n R n ' , and
여기에서 C1- 6알킬, C1- 6알콕시, C2- 6알케닐, C2- 6알키닐, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 12아릴, 5 내지 7-원 헤테로아릴이 치환되는 경우, C1- 6알킬, C1- 6알콕시, C2- 6알케닐, C2- 6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 12아릴, 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로C1-6알킬, C1- 6알콕시, C2-6알케닐, C2- 6알키닐, C3-C6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 5 내지 7-원 헤테로아릴, -ORp, -OC(O)Rp, -OC(O)NRpRp ', -OS(O)Rp, -OS(O)2Rp, -SRp, -S(O)Rp, -S(O)2Rp, -S(O)NRpRp ', -S(O)2NRpRp ', -OS(O)NRpRp', -OS(O)2NRpRp ', -NRpRp ', -NRpC(O)Rq, -NRpC(O)ORq, -NRpC(O)NRqRq ', -NRpS(O)Rq, -NRpS(O)2Rq, -NRpS(O)NRqRq ', -NRpS(O)2NRqRq ', -C(O)Rp, -C(O)ORp 또는 -C(O)NRpRp로 치환될 수 있으며,Here, C 1- 6 alkyl, C 1- 6 alkoxy, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 12 aryl, 5 to 7 membered heterocyclic when aryl is substituted, C 1- 6 alkyl, C 1- 6 alkoxy, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 12 aryl, 5 to 7 membered each hydrogen atom of the heteroaryl are each independently a C 1 - 6 alkyl, C 1- 6 alkoxy, C 2 - 6 alkenyl, C 2- 6 alkynyl , C 3- C 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5 - 10 aryl, 5- to 7-membered heteroaryl group, -OR p, -OC (O) R p, -OC (O) NR p R p ' , -OS (O) R p , -OS (O) 2 R p , -SR p , -S (O) R p , -S (O) 2 R p , -S (O) NR p R p ' , -S (O) 2 NR p R p ' , -OS (O) NR p R p ' , -OS (O) 2 NR p R p ' , -NR p R p ' , -NR p C (O) R q , -NR p C (O) OR q , -NR p C (O) NR q R q ' , -NR p S (O) R q , -NR p S (O) 2 R q , -NR p S (O) NR q R q ' , -NR p S (O) 2 NR q R q ' , -C (O) R p , -C (O) OR p Or -C (O) NR p R p ,
여기에서, Rn, Ro, Rp, 및 Rq는 각각 독립적으로 H, C1-7알킬, C2-7알케닐, C2- 7알키닐, C3- 13사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되고; Here, R n, R o, R p, and R q is independently H, C 1 - 7 alkyl, C 2 - 7 alkenylene, C 2- 7 alkynyl, C 3- 13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10, selected from aryl, and a 5- to 7-membered group consisting of heteroaryl, and;
X 및 X'은 각각 독립적으로 -C(O)O*, -S(O)O*, -C(O)*, -C(O)NR*, -S(O)2NR*, -P(O)R'NR*, -S(O)NR*, 및 -PO2NR*기로 이루어진 그룹으로부터 선택되는 어느 하나가 부착되며,X and X 'are each independently -C (O) O *, -S (O) O *, -C (O) *, -C (O) NR *, -S (O) 2 NR *, -P Any one selected from the group consisting of (O) R'NR *, -S (O) NR *, and -PO 2 NR * is attached,
여기에서 *은 링커가 부착되는 부분이고,Where * is where the linker is attached,
여기에서, R, 및 R'은 각각 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, 치환되거나 비치환된 C1- 8알킬, 치환되거나 비치환된 C3- 8사이클로알킬, 치환되거나 비치환된 C1- 8알콕시, 치환되거나 비치환된 C1- 8알킬티오, 치환되거나 비치환된 C3- 20헤테로아릴, 치환되거나 비치환된 C5- 20아릴 또는 모노- 또는 다이-C1- 8알킬아미노이고, Here, R, and R 'are each independently H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NHNH 2, halo, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 3- 8 cycloalkyl, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 1- 8 alkylthio, substituted or unsubstituted C 3- 20 heteroaryl, substituted or unsubstituted and 1- or di -C 8 alkylamino, - C 20 aryl or 5- mono-
여기에서 C1- 8알킬, C3- 8사이클로알킬, C1- 8알콕시, C1- 8알킬티오, C3- 20헤테로아릴, C5- 20아릴이 치환되는 경우, H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 할로, C1- 6알킬, C1- 6알콕시 및 C5- 12아릴로 이루어진 그룹으로부터 선택되는 치환기로 치환되며;Here, C 1- 8 alkyl, C 3- 8 cycloalkyl, C 1- 8 alkoxy, C 1- 8 alkyl thio, C 3- 20 heteroaryl, C 5- 20 when aryl is substituted, H, OH, N 3, CN, NO 2, SH , NH 2, ONH 2, NNH 2, halo, C 1- 6 alkyl, C 1- 6 alkoxy and 5- C 12 aryl is substituted with substituents selected from the group consisting of;
Y 및 Y'은 각각 독립적으로 O, S, 및 N(H)로 이루어진 그룹으로부터 선택되며;Y and Y 'are each independently selected from the group consisting of O, S, and N (H);
R6은 치환되거나 비치환된 포화 또는 불포화 C3-12탄화수소 쇄이고,R 6 is a substituted or unsubstituted saturated or unsaturated C 3-12 hydrocarbon chain,
여기에서 이의 쇄(chain)는 하나 이상의 헤테로원자, NMe 또는 치환되거나 비치환된 방향족 고리에 의해 차단(interrupt)될 수 있고, Wherein the chain thereof may be interrupted by one or more heteroatoms, NMe or substituted or unsubstituted aromatic rings,
여기에서 이의 쇄(chain) 또는 방향족 고리는 이의 쇄 또는 방향족 고리 상의 수소원자 중 어느 하나 이상의 위치가 -NH, -NRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-R, 또는 -[CH2CH2O]n-R로 치환되거나 비치환될 수 있고,Wherein a chain or aromatic ring thereof has at least one position of hydrogen atom on its chain or aromatic ring, -NH, -NR m , -NHC (O) R m , -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or -May be unsubstituted or substituted with [CH 2 CH 2 O] n -R,
여기에서 Rm 및 R은 각각 상기 Rm 및 R의 정의와 같으며, Where R m and R are the same as defined above for R m and R,
여기에서 n은 1 내지 12의 정수이고;Where n is an integer from 1 to 12;
R7은 H, 치환되거나 비치환된 C1-6알킬, 치환되거나 비치환된 C2-6알케닐, 치환되거나 비치환된 C2- 6알키닐, 치환되거나 비치환된 C3- 6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C6-10아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -ORr, -OC(O)Rr, -OC(O)NRrRr ', -OS(O)Rr, -OS(O)2Rr, -SRr, -S(O)Rr, -S(O)2Rr, -S(O)NRrRr ', -S(O)2NRrRr ', -OS(O)NRrRr ', -OS(O)2NRrRr', -NRrRr ', -NRrC(O)Rs, -NRrC(O)ORs, -NRrC(O)NRsRs ', -NRrS(O)Rs, -NRrS(O)2Rs, -NRrS(O)NRsRs', -NRrS(O)2NRsRs, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'이고,R 7 is H, substituted or unsubstituted C 1 - 6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl alkyl, substituted or unsubstituted 3 to 7-membered optionally substituted heterocycloalkyl, unsubstituted or unsubstituted C 6 - 10 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -OR r, -OC (O) r r , -OC (O) NR r R r ' , -OS (O) R r , -OS (O) 2 R r , -SR r , -S (O) R r , -S (O) 2 R r , -S (O) NR r R r ' , -S (O) 2 NR r R r ' , -OS (O) NR r R r ' , -OS (O) 2 NR r R r' , -NR r R r ' , -NR r C (O) R s , -NR r C (O) OR s , -NR r C (O) NR s R s ' , -NR r S (O) R s , -NR r S (O) 2 R s , -NR r S (O) NR s R s' , -NR r S (O) 2 NR s R s , -C (O) R r , -C (O) OR s or -C (O) NR r R r ' ,
여기에서 C1-6알킬, C2-6알케닐, C2- 6알키닐, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 5 내지 7-원 헤테로아릴이 치환되는 경우, C1-6알킬, C2-6알케닐, C2- 6알키닐, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로 C1-6알킬, C2-6알케닐, C2- 6알키닐, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 5 내지 7-원 헤테로아릴, -ORt, -OC(O)Rt, -OC(O)NRtRt ', -OS(O)Rt, -OS(O)2Rt, -SRt, -S(O)Rt, -S(O)2Rt, -S(O)NRtRt ', -S(O)2NRtRt ', -OS(O)NRtRt ', -OS(O)2NRtRt ', -NRtRt ', -NRtC(O)Ru, -NRtC(O)ORu, -NRtC(O)NRuRu ', -NRtS(O)Ru, -NRtS(O)2Ru, -NRtS(O)NRuRu ', -NRtS(O)2NRuRu', -C(O)Rt, -C(O)ORt 또는 -C(O)NRtRt'로 치환되며,Here, C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5- to 7-membered heterocyclic when the aryl is substituted, C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5 to 7-membered each hydrogen atom of the heteroaryl are each independently a C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5-7 membered heteroaryl, -OR t, -OC (O) R t, -OC (O) NR t R t ', -OS (O) R t, -OS (O) 2 R t , -SR t , -S (O) R t , -S (O) 2 R t , -S (O) NR t R t ' , -S (O) 2 NR t R t ' , -OS ( O) NR t R t ' , -OS (O) 2 NR t R t ' , -NR t R t ' , -NR t C (O) R u , -NR t C (O) OR u , -NR t C (O) NR u R u ' , -NR t S (O) R u , -NR t S (O) 2 R u , -NR t S (O) NR u R u ' , -NR t S (O ) 2 NR u R u ' , -C (O) R t , -C (O) OR t or -C (O) NR t R t' ,
여기에서, Rr, Rr ', Rs, Rs ', Rt, Rt ', Ru 및 Ru '은 각각 독립적으로 H, C1- 7알킬, C2-7알케닐, C2- 7알키닐, C3- 13사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되고; Here, R r, R r ', R s, R s', R t, R t ', R u and R u' are each independently H, C 1- 7 alkyl, C 2-7 alkenyl, C 1-7 alkynyl, C 3- 13 is selected from cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5- to 7-membered group consisting of-heteroaryl;
[화학식 Ia']Formula Ia '
Figure PCTKR2018003744-appb-I000003
Figure PCTKR2018003744-appb-I000003
상기 식에서,Where
R1, R2, R3, R4, R6, R7, 및 X는 상기 화학식 Ia에서의 정의와 같고,R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and X are as defined above in Formula Ia,
R8은 H, 할로, 치환되거나 비치환된 C1- 6알킬, 치환되거나 비치환된 C2- 6알케닐, 치환되거나 비치환된 C2-6알키닐, 치환되거나 비치환된 C3- 6헤테로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C5- 10아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -CN, -NO2, -NCO, -OH, ORm, -OC(O)Rm, -OC(O)NRmRm', -OS(O)Rm, -OS(O)2Rm, -SRm, -S(O)Rm, -S(O)2Rm, -S(O)NRmRm ', -S(O)2NRmRm', -OS(O)NRmRm ', -OS(O)2NRmRm ', -NRmRm ', -NRmC(O)Rm, -NRmC(O)ORn, -NRmC(O)NRnRn', -NRmS(O)Rn, -NRmS(O)2Rn, -NRmS(O)NRnRn ', -NRmS(O)2NRnRn ', -C(O)Rm, -C(O)ORm 및 -C(O)NRmRm'로 이루어진 그룹으로부터 선택되며,R 8 is H, halo, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3- 6 heteroalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted C 5- 10 arylalkyl, substituted or unsubstituted 5 to 7 membered heteroaryl, -CN, -NO 2, - NCO, -OH, OR m , -OC (O) R m , -OC (O) NR m R m ', -OS (O) R m , -OS (O) 2 R m , -SR m , -S (O) R m , -S (O) 2 R m , -S (O) NR m R m ' , -S (O) 2 NR m R m' , -OS (O) NR m R m ' ,- OS (O) 2 NR m R m ' , -NR m R m ' , -NR m C (O) R m , -NR m C (O) OR n , -NR m C (O) NR n R n ' , -NR m S (O) R n , -NR m S (O) 2 R n , -NR m S (O) NR n R n ' , -NR m S (O) 2 NR n R n ' ,- C (O) R m , -C (O) OR m and -C (O) NR m R m ' ,
여기에서 C1- 6알킬, C2- 6알케닐, C2- 6알키닐, C3- 6헤테로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 또는 5 내지 7-원 헤테로아릴이 치환되는 경우, C1- 6알킬, C2- 6알케닐, C2- 6알키닐, C3- 6헤테로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 또는 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로 C1-6알킬, C2- 6알케닐, C2- 6알키닐, C3- 6헤테로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 5 내지 7-원 헤테로아릴, -ORm, -OC(O)Rm, -OC(O)NRmRm ', -OS(O)Rm, -OS(O)2Rm, -SRm, -S(O)Rm, -S(O)2Rm, -S(O)NRmRm ', -S(O)2NRmRm ', -OS(O)NRmRm ', -OS(O)2NRmRm ', -NRmRm ', -NRmC(O)Rn, -NRmC(O)ORn, -NRmC(O)NRnRn ', -NRmS(O)Rn, -NRmS(O)2Rn, -NRmS(O)NRnRn ', -NRmS(O)2NRnRn', -C(O)Rm, -C(O)ORm 또는-C(O)NRmRm'로 치환되고, Here, C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, or a 5- to 7-membered when a heteroaryl group optionally substituted, C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, or 5 to 7 membered each hydrogen atom of the heteroaryl are each independently C 1-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl , 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR m, -OC (O) R m, -OC (O) NR m R m ', -OS (O) R m, -OS (O ) 2 R m , -SR m , -S (O) R m , -S (O) 2 R m , -S (O) NR m R m ' , -S (O) 2 NR m R m ' ,- OS (O) NR m R m ' , -OS (O) 2 NR m R m ' , -NR m R m ' , -NR m C (O) R n , -NR m C (O) OR n ,- NR m C (O) NR n R n ' , -NR m S (O) R n , -NR m S (O) 2 R n , -NR m S (O) NR n R n ' , -NR m S (O) 2 NR n R n ' , -C (O) R m , -C (O) OR m or -C (O) NR m R m' ,
Rm, Rm ', Rn 및 Rn '은 상기 화학식 Ia에서의 정의와 같으며, R m , R m ' , R n and R n ' are as defined in Formula Ia,
Za 및 Zb는 각각 독립적으로 O, N, 또는 S이고,Z a and Z b are each independently O, N, or S,
R12a, R13a, 및 R14a는 각각 독립적으로 H, 치환되거나 비치환된 C1- 6알킬, 치환되거나 비치환된 C2- 6알케닐, 치환되거나 비치환된 C2- 6알키닐, 치환되거나 비치환된 C3- 6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C5- 10아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -C(O)R15a, -C(O)OR15a 및 -C(O)NR15aR15a'이고, 여기에서 R15a 및 R15a'은 Rm의 정의와 같고,R 12a, R 13a, and R 14a are each independently selected from H, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5- C 10 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -C (O) R 15a , -C (O) OR 15a and -C (O) NR 15a R 15a ' , wherein R 15a and R 15a' are as defined in R m ,
여기에서 C1- 6알킬, C2- 6알케닐, C2- 6알키닐, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 5 내지 7-원 헤테로아릴이 치환되는 경우 각 수소원자는 C1- 6알킬, C2- 6알케닐, C2- 6알키닐, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 5 내지 7-원 헤테로아릴, -ORo, -OC(O)Ro, -OC(O)NRoRo ', -OS(O)Ro, -OS(O)2Ro, -SRo, -S(O)Ro, -S(O)2Ro, -S(O)NRoRo ', -S(O)2NRoRo', -OS(O)NRoRo ', -OS(O)2NRoRo ', -NRoRo ', -NRoC(O)Rp, -NRoC(O)ORp, -NRoC(O)NRpRp', -NRoS(O)Rp, -NRoS(O)2Rp, -NRoS(O)NRpRp ', -NRoS(O)2NRpRp ', -C(O)Ro, -C(O)ORo 또는 -C(O)NRoRo'로 치환되고; Here, C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl when the aryl is substituted, each is hydrogen C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR o, -OC (O) R o, -OC (O) NR o R o ', -OS (O) R o, - OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o ' , -S (O) 2 NR o R o ' , -OS (O) NR o R o ' , -OS (O) 2 NR o R o ' , -NR o R o ' , -NR o C (O) R p , -NR o C (O) OR p , -NR o C (O) NR p R p ' , -NR o S (O) R p , -NR o S (O) 2 R p , -NR o S (O) NR p R p ' ,- NR o S (O) 2 NR p R p ' , -C (O) R o , -C (O) OR o or -C (O) NR o R o' ;
여기에서, R13a 및 R14a는 이들이 부착된 원자와 함께 결합하여 3 내지 7-원 헤테로사이클릴, 또는 3 내지 7-원 헤테로사이클로알킬을 형성하거나, 또는 R13a 및 R14a는 이들이 부착되는 원자와 함께 결합하여 3 내지 7-원 헤테로아릴을 형성할 수 있고, Wherein R 13a and R 14a combine with the atoms to which they are attached to form a 3 to 7-membered heterocyclyl, or 3 to 7-membered heterocycloalkyl, or R 13a and R 14a to which they are attached Can be combined together to form a 3 to 7 membered heteroaryl,
여기에서 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬 또는 3 내지 7-원 헤테로아릴에 존재하는 각 수소원자는 각각 독립적으로 C1- 6알킬, C2- 6알케닐, C2- 6알키닐, C3- 6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 5 내지 7-원 헤테로아릴, -ORo, -OC(O)Ro, -OC(O)NRoRo ', -OS(O)Ro, -OS(O)2Ro, -SRo, -S(O)Ro, -S(O)2Ro, -S(O)NRoRo ', -S(O)2NRoRo ', -OS(O)NRoRo ', -OS(O)2NRoRo ', -NRoRo ', -NRoC(O)Rp, -NRoC(O)ORp, -NRoC(O)NRpRp ', -NRoS(O)Rp, -NRoS(O)2Rp, -NRoS(O)NRpRp ', -NRoS(O)2NRpRp', -C(O)Ro, -C(O)ORo 또는 -C(O)NRoRo'로 치환되고; Here in the 3 to 7-membered heterocyclyl, 3 to each of the hydrogen atoms present in the 7-membered heterocycloalkyl or 3 to 7-membered heteroaryl are each independently a C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR o, -OC (o) R o, - OC (O) NR o R o ' , -OS (O) R o , -OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o ' , -S (O) 2 NR o R o ' , -OS (O) NR o R o ' , -OS (O) 2 NR o R o ' , -NR o R o ' , -NR o C (O) R p , -NR o C (O) OR p , -NR o C (O) NR p R p ' , -NR o S (O) R p , -NR o S (O ) 2 R p , -NR o S (O) NR p R p ' , -NR o S (O) 2 NR p R p' , -C (O) R o , -C (O) OR o or -C (O) NR o R o ' ;
여기에서, Rn, Rn ', Ro, Ro ', Rp, 및 Rp '은 각각 독립적으로 H, C1- 7알킬, C2- 7알케닐, C2- 7알키닐, C3- 13사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되며;Here, R n, R n ', R o, R o', R p, and R p 'are each independently H, C 1- 7 alkyl, 2- C 7 alkenyl, C 2- 7 alkynyl, C 3- 13 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, and a 5- to 7-membered heteroaryl is selected from the group consisting of;
R1 ', R2 ', R3 ', R4 ', R5 ', R7 ' 및 R8 '은 각각 R1, R2, R3, R4, R5, R7 및 R8에 대해서 정의한 바와 같다.R 1 ′ , R 2 ′ , R 3 ′ , R 4 ′ , R 5 ′ , R 7 ′, and R 8 ′ are R 1 , R 2 , R 3 , R 4, R 5 , It is as defined about R <7> and R <8> .
본 발명의 일 양태에서, 점선은 C2 및 C3 사이의 이중결합의 존재를 나타낸다.In one aspect of the invention, the dashed line indicates the presence of a double bond between C2 and C3.
본 발명의 일 양태에서, R1은 치환되거나 비치환된 C1- 6알킬, 치환되거나 비치환된 C2- 6알케닐, 치환되거나 비치환된 C5-7아릴 및 치환되거나 비치환된 C3-6헤테로아릴로 이루어진 그룹으로부터 선택된다.In one aspect of the invention, R 1 is a substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 5-7 aryl, and substituted or unsubstituted C It is selected from the group consisting of 3-6 heteroaryl.
본 발명의 일 양태에서, R2, R3 및 R5는 각각 독립적으로 H 또는 OH이다.In one aspect of the invention, R 2 , R 3 and R 5 are each independently H or OH.
본 발명의 일 양태에서, R4는 C1-6알콕시, 보다 구체적으로는 메톡시, 에톡시 또는 부톡시이다.In one aspect of the invention, R 4 is C 1-6 alkoxy, more specifically methoxy, ethoxy or butoxy.
본 발명의 일 양태에서, X 및 X'은 각각 독립적으로 -C(O)O*, -C(O)* 및 -C(O)NR*로 이루어진 그룹으로부터 선택되고,In one aspect of the invention, X and X 'are each independently selected from the group consisting of -C (O) O *, -C (O) * and -C (O) NR *,
여기서 R은 각각 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 할로, 치환되거나 비치환된 C1-8알킬 또는 치환되거나 비치환된 C1- 8알콕시이며, 여기에서 C1- 8알킬 또는 C1- 8알콕시가 치환되는 경우, H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 또는 할로로 치환된다.Wherein R is each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, substituted or unsubstituted C 1-8 alkyl or substituted or unsubstituted C 1- 8 alkoxy, in the case where C 1- 8 alkyl, C 1- 8 alkoxy which is substituted, H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NNH is substituted by 2, or halo .
본 발명의 일 양태에서, Y 및 Y'은 O이다.In one aspect of the invention, Y and Y 'are O.
본 발명의 일 양태에서, R6는 치환되거나 비치환된 포화 또는 불포화 C3-8탄화수소 쇄이고, In one aspect of the invention, R 6 is a substituted or unsubstituted saturated or unsaturated C 3-8 hydrocarbon chain,
이의 쇄(chain)는 하나 이상의 헤테로원자 또는 치환되거나 비치환된 방향족 고리에 의해 차단(interrupt)될 수 있으며,Its chain may be interrupted by one or more heteroatoms or substituted or unsubstituted aromatic rings,
여기에서 헤테로원자는 O, S 또는 N(H)이고, 방향족 고리는 벤젠, 피리딘, 이미다졸 또는 피라졸이며,Wherein the heteroatom is O, S or N (H), the aromatic ring is benzene, pyridine, imidazole or pyrazole,
여기에서 이의 쇄(chain) 또는 방향족 고리는, 이의 쇄 또는 방향족 고리 상의 수소원자 중 어느 하나 이상의 위치가 -NHC(O)CH2-[OCH2CH2]n-R, 또는 -[CH2CH2O]n-R로 치환될 수 있고,Wherein in the chain or aromatic ring thereof, at least one position of a hydrogen atom on the chain or aromatic ring is -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or -[CH 2 CH 2 O] n -R can be substituted,
여기에서 R의 정의는 상기 R의 정의와 같으며,Wherein the definition of R is the same as the definition of R,
n은 1 내지 6의 정수이다. n is an integer of 1-6.
본 발명의 일 양태에서, 하기로부터 선택된 피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물이 제공된다:In one aspect of the invention, there is provided a pyrrolobenzodiazepine dimer precursor, pharmaceutically acceptable salt or solvate thereof selected from:
Figure PCTKR2018003744-appb-I000004
Figure PCTKR2018003744-appb-I000004
상기 식에서,Where
RO 및 R'O는 각각 산소보호기로서, 서로 동일하거나, 서로 다를 수 있다.R O and R ′ O are each an oxygen protecting group and may be the same as or different from each other.
본 발명에서, 다음과 같은 구조의 화합물은 제외된다:In the present invention, compounds having the following structure are excluded:
Figure PCTKR2018003744-appb-I000005
Figure PCTKR2018003744-appb-I000005
본 발명은 또한, 하기 화학식 IIa의 구조를 갖는 접합체 또는 이의 약학적으로 허용되는 염 또는 용매화물을 제공한다:The present invention also provides a conjugate having the structure of formula IIa or a pharmaceutically acceptable salt or solvate thereof:
[화학식 IIa]Formula IIa]
Ligand - (L - D)n Ligand-(L-D) n
상기 식에서,Where
Ligand는 리간드이고,Ligand is a ligand,
L은 링커이며,L is a linker,
D는 전술한 바와 같은 피롤로벤조디아제핀 이량체 전구체이고, 여기서 링커는 전술한 바와 같은 D의 N10 위치, N10' 위치, 또는 N10 및 N10' 위치, 또는 D의 X, X' 또는 X 및 X'을 통해 D와 결합되며,D is a pyrrolobenzodiazepine dimer precursor as described above, wherein the linker is selected from the N10, N10 ', or N10 and N10' positions of D, or X, X 'or X and X' of D as described above. Through D and
n은 1 내지 20의 정수이다.n is an integer from 1 to 20.
본 발명의 일 양태에서, 링커는, D의 N10 및 N10' 위치, 또는 D의 X 및 X'을 통해 D와 결합된다.In one aspect of the invention, the linker is bonded to D via the N10 and N10 'positions of D, or X and X' of D.
본 발명의 일 양태에서, n은 1 내지 10의 정수이다.In one aspect of the invention, n is an integer from 1 to 10.
본 발명은 또한, 하기 화학식 IIb 또는 화학식 IIb'의 구조를 갖는 피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물을 제공한다:The present invention also provides a pyrrolobenzodiazepine dimer precursor-linker compound having the structure of Formula IIb or Formula IIb ', a pharmaceutically acceptable salt or solvate thereof:
[화학식 IIb]Formula IIb]
Figure PCTKR2018003744-appb-I000006
Figure PCTKR2018003744-appb-I000006
[화학식 IIb']Formula IIb '
Figure PCTKR2018003744-appb-I000007
Figure PCTKR2018003744-appb-I000007
상기 식에서,Where
점선, R1, R2, R3, R4, R5, R6, R7, X, Y, R1', R2', R3', R4', R5', R7', X', Y', R8, Za, Zb, R12a, R13a, R14a, R8', Za', Zb', R12a', R13a', 및 R14a'은 각각 제2항에서 화학식 Ia 및 화학식 Ia'의 화합물에 대해 정의한 바와 동일하고,Dashed line, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
Xa 및 Xa'은 각각 독립적으로 결합(bond), 또는 치환되거나 비치환된 C1- 6알킬렌이며, 여기에서 C1- 6알킬렌이 치환되는 경우, 수소, C1-8알킬 또는 C3-8사이클로알킬로 치환되고,Combining each independently are Xa and Xa '(bond), or a substituted or unsubstituted C 1- 6 alkylene, and, if this is a C 1- 6 alkylene substituted with a hydrogen, C 1-8 alkyl or C 3 Substituted with -8 cycloalkyl,
G 및 G'은 글루쿠로나이드(glucuronide)기, 갈락토사이드기 또는 이의 유도체이고,G and G 'are glucuronide groups, galactoside groups or derivatives thereof,
Z는 H, C1- 8알킬, 할로, NO2, CN,
Figure PCTKR2018003744-appb-I000008
,
Figure PCTKR2018003744-appb-I000009
및 -(CH2)m-OCH3로 이루어진 그룹으로부터 선택되며, Z is H, C 1- 8 alkyl, halo, NO 2, CN,
Figure PCTKR2018003744-appb-I000008
,
Figure PCTKR2018003744-appb-I000009
And-(CH 2 ) m -OCH 3 ,
R8, R9 및 R10은 각각 독립적으로 H, C1- 8알킬, C2- 6알케닐, 및 C1- 6알콕시로 이루어진 그룹으로부터 선택되고, m은 0 내지 12이며,R 8, R 9 and R 10 is selected from each independently H, C 1- 8 alkyl, C 2- 6 alkenyl, and the group consisting of C 1- 6 alkoxy, m is 0 to 12,
n은 1 내지 3의 정수이고, n이 2 이상의 정수인 경우 각각의 Z는 서로 동일하거나 상이할 수 있으며,n is an integer of 1 to 3, when n is an integer of 2 or more, each Z may be the same or different from each other,
W는 -C(O)-, -C(O)NR''-, -C(O)O-, -S(O)2NR''-, -P(O)R'''NR''-, -S(O)NR''-, 또는 -PO2NR''-이고, 상기 R'' 및 R'''은 각각 독립적으로 H, C1- 8알킬, C3- 8사이클로알킬, C1- 8알콕시, C1- 8알킬티오, 모노- 또는 다이-C1-8알킬아미노, C3-20헤테로아릴, 또는 C6-20아릴이며,W is -C (O)-, -C (O) NR ''-, -C (O) O-, -S (O) 2 NR ''-, -P (O) R '''NR'' -, -S (O) NR '' -, or -PO 2 NR '' -, and wherein R '' and R '''are each independently H, C 1- 8 alkyl, C 3- 8 cycloalkyl, 1- C 8 alkoxy, C 1- 8 alkyl thio, mono- or di -C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl,
L은 브랜칭 유닛(branching unit), 연결 유닛(connection unit) 및 결합 유닛(binding unit)으로 이루어진 그룹으로부터 선택되는 하나 이상의 유닛, 또는 이들 유닛의 조합이며, 여기에서 연결 유닛은 W와 결합 유닛을, W와 브랜칭 유닛을, 브랜칭 유닛과 브랜칭 유닛을, 또는 브랜칭 유닛과 결합 유닛을 연결하고, 여기에서 브랜칭 유닛은 연결 유닛과 W를, 또는 연결 유닛과 또 다른 연결 유닛을 연결하며,L is one or more units selected from the group consisting of a branching unit, a connection unit and a binding unit, or a combination of these units, wherein the connection unit is a combination of W, Connecting the W and the branching unit, the branching unit and the branching unit, or the branching unit and the coupling unit, wherein the branching unit connects the connection unit and the W, or the connection unit and another connection unit,
브랜칭 유닛은 C2- 100알케닐(여기서, 알케닐의 탄소 원자는 하나 또는 그 이상의 N, O 및 S로 이루어진 그룹으로부터 선택되는 헤테로원자로 치환될 수 있으며, 알케닐은 하나 또는 그 이상의 C1- 20알킬로 더 치환될 수 있다), 친수성(hydrophilic) 아미노산, -C(O)-, -C(O)NR''''-, -C(O)O-, -(CH2)s-NHC(O)-(CH2)t-, -(CH2)u-C(O)NH-(CH2)v-, -(CH2)s-NHC(O)-(CH2)t-C(O)-, -(CH2)u-C(O)NH-(CH2)v-C(O)-, -S(O)2NR''''-, -P(O)R'''''NR''''-, -S(O)NR''''-, 또는 -PO2NR''''- (여기서, R'''' 및 R'''''는 각각 독립적으로 H, C1- 8알킬, C3- 8사이클로알킬, C1- 8알콕시, C1- 8알킬티오, 모노- 또는 다이-C1- 8알킬아미노, C3- 20헤테로아릴 또는 C5-20아릴이며, s, t, u 및 v는 각각 독립적으로 0 내지 10의 정수이고),Branching unit 100 C 2- alkenyl (wherein the carbon atom of the alkenyl group is one or more N, O and may be substituted with a hetero atom selected from the group consisting of S, alkenyl has one or more C 1- 20 may be further substituted with alkyl), hydrophilic amino acid, -C (O)-, -C (O) NR ''''-, -C (O) O-,-(CH 2 ) s- NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t- C (O)-,-(CH 2 ) u -C (O) NH- (CH 2 ) v -C (O)-, -S (O) 2 NR ''''-, -P (O) R '''''NR''''-, -S (O) NR''''-, or -PO 2 NR''''-(whereR''''andR''''' are each independently is H, C 1- 8 alkyl, C 3- 8 cycloalkyl, C 1- 8 alkoxy, C 1- 8 alkyl thio, mono- or di -C 1- 8 alkylamino, C 3- 20 heteroaryl or C 5-20 aryl, s, t, u and v are each independently an integer from 0 to 10),
연결 유닛은 -(CH2)r(V(CH2)p)q-이고, 여기에서, r은 0 내지 10의 정수이고, p는 0 내지 12의 정수이며, q는 1 내지 20의 정수이고, V는 단일결합, -O-, 또는 S-이며,The connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, -O-, or S-,
결합 유닛은
Figure PCTKR2018003744-appb-I000010
,
Figure PCTKR2018003744-appb-I000011
,
Figure PCTKR2018003744-appb-I000012
또는
Figure PCTKR2018003744-appb-I000013
이고, 여기에서 L1은 단일결합 또는 C2- 30알케닐이며, R11은 H 또는 C1-10알킬이고, L2는 C2- 30알케닐이며;Coupling unit
Figure PCTKR2018003744-appb-I000010
,
Figure PCTKR2018003744-appb-I000011
,
Figure PCTKR2018003744-appb-I000012
or
Figure PCTKR2018003744-appb-I000013
And, in which L 1 is a single bond or a C 2- 30 alkenyl Al, R 11 is H or C 1-10 alkyl, L 2 is a C 2- 30 alkenyl group, and;
Rv는 -NH2, N3, 치환되거나 비치환된 C1- 12알킬, C1- 12알키닐, C1- 3알콕시, 치환되거나 비치환된 C3- 20헤테로아릴, C3-20헤테로사이클릴 또는 치환되거나 비치환된 C5-20아릴이고, R v is -NH 2, N 3, substituted or unsubstituted C 1- 12 alkyl, C 1- 12 alkynylene, C 1- 3 alkoxy, substituted or unsubstituted C 3- 20 heteroaryl, C 3-20 ring Heterocyclyl or substituted or unsubstituted C 5-20 aryl,
여기에서 C1- 12알킬, C3- 20헤테로아릴, C3- 20헤테로사이클릴 또는 C5- 20아릴이 치환되는 경우, C3- 20헤테로아릴, C3- 20헤테로사이클릴 또는 C5- 20아릴에 존재하는 하나 이상의 수소원자는 각각 독립적으로 OH, =O, 할로, C1- 6알킬, C1- 6알콕시, C2- 6알케닐옥시, 카르복시, C1- 6알콕시카르보닐, C1- 6알킬카르보닐, 포르밀, C3- 8아릴, C5-12아릴옥시, C5-12아릴카르보닐, 또는 C3-6헤테로아릴로 치환된다.Here, C 1- 12 alkyl, C 3- 20 heteroaryl, C 3- 20 when heterocyclic 5- C 20 aryl which is optionally substituted, C 3- 20 heteroaryl, C 3- 20 heterocyclyl or C 5 - one or more hydrogen atoms present in 20 aryl are each independently selected from OH, = O, halo, C 1- 6 alkyl, C 1- 6 alkoxy, C 2- 6 alkenyloxy, carboxy, C 1- 6 alkoxycarbonyl , C 1- 6 are replaced by alkyl-carbonyl, formyl, C 3- 8 aryl, C 5-12 aryloxy, C 5-12 aryl-carbonyl, or C 3-6 heteroaryl;
본 발명의 일 양태에서, Xa 및 Xa'은 각각 독립적으로 결합(bond) 또는 C1-3알킬이다.In one aspect of the invention, Xa and Xa 'are each independently a bond or C 1-3 alkyl.
본 발명의 일 양태에서, Z는 H,
Figure PCTKR2018003744-appb-I000014
,
Figure PCTKR2018003744-appb-I000015
및 -(CH2)m-OCH3로 이루어진 그룹으로부터 선택되며, In one aspect of the invention Z is H,
Figure PCTKR2018003744-appb-I000014
,
Figure PCTKR2018003744-appb-I000015
And-(CH 2 ) m -OCH 3 ,
R8, R9 및 R10은 각각 독립적으로 H, C1- 3알킬, 및 C1- 3알콕시로 이루어진 그룹으로부터 선택되고, m은 1 내지 6이다.R 8, R 9 and R 10 is selected from each independently H, C 1- 3 alkyl, and the group consisting of C 1- 3 alkoxy, m = 1-6.
본 발명의 일 양태에서, W는 -C(O)-, -C(O)NR'''- 또는 -C(O)O-이고, 여기서 R'''은 H 또는 C1-8알킬이며,In one aspect of the invention, W is -C (O)-, -C (O) NR '''-or -C (O) O-, wherein R''' is H or C 1-8 alkyl ,
L은 브랜칭 유닛(branching unit), 연결 유닛(connection unit) 및 결합 유닛(binding unit)으로 이루어진 그룹으로부터 선택되는 하나 이상의 유닛, 또는 이들 유닛의 조합이며, 여기에서 연결 유닛은 W와 결합 유닛을, W와 브랜칭 유닛을, 브랜칭 유닛과 브랜칭 유닛을, 또는 브랜칭 유닛과 결합 유닛을 연결하고, 여기에서 브랜칭 유닛은 연결 유닛과 W를, 또는 연결 유닛과 또 다른 연결 유닛을 연결하며,L is one or more units selected from the group consisting of a branching unit, a connection unit and a binding unit, or a combination of these units, wherein the connection unit is a combination of W, Connecting the W and the branching unit, the branching unit and the branching unit, or the branching unit and the coupling unit, wherein the branching unit connects the connection unit and the W, or the connection unit and another connection unit,
브랜칭 유닛은 C2- 8알케닐(여기서, 알케닐의 탄소 원자는 하나 또는 그 이상의 N, O 및 S로 이루어진 그룹으로부터 선택되는 헤테로원자로 치환될 수 있으며, 알케닐은 하나 또는 그 이상의 C1- 6알킬로 더 치환될 수 있다), 또는 친수성(hydrophilic) 아미노산, -C(O)-, -C(O)NR''''-, -C(O)O-, -(CH2)s-NHC(O)-(CH2)t-, -(CH2)u-C(O)NH-(CH2)v-, -(CH2)s-NHC(O)-(CH2)t-C(O)-, 또는 -(CH2)u-C(O)NH-(CH2)v-C(O)-이고(여기서, R''''은 H, C1- 8알킬, C3- 8사이클로알킬, C1- 8알콕시, C1-8알킬티오, 모노- 또는 다이-C1- 8알킬아미노, C3- 20헤테로아릴 또는 C5-20아릴이며, s, t, u 및 v는 각각 독립적으로 0 내지 5의 정수이고),Branching units C 2- 8 alkenyl (wherein the carbon atom of the alkenyl group is one or more N, O and may be substituted with a hetero atom selected from the group consisting of S, alkenyl has one or more C 1- 6 may be further substituted with alkyl), or a hydrophilic amino acid, -C (O)-, -C (O) NR ''''-, -C (O) O-,-(CH 2 ) s -NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t -C (O) -, or - (CH 2) u -C ( O) NH- (CH 2) v -C (O) - , and (wherein, R '''' is H, C 1- 8 alkyl, C 3- 8 cycloalkyl, C 1- 8 alkoxy, C 1-8 alkylthio, mono- or di -C 1- 8 alkylamino, C 3- 20 heteroaryl or C 5-20 aryl, and, s, t, u and v are each independently an integer from 0 to 5),
연결 유닛은 -(CH2)r(V(CH2)p)q-이며, 여기에서, r은 0 내지 10의 정수이고, p는 0 내지 12의 정수이며, q는 1 내지 20의 정수이고, V는 단일결합, 또는 -O-이며,The connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, or -O-,
결합 유닛은
Figure PCTKR2018003744-appb-I000016
,
Figure PCTKR2018003744-appb-I000017
,
Figure PCTKR2018003744-appb-I000018
또는
Figure PCTKR2018003744-appb-I000019
이고, 여기에서 L1은 단일결합 또는 C2- 8알케닐이며, R11은 H 또는 C1- 6알킬이고, L2는 C2- 8알케닐이며;Coupling unit
Figure PCTKR2018003744-appb-I000016
,
Figure PCTKR2018003744-appb-I000017
,
Figure PCTKR2018003744-appb-I000018
or
Figure PCTKR2018003744-appb-I000019
And, in which L 1 is a single bond or a C 2- 8 alkenyl Al, R 11 is H or C 1- 6 alkyl, L 2 is C 2- 8 alkenyl, and;
여기서, 연결 유닛은 -(CH2)r(V(CH2)p)q-이며, Wherein the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- ,
여기서, r은 0 내지 8의 정수이고, p는 1 내지 12의 정수이며, q는 1 내지 10의 정수이고, V는 단일결합 또는 -O-이다.Where r is an integer from 0 to 8, p is an integer from 1 to 12, q is an integer from 1 to 10, and V is a single bond or -O-.
본 발명의 일 양태에서, G 및 G'은 각각 독립적으로 β-글루쿠로나이드기, 갈락토사이드기 또는 이의 유도체일 수 있다.In one embodiment of the present invention, G and G 'may each independently be a β-glucuronide group, galactoside group or derivative thereof.
본 발명의 일 양태에서, 하기 화학식 IIc의 피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물이 제공된다:In one aspect of the invention, there is provided a pyrrolobenzodiazepine dimer precursor-linker compound of Formula IIc, a pharmaceutically acceptable salt or solvate thereof:
[화학식 IIc]Formula IIc]
Figure PCTKR2018003744-appb-I000020
Figure PCTKR2018003744-appb-I000020
상기 식에서,Where
점선은 C1 및 C2, 또는 C2 및 C3 사이의 이중결합의 임의의 존재를 나타내고,Dashed lines indicate any presence of a double bond between C1 and C2, or C2 and C3,
R1은 메틸, 에틸, 메틸렌, 메톡시 및 치환되거나 비치환된 페닐로 이루어진 그룹으로부터 선택되되, 페닐이 치환되는 경우 H, OH, 할로, C1- 6알킬, C1- 6알콕시 및 C6- 12아릴로 이루어진 그룹으로부터 선택되는 치환기로 치환되며,R 1 is methyl, ethyl, methylene, methoxy and substituted or doedoe selected from the group consisting of unsubstituted phenyl, when phenyl is substituted with H, OH, halo, C 1- 6 alkyl, C 1- 6 alkoxy and C 6 - is substituted with substituents selected from the group consisting of 12-aryl,
m은 1 내지 10의 정수이고,m is an integer from 1 to 10,
n은 1 내지 10의 정수이다.n is an integer from 1 to 10.
본 발명의 일 양태에서, 상기 화학식 IIc에서, R1은 메틸, 메틸렌; 및 H, OH, 할로, C1- 6알킬 및 C1- 6알콕시로 이루어진 그룹으로부터 선택되는 치환기로 치환되거나 비치환된 페닐일 수 있다.In one embodiment of the present invention, in Chemical Formula IIc, R 1 is methyl, methylene; And substituted with H, OH, halo, C 1- 6 substituents selected from the group consisting of alkyl and C 1- 6 alkoxy or may be an unsubstituted phenyl.
본 발명의 일 양태에서, 상기 화학식 IIc에서, m은 2 내지 8의 정수, 구체적으로 3 내지 7의 정수, 보다 구체적으로 4 내지 6의 정수일 수 있다.In one embodiment of the present invention, in Chemical Formula IIc, m may be an integer of 2 to 8, specifically an integer of 3 to 7, more specifically an integer of 4 to 6.
본 발명의 일 양태에서, 상기 화학식 IIc에서, n은 2 내지 8의 정수, 구체적으로 3 내지 7의 정수, 보다 구체적으로 4 내지 6의 정수일 수 있다.In one embodiment of the present invention, in Formula IIc, n may be an integer of 2 to 8, specifically an integer of 3 to 7, more specifically an integer of 4 to 6.
본 발명은 또한, 하기 화학구조를 갖는, 피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물을 제공한다. 다만 하기 피롤로벤조디아제핀 이량체 전구체-링커 화합물은 예시이고, 이 기술분야에서 통상의 지식을 가진 자는 상기 기술한 범위 내에서 다양한 피롤로벤조디아제핀 이량체-링커 화합물을 제조 및 사용할 수 있다:The present invention also provides a pyrrolobenzodiazepine dimer precursor-linker compound, a pharmaceutically acceptable salt or solvate thereof, having the following chemical structure. However, the following pyrrolobenzodiazepine dimer precursor-linker compounds are illustrative, and one of ordinary skill in the art can make and use various pyrrolobenzodiazepine dimer-linker compounds within the scope described above:
Figure PCTKR2018003744-appb-I000021
Figure PCTKR2018003744-appb-I000021
Figure PCTKR2018003744-appb-I000022
Figure PCTKR2018003744-appb-I000022
Figure PCTKR2018003744-appb-I000023
Figure PCTKR2018003744-appb-I000023
Figure PCTKR2018003744-appb-I000024
Figure PCTKR2018003744-appb-I000024
Figure PCTKR2018003744-appb-I000025
Figure PCTKR2018003744-appb-I000025
Figure PCTKR2018003744-appb-I000026
Figure PCTKR2018003744-appb-I000026
Figure PCTKR2018003744-appb-I000027
Figure PCTKR2018003744-appb-I000027
Figure PCTKR2018003744-appb-I000028
Figure PCTKR2018003744-appb-I000028
Figure PCTKR2018003744-appb-I000029
Figure PCTKR2018003744-appb-I000029
Figure PCTKR2018003744-appb-I000030
Figure PCTKR2018003744-appb-I000030
Figure PCTKR2018003744-appb-I000031
Figure PCTKR2018003744-appb-I000031
Figure PCTKR2018003744-appb-I000032
Figure PCTKR2018003744-appb-I000032
Figure PCTKR2018003744-appb-I000033
Figure PCTKR2018003744-appb-I000033
Figure PCTKR2018003744-appb-I000034
Figure PCTKR2018003744-appb-I000034
Figure PCTKR2018003744-appb-I000035
Figure PCTKR2018003744-appb-I000035
Figure PCTKR2018003744-appb-I000036
Figure PCTKR2018003744-appb-I000036
Figure PCTKR2018003744-appb-I000037
Figure PCTKR2018003744-appb-I000037
Figure PCTKR2018003744-appb-I000038
Figure PCTKR2018003744-appb-I000038
Figure PCTKR2018003744-appb-I000039
Figure PCTKR2018003744-appb-I000039
Figure PCTKR2018003744-appb-I000040
Figure PCTKR2018003744-appb-I000040
Figure PCTKR2018003744-appb-I000041
Figure PCTKR2018003744-appb-I000041
Figure PCTKR2018003744-appb-I000042
Figure PCTKR2018003744-appb-I000042
Figure PCTKR2018003744-appb-I000043
Figure PCTKR2018003744-appb-I000043
Figure PCTKR2018003744-appb-I000044
Figure PCTKR2018003744-appb-I000044
Figure PCTKR2018003744-appb-I000045
및
Figure PCTKR2018003744-appb-I000045
And
Figure PCTKR2018003744-appb-I000046
.
Figure PCTKR2018003744-appb-I000046
.
본 발명은 또한 하기 화학식 IIIa 또는 IIIb의 구조를 갖는 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물을 제공한다:The present invention also provides a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate having the structure of Formula IIIa or IIIb, a pharmaceutically acceptable salt or solvate thereof:
[화학식 IIIa][Formula IIIa]
Figure PCTKR2018003744-appb-I000047
Figure PCTKR2018003744-appb-I000047
[화학식 IIIb][Formula IIIb]
Figure PCTKR2018003744-appb-I000048
Figure PCTKR2018003744-appb-I000048
상기 식에서,Where
점선, R1, R2, R3, R4, R5, R6, R7, X, Y, R1', R2', R3', R4', R5', R7', X', Y', R8, Za, Zb, R12a, R13a, R14a, R8', Za', Zb', R12a', R13a', 및 R14a'은 각각 제2항에서 화학식 Ia 및 화학식 Ia'의 화합물에 대해 정의한 바와 동일하고,Dashed line, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
Xa, G, Z, W, L, Xa', G', Z'은 각각 제11항에서 화학식 IIb의 화합물에 대해 정의한 바와 동일하며;Xa, G, Z, W, L, Xa ', G', Z 'are the same as defined for the compound of formula IIb in claim 11, respectively;
Ligand는 항원 결합 모이어티이다.Ligand is an antigen binding moiety.
본 발명의 일 양태에서, Ligand는 단백질이다.In one aspect of the invention, Ligand is a protein.
본 발명의 일 양태에서, 상기 단백질은 올리고펩티드, 폴리펩티드, 항체, 항원성 폴리펩티드의 단편 또는 인공항체(repebody)이다.In one embodiment of the invention, the protein is an oligopeptide, polypeptide, antibody, fragment of an antigenic polypeptide, or a phosphor.
본 발명의 일 양태에서, 상기 단백질은 이소프레노이드 트랜스퍼라아제에 의하여 인식될 수 있는 하나 이상의 아미노산 모티프를 갖는 것이다. 즉, 단백질의 C-말단(단편, 이의 유사체 또는 유도체)은 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 아미노산 모티프에 결합될 수 있다. In one aspect of the invention, the protein has one or more amino acid motifs that can be recognized by isoprenoid transferases. That is, the C-terminus (fragment, analog or derivative thereof) of a protein can be bound to an amino acid motif that can be recognized by an isoprenoid transferase.
본 발명의 일 양태에서, 상기 단백질과 아미노산 모티프 사이에 아미노산, 올리고펩티드 또는 폴리펩티드로 구성된 스페이서 유닛을 더 포함할 수 있다.In one aspect of the present invention, the protein and the amino acid motif may further comprise a spacer unit consisting of an amino acid, oligopeptide or polypeptide.
본 발명의 일 양태에서, 상기 단백질은 아미노산 모티프를 통하여 링커에 공유결합된다.In one aspect of the invention, the protein is covalently linked to the linker via an amino acid motif.
본 발명의 일 양태에서, 상기 아미노산 모티프는 단백질의 C-말단에 공유결합되거나, 단백질의 C-말단에 공유결합되는 적어도 하나의 스페이서 유닛에 공유결합될 수 있다. 단백질은 아미노산 모티프와 바로 공유결합되거나 스페이서 유닛과 공유결합되어 아미노산 모티프와 연결될 수 있다. 상기 아미노산 스페이서 유닛은 1 내지 20개의 아미노산으로 구성되며, 그 중에서 글리신(Glycin) 유닛이 바람직하다.In one aspect of the invention, the amino acid motif may be covalently bonded to the C-terminus of the protein, or covalently bonded to at least one spacer unit covalently to the C-terminus of the protein. A protein may be directly covalently linked to an amino acid motif or covalently linked to a spacer unit to be linked to an amino acid motif. The amino acid spacer unit is composed of 1 to 20 amino acids, of which a glycine unit is preferable.
본 발명의 일 양태에서, 상기 단백질의 C-말단은 항체의 경쇄 또는 중쇄의 것이다.In one aspect of the invention, the C-terminus of the protein is that of the light or heavy chain of the antibody.
본 발명의 일 양태에서, 상기 단백질은 단일클론 항체이다.In one aspect of the invention, the protein is a monoclonal antibody.
본 발명의 일 양태에서, 상기 이소프레노이드 트랜스퍼라아제는 FTase(farnesyl protein transferase) 또는 GGTase(geranylgeranyl transferase)를 포함하고, 이들은 각각 파네실 또는 게라닐-게라닐 잔기의 표적 단백질의 C-말단 시스테인(들)로의 전이를 수반한다. GGTase는 GGTase I 및 GGTase II로 분류될 수 있다. FTase 및 GGTase I은 CAAX 모티프를 인식할 수 있다.In one aspect of the invention, the isoprenoid transferase comprises a farnesyl protein transferase (FTase) or a geranylgeranyl transferase (GGTase), which are the C-terminal cysteines of the target protein of the farnesyl or geranyl-geranyl residues, respectively. Involves transition to (s). GGTase can be classified into GGTase I and GGTase II. FTase and GGTase I can recognize CAAX motifs.
본 발명의 일 양태에서, 상기 아미노산 모티프가 CYYX, XXCC, XCXC 또는 CXX이고, 여기에서 C는 시스테인, Y는 지방족 아미노산, X는 이소프레노이드 트랜스퍼라아제의 기질 특이성을 결정하는 아미노산이다.In one aspect of the invention, the amino acid motif is CYYX, XXCC, XCXC or CXX, wherein C is cysteine, Y is an aliphatic amino acid, and X is an amino acid that determines the substrate specificity of the isoprenoid transferase.
발명의 일 실시예에 있어서, 상기 아미노산 모티프를 갖는 단백질은 A-HC-(G)ZCVIM, A-HC-(G)zCVLL, A-LC-(G)ZCVIM 및 A-LC-(G)ZCVLL로 이루어진 군으로부터 선택되고, 상기 A는 항체를 나타내고, HC 는 중쇄를 나타내고, LC 는 경쇄를 나타내고, G는 글리신 유닛을 나타내고, z는 0 내지 20의 정수이다.In one embodiment of the invention, the protein having the amino acid motif is A-HC- (G) Z CVIM, A-HC- (G) zCVLL, A-LC- (G) Z CVIM and A-LC- (G ) Z CVLL, wherein A represents an antibody, HC represents a heavy chain, LC represents a light chain, G represents a glycine unit and z is an integer from 0 to 20.
이소프레노이드 트랜스퍼라제는 이소기질(isosubstrate)뿐만 아니라 기질을 인식할 수 있다. 이소기질은 기질에 변형을 갖는 기질 유사체를 말한다. 이소프레노이드 트랜스퍼라제는 단백질의 C-말단에서 특정 아미노산 모티프(예: CAAX 모티프)를 알킬화시킨다(참조: Benjamin P. Duckworth et al, ChemBioChem 2007, 8, 98; Uyen T. T. Nguyen et al, ChemBioChem 2007, 8, 408; Guillermo R. Labadie et al, J. Org. Chem. 2007, 72(24), 9291; James W. Wollack et al, ChemBioChem 2009, 10, 2934). 관능화 단백질은 C-말단 시스테인(들)에서 알킬화를 통하여 이소프레노이드 트랜스퍼라제 및 이소기질을 사용하여 생성할 수 있다.Isoprenoid transferases can recognize substrates as well as isosubstrates. Iso substrates refer to substrate analogs with modifications to the substrate. Isoprenoid transferases alkylate specific amino acid motifs (eg, CAAX motifs) at the C-terminus of the protein (see Benjamin P. Duckworth et al, ChemBioChem 2007, 8, 98; Uyen TT Nguyen et al, ChemBioChem 2007, 8, 408; Guillermo R. Labadie et al, J. Org.Chem. 2007, 72 (24), 9291; James W. Wollack et al, Chem BioChem 2009, 10, 2934). Functionalized proteins can be produced using isoprenoid transferases and iso substrates via alkylation in the C-terminal cysteine (s).
예를 들면, C-말단 CAAX 모티프의 시스테인 잔기는 이소프레노이드 트랜스퍼라제를 사용하여 이소기질과 반응시킬 수 있다. 특정 경우, AAX는 이어서 프로테아제에 의하여 제거할 수 있다. 수득한 시스테인은 이어서 효소에 의하여 카복시 말단에서 메틸화시킬 수 있다(참조: Iran M. Bell, J. Med. Chem. 2004, 47(8), 1869).For example, cysteine residues of the C-terminal CAAX motif can be reacted with iso substrates using isoprenoid transferases. In certain cases, AAX can then be removed by proteases. The obtained cysteine can then be methylated at the carboxy terminus by enzyme (Iran M. Bell, J. Med. Chem. 2004, 47 (8), 1869).
본 발명의 단백질은 당해 기술분야에 익히 공지된 어떠한 분자 생물 또는 세포 생물법을 사용하여 제조할 수 있다. 예를 들면, 일시적 트랜스펙션법이 사용될 수 있다. 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 특정 아미노산 모티프를 인코딩하는 유전적 서열은 이의 C-말단에 특정 아미노산 모티프를 갖는 단백질(단편 또는 이의 유사체)을 발현하도록 표준 PCR 기술을 사용하여 공지된 프라스미드 벡터로 삽입할 수 있다. 이와 같이, 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하나 이상의 아미노산 모티프를 갖는 단백질이 발현될 수 있다.Proteins of the present invention can be prepared using any molecular or cellular biology well known in the art. For example, transient transfection may be used. Genetic sequences encoding specific amino acid motifs that can be recognized by isoprenoid transferases are known phrases using standard PCR techniques to express a protein (fragment or analog thereof) having a specific amino acid motif at its C-terminus. Can be inserted into the mid vector. As such, proteins having one or more amino acid motifs that can be recognized by isoprenoid transferases can be expressed.
본 발명의 일 양태에서, 단백질이 단일클론 항체인 경우, 단일클론 항체의 하나 이상의 경쇄, 단일클론 항체의 하나 이상의 중쇄 또는 둘 다는 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 아미노산 모티프를 갖는 아미노산 부위를 포함할 수 있으며, 당업자는 관심 있는 표적을 선택적으로 결합시키는 단백질(예: 피검체의 표적 세포)을 즉시 선택할 수 있다.In one aspect of the invention, where the protein is a monoclonal antibody, at least one light chain of the monoclonal antibody, at least one heavy chain of the monoclonal antibody, or both, has an amino acid site having an amino acid motif that can be recognized by an isoprenoid transferase It may include, and those skilled in the art can immediately select a protein (eg target cells of the subject) to selectively bind the target of interest.
본 발명의 일 양태에서, 관심 있는 표적에 특이적으로 결합하는 항체 또는 항원의 단편을 포함할 수 있다.In one aspect of the invention, it may comprise a fragment of an antibody or antigen that specifically binds to a target of interest.
본 발명의 일 양태에서, 상기 아미노산 모티프는 CYYX, XXCC, XCXC 또는 CXX(여기서, C가 시스테인이고, Y가 지방족 아미노산이고, X가 이소프레노이드 트랜스퍼라제의 기질 특이성을 결정하는 아미노산이다)로, 상기 아미노산 모티프가 CYYX인 것이 보다 바람직하다. In one aspect of the invention, the amino acid motif is CYYX, XXCC, XCXC or CXX (wherein C is cysteine, Y is aliphatic amino acid and X is amino acid that determines the substrate specificity of isoprenoid transferase), More preferably, the amino acid motif is CYYX.
본 발명은 또한 상기 기재된 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물을 포함하는, 증식성 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating a proliferative disease, comprising the pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, pharmaceutically acceptable salts or solvates thereof described above.
본 발명은 또한 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물; 및 약학적으로 허용되는 부형제를 포함하는, 증식성 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention also relates to pyrrolobenzodiazepine dimer precursor-linker-ligand conjugates, pharmaceutically acceptable salts or solvates thereof; And it provides a pharmaceutical composition for the prevention or treatment of proliferative disease, comprising a pharmaceutically acceptable excipient.
본 발명은 또한 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물; 1종 이상의 치료적 공동-작용제(therapeutic co-agent); 및 약학적으로 허용되는 부형제를 포함하는, 증식성 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention also relates to pyrrolobenzodiazepine dimer precursor-linker-ligand conjugates, pharmaceutically acceptable salts or solvates thereof; One or more therapeutic co-agents; And it provides a pharmaceutical composition for the prevention or treatment of proliferative disease, comprising a pharmaceutically acceptable excipient.
본 발명의 일 양태에서, 상기 치료적 공동-작용제는 증식성 질환에 대한 예방, 개선 또는 치료효과를 나타내는 작용제, 또는 증식성 질환 치료제 투약 시 나타나는 부작용의 발현을 감소시킬 수 있는 작용제, 또는 면역력 증진 효과를 나타내는 작용제 등일 수 있으나 이로 제한되는 것은 아니고, 피롤로벤조디아제핀과 함께 배합제의 형태로 적용하였을 때 치료적으로 유용한 효과를 나타내고/거나, 피롤로벤조디아제핀의 안정성을 보다 향상시키고/거나, 피롤로벤조디아제핀 투여 시 나타날 수 있는 부작용을 감소시키고/거나, 면역력의 증진을 통해 치료효과를 극대화할 수 있는 효과를 나타내는 제제라면 어떤 것이든 배합하여 적용할 수 있음을 의미한다.In one aspect of the invention, the therapeutic co-agent is an agent that exhibits a prophylactic, ameliorating or therapeutic effect on a proliferative disease, or an agent that can reduce the onset of side effects that occur when administering a proliferative disease treatment, or enhances immunity. Agents, which may be effective, and the like, but are not limited thereto, and have a therapeutically useful effect when applied in the form of a combination with pyrrolobenzodiazepines, and / or further improve the stability of pyrrolobenzodiazepines, and / or This means that any agent that can reduce the side effects that may occur when benzodiazepines are administered and / or enhance the immunity to maximize the therapeutic effect may be applied in any combination.
본 발명의 일 양태에서, 상기 증식성 질환은 시험관내이든 생체내이든, 신생물 또는 과형성성 성장과 같은 바람직하지 않게 과도하거나 비정상적인 세포가 원치 않게 제어되지 않는 세포 증식관련 질환을 말한다. 증식성 질환은 신생물, 종양, 암, 백혈병, 건선, 뼈 질환, 섬유증식성 장애, 및 죽상동맥경화증으로 이루어진 그룹으로부터 선택될 수 있다. 신생물 및 종양의 예로는 조직구종, 신경교종, 성상세포종, 골종 등을 들 수 있다. In one aspect of the invention, the proliferative disease refers to a cell proliferation related disease in which undesirably excessive or abnormal cells, such as neoplasia or hyperplastic growth, are undesirably controlled in vitro or in vivo. Proliferative diseases can be selected from the group consisting of neoplasms, tumors, cancers, leukemias, psoriasis, bone diseases, fibrotic disorders, and atherosclerosis. Examples of neoplasms and tumors include histiocytoma, glioma, astrocytoma, osteoma and the like.
본 발명의 일 양태에서, 암은 폐암, 소세포성 폐암, 위장관암, 대장암, 장암, 유방암, 난소암, 전립선암, 고환암, 간암, 신장암, 방광암, 췌장암, 뇌암, 육종, 골육종, 카포시 육종 및 흑색종으로 이루어진 그룹으로부터 선택될 수 있으나, 피롤로벤조디아제핀이 치료효과를 나타낼 수 있는 암종이라면 모두 적용이 가능하다.In one aspect of the invention, the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma And melanoma may be selected from the group, but if the pyrolobenzodiazepine is a carcinoma that can exhibit a therapeutic effect is applicable to all.
본 발명은 또한, 증식성 질환을 치료하기 위한 유효량의 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물을 대상체에게 투여하는 단계를 포함하는 증식성 질환을 갖는 대상체에서의 증식성 질환의 치료 방법을 제공한다.The invention also has a proliferative disease, comprising administering to a subject an effective amount of a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, a pharmaceutically acceptable salt or solvate thereof, for treating a proliferative disease. Provided are methods of treating proliferative diseases in a subject.
본 발명의 일 양태에서, 상기 약학적 조성물을 환자에 투여하는 단계를 포함하는, 암 치료방법이 제공된다.In one aspect of the invention, there is provided a method of treating cancer, comprising administering the pharmaceutical composition to a patient.
본 발명은 대상체의 목표 위치에 PBD 화합물을 제공하는데 사용하기에 적합하다. 본 발명에 따른 접합체는 링커 부분을 전혀 보유하지 않는 활성 PBD 화합물을 방출시키며, PBD 화합물의 반응성에 영향을 줄 수 있는 것은 존재하지 않는다.The present invention is suitable for use in providing a PBD compound at a target position in a subject. The conjugate according to the invention releases an active PBD compound which has no linker moiety, and there is nothing that can affect the reactivity of the PBD compound.
[정의][Justice]
본 명세서에서 하기 정의가 적용된다:The following definitions apply here:
본 명세서에서 "접합체(conjugates)"는 세포독성 화합물의 하나 이상의 분자에 공유결합되는 세포 결합제를 말한다. 여기서, "세포 결합제"는 생물학적 타깃에 대한 친화도를 갖는 분자로서, 예를 들어 리간드, 단백질, 항체, 구체적으로 모노클로날 항체, 단백질 또는 항체 단편, 펩타이드, 올리고뉴클레오티드, 올리고사카라이드일 수 있으며, 결합제는 생물학적 활성 화합물을 생물학적 타깃으로 유도하는 기능을 한다. 본 발명의 일 양태에서, 접합체는 세포 표면 항원을 통해 종양 세포를 표적화하도록 설계될 수 있다. 항원은 비정상적인 세포 타입에서 과다 발현되거나 또는 발현되는 세포 표면 항원일 수 있다. 구체적으로, 표적 항원은 증식성 세포(예컨대 종양 세포) 상에서만 발현되는 것일 수 있다. 표적 항원은 통상 증식성 조직 및 정상 조직 사이의 상이한 발현에 기초하여 선택될 수 있다. 본 발명에서 리간드는 링커에 결합된다.As used herein, "conjugates" refers to cell binders that are covalently bound to one or more molecules of a cytotoxic compound. Here, a "cell binding agent" is a molecule having affinity for a biological target, and may be, for example, a ligand, a protein, an antibody, specifically a monoclonal antibody, a protein or antibody fragment, peptide, oligonucleotide, oligosaccharide, The binder serves to induce the biologically active compound to the biological target. In one aspect of the invention, the conjugate can be designed to target tumor cells via cell surface antigens. The antigen may be a cell surface antigen that is overexpressed or expressed in an abnormal cell type. Specifically, the target antigen may be one expressed only on proliferative cells (eg tumor cells). Target antigens can usually be selected based on different expressions between proliferative and normal tissues. In the present invention, the ligand is bound to the linker.
본 명세서에서 "항체"는 이뮤노글로불린 분자의 가변 영역에 위치하는 적어도 1개의 항원 인식 부위를 통해 표적, 예컨대 탄수화물, 폴리뉴클레오티드, 지질, 폴리펩티드 등에 특이적으로 결합할 수 있는 이뮤노글로불린 분자이다. 본 명세서에 사용된 용어 "항체"는 무손상 폴리클로날 또는 모노클로날 항체뿐만 아니라, 소정의 항원에 특이적으로 결합하는 능력을 보유하는 무손상 항체의 임의의 항원 결합 부분 (예를 들어, "항원-결합 단편") 또는 그의 단일 쇄, 항체를 포함하는 융합 단백질, 및 항원 인식 부위를 포함하는 이뮤노글로불린 분자의 임의의 다른 변형된 배열, 예를 들어 비제한적으로, Fab; Fab'; F(ab')2 Fd 단편; Fv 단편; 단일 도메인 항체 (dAb) 단편; 단리된 상보성 결정 영역 (CDR); 단일 쇄 (scFv) 및 단일 도메인 항체 (예를 들어, 상어 및 낙타류 항체), 맥시바디, 미니바디, 인트라바디, 디아바디, 트리아바디, 테트라바디, v-NAR 및 비스-scFv를 포괄한다 (예를 들어, 문헌 [Hollinger and Hudson, 2005, Nature Biotechnology 23(9): 1126-1136] 참조). An “antibody” herein is an immunoglobulin molecule capable of specifically binding to a target such as carbohydrates, polynucleotides, lipids, polypeptides, and the like through at least one antigen recognition site located in the variable region of an immunoglobulin molecule. As used herein, the term “antibody” refers to an intact polyclonal or monoclonal antibody, as well as any antigen binding portion of an intact antibody that possesses the ability to specifically bind a given antigen (eg, "Antigen-binding fragment") or a single chain thereof, a fusion protein comprising an antibody, and any other modified arrangement of an immunoglobulin molecule comprising an antigen recognition site, such as, but not limited to, Fab; Fab '; F (ab ') 2 Fd fragments; Fv fragments; Single domain antibody (dAb) fragments; Isolated complementarity determining regions (CDRs); Encompasses single chain (scFv) and single domain antibodies (e.g., shark and camel antibodies), maxibody, minibody, intrabody, diabody, tribody, tetrabody, v-NAR and bis-scFv ( See, eg, Hollinger and Hudson, 2005, Nature Biotechnology 23 (9): 1126-1136).
항체는 임의의 부류의 항체, 예컨대 IgG, IgA 또는 IgM (또는 그의 하위부류)을 포함하며, 항체가 임의의 특정한 부류일 필요는 없다. 항체의 중쇄의 불변 영역의 아미노산 서열에 따라, 이뮤노글로불린은 상이한 부류로 배정될 수 있다. 5가지 주요 부류의 이뮤노글로불린: IgA, IgD, IgE, IgG 및 IgM이 존재하고, 이들 중 몇몇은 하위부류 (이소형), 예를 들어 IgG1, IgG2, IgG3, IgG4, IgA1 및 IgA2로 추가로 분류될 수 있다. 상이한 부류의 이뮤노글로불린에 상응하는 중쇄 (HC) 불변 도메인은 각각 알파, 델타, 엡실론, 감마 및 뮤로 불린다. 상이한 부류의 이뮤노글로불린의 서브유닛 구조 및 3차원 배위는 널리 공지되어 있다. 본 발명의 항체는 관련 기술분야에 널리 공지된 기술, 예컨대 재조합 기술, 파지 디스플레이 기술, 합성 기술 또는 상기 기술들의 조합 또는 관련 기술분야에 용이하게 공지되어 있는 다른 기술을 이용하여 제조될 수 있다.Antibodies include any class of antibody, such as IgG, IgA or IgM (or a subclass thereof), and the antibody need not be in any particular class. Depending on the amino acid sequence of the constant region of the heavy chain of the antibody, immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, some of which are additionally in subclasses (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. Can be classified. The heavy chain (HC) constant domains corresponding to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma and mu, respectively. Subunit structures and three-dimensional coordination of different classes of immunoglobulins are well known. Antibodies of the invention can be prepared using techniques well known in the art, such as recombinant techniques, phage display techniques, synthetic techniques, or combinations of these techniques, or other techniques that are readily known in the art.
본 명세서에서 "단리된 항체"는 상이한 항원 특이성을 갖는 다른 항체를 실질적으로 함유하지 않는 항체를 지칭하며, 다른 세포 물질 및/또는 화학물질을 실질적으로 함유하지 않을 수 있다.As used herein, an “isolated antibody” refers to an antibody that is substantially free of other antibodies with different antigen specificity and may be substantially free of other cellular materials and / or chemicals.
본 명세서에서 "생물학적 타깃"은 종양, 암세포, 세포간질(extracellular matrix) 표면에 위치하는 항원을 말한다.As used herein, "biological target" refers to an antigen located on the surface of a tumor, cancer cell, or extracellular matrix.
본 명세서에서 "링커"는 세포독성 화합물을 리간드에 공유결합시키는 화합물을 말한다. 본 발명의 일 양태에서, 링커로는 PCT/US2016/063564호 및 PCT/US2016/063595호에 개시된 링커를 사용할 수 있다.As used herein, "linker" refers to a compound that covalently binds a cytotoxic compound to a ligand. In one aspect of the invention, the linker disclosed in PCT / US2016 / 063564 and PCT / US2016 / 063595 can be used.
본 명세서에서 "치료제"는 증식성 질환, 예를 들어 암 세포 또는 활성화된 면역 세포에 세포독성, 세포증식억제 및/또는 면역조절 효과를 행사하는 작용제이다. 치료제의 예는 세포독성제, 화학요법제, 세포증식억제제 및 면역조절제를 포함한다.A “therapeutic agent” herein is an agent that exerts cytotoxic, cytostatic and / or immunomodulatory effects on proliferative diseases, such as cancer cells or activated immune cells. Examples of therapeutic agents include cytotoxic agents, chemotherapeutic agents, cytostatic agents and immunomodulators.
본 명세서에서 "화학요법제"는 암의 치료에 유용한 화학적 화합물이다.As used herein, a "chemotherapeutic agent" is a chemical compound useful for the treatment of cancer.
본 명세서에서 “대상체”는 인간 및 비-인간 동물, 특히 포유동물을 포함하는 것으로 의도된다. 대상체의 예로는 인간 대상체를 들 수 있으며, 예컨대 본 명세서에 기재된 장애, 보다 구체적으로는 암을 갖는 인간 환자 또는 정상 대상체를 포함하는 개념이다. "비-인간 동물"은 모든 척추동물, 예를 들어, 비-포유동물(예를 들어, 닭, 양서류, 파충류) 및 포유동물, 예를 들어, 비-인간 영장류, 가축 및/또는 농업에 유용한 동물(예를 들어, 양, 개, 고양이, 소, 돼지 등) 및 설치류(예를 들어, 마우스, 랫트, 햄스터, 기니피그 등)를 포함한다. 특정 구현예에서, 대상체는 인간 환자이다.As used herein, a “subject” is intended to include humans and non-human animals, especially mammals. Examples of subjects include human subjects, such as the concept comprising a human patient or a normal subject having a disorder described herein, more specifically cancer. “Non-human animals” are useful for all vertebrates, eg, non-mammals (eg, chickens, amphibians, reptiles) and mammals, eg, non-human primates, livestock, and / or agriculture. Animals (eg, sheep, dogs, cats, cattle, pigs, etc.) and rodents (eg, mice, rats, hamsters, guinea pigs, etc.). In certain embodiments, the subject is a human patient.
본 명세서에서 "치료" 또는 "치료한다"는 치료적 처치 및 예방학적 또는 예방적 조치 둘 모두를 지칭한다. 치료를 필요로 하는 대상체는 이미 질병을 갖는 대상체, 및 질병을 갖기 쉬운 대상체 또는 질병이 예방되어야 할 대상체를 포함한다. 따라서, 질병 또는 치료를 필요로 하는 대상체에 관하여 사용되는 경우, 상기 용어는 미처리 대상체에 비하여, 질병 진행의 저지 또는 둔화, 증상의 예방, 질병 및/또는 증상 중증도의 감소 또는 질병 기간의 감소를 포함하나 이로 한정되지 않는다. As used herein, "treatment" or "treat" refers to both therapeutic treatment and prophylactic or prophylactic measures. Subjects in need of treatment include those already with the disease and subjects susceptible to the disease or subjects to which the disease is to be prevented. Thus, when used with respect to a subject in need of a disease or treatment, the term includes, compared to untreated subjects, slowing or slowing disease progression, preventing symptoms, reducing disease and / or symptom severity, or reducing disease duration. It is not limited to one.
본 명세서에서, "투여" 또는 "투여하는"은 요망되는 효과를 달성하기 위하여 임의의 적절한 경로에 의해 화합물 또는 화합물들을 제공하고/거나 접촉시키고/거나 전달하는 것을 지칭한다. 투여는 경구, 설하, 비경구(예를 들어, 정맥내, 피하, 피내, 근육내, 관절내, 동맥내, 활막내, 흉골내, 척수강내, 병변내 또는 두개내 주사), 경피, 국소, 협측, 직장, 질, 비강, 안과적, 흡입 및 이식물을 통한 투여를 포함할 수 있지만, 이로 한정되지 않는다.As used herein, “administering” or “administering” refers to providing and / or contacting and / or delivering a compound or compounds by any suitable route to achieve the desired effect. Administration may be oral, sublingual, parenteral (eg, intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intravitreal, intrasternal, intrathecal, intralesional or intracranial injection), transdermal, topical, Buccal, rectal, vaginal, nasal, ophthalmic, inhalation and administration via implants may include, but is not limited to.
본 명세서에서 "비치환되거나 치환된"은 비치환될 수 있거나 또는 치환될 수 있는 모기(parent group)를, "치환된"은 1 이상의 치환기를 갖는 모기(parent group)를, "치환기"는 모기(parent group)에 공유결합되거나 모기(parent group)에 융합된 화학적 부분을 의미한다.As used herein, "unsubstituted or substituted" refers to a parent group which may be unsubstituted or substituted, "substituted" refers to a parent group having one or more substituents, and "substituent" refers to a mosquito refers to a chemical moiety covalently bonded to a parent group or fused to a parent group.
본 명세서에서 "할로"는 플루오린, 클로라인, 브로마인, 요오드 등을 말한다."Halo" as used herein refers to fluorine, chlorine, bromine, iodine and the like.
본 명세서에서 "알킬"은 지방족 또는 지환족, 포화 또는 불포화(불포화, 완전 불포화) 탄화수소 화합물의 탄소 원자로부터 수소 원자를 제거하여 얻어진 1가 부분으로서, 포화 알킬의 예로는 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵틸 등을, 포화 직쇄형 알킬의 예로는 메틸, 에틸, n-프로필, n-부틸, n-펜틸(아밀), n-헥실, n-헵틸 등, 포화 분지쇄형 알킬의 예로는 이소프로필, 이소부틸, sec-부틸, tert-부틸, 이소펜틸, 네오펜틸 등을 들 수 있다.As used herein, "alkyl" is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or cycloaliphatic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound, examples of saturated alkyl are methyl, ethyl, propyl, butyl Examples of saturated linear alkyl include pentyl, hexyl, heptyl and the like, and examples of saturated branched alkyl such as methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-hexyl and n-heptyl Isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl and the like.
본 명세서에서 "알콕시"는 -OR[여기서, R은 알킬기]을 의미하며, 예로는 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시, sec-부톡시, 이소부톡시, tert-부톡시 등을 들 수 있다.As used herein, "alkoxy" means -OR [where R is an alkyl group], for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy etc. are mentioned.
본 명세서에서 "아릴"은 고리 원자를 갖는 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거하여 얻어진 1가 부분을 의미한다.As used herein, "aryl" means a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.
본 명세서에서 "알케닐"은 1 이상의 탄소-탄소 이중 결합을 갖는 알킬로서, 불포화 알케닐기의 예로는 에테닐(비닐, -CH=CH2), 1-프로페닐(-CH=CH-CH3), 2-프로페닐, 이소프로페닐, 부테닐, 펜테닐, 헥세닐 등을 들 수 있다.As used herein, "alkenyl" is an alkyl having at least one carbon-carbon double bond. Examples of unsaturated alkenyl groups include ethenyl (vinyl, -CH = CH 2 ), 1-propenyl (-CH = CH-CH 3). ), 2-propenyl, isopropenyl, butenyl, pentenyl, hexenyl and the like.
본 명세서에서 “알키닐”은 1 이상의 탄소-탄소 삼중 결합을 갖는 알킬기로서, 불포화 알키닐기의 예는 에티닐 및 2-프로피닐 등을 들 수 있다.As used herein, "alkynyl" is an alkyl group having at least one carbon-carbon triple bond, and examples of the unsaturated alkynyl group include ethynyl and 2-propynyl.
본 명세서에서 "카르복시"는 -C(=O)OH를 말한다.As used herein, "carboxy" refers to -C (= 0) OH.
본 명세서에서 "포르밀"은 -C(=O)H를 말한다.As used herein, "formyl" refers to -C (= 0) H.
본 명세서에서 “아릴”은 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거하여 얻어진 1가 모이어티에 관한 것이다. 예를 들어 "C5- 7아릴"은 모이어티가 5 내지 7 개의 고리 원자를 갖는 것으로서, 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거함으로써 수득되는 1 가 모이어티를 의미하고,"C5 -10아릴"은 모이어티가 5 내지 10 개의 고리 원자를 갖는 것으로서, 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거함으로써 수득되는 1 가 모이어티를 의미한다. 여기에서 접두사(C5-7, C5-10 등)는 탄소 원자 또는 헤테로 원자인지 여부와 상관없이 고리원자의 수 또는 고리 원자의 수의 범위를 지칭한다. 예를 들어 "C5- 6아릴"은 5 또는 6개의 고리 원자를 갖는 아릴기에 관한 것이다. 여기에서, 고리 원자는 "카르보아릴기"에서와 같이 모두 탄소 원자일 수 있다. 카르보아릴기의 예는 벤젠, 나프탈렌, 아줄렌, 안트라센, 페난트렌, 나프타센 및 피렌으로부터 유도된 것들을 포함하나, 이로 제한되지 않는다. 적어도 하나가 방향족 고리인 융합 고리를 포함하는 아릴기의 예는 인단, 인덴, 이소인덴, 테트랄린, 아세나프텐, 플루오렌, 페날렌, 아세페난트렌 및 아세안트렌으로부터 유도된 기를 포함하나, 이로 제한되지 않는다. 또는, 고리 원자는 "헤테로아릴기"에서와 같이 하나 이상의 헤테로 원자를 포함할 수 있다. As used herein, "aryl" relates to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. For example, "C 5- 7 aryl" as a moiety having from 5 to 7 ring atoms, and 1 is obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound means a moiety, and "C 5 - 10 aryl "means that the moiety has 5 to 10 ring atoms, and is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. The prefix (C 5-7 , C 5-10, etc.) herein refers to the range of the number of ring atoms or the number of ring atoms, whether they are carbon atoms or hetero atoms. For example, "C 5- 6 aryl" relates to an aryl group having 5 or 6 ring atoms. Here, the ring atoms may all be carbon atoms as in the "carboaryl group". Examples of carboaryl groups include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene and pyrene. Examples of aryl groups including fused rings wherein at least one is an aromatic ring include, but are not limited to, groups derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, penalene, acefenanthrene and aceanthrene It is not limited. Alternatively, the ring atom may comprise one or more hetero atoms as in a "heteroaryl group".
본 명세서에서 "헤테로아릴"은 1 이상의 헤테로 원자를 포함하는 아릴로서, 예로는 피리딘, 피리미딘, 벤조티오펜, 푸릴, 디옥살라닐, 피롤릴, 옥사졸릴, 피리딜, 피리다지닐, 피리미디닐 등, 보다 구체적으로 벤조푸란, 이소벤조푸란, 인돌, 이소인돌, 인돌리진, 인돌린, 이소인돌린, 푸린(아데닌 또는 구아닌), 벤즈이미다졸, 인다졸, 벤즈옥사졸, 벤즈이속사졸, 벤조디옥솔, 벤조푸란, 벤조트리아졸, 벤조티오푸란, 벤조티아졸, 벤조티아디아졸로부터 유도된 2개의 융합고리를 갖는 C9, 크로멘, 이소크로멘, 크로만, 이소크로만, 벤조디옥산, 퀴놀린, 이소퀴놀린, 퀴놀리진, 벤족사진, 벤조디아진, 피리도피리딘, 퀴녹살린, 퀴나졸린, 신놀린, 프탈라진, 나프티리딘, 프테리딘으로부터 유도된 2개의 융합고리를 갖는 C10, 벤조디아제핀으로부터 유도된 2개의 융합고리를 갖는 C11, 카르바졸, 디벤조푸란, 디벤조티오펜, 카르볼린, 페리미딘, 피리도인돌로부터 유도된 3개의 융합고리를 갖는 C13, 아크리딘, 크산텐, 티오크산텐, 옥산트렌, 페녹사티인, 페나진, 페녹사진, 페노티아진, 티안트렌, 페난트리딘, 페난트롤린, 페나진으로부터 유도된 3개의 융합고리를 갖는 C14를 들 수 있다.As used herein, "heteroaryl" is an aryl containing one or more hetero atoms, for example pyridine, pyrimidine, benzothiophene, furyl, dioxalanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidy More specifically, benzofuran, isobenzofuran, indole, isoindole, indolizine, indolin, isoindolin, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, C 9 , chrome, isochromen, chromman, isochrome, benzo with two fused rings derived from benzodioxol, benzofuran, benzotriazole, benzothiofuran, benzothiazole, benzothiadiazole Two fused rings derived from dioxane, quinoline, isoquinoline, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and putridine C 10 having, two derived from benzodiazepines C 13 , acridine, xanthene, thioxanthene having three fused rings derived from C 11 , carbazole, dibenzofuran, dibenzothiophene, carboline, perimidine, pyridoindole with fused ring And C 14 having three fused rings derived from oxanthrene, phenoxatiin, phenazine, phenoxazine, phenothiazine, thianthrene, phenanthridine, phenanthroline, and phenazine.
본 명세서에서, "사이클로알킬"은 시클릴기인 알킬기이고, 고리(cyclic) 탄화수소 화합물의 지환족 고리 원자로부터 수소 원자를 제거하여 얻어진 1가 부분에 관한 것이다. 사이클로알킬기의 예는 하기로부터 유도된 것들을 포함하나, 이로 제한되지 않는다:In the present specification, "cycloalkyl" is an alkyl group which is a cyclyl group and relates to a monovalent portion obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups include, but are not limited to, those derived from:
포화 단일고리 탄화수소 화합물: 사이클로프로판, 사이클로부탄, 사이클로펜탄, 사이클로헥산, 사이클로헵탄, 메틸사이클로프로판, 디메틸사이클로프로판, 메틸사이클로부탄, 디메틸사이클로부탄, 메틸사이클로펜탄, 디메틸사이클로펜탄 및 메틸사이클로헥산;Saturated monocyclic hydrocarbon compounds: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane and methylcyclohexane;
불포화 단일고리 탄화수소 화합물: 사이클로프로펜, 사이클로부텐, 사이클로펜텐, 사이클로헥센, 메틸사이클로프로펜, 디메틸사이클로프로펜, 메틸사이클로부텐, 디메틸사이클로부텐, 메틸사이클로펜텐, 디메틸사이클로펜텐 및 메틸사이클로헥센; 및Unsaturated monocyclic hydrocarbon compounds: cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene and methylcyclohexene; And
포화 헤테로사이클릭 탄화수소 화합물: 노르카란, 노르피난, 노르보르난.Saturated heterocyclic hydrocarbon compounds: norcaran, norpinan, norbornane.
본 명세서에서, "헤테로사이클릴"은 헤테로사이클릭 화합물의 고리원자로부터 수소 원자를 제거하여 얻어진 1가 부분에 관한 것이다.As used herein, "heterocyclyl" relates to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound.
본 명세서에서 접두사(예를 들어 C1-12, C3-8 등)는 탄소 원자 또는 헤테로 원자인지 여부와 상관없이 고리 원자의 수 또는 고리 원자의 수의 범위를 지칭한다. 예를 들어 본 명세서에서 사용된 용어 "C3- 6헤테로사이클릴"은 3 내지 6개의 고리 원자를 갖는 헤테로사이클릴기에 관한 것이다. Prefixes (eg, C 1-12 , C 3-8, etc.) herein refer to the number of ring atoms or the range of number of ring atoms, whether they are carbon atoms or hetero atoms. For example, As used herein, the term "C 3- 6 heterocyclyl" relates heterocyclyl groups having from 3 to 6 ring atoms.
단일고리 헤테로사이클릴기의 예는 하기로부터 유도된 것들을 포함하지만, 이로 제한되지 않는다:Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from:
N1: 아지리딘, 아제티딘, 피롤리딘, 피롤린, 2H- 또는 3H-피롤, 피페리딘, 디하이드로피리딘, 테트라하이드로피리딘, 아제핀;N 1 : aziridine, azetidine, pyrrolidine, pyrroline, 2H- or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine;
N2: 이미다졸리딘, 피라졸리딘, 이미다졸린, 피라졸린, 피페라진;N 2 : imidazolidine, pyrazolidine, imidazoline, pyrazoline, piperazine;
O1: 옥시란, 옥세탄, 옥솔란, 옥솔, 옥산, 디하이드로피란, 피란, 옥세핀;O 1 : oxirane, oxetane, oxolane, oxol, oxane, dihydropyran, pyran, oxepin;
O2: 디옥솔란, 디옥산 및 디옥세판;O 2 : dioxolane, dioxane and dioxepane;
O3: 트리옥산;O 3 : trioxane;
N1O1: 테트라하이드로옥사졸, 디하이드로옥사졸, 테트라하이드로이속사졸, 디하이드로이속사졸, 모르폴린, 테트라하이드로옥사진, 디하이드로옥사진, 옥사진N 1 O 1 : tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, oxazine
S1: 티이란, 티에탄, 티올란, 티안, 티에판;S 1 : thiirane, thianetan, thiolane, thian, thiane;
N1S1: 티아졸린, 티아졸리딘, 티오모르폴린;N 1 S 1 : thiazolin, thiazolidine, thiomorpholine;
N2O1: 옥사디아진;N 2 O 1 : oxadiazine;
O1S1: 옥사티올, 옥사티안; 및O 1 S 1 : oxathiol, oxatian; And
N1O1S1: 옥사티아진.N 1 O 1 S 1 : Oxathiazine.
본 명세서에서 "전구체(prodrug)"는 생체내 생리학적 조건 하(예를 들어 효소 산화(enzymatic oxidation), 환원(reduction) 및/또는 가수분해 등)에서 효소, 위산의 작용에 의해 피롤로벤조다이아제핀 약물로 직접적으로 또는 간접적으로 변환할 수 있는 화합물을 말한다.As used herein, a "prodrug" refers to pyrrolobenzodia by the action of an enzyme, gastric acid under in vivo physiological conditions (e.g., enzymatic oxidation, reduction and / or hydrolysis). It refers to a compound that can be converted directly or indirectly to zepin drugs.
본 명세서에서 "약학적으로 허용되는 염"으로는 약학적으로 허용가능한 유리산(free acid)에 의하여 형성된 산 부가염을 사용할 수 있고, 상기 유리산으로는 유기산 또는 무기산을 사용할 수 있다. As the "pharmaceutically acceptable salt" herein, an acid addition salt formed by a pharmaceutically acceptable free acid may be used, and an organic acid or an inorganic acid may be used as the free acid.
상기 유기산은 이로 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이로 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다.The organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid. The inorganic acid also includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
예컨대, 화합물이 음이온이거나 또는 음이온일 수 있는 작용기를 갖는 경우(예컨대 -COOH는 -COO-일 수 있음), 적절한 양이온으로 염을 형성할 수 있다. 적절한 무기 양이온의 예는 알칼리 금속 이온, 예컨대 Na+ 및 K+, 알칼리 토금속 양이온, 예컨대 Ca2 + 및 Mg2 + 및 다른 양이온, 예컨대 Al3 +을 포함하지만, 이에 한정되지 않는다. 적절한 유기 양이온의 예는 암모늄 이온(즉, NH4 +) 및 치환된 암모늄 이온(예컨대 NH3R+, NH2R2 +, NHR3 +, NR4 +)을 포함하지만, 이에 한정되지 않는다. For example, if the compound has a functional group that may be an anion or an anion (eg -COOH may be -COO-), the salt may be formed with a suitable cation. Examples of suitable inorganic cations include alkali metal ions such as Na + and K +, alkaline earth cations such as Ca 2 + and Mg 2 +, and other cations such as Al + 3, but is not limited to this. Examples of suitable organic cations include, but are not limited to, ammonium ions (ie, NH 4 + ) and substituted ammonium ions (eg, NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
일부 적절한 치환된 암모늄 이온의 예는 하기로부터 유도된 것들이다: 에틸아민, 디에틸아민, 디사이클로헥실아민, 트리에틸아민, 부틸아민, 에틸렌디아민, 에탄올아민, 디에탄올아민, 피페라진, 벤질아민, 페닐벤질아민, 콜린, 메글루민 및 트로메타민 뿐 아니라, 아미노산, 예컨대 리신 및 아르기닌. 통상적인 4급 암모늄 이온의 예는 N(CH3)4 +이다.Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine , Phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a typical quaternary ammonium ion is N (CH 3 ) 4 + .
화합물이 양이온이거나 또는 양이온일 수 있는 작용기를 갖는 경우(예컨대 -NH2는 -NH3 +일 수 있음), 적절한 음이온으로 염을 형성할 수 있다. 적절한 무기 음이온의 예는 하기 무기 산으로부터 유도된 것들을 포함하지만, 이에 한정되지 않는다: 염산, 브롬화수소산, 요오드화수소산, 황산, 아황산, 질산, 아질산, 인산 및 아인산 등을 예로 들 수 있다.When a compound has functional groups which may be a cation or cations, or may form a salt (e.g., -NH 2 may be that one -NH 3 +), suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid, and the like.
적절한 유기 음이온의 예는 하기 유기산으로부터 유도된 것들을 포함하지만, 이로 한정되지 않는다: 2-아세티옥시벤조산, 아세트산, 아스코르브산, 아스파르트산, 벤조산, 캠퍼설폰산, 신남산, 시트르산, 에데트산, 에탄디설폰산, 에탄설폰산, 푸마르산, 글루쳅톤산, 글루콘산, 글루탐산, 글리콜산, 히드록시말레산, 히드록시나프탈렌 카르복실산, 이세티온산, 락트산, 락토비온산, 라우르산, 말레산, 말산, 메탄설폰산, 점액산, 올레산, 옥살산, 팔미트산, 팜산, 판토텐산, 페닐아세트산, 페닐설폰산, 프로피온산, 피루브산, 살리실산, 스테아르산, 숙신산, 설파닐산, 타르타르산, 톨루엔설폰산 및 발레르산 등을 예로 들 수 있다. 적절한 중합체 유기 음이온의 예는 하기 중합체 산으로부터 유도된 것들을 포함하지만, 이에 한정되지 않는다: 타닌산, 카르복시메틸 셀룰로오스 등을 예로 들 수 있다.Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-aceticoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethane Disulfonic acid, ethanesulfonic acid, fumaric acid, glutenic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalene carboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, Malic acid, methanesulfonic acid, slime acid, oleic acid, oxalic acid, palmitic acid, palmic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanic acid, tartaric acid, toluenesulfonic acid and valeric acid Etc. can be mentioned. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose and the like.
본 명세서에서 "용매화물(solvate)"은 본 발명에 따른 화합물과 용매 분자(solvent molecules) 사이의 분자 복합체(molecular complex)를 말하며, 용매화물의 예는 물, 이소프로판올, 에탄올, 메탄올, 디메틸설폭사이드(dimethylsulfoxide), 에틸 아세테이트, 아세트산, 에탄올아민 또는 이의 혼합용매와 결합한 본 발명에 따른 화합물을 포함하나, 이로 제한되는 것은 아니다.As used herein, "solvate" refers to a molecular complex between a compound according to the invention and a solvent molecule, examples of solvates are water, isopropanol, ethanol, methanol, dimethylsulfoxide (dimethylsulfoxide), ethyl acetate, acetic acid, ethanolamine, or a compound according to the present invention in combination with a solvent thereof, but is not limited thereto.
활성 화합물의 상당하는 용매화물을 제조, 정제 및/또는 취급하는 것이 편리하거나 또는 바람직할 수 있다. 용어 "용매화물"은 본 명세서에서 용질(예컨대 활성 화합물, 활성 화합물의 염) 및 용매의 착체를 지칭하기 위해 통상적인 의미로 사용된다. 용매가 물인 경우, 용매화물을 편리하게 수화물, 예컨대 일수화물, 이수화물, 삼수화물 등으로 지칭할 수 있다.It may be convenient or desirable to prepare, purify and / or handle the corresponding solvates of the active compounds. The term “solvate” is used herein to refer to the complex of solute (eg, active compound, salt of active compound) and solvent in the conventional sense. When the solvent is water, solvates may conveniently be referred to as hydrates such as monohydrate, dihydrate, trihydrate and the like.
상기 본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용 가능한 담체는 통상적으로 서서히 대사되는 거대분자, 예를 들어 단백질, 다당류, 폴리락트산, 폴리글리콜산, 중합체성 아미노산, 아미노산 공중합체, 지질 응집물 등을 포함할 수 있으며, 이러한 약학적으로 허용 가능한 담체는 당업자가 적절히 선택하여 사용할 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can include macromolecules that are typically slowly metabolized, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, lipid aggregates, and the like. Acceptable carriers may be appropriately selected and used by those skilled in the art.
약학적으로 허용 가능한 담체를 포함하는 상기 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.The composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. Mix is prepared. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like can also be used.
경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.
비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
상기 약학적 조성물은 주사제, 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다.The pharmaceutical composition is selected from the group consisting of injections, tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have any one formulation.
정맥내, 피부 또는 피하 주사 등을 위해, 활성 성분은 무발열성(pyrogen-free)이고 적절한 pH, 등장성 및 안정성을 갖는 비경구 투여용의, 허용가능한 수용액의 형태일 수 있다. 당업자는 예를 들어 염화나트륨 수용액, 링거액, 락테이트 링거액 등과 같은 등장성 비히클을 사용하여 적절한 용액을 제조할 수 있으며, 보존제, 안정화제, 완충제, 산화 방지제 또는 기타 다른 첨가제로 필요한 경우 포함될 수 있다. 주사에 적합한 고체 형태는 또한 에멀젼으로서 또는 리포솜에 캡슐화된 폴리펩티드의 형태로 제조될 수 있다. For intravenous, dermal or subcutaneous injection, and the like, the active ingredient may be in the form of an acceptable aqueous solution for parenteral administration with pyrogen-free and suitable pH, isotonicity and stability. Those skilled in the art can prepare suitable solutions using, for example, isotonic vehicles, such as aqueous sodium chloride solution, Ringer's solution, lactate Ringer's solution, and the like, and can be included as necessary as preservatives, stabilizers, buffers, antioxidants or other additives. Solid forms suitable for injection can also be prepared as emulsions or in the form of polypeptides encapsulated in liposomes.
본 명세서에 사용된 어구 "유효량" 또는 "치료 유효량"은 목적 치료 결과를 달성하는데 (투여량 및 투여 기간 및 수단에 대해) 필요한 양을 지칭한다. 유효량은 적어도 대상체에게 치료 이익을 부여하는데 필요한 활성제의 최소량이며, 독성량 미만이다. 예를 들어 투여량은 환자 당 약 100 ng 내지 약 100 mg/kg 범위로, 보다 전형적으로 약 1 μg/kg 내지 약 10 mg/kg의 범위로 투여할 수 있다. 활성 화합물이 염, 에스테르, 아미드, 전구체약물(prodrug) 등인 경우에 투여양은 모 화합물을 기준으로 계산되므로, 사용되는 실제 중량은 비례하여 증가된다. 본 발명에 따른 피롤로벤조디아제핀 화합물은 단위 제형(dosage form)당 활성 성분 0.1 mg 내지 3000 mg, 1 mg 내지 2000 mg, 10 mg 내지 1000 mg을 포함하도록 제형화될 수 있으나 이로 한정되지 않는다. 활성 성분은 약 0.05 μM 내지 100 μM, 1 μM 내지 50 μM, 5 μM 내지 30 μM의 활성 화합물의 피크 플라즈마 농도를 얻도록 투여될 수 있다. 예를 들어 임의로 식염수내에서 활성 성분 0.1 w/v% 내지 5 w/v% 용액의 정맥 주사에 의해 투여될 수 있다. As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount necessary (relative to dosage and administration period and means) to achieve the desired therapeutic result. An effective amount is at least the minimum amount of active agent necessary to confer a therapeutic benefit to a subject and is below the toxic amount. For example, the dosage can be administered in the range of about 100 ng to about 100 mg / kg per patient, more typically in the range of about 1 μg / kg to about 10 mg / kg. When the active compound is a salt, ester, amide, prodrug, or the like, the dosage is calculated based on the parent compound, so the actual weight used is increased proportionally. The pyrrolobenzodiazepine compound according to the present invention may be formulated to include, but is not limited to, 0.1 mg to 3000 mg, 1 mg to 2000 mg, 10 mg to 1000 mg of active ingredient per dosage form. The active ingredient may be administered to obtain a peak plasma concentration of the active compound of about 0.05 μM to 100 μM, 1 μM to 50 μM, 5 μM to 30 μM. For example, by intravenous injection of a 0.1 w / v% to 5 w / v% solution of the active ingredient, optionally in saline.
약학 조성물에서 활성 화합물의 농도는 약물의 흡수, 불활성화 및 배출율 및 당 기술분야의 숙련자에게 알려진 다른 인자에 의해 결정될 수 있다. 투여량은 증상/질환의 심각도에 따라 달라질 수 있다. 또한 어떤 특정 환자에 대한 투여량 및 투여요법은 환자의 증상/질환의 정도, 필요성, 나이, 약물에 대한 반응성 등을 종합적으로 고려하여 투여 감독자의 직업적 판단에 따라 조정될 수 있으며, 본 발명에서 제시된 농도 범위는 단지 일예이며 청구된 조성물의 실시양태를 이로 한정하는 것을 의도하지 않는다. 또한 활성 성분은 1회 투여될 수 있거나, 보다 적은 투여량을 수 회 나누어 투여할 수도 있다.The concentration of the active compound in the pharmaceutical composition can be determined by the rate of absorption, inactivation and excretion of the drug and other factors known to those skilled in the art. Dosage may vary depending on the severity of the condition / disease. In addition, the dosage and dosing regimen for a particular patient may be adjusted according to the occupational supervisor's professional judgment, taking into account the degree, necessity, age, responsiveness to the drug, etc. of the patient's symptoms / diseases. The scope is merely one example and is not intended to limit the embodiments of the claimed compositions thereto. The active ingredient may also be administered once, or several smaller doses may be administered.
본 발명에 따른 전구체 화합물, 또는 전구체-링커 화합물, 전구체-링커-리간드 접합체 화합물은 증식성 질환, 특히 암 질환을 치료하기 위해 사용될 수 있다. 용어 "증식성 질환"은 시험관내 또는 생체 내에서 신생 또는 과다형성 성장과 같은 바람직하지 않은 과도하거나 비정상적인 세포의 원치 않거나 조절되지 않는 세포 증식을 말한다. 증식성 질환은 예를 들어 신생물, 종양, 암, 백혈병, 건선, 뼈 질환, 섬유증식성 장애, 죽상동맥경화증 등을 포함하며, 양성, 전악성 또는 악성 세포 증식을 포함할 수 있으나 이로 제한되지 않는다. 상기 암은 폐암, 소세포성 폐암, 위장관암, 대장암, 장암, 유방암, 난소암, 전립선암, 고환암, 간암, 신장암, 방광암, 췌장암, 뇌암, 육종, 골육종, 카포시 육종 또는 흑색종일 수 있으나 이로 제한되는 것은 아니다. The precursor compounds, or precursor-linker compounds, precursor-linker-ligand conjugate compounds according to the invention can be used to treat proliferative diseases, in particular cancer diseases. The term "proliferative disease" refers to unwanted or uncontrolled cell proliferation of undesirable excessive or abnormal cells, such as neoplasia or hyperplasia, in vitro or in vivo. Proliferative diseases include, for example, neoplasia, tumors, cancer, leukemia, psoriasis, bone diseases, fibrotic disorders, atherosclerosis, and the like, and may include, but are not limited to, benign, premalignant or malignant cell proliferation. . The cancer may be lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma or melanoma It is not limited.
본 명세서에서 달리 정의되지 않는 한, 본 발명과 관련하여 사용된 과학용어 및 전문용어는 이 기술분야에 속하는 통상의 기술자에 의해 통상적으로 이해되는 의미를 가진다. Unless defined otherwise herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by one of ordinary skill in the art.
본 발명의 일 양태에서, 본 발명에 따른 피롤로벤조디아제핀 전구체, 피롤로벤조디아제핀 전구체-링커 화합물, 및 피롤로벤조디아제핀-링커-리간드 접합체는 다음과 같은 과정에 따라 합성될 수 있다.In one aspect of the invention, the pyrrolobenzodiazepine precursor, pyrrolobenzodiazepine precursor-linker compound, and pyrrolobenzodiazepine-linker-ligand conjugate according to the invention can be synthesized according to the following procedure.
피롤로벤조디아제핀 전구체의 합성 경로Synthetic route of pyrrolobenzodiazepine precursor
Figure PCTKR2018003744-appb-I000049
Figure PCTKR2018003744-appb-I000049
Figure PCTKR2018003744-appb-I000050
Figure PCTKR2018003744-appb-I000050
피롤로벤조디아제핀 전구체-링커 및 피롤로벤조디아제핀 전구체-링커-리간드 접합체의 합성 경로Synthetic route of pyrrolobenzodiazepine precursor-linker and pyrrolobenzodiazepine precursor-linker-ligand conjugate
본 발명에 따른 피롤로벤조디아제핀 전구체-링커 화합물, 및 피롤로벤조디아제핀 전구체-링커-리간드 접합체는, 본 명세서에서 제공되는 기술을 사용하여 당업자의 지식을 이용해 제조될 수 있다. Pyrrolobenzodiazepine precursor-linker compounds, and pyrrolobenzodiazepine precursor-linker-ligand conjugates according to the present invention can be prepared using the knowledge of those skilled in the art using the techniques provided herein.
예를 들어 링커는, 본 명세서에 전체적으로 참고로서 포함되는 PCT/US2016/063564호 및 PCT/US2016/063595호에 기술되어 있으며, 여기에 기술되어 있지 않다 하더라도 본 명세서에 인용되거나 이 기술분야의 숙련된 기술자는 공지된 참고문헌에 따라 제조할 수 있다.Linkers, for example, are described in PCT / US2016 / 063564 and PCT / US2016 / 063595, which are incorporated by reference in their entirety, and although not described herein, are cited herein or are skilled in the art. The skilled person can be prepared according to known references.
본 발명에 따른 피롤로벤조디아제핀 이량체 전구체(prodrug), 피롤로벤조디아제핀 이량체 전구체(prodrug)-링커, 또는 피롤로벤조디아제핀 이량체 전구체(prodrug)-링커-리간드 접합체는, 화합물 자체의 안정성 및 혈장 내 안정성이 우수하고, 독성 발현 측면에서 장점을 가지는바, 암과 같은 증식성 질환의 표적화, 특이적 치료, 약효의 극대화 및 부작용 발현의 최소화가 가능하다는 점에서 산업상 유용하다.The pyrrolobenzodiazepine dimer precursor (prodrug), pyrrolobenzodiazepine dimer precursor (prodrug) -linker, or pyrrolobenzodiazepine dimer precursor (prodrug) -linker-ligand conjugate according to the present invention, the stability of the compound itself and in the plasma It is excellent in stability and has an advantage in terms of toxic expression, and is industrially useful in that it is possible to target a proliferative disease such as cancer, specific treatment, maximization of drug efficacy and minimization of side effects.
도 1은 본 발명에 따른 28번 화합물의 합성과정을, 예시로서 나타낸 것이다.1 shows the synthesis process of compound No. 28 according to the present invention, as an example.
이하 본 발명을 실시예를 통해 보다 상세히 설명한다. 다만 하기 실시예는 본 발명의 이해를 돕기 위한 것이고, 본 발명의 권리범위를 이로 한정하는 것을 의도하지 않는다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are provided to help the understanding of the present invention, and are not intended to limit the scope of the present invention thereto.
<실시예 1> 화합물 4의 제조Example 1 Preparation of Compound 4
Figure PCTKR2018003744-appb-I000051
Figure PCTKR2018003744-appb-I000051
화합물 2의 제조Preparation of Compound 2
옥살릴 클로라이드 (3.1 mL, 36.2 mmol)를 다이클로로메테인 (40 mL)에 녹인 후 -78 ℃, 질소 대기 하에서 다이메틸 설폭사이드 (4.7 mL, 66.4 mmol)을 첨가하였다. 10 분 후 화합물 1 (10 g, 30.2 mmol, 화합물 1 은 J. Org . Chem ., 2003, 68, 3923-3931 에 기술된 방법으로 제조하였다)을 다이클로로메테인 (140 mL)에 녹인 용액을 서서히 첨가하고, 반응 용액을 1 시간 동안 교반한 후 트라이에틸아민 (16.7 mL, 120.6 mmol)을 넣고 2 시간 동안 서서히 반응 온도를 0 ℃ 까지 올려주었다. 반응 용액을 다이클로로메테인 (200 mL)로 묽히고, 유기층을 포화 암모늄 클로라이드 수용액 (200 mL)과 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 2 (9.5 g, 95%)를 수득하였다. Oxalyl chloride (3.1 mL, 36.2 mmol) was dissolved in dichloromethane (40 mL) and then dimethyl sulfoxide (4.7 mL, 66.4 mmol) was added at -78 ° C under nitrogen atmosphere. After 10 minutes, compound 1 (10 g, 30.2 mmol, Compound 1 J. Org. Chem., 2003, 68, was prepared by a method described in the 3923-3931) to a solution in dichloromethane (140 mL) Slowly added, the reaction solution was stirred for 1 hour, triethylamine (16.7 mL, 120.6 mmol) was added thereto, and the reaction temperature was slowly raised to 0 ° C. for 2 hours. The reaction solution was diluted with dichloromethane (200 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 2 (9.5 g, 95%).
1H-NMR (400 MHz, CDCl3) (rotamers) δ 4.39-4.26 (m, 1H), 4.03-3.80 (m, 2H), 3.69-3.64 (m, 1H), 3.63-3.51 (m, 1H), 2.70-2.60 (m, 1H), 2.43 (d, J = 17.6 Hz), 1.61-1.41 (m, 10H), 0.98-0.67 (m, 6H), 0.08-0.05 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 4.39-4.26 (m, 1H), 4.03-3.80 (m, 2H), 3.69-3.64 (m, 1H), 3.63-3.51 (m, 1H) , 2.70-2.60 (m, 1H), 2.43 (d, J = 17.6 Hz), 1.61-1.41 (m, 10H), 0.98-0.67 (m, 6H), 0.08-0.05 (s, 6H).
화합물 3의 제조Preparation of Compound 3
메틸트라이페닐포스포늄 브로마이드 (7.6 g, 21.2 mmol)를 테트라하이드로퓨란 (80 mL)로 묽힌 후 0 ℃, 질소 대기 하에서 포테슘 t-뷰톡사이드 (1 M in THF, 21.2 mL, 21.2 mmol)를 첨가하였다. 1 시간 동안 교반한 후, 화합물 2 (5.0 g, 15.2 mmol)를 테트라하이드로퓨란 (10 mL)에 녹인 용액을 서서히 첨가하였다. 반응 온도를 서서히 상온으로 올리면서 4 시간 동안 교반하였다. 포화 암모늄 클로라이드 수용액 (200 mL)를 반응 용액에 넣은 후 다이에틸이써 (2 x 200 mL)로 추출하였다. 모인 유기층을 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 3 (4.27 g, 86%)을 수득하였다. Dilute methyltriphenylphosphonium bromide (7.6 g, 21.2 mmol) with tetrahydrofuran (80 mL) and add potassium t -butoxide (1 M in THF, 21.2 mL, 21.2 mmol) under nitrogen atmosphere at 0 ° C. It was. After stirring for 1 hour, a solution of compound 2 (5.0 g, 15.2 mmol) in tetrahydrofuran (10 mL) was slowly added. Stirred for 4 hours while slowly raising the reaction temperature to room temperature. Saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution and extracted with diethylether (2 x 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 3 (4.27 g, 86%).
1H-NMR (400 MHz, CDCl3) (rotamers) δ 4.97-4.91 (m, 2H), 4.09-3.93 (m, 2H), 3.84-3.80 (m, 1H), 3.65-3.61 (m, 1H), 3.59-3.34 (m, 1H), 2.64-2.55 (m, 2H), 1.69 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 4.97-4.91 (m, 2H), 4.09-3.93 (m, 2H), 3.84-3.80 (m, 1H), 3.65-3.61 (m, 1H) , 3.59-3.34 (m, 1H), 2.64-2.55 (m, 2H), 1.69 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H).
화합물 4의 제조Preparation of Compound 4
화합물 3 (15.5 g, 47.2 mmol)을 다이클로로메테인 (120 mL)에 녹인 후 0 ℃ 에서 염산 (4 N 1,4-다이옥세인 용액, 82.6 mL, 330.4 mmol)을 첨가하고 질소 대기 하에서 2 시간 동안 교반하였다. 반응 용액을 감압 농축하여 화합물 4 (6.53 g, 92%)를 흰색 고체로 수득하였다. Compound 3 (15.5 g, 47.2 mmol) was dissolved in dichloromethane (120 mL), followed by addition of hydrochloric acid (4 N 1,4-dioxane solution, 82.6 mL, 330.4 mmol) at 0 ° C., and nitrogen for 2 hours. Was stirred. The reaction solution was concentrated under reduced pressure to give compound 4 (6.53 g, 92%) as a white solid.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 9.79 (br s, 1H), 9.17 (br s, 1H), 5.15 (d, J = 8 Hz, 1H), 4.91 (br s, 1H), 4.10 (m, 5H), 2.76-2.70 (m, 1H), 2.60-2.54 (m, 1H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 9.79 (br s, 1H), 9.17 (br s, 1H), 5.15 (d, J = 8 Hz, 1H), 4.91 (br s, 1H) , 4.10 (m, 5H), 2.76-2.70 (m, 1H), 2.60-2.54 (m, 1H).
<실시예 2> 화합물 9의 제조Example 2 Preparation of Compound 9
Figure PCTKR2018003744-appb-I000052
Figure PCTKR2018003744-appb-I000052
화합물 6의 제조Preparation of Compound 6
화합물 5 (10 g, 20.2 mmol, 화합물 5는 J. Med. Chem., 2004, 47, 1161-1174 에 기술된 방법으로 제조하였다)를 다이클로로메테인 (100 mL)에 녹인 후 0 ℃, 질소 대기 하에서 옥살릴 클로라이드 (6.1 mL, 70.8 mmol)와 N,N-다이메틸폼아마이드 (2 방울)를 첨가하였다. 반응 용액을 4 시간 동안 교반한 후 상온으로 온도를 올려 10 시간 동안 교반하고, 감압 농축한 후 진공 건조하였다. 수득한 화합물을 다이클로로메테인 (120 mL)에 녹인 후 화합물 4 (6.2 g, 41.4 mmol)와 트라이에틸아민 (9.9 mL, 70.8 mmol)을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 온도를 상온으로 올리고 3 시간 교반한 후, 포화 암모늄 클로라이드 수용액 (200 mL)를 반응 용액에 넣고 다이클로로메테인 (2 x 200 mL)으로 추출하였다. 모인 유기층을 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 6 (12 g, 87%)을 수득하였다. Compound 5 (10 g, 20.2 mmol, Compound 5 was prepared by the method described in J. Med. Chem. , 2004, 47 , 1161-1174) was dissolved in dichloromethane (100 mL), followed by nitrogen at 0 ° C. Oxalyl chloride (6.1 mL, 70.8 mmol) and N, N -dimethylformamide (2 drops) were added under air. The reaction solution was stirred for 4 hours, heated to room temperature, stirred for 10 hours, concentrated under reduced pressure, and dried in vacuo. The obtained compound was dissolved in dichloromethane (120 mL), and then compound 4 (6.2 g, 41.4 mmol) and triethylamine (9.9 mL, 70.8 mmol) were added at 0 ° C. under a nitrogen atmosphere. After raising the reaction temperature to room temperature and stirring for 3 hours, saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution and extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 6 (12 g, 87%).
1H-NMR (400 MHz, CDCl3) δ 7.71 (s, 2H), 6.80 (s, 2H), 5.13 (s, 2H), 4.88 (s, 2H), 4.61 (m, 2H), 4.17-4.14 (t, J = 6.2 Hz, 4H), 3.98 (s, 6H), 3.94-3.74 (m, 10H), 2.89-2.83 (m, 2H), 2.52-2.48(m, 2H), 2.04-1.96 (m, 4H), 1.77-1.71 (m, 2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.71 (s, 2H), 6.80 (s, 2H), 5.13 (s, 2H), 4.88 (s, 2H), 4.61 (m, 2H), 4.17-4.14 (t, J = 6.2 Hz, 4H), 3.98 (s, 6H), 3.94-3.74 (m, 10H), 2.89-2.83 (m, 2H), 2.52-2.48 (m, 2H), 2.04-1.96 (m , 4H), 1.77-1.71 (m, 2H).
화합물 7의 제조Preparation of Compound 7
화합물 6 (6.4 g, 9.36 mmol)을 다이클로로메테인 (100 mL)에 녹인 후 이미다졸 (2.5 g, 37.4 mmol)과 t-뷰틸다이메틸실릴 클로라이드 (3.5 g, 23.4 mmol)를 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 2 시간 동안 교반한 후 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 다이클로로메테인 (2 x 100 mL)으로 추출하였다. 모인 유기층을 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 7 (6.88 g, 75%)을 수득하였다. Compound 6 (6.4 g, 9.36 mmol) was dissolved in dichloromethane (100 mL), followed by imidazole (2.5 g, 37.4 mmol) and t -butyldimethylsilyl chloride (3.5 g, 23.4 mmol) at 0 ° C. and nitrogen. Added under atmosphere. The reaction solution was stirred for 2 hours and then saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution and extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 7 (6.88 g, 75%).
1H-NMR (400 MHz, CDCl3) (rotamers) δ 7.70 (s, 1H), 6.76 (s, 2H), 4.99 (s, 2H), 4.83 (s, 2H), 4.59 (br s, 2H), 4.14, (t, 4H), 3.95 (s, 6H), 3.90 (d, 2H), 3.77-3.69 (m, 4H), 3.57 (q, J = 6.2 Hz, 1H), 3.31-3.29 (m, 1H), 2.82-2.67 (m, 4H), 1.99 (t, J = 7.2 Hz, 4H), 1.75-1.72 (m, 2H), 0.89 (s, 18H), 0.09 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 7.70 (s, 1H), 6.76 (s, 2H), 4.99 (s, 2H), 4.83 (s, 2H), 4.59 (br s, 2H) , 4.14, (t, 4H), 3.95 (s, 6H), 3.90 (d, 2H), 3.77-3.69 (m, 4H), 3.57 (q, J = 6.2 Hz, 1H), 3.31-3.29 (m, 1H), 2.82-2.67 (m, 4H), 1.99 (t, J = 7.2 Hz, 4H), 1.75-1.72 (m, 2H), 0.89 (s, 18H), 0.09 (s, 12H).
화합물 8의 제조Preparation of Compound 8
화합물 7 (3.0 g, 3.29 mmol)을 에탄올 (44 mL)에 녹인 후 아연 가루 (Zinc dust, 12.9 g, 197 mmol)와 포름산 (5 % 에탄올 용액, 128 mL)을 첨가하였다. 상온에서 반응 용액을 15 분간 교반한 후, 셀라이트로 여과하고 에틸 아세테이트 (500 mL) 를 첨가하였다. 유기층을 증류수 (200 mL), 포화 탄산수소나트륨 수용액 (200 mL), 그리고 소금물 (200 mL)순으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 8 (2.76 g, 98%)을 수득하였다.Compound 7 (3.0 g, 3.29 mmol) was dissolved in ethanol (44 mL), and zinc powder (Zinc dust, 12.9 g, 197 mmol) and formic acid (5% ethanol solution, 128 mL) were added. The reaction solution was stirred at room temperature for 15 minutes, then filtered through celite and ethyl acetate (500 mL) was added. The organic layer was washed with distilled water (200 mL), saturated aqueous sodium hydrogen carbonate solution (200 mL), and brine (200 mL) and then dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 8 (2.76 g, 98%).
1H-NMR (400 MHz, CDCl3) δ 6.74 (s, 2H), 6.24 (s, 2H), 4.97 (s, 2H), 4.90 (s, 2H), 4.54 (br s, 2H), 4.33 (br s, 4H), 4.18 (br s, 1H), 4.14 (br s, 2H), 4.14-4.09 (m, 2H), 4.00 (t, J = 8 Hz, 4H), 3.77 (s, 6H), 3.62 (br s. 2H), 2.68 (s, 4H), 1.95-1.88 (m, 4H), 1.66-1.64 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 6.74 (s, 2H), 6.24 (s, 2H), 4.97 (s, 2H), 4.90 (s, 2H), 4.54 (br s, 2H), 4.33 ( br s, 4H), 4.18 (br s, 1H), 4.14 (br s, 2H), 4.14-4.09 (m, 2H), 4.00 (t, J = 8 Hz, 4H), 3.77 (s, 6H), 3.62 (br s. 2H), 2.68 (s, 4H), 1.95-1.88 (m, 4H), 1.66-1.64 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H).
화합물 9의 제조Preparation of Compound 9
화합물 8 (5.0 g, 5.86 mmol)을 다이클로로메테인 (300 mL)에 녹인 후 피리딘 (0.94 mL, 11.7 mmol)과 알릴 클로로포메이트 (0.62 mL, 5.86 mmol)를 -78 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 1 시간 동안 교반한 후 반응 온도를 상온으로 올리고, 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 9 (2.23 g, 41%)를 수득하였다. Compound 8 (5.0 g, 5.86 mmol) was dissolved in dichloromethane (300 mL), and then pyridine (0.94 mL, 11.7 mmol) and allyl chloroformate (0.62 mL, 5.86 mmol) were added under -78 ° C under a nitrogen atmosphere. It was. After stirring the reaction solution for 1 hour, the reaction temperature was raised to room temperature, concentrated and purified by column chromatography to give compound 9 (2.23 g, 41%).
1H-NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.81 (s, 1H), 6.74 (s, 1H), 6.24 (s, 1H), 5.98-5.92 (m, 1H), 5.37, (dd, J = 17.6 Hz, J = 1.2 Hz, 1H), 5.25 (dd, J = 10.4 Hz, J = 1.2 Hz, 1H), 4.97 (br s, 2H), 4.90 (br s, 2H), 4.63-4.62 (m, 4H), 4.34 (br s, 2H), 4.21-4.18 (m, 2H), 4.10 (t, J = 6.4 Hz, 3H), 3.99 (t, J = 6.4 Hz, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.63 (bs, 1H), 2.68 (br s, 4H), 1.97-1.89 (m, 4H), 1.69-1.61 (m, 2H), 0.87 (s, 18H), 0.02 (br s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.84 (s, 1H), 6.81 (s, 1H), 6.74 (s, 1H), 6.24 (s, 1H), 5.98-5.92 (m, 1H), 5.37 , (dd, J = 17.6 Hz, J = 1.2 Hz, 1H), 5.25 (dd, J = 10.4 Hz, J = 1.2 Hz, 1H), 4.97 (br s, 2H), 4.90 (br s, 2H), 4.63-4.62 (m, 4H), 4.34 (br s, 2H), 4.21-4.18 (m, 2H), 4.10 (t, J = 6.4 Hz, 3H), 3.99 (t, J = 6.4 Hz, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.63 (bs, 1H), 2.68 (br s, 4H), 1.97-1.89 (m, 4H), 1.69-1.61 (m, 2H), 0.87 (s , 18H), 0.02 (br s, 12H).
<실시예 3> 화합물 12의 제조Example 3 Preparation of Compound 12
Figure PCTKR2018003744-appb-I000053
Figure PCTKR2018003744-appb-I000053
화합물 11의 제조Preparation of Compound 11
4-하이드록시벤즈알데히드 (475 mg, 3.89 mmol)와 화합물 10 (1.7 g, 4.28 mmol, 화합물 10은 한국등록특허 1,628,872호에 기술된 방법으로 제조하였다)을 아세토나이트릴 (40 mL)에 녹인 후 4 Å 분자체 (4 g)와 산화은(I) (3.6 g, 15.6 mmol)을 첨가하고, 질소 대기, 상온 하에서 3 시간 동안 교반하였다. 반응 용액을 감압 농축하고, 증류수 (40 mL)로 묽힌 뒤 에틸 아세테이트 (2 x 50 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 11 (1.3 g, 69%)을 수득하였다. 4-hydroxybenzaldehyde (475 mg, 3.89 mmol) and compound 10 (1.7 g, 4.28 mmol, compound 10 were prepared by the method described in Korean Patent No. 1,628,872) were dissolved in acetonitrile (40 mL), and 4 Å Molecular sieve (4 g) and silver oxide (I) (3.6 g, 15.6 mmol) were added and stirred under nitrogen atmosphere at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with distilled water (40 mL) and extracted with ethyl acetate (2 x 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound 11 (1.3 g, 69%).
1H-NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.86 (d, J = 8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 5.38-5.29 (m, 4H), 4.25-4.23 (m, 1H), 3.71 (s, 3H), 2.06 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.93 (s, 1H), 7.86 (d, J = 8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 5.38-5.29 (m, 4H ), 4.25-4.23 (m, 1 H), 3.71 (s, 3 H), 2.06 (s, 9 H).
화합물 12의 제조Preparation of Compound 12
화합물 11 (1.3 g, 2.96 mmol)을 클로로폼/아이소프로판올 (50 mL/10 mL)에 녹인 후 0 ℃, 질소 대기 하에서 실리카겔 (1.3 g)과 소듐 보로하이드라이드 (134 mg, 3.55 mmol)를 가한 후 2 시간 동안 교반하였다. 증류수 (40 mL)를 반응 용액에 첨가한 후 에틸 아세테이트 (2 x 50 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 12 (600 mg, 45%)를 수득하였다. Compound 11 (1.3 g, 2.96 mmol) was dissolved in chloroform / isopropanol (50 mL / 10 mL), and silica gel (1.3 g) and sodium borohydride (134 mg, 3.55 mmol) were added at 0 ° C. under a nitrogen atmosphere. After stirring for 2 hours. Distilled water (40 mL) was added to the reaction solution and extracted with ethyl acetate (2 x 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound 12 (600 mg, 45%).
1H-NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz 2H), 5.35-5.26 (m, 3H), 5.13 (d, J = 7.6 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H), 4.18-4.16 (m, 1H), 3.73 (s, 3H), 2.06-2.04 (m, 9H), 1.61 (t, J = 5.6 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.31 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz 2H), 5.35-5.26 (m, 3H), 5.13 (d, J = 7.6 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H), 4.18-4.16 (m, 1H), 3.73 (s, 3H), 2.06-2.04 (m, 9H), 1.61 (t, J = 5.6 Hz, 1H).
<실시예 4> 화합물 15의 제조Example 4 Preparation of Compound 15
Figure PCTKR2018003744-appb-I000054
Figure PCTKR2018003744-appb-I000054
화합물 13의 제조Preparation of Compound 13
5-포밀살리실산 (5.0 g, 30.1 mmol)을 메탄올 (50 mL)에 녹인 후 진한 황산 (2 mL)을 첨가하였다. 반응 용액을 24 시간 동안 가열 환류시킨 후 감압 농축하고 에틸 아세테이트 (100 mL)로 희석하였다. 유기층을 증류수 (100 mL), 포화 탄산수소나트륨 수용액 (200 mL), 그리고 소금물 (200 mL)순으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 진공 건조하여 화합물 13 (4.62 g, 85%)을 흰색의 고체로 수득하였다. 5-formylsalicylic acid (5.0 g, 30.1 mmol) was dissolved in methanol (50 mL) and concentrated sulfuric acid (2 mL) was added. The reaction solution was heated to reflux for 24 hours, then concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The organic layer was washed with distilled water (100 mL), saturated aqueous sodium hydrogen carbonate solution (200 mL), and brine (200 mL) and then dried over anhydrous sodium sulfate. After filtration, concentration and vacuum drying gave compound 13 (4.62 g, 85%) as a white solid.
1H-NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 9.88 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.01 (s, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 11.36 (s, 1H), 9.88 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.01 (s, 3H).
화합물 14의 제조Preparation of Compound 14
화합물 13 (1.7 g, 9.38 mmol)과 화합물 10 (4.1 g, 10.3 mmol)을 아세토나이트릴 (50 mL)에 녹인 후 4 Å 분자체 (4 g)와 산화은(I) (8.7 g, 37.5 mmol)을 첨가하고, 질소 대기, 상온 하에서 3 시간 동안 교반하였다. 반응 용액을 감압 농축하고, 증류수 (50 mL)로 묽힌 뒤 에틸 아세테이트 (2 x 50 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 14 (2.85 g, 61%)를 수득하였다. Compound 13 (1.7 g, 9.38 mmol) and compound 10 (4.1 g, 10.3 mmol) were dissolved in acetonitrile (50 mL), followed by 4 'molecular sieves (4 g) and silver oxide (I) (8.7 g, 37.5 mmol). Was added, and the mixture was stirred under nitrogen atmosphere at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with distilled water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound 14 (2.85 g, 61%).
1H-NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.29 (d, J = 2 Hz, 1H), 8.01 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 5.42-5.30 (m, 4H), 4.27 (d, J = 9.2 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.95 (s, 1H), 8.29 (d, J = 2 Hz, 1H), 8.01 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 7.26 ( d, J = 8.8 Hz, 1H), 5.42-5.30 (m, 4H), 4.27 (d, J = 9.2 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 2.08 (s, 3H ), 2.07 (s, 3 H), 2.06 (s, 3 H).
화합물 15의 제조Preparation of Compound 15
화합물 14 (2.85 g, 5.74 mmol)를 클로로폼:아이소프로판올 (50 mL/10 mL)에 녹인 후 0 ℃, 질소 대기 하에서 실리카겔 (2.8 g)과 소듐 보로하이드라이드 (434 mg, 11.5 mmol)를 가한 후 2 시간 동안 교반하였다. 증류수 (40 mL)를 반응 용액에 첨가한 후 다이클로로메테인 (2 x 50 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 15 (1.42 g, 49%)를 수득하였다.Compound 14 (2.85 g, 5.74 mmol) was dissolved in chloroform: isopropanol (50 mL / 10 mL), and silica gel (2.8 g) and sodium borohydride (434 mg, 11.5 mmol) were added under a nitrogen atmosphere at 0 ° C. After stirring for 2 hours. Distilled water (40 mL) was added to the reaction solution and extracted with dichloromethane (2 x 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound 15 (1.42 g, 49%).
<실시예 5> 화합물 20의 제조Example 5 Preparation of Compound 20
Figure PCTKR2018003744-appb-I000055
Figure PCTKR2018003744-appb-I000055
화합물 16의 제조Preparation of Compound 16
5-포밀살리실산 (10.0 g, 60.1 mmol)을 테트라하이드로퓨란 (30 mL)에 묽힌 뒤 N,N-다이아이소프로필에틸아민 (29.8 mL, 180 mmol)과 벤질 브로마이드 (7.15 mL, 60.1 mmol)를 상온에서 첨가하였다. 반응 용액을 18 시간 동안 가열 환류시킨 후 온도를 상온으로 식히고 2 N 염산 수용액 (100 mL)을 첨가하였다. 이 혼합물을 에틸 아세테이트 (2 x 100 mL)로 추출하고 모인 유기층을 무수 황산나트륨으로 건조하였다. 여과 후 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 16 (12.9 g, 83%)을 수득하였다. Dilute 5-formylsalicylic acid (10.0 g, 60.1 mmol) to tetrahydrofuran (30 mL), and then N, N -diisopropylethylamine (29.8 mL, 180 mmol) and benzyl bromide (7.15 mL, 60.1 mmol) at room temperature. Was added. The reaction solution was heated to reflux for 18 hours, then cooled to room temperature and 2N hydrochloric acid aqueous solution (100 mL) was added. The mixture was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure and purification by column chromatography gave Compound 16 (12.9 g, 83%).
1H-NMR (400 MHz, CDCl3) δ 11.38 (s, 1H), 9.86 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.44 (m, 5H), 7.12 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 11.38 (s, 1H), 9.86 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.44 (m, 5H ), 7.12 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H).
화합물 17의 제조Preparation of Compound 17
화합물 16 (5.0 g, 19.5 mmol)과 화합물 10 (8.5 g, 21.4 mmol)을 아세토나이트릴 (100 mL)에 녹인 후 4 Å 분자체 (10 g)와 산화은(I) (18.0 g, 78.0 mmol)을 첨가하고, 질소 대기, 상온 하에서 12 시간 동안 교반하였다. 반응용액을 감압 농축하고, 증류수 (100 mL)로 묽힌 뒤 에틸 아세테이트 (2 x 200 mL)로 추출하였다. 추출된 유기층을 무수 황산 마그네슘으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 17 (8.63 g, 77%)을 수득하였다. Compound 16 (5.0 g, 19.5 mmol) and compound 10 (8.5 g, 21.4 mmol) were dissolved in acetonitrile (100 mL), followed by 4 Å molecular sieve (10 g) and silver oxide (I) (18.0 g, 78.0 mmol). Was added and stirred for 12 hours under a nitrogen atmosphere and room temperature. The reaction solution was concentrated under reduced pressure, diluted with distilled water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 17 (8.63 g, 77%).
1H-NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.46-7.28 (m, 6H), 5.41-5.32 (m, 6H), 4.27 (d, J = 9.2 Hz, 1H), 3.71 (s, 3H), 2.06-2.04 (m, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.94 (s, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.46-7.28 (m, 6H), 5.41-5.32 (m, 6H), 4.27 (d, J = 9.2 Hz, 1H), 3.71 (s, 3H), 2.06-2.04 (m, 9H).
화합물 18의 제조Preparation of Compound 18
화합물 17 (3.10 g, 5.41 mmol)을 클로로폼/아이소프로판올 (45 mL/9 mL)에 녹인 후 0 ℃, 질소 대기 하에서 실리카겔 (3 g)과 소듐 보로하이드라이드 (0.41 g, 10.8 mmol)를 가한 후 2 시간 동안 교반하였다. 증류수 (100 mL)를 반응 용액에 첨가한 후 에틸 아세테이트 (200 mL)로 추출하였다. 추출된 유기층을 무수 황산 마그네슘으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 18 (2.73 g, 87%)을 흰색의 고체로 수득하였다. Compound 17 (3.10 g, 5.41 mmol) was dissolved in chloroform / isopropanol (45 mL / 9 mL), and silica gel (3 g) and sodium borohydride (0.41 g, 10.8 mmol) were added under a nitrogen atmosphere at 0 ° C. After stirring for 2 hours. Distilled water (100 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 18 (2.73 g, 87%) as a white solid.
1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.48-7.34 (m, 6H), 7.16 (d, J = 8.8 Hz, 1H), 5.35-5.26 (m, 5H), 5.16-5.14 (m, 1H), 4.17-4.15 (m, 1H), 3.73 (s, 3H), 2.04 (s, 9H), 1.73 (t, J = 7.2 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.48-7.34 (m, 6H), 7.16 (d, J = 8.8 Hz, 1H), 5.35-5.26 (m, 5H), 5.16 -5.14 (m, 1H), 4.17-4.15 (m, 1H), 3.73 (s, 3H), 2.04 (s, 9H), 1.73 (t, J = 7.2 Hz, 1H).
화합물 19의 제조Preparation of Compound 19
화합물 18 (2.40 g, 4.17 mmol)을 에탄올 (150 mL)에 녹인 후 레이니 니켈 (Raney Ni, 240 mg)를 첨가하였다. 반응 용액을 상온, 수소 대기 하에서 10 분간 교반하였다. 반응 용액을 셀라이트로 여과하고 농축하여 화합물 19 (2.10 g)를 흰색의 고체로 수득하였다. Compound 18 (2.40 g, 4.17 mmol) was dissolved in ethanol (150 mL) and Raney Ni (240 mg) was added. The reaction solution was stirred for 10 minutes under normal temperature and hydrogen atmosphere. The reaction solution was filtered through celite and concentrated to give compound 19 (2.10 g) as a white solid.
1H-NMR (400 MHz, CDCl3) δ 8.06 (s, 1H) 7.61 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.0 Hz 1H), 5.43-5.29 (m, 5H), 4.17 (s, 2H), 4.32 (d, J = 8.4 Hz, 1H) 3.69 (s, 3H), 2.11-2.08 (m, 9H), 1.24 (t, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H) 7.61 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.0 Hz 1H), 5.43-5.29 (m, 5H), 4.17 (s, 2H), 4.32 (d, J = 8.4 Hz, 1H) 3.69 (s, 3H), 2.11-2.08 (m, 9H), 1.24 (t, 1H).
화합물 20의 제조Preparation of Compound 20
화합물 19 (7.0 g, 14.5 mmol)와 2-메톡시에틸아민 (1.38 mL, 1.59 mmol)을 N,N-다이메틸폼아마이드 (14 mL)에 녹인 후 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (6.57 g, 17.3 mmol)과 N,N-다이아이소프로필에틸아민 (5 mL, 28.9 mmol)을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 2 시간 동안 상온 교반한 후 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출하였다. 모인 유기층을 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 20 (7.53 g, 96%)을 수득하였다. Compound 19 (7.0 g, 14.5 mmol) and 2-methoxyethylamine (1.38 mL, 1.59 mmol) were dissolved in N, N -dimethylformamide (14 mL) and then N, N, N ', N' -tetra Methyl- O- ( 1H -benzotriazol-1-yl) uronium hexafluorophosphate (6.57 g, 17.3 mmol) and N, N -diisopropylethylamine (5 mL, 28.9 mmol) were added at 0 ° C., Added under nitrogen atmosphere. After the reaction solution was stirred at room temperature for 2 hours, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 20 (7.53 g, 96%).
1H-NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2 Hz, 1H), 7.49 (br s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.42-5.28 (m, 4H), 4.66 (s, 1H), 4.19 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H), 3.42 (s, 3H), 2.05 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 2 Hz, 1H), 7.49 (br s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.42-5.28 (m, 4H), 4.66 (s, 1H), 4.19 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H), 3.42 (s, 3H), 2.05 (s, 9H).
<실시예 6> 화합물 22의 제조Example 6 Preparation of Compound 22
Figure PCTKR2018003744-appb-I000056
Figure PCTKR2018003744-appb-I000056
화합물 19 (1.0 g, 2.06 mmol)와 화합물 21 (1.49 g, 2.80 mmol, 화합물 21은 PCT/US2016/063564 에 기술된 방법으로 제조하였다)을 N,N-다이메틸폼아마이드 (10 mL)에 녹인 후 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (1.56 g, 4.12 mmol)과 N,N-다이아이소프로필에틸아민 (1.07 mL, 6.18 mmol)을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 12 시간 동안 상온 교반한 후 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출하였다. 모인 유기층을 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 22 (1.6 g, 80%)를 수득하였다. Compound 19 (1.0 g, 2.06 mmol) and Compound 21 (1.49 g, 2.80 mmol, Compound 21 prepared by the method described in PCT / US2016 / 063564) were dissolved in N, N -dimethylformamide (10 mL). N, N, N ', N' -tetramethyl- O- ( 1H -benzotriazol-1-yl) uronium hexafluorophosphate (1.56 g, 4.12 mmol) and N, N -diisopropylethyl Amine (1.07 mL, 6.18 mmol) was added at 0 ° C under nitrogen atmosphere. After stirring the reaction solution at room temperature for 12 hours, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 22 (1.6 g, 80%).
1H-NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.41 (br s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.93-5.25 (m, 4H), 4.67 (d, J = 5.2 Hz, 2H), 4.20 (d, J = 9.6 Hz, 1H), 4.08 (t, J = 4.8 Hz, 2H), 3.74 (s, 6H), 3.72-3.49 (m, 22H), 2.06 (s, 9H), 1.53 (s, 18H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.98 (s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.41 (br s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.93-5.25 (m, 4H), 4.67 (d, J = 5.2 Hz, 2H), 4.20 (d, J = 9.6 Hz, 1H), 4.08 (t, J = 4.8 Hz, 2H) , 3.74 (s, 6H), 3.72-3.49 (m, 22H), 2.06 (s, 9H), 1.53 (s, 18H).
<실시예 7> 화합물 25의 제조Example 7 Preparation of Compound 25
Figure PCTKR2018003744-appb-I000057
Figure PCTKR2018003744-appb-I000057
화합물 23의 제조Preparation of Compound 23
화합물 9 (2.2 g, 2.34 mmol)를 톨루엔 (65 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (250 mg, 0.84 mmol)과 트라이에틸아민 (0.44 mL, 3.16 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 20 (1.39 g, 2.58 mmol)을 건조한 테트라하이드로퓨란 (65 mL)에 녹이고 트라이에틸아민 (0.44 mL, 3.16 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (100 mL)으로 희석한 후 소금물 (50 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 23 (2.5 g, 72%)을 수득하였다. Compound 9 (2.2 g, 2.34 mmol) was dissolved in toluene (65 mL), and then triphosgene (250 mg, 0.84 mmol) and triethylamine (0.44 mL, 3.16 mmol) were added at -10 ° C. for 1 hour under a nitrogen atmosphere. Was stirred. Compound 20 (1.39 g, 2.58 mmol) was dissolved in dry tetrahydrofuran (65 mL), triethylamine (0.44 mL, 3.16 mmol) was added and the solution was slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography yielded compound 23 (2.5 g, 72%).
EI-MS m/z : [M+H]+ 1504.7, 1/2[M+H]+ 753.5.EI-MS m / z: [M + H] + 1504.7, 1/2 [M + H] + 753.5.
화합물 24의 제조Preparation of Compound 24
화합물 23 (2.0 g, 1.33 mmol)을 다이클로로메테인 (15 mL)에 녹인 후 피롤리딘 (0.13 mL, 1.59 mmol)과 테트라키스(트라이페닐포스핀)팔라듐(0) (76 mg, 0.066 mmol)을 첨가하고 상온, 질소 대기 하에서 6 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 24 (1.7 g, 90%)를 수득하였다. Compound 23 (2.0 g, 1.33 mmol) was dissolved in dichloromethane (15 mL), followed by pyrrolidine (0.13 mL, 1.59 mmol) and tetrakis (triphenylphosphine) palladium (0) (76 mg, 0.066 mmol ) Was added and stirred for 6 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 24 (1.7 g, 90%).
EI-MS m/z : [M+H]+ 1420.6, 1/2[M+H]+ 711.2.EI-MS m / z: [M + H] + 1420.6, 1/2 [M + H] + 711.2.
화합물 25의 제조Preparation of Compound 25
화합물 24 (1.2 g, 0.84 mmol)를 톨루엔 (24 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (90 mg, 0.30 mmol)과 피리딘 (0.33 mL, 4.22 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 22 (974 mg, 1.01 mmol)를 건조한 테트라하이드로퓨란 (24 mL)에 녹이고 N,N-다이아이소프로필에틸아민 (0.21 mL, 1.26 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (50 mL)로 희석한 후 소금물 (30 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 25 (800 mg, 40%)를 수득하였다. Compound 24 (1.2 g, 0.84 mmol) was dissolved in toluene (24 mL), then triphosphogen (90 mg, 0.30 mmol) and pyridine (0.33 mL, 4.22 mmol) were added at -10 ° C and stirred for 1 hour under a nitrogen atmosphere. It was. Compound 22 (974 mg, 1.01 mmol) was dissolved in dry tetrahydrofuran (24 mL) and N , N -diisopropylethylamine (0.21 mL, 1.26 mmol) was added to the reaction solution and then slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography yielded compound 25 (800 mg, 40%).
EI-MS m/z : [M+H]+ 2409.9, 1/2[M+Na]+ 1214.3.EI-MS m / z: [M + H] + 2409.9, 1/2 [M + Na] + 1214.3.
<실시예 8> 화합물 28의 제조Example 8 Preparation of Compound 28
Figure PCTKR2018003744-appb-I000058
Figure PCTKR2018003744-appb-I000058
화합물 26의 제조Preparation of Compound 26
화합물 25 (800 mg, 0.33 mmol)를 테트라하이드로퓨란/증류수 (4 mL/4 mL)에 녹이고 아세트산 (8 mL)를 첨가한 후 상온, 질소 대기 하에서 16 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 26 (660 mg, 90%)를 수득하였다. Compound 25 (800 mg, 0.33 mmol) was dissolved in tetrahydrofuran / distilled water (4 mL / 4 mL) and acetic acid (8 mL) was added, followed by stirring for 16 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 26 (660 mg, 90%).
EI-MS m/z : [M+H]+ 2181.6, 1/2[M-Boc+H]+ 1041.5.EI-MS m / z: [M + H] + 2181.6, 1/2 [M-Boc + H] + 1041.5.
화합물 27의 제조Preparation of Compound 27
화합물 26 (660 mg, 0.15 mmol)을 다이클로로메테인 (15 mL)에 녹인 후 데스-마틴 펄아이오디네인 (Dess-Martin periodinane, 141 mg, 0.33 mmol)를 첨가하고 상온, 질소 대기 하에서 3.5 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 27 (477 mg, 70%)을 수득하였다. Compound 26 (660 mg, 0.15 mmol) was dissolved in dichloromethane (15 mL), and then Dess-Martin periodinane (141 mg, 0.33 mmol) was added thereto, and the mixture was cooled to 3.5 at room temperature and nitrogen atmosphere. Stir for hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 27 (477 mg, 70%).
EI-MS m/z : [M+H]+ 2177.6, 1/2[M+H]+ 1089.5.EI-MS m / z: [M + H] + 2177.6, 1/2 [M + H] + 1089.5.
화합물 28의 제조Preparation of Compound 28
화합물 27 (150 mg, 0.068 mmol)을 메탄올/테트라하이드로퓨란 (3 mL/3 mL)에 녹인 후 수산화 리튬 (26 mg, 0.62 mmol)을 증류수 (3 mL)에 녹인 용액을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 0 ℃로 올리면서 2 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축하고 진공 건조 하였다. 얻어진 고체를 다이클로로메테인 (5 mL)으로 묽힌 후 트라이플루오로아세트산 (1.2 mL)를 0 ℃에서 첨가하고 2 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 28 (20 mg, 16%)을 흰색의 고체로 수득하였다. Compound 27 (150 mg, 0.068 mmol) was dissolved in methanol / tetrahydrofuran (3 mL / 3 mL), and then a solution of lithium hydroxide (26 mg, 0.62 mmol) in distilled water (3 mL) was added slowly at -40 ° C. It was. Stirred for 2 hours while slowly raising the reaction temperature to 0 ℃. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure and dried in vacuo. The resulting solid was diluted with dichloromethane (5 mL), then trifluoroacetic acid (1.2 mL) was added at 0 ° C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, purified by HPLC and lyophilized to give compound 28 (20 mg, 16%) as a white solid.
EI-MS m/z : [M+H]+ 1697.5, 1/2[M+H]+ 849.3.EI-MS m / z: [M + H] + 1697.5, 1/2 [M + H] + 849.3.
<실시예 9> 화합물 29의 제조Example 9 Preparation of Compound 29
Figure PCTKR2018003744-appb-I000059
Figure PCTKR2018003744-appb-I000059
화합물 29는 화합물 9와 화합물 12로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1596.9, 1/2[M+H]+ 799.3.Compound 29 was prepared by a method analogous to the synthesis of compound 28 from compound 9 and compound 12. EI-MS m / z: [M + H] + 1596.9, 1/2 [M + H] + 799.3.
<실시예 10> 화합물 30의 제조Example 10 Preparation of Compound 30
Figure PCTKR2018003744-appb-I000060
Figure PCTKR2018003744-appb-I000060
화합물 30은 화합물 9와 화합물 15로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1655.3, 1/2[M+H]+ 828.1.Compound 30 was prepared by a method analogous to the synthesis of compound 28 from compound 9 and compound 15. EI-MS m / z: [M + H] + 1655.3, 1/2 [M + H] + 828.1.
<실시예 11> 화합물 31의 제조Example 11 Preparation of Compound 31
Figure PCTKR2018003744-appb-I000061
Figure PCTKR2018003744-appb-I000061
화합물 32는 화합물 19와 화합물 31 (화합물 31은 PCT/US2016/063564에 기술된 방법으로 제조하였다)로부터 화합물 22의 합성과 유사한 방법으로 제조하였다. 1H-NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.41 (bs, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.72 (s, 1H), 5.42-5.27 (m, 4H), 4.66 (d, J = 5.2 Hz, 2H), 4.25 (d, J = 9.6 Hz, 1H), 3.97 (t, J = 4.8 Hz, 2H), 3.78 (s, 3H), 3.74-3.64 (m, 10H), 2.04 (s, 9H), 1.53 (s, 9H). EI-MS m/z : [M+H]+ 731.5.Compound 32 was prepared in a similar manner to the synthesis of Compound 22 from Compound 19 and Compound 31 (Compound 31 was prepared by the method described in PCT / US2016 / 063564). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.41 (bs, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.72 (s, 1H), 5.42-5.27 (m, 4H), 4.66 (d, J = 5.2 Hz, 2H), 4.25 (d, J = 9.6 Hz, 1H), 3.97 (t, J = 4.8 Hz, 2H), 3.78 (s, 3H), 3.74-3.64 (m, 10H), 2.04 (s, 9H), 1.53 (s, 9H). EI-MS m / z: [M + H] + 731.5.
<실시예 12> 화합물 34의 제조Example 12 Preparation of Compound 34
Figure PCTKR2018003744-appb-I000062
Figure PCTKR2018003744-appb-I000062
화합물 34는 화합물 24와 화합물 32로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1565.5, 1/2[M+H]+ 783.4.Compound 34 was prepared by a method analogous to the synthesis of compound 28 from compound 24 and compound 32. EI-MS m / z: [M + H] + 1565.5, 1/2 [M + H] + 783.4.
<실시예 13> 화합물 39의 제조Example 13 Preparation of Compound 39
Figure PCTKR2018003744-appb-I000063
Figure PCTKR2018003744-appb-I000063
화합물 35와 화합물 36은 PCT/US2016/063564에 기술된 방법으로 제조하였다.Compound 35 and Compound 36 were prepared by the method described in PCT / US2016 / 063564.
Figure PCTKR2018003744-appb-I000064
Figure PCTKR2018003744-appb-I000064
화합물 37의 제조Preparation of Compound 37
화합물 24 (400 mg, 0.28 mmol)를 톨루엔 (10 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (30 mg, 0.10 mmol)과 트라이에틸아민 (0.053 mL, 0.38 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 35 (177 mg, 0.33 mmol)를 건조한 테트라하이드로퓨란 (10 mL)에 녹이고 트라이에틸아민 (0.053 mL, 0.38 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (50 mL)로 희석한 후 소금물 (30 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 37 (192 mg, 34%)을 수득하였다. Compound 24 (400 mg, 0.28 mmol) was dissolved in toluene (10 mL), and then triphosgene (30 mg, 0.10 mmol) and triethylamine (0.053 mL, 0.38 mmol) were added at -10 ° C, and the mixture was kept for 1 hour under a nitrogen atmosphere. Was stirred. Compound 35 (177 mg, 0.33 mmol) was dissolved in dry tetrahydrofuran (10 mL), triethylamine (0.053 mL, 0.38 mmol) was added and the solution was slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 37 (192 mg, 34%) was obtained.
EI-MS m/z : [M+H]+ 1971.8, 1/2[M+H]+ 986.6.EI-MS m / z: [M + H] + 1971.8, 1/2 [M + H] + 986.6.
화합물 38의 제조Preparation of Compound 38
화합물 37 (192 mg, 0.097 mmol)을 다이클로로메테인 (5 mL)에 녹인 후 피롤리딘 (0.012 mL, 0.14 mmol)과 테트라키스(트라이페닐포스핀)팔라듐(0) (11.2 mg, 0.096 mmol)을 첨가하고 상온, 질소 대기 하에서 6 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 38 (180 mg, 96%)을 수득하였다. Compound 37 (192 mg, 0.097 mmol) was dissolved in dichloromethane (5 mL), followed by pyrrolidine (0.012 mL, 0.14 mmol) and tetrakis (triphenylphosphine) palladium (0) (11.2 mg, 0.096 mmol ) Was added and stirred for 6 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 38 (180 mg, 96%).
EI-MS m/z : [M+H]+ 1932.8, 1/2[M+H]+ 966.5EI-MS m / z: [M + H] + 1932.8, 1/2 [M + H] + 966.5
화합물 39의 제조Preparation of Compound 39
화합물 38 (180 mg, 0.093 mmol)과 화합물 36 (112 mg, 0.116 mmol)을 N,N-다이메틸폼아마이드 (2 mL)에 녹인 후 1-[비스(다이메틸아미노)메틸렌]-1H-1,2,3-트리아졸로[4,5-b]피리디늄 3-옥사이드 헥사플루오로포스페이트 (HATU, 46 mg, 0.121 mmol)와 N,N-다이아이소프로필에틸아민 (0.032 mL, 0.186 mmol)을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 36 시간 동안 상온 교반한 후 증류수(20 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 20 mL)로 추출하였다. 모인 유기층을 소금물 (20 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 39 (133 mg, 50%)를 수득하였다. Compound 38 (180 mg, 0.093 mmol) and Compound 36 (112 mg, 0.116 mmol) were dissolved in N , N -dimethylformamide (2 mL) and then 1- [bis (dimethylamino) methylene] -1 H- 1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 46 mg, 0.121 mmol) and N , N -diisopropylethylamine (0.032 mL, 0.186 mmol) Was added at 0 ° C. under a nitrogen atmosphere. After stirring the reaction solution at room temperature for 36 hours, distilled water (20 mL) was added to the reaction solution and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 39 (133 mg, 50%) was obtained.
EI-MS m/z : [M+H]+ 2876.4, 1/2[M+H]+ 1438.6.EI-MS m / z: [M + H] + 2876.4, 1/2 [M + H] + 1438.6.
<실시예 14> 화합물 42의 제조Example 14 Preparation of Compound 42
Figure PCTKR2018003744-appb-I000065
Figure PCTKR2018003744-appb-I000065
화합물 40의 제조Preparation of Compound 40
화합물 39 (133 mg, 0.046 mmol)를 테트라하이드로퓨란/증류수 (1 mL/1 mL)에 녹이고 아세트산 (2 mL)를 첨가한 후 상온, 질소 대기 하에서 16 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 40 (67.4 mg, 55%)을 수득하였다. Compound 39 (133 mg, 0.046 mmol) was dissolved in tetrahydrofuran / distilled water (1 mL / 1 mL) and acetic acid (2 mL) was added, followed by stirring at room temperature and nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give a compound 40 (67.4 mg, 55%) was obtained.
EI-MS m/z : [M+H]+ 2647.4, 1/2[M+H]+ 1324.5.EI-MS m / z: [M + H] + 2647.4, 1/2 [M + H] + 1324.5.
화합물 41의 제조Preparation of Compound 41
화합물 40 (67.4 mg, 0.025 mmol)을 다이클로로메테인 (2 mL)에 녹인 후 데스-마틴 펄아이오디네인 (Dess-Martin periodinane, 23.7 mg, 0.056 mmol)을 첨가하고 상온, 질소 대기 하에서 3.5 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 41 (43 mg, 65%)을 수득하였다. Compound 40 (67.4 mg, 0.025 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of Dess-Martin periodinane (23.7 mg, 0.056 mmol), followed by 3.5 at room temperature and nitrogen atmosphere. Stir for hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give a compound 41 (43 mg, 65%) was obtained.
EI-MS m/z : [M+H]+ 2643.1, 1/2[M+H]+ 1322.5.EI-MS m / z: [M + H] + 2643.1, 1/2 [M + H] + 1322.5.
화합물 42의 제조Preparation of Compound 42
화합물 41 (43 mg, 0.016 mmol)을 메탄올/테트라하이드로퓨란 (0.5 mL/0.5 mL)에 녹인 후 수산화 리튬 (6.8 mg, 0.16 mmol)을 증류수 (0.5 mL)에 녹인 용액을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 -10 ℃로 올리면서 2 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축하고 진공 건조 하였다. 얻어진 고체를 다이클로로메테인 (1 mL)로 묽힌 후 트라이플루오로아세트산 (0.2 mL)를 0 ℃에서 첨가하고 2 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 42를 흰색의 고체 (7.0 mg)로 수득하였다. Compound 41 (43 mg, 0.016 mmol) was dissolved in methanol / tetrahydrofuran (0.5 mL / 0.5 mL), and a solution of lithium hydroxide (6.8 mg, 0.16 mmol) in distilled water (0.5 mL) was added slowly at -40 ° C. It was. Stirred for 2 hours while slowly raising the reaction temperature to -10 ℃. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure and dried in vacuo. The resulting solid was diluted with dichloromethane (1 mL), then trifluoroacetic acid (0.2 mL) was added at 0 ° C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to give compound 42 as a white solid (7.0 mg).
EI-MS m/z : [M+H]+ 2263.4, 1/2[M+H]+ 1132.3.EI-MS m / z: [M + H] + 2263.4, 1/2 [M + H] + 1132.3.
<실시예 15> 화합물 48의 제조Example 15 Preparation of Compound 48
Figure PCTKR2018003744-appb-I000066
Figure PCTKR2018003744-appb-I000066
화합물 44의 제조Preparation of Compound 44
화합물 43 (37 g, 40.2 mmol, 화합물 43은 J. Med . Chem ., 2004, 47, 1161-1174 에 기술된 방법으로 제조하였다)을 다이클로로메테인 (400 mL)에 녹인 후 0 ℃에서 트라이클로로아이소시아뉴릭 에시드 (14.9 g, 64.3 mmol)와 2,2,6,6-테트라메틸-1-피페리디닐옥시 (1.3 g, 8.0 mmol)를 첨가 하고 질소 대기 하에서 1 시간 동안 교반하였다. 반응 용액에 다이클로로메테인 (400 mL)을 첨가하여 희석하고 포화 탄산수소나트륨 수용액 (400 mL), 싸이오 황산 나트륨 (0.2 M, 400 mL)수용액, 그리고 소금물 (200 mL)순으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 44 (35 g, 83%)를 수득하였다. Compound 43 (37 g, 40.2 mmol, Compound 43 prepared by the method described in J. Med . Chem . , 2004, 47 , 1161-1174) was dissolved in dichloromethane (400 mL) and then tri-treated at 0 ° C. Chloroisocyanuric acid (14.9 g, 64.3 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy (1.3 g, 8.0 mmol) were added and stirred under nitrogen atmosphere for 1 hour. Dichloromethane (400 mL) was added to the reaction solution, diluted with saturated aqueous sodium bicarbonate solution (400 mL), aqueous sodium thiosulfate solution (0.2 M, 400 mL), and brine (200 mL). Dried over sodium sulfate. Filtration and concentration under reduced pressure, purified by column chromatography Compound 44 (35 g, 83%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 7.72 (s, 2H), 6.73 (s, 2H), 4.97 (d, 2H), 4.31 (d, 2H), 4.12 (t, 4H), 3.95-3.96 (m, 6H), 3.71 (d, 2H), 3.64 (d, 2H), 3.45 (d, 2H), 2.82-2.75 (m, 2H), 2.55 (d, 2H), 1.99 (m, 4H), 1.72 (m, 2H), 0.85 (s, 18H), 0.08 (d, 12H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 7.72 (s, 2H), 6.73 (s, 2H), 4.97 (d, 2H), 4.31 (d, 2H), 4.12 (t, 4H), 3.95-3.96 (m, 6H), 3.71 (d, 2H), 3.64 (d, 2H), 3.45 (d, 2H), 2.82-2.75 (m, 2H), 2.55 (d, 2H), 1.99 (m, 4H), 1.72 (m, 2H), 0.85 (s, 18H), 0.08 (d, 12H).
화합물 45의 제조Preparation of Compound 45
화합물 44 (5 g, 5.45 mmol)를 다이클로로메테인 (90 mL)에 녹인 후 -40 ℃에서 2,6-루티딘 (5.1 ml, 43.8 mmol)과 트라이플릭 언하이드라이드 (5.5 ml, 39.0 mmol)를 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 반응 용액에 다이클로로메테인 (90 mL)을 첨가하여 희석하고 포화 탄산수소나트륨 수용액 (90 mL), 증류수 (90 mL) 그리고 소금물 (90 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 45 (4.0 g, 62%)를 수득하였다. Compound 44 (5 g, 5.45 mmol) was dissolved in dichloromethane (90 mL) and then 2,6-lutidine (5.1 ml, 43.8 mmol) and triplic anhydride (5.5 ml, 39.0 mmol) at -40 ° C. ) Was added and stirred for 1 h under a nitrogen atmosphere. Dichloromethane (90 mL) was added to the reaction solution, and the mixture was diluted with saturated aqueous sodium bicarbonate solution (90 mL), distilled water (90 mL) and brine (90 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, purified by column chromatography Compound 45 (4.0 g, 62%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 7.71 (s, 2H), 6.77 (s, 2H), 6.08 (s, 2H), 4.79-4.78 (m, 2H), 4.18-4.09 (m, 6H), 4.02-3.92 (m, 8H), 3.22-3.14 (m, 2H), 3.01-2.97 (m, 2H), 2.02-1.97 (m, 4H), 0.91 (s, 18H), 0.11 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 7.71 (s, 2H), 6.77 (s, 2H), 6.08 (s, 2H), 4.79-4.78 (m, 2H), 4.18-4.09 (m , 6H), 4.02-3.92 (m, 8H), 3.22-3.14 (m, 2H), 3.01-2.97 (m, 2H), 2.02-1.97 (m, 4H), 0.91 (s, 18H), 0.11 (s , 12H).
화합물 46의 제조Preparation of Compound 46
화합물 45 (3.1 g, 2.6 mmol)를 톨루엔 (45 mL)에 녹인 후 아르곤 대기 하에서 메틸보로닉 에시드 (1.1 g, 18.2 mmol), 산화은(I) (4.8 g, 20.9 mmol), 포태슘 포스페이트 (6.6 g, 31.5 mmol), 트라이페닐아르신 (642 mg, 2.1 mmol)과 비스(트라이페닐포스핀)팔라듐(II) 다이클로라이드 (184 mg, 0.3 mmol)를 첨가 하고 80 ℃에서 3 시간 동안 가열 교반하였다. 반응 용액을 셀라이트로 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 46 (955 mg, 40%)을 수득하였다. Compound 45 (3.1 g, 2.6 mmol) was dissolved in toluene (45 mL) and then methylboronic acid (1.1 g, 18.2 mmol), silver oxide (I) (4.8 g, 20.9 mmol), potassium phosphate ( 6.6 g, 31.5 mmol), triphenylarcin (642 mg, 2.1 mmol) and bis (triphenylphosphine) palladium (II) dichloride (184 mg, 0.3 mmol) were added and stirred by heating at 80 ° C. for 3 hours. It was. The reaction solution was filtered through celite, concentrated and purified by column chromatography to give a compound 46 (955 mg, 40%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 7.68 (s, 2H), 6.77 (s, 2H), 5.52 (s, 2H), 4.66-4.64 (m, 2H), 4.14-4.07 (m, 6H), 3.94-3.92 (m, 8H), 2.75-2.73 (m, 2H), 2.55-2.51 (m, 2H), 1.99-1.93 (m, 4H), 1.72-1.68 (m, 2H), 1.60 (s, 6H), 0.88 (s, 18H), 0.09 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 7.68 (s, 2H), 6.77 (s, 2H), 5.52 (s, 2H), 4.66-4.64 (m, 2H), 4.14-4.07 (m , 6H), 3.94-3.92 (m, 8H), 2.75-2.73 (m, 2H), 2.55-2.51 (m, 2H), 1.99-1.93 (m, 4H), 1.72-1.68 (m, 2H), 1.60 (s, 6H), 0.88 (s, 18H), 0.09 (s, 12H).
화합물 47의 제조Preparation of Compound 47
화합물 46 (2.9 g, 3.17 mmol)을 에탄올 (44 mL)에 녹인 후 아연 가루 (Zinc dust, 12.9 g, 197 mmol)와 포름산 (5 % 에탄올 용액, 128 mL)을 첨가하였다. 상온에서 반응 용액을 15 분간 교반한 후, 셀라이트로 여과하고 에틸 아세테이트 (500 mL) 를 첨가하였다. 유기층을 증류수 (200 mL), 포화 탄산수소나트륨 수용액 (200 mL) 그리고 소금물 (200 mL)순으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 47 (3.0 g, 82%)을 수득하였다. Compound 46 (2.9 g, 3.17 mmol) was dissolved in ethanol (44 mL), and zinc powder (Zinc dust, 12.9 g, 197 mmol) and formic acid (5% ethanol solution, 128 mL) were added. The reaction solution was stirred at room temperature for 15 minutes, then filtered through celite and ethyl acetate (500 mL) was added. The organic layer was washed with distilled water (200 mL), saturated aqueous sodium hydrogen carbonate solution (200 mL), and brine (200 mL) and then dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 47 (3.0 g, 82%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 6.74 (s, 2H), 6.23 (s, 2H), 6.18 (bs, 2H), 4.64 (bs, 2H), 4.34 (s, 3H), 4.07-3.93 (m, 6H), 3.80-3.76 (m, 7H), 2.74-2.68 (m, 2H), 2.53 (d, 2H), 1.91 (m, 4H), 1.67-1.62 (m, 8H), 0.88 (s, 18H), 0.05 (d, 12H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 6.74 (s, 2H), 6.23 (s, 2H), 6.18 (bs, 2H), 4.64 (bs, 2H), 4.34 (s, 3H), 4.07-3.93 (m, 6H), 3.80-3.76 (m, 7H), 2.74-2.68 (m, 2H), 2.53 (d, 2H), 1.91 (m, 4H), 1.67-1.62 (m, 8H), 0.88 (s, 18 H), 0.05 (d, 12 H).
화합물 48의 제조Preparation of Compound 48
화합물 47 (3.0 g, 3.51 mmol)을 다이클로로메테인 (175 mL)에 녹인 후 피리딘 (0.57 mL, 7.03 mmol)과 알릴 클로로포메이트 (0.34 mL, 3.16 mmol)를 -78 ℃,질소 대기 하에서 첨가하였다. 반응 용액을 1 시간 동안 교반한 후 반응 온도를 상온으로 올리고, 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 48 (1.33 g, 44%)을 수득하였다. Compound 47 (3.0 g, 3.51 mmol) was dissolved in dichloromethane (175 mL), and then pyridine (0.57 mL, 7.03 mmol) and allyl chloroformate (0.34 mL, 3.16 mmol) were added under -78 ° C under a nitrogen atmosphere. It was. After stirring the reaction solution for 1 hour, the reaction temperature was raised to room temperature, concentrated and purified by column chromatography to give a compound 48 (1.33 g, 44%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 8.80 (br s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.23 (s, 1H), 6.19 (br s, 2H), 5.99-5.90 (m, 1H), 5.34 (d, 1H), 5.23 (d, 1H), 4.63 (m, 4H), 4.35 (br s, 2H), 4.10 (t, 2H), 3.99 (t, 3H), 3.99 (m, 2H), 3.80 (s, 5H), 3.76 (s, 4H), 2.73 (m, 2H), 2.55 (m, 2H), 1.95-1.90 (m, 4H), 1.68-1.63 (m, 8H), 0.88 (s, 18H), 0.05 (d, 12H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 8.80 (br s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.23 (s, 1H) , 6.19 (br s, 2H), 5.99-5.90 (m, 1H), 5.34 (d, 1H), 5.23 (d, 1H), 4.63 (m, 4H), 4.35 (br s, 2H), 4.10 (t , 2H), 3.99 (t, 3H), 3.99 (m, 2H), 3.80 (s, 5H), 3.76 (s, 4H), 2.73 (m, 2H), 2.55 (m, 2H), 1.95-1.90 ( m, 4H), 1.68-1.63 (m, 8H), 0.88 (s, 18H), 0.05 (d, 12H).
<실시예 16> 화합물 49의 제조Example 16 Preparation of Compound 49
Figure PCTKR2018003744-appb-I000067
Figure PCTKR2018003744-appb-I000067
화합물 19 (3.7 g, 7.56 mmol)와 프로파질 아민 (0.43 mL, 7.07 mmol)을 N,N-다이메틸폼아마이드 (50 mL)에 녹인 후 N-(3-다이메틸아미노프로필)-N'-에틸카보다이이마이드 염산염 (2.32 g, 12.1 mmol)과 1-하이드록시벤조트리아졸 (2.04 g 15.1 mmol)을 첨가하였다. 반응 용액을 12 시간 동안 상온 교반한 후 증류수 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출하였다. 모인 유기층을 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 49 (3.4 g, 86%)를 수득하였다. Compound 19 (3.7 g, 7.56 mmol) and propargyl amine (0.43 mL, 7.07 mmol) of N, N - dimethyl was dissolved in dimethylformamide (50 mL) N - (3- dimethylaminopropyl) - N '- ethyl carbonyl Diimide hydrochloride (2.32 g, 12.1 mmol) and 1-hydroxybenzotriazole (2.04 g 15.1 mmol) were added. After stirring the reaction solution for 12 hours at room temperature, distilled water (100 mL) was added to the reaction solution and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 49 (3.4 g, 86%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.57 (t, 1H), 7.49 (dd, 1H), 7.02 (d, 1H), 5.42-5.38 (m, 1H), 5.36-5.28 (m, 2H), 4.67 (d, 2H), 4.31-4.13 (m, 3H), 2.23 (t, 1H), 2.07-2.06 (m, 9H), 1.88 (t, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.01 (d, 1H), 7.57 (t, 1H), 7.49 (dd, 1H), 7.02 (d, 1H), 5.42-5.38 (m, 1H), 5.36 -5.28 (m, 2H), 4.67 (d, 2H), 4.31-4.13 (m, 3H), 2.23 (t, 1H), 2.07-2.06 (m, 9H), 1.88 (t, 1H).
<실시예 17> 화합물 53의 제조Example 17 Preparation of Compound 53
Figure PCTKR2018003744-appb-I000068
Figure PCTKR2018003744-appb-I000068
화합물 51의 제조Preparation of Compound 51
화합물 50 (4.5 g, 25.68 mmol)을 N,N-다이메틸폼아마이드 (50 mL)에 녹인 후 0 ℃, 질소 대기 하에서 소듐 하이드라이드 (1.23 g, 30.82 mmol)을 첨가하고 30분간 교반한 후 프로파질 브로마이드 (~80 % 톨루엔 용액, 4.96 mL, 33.4 mmol)를 가한 후 상온에서 3 시간 동안 교반하였다. 증류수 (40 mL)를 반응 용액에 첨가한 후 에틸 아세테이트 (2 x 50 mL)로 추출하였다. 모인 유기층을 소금물 (100 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 51 (4.35 g, 79%)을 수득하였다. Compound 50 (4.5 g, 25.68 mmol) was dissolved in N , N -dimethylformamide (50 mL), and sodium hydride (1.23 g, 30.82 mmol) was added under a nitrogen atmosphere at 0 ° C. and stirred for 30 minutes, followed by propazyl bromide (~ 80% toluene solution, 4.96 mL, 33.4 mmol) was added thereto, followed by stirring at room temperature for 3 hours. Distilled water (40 mL) was added to the reaction solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 51 (4.35 g, 79%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 4.21 (d, J = 2.4 Hz, 2H), 3.70-3.38 (m, 10 H), 3.39 (t, J = 5.2 Hz, 2H), 2.43 (t, J = 2.4 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 4.21 (d, J = 2.4 Hz, 2H), 3.70-3.38 (m, 10 H), 3.39 (t, J = 5.2 Hz, 2H), 2.43 (t, J = 2.4 Hz, 1H).
화합물 52의 제조Preparation of Compound 52
화합물 51 (1.55 g, 7.03 mmol)을 건조한 테트라하이드로퓨란 (30 mL)/증류수 (2.53 mL)에 녹인 다음 트라이페닐포스핀 (2.21 g, 8.44 mmol)을 넣고 상온에서 24 시간 동안 교반하였다. 농축하고 컬럼 크로마토그래피로 정제하여 화합물 52 (1.3 g, 99%)를 수득하였다. Compound 51 (1.55 g, 7.03 mmol) was dissolved in dry tetrahydrofuran (30 mL) / distilled water (2.53 mL), triphenylphosphine (2.21 g, 8.44 mmol) was added thereto, and the resultant was stirred at room temperature for 24 hours. Concentrate and purify by column chromatography Compound 52 (1.3 g, 99%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 4.21 (s, 2H), 3.69-3.64 (m, 8H), 3.52-3.49 (m, 2H), 2.88-2.85 (m, 2H), 4.23 (s, 1H). EI-MS m/z : [M+H]+ 188.2. 1 H-NMR (400 MHz, CDCl 3 ) δ 4.21 (s, 2H), 3.69-3.64 (m, 8H), 3.52-3.49 (m, 2H), 2.88-2.85 (m, 2H), 4.23 (s, 1H). EI-MS m / z: [M + H] + 188.2.
화합물 53의 제조Preparation of Compound 53
화합물 52 (2.0 g, 10.68 mmol)와 화합물 19 (4.7 g, 9.71 mmol)를 N,N-다이메틸폼아마이드 (50 mL)에 녹인 후 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (3.71 g, 11.6 mmol)와 N,N-다이아이소프로필에틸아민 (3.38 mL, 19.4 mmol)을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 24 시간 동안 상온 교반한 후 증류수 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출하였다. 모인 유기층을 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 53 (4.78 g, 75%)을 수득하였다. Compound 52 (2.0 g, 10.68 mmol) and compound 19 (4.7 g, 9.71 mmol) were dissolved in N , N -dimethylformamide (50 mL), and then N, N, N ', N' -tetramethyl- O- ( 1H -Benzotriazol-1-yl) uronium hexafluorophosphate (3.71 g, 11.6 mmol) and N , N -diisopropylethylamine (3.38 mL, 19.4 mmol) were added under 0 ° C. under a nitrogen atmosphere. It was. After stirring the reaction solution for 24 hours at room temperature, distilled water (100 mL) was added to the reaction solution and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 53 (4.78 g, 75%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.41-7.37 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H), 5.41-5.25 (m, 4H), 4.65 (d, J = 4.4 Hz, 2H), 4.21 (d, J = 9.2 Hz, 1H), 4.17 (s, 2H), 3.74 (s, 3H), 3.68 (s, 11H), 3.56-3.50 (m, 1H), 2.05 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.95 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.41-7.37 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H ), 5.41-5.25 (m, 4H), 4.65 (d, J = 4.4 Hz, 2H), 4.21 (d, J = 9.2 Hz, 1H), 4.17 (s, 2H), 3.74 (s, 3H), 3.68 (s, 11 H), 3.56-3.50 (m, 1 H), 2.05 (s, 9 H).
<실시예 18> 화합물 55의 제조Example 18 Preparation of Compound 55
Figure PCTKR2018003744-appb-I000069
Figure PCTKR2018003744-appb-I000069
화합물 55의 제조Preparation of Compound 55
화합물 19 (3.68 g, 7.60 mmol)와 화합물 54 (1.46 g, 8.40 mmol, 화합물 54는 PCT/US2016/063564에 기술된 방법으로 제조하였다)를 N,N-다이메틸폼아마이드 (10 mL)에 녹인 후 0 ℃, 질소 대기 하에서 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (4.53 g, 11.40 mmol)와 N,N-다이아이소프로필에틸아민 (3.97 mL, 22.80 mmol)을 첨가한 후 상온에서 12 시간 교반하였다. 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 55 (3.31 g, 68%)를 수득하였다. Compound 19 (3.68 g, 7.60 mmol) and Compound 54 (1.46 g, 8.40 mmol, Compound 54 prepared by the method described in PCT / US2016 / 063564) were dissolved in N , N -dimethylformamide (10 mL). N0, N, N ', N' -tetramethyl- O- ( 1H -benzotriazol-1-yl) uronium hexafluorophosphate (4.53 g, 11.40 mmol) and N , N -diisopropylethylamine (3.97 mL, 22.80 mmol) were added, followed by stirring at room temperature for 12 hours. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 55 (3.31 g, 68%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 5.42-5.25 (m, 4H), 4.68 (d, J = 5.6 Hz, 2H), 4.20 (d, J = 9.2 Hz, 1H), 3.78-3.68 (m, 11H), 3.58-3.52 (m, 1H), 3.39-3.36 (m, 2H), 2.06 (s, 9H), 1.89-1.86 (m, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 5.42-5.25 (m, 4H), 4.68 (d , J = 5.6 Hz, 2H), 4.20 (d, J = 9.2 Hz, 1H), 3.78-3.68 (m, 11H), 3.58-3.52 (m, 1H), 3.39-3.36 (m, 2H), 2.06 ( s, 9H), 1.89-1.86 (m, 1H).
<실시예 19> 화합물 58의 제조Example 19 Preparation of Compound 58
Figure PCTKR2018003744-appb-I000070
Figure PCTKR2018003744-appb-I000070
화합물 56의 제조Preparation of Compound 56
화합물 48 (1.33 g, 1.41 mmol)을 톨루엔 (40 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (151 mg, 0.51 mmol)과 트라이에틸아민 (0.26 mL, 1.91 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 20 (845 mg, 1.56 mmol)을 건조한 테트라하이드로퓨란 (40 mL)에 녹이고 트라이에틸아민 (0.26 mL, 1.91 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (30 mL)로 희석한 후 소금물 (20 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 56 (1.15 mg, 54%)을 수득하였다. Compound 48 (1.33 g, 1.41 mmol) was dissolved in toluene (40 mL), and then triphosphogen (151 mg, 0.51 mmol) and triethylamine (0.26 mL, 1.91 mmol) were added at -10 ° C., and the mixture was kept for 1 hour under a nitrogen atmosphere. Was stirred. Compound 20 (845 mg, 1.56 mmol) was dissolved in dry tetrahydrofuran (40 mL), triethylamine (0.26 mL, 1.91 mmol) was added and the solution was slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 56 (1.15 mg, 54%) was obtained.
EI-MS m/z : [M+H]+ 1504.7, 1/2[M+H]+ 753.5.EI-MS m / z: [M + H] + 1504.7, 1/2 [M + H] + 753.5.
화합물 57의 제조Preparation of Compound 57
화합물 56 (1.15 g, 0.79 mmol)을 다이클로로메테인 (10 mL)에 녹인 후 피롤리딘 (0.08 mL, 1.35 mmol)과 테트라키스(트라이페닐포스핀)팔라듐(0) (45 mg, 0.057 mmol)을 첨가하고 상온, 질소 대기 하에서 2 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 57 (820 mg, 72%)을 수득하였다. Compound 56 (1.15 g, 0.79 mmol) was dissolved in dichloromethane (10 mL), followed by pyrrolidine (0.08 mL, 1.35 mmol) and tetrakis (triphenylphosphine) palladium (0) (45 mg, 0.057 mmol ) Was added and stirred for 2 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 57 (820 mg, 72%).
EI-MS m/z : [M+H]+ 1420.6, 1/2[M+H]+ 711.2.EI-MS m / z: [M + H] + 1420.6, 1/2 [M + H] + 711.2.
화합물 58의 제조Preparation of Compound 58
화합물 57 (730 mg, 0.51 mmol)을 톨루엔 (20 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (54 mg, 0.36 mmol)과 피리딘 (0.2 mL, 2.56 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 49 (321 mg, 0.61 mmol)를 건조한 테트라하이드로퓨란 (20 mL)에 녹이고 N,N-다이아이소프로필에틸아민 (0.14 mL, 0.77 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (50 mL)으로 희석한 후 소금물 (30 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 58 (650 mg, 64%)을 수득하였다. Compound 57 (730 mg, 0.51 mmol) was dissolved in toluene (20 mL), and then triphosphogen (54 mg, 0.36 mmol) and pyridine (0.2 mL, 2.56 mmol) were added at -10 ° C and stirred for 1 hour under a nitrogen atmosphere. It was. Compound 49 (321 mg, 0.61 mmol) was dissolved in dry tetrahydrofuran (20 mL) and N , N -diisopropylethylamine (0.14 mL, 0.77 mmol) was added and the solution was slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 58 (650 mg, 64%) was obtained.
EI-MS m/z : [M+H]+ 1969.2, 1/2[M+H]+ 985.2.EI-MS m / z: [M + H] + 1969.2, 1/2 [M + H] + 985.2.
<실시예 20> 화합물 61의 제조Example 20 Preparation of Compound 61
Figure PCTKR2018003744-appb-I000071
Figure PCTKR2018003744-appb-I000071
화합물 59의 제조Preparation of Compound 59
화합물 58 (650 mg, 0.33 mmol)을 테트라하이드로퓨란/증류수 (3.5 mL/3.5 mL)에 녹이고 아세트산 (7 mL)을 첨가한 후 상온, 질소 대기 하에서 16 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 59 (440 mg, 78%)를 수득하였다. Compound 58 (650 mg, 0.33 mmol) was dissolved in tetrahydrofuran / distilled water (3.5 mL / 3.5 mL) and acetic acid (7 mL) was added, followed by stirring for 16 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 59 (440 mg, 78%).
EI-MS m/z : [M+H]+ 1740.0, [M+Na]+ 1762.0, 1/2[M+H]+ 871.0.EI-MS m / z: [M + H] + 1740.0, [M + Na] + 1762.0, 1/2 [M + H] + 871.0.
화합물 60의 제조Preparation of Compound 60
화합물 59 (440 mg, 0.25 mmol)를 다이클로로메테인 (25 mL)에 녹인 후 데스-마틴 펄아이오디네인 (Dess-Martin periodinane, 236 mg, 0.55 mmol)을 첨가하고 상온, 질소 대기 하에서 2.5 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 60 (365 mg, 84%)을 수득하였다. Compound 59 (440 mg, 0.25 mmol) was dissolved in dichloromethane (25 mL), and then Dess-Martin periodinane (236 mg, 0.55 mmol) was added thereto, and the mixture was cooled to 2.5 at room temperature and nitrogen atmosphere. Stir for hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give a compound 60 (365 mg, 84%) was obtained.
EI-MS m/z : [M+H]+ 1736.0, 1/2[M+H]+ 869.5.EI-MS m / z: [M + H] + 1736.0, 1/2 [M + H] + 869.5.
화합물 61의 제조Preparation of Compound 61
화합물 60 (365 mg, 0.21 mmol)을 메탄올/테트라하이드로퓨란 (9 mL/2 mL)에 녹인 후 수산화 리튬 (58 mg, 1.4 mmol)을 증류수 (9 mL)에 녹인 용액을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 0 ℃로 올리면서 2 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 61 (100 mg, 32%)을 흰색의 고체로 수득하였다. Compound 60 (365 mg, 0.21 mmol) was dissolved in methanol / tetrahydrofuran (9 mL / 2 mL), and then a solution of lithium hydroxide (58 mg, 1.4 mmol) in distilled water (9 mL) was added slowly at -40 ° C. It was. Stirred for 2 hours while slowly raising the reaction temperature to 0 ℃. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure, purified by HPLC and freeze-dried to give a compound 61 (100 mg, 32%) was obtained as a white solid.
EI-MS m/z : [M+H]+ 1456.8, 1/2[M+H]+ 729.5.EI-MS m / z: [M + H] + 1456.8, 1/2 [M + H] + 729.5.
<실시예 21> 화합물 62의 제조Example 21 Preparation of Compound 62
Figure PCTKR2018003744-appb-I000072
Figure PCTKR2018003744-appb-I000072
화합물 62는 화합물 53과 화합물 57로부터 화합물 61의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1588.7, 1/2[M+H]+ 795.3.Compound 62 was prepared by a method analogous to the synthesis of compound 61 from compound 53 and compound 57. EI-MS m / z: [M + H] + 1588.7, 1/2 [M + H] + 795.3.
<실시예 22> 화합물 63의 제조Example 22 Preparation of Compound 63
Figure PCTKR2018003744-appb-I000073
Figure PCTKR2018003744-appb-I000073
화합물 63은 화합물 55와 화합물 57로부터 화합물 61의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1575.8, 1/2[M+H]+ 788.7.Compound 63 was prepared by a method analogous to the synthesis of compound 61 from compound 55 and compound 57. EI-MS m / z: [M + H] + 1575.8, 1/2 [M + H] + 788.7.
<실시예 23> 화합물 65의 제조Example 23 Preparation of Compound 65
Figure PCTKR2018003744-appb-I000074
Figure PCTKR2018003744-appb-I000074
화합물 65의 제조Preparation of Compound 65
화합물 61 (100 mg, 0.068 mmol)을 다이메틸 설폭사이드 (1.6 mL)에 녹인 후 질소 대기 하에서 화합물 64 (136 mg, 0.302 mmol, 화합물 64는 PCT/US2016/063564에 기술된 방법으로 제조하였다)을 넣은 후 증류수 (0.4 ml)에 카퍼(II) 설페이트 펜타하이드레이트 (7.4 mg, 0.03 mml)와 소듐 아스코르베이트 (28 mg, 0.15 mmol)를 녹여 반응용액에 첨가하였다. 30 분간 상온에서 교반하고 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 65 (15.2 mg, 13%)를 흰색의 고체로 수득하였다. Compound 61 (100 mg, 0.068 mmol) was dissolved in dimethyl sulfoxide (1.6 mL) and then under compound nitrogen (136 mg, 0.302 mmol, compound 64 was prepared by the method described in PCT / US2016 / 063564) under a nitrogen atmosphere. Copper (II) sulfate pentahydrate (7.4 mg, 0.03 mml) and sodium ascorbate (28 mg, 0.15 mmol) were dissolved in distilled water (0.4 ml) and added to the reaction solution. After stirring for 30 minutes at room temperature, the reaction solution was concentrated under reduced pressure, purified by HPLC and freeze-dried to give 65 (15.2 mg, 13%) was obtained as a white solid.
EI-MS m/z : [M+H]+ 1645.8, 1/2[M+H]+ 823.9.EI-MS m / z: [M + H] + 1645.8, 1/2 [M + H] + 823.9.
<실시예 24> 화합물 70의 제조Example 24 Preparation of Compound 70
Figure PCTKR2018003744-appb-I000075
Figure PCTKR2018003744-appb-I000075
화합물 66의 제조Preparation of Compound 66
3-아미노-1-프로판올 (3.0 g, 66.57 mmol)을 다이클로로메테인 (150 mL)에 녹인 후 0 ℃, 질소 대기 하에서 다이-t-부틸 다이카보네이트 (16 g, 73.2 mmol)를 첨가하였다. 상온에서 12 시간 동안 교반한 후 반응 용액을 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 66 (6.4g, 92%)을 수득하였다. 3-amino-1-propanol (3.0 g, 66.57 mmol) was dissolved in dichloromethane (150 mL) and then di- t -butyl dicarbonate (16 g, 73.2 mmol) was added at 0 ° C. under nitrogen atmosphere. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain Compound 66 (6.4 g, 92%).
1H-NMR (400 MHz, CDCl3) δ 4.78 (s, 1H), 3.65 (m, 2H), 3.30 (m, 2H), 2.90 (s, 1H), 1.68 (m, 2H), 1.48 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 4.78 (s, 1H), 3.65 (m, 2H), 3.30 (m, 2H), 2.90 (s, 1H), 1.68 (m, 2H), 1.48 (s , 9H).
화합물 67의 제조Preparation of Compound 67
화합물 66 (6.04 g, 34.47 mmol)과 트라이에틸아민 (14.4 mL, 103.4 mmol)을 테트라하이드로퓨란 (100 mL)에 녹인 후 0 ℃, 질소 대기 하에서 메탄설포닉 언하이드라이드 (7.21 g, 41.36 mmol)를 서서히 첨가하였다. 서서히 상온으로 올린 후 12 시간 동안 교반하였다. 반응 용액을 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 67 (9.01 g, 98%)을 수득하였다. Compound 66 (6.04 g, 34.47 mmol) and triethylamine (14.4 mL, 103.4 mmol) were dissolved in tetrahydrofuran (100 mL) and then methanesulphonic unhydride (7.21 g, 41.36 mmol) under nitrogen atmosphere at 0 ° C. Was added slowly. After slowly raising to room temperature, the mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 67 (9.01 g, 98%).
1H-NMR (400 MHz, CDCl3) δ 4.73 (s, 1H), 4.30 (t, J = 5.9 Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J = 6.1 Hz, 2H), 1.44 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 4.73 (s, 1H), 4.30 (t, J = 5.9 Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t , J = 6.1 Hz, 2H), 1.44 (s, 9H).
화합물 68의 제조Preparation of Compound 68
화합물 67 (3.0 g, 11.84 mol)을 N,N-다이메틸폼아마이드 (40 mL)에 녹인 후 상온, 질소 대기 하에서 소듐 아자이드 (924 mg, 14.21 mmol)를 첨가하고, 반응 혼합물을 60 ℃에서 12 시간 동안 교반하였다. 증류수 (50 mL)와 1 N 염산 수용액 (5 mL)을 반응 용액에 넣고 에틸 아세테이트 (100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 68 (2.3 g, 99%)을 수득하였다. Compound 67 (3.0 g, 11.84 mol) was dissolved in N , N -dimethylformamide (40 mL), and sodium azide (924 mg, 14.21 mmol) was added at room temperature and under nitrogen atmosphere, and the reaction mixture was stirred at 60 ° C. Stir for 12 hours. Distilled water (50 mL) and 1N aqueous hydrochloric acid solution (5 mL) were added to the reaction solution, extracted with ethyl acetate (100 mL), and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 68 (2.3 g, 99%) was obtained.
1H-NMR (600 MHz, CDCl3) δ 4.63 (s, 1H), 3.36 (t ,J = 6.6 Hz, 2H), 3.24-3.18 (m, 2H), 1.80-1.75 (m, 2H), 1.45 (s, 9H). 1 H-NMR (600 MHz, CDCl 3 ) δ 4.63 (s, 1H), 3.36 (t, J = 6.6 Hz, 2H), 3.24-3.18 (m, 2H), 1.80-1.75 (m, 2H), 1.45 (s, 9H).
화합물 69의 제조Preparation of Compound 69
화합물 68 (3.8 g, 18.98 mmol)을 다이클로로메테인 (10 mL)에 녹이고 0 ℃, 질소 대기 하에서 염산 (4 M 1,4-다이옥세인 용액, 10 mL)을 서서히 첨가하였다. 반응 혼합물을 12 시간 동안 교반한 후, 감압 농축시켜 화합물 69 (2.5 g, 99%)를 수득하였다. Compound 68 (3.8 g, 18.98 mmol) was dissolved in dichloromethane (10 mL) and hydrochloric acid (4M 1,4-dioxane solution, 10 mL) was added slowly at 0 ° C. under nitrogen atmosphere. The reaction mixture was stirred for 12 hours and then concentrated under reduced pressure to give compound 69 (2.5 g, 99%).
1H-NMR (600 MHz, DMSO-d6) δ 8.06 (s, 3H), 3.47 (t, J = 6.6 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 1.84-1.79 (m, 2H). 1 H-NMR (600 MHz, DMSO-d 6 ) δ 8.06 (s, 3H), 3.47 (t, J = 6.6 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 1.84-1.79 (m , 2H).
화합물 70의 제조Preparation of Compound 70
화합물 19 (4.1 g, 8.46 mmol)와 화합물 69 (1.1 g, 11.0 mmol)를 N,N-다이메틸폼아마이드 (20 mL)에 녹인 후 0 oC, 질소 대기 하에서 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (4.39 g, 11.0 mmol)과 N,N-다이아이소프로필에틸아민 (2.96 mL, 16.92 mmol)을 첨가한 후 상온에서 12 시간 교반하였다. 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 70 (5.48 g, 88%)을 수득하였다. Compound 19 (4.1 g, 8.46 mmol) and compound 69 (1.1 g, 11.0 mmol) were dissolved in N , N -dimethylformamide (20 mL), followed by 0 o C, N, N, N ', N under nitrogen atmosphere. '- tetramethyl - O - (1 H-benzo Tra-1-yl) uronium hexafluorophosphate (4.39 g, 11.0 mmol) and N , N -diisopropylethylamine (2.96 mL, 16.92 mmol) were added, followed by stirring at room temperature for 12 hours. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 70 (5.48 g, 88%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.50-7.46 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.45-5.30 (m, 4H), 4.69 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.67-3.60 (m, 1H), 3.47-3.41 (m, 3H), 2.80 (s, 2H), 2.07-2.05 (m, 9H), 1.98-1.91 (m, 2H), 1.80-1.77 (m, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.07 (s, 1H), 7.50-7.46 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.45-5.30 (m, 4H), 4.69 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.67-3.60 (m, 1H), 3.47-3.41 (m, 3H), 2.80 ( s, 2H), 2.07-2.05 (m, 9H), 1.98-1.91 (m, 2H), 1.80-1.77 (m, 1H).
<실시예 25> 화합물 72의 제조Example 25 Preparation of Compound 72
Figure PCTKR2018003744-appb-I000076
Figure PCTKR2018003744-appb-I000076
화합물 72의 제조Preparation of Compound 72
화합물 19 (3.6 g, 7.42 mmol)와 화합물 71 (1.0 g, 8.16 mmol, 화합물 71은 화합물 69와 유사한 방법으로 제조하였다)을 N,N-다이메틸폼아마이드 (15 mL)에 녹인 후 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (4.2 g, 11.2 mmol)와 N,N-다이아이소프로필에틸아민 (3.2 mL, 18.6 mmol)을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 14 시간 동안 상온 교반 후, 포화 암모늄 클로라이드 수용액 (50 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 50 mL)로 추출하였다. 모인 유기층을 소금물 (50 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 72 (3.9 g, 95%)를 수득하였다. Compound 19 (3.6 g, 7.42 mmol) and compound 71 (1.0 g, 8.16 mmol, Compound 71 was prepared in a similar manner to Compound 69) in N , N -dimethylformamide (15 mL) and then N, N, N ', N' -tetramethyl- O- ( 1H -Benzotriazol-1-yl) uronium hexafluorophosphate (4.2 g, 11.2 mmol) and N , N -diisopropylethylamine (3.2 mL, 18.6 mmol) were added under 0 ° C. under a nitrogen atmosphere. It was. After stirring the reaction solution for 14 hours at room temperature, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, purified by column chromatography Compound 72 (3.9 g, 95%) was obtained.
EI-MS m/z : [M+H]+ 553.3, [M+Na]+ 575.4.EI-MS m / z: [M + H] + 553.3, [M + Na] + 575.4.
<실시예 26> 화합물 73의 제조Example 26 Preparation of Compound 73
Figure PCTKR2018003744-appb-I000077
Figure PCTKR2018003744-appb-I000077
화합물 73은 화합물 24와 화합물 55로부터 화합물 63의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1575.7, 1/2[M+H]+ 788.8.Compound 73 was prepared by a method analogous to the synthesis of compound 63 from compound 24 and compound 55. EI-MS m / z: [M + H] + 1575.7, 1/2 [M + H] + 788.8.
<실시예 27> 화합물 74의 제조Example 27 Preparation of Compound 74
Figure PCTKR2018003744-appb-I000078
Figure PCTKR2018003744-appb-I000078
화합물 74는 화합물 24와 화합물 70으로부터 화합물 63의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1500.9, 1/2[M+H]+ 751.2.Compound 74 was prepared by a method analogous to the synthesis of compound 63 from compound 24 and compound 70. EI-MS m / z: [M + H] + 1500.9, 1/2 [M + H] + 751.2.
<실시예 28> 화합물 75의 제조Example 28 Preparation of Compound 75
Figure PCTKR2018003744-appb-I000079
Figure PCTKR2018003744-appb-I000079
화합물 75는 화합물 24와 화합물 72로부터 화합물 63의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1486.42, [M+Na]+ 1509.31.Compound 75 was prepared by a method analogous to the synthesis of compound 63 from compound 24 and compound 72. EI-MS m / z: [M + H] + 1486.42, [M + Na] + 1509.31.
<실시예 29> 화합물 80의 제조Example 29 Preparation of Compound 80
Figure PCTKR2018003744-appb-I000080
Figure PCTKR2018003744-appb-I000080
화합물 77의 제조Preparation of Compound 77
화합물 76 (7.30 g, 28.5 mmol, 화합물 76은 Angew. Chem. Int. Ed., 2016, 55, 12338-12342에 기술된 방법으로 제조하였다)과 화합물 16 (14.0 g, 29.4 mmol)을 아세토나이트릴 (145 mL)에 녹인 후 4 Å 분자체 (14.6 g)와 산화은(I) (27.0 g, 116.4 mmol)을 첨가하고 질소 대기, 상온 하에서 12 시간 동안 교반하였다. 반응 용액을 셀라이트로 여과하고 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 77 (15.3 g, 92%)을 수득하였다. Compound 76 (7.30 g, 28.5 mmol, Compound 76 was Angew . Chem . Int . Prepared by the method described in Ed ., 2016 , 55, 12338-12342) and Compound 16 (14.0 g, 29.4 mmol) in acetonitrile (145 mL), followed by 4 Å molecular sieve (14.6 g) and silver oxide ( I) (27.0 g, 116.4 mmol) was added and stirred under nitrogen atmosphere, room temperature for 12 hours. The reaction solution was filtered through celite, concentrated and purified by column chromatography to give a compound 77 (15.3 g, 92%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.27 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.46-7.29 (m, 6H), 5.64-5.59 (m, 1H), 5.49-5.48 (m, 1H), 5.36 (s, 2H), 5.18 (d, J = 8.0 Hz, 1H), 5.19-5.11 (m, 1H), 4.27-4.10 (m, 3H), 2.19 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.94 (s, 1H), 8.27 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.46-7.29 (m, 6H), 5.64-5.59 (m, 1H), 5.49-5.48 (m, 1H), 5.36 (s, 2H), 5.18 (d, J = 8.0 Hz, 1H), 5.19-5.11 (m, 1H), 4.27-4.10 (m, 3H ), 2.19 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H).
화합물 78의 제조Preparation of Compound 78
화합물 77 (15.30 g, 26.10 mmol)을 클로로폼/아이소프로판올 (200 mL/40 mL)에 녹인 후 0 oC, 질소 대기 하에서 실리카겔 (16 g)과 소듐 보로하이드라이드 (1.53 g, 40.50 mmol)를 가한 후 30 분 동안 교반하였다. 증류수 (200 mL)를 반응 용액에 첨가한 후 에틸 아세테이트 (400 mL)로 추출하였다. 추출된 유기층을 무수 황산 마그네슘으로 건조하고 여과 및 감압 농축하여 화합물 78 (14.0 g, 91%)을 수득하였다. Compound 77 (15.30 g, 26.10 mmol) was dissolved in chloroform / isopropanol (200 mL / 40 mL), followed by addition of silica gel (16 g) and sodium borohydride (1.53 g, 40.50 mmol) under a nitrogen atmosphere at 0 ° C. Stir for 30 minutes. Distilled water (200 mL) was added to the reaction solution and extracted with ethyl acetate (400 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Compound 78 (14.0 g, 91%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.47-7.31 (m, 6H), 7.19 (d, J = 8.4 Hz, 1H), 5.57 (t, J = 9.2 Hz, 1H), 5.46 (d, J = 3.2 Hz, 1H), 5.36-5.28 (m, 2H), 5.12-5.04 (m, 2H), 4.66 (d, J = 6.0 Hz, 2H), 4.26-4.04 (m, 3H), 2.18 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.67 (t, J = 5.6 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.73 (s, 1H), 7.47-7.31 (m, 6H), 7.19 (d, J = 8.4 Hz, 1H), 5.57 (t, J = 9.2 Hz, 1H ), 5.46 (d, J = 3.2 Hz, 1H), 5.36-5.28 (m, 2H), 5.12-5.04 (m, 2H), 4.66 (d, J = 6.0 Hz, 2H), 4.26-4.04 (m, 3H), 2.18 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.67 (t, J = 5.6 Hz, 1H).
화합물 79의 제조Preparation of Compound 79
화합물 78 (14.0 g, 23.8 mmol)를 에탄올 (550 mL)에 녹인 후 레이니 니켈 (Raney Ni, 14.0 g)을 첨가하였다. 반응 용액을 상온, 수소 대기 하에서 12 시간 동안 교반하였다. 반응 용액을 셀라이트로 여과하고 농축하여 화합물 79 (11.4 g, 96%)를 수득하였다. Compound 78 (14.0 g, 23.8 mmol) was dissolved in ethanol (550 mL) and Raney Ni (14.0 g) was added. The reaction solution was stirred at room temperature under hydrogen atmosphere for 12 hours. The reaction solution was filtered through celite and concentrated to compound 79 (11.4 g, 96%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H) 7.58 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz 1H), 5.57 (t, J = 9.2 Hz, 1H), 5.49 (d, J = 3.2 Hz, 1H), 5.22 (d, J = 8.0 Hz, 1H), 5.17-5.14 (m, 1H), 4.71 (s, 2H), 4.25-4.10 (m, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.07 (s, 1H) 7.58 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz 1H), 5.57 (t, J = 9.2 Hz, 1H), 5.49 (d, J = 3.2 Hz, 1H), 5.22 (d, J = 8.0 Hz, 1H), 5.17-5.14 (m, 1H), 4.71 (s, 2H), 4.25-4.10 (m, 3H ), 2.20 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H).
화합물 80의 제조Preparation of Compound 80
화합물 79 (3.00 g, 6.00 mmol)와 2-메톡시에틸아민 (0.57 mL, 6.6 mmol)을 N,N-다이메틸폼아마이드 (15 mL)에 녹인 후 0 ℃, 질소 대기 하에서 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (2.86 g, 7.20 mmol)와 N,N-다이아이소프로필에틸아민 (2.10 mL, 12.0 mmol)을 첨가한 후 상온에서 12 시간 교반하였다. 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 80 (2.3 g, 68%)을 수득하였다. Compound 79 (3.00 g, 6.00 mmol) and 2-methoxyethylamine (0.57 mL, 6.6 mmol) were dissolved in N , N -dimethylformamide (15 mL), and then 0, N, N and N under nitrogen atmosphere. ', N' -tetramethyl- O- ( 1H -benzotriazol-1-yl) uronium hexafluorophosphate (2.86 g, 7.20 mmol) and N , N -diisopropylethylamine (2.10 mL, 12.0 mmol) were added, followed by stirring at room temperature for 12 hours. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 80 (2.3 g, 68%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.48-7.44 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 5.55 (t, J = 9.2 Hz, 1H), 5.49 (d, J = 2.8 Hz, 1H), 5.20-5.14 (m, 2H), 4.69 (d, J = 5.2 Hz, 2H), 4.25-4.09 (m, 3H), 3.78-3.74 (m, 1H), 3.62-3.51 (m, 3H), 3.40 (s, 3H), 2.21 (s, 3H), 2.07 (m, 6H), 2.02 (s, 3H), 1.71 (t, J = 6.0 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.07 (s, 1H), 7.48-7.44 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 5.55 (t, J = 9.2 Hz, 1H ), 5.49 (d, J = 2.8 Hz, 1H), 5.20-5.14 (m, 2H), 4.69 (d, J = 5.2 Hz, 2H), 4.25-4.09 (m, 3H), 3.78-3.74 (m, 1H), 3.62-3.51 (m, 3H), 3.40 (s, 3H), 2.21 (s, 3H), 2.07 (m, 6H), 2.02 (s, 3H), 1.71 (t, J = 6.0 Hz, 1H ).
<< 실시예Example 30> 화합물 81의 제조 30> Preparation of Compound 81
Figure PCTKR2018003744-appb-I000081
Figure PCTKR2018003744-appb-I000081
화합물 81의 제조Preparation of Compound 81
화합물 79 (2.19 g, 4.38 mmol)와 화합물 31 (1.50 g, 5.70 mmol)을 N,N-다이메틸폼아마이드 (10 mL)에 녹인 후 0 ℃, 질소 대기 하에서 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (2.26 g, 5.7 mmol)와 N,N-다이아이소프로필에틸아민 (1.53 mL, 8.76 mmol)을 첨가한 후 상온에서 12 시간 교반하였다. 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 81 (2.73 g, 84%)을 수득하였다. Compound 79 (2.19 g, 4.38 mmol) and compound 31 (1.50 g, 5.70 mmol) were dissolved in N , N -dimethylformamide (10 mL), and then N, N, N ', N' was added at 0 ° C under a nitrogen atmosphere . Tetramethyl- O- ( 1H -benzotriazol-1-yl) uronium hexafluorophosphate (2.26 g, 5.7 mmol) and N , N -diisopropylethylamine (1.53 mL, 8.76 mmol) were added, followed by stirring at room temperature for 12 hours. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 81 (2.73 g, 84%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.68 (s, 1H), 7.46-7.44 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 5.56-5.49 (m, 2H), 5.18-5.14 (m, 2H), 4.68 (d, J = 4.8 Hz, 2H), 4.27-4.10 (m, 3H), 3.97-3.95 (m, 2H), 3.83-3.78 (m, 1H), 3.71-3.67 (m, 7H), 3.57-3.52 (m, 1H), 2.22 (s, 3H), 2.07 (m, 6H), 2.03 (s, 3H), 1.47 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.07 (s, 1H), 7.68 (s, 1H), 7.46-7.44 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 5.56-5.49 (m, 2H), 5.18-5.14 (m, 2H), 4.68 (d, J = 4.8 Hz, 2H), 4.27-4.10 (m, 3H), 3.97-3.95 (m, 2H), 3.83-3.78 (m , 1H), 3.71-3.67 (m, 7H), 3.57-3.52 (m, 1H), 2.22 (s, 3H), 2.07 (m, 6H), 2.03 (s, 3H), 1.47 (s, 9H).
<실시예 31> 화합물 82의 제조Example 31 Preparation of Compound 82
Figure PCTKR2018003744-appb-I000082
Figure PCTKR2018003744-appb-I000082
화합물 82는 화합물 9, 화합물 80 그리고 화합물 81로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1537.7, 1/2[M+H]+ 769.7.Compound 82 was prepared by a similar method to the synthesis of compound 28 from compound 9, compound 80 and compound 81. EI-MS m / z: [M + H] + 1537.7, 1/2 [M + H] + 769.7.
<실시예 32> 화합물 83의 제조Example 32 Preparation of Compound 83
Figure PCTKR2018003744-appb-I000083
Figure PCTKR2018003744-appb-I000083
화합물 83은 화합물 9, 화합물 80, 그리고 화합물 32로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1551.6, 1/2[M+H]+ 776.7.Compound 83 was prepared in a similar manner to the synthesis of compound 28 from compound 9, compound 80, and compound 32. EI-MS m / z: [M + H] + 1551.6, 1/2 [M + H] + 776.7.
<실시예 33> 화합물 85의 제조Example 33 Preparation of Compound 85
Figure PCTKR2018003744-appb-I000084
Figure PCTKR2018003744-appb-I000084
화합물 85는 화합물 9, 화합물 84 (화합물 84는 WO2011/130598 A1에 기술된 방법으로 제조하였다), 그리고 화합물 32로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1587.8, 1/2[M+H]+ 794.7.Compound 85 was prepared by a method analogous to the synthesis of compound 28 from compound 9, compound 84 (compound 84 was prepared by the method described in WO2011 / 130598 A1), and compound 32. EI-MS m / z: [M + H] + 1587.8, 1/2 [M + H] + 794.7.
<비교예 1> 화합물 86, 화합물 87, 그리고 화합물 88의 제조Comparative Example 1 Preparation of Compound 86, Compound 87, and Compound 88
Figure PCTKR2018003744-appb-I000085
Figure PCTKR2018003744-appb-I000085
화합물 86, 화합물 87, 및 화합물 88은 PCT/US2016/063564에 기술된 방법으로 제조하였다.Compound 86, compound 87, and compound 88 were prepared by the method described in PCT / US2016 / 063564.
<실시예 34> 화합물 94의 제조Example 34 Preparation of Compound 94
Figure PCTKR2018003744-appb-I000086
Figure PCTKR2018003744-appb-I000086
화합물 90의 제조Preparation of Compound 90
화합물 89 (4.5 g, 4.88 mmol, 화합물 89는 J. Med . Chem ., 2004, 47, 1161-1174 에 기술된 방법으로 제조하였다)를 다이클로로메테인 (100 mL)에 녹인 후 상온, 질소 대기 하에서 2,2,6,6-테트라메틸-1-피페리디닐옥시 (153 mg, 0.98 mmol)와 (다이아세톡시아이오도)벤젠 (7.0 g, 21.7 mmol)을 첨가하였다. 반응 용액을 24 시간 동안 교반한 후 증류수 (200 mL)를 반응 용액에 첨가하고 다이클로로메테인 (2 x 200 mL)으로 추출하였다. 모인 유기층을 무수 황산 나트륨으로 건조하고 여과 후 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 90 (4.25 g, 95%)을 수득하였다. Compound 89 (4.5 g, 4.88 mmol, Compound 89 was prepared by the method described in J. Med . Chem . , 2004, 47 , 1161-1174) was dissolved in dichloromethane (100 mL) at room temperature, nitrogen atmosphere. 2,2,6,6-tetramethyl-1-piperidinyloxy (153 mg, 0.98 mmol) and (diacetoxyiodo) benzene (7.0 g, 21.7 mmol) were added. The reaction solution was stirred for 24 hours, then distilled water (200 mL) was added to the reaction solution and extracted with dichloromethane (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 90 (4.25 g, 95%).
1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 6.73 (s, 2H), 4.97 (d, J = 8.8 Hz, 1H), 4.39-4.27 (m, 8H), 3.96 (s, 6H), 3.80-3.70 (m, 2H), 3.58-3.52 (m, 2H), 3.42-2.79 (m, 2H), 2.74-2.56 (m, 2H), 2.52-2.44 (m, 2H), 2.08 (s, 2H), 0.85 (s, 18H), 0.97 (s, 12 H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 2H), 6.73 (s, 2H), 4.97 (d, J = 8.8 Hz, 1H), 4.39-4.27 (m, 8H), 3.96 (s , 6H), 3.80-3.70 (m, 2H), 3.58-3.52 (m, 2H), 3.42-2.79 (m, 2H), 2.74-2.56 (m, 2H), 2.52-2.44 (m, 2H), 2.08 (s, 2H), 0.85 (s, 18H), 0.97 (s, 12H).
화합물 91의 제조Preparation of Compound 91
화합물 90 (10.0 g, 10.9 mmol)을 다이클로로메테인 (450 mL)에 녹인 후 -40 ℃, 질소 대기 하에서 2,6-루티딘 (10.0 mL, 87.2 mmol)과 트라이플릭 언하이드라이드 (11.0 mL, 65.4 mmol)를 첨가하였다. 반응 용액을 2 시간 동안 교반한 후 포화 탄산수소 나트륨 수용액 (500 mL)를 반응 용액에 첨가하고 다이클로로메테인 (2 x 500 mL)으로 추출하였다. 모인 유기층을 무수 황산 나트륨으로 건조하고 여과 후 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 91 (10.6 g, 47%)을 수득하였다.Compound 90 (10.0 g, 10.9 mmol) was dissolved in dichloromethane (450 mL) and then 2,6-lutidine (10.0 mL, 87.2 mmol) and triplic anhydride (11.0 mL) at -40 ° C under nitrogen atmosphere. , 65.4 mmol) was added. The reaction solution was stirred for 2 hours, then saturated aqueous sodium hydrogen carbonate solution (500 mL) was added to the reaction solution and extracted with dichloromethane (2 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain Compound 91 (10.6 g, 47%).
화합물 92의 제조Preparation of Compound 92
화합물 91 (1.7 g, 1.44 mmol)을 에탄올/톨루엔/증류수 (12 mL/24 mL/12 mL)에 녹인 후 상온, 질소 대기 하에서 4-메틸페닐보로닉 에시드 (568 mg, 3.74 mmol), 탄산 나트륨 (793 mg, 7.48 mmol), 그리고 테트라키스(트라이페닐포스핀)팔라듐 (0) (133 mg, 0.115 mmol)을 첨가하였다. 반응 용액을 2 시간 동안 교반한 후 에틸 아세테이트 (100 mL)로 반응 용액을 묽히고 소금물 (100 mL)과 증류수 (100 mL)로 유기층을 세척하였다. 모인 유기층을 무수 황산 나트륨으로 건조하고 여과 후 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 92 (1.25 g, 79%)를 수득하였다. Compound 91 (1.7 g, 1.44 mmol) was dissolved in ethanol / toluene / distilled water (12 mL / 24 mL / 12 mL) and then 4-methylphenylboronic acid (568 mg, 3.74 mmol), sodium carbonate, at room temperature and nitrogen atmosphere. (793 mg, 7.48 mmol), and tetrakis (triphenylphosphine) palladium (0) (133 mg, 0.115 mmol) were added. After stirring the reaction solution for 2 hours, the reaction solution was diluted with ethyl acetate (100 mL) and the organic layer was washed with brine (100 mL) and distilled water (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 92 (1.25 g, 79%).
1H-NMR (400 MHz, CDCl3) δ 7.80 (s, 2H), 7.13 (d, J = 8.8 Hz, 4H), 6.90 (s, 2H), 6.79 (d, J = 8.0 Hz, 4H), 6.14 (s, 2H), 4.80-4.50 (m, 2H), 4.39-4.36 (m, 4H), 3.98 (s, 6H), 3.79 (s, 6H), 3.17 (bs, 2H), 3.02-2.98 (m, 2H), 2.50-2.47 (m, 2H), 0.88 (s, 18H), 0.11 (s, 12 H). EI-MS m/z : [M+H]+ 1069.8, 1/2[M+H]+ 535.6. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.80 (s, 2H), 7.13 (d, J = 8.8 Hz, 4H), 6.90 (s, 2H), 6.79 (d, J = 8.0 Hz, 4H), 6.14 (s, 2H), 4.80-4.50 (m, 2H), 4.39-4.36 (m, 4H), 3.98 (s, 6H), 3.79 (s, 6H), 3.17 (bs, 2H), 3.02-2.98 ( m, 2H), 2.50-2.47 (m, 2H), 0.88 (s, 18H), 0.11 (s, 12H). EI-MS m / z: [M + H] + 1069.8, 1/2 [M + H] + 535.6.
화합물 93의 제조Preparation of Compound 93
화합물 92 (8.0 g, 7.48 mmol)를 에탄올 (300 mL)에 녹인 후 아연 가루 (Zinc dust, 29 g, 28.1 mmol)와 포름산 (5 % in EtOH, 320 mL)을 첨가하였다. 상온에서 반응 용액을 20 분간 교반한 후, 셀라이트로 여과하고 에틸 아세테이트 (1 L) 를 첨가하였다. 유기층을 증류수 (500 mL), 포화 탄산수소 나트륨 수용액 (500 mL), 그리고 소금물 (500 mL)순으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 93 (4.85 g, 64%)을 수득하였다. Compound 92 (8.0 g, 7.48 mmol) was dissolved in ethanol (300 mL), and zinc powder (Zinc dust, 29 g, 28.1 mmol) and formic acid (5% in EtOH, 320 mL) were added. The reaction solution was stirred at room temperature for 20 minutes, then filtered through celite and ethyl acetate (1 L) was added. The organic layer was washed with distilled water (500 mL), saturated aqueous sodium hydrogen carbonate solution (500 mL), and brine (500 mL), and then dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 93 (4.85 g, 64%).
1H-NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.4 Hz, 4H), 6.78 (d, J = 6.4 Hz, 8H), 6.30 (s, 2H), 4.71-4.41 (m, 2H), 4.25 (br s, 4H), 4.19-4.17 (m, 4H), 4.10-4.05 (m, 2H), 3.95-3.81 (m, 2H), 3.73 (s, 6H), 3.72 (s, 6H), 3.64-3.10 (m, 2H), 3.03-2.93 (m, 2H), 2.36-2.34 (m, 2H), 0.81 (s, 18H), 0.11 (s, 12 H). EI-MS m/z : [M+H]+ 1010.4, 1/2[M+H]+ 505.7. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.16 (d, J = 8.4 Hz, 4H), 6.78 (d, J = 6.4 Hz, 8H), 6.30 (s, 2H), 4.71-4.41 (m, 2H ), 4.25 (br s, 4H), 4.19-4.17 (m, 4H), 4.10-4.05 (m, 2H), 3.95-3.81 (m, 2H), 3.73 (s, 6H), 3.72 (s, 6H) , 3.64-3.10 (m, 2H), 3.03-2.93 (m, 2H), 2.36-2.34 (m, 2H), 0.81 (s, 18H), 0.11 (s, 12H). EI-MS m / z: [M + H] + 1010.4, 1/2 [M + H] + 505.7.
화합물 94의 제조Preparation of Compound 94
화합물 93 (4.6 g, 4.56 mmol)을 다이클로로메테인 (300 mL)에 녹인 후 피리딘 (0.74 mL, 9.11 mmol)과 알릴 클로로포메이트 (0.48 mL, 4.56 mmol)를 -78 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 1 시간 동안 교반한 후 반응 온도를 상온으로 올리고, 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 94 (1.46 g, 29%)를 수득하였다. Compound 93 (4.6 g, 4.56 mmol) was dissolved in dichloromethane (300 mL), and then pyridine (0.74 mL, 9.11 mmol) and allyl chloroformate (0.48 mL, 4.56 mmol) were added under -78 ° C under a nitrogen atmosphere. It was. After stirring the reaction solution for 1 hour, the reaction temperature was raised to room temperature, concentrated and purified by column chromatography to give the compound 94 (1.46 g, 29%).
EI-MS m/z : [M+H]+ 1093.6.EI-MS m / z: [M + H] + 10 93.6.
<실시예 35> 화합물 97의 제조Example 35 Preparation of Compound 97
Figure PCTKR2018003744-appb-I000087
Figure PCTKR2018003744-appb-I000087
화합물 95의 제조Preparation of Compound 95
화합물 94 (200 mg, 0.18 mmol)를 톨루엔 (7.5 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (19 mg, 0.067 mmol)과 트라이에틸아민 (0.035 mL, 0.25 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 20을 건조한 테트라하이드로퓨란 (7.5 mL)에 녹이고 트라이에틸아민 (0.035 mL, 0.25 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (30 mL)으로 희석한 후 소금물 (20 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 95 (130 mg, 43%)를 수득하였다. Compound 94 (200 mg, 0.18 mmol) was dissolved in toluene (7.5 mL), and then triphosgene (19 mg, 0.067 mmol) and triethylamine (0.035 mL, 0.25 mmol) were added at -10 ° C, and the mixture was kept under nitrogen atmosphere for 1 hour. Was stirred. Compound 20 was dissolved in dry tetrahydrofuran (7.5 mL) and triethylamine (0.035 mL, 0.25 mmol) was added followed by the slow addition of the solution to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography gave compound 95 (130 mg, 43%).
EI-MS m/z : [M+H]+ 1661.6, 1/2[M+H]+ 831.4.EI-MS m / z: [M + H] + 1661.6, 1/2 [M + H] + 831.4.
화합물 96의 제조Preparation of Compound 96
화합물 95 (380 mg, 0.23 mmol)를 다이클로로메테인 (10 mL)에 녹인 후 피롤리딘 (0.023 mL, 0.27 mmol), 테트라키스(트라이페닐포스핀)팔라듐(0) (13 mg, 0.011 mmol), 그리고 트라이페닐포스핀 (15 mg, 0.057 mmol)을 차례로 첨가하고 상온, 질소 대기 하에서 6 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 96 (260 mg, 72%)을 수득하였다. Compound 95 (380 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL) and then pyrrolidine (0.023 mL, 0.27 mmol), tetrakis (triphenylphosphine) palladium (0) (13 mg, 0.011 mmol ), And triphenylphosphine (15 mg, 0.057 mmol) was added sequentially and stirred for 6 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 96 (260 mg, 72%).
EI-MS m/z : [M+H]+ 1577.6, 1/2[M+H]+ 789.4.EI-MS m / z: [M + H] + 1577.6, 1/2 [M + H] + 789.4.
화합물 97의 제조Preparation of Compound 97
화합물 96 (260 mg, 0.16 mmol)을 톨루엔 (5 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (17.6 mg, 0.06 mmol)과 다이아이소프로필에틸아민 (0.053 mL, 0.30 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 22를 건조한 테트라하이드로퓨란 (5 mL)에 녹이고 피리딘 (0.066 mL, 0.80 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (50 mL)로 희석한 후 소금물 (30 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 97 (168 mg, 41%)을 수득하였다. Compound 96 (260 mg, 0.16 mmol) was dissolved in toluene (5 mL), and then triphosphogen (17.6 mg, 0.06 mmol) and diisopropylethylamine (0.053 mL, 0.30 mmol) were added at -10 ° C. under nitrogen atmosphere. Stir for 1 hour. Compound 22 was dissolved in dry tetrahydrofuran (5 mL) and pyridine (0.066 mL, 0.80 mmol) was added followed by the slow addition of this solution to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure were followed by purification by column chromatography to give compound 97 (168 mg, 41%).
EI-MS m/z : [M+H]+ 2567.1, 1/2[M+H]+ 1283.8.EI-MS m / z: [M + H] + 2567.1, 1/2 [M + H] + 1283.8.
<실시예 36> 화합물 100의 제조Example 36 Preparation of Compound 100
Figure PCTKR2018003744-appb-I000088
Figure PCTKR2018003744-appb-I000088
화합물 98의 제조Preparation of Compound 98
화합물 97 (168 mg, 0.065 mmol)을 테트라하이드로퓨란/증류수 (1 mL/1 mL)에 녹이고 아세트산 (2 mL)을 첨가한 후 상온, 질소 대기 하에서 16 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 98 (130 mg, 85%)을 수득하였다. Compound 97 (168 mg, 0.065 mmol) was dissolved in tetrahydrofuran / distilled water (1 mL / 1 mL) and acetic acid (2 mL) was added, followed by stirring for 16 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 98 (130 mg, 85%).
EI-MS m/z : [M+H]+ 2337.8, 1/2[M+H]+ 1169.5.EI-MS m / z: [M + H] + 2337.8, 1/2 [M + H] + 1169.5.
화합물 99의 제조Preparation of Compound 99
화합물 98 (130 mg, 0.055 mmol)을 다이클로로메테인 (5 mL)에 녹인 후 데스-마틴 펄아이오디네인 (Dess-Martin periodinane, 57 mg, 0.13 mmol)를 첨가하고 상온, 질소 대기 하에서 3.5 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 99 (96 mg, 82%)를 수득하였다. Compound 98 (130 mg, 0.055 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of Dess-Martin periodinane (57 mg, 0.13 mmol), followed by 3.5 at room temperature and nitrogen atmosphere. Stir for hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to give compound 99 (96 mg, 82%).
EI-MS m/z : [M+H]+ 2333.7, 1/2[M+H]+ 1167.5.EI-MS m / z: [M + H] + 2333.7, 1/2 [M + H] + 1167.5.
화합물 100의 제조Preparation of Compound 100
화합물 99 (96 mg, 0.041 mmol)를 메탄올/테트라하이드로퓨란 (1 mL/1 mL)에 녹인 후 수산화 리튬 (16 mg, 0.41 mmol)을 증류수 (1 mL)에 녹인 용액을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 0 ℃로 올리면서 2 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축하고 진공 건조 하였다. 얻어진 고체를 다이클로로메테인 (2 mL)로 묽힌 후 트라이플루오로아세트산 (0.5 mL)를 0 ℃에서 첨가하고 2 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 100 (2.4 mg)을 연한 노란색의 고체로 수득하였다. Compound 99 (96 mg, 0.041 mmol) was dissolved in methanol / tetrahydrofuran (1 mL / 1 mL), and then a solution of lithium hydroxide (16 mg, 0.41 mmol) in distilled water (1 mL) was added slowly at -40 ° C. It was. Stirred for 2 hours while slowly raising the reaction temperature to 0 ℃. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure and dried in vacuo. The solid obtained was diluted with dichloromethane (2 mL), then trifluoroacetic acid (0.5 mL) was added at 0 ° C. and stirred for 2 h. The reaction solution was concentrated under reduced pressure, purified by HPLC and freeze-dried to give compound 100 (2.4 mg) as a pale yellow solid.
EI-MS m/z : [M+H]+ 1853.8, 1/2[M+H]+ 927.4.EI-MS m / z: [M + H] + 1853.8, 1/2 [M + H] + 927.4.
<실시예 37> 화합물 102의 제조Example 37 Preparation of Compound 102
Figure PCTKR2018003744-appb-I000089
Figure PCTKR2018003744-appb-I000089
화합물 101의 제조Preparation of Compound 101
1,3-다이아미노프로판 (0.93 mL, 11.1 mmol)을 다이클로로메테인 (30 mL)에 녹이고 0 ℃, 질소 대기 하에서 다이-t-부틸 다이카보네이트 (0.84 mL, 3.7 mmol)를 첨가하였다. 상온에서 3 시간 동안 교반한 후 소금물 (50 mL)을 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후반응 용액을 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 101 (658 mg, 100% Boc2O 기준)을 수득하였다. 1,3-Diaminopropane (0.93 mL, 11.1 mmol) was dissolved in dichloromethane (30 mL) and di- t -butyl dicarbonate (0.84 mL, 3.7 mmol) was added at 0 ° C. under nitrogen atmosphere. After stirring for 3 hours at room temperature, brine (50 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. After filtration the reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 101 (658 mg, based on 100% Boc 2 O).
1H-NMR (400 MHz, CDCl3) δ 4.88 (br s, 1H), 3.26-3.14 (m, 2H), 2.77 (t, J = 6.8 Hz, 2H), 1.66-1.57 (m, 2H), 1.44 (s, 9H), 1.32 (br, 2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 4.88 (br s, 1H), 3.26-3.14 (m, 2H), 2.77 (t, J = 6.8 Hz, 2H), 1.66-1.57 (m, 2H), 1.44 (s, 9 H), 1.32 (br, 2 H).
화합물 102의 제조Preparation of Compound 102
화합물 19 (1.50 g, 3.10 mmol)와 화합물 101 (0.65 g, 3.73 mmol)을 N,N-다이메틸폼아마이드 (10 mL)에 녹이고, 0 ℃, 질소 대기 하에서 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (1.60 g, 4.03 mmol)와 N,N-다이아이소프로필에틸아민 (1.08 mL, 6.20 mmol)을 첨가한 후 상온에서 12 시간 교반하였다. 포화 암모늄 클로라이드 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (2 x 100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 102 (1.67 g, 84%)를 수득하였다. Compound 19 (1.50 g, 3.10 mmol) and compound 101 (0.65 g, 3.73 mmol) were dissolved in N , N -dimethylformamide (10 mL), and N, N, N ', N' was added at 0 ° C under a nitrogen atmosphere . Tetramethyl- O- ( 1H -benzotriazol-1-yl) uronium hexafluorophosphate (1.60 g, 4.03 mmol) and N , N -diisopropylethylamine (1.08 mL, 6.20 mmol) were added, followed by stirring at room temperature for 12 hours. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 102 (1.67 g, 84%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.49-7.47 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 5.42-5.30 (m, 4H), 4.69 (d, J = 6.0 Hz, 2H), 4.21 (d, J = 9.2 Hz, 1H), 3.74 (s, 3H), 3.63-3.58 (m, 1H), 3.44-3.39 (m, 1H), 322-3.13 (m, 2H), 2.06-2.05 (m, 9H), 1.79-1.74 (m, 2H), 1.45 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.05 (s, 1H), 7.49-7.47 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 5.42-5.30 (m, 4H), 4.69 (d, J = 6.0 Hz, 2H), 4.21 (d, J = 9.2 Hz, 1H), 3.74 (s, 3H), 3.63-3.58 (m, 1H), 3.44-3.39 (m, 1H), 322- 3.13 (m, 2H), 2.06-2.05 (m, 9H), 1.79-1.74 (m, 2H), 1.45 (s, 9H).
<실시예 38> 화합물 103의 제조Example 38 Preparation of Compound 103
Figure PCTKR2018003744-appb-I000090
Figure PCTKR2018003744-appb-I000090
화합물 103은 화합물 24와 화합물 102로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1475.8, 1/2[M+H]+ 738.3.Compound 103 was prepared by a method analogous to the synthesis of compound 28 from compound 24 and compound 102. EI-MS m / z: [M + H] + 1475.8, 1/2 [M + H] + 738.3.
<실시예 39> 화합물 104의 제조Example 39 Preparation of Compound 104
Figure PCTKR2018003744-appb-I000091
Figure PCTKR2018003744-appb-I000091
화합물 103 (35 mg, 0.024 mmol)과 말레이미도아세트산 N-하이드록시숙신이마이드 에스터 (9 mg, 0.035 mmol)를 N,N-다이메틸폼아마이드 (1.5 mL)에 녹인 후 N,N-다이아이소프로필에틸아민 (0.021 mL, 0.23 mmol)을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 온도를 서서히 상온으로 올린 후 3 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 104 (15.1 mg, 37%)를 흰색의 고체로 수득하였다. Compound 103 (35 mg, 0.024 mmol) and maleimidoacetic acid N -hydroxysuccinimide ester (9 mg, 0.035 mmol) were dissolved in N , N -dimethylformamide (1.5 mL) and then N , N -diiso Propylethylamine (0.021 mL, 0.23 mmol) was added at 0 ° C under nitrogen atmosphere. The reaction temperature was slowly raised to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to give compound 104 (15.1 mg, 37%) was obtained as a white solid.
EI-MS m/z : [M+H]+ 1612.6, 1/2[M+H]+ 807.2.EI-MS m / z: [M + H] + 1612.6, 1/2 [M + H] + 807.2.
<실시예 40> 화합물 110의 제조Example 40 Preparation of Compound 110
Figure PCTKR2018003744-appb-I000092
Figure PCTKR2018003744-appb-I000092
화합물 105의 제조Preparation of Compound 105
L-아스파라진 (3.0 g, 22.7 mmol)을 1 N 소듐 카보네이트 수용액 (30 mL)에 녹인 후 0 ℃에서 벤질 클로로포메이트 (6.3 mL, 45.4 mmol)를 첨가하고, 질소 대기 하에서 12 시간 동안 교반하였다. 증류수 (50 ml)를 반응 용액에 첨가한 후 1 N 염산 수용액으로 산성화 (pH 2) 하였다. 이 혼합물을 에틸 아세테이트 (3 x 50 mL)로 추출하고 모인 유기층을 무수 황산나트륨으로 건조하였다. 여과 후 감압 농축하여 화합물 105 (3.5 g, 58%)를 수득하였다. L-asparagine (3.0 g, 22.7 mmol) was dissolved in 1 N aqueous sodium carbonate solution (30 mL), and benzyl chloroformate (6.3 mL, 45.4 mmol) was added at 0 ° C., and stirred for 12 hours under a nitrogen atmosphere. . Distilled water (50 ml) was added to the reaction solution followed by acidification (pH 2) with 1N aqueous hydrochloric acid solution. This mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave compound 105 (3.5 g, 58%).
1H-NMR (400 MHz, DMSO-d6) δ 7.51-7.40 (d, J = 8.0 Hz, 1H), 7.35 (s, 6H), 6.92 (s, 1H), 5.02 (s, 2 H), 2.61-2.35 (m, 2H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.51-7.40 (d, J = 8.0 Hz, 1H), 7.35 (s, 6H), 6.92 (s, 1H), 5.02 (s, 2H), 2.61-2.35 (m, 2 H).
화합물 106의 제조Preparation of Compound 106
화합물 105 (3.5 g, 13.1 mmol)를 에틸아세테이트/아세토나이트릴/증류수 (30 mL/30 mL/15 mL)에 녹인 후 (다이아세톡시아이오도)벤젠 (5.1 g, 15.7 mmol)을 첨가하고, 질소 대기 하에서 10 시간 동안 교반하였다. 형성 된 고체를 여과 및 감압 농축하여 화합물 106 (2.8 g, 89%)을 수득하였다. Compound 105 (3.5 g, 13.1 mmol) was dissolved in ethyl acetate / acetonitrile / distilled water (30 mL / 30 mL / 15 mL) and (diacetoxyiodo) benzene (5.1 g, 15.7 mmol) was added, Stirred under nitrogen atmosphere for 10 hours. The solid formed was filtered and concentrated under reduced pressure to give compound 106 (2.8 g, 89%).
1H-NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.96 (s, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.37 (s, 5H), 5.07 (s, 2H), 4.29 (s, 1H), 3.23 (br, 1H), 3.02 (br, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.96 (s, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.37 (s, 5H), 5.07 (s , 2H), 4.29 (s, 1 H), 3.23 (br, 1 H), 3.02 (br, 1 H).
화합물 107의 제조Preparation of Compound 107
화합물 106 (2.8 g, 11.7 mmol)을 1,4-다이옥세인/증류수 (25 mL/46 mL)에 녹인 후 수산화 나트륨 (0.5 g, 11.7 mmol)과 다이-t-뷰틸 다이카보네이트 (3.0 mL, 12.9 mmol)을 첨가하고 질소 대기 하에서 상온에서 8 시간 동안 교반하였다. 증류수 (50 ml)를 반응 용액에 첨가한 후 에틸 아세테이트 (2 x 50 ml)으로 씻어주었다. 수용액층에 시트르산을 첨가하여 산성화하고 에틸 아세테이트 (3 x 50 mL)로 추출한 후 무수 황산나트륨으로 건조하였다. 여과 및 감압 농축하여 화합물 107 (2.7 g, 68%)을 수득하였다. Compound 106 (2.8 g, 11.7 mmol) was dissolved in 1,4-dioxane / distilled water (25 mL / 46 mL), followed by sodium hydroxide (0.5 g, 11.7 mmol) and di- t -butyl dicarbonate (3.0 mL, 12.9 mmol) was added and stirred for 8 hours at room temperature under a nitrogen atmosphere. Distilled water (50 ml) was added to the reaction solution and washed with ethyl acetate (2 × 50 ml). The aqueous layer was acidified by addition of citric acid, extracted with ethyl acetate (3 × 50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave compound 107 (2.7 g, 68%).
1H-NMR (400 MHz, CDCl3) δ 7.31 (s, 5H), 5.15-5.01 (m, 2H), 4.82-4.02 (m, 1H), 3.68-3.43 (m, 2H), 1.39 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.31 (s, 5H), 5.15-5.01 (m, 2H), 4.82-4.02 (m, 1H), 3.68-3.43 (m, 2H), 1.39 (s, 9H).
화합물 108의 제조Preparation of Compound 108
화합물 107 (2.7 g, 7.9 mmol)을 메탄올 (40 mL)에 녹인 후 팔라듐/차콜 (10%) (Pd/C, 0.5 g)을 첨가하였다. 반응 용액을 상온, 수소 대기 하에서 4 시간 동안 교반하였다. 반응 용액을 셀라이트로 여과하고 농축하여 화합물 108 (1.2 g, 75%)을 수득하였다. Compound 107 (2.7 g, 7.9 mmol) was dissolved in methanol (40 mL) and then palladium / charcoal (10%) (Pd / C, 0.5 g) was added. The reaction solution was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction solution was filtered through celite and concentrated to compound 108 (1.2 g, 75%) was obtained.
1H-NMR (400 MHz, D2O) δ 3.70-3.65 (m, 1H), 3.55-3.25 (m, 2H), 1.28 (s, 9H). 1 H-NMR (400 MHz, D 2 O) δ 3.70-3.65 (m, 1H), 3.55-3.25 (m, 2H), 1.28 (s, 9H).
화합물 109의 제조Preparation of Compound 109
화합물 108 (0.40 g, 1.96 mmol)과 말레익 언하이드라이드 (192 mg, 1.96 mmol)을 아세트산 (1.6 mL)에 녹인 후 상온에서 3 시간 동안 교반하였다. 반응 용액을 감압 농축하고 다이클로로메테인 (10 mL)을 가하여 생긴 고체를 필터 후 진공 건조하였다. 건조된 이 고체를 톨루엔 (15 mL)에 묽힌 후 트라이에틸아민 (1.2 mL, 8.6 mmol)과 N,N-다이메틸아세트아마이드 (0.75 mL)를 첨가하고 가열 환류하였다. 반응 16 시간 후 반응 용액을 감압 농축하고, HPLC로 정제한 후 동결 건조하여 화합물 109 (287 mg, 52%)를 수득하였다. Compound 108 (0.40 g, 1.96 mmol) and maleic anhydride (192 mg, 1.96 mmol) were dissolved in acetic acid (1.6 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (10 mL) was added, and the resulting solid was filtered and dried in vacuo. This dried solid was diluted with toluene (15 mL), triethylamine (1.2 mL, 8.6 mmol) and N, N -dimethylacetamide (0.75 mL) were added and heated to reflux. After 16 hours, the reaction solution was concentrated under reduced pressure, purified by HPLC, and then freeze-dried to give 109 (287 mg, 52%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 6.66 (s, 2H), 5.17 (br, 1H), 4.61 (br, 1H), 3.68 (br, 1H),1.35 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 6.66 (s, 2H), 5.17 (br, 1H), 4.61 (br, 1H), 3.68 (br, 1H), 1.35 (s, 9H).
화합물 110의 제조Preparation of Compound 110
화합물 109 (0.15 g, 0.52 mmol)를 N,N-다이아이소프로필에틸아민 (3 mL)에 녹인 후 N-(3-다이메틸아미노프로필)-N'-에틸카보다이이마이드 염산염 (0.15 g, 0.79 mmol)과 N-하이드록시석신이마이드 (0.09 g, 0.79 mmol)를 첨가하였다. 반응 용액을 상온 하에서 12 시간 동안 교반하였다. 증류수 (30 mL)를 반응 용액에 첨가한 후 에틸 아세테이트 (30 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 110 (0.08 g, 40%)을 수득하였다. Compound 109 (0.15 g, 0.52 mmol) of N, N - diisopropylethylamine (3 mL) was dissolved in N - (3- dimethylaminopropyl) - N '- ethyl carbonyl dayiyi polyimide hydrochloride (0.15 g, 0.79 mmol) and N -hydroxysuccinimide (0.09 g, 0.79 mmol) were added. The reaction solution was stirred at room temperature for 12 hours. Distilled water (30 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound 110 (0.08 g, 40%) was obtained.
EI-MS m/z : [M+Na]+ 404.3.EI-MS m / z: [M + Na] + 404.3.
<실시예 41> 화합물 112의 제조Example 41 Preparation of Compound 112
Figure PCTKR2018003744-appb-I000093
Figure PCTKR2018003744-appb-I000093
화합물 111의 제조Preparation of Compound 111
화합물 103 (57 mg, 0.04 mmol)과 화합물 110 (0.016 g, 0.04 mmol)을 N,N-다이메틸폼아마이드 (3 mL)에 녹인 후 N,N-다이아이소프로필에틸아민 (0.02 mL, 0.12 mmol)을 첨가하고, 질소 대기, 상온 하에서 6 시간 동안 상온 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 111 (37 mg, 58%)을 수득하였다. Compound 103 (57 mg, 0.04 mmol) and compound 110 (0.016 g, 0.04 mmol) were dissolved in N , N -dimethylformamide (3 mL) and then N , N -diisopropylethylamine (0.02 mL, 0.12 mmol ) Was added and stirred at room temperature for 6 hours under a nitrogen atmosphere and room temperature. The reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to give compound 111 (37 mg, 58%) was obtained.
EI-MS m/z : [M+H]+ 1741.7, 1/2[M+H]+ 871.7.EI-MS m / z: [M + H] + 1741.7, 1/2 [M + H] + 871.7.
화합물 112의 제조Preparation of Compound 112
화합물 111 (0.035 g, 0.02 mmol)을 다이클로로메테인 (3 mL)으로 묽힌 후 트라이플루오로아세트산 (0.3 mL)을 0 ℃에서 첨가하고 3 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 112 (6.5 mg, 20%)를 흰색의 고체로 수득하였다. Compound 111 (0.035 g, 0.02 mmol) was diluted with dichloromethane (3 mL), then trifluoroacetic acid (0.3 mL) was added at 0 ° C. and stirred for 3 h. The reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to give compound 112 (6.5 mg, 20%) as a white solid.
EI-MS m/z : [M+H]+ 1641.9, 1/2[M+H]+ 821.8.EI-MS m / z: [M + H] + 1641.9, 1/2 [M + H] + 821.8.
<실시예 42> 화합물 115의 제조Example 42 Preparation of Compound 115
Figure PCTKR2018003744-appb-I000094
Figure PCTKR2018003744-appb-I000094
화합물 114의 제조Preparation of Compound 114
2-[2-[2-(2-아지도에톡시)에톡시]에톡시]아세트산 (1.1 g, 4.71 mmol)을 다이클로로메테인 (10 mL)에 녹인 후 0 ℃, 질소 대기 하에서 1-하이드록시벤조트리아졸 (0.75 g 5.60 mmol), 1-(3-다이메틸아미노프로필)-3-에틸카보다이이마이드 염산염 (1.15 g, 6.03 mmol) 순으로 첨가한 후 30 분간 교반하였다. 다이클로로메테인 (10 mL)에 녹인 화합물 113 (1.5 g, 4.31 mmol, 화합물 113은 WO2017/160569 A1에 기술된 방법으로 제조하였다)과 트라이에틸아민 (1.08 mL, 7.76 mmol) 용액을 질소 대기 하에서 첨가하였다. 반응 온도를 상온으로 올리고 12 시간 교반한 후, 다이클로로메테인 (100 mL)으로 희석하고 포화 탄산수소나트륨 수용액 (100 mL)으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 114 (2.1 g, 87%)를 수득하였다. 2- [2- [2- (2-azidoethoxy) ethoxy] ethoxy] acetic acid (1.1 g, 4.71 mmol) was dissolved in dichloromethane (10 mL), followed by 1- under nitrogen atmosphere. Hydroxybenzotriazole (0.75 g 5.60 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.15 g, 6.03 mmol) were added in this order and stirred for 30 minutes. Compound dissolved in dichloromethane (10 mL) 113 (1.5 g, 4.31 mmol, compound 113 was prepared by the method described in WO2017 / 160569 A1) and Triethylamine (1.08 mL, 7.76 mmol) The solution was added under nitrogen atmosphere. The reaction temperature was raised to room temperature, stirred for 12 hours, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium hydrogen carbonate solution (100 mL), and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 114 (2.1 g, 87%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 6.83 (d, 1H), 4.15-4.11 (m, 1H), 3.96 (s, 2H), 3.72-3.62 (m, 14H), 3.39-3.37 (m, 2H) 1.81-1.60 (m, 4H), 0.88 (s, 18H) 0.42 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 6.83 (d, 1H), 4.15-4.11 (m, 1H), 3.96 (s, 2H), 3.72-3.62 (m, 14H), 3.39-3.37 (m, 2H) 1.81-1.60 (m, 4H), 0.88 (s, 18H) 0.42 (s, 12H).
화합물 115의 제조Preparation of Compound 115
화합물 114 (2.1 g, 3.73 mmol)를 메탄올 (30 mL)에 녹인 후 0 ℃, 질소 대기 하에서 진한 염산 (0.5 mL)을 첨가한 후 상온에서 2 시간 동안 교반하였다. 반응 용액을 트라이에틸아민으로 중화한 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 115 (1.2 mg, 98%)를 수득하였다. Compound 114 (2.1 g, 3.73 mmol) was dissolved in methanol (30 mL), followed by addition of concentrated hydrochloric acid (0.5 mL) at 0 ° C. under a nitrogen atmosphere, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with triethylamine, concentrated and purified by column chromatography to give the compound 115 (1.2 mg, 98%) was obtained.
1H-NMR (400 MHz, CDCl3) δ7.54 (br s,1H), 4.31-4.28 (m, 1H), 4.02 (s, 2H), 3.68-3.65 (m, 14H), 3.43-3.40 (m, 2H), 3.21 (br s, 2H), 1.93-1.85 (m, 2H), 1.64-1.57 (m, 2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.54 (br s, 1H), 4.31-4.28 (m, 1H), 4.02 (s, 2H), 3.68-3.65 (m, 14H), 3.43-3.40 ( m, 2H), 3.21 (br s, 2H), 1.93-1.85 (m, 2H), 1.64-1.57 (m, 2H).
<실시예 43> 화합물 118의 제조Example 43 Preparation of Compound 118
Figure PCTKR2018003744-appb-I000095
Figure PCTKR2018003744-appb-I000095
화합물 117의 제조Preparation of Compound 117
화합물 116 (1.32 g, 4.73 mmol, 화합물 116은 PCT/US2016/063564에 기술된 방법으로 제조하였다)을 다이클로로메테인 (20 mL)에 녹인 후 0 ℃, 질소 대기 하에서 1-하이드록시벤조트리아졸 (0.86 g, 5.59 mmol)과 1-(3-다이메틸아미노프로필)-3-에틸카보다이이마이드 염산염 (1.15 g, 6.02 mmol)을 첨가하였다. 다이클로로메테인 (5 mL)에 녹아있는 화합물 113 (1.5 g, 4.31 mmol)과 트라이에틸아민 (1.08 mL, 7.74 mmol) 용액을 0 ℃, 질소 대기 하에서 첨가하였다. 반응 온도를 상온으로 올리고 12 시간 교반한 후, 다이클로로메테인 (100 mL)으로 희석하고 포화 탄산수소나트륨 수용액 (100 mL)으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 117 (2.05 g, 79%)을 수득하였다. Compound 116 (1.32 g, 4.73 mmol, Compound 116 prepared by the method described in PCT / US2016 / 063564) was dissolved in dichloromethane (20 mL) and then 1-hydroxybenzotriazole under 0 ° C. and nitrogen atmosphere. (0.86 g, 5.59 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.15 g, 6.02 mmol) were added. Compound dissolved in dichloromethane (5 mL) 113 (1.5 g, 4.31 mmol) and Triethylamine (1.08 mL, 7.74 mmol) The solution was added at 0 ° C. under a nitrogen atmosphere. The reaction temperature was raised to room temperature, stirred for 12 hours, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium hydrogen carbonate solution (100 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 117 (2.05 g, 79%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.15-4.10 (m, 1H), 4.05-4.03 (m, 2H), 3.97 (s, 1H), 3.73-3.66 (m, 10H), 1.84-1.72 (m, 4H), 1.48 (s, 9H), 0.89 (m, 18H), 0.05 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.15-4.10 (m, 1H), 4.05-4.03 (m, 2H), 3.97 (s, 1H), 3.73-3.66 (m, 10H), 1.84-1.72 (m, 4H), 1.48 (s, 9H), 0.89 (m, 18H), 0.05 (s, 12H).
화합물 118의 제조Preparation of Compound 118
화합물 117 (2.05 g, 3.37 mmol)을 메탄올 (10 mL)에 녹인 후 0 ℃, 질소 대기 하에서 캠포설폰산 (158 mg, 0.68 mmol)을 첨가한 후 0 ℃에서 4 시간 동안 교반하였다. 반응 용액을 트라이에틸아민 (1 mL)으로 중화한 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 118 (1.28 g, 99%)을 수득하였다. Compound 117 (2.05 g, 3.37 mmol) was dissolved in methanol (10 mL), followed by addition of camphorsulfonic acid (158 mg, 0.68 mmol) at 0 ° C. and nitrogen atmosphere, followed by stirring at 0 ° C. for 4 hours. The reaction solution was neutralized with triethylamine (1 mL), concentrated and purified by column chromatography to give 118 (1.28 g, 99%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 4.32-4.29 (m, 1H), 4.05-4.03 (m, 4H), 3.75-3.69 (m, 10H), 3.48 (br s, 2H), 1.94-1.85 (m, 2H), 1.68-1.61 (m, 4H), 1.48 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 4.32-4.29 (m, 1H), 4.05-4.03 (m, 4H), 3.75 -3.69 (m, 10H), 3.48 (br s, 2H), 1.94-1.85 (m, 2H), 1.68-1.61 (m, 4H), 1.48 (s, 9H).
<실시예 44> 화합물 124의 제조Example 44 Preparation of Compound 124
Figure PCTKR2018003744-appb-I000096
Figure PCTKR2018003744-appb-I000096
화합물 119의 제조Preparation of Compound 119
3,5-피라졸다이카르복시산 수화물 (5 g, 28.71 mmol)을 메탄올 (50 mL)에 녹인 후 싸이오닐 클로라이드(6.28 mL, 86.15 mmol)를 0 ℃, 질소 대기 하에서 첨가 후 80 ℃로 가열하였다. 반응 용액을 4 시간 동안 교반한 후 농축하여 화합물 119 (7.1 g, 99%)를 수득하였다. 3,5-pyrazoledicarboxylic acid hydrate (5 g, 28.71 mmol) was dissolved in methanol (50 mL) and then thionyl chloride (6.28 mL, 86.15 mmol) was added to 0 ° C under nitrogen atmosphere and then heated to 80 ° C. The reaction solution was stirred for 4 hours and then concentrated to compound 119 (7.1 g, 99%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 3.96 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.34 (s, 1H), 3.96 (s, 6H).
화합물 120의 제조Preparation of Compound 120
화합물 119 (3.8 g, 20.63 mmol)를 테트라하이드로퓨란 (200 mL)에 녹인 후 리튬 알루미늄 하이드라이드 (1 M 테트라하이드로퓨란 용액, 41.2 mL, 41.26 mmol)를 0 ℃, 질소 대기 하에서 첨가한 후 가열 환류하여 12 시간 동안 교반하였다. 반응 혼합물을 0 ℃로 낮추고 증류수 (50 mL)를 서서히 가한 후 농축하고, 메탄올 (200 mL)로 희석한 후 다시 80 ℃로 가열하였다. 뜨거운 반응물을 여과하고 여액을 농축하였다. 여액을 에탄올 (10 mL)로 희석한 후 염산 (4 N 1,4-다이옥세인 용액, 82.6 mL, 22.7 mmol)을 첨가하고 20 분 동안 교반하였다. 반응 용액에 다이에틸이써 (200 mL)를 첨가하여 생성된 고체를 여과하고 건조하여 화합물 120 (2.6 g, 78%)을 수득하였다. Compound 119 (3.8 g, 20.63 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium aluminum hydride (1 M tetrahydrofuran solution, 41.2 mL, 41.26 mmol) was added at 0 ° C. under nitrogen atmosphere, and then heated to reflux. And stirred for 12 hours. The reaction mixture was lowered to 0 ° C., distilled water (50 mL) was added slowly and concentrated, diluted with methanol (200 mL) and heated to 80 ° C. again. The hot reaction was filtered off and the filtrate was concentrated. The filtrate was diluted with ethanol (10 mL) and then hydrochloric acid (4 N 1,4-dioxane solution, 82.6 mL, 22.7 mmol) was added and stirred for 20 minutes. Diethyl ether (200 mL) was added to the reaction solution, and the resulting solid was filtered and dried to yield 120 compound. (2.6 g, 78%) was obtained.
1H-NMR (400 MHz, DMSO-d6) δ 6.32 (s, 1H), 4.52 (s, 4H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 6.32 (s, 1H), 4.52 (s, 4H).
화합물 121의 제조Preparation of Compound 121
화합물 120 (2.59 g, 15.73 mmol)을 N,N-다이메틸폼아마이드 (75 mL)에 녹인 후 이미다졸 (5.35 g, 78.68 mmol)과 t-뷰틸다이메틸실릴 클로라이드 (5.69 g, 37.8 mmol)를 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 4 시간 동안 교반한 후 에틸 아세테이트 (100 mL)로 희석한 다음 포화 암모늄 클로라이드 수용액 (100 mL), 소금물 (100 mL) 순으로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 121 (4.56 g, 81%)을 수득하였다. Compound 120 (2.59 g, 15.73 mmol) was dissolved in N, N -dimethylformamide (75 mL), followed by imidazole (5.35 g, 78.68 mmol) and t -butyldimethylsilyl chloride (5.69 g, 37.8 mmol). 0 ° C., added under nitrogen atmosphere. The reaction solution was stirred for 4 hours, diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 121 (4.56 g, 81%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 6.09 (s, 1H), 4.74 (s, 4H), 0.88 (s, 18H), 0.09 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 6.09 (s, 1H), 4.74 (s, 4H), 0.88 (s, 18H), 0.09 (s, 12H).
화합물 122의 제조Preparation of Compound 122
화합물 121 (1.6 g, 4.48 mmol)을 N,N-다이메틸폼아마이드 (25 mL)에 녹인 후 세슘 카보네이트 (3.2 g, 9.8 mmol)와 트라이에틸렌글리콜 다이토실레이트 (4.05 g, 8.97 mmol)를 0 ℃, 질소 대기 하에서 첨가한 후 50 ℃로 가열하였다. 반응 용액을 4 시간 동안 교반한 후 에틸 아세테이트 (100 mL)로 희석한 다음 소금물(100 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 122 (1.69 g, 60%)를 수득하였다. Compound 121 (1.6 g, 4.48 mmol) was dissolved in N, N -dimethylformamide (25 mL), followed by cesium carbonate (3.2 g, 9.8 mmol) and triethylene glycol ditosylate (4.05 g, 8.97 mmol). It was added under nitrogen atmosphere and then heated to 50 ° C. The reaction solution was stirred for 4 hours, diluted with ethyl acetate (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 122 (1.69 g, 60%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 6.10 (s, 1H), 4.67 (d, J = 5.2 Hz, 4H), 4.25-4.22 (m, 2H), 4.13-4.11 (m, 2H), 3.79-3.76 (m, 2H), 3.62-3.60 (m, 2H), 3.49-3.48 (m, 2H), 3.46-3.45 (m, 2H), 0.89 (d, J = 18 Hz, 18H), 0.06 (d, J = 5.6 Hz, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 6.10 (s, 1H), 4.67 (d, J = 5.2 Hz, 4H), 4.25-4.22 (m, 2H), 4.13-4.11 (m, 2H), 3.79-3.76 (m, 2H), 3.62-3.60 (m, 2H), 3.49-3.48 (m, 2H), 3.46-3.45 (m, 2H), 0.89 (d, J = 18 Hz, 18H), 0.06 (d, J = 5.6 Hz, 12H).
화합물 123의 제조Preparation of Compound 123
화합물 122 (1.69 g, 2.62 mmol)를 아세토나이트릴 (25 mL)에 녹인 후 t-뷰틸 N-하이드록시카바메이트 (1.35 g, 5.51 mmol)와 1,8-다이아자바이사이클로[5.4.0]-7-운데신 (0.8 mL, 5.38 mmol)을 0 ℃, 질소 대기 하에서 첨가한 후 50 ℃로 가열하였다. 반응 용액을 12 시간 동안 교반한 후 에틸 아세테이트 (100 mL)로 희석한 다음 소금물(100 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 123 (1.5 g, 60%)을 수득하였다. Compound 122 (1.69 g, 2.62 mmol) was dissolved in acetonitrile (25 mL) and then t -butyl N -hydroxycarbamate (1.35 g, 5.51 mmol) and 1,8-diazabicyclo [5.4.0]- 7-Undecine (0.8 mL, 5.38 mmol) was added at 0 ° C under nitrogen atmosphere and then heated to 50 ° C. The reaction solution was stirred for 12 hours, diluted with ethyl acetate (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 123 (1.5 g, 60%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 6.14 (s, 1H), 4.70 (d, J = 8 Hz, 4H), 4.29-4.26 (m, 2H), 3.83-3.74 (m, 4H), 3.63-3.62 (m, 2H), 3.55-3.53 (m, 2H), 1.49 (s, 9H), 0.92 (d, J = 18 Hz, 18H), 0.09 (d, J = 0.8 Hz, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 6.14 (s, 1H), 4.70 (d, J = 8 Hz, 4H), 4.29-4.26 (m, 2H), 3.83-3.74 (m, 4H), 3.63 -3.62 (m, 2H), 3.55-3.53 (m, 2H), 1.49 (s, 9H), 0.92 (d, J = 18 Hz, 18H), 0.09 (d, J = 0.8 Hz, 12H).
화합물 124의 제조Preparation of Compound 124
화합물 123 (1.5 g, 2.13 mmol)을 테트라하이드로퓨란 (20 mL)에 녹인 후 테트라뷰틸암모늄 플루오라이드 (1 M 테트라하이드로퓨란 용액, 8.18 mL, 8.18 mmol)를 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 12 시간 동안 교반한 후 에틸 아세테이트 (50 mL)로 희석하고 포화 암모늄 클로라이드 수용액 (50 mL)로 닦아준 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 124 (660 mg, 66%)를 수득하였다. Compound 123 (1.5 g, 2.13 mmol) was dissolved in tetrahydrofuran (20 mL) and then tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 8.18 mL, 8.18 mmol) was added at 0 ° C. under a nitrogen atmosphere. The reaction solution was stirred for 12 hours, diluted with ethyl acetate (50 mL), washed with saturated aqueous ammonium chloride solution (50 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 124 (660 mg, 66%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 6.22 (s, 1H), 4.65 (d, J = 4.8 Hz, 2H), 4.57 (d, J = 6 Hz, 2H), 4.34-4.31 (m, 2H), 3.38-3.38 (m, 2H), 3.66-3.54 (m, 8H), 1.52 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 6.22 (s, 1H), 4.65 (d, J = 4.8 Hz, 2H), 4.57 (d, J = 6 Hz, 2H), 4.34-4.31 (m, 2H ), 3.38-3.38 (m, 2H), 3.66-3.54 (m, 8H), 1.52 (s, 9H).
<실시예 45> 화합물 131의 제조Example 45 Preparation of Compound 131
Figure PCTKR2018003744-appb-I000097
Figure PCTKR2018003744-appb-I000097
화합물 126의 제조Preparation of Compound 126
화합물 125 (1.12 g, 5.67 mmol, 화합물 125는 WO2016/148674 A1에 기술된 방법으로 제조하였다)를 다이클로로메테인 (30 mL)에 녹인 후 피리딘 (0.67 mL, 8.51 mmol)과 알릴 클로로포메이트 (0.66 mL, 6.24 mmol)를 0 ℃, 질소 대기 하에서 첨가한 후 1 시간 동안 교반하였다. 반응 용액을 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 126 (1.17 g, 73%)을 수득하였다. Compound 125 (1.12 g, 5.67 mmol, Compound 125 was prepared by the method described in WO2016 / 148674 A1) was dissolved in dichloromethane (30 mL), followed by pyridine (0.67 mL, 8.51 mmol) and allyl chloroformate ( 0.66 mL, 6.24 mmol) was added under 0 ° C. under a nitrogen atmosphere and then stirred for 1 hour. The reaction solution was concentrated and purified by column chromatography to give 126 (1.17 g, 73%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.06 (s, 1H), 7.44 (s, 1H), 6.07 (s, 1H), 6.02-5.92 (m, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.66 (d, J = 5.2, 2H), 3.89 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) δ 10.52 (s, 1H), 8.06 (s, 1H), 7.44 (s, 1H), 6.07 (s, 1H), 6.02-5.92 (m, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.66 (d, J = 5.2, 2H), 3.89 (s, 6H).
화합물 127의 제조Preparation of Compound 127
화합물 115 (920 mg, 2.75 mmol), 화합물 126 (1.7 g 6.05 mmol), 그리고 트라이페닐포스핀 (2.52 g, 9.35 mmol)을 건조한 테트라하이드로퓨란 (20 mL)에 녹인 후 0 ℃, 질소 대기 하에서 다이아이소프로필 아조다이카르복실레이트 (1.66 mL, 8.52 mmol)를 첨가한 후 상온에서 2 시간 교반하였다. 농축하고 컬럼 크로마토그래피로 정제하여 화합물 127 (1.54 g, 65%)을 수득하였다. Compound 115 (920 mg, 2.75 mmol), Compound 126 (1.7 g 6.05 mmol), and triphenylphosphine (2.52 g, 9.35 mmol) were dissolved in dry tetrahydrofuran (20 mL), followed by dialysis at 0 ° C. under nitrogen atmosphere. Isopropyl azodicarboxylate (1.66 mL, 8.52 mmol) was added and stirred at room temperature for 2 hours. Concentrate and purify by column chromatography Compound 127 (1.54 g, 65%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 10.54 (s, 2H), 8.07 (s, 2H), 7.41 (s, 2H), 6.00-5.93 (m, 2H), 5.36 (d, J = 17.2 Hz, 2H), 5.25 (d, J = 10.0 Hz, 2H), 4.64-4.63 (m, 4H), 4.44 (bs, 1H), 4.23-4.20 (m, 4H), 3.99 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.66-3.60 (m, 11H), 3.35-3.34 (m, 2H), 2.25-2.13 (m, 4H). 1 H-NMR (400 MHz, CDCl 3 ) δ 10.54 (s, 2H), 8.07 (s, 2H), 7.41 (s, 2H), 6.00-5.93 (m, 2H), 5.36 (d, J = 17.2 Hz , 2H), 5.25 (d, J = 10.0 Hz, 2H), 4.64-4.63 (m, 4H), 4.44 (bs, 1H), 4.23-4.20 (m, 4H), 3.99 (s, 2H), 3.89 ( s, 3H), 3.83 (s, 3H), 3.66-3.60 (m, 11H), 3.35-3.34 (m, 2H), 2.25-2.13 (m, 4H).
화합물 128의 제조Preparation of Compound 128
화합물 127 (1.54 g, 1.78 mmol)을 메탄올/테트라하이드로퓨란/증류수 (15 mL/15 mL/15 mL)에 녹인 후 수산화나트륨 (0.28 g, 7.15 mmol)을 첨가한 후 40 ℃에서 5 시간 교반하였다. 반응 용액을 에틸아세테이트(100 mL)로 희석한 후 증류수 (100 mL)로 추출하였다. 모인 수용액층을 1 N 염산 수용액으로 산성화 시킨 후 에틸아세테이트(100 mL)로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하여 화합물 128 (1.48 g)을 수득하였다. Compound 127 (1.54 g, 1.78 mmol) was dissolved in methanol / tetrahydrofuran / distilled water (15 mL / 15 mL / 15 mL), and sodium hydroxide (0.28 g, 7.15 mmol) was added and stirred at 40 ° C. for 5 hours. . The reaction solution was diluted with ethyl acetate (100 mL) and extracted with distilled water (100 mL). The combined aqueous layers were acidified with 1N hydrochloric acid aqueous solution, extracted with ethyl acetate (100 mL), and dried over anhydrous sodium sulfate. Filtration and Concentration Compound 128 (1.48 g) was obtained.
1H-NMR (400 MHz, DMSO-d6) δ 10.84 (s, 2H), 7.94 (s, 2H), 7.40 (s, 2H), 6.00-5.95 (m, 2H), 5.34 (d, J = 17.2 Hz, 2H), 5.24 (d, J = 10.0 Hz, 2H), 4.64-4.63 (m, 4H), 4.18 (br s, 1H), 4.04-4.01 (m, 4H), 3.88 (s, 2H), 3.74 (s, 6H), 3.55-3.51 (m, 12H), 2.05-1.98 (m, 4H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 2H), 7.94 (s, 2H), 7.40 (s, 2H), 6.00-5.95 (m, 2H), 5.34 (d, J = 17.2 Hz, 2H), 5.24 (d, J = 10.0 Hz, 2H), 4.64-4.63 (m, 4H), 4.18 (br s, 1H), 4.04-4.01 (m, 4H), 3.88 (s, 2H) , 3.74 (s, 6H), 3.55-3.51 (m, 12H), 2.05-1.98 (m, 4H).
화합물 129의 제조Preparation of Compound 129
화합물 128 (1.63 g, 1.95 mmol)을 N,N-다이메틸폼아마이드 (5 mL)에 녹인 후 0 ℃, 질소 대기 하에서 N,N,N ',N'-테트라메틸-O-(1H-벤조트라아졸-1-일)우로늄 헥사플루오로포스페이트 (2.22 g, 5.87 mmol)를 첨가한 후 30 분간 교반하였다. N,N-다이메틸폼아마이드 (5 mL)에 녹인 화합물 4 (0.64 g, 4.3 mmol)와 N,N-다이아이소프로필에틸아민 (1.7 mL, 9.78 mmol) 용액을 질소 대기 하에서 첨가하였다. 반응 온도를 상온으로 올리고 12 시간 교반한 후, 에틸 아세테이트 (100 mL)로 희석하고 포화 탄산수소나트륨 수용액 (200 mL)으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 129 (1.2 g)를 수득하였다. Compound 128 (1.63 g, 1.95 mmol) was dissolved in N, N -dimethylformamide (5 mL), followed by nitrogen at 0 ° C. under nitrogen atmosphere. N, N, N ', N' -tetramethyl- O- ( 1H -benzotriazol-1-yl) uronium hexafluorophosphate (2.22 g, 5.87 mmol) was added and stirred for 30 minutes. Compound 4 dissolved in N, N -dimethylformamide (5 mL) (0.64 g, 4.3 mmol) and A solution of N , N -diisopropylethylamine (1.7 mL, 9.78 mmol) was added under nitrogen atmosphere. The reaction temperature was raised to room temperature, stirred for 12 hours, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium hydrogen carbonate solution (200 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 129 (1.2 g) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.65 (br s, 2H), 7.34 (br s, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.75 (s, 2H), 6.00-5.90 (m, 2H), 5.35 (d, J = 16.8 Hz, 2H), 5.23 (d, J = 10.4 Hz, 2H), 5.00-4.92 (m, 4H), 4.68-4.57 (m, 6H), 4.48-4.40 (m, 1H), 4.20-4.08 (m, 8H), 3.97 (s, 2H), 3.79 (s, 6H), 3.67-3.63 (m, 14H), 3.39-3.37 (m, 2H), 2.80-2.72 (m, 2H), 2.48-2.44 (m, 2H), 2.22-2.17 (m, 2H), 2.10-2.04 (m, 2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.65 (br s, 2H), 7.34 (br s, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.75 (s, 2H), 6.00-5.90 (m, 2H), 5.35 (d, J = 16.8 Hz, 2H), 5.23 (d, J = 10.4 Hz, 2H), 5.00-4.92 (m, 4H), 4.68-4.57 (m, 6H), 4.48- 4.40 (m, 1H), 4.20-4.08 (m, 8H), 3.97 (s, 2H), 3.79 (s, 6H), 3.67-3.63 (m, 14H), 3.39-3.37 (m, 2H), 2.80- 2.72 (m, 2H), 2.48-2.44 (m, 2H), 2.22-2.17 (m, 2H), 2.10-2.04 (m, 2H).
화합물 130의 제조Preparation of Compound 130
화합물 129 (1.2 g, 1.17 mmol)를 다이클로로메테인 (10 mL)에 녹인 후 이미다졸 (0.4 g, 5.86 mmol)과 t-뷰틸다이메틸실릴 클로라이드 (0.53 g, 3.5 mmol)를 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 12 시간 동안 교반한 후 소금물 (50 mL)을 반응 용액에 넣고 다이클로로메테인 (2 x 100 mL)으로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 130 (0.98 g, 3 steps 40%)을 수득하였다. Compound 129 (1.2 g, 1.17 mmol) was dissolved in dichloromethane (10 mL), followed by imidazole (0.4 g, 5.86 mmol) and t -butyldimethylsilyl chloride (0.53 g, 3.5 mmol) at 0 ° C. and nitrogen. Added under atmosphere. After stirring the reaction solution for 12 hours, brine (50 mL) was added to the reaction solution, extracted with dichloromethane (2 x 100 mL) and dried over anhydrous sodium sulfate. Concentrate after filtration and purify by column chromatography Compound 130 (0.98 g, 3 steps 40%) were obtained.
1H-NMR (400 MHz, CDCl3) δ 8.81 (br s, 2H), 7.77 (s, 2H), 7.12 (d, J = 8 Hz, 1H), 6.80 (s, 2H), 5.99-5.89 (m, 2H), 5.34 (d, J = 17.2 Hz, 2H) 5.23 (d, J = 10.4 Hz, 2H), 4.98-4.91 (m, 4H), 4.65-4.56 (m, 6H), 4.54-4.44 (m, 1H), 4.19-4.14 (m, 8H) 4.01 (s, 2H), 3.80 (s, 6H), 3.66-3.61 (m, 14H), 3.39-3.36 (m, 2H), 2.69 (s, 4H), 2.28-2.19 (m, 2H), 2.15-2..05 (m, 2H), 0.87 (s, 18H), 0.03 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.81 (br s, 2H), 7.77 (s, 2H), 7.12 (d, J = 8 Hz, 1H), 6.80 (s, 2H), 5.99-5.89 ( m, 2H), 5.34 (d, J = 17.2 Hz, 2H) 5.23 (d, J = 10.4 Hz, 2H), 4.98-4.91 (m, 4H), 4.65-4.56 (m, 6H), 4.54-4.44 ( m, 1H), 4.19-4.14 (m, 8H) 4.01 (s, 2H), 3.80 (s, 6H), 3.66-3.61 (m, 14H), 3.39-3.36 (m, 2H), 2.69 (s, 4H ), 2.28-2.19 (m, 2H), 2.15-2..05 (m, 2H), 0.87 (s, 18H), 0.03 (s, 12H).
화합물 131의 제조Preparation of Compound 131
화합물 130 (0.98 g, 0.78 mmol)을 다이클로로메테인 (5 mL)에 녹인 후 피롤리딘 (0.16 mL, 1.95 mmol)과 테트라키스(트라이페닐포스핀)팔라듐(0) (18 mg, 0.015 mmol)을 첨가하고 상온, 질소 대기 하에서 6 시간 동안 교반하였다. 증류수 (50 mL)를 반응 용액에 넣고 다이클로로메테인 (50 mL)으로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 131 (0.59 g, 70%)을 수득하였다. Compound 130 (0.98 g, 0.78 mmol) was dissolved in dichloromethane (5 mL), followed by pyrrolidine (0.16 mL, 1.95 mmol) and tetrakis (triphenylphosphine) palladium (0) (18 mg, 0.015 mmol ) Was added and stirred for 6 hours at room temperature and nitrogen atmosphere. Distilled water (50 mL) was added to the reaction solution, extracted with dichloromethane (50 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 131 (0.59 g, 70%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.12. (d, J = 9.2 Hz, 1H), 6.73 (s, 2H), 6.26 (s, 2H), 4.96-4.90 (m, 4H), 4.52 (bs, 1H), 4.38-4.35 (m, 4H), 4.21-4.17 (m, 2H), 4.11-4.03 (m, 6H), 4.00 (s, 2H), 3.75 (s, 6H), 3.66-3.61 m, 12H), 3.37-3.34 (m, 2H), 2.7-2.68 (m, 4H) 2.21-2.18 (m, 2H), 2.12-2.05 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.12. (d, J = 9.2 Hz, 1H), 6.73 (s, 2H), 6.26 (s, 2H), 4.96-4.90 (m, 4H), 4.52 (bs, 1H), 4.38-4.35 (m, 4H), 4.21-4.17 (m, 2H), 4.11-4.03 (m, 6H), 4.00 (s, 2H), 3.75 (s, 6H), 3.66-3.61 m, 12H), 3.37-3.34 (m, 2H), 2.7 -2.68 (m, 4H) 2.21-2.18 (m, 2H), 2.12-2.05 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H).
<실시예 46> 화합물 135의 제조
Figure PCTKR2018003744-appb-I000098
 Example 46 Preparation of Compound 135
Figure PCTKR2018003744-appb-I000098
화합물 132의 제조Preparation of Compound 132
화합물 131 (590 mg, 0.54 mmol)을 건조한 테트라하이드로퓨란 (5 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (116 mg, 0.39 mmol)과 트라이에틸아민 (0.2 mL, 1.47 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 20 (707 mg, 1.30 mmol)을 건조한 테트라하이드로퓨란 (5 mL)에 녹이고 트라이에틸아민 (0.2 mL, 01.47 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 1 시간 후 반응 용액을 가열 환류시키고 12 시간 동안 교반하였다. 반응 용액을 에틸 아세테이트 (30 mL)로 희석한 후 소금물 (20 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 132 (1.0 g, 83%)를 수득하였다. Compound 131 (590 mg, 0.54 mmol) was dissolved in dry tetrahydrofuran (5 mL), followed by addition of triphosgen (116 mg, 0.39 mmol) and triethylamine (0.2 mL, 1.47 mmol) at -10 ° C and nitrogen atmosphere. Under stirring for 1 hour. Compound 20 (707 mg, 1.30 mmol) was dissolved in dry tetrahydrofuran (5 mL), triethylamine (0.2 mL, 01.47 mmol) was added and the solution was slowly added to the reaction solution. After 1 hour the reaction solution was heated to reflux and stirred for 12 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 132 (1.0 g, 83%) was obtained.
EI-MS m/z : [M+H]+ 2219.10, 1/2[M+H]+ 1110.30EI-MS m / z: [M + H] + 2219.10, 1/2 [M + H] + 1110.30
화합물 133의 제조Preparation of Compound 133
화합물 132 (1 g, 0.45 mmol)를 테트라하이드로퓨란/증류수 (5 mL/5 mL)에 녹이고 아세트산 (15 mL)을 첨가한 후 상온, 질소 대기 하에서 16 시간 동안 교반하였다. 반응 용액을 에틸 아세테이트 (50 mL)로 희석한 후 증류수 (50 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 133 (720 mg, 80%)을 수득하였다. Compound 132 (1 g, 0.45 mmol) was dissolved in tetrahydrofuran / distilled water (5 mL / 5 mL) and acetic acid (15 mL) was added, followed by stirring for 16 hours at room temperature and nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (50 mL), washed with distilled water (50 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 133 (720 mg, 80%) was obtained.
EI-MS m/z : [M+H]+ 1990.95, 1/2[M+H]+ 996.06.EI-MS m / z: [M + H] + 1990.95, 1/2 [M + H] + 996.06.
화합물 134의 제조Preparation of Compound 134
화합물 133 (370 mg, 0.18 mmol)을 다이클로로메테인 (10 mL)에 녹인 후 데스-마틴 펄아이오디네인 (Dess-Martin periodinane, 181 mg, 0.42 mmol)을 첨가하고 상온, 질소 대기 하에서 16 시간 동안 교반하였다. 반응 용액을 다이클로로메테인(20 mL)으로 희석한 후 포화 탄산수소나트륨 수용액 (20 mL)으로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 134 (350 mg, 90%)를 수득하였다. Compound 133 (370 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of Dess-Martin periodinane (181 mg, 0.42 mmol). Stir for hours. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 134 (350 mg, 90%) was obtained.
EI-MS m/z : [M+H]+ 1986.61, 1/2[M+H]+ 994.11.EI-MS m / z: [M + H] + 1986.61, 1/2 [M + H] + 994.11.
화합물 135의 제조Preparation of Compound 135
화합물 134 (350 mg, 0.17 mmol)를 메탄올/테트라하이드로퓨란 (7.5 mL/7.5 mL)에 녹인 후 증류수 (7.5 mL)에 녹아있는 수산화 리튬 (66 mg, 1.58 mmol)을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 0 ℃로 올리고 2 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축 후 HPLC로 정제하고 동결 건조하여 화합물 135 (150 mg, 50%)를 흰색의 고체로 수득하였다. Compound 134 (350 mg, 0.17 mmol) was dissolved in methanol / tetrahydrofuran (7.5 mL / 7.5 mL) and lithium hydroxide (66 mg, 1.58 mmol) dissolved in distilled water (7.5 mL) was added slowly at -40 ° C. . The reaction temperature was slowly raised to 0 ° C and stirred for 2 hours. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to compound 135 (150 mg, 50%) was obtained as a white solid.
EI-MS m/z : [M+H]+ 1706.20, 1/2[M+H]+ 854.00.EI-MS m / z: [M + H] + 1706.20, 1/2 [M + H] + 854.00.
<실시예 47> 화합물 137의 제조Example 47 Preparation of Compound 137
Figure PCTKR2018003744-appb-I000099
Figure PCTKR2018003744-appb-I000099
화합물 136의 제조Preparation of Compound 136
화합물 136은 화합물 126과 화합물 118로부터 화합물 134의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 2032.98, 1/2[M+H]+ 1017.03.Compound 136 was prepared by a method analogous to the synthesis of compound 134 from compound 126 and compound 118. EI-MS m / z: [M + H] + 2032.98, 1/2 [M + H] + 1017.03.
화합물 137의 제조Preparation of Compound 137
화합물 136 (205 mg, 0.10 mmol)을 메탄올/테트라하이드로퓨란 (4 mL/6 mL)에 녹인 후 수산화 리튬 (38 mg, 0.91 mmol)을 증류수 (4 mL)에 녹인 용액을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 0 ℃로 올리면서 4 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축하고 동결 건조하였다. 얻어진 고체를 다이클로로메테인 (5 mL)으로 묽힌 후 트라이플루오로아세트산 (1.5 mL)을 0 ℃에서 첨가하고 4 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 137 (29 mg, 17%)을 흰색의 고체로 수득하였다. compound 136 (205 mg, 0.10 mmol) was dissolved in methanol / tetrahydrofuran (4 mL / 6 mL) and then a solution of lithium hydroxide (38 mg, 0.91 mmol) in distilled water (4 mL) was added slowly at -40 ° C. . Stirred for 4 hours while slowly raising the reaction temperature to 0 ℃. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure and freeze-dried. The resulting solid was diluted with dichloromethane (5 mL), then trifluoroacetic acid (1.5 mL) was added at 0 ° C and stirred for 4 h. The reaction solution was concentrated under reduced pressure, purified by HPLC and freeze dried to give 137 (29 mg, 17%) was obtained as a white solid.
EI-MS m/z : [M+H]+ 1653.01, 1/2[M+H]+ 826.89.EI-MS m / z: [M + H] + 1653.01, 1/2 [M + H] + 826.89.
<< 실시예Example 48> 화합물 138의 제조 48> Preparation of Compound 138
Figure PCTKR2018003744-appb-I000100
Figure PCTKR2018003744-appb-I000100
화합물 138은 화합물 126과 화합물 124로부터 화합물 137의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1647.60, 1/2[M+H]+ 824.31.Compound 138 was prepared by a method similar to the synthesis of compound 137 from compound 126 and compound 124. EI-MS m / z: [M + H] + 1647.60, 1/2 [M + H] + 824.31.
<실시예 49> 화합물 142의 제조Example 49 Preparation of Compound 142
Figure PCTKR2018003744-appb-I000101
Figure PCTKR2018003744-appb-I000101
화합물 139의 제조Preparation of Compound 139
다이메틸 설폭사이드 (3.53 mL, 3.88 mmol)를 다이클로로메테인 (30 mL)에 녹인 후 -78 ℃, 질소 대기 하에서 옥살릴 클로라이드 (2.0 M 다이클로로메테인 용액, 13 mL, 23.9 mmol)를 첨가하였다. 화합물 6 (6.8 g, 9.94 mmol)를 다이클로로메테인 (20 mL)에 녹인 후 -78 ℃, 질소 대기 하에서 천천히 첨가하였다. 반응 용액을 10 분 동안 교반한 후 0 ℃로 온도를 올리고 트라이에틸아민 (13.85 mL, 4.41 mmol)을 천천히 첨가한 후 상온에서 2 시간 동안 교반하였다. 포화 암모늄 클로라이드 수용액 (200 mL)을 반응 용액에 첨가하고 다이클로로메테인 (3 x 100 mL)으로 추출하였다. 모인 유기층을 소금물 (2 x 100 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 139 (5.76 g, 85%)를 수득하였다. Dimethyl sulfoxide (3.53 mL, 3.88 mmol) was dissolved in dichloromethane (30 mL) and oxalyl chloride (2.0 M dichloromethane solution, 13 mL, 23.9 mmol) was added at -78 ° C under nitrogen atmosphere. It was. Compound 6 (6.8 g, 9.94 mmol) was dissolved in dichloromethane (20 mL) and slowly added to -78 ° C under nitrogen atmosphere. After the reaction solution was stirred for 10 minutes, the temperature was raised to 0 ° C. and triethylamine (13.85 mL, 4.41 mmol) was added slowly, followed by stirring at room temperature for 2 hours. Saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 139 (5.76 g, 85%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 9.80 (s, 2H), 7.72 (s, 2H), 6.85 (s, 2H), 5.07 (s, 2H), 4.93 (s, 2H), 4.22-4.10 (m, 6H), 4.00 (s, 6H), 3.94-3.80 (m, 4H), 3.15-2.70 (m, 4H), 2.30-2.10(m, 2H), 2.12-1.90 (m, 4H), 1.75-1.68 (m, 6H). EI-MS m/z : [M+H]+ 681.6. 1 H-NMR (400 MHz, CDCl 3 ) δ 9.80 (s, 2H), 7.72 (s, 2H), 6.85 (s, 2H), 5.07 (s, 2H), 4.93 (s, 2H), 4.22-4.10 (m, 6H), 4.00 (s, 6H), 3.94-3.80 (m, 4H), 3.15-2.70 (m, 4H), 2.30-2.10 (m, 2H), 2.12-1.90 (m, 4H), 1.75 -1.68 (m, 6 H). EI-MS m / z: [M + H] + 681.6.
화합물 140의 제조Preparation of Compound 140
화합물 139 (1.84 g, 2.71 mmol)를 벤젠과 N,N-다이메틸폼아마이드 (v/v=10:1, 30 mL)에 녹인 후 상온에서 에틸렌글리콜 (1.5 mL, 27.11 mmol)과 캠퍼설폰산 (251 mg, 0.81 mmol)을 질소 대기 하에서 순차적으로 첨가하였다. 반응 용액을 5 분 동안 교반한 후, 딘-스탁 (Dean-Stark)장치를 이용하여 가열 환류시키고 2 시간 동안 교반하였다. 반응 용액을 농축하고 에틸 아세테이트 (100 mL)로 희석한 후 포화 탄산수소나트륨 수용액 (100 mL)를 반응 용액에 넣고 에틸 아세테이트 (3 x 100 mL)로 추출하였다. 모인 유기층을 소금물 (2 x 100 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 140 (1.53 g, 72%)을 수득하였다. Compound 139 (1.84 g, 2.71 mmol) was dissolved in benzene and N, N -dimethylformamide (v / v = 10: 1, 30 mL), followed by ethylene glycol (1.5 mL, 27.11 mmol) and camphorsulfonic acid at room temperature. (251 mg, 0.81 mmol) were added sequentially under a nitrogen atmosphere. The reaction solution was stirred for 5 minutes, then heated to reflux using a Dean-Stark apparatus and stirred for 2 hours. The reaction solution was concentrated and diluted with ethyl acetate (100 mL), then saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the reaction solution, and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 140 (1.53 g, 72%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.70 (s, 2H), 6.78 (s, 2H), 5.07 (s, 2H), 4.81 (s, 2H), 4.69 (s, 2H), 4.20-4.02 (m, 6H), 4.00-3.90 (m, 8H), 3.87-3.80 (m, 2H), 3.78-3.70 (m, 4H), 3.60-3.68 (m, 4H), 2.72-2.60 (m, 4H), 2.12-1.92 (m, 4H), 1.65-1.60 (m, 2H). EI-MS m/z : [M+H]+ 769.8. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.70 (s, 2H), 6.78 (s, 2H), 5.07 (s, 2H), 4.81 (s, 2H), 4.69 (s, 2H), 4.20-4.02 (m, 6H), 4.00-3.90 (m, 8H), 3.87-3.80 (m, 2H), 3.78-3.70 (m, 4H), 3.60-3.68 (m, 4H), 2.72-2.60 (m, 4H) , 2.12-1.92 (m, 4H), 1.65-1.60 (m, 2H). EI-MS m / z: [M + H] + 769.8.
화합물 141의 제조Preparation of Compound 141
화합물 140 (1.11 g, 1.45 mmol)을 에탄올 (22 mL)에 녹인 후 아연 가루 (Zinc dust, 2.84 g, 43.39 mmol)와 포름산 (5 % 에탄올 용액, 1.96 mL)을 첨가하였다. 상온에서 반응 용액을 3 시간 교반한 후, 셀라이트로 여과하고 에틸 아세테이트 (300 mL)를 첨가하였다. 유기층을 증류수 (2 x 100 mL), 포화 탄산수소나트륨 수용액 (2 X 200 mL), 그리고 소금물 (200 mL)순으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 141 (800 mg, 78%)을 수득하였다. Compound 140 (1.11 g, 1.45 mmol) was dissolved in ethanol (22 mL), and zinc powder (Zinc dust, 2.84 g, 43.39 mmol) and formic acid (5% ethanol solution, 1.96 mL) were added. The reaction solution was stirred for 3 hours at room temperature, filtered through Celite and ethyl acetate (300 mL) was added. The organic layer was washed with distilled water (2 × 100 mL), saturated aqueous sodium hydrogen carbonate solution (2 × 200 mL), and brine (200 mL) and then dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 141 (800 mg, 78%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 6.78 (s, 2H), 6.23 (s, 2H), 5.12 (s, 2H), 4.97 (s, 2H), 4.91 (s, 2H), 4.78 (br s, 2H), 4.54 (br s, 2H), 4.33-4.21 (m, 2H), 4.10-3.91 (m, 12H), 3.90-3.82 (m, 4H), 3.78 (s, 6H), 2.72-2.58 (m, 4H), 1.98-1.84 (m, 4H), 1.74-1.58 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H). EI-MS m/z : [M+H]+ 709.8. 1 H-NMR (400 MHz, CDCl 3 ) δ 6.78 (s, 2H), 6.23 (s, 2H), 5.12 (s, 2H), 4.97 (s, 2H), 4.91 (s, 2H), 4.78 (br s, 2H), 4.54 (br s, 2H), 4.33-4.21 (m, 2H), 4.10-3.91 (m, 12H), 3.90-3.82 (m, 4H), 3.78 (s, 6H), 2.72-2.58 (m, 4H), 1.98-1.84 (m, 4H), 1.74-1.58 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H). EI-MS m / z: [M + H] + 709.8.
화합물 142의 제조Preparation of Compound 142
화합물 141 (640 mg, 0.90 mmol)을 다이클로로메테인 (45 mL)에 녹인 후 피리딘 (0.15 mL, 1.80 mmol)과 알릴 클로로포메이트 (86 μL, 0.81 mmol)를 -78 ℃,질소 대기 하에서 첨가하였다. 반응 용액을 1 시간 동안 교반한 후 반응 온도를 상온으로 올리고, 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 142 (320 mg, 43%)를 수득하였다. Compound 141 (640 mg, 0.90 mmol) was dissolved in dichloromethane (45 mL), and then pyridine (0.15 mL, 1.80 mmol) and allyl chloroformate (86 μL, 0.81 mmol) were added under -78 ° C under a nitrogen atmosphere. It was. After stirring the reaction solution for 1 hour, the reaction temperature was raised to room temperature, concentrated and purified by column chromatography to give 142 (320 mg, 43%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.75 (br, 1H), 7.83 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.23 (s, 1H), 5.97-5.91 (m, 1H), 5.34,(d, J = 17.2 Hz, 1H), 5.23 (d, J = 10.0 Hz, 1H), 5.08 (br s, 1H), 5.02-4.88 (m, 6H), 4.80 (br s, 1H), 4.68-4.56 (m, 2H), 4.44 (br s, 2H), 4.30-4.18 (m, 2H), 4.16-4.06 (m, 3H), 3.92-3.84 (m, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 2.74-2.56 (m, 4H), 1.99-1.86 (m, 4H), 1.72-1.60 (m, 2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.75 (br, 1H), 7.83 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.23 (s, 1H), 5.97-5.91 (m, 1H), 5.34, (d, J = 17.2 Hz, 1H), 5.23 (d, J = 10.0 Hz, 1H), 5.08 (br s, 1H), 5.02-4.88 (m, 6H), 4.80 ( br s, 1H), 4.68-4.56 (m, 2H), 4.44 (br s, 2H), 4.30-4.18 (m, 2H), 4.16-4.06 (m, 3H), 3.92-3.84 (m, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 2.74-2.56 (m, 4H), 1.99-1.86 (m, 4H), 1.72-1.60 (m, 2H).
<실시예 50> 화합물 146의 제조Example 50 Preparation of Compound 146
Figure PCTKR2018003744-appb-I000102
Figure PCTKR2018003744-appb-I000102
화합물 143의 제조Preparation of Compound 143
화합물 142 (260 mg, 0.35 mmol)를 테트라하이드로퓨란 (4 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (40 mg, 0.13 mmol)과 트라이에틸아민 (0.078 mL, 0.56 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 20 (208 mg, 0.39 mmol)과 트라이에틸아민 (0.087 mL, 0.62 mmol)을 건조한 테트라하이드로퓨란 (3 mL)에 녹이고, 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 3 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (50 mL)로 희석한 후, 소금물 (2 x 20 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 143 (340 mg, 71 %)을 수득하였다. Compound 142 (260 mg, 0.35 mmol) was dissolved in tetrahydrofuran (4 mL), and then triphosgen (40 mg, 0.13 mmol) and triethylamine (0.078 mL, 0.56 mmol) were added at -10 ° C under nitrogen atmosphere. Stir for 1 hour. Compound 20 (208 mg, 0.39 mmol) and triethylamine (0.087 mL, 0.62 mmol) were dissolved in dry tetrahydrofuran (3 mL) and this solution was slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 3 hours. The reaction solution was concentrated and diluted with dichloromethane (50 mL), washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 143 (340 mg, 71%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.95 (d, J = 12.2 Hz, 1H), 7.83 (br s, 1H), 7.52-7.41 (m, 2H), 7.27 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 6.00-5.88 (m, 1H), 5.42-5.23, (m, 10H), 5.20-5.08 (m, 4H), 5.06-4.82 (m, 8H), 4.67 (s, 1H), 4.28-4.18 (m, 6H), 4.16-4.06 (m, 8H), 4.05-3.86 (m, 6H), 3.86 (s, 3H), 3.76 (s, 3H), 3.52-3.62 (m, 3H), 3.41 (s, 3H), 2.78-2.58 (m, 2H), 2.12-2.06 (m, 2H), 2.05 (s, 9H), 1.86-2.01 (m, 4H), 1.72-1.60 (m, 2H), 1.27 (t, J = 7.2 Hz, 2H). EI-MS m/z : [M+H]+ 1361.5, 1/2[M+H]+ 681.6. 1 H-NMR (400 MHz, CDCl 3 ) δ 8.78 (br s, 1H), 7.95 (d, J = 12.2 Hz, 1H), 7.83 (br s, 1H), 7.52-7.41 (m, 2H), 7.27 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 6.00-5.88 (m, 1H), 5.42-5.23, (m, 10H), 5.20-5.08 (m, 4H), 5.06-4.82 (m, 8H), 4.67 (s, 1H), 4.28-4.18 (m, 6H), 4.16-4.06 (m, 8H), 4.05-3.86 ( m, 6H), 3.86 (s, 3H), 3.76 (s, 3H), 3.52-3.62 (m, 3H), 3.41 (s, 3H), 2.78-2.58 (m, 2H), 2.12-2.06 (m, 2H), 2.05 (s, 9H), 1.86-2.01 (m, 4H), 1.72-1.60 (m, 2H), 1.27 (t, J = 7.2 Hz, 2H). EI-MS m / z: [M + H] + 1361.5, 1/2 [M + H] + 681.6.
화합물 144의 제조Preparation of Compound 144
화합물 143 (330 mg, 0.24 mmol)을 다이클로로메테인 (5 mL)에 녹인 후 피롤리딘 (0.026 mL, 0.365 mmol)과 테트라키스(트라이페닐포스핀)팔라듐(0) (14 mg, 0.012 mmol)을 첨가하고 상온, 질소 대기 하에서 5 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 144 (290 mg, 90 %)를 수득하였다. Compound 143 (330 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), followed by pyrrolidine (0.026 mL, 0.365 mmol) and tetrakis (triphenylphosphine) palladium (0) (14 mg, 0.012 mmol ) Was added and stirred for 5 hours at room temperature and nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give the compound 144 (290 mg, 90%).
1H-NMR (400 MHz, CDCl3) δ 8.82 (br s, 1H), 8.05 (s, 1H), 7.52-7.42 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 6.24 (s, 1H), 5.44-5.26, (m, 4H), 5.16-5.04 (m, 4H), 5.02-4.86 (m, 5H), 4.52-4.38 (m, 2H), 4.30-4.10 (m, 6H), 4.16-4.07 (m, 5H), 4.04-3.92 (m, 6H), 3.91-3.84 (m, 6H), 3.83 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 3.60-3.52 (m, 3H), 3.41 (s, 3H), 2.71-2.58 (m, 4H), 2.05 (s, 9H), 1.97-1.85 (m, 4H), 1.72-1.58 (m, 4H), 1.25 (t, J = 7.2 Hz, 2H). EI-MS m/z : [M+H]+ 1277.2, 1/2[M+H]+ 639.4. 1 H-NMR (400 MHz, CDCl 3 ) δ 8.82 (br s, 1H), 8.05 (s, 1H), 7.52-7.42 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 6.24 (s, 1H), 5.44-5.26, (m, 4H), 5.16-5.04 (m, 4H), 5.02-4.86 (m, 5H), 4.52-4.38 (m, 2H), 4.30-4.10 (m, 6H), 4.16-4.07 (m, 5H), 4.04- 3.92 (m, 6H), 3.91-3.84 (m, 6H), 3.83 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 3.60-3.52 (m, 3H), 3.41 (s, 3H), 2.71-2.58 (m, 4H), 2.05 (s, 9H), 1.97-1.85 (m, 4H), 1.72-1.58 (m, 4H), 1.25 (t, J = 7.2 Hz, 2H). EI-MS m / z: [M + H] + 1277.2, 1/2 [M + H] + 639.4.
화합물 145의 제조Preparation of Compound 145
화합물 144 (340 mg, 0.29 mmol)를 건조한 테트라하이드로퓨란 (3 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (25 mg, 0.09 mmol)과 트라이에틸아민 (0.060 mL, 0.43 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 32 (229 mg, 0.31 mmol)를 건조한 테트라하이드로퓨란 (3 mL)에 녹이고 트라이에틸아민 (0.060 mL, 0.43 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (100 mL)로 희석한 후 소금물 (2 x 50 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 145 (250 mg, 43%)를 수득하였다. Compound 144 (340 mg, 0.29 mmol) was dissolved in dry tetrahydrofuran (3 mL), and then triphosgene (25 mg, 0.09 mmol) and triethylamine (0.060 mL, 0.43 mmol) were added at -10 ° C and nitrogen atmosphere. Under stirring for 1 hour. Compound 32 (229 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran (3 mL), triethylamine (0.060 mL, 0.43 mmol) was added and the solution was slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (2 x 50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 145 (250 mg, 43%) was obtained.
EI-MS m/z : [M+Na]+ 2056.4, 1/2[M+H]+ 967.7.EI-MS m / z: [M + Na] + 2056.4, 1/2 [M + H] + 967.7.
화합물 146의 제조Preparation of Compound 146
화합물 145 (230 mg, 0.113 mmol)를 메탄올/테트라하이드로퓨란 (3 mL/3 mL)에 녹인 후 수산화 리튬 (48 mg, 1.13 mmol)을 증류수 (6 mL)에 녹인 용액을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 0 ℃로 올리면서 2 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축하고 진공 건조 하였다. 얻어진 고체를 다이클로로메테인 (10 mL)으로 묽힌 후, 트라이플루오로아세트산 (2 mL)을 0 ℃에서 첨가하고 2 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 146 (15.6 mg)을 흰색의 고체로 수득하였다. Compound 145 (230 mg, 0.113 mmol) was dissolved in methanol / tetrahydrofuran (3 mL / 3 mL), and then a solution of lithium hydroxide (48 mg, 1.13 mmol) in distilled water (6 mL) was added slowly at -40 ° C. It was. Stirred for 2 hours while slowly raising the reaction temperature to 0 ℃. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure and dried in vacuo. The solid obtained was diluted with dichloromethane (10 mL), then trifluoroacetic acid (2 mL) was added at 0 ° C. and stirred for 2 h. The reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to give compound 146 (15.6 mg) as a white solid.
EI-MS m/z : [M+H]+ 1653.7, 1/2[M+H]+ 827.6.EI-MS m / z: [M + H] + 1653.7, 1/2 [M + H] + 827.6.
<실시예 51> 화합물 148의 제조Example 51 Preparation of Compound 148
Figure PCTKR2018003744-appb-I000103
Figure PCTKR2018003744-appb-I000103
화합물 147의 제조Preparation of Compound 147
화합물 144 (266 mg, 0.21 mmol)를 건조한 테트라하이드로퓨란 (3 mL)에 녹인 후 -10 ℃에서 트라이포스겐 (16 mg, 0.06 mmol)과 트라이에틸아민 (0.044 mL, 0.31 mmol)을 첨가하고 질소 대기 하에서 1 시간 동안 교반하였다. 화합물 55 (147 mg, 0.23 mmol)를 건조한 테트라하이드로퓨란 (3 mL)에 녹이고 트라이에틸아민 (0.044 mL, 0.31 mmol)을 첨가한 후 이 용액을 반응 용액에 서서히 첨가하였다. 30 분 후 반응 용액을 가열 환류시키고 4 시간 동안 교반하였다. 반응 용액을 농축하고 다이클로로메테인 (100 mL)로 희석한 후 소금물 (2 x 50 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 147 (170 mg, 42%)를 수득하였다. Compound 144 (266 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran (3 mL), and then triphosgene (16 mg, 0.06 mmol) and triethylamine (0.044 mL, 0.31 mmol) were added at -10 ° C and nitrogen atmosphere. Under stirring for 1 hour. Compound 55 (147 mg, 0.23 mmol) was dissolved in dry tetrahydrofuran (3 mL), triethylamine (0.044 mL, 0.31 mmol) was added and the solution was slowly added to the reaction solution. After 30 minutes the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (2 x 50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 147 (170 mg, 42%) was obtained.
EI-MS m/z : [M+Na]+ 1944.6, 1/2[M+H]+ 972.8.EI-MS m / z: [M + Na] + 1944.6, 1/2 [M + H] + 972.8.
화합물 148의 제조Preparation of Compound 148
화합물 147 (120 mg, 0.087 mmol)을 메탄올/테트라하이드로퓨란 (3 mL/3 mL)에 녹인 후 수산화 리튬 (37 mg, 0.87 mmol)을 증류수 (6 mL)에 녹인 용액을 -40 ℃에서 서서히 첨가하였다. 반응 온도를 서서히 0 ℃로 올리면서 2 시간 동안 교반하였다. 반응 용액을 아세트산으로 중화한 후 반응 용액을 감압 농축하고 진공 건조 하였다. 얻어진 고체를 다이클로로메테인 (8 mL)으로 묽힌 후, 트라이플루오로아세트산 (2 mL)을 0 ℃에서 첨가하고 2 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 148 (31 mg)을 흰색의 고체로 수득하였다. Compound 147 (120 mg, 0.087 mmol) was dissolved in methanol / tetrahydrofuran (3 mL / 3 mL), and then a solution of lithium hydroxide (37 mg, 0.87 mmol) in distilled water (6 mL) was added slowly at -40 ° C. It was. Stirred for 2 hours while slowly raising the reaction temperature to 0 ℃. After neutralizing the reaction solution with acetic acid, the reaction solution was concentrated under reduced pressure and dried in vacuo. The solid obtained was diluted with dichloromethane (8 mL), then trifluoroacetic acid (2 mL) was added at 0 ° C. and stirred for 2 h. The reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to give compound 148 (31 mg) as a white solid.
EI-MS m/z : [M+H]+ 1663.4, 1/2[M+H]+ 832.7.EI-MS m / z: [M + H] + 1663.4, 1/2 [M + H] + 832.7.
<실시예 52> 화합물 155의 제조Example 52 Preparation of Compound 155
Figure PCTKR2018003744-appb-I000104
Figure PCTKR2018003744-appb-I000104
Figure PCTKR2018003744-appb-I000105
Figure PCTKR2018003744-appb-I000105
화합물 149의 제조Preparation of Compound 149
화합물 4 (13.8 g, 92.5 mmol)를 다이클로로메테인 (400 mL)에 녹인 후 이미다졸 (18.8 g, 277.5 mmol)과 다이클로로메테인 (100 mL)에 녹아있는 t-뷰틸다이메틸실릴 클로라이드 (15.3 g, 101.7 mmol)를 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 상온에서 2 시간 동안 교반한 후 소금물 (30 mL) 를 반응 용액에 넣고 다이클로로메테인 (2 x 300 mL)으로 추출한 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 149 (17 g, 80%)를 수득하였다. Compound 4 (13.8 g, 92.5 mmol) was dissolved in dichloromethane (400 mL), and then t -butyldimethylsilyl chloride dissolved in imidazole (18.8 g, 277.5 mmol) and dichloromethane (100 mL) ( 15.3 g, 101.7 mmol) were added at 0 ° C. under a nitrogen atmosphere. After the reaction solution was stirred at room temperature for 2 hours, brine (30 mL) was added to the reaction solution, extracted with dichloromethane (2 x 300 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 149 (17 g, 80%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 4.91, (d, J = 14.4 Hz, 2H), 3.66-3.47 (m, 4H), 3.27-3.24 (m, 1H), 2.47-2.42 (m, 1H), 2.24-2.18 (m, 1H), 0.91 (s, 9H), 0.05 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 4.91, (d, J = 14.4 Hz, 2H), 3.66-3.47 (m, 4H), 3.27-3.24 (m, 1H), 2.47-2.42 ( m, 1H), 2.24-2.18 (m, 1H), 0.91 (s, 9H), 0.05 (s, 6H).
화합물 151의 제조Preparation of Compound 151
화합물 150 (17.3 g, 46.8 mmol, 화합물 150은 ACS Med . Chem . Lett . 2016, 7, 983에 기술된 방법으로 제조하였다)을 N,N-다이메틸폼아마이드 (100 mL)에 녹인 후 0 ℃, 질소 대기 하에서 1-하이드록시벤조트리아졸 (6.8 g 50.7 mmol), 1-(3-다이메틸아미노프로필)-3-에틸카보다이이미드 염산염 (10.4 g, 54.6 mmol) 순으로 첨가한 후 30 분간 교반하였다. 다이클로로메테인 (50 mL)에 녹아있는 화합물 149 (8.8 g, 39.0 mmol)와 트라이에틸아민 (9.78 mL, 70.2 mmol) 용액을 질소 대기 하에서 첨가하였다. 반응 온도를 상온으로 올리고 12 시간 동안 교반한 후, 다이클로로메테인 (100 mL)으로 희석하고, 포화 탄산수소나트륨 수용액 수용액 (100 mL)으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 151 (19.9 g, 89%)을 수득하였다. Compound 150 (17.3 g, 46.8 mmol, Compound 150 was prepared by the method described in ACS Med . Chem . Lett . 2016, 7, 983) was dissolved in N, N -dimethylformamide (100 mL) and then 0 ° C. 1-hydroxybenzotriazole (6.8 g 50.7 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.4 g, 54.6 mmol) under nitrogen atmosphere, and then 30 minutes Stirred. Compound 149 dissolved in dichloromethane (50 mL) (8.8 g, 39.0 mmol) and Triethylamine (9.78 mL, 70.2 mmol) The solution was added under nitrogen atmosphere. The reaction temperature was raised to room temperature, stirred for 12 hours, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium hydrogen carbonate solution (100 mL), and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 151 (19.9 g, 89%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 7.69 (s, 1H), 6.72 (s, 1H), 4.97 (s, 1H), 4.82 (s, 1H), 4.57-4.54 (m, 1H) 3.89 (s, 4H), 3.74-3.71 (m, 2H) 3.30-3.27 (m, 1H), 2.76-2.52 (m, 2H), 1.31-1.23 (m, 3H), 1.08 (s, 18H), 0.89 (s, 9H), 0.08 (s, 3H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 7.69 (s, 1H), 6.72 (s, 1H), 4.97 (s, 1H), 4.82 (s, 1H), 4.57-4.54 (m, 1H ) 3.89 (s, 4H), 3.74-3.71 (m, 2H) 3.30-3.27 (m, 1H), 2.76-2.52 (m, 2H), 1.31-1.23 (m, 3H), 1.08 (s, 18H), 0.89 (s, 9 H), 0.08 (s, 3 H).
화합물 152의 제조Preparation of Compound 152
화합물 151 (29.5 g, 50.9 mmol)을 에탄올 (720 mL)에 녹인 후 아연 가루 (Zinc dust, 66.6 g, 1019.1 mmol)와 포름산 (38 mL, 1019.1 mmol)을 첨가하였다. 상온에서 반응 용액을 40 분간 교반한 후, 셀라이트로 여과하고 에틸 아세테이트 (500 mL)를 첨가하였다. 유기층을 증류수 (500 mL), 포화 탄산수소나트륨 수용액 (500 mL), 그리고 소금물 (500 mL)순으로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 152 (27.9 g, 99%)를 수득하였다. Compound 151 (29.5 g, 50.9 mmol) was dissolved in ethanol (720 mL), and zinc powder (Zinc dust, 66.6 g, 1019.1 mmol) and formic acid (38 mL, 1019.1 mmol) were added thereto. The reaction solution was stirred for 40 minutes at room temperature, filtered through Celite and ethyl acetate (500 mL) was added. The organic layer was washed with distilled water (500 mL), saturated aqueous sodium hydrogen carbonate solution (500 mL), and brine (500 mL) and then dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 152 (27.9 g, 99%) was obtained.
1H-NMR (400MHz, CDCl3) (rotamers) δ 6.71 (s, 1H), 6.25 (s, 1H), 4.96-4.89 (m, 2H), 4.53 (br s, 1H), 4.21-4.09 (m, 4H), 3.74 (br s, 1H), 3.71 (s, 3H), 3.62 (br s, 1H), 2.73-2.63 (m, 2H), 1.29-1.21 (m, 3H), 1.05 (s, 18H), 0.87 (s, 9H), 0.02 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 6.71 (s, 1H), 6.25 (s, 1H), 4.96-4.89 (m, 2H), 4.53 (br s, 1H), 4.21-4.09 (m , 4H), 3.74 (br s, 1H), 3.71 (s, 3H), 3.62 (br s, 1H), 2.73-2.63 (m, 2H), 1.29-1.21 (m, 3H), 1.05 (s, 18H ), 0.87 (s, 9H), 0.02 (s, 6H).
화합물 153의 제조Preparation of Compound 153
화합물 152 (27.9 g, 50.8 mmol)를 다이클로로메테인 (300 mL)에 녹인 후 피리딘 (9 mL, 111.8 mmol)과 알릴 클로로포메이트 (5.9 mL, 55.9 mmol)를 -78 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 1 시간 동안 교반한 후 반응 온도를 상온으로 올리고, 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 153 (31.8 g, 99%)을 수득하였다. Compound 152 (27.9 g, 50.8 mmol) was dissolved in dichloromethane (300 mL), and then pyridine (9 mL, 111.8 mmol) and allyl chloroformate (5.9 mL, 55.9 mmol) were added at -78 ° C under a nitrogen atmosphere. It was. After stirring the reaction solution for 1 hour, the reaction temperature was raised to room temperature, concentrated and purified by column chromatography to give compound 153 (31.8 g, 99%) was obtained.
1H-NMR (400MHz, CDCl3) (rotamers) δ 8.67 (br s, 1H), 7.75 (s, 1H), 6.78 (s, 1H), 5.99-5.89 (m, 1H), 5.33, (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.98-4.90 (m, 2H), 4.66-4.57 (m, 3H), 4.19-4.11 (m, 1H), 4.01 (br s, 1H), 3.86 (br s, 1H), 3.76 (s, 3H), 3.65 (br s, 1H), 2.68 (s, 2H), 1.33-1.24 (m, 3H), 1.05 (s, 18), 0.87 (s, 9H), 0.03 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 8.67 (br s, 1H), 7.75 (s, 1H), 6.78 (s, 1H), 5.99-5.89 (m, 1H), 5.33, (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.98-4.90 (m, 2H), 4.66-4.57 (m, 3H), 4.19-4.11 (m, 1H), 4.01 (br s, 1H), 3.86 (br s, 1H), 3.76 (s, 3H), 3.65 (br s, 1H), 2.68 (s, 2H), 1.33-1.24 (m, 3H), 1.05 (s, 18) , 0.87 (s, 9 H), 0.03 (s, 6 H).
화합물 154의 제조Preparation of Compound 154
화합물 153 (31.8 g, 50.2 mmol)을 N,N-다이메틸폼아마이드 (300 mL)와 증류수 (6 mL)에 녹인 후 0 ℃, 질소 대기 하에서 아세트산 나트륨 (5 g, 60.2 mmol)을 첨가하고 상온에서 2 시간 교반하였다. 반응 용액을 에틸아세테이트(300 mL)로 희석한 후, 증류수 (300 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 154 (17.7 g, 74 %)를 수득하였다.Compound 153 (31.8 g, 50.2 mmol) was dissolved in N, N -dimethylformamide (300 mL) and distilled water (6 mL), and sodium acetate (5 g, 60.2 mmol) was added at 0 ° C. and nitrogen atmosphere. Stirred for 2 hours. The reaction solution was diluted with ethyl acetate (300 mL), washed with distilled water (300 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 154 (17.7 g, 74%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 8.75 (br s, 1H), 7.75 (s, 1H), 6.78 (s, 1H), 6.14 (s, 1H), 5.94-5.90 (m, 1H), 5.32, (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.97-4.90 (m, 2H), 4.65-4.56 (m, 3H), 4.18-4.15 (m, 1H), 4.01 (br s, 1H), 3.85 (s, 4H), 3.65 (br s, 1H), 2.68 (s, 2H), 0.87 (s, 9H), 0.02 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 8.75 (br s, 1H), 7.75 (s, 1H), 6.78 (s, 1H), 6.14 (s, 1H), 5.94-5.90 (m, 1H), 5.32, (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.97-4.90 (m, 2H), 4.65-4.56 (m, 3H), 4.18-4.15 ( m, 1H), 4.01 (br s, 1H), 3.85 (s, 4H), 3.65 (br s, 1H), 2.68 (s, 2H), 0.87 (s, 9H), 0.02 (s, 6H).
화합물 155의 제조Preparation of Compound 155
화합물 154 (18.6 g, 39.0 mmol)를 아세톤 (200 mL)에 녹인 다음 질소 대기하에서 1,5-다이아이오도펜테인 (11.6 mL, 156 mmol)과 탄산 칼륨 (5.9 g, 42.9 mmol) 순으로 첨가한 후 60 ℃에서 12 시간 동안 교반하였다. 반응 용액을 농축하고 컬럼 크로마토그래피로 정제하여 화합물 155 (23 g, 87 %)를 수득하였다. Compound 154 (18.6 g, 39.0 mmol) was dissolved in acetone (200 mL) and then added in the order of 1,5-dioiopentane (11.6 mL, 156 mmol) and potassium carbonate (5.9 g, 42.9 mmol) in a nitrogen atmosphere. After stirring at 60 ° C for 12 hours. The reaction solution was concentrated and purified by column chromatography to give compound 155 (23 g, 87%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 8.88 (br s, 1H), 7.83 (s, 1H), 6.81 (s, 1H), 5.98-5.90 (m, 1H), 5.34, (d, J = 17.2 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.98-4.90 (m, 2H), 4.67-4.58 (m, 3H), 4.21-4.12 (m, 1H), 4.10-4.06 (m, 3H) 3.82 (s, 4H), 3.64 (br s, 1H), 3.23-3.19 (m, 2H), 2.69 (s, 2H), 1.94-1.84 (m, 4H), 1.62-1.55 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 8.88 (br s, 1H), 7.83 (s, 1H), 6.81 (s, 1H), 5.98-5.90 (m, 1H), 5.34, (d , J = 17.2 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.98-4.90 (m, 2H), 4.67-4.58 (m, 3H), 4.21-4.12 (m, 1H), 4.10- 4.06 (m, 3H) 3.82 (s, 4H), 3.64 (br s, 1H), 3.23-3.19 (m, 2H), 2.69 (s, 2H), 1.94-1.84 (m, 4H), 1.62-1.55 ( m, 2H), 0.87 (s, 9H), 0.03 (s, 6H).
<실시예 53> 화합물 162의 제조Example 53 Preparation of Compound 162
Figure PCTKR2018003744-appb-I000106
Figure PCTKR2018003744-appb-I000106
화합물 156의 제조Preparation of Compound 156
화합물 151 (9.3 g, 16.0 mmol)을 N,N-다이메틸폼아마이드 (100 mL)와 증류수 (2 mL)에 녹인 후 0 ℃, 질소 대기 하에서 아세트산 나트륨 (1.6 g, 19.2 mmol)을 첨가하고 상온에서 30 분간 교반하였다. 반응 용액을 에틸아세테이트(100 mL)로 희석한 후, 증류수 (100 mL)로 닦아주고 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 156 (5.4 g, 80%)을 수득하였다.Compound 151 (9.3 g, 16.0 mmol) was dissolved in N, N -dimethylformamide (100 mL) and distilled water (2 mL), followed by addition of sodium acetate (1.6 g, 19.2 mmol) under a nitrogen atmosphere at 0 ° C. Stirred for 30 min. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (100 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 156 (5.4 g, 80%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 7.75 (s, 1H), 6.76 (s, 1H), 6.07 (s, 1H), 4.98 (s, 1H), 4.83 (s, 1H), 4.58-4.54 (m, 1H), 3.99 (s, 3H), 3.89-3.87 (m, 1H), 3.77-3.70 (m, 2H), 3.33-3.29 (m, 1H), 2.81-2.53 (m, 2H), 0.89 (s, 9H), 0.09 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 7.75 (s, 1H), 6.76 (s, 1H), 6.07 (s, 1H), 4.98 (s, 1H), 4.83 (s, 1H), 4.58-4.54 (m, 1H), 3.99 (s, 3H), 3.89-3.87 (m, 1H), 3.77-3.70 (m, 2H), 3.33-3.29 (m, 1H), 2.81-2.53 (m, 2H ), 0.89 (s, 9H), 0.09 (s, 6H).
화합물 157의 제조Preparation of Compound 157
화합물 156 (3.0 g, 7.1 mmol)을 N,N-다이메틸폼아마이드 (30 mL)에 녹인 후 탄산 칼륨 (1.1 g, 7.8 mmol)과 벤질 브로마이드 (0.9 ml, 7.8 mmol)를 0 ℃, 질소 대기 하에서 첨가하였다. 반응 용액을 3 시간 동안 교반한 후 포화 암모늄 클로라이드 수용액 (50 mL)을 반응 용액에 넣고 에틸 아세테이트 (2 x 50 mL)로 추출하였다. 모인 유기층을 증류수 (2 x 100 mL), 소금물 (100 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 157 (3.6 g, 97%)을 수득하였다.Compound 156 (3.0 g, 7.1 mmol) was dissolved in N , N -dimethylformamide (30 mL), followed by potassium carbonate (1.1 g, 7.8 mmol) and benzyl bromide (0.9 ml, 7.8 mmol) at 0 ° C. in a nitrogen atmosphere. Added under. After stirring the reaction solution for 3 hours, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with distilled water (2 × 100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 157 (3.6 g, 97%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 7.77 (d, J = 4.8 Hz, 1H), 7.46-7.33 (m, 5H), 6.79 (d, J = 18.8 Hz, 1H), 5.22 (d, J = 5.2 Hz, 2H), 5.09 (d, J = 7.6 Hz, 1H), 4.98 (s, 1H), 4.83 (s, 1H), 4.58 (br s, 1H), 3.96 (s, 3H), 3.87 (br s, 1H), 3.77-3.69 (m, 2H), 3.30-3.28 (m, 1H), 2.81-2.53 (m, 2H), 0.89 (s, 9H), 0.09 (s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 7.77 (d, J = 4.8 Hz, 1H), 7.46-7.33 (m, 5H), 6.79 (d, J = 18.8 Hz, 1H), 5.22 ( d, J = 5.2 Hz, 2H), 5.09 (d, J = 7.6 Hz, 1H), 4.98 (s, 1H), 4.83 (s, 1H), 4.58 (br s, 1H), 3.96 (s, 3H) , 3.87 (br s, 1H), 3.77-3.69 (m, 2H), 3.30-3.28 (m, 1H), 2.81-2.53 (m, 2H), 0.89 (s, 9H), 0.09 (s, 6H).
화합물 158의 제조Preparation of Compound 158
화합물 157 (3.6 mg, 6.9 mmol)을 테트라하이드로퓨란/증류수 (15 mL/15 mL)에 녹이고 아세트산 (30 mL)을 첨가한 후 상온, 질소 대기 하에서 16 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 158 (2.8 g, 99%)을 수득하였다.Compound 157 (3.6 mg, 6.9 mmol) was dissolved in tetrahydrofuran / distilled water (15 mL / 15 mL) and acetic acid (30 mL) was added, followed by stirring at room temperature and nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure, and then purified by column chromatography to give Compound 158 (2.8 g, 99%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ7.77 (s, 1H), 7.47-7.35 (m, 5H), 6.81 (s, H), 5.22 (s, 2H), 5.02 (s, 1H), 4.87 (s, 1H), 4.60 (br s, 1H), 3.99 (s, 3H), 3.88 (br s, 1H), 3.83-3.72 (m, 3H), 3.54 (br s, 1H), 2.88-2.82 (m,1H), 2.52-2.48 (m,1H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ7.77 (s, 1H), 7.47-7.35 (m, 5H), 6.81 (s, H), 5.22 (s, 2H), 5.02 (s, 1H), 4.87 (s, 1H), 4.60 (br s, 1H), 3.99 (s, 3H), 3.88 (br s, 1H), 3.83-3.72 (m, 3H), 3.54 (br s, 1H), 2.88-2.82 (m, 1 H), 2.52-2.48 (m, 1 H).
화합물 159의 제조Preparation of Compound 159
옥살릴 클로라이드 (2.1 mL, 14.1 mmol)를 다이클로로메테인 (20 mL)에 녹인 후 -78 ℃, 질소 대기 하에서 다이메틸 설폭사이드 (1.5 mL, 21.1 mmol)를 첨가하였다. 1 시간 후 화합물 158 (2.7 g, 6.9 mmol)을 다이클로로메테인 (50 mL)에 녹인 용액을 서서히 첨가하였다. 반응 용액을 2 시간 동안 교반한 후 트라이에틸아민 (3.4 mL, 42.3 mmol)을 다이클로로메테인 (30 mL)에 희석하여 서서히 첨가하였다. 2 시간 동안 서서히 반응 온도를 0 ℃까지 올려주었다. 반응 용액을 다이클로로메테인 (100 mL)으로 묽히고, 유기층을 포화 암모늄 클로라이드 수용액 (200 mL)과 소금물 (200 mL)로 닦은 후 무수 황산 나트륨으로 건조하였다. 여과 후 농축하고 컬럼 크로마토그래피로 정제하여 화합물 159 (2.7 g, 96%)를 수득하였다. Oxalyl chloride (2.1 mL, 14.1 mmol) was dissolved in dichloromethane (20 mL) and then dimethyl sulfoxide (1.5 mL, 21.1 mmol) was added at −78 ° C. under nitrogen atmosphere. After 1 h, a solution of compound 158 (2.7 g, 6.9 mmol) in dichloromethane (50 mL) was added slowly. The reaction solution was stirred for 2 hours and then triethylamine (3.4 mL, 42.3 mmol) was diluted in dichloromethane (30 mL) and added slowly. The reaction temperature was slowly raised to 0 ° C. for 2 hours. The reaction solution was diluted with dichloromethane (100 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 159 (2.7 g, 96%).
1H-NMR (400 MHz, CDCl3) (rotamers) δ 9.79 (s, 1H), 7.79 (s, 1H), 7.46-7.26 (m, 5H), 6.87 (s, 1H), 5.22 (s, 2H), 5.06-4.96 (m, 1H), 4.93-4.90 (m, 1H), 4.78 (br s,1H), 4.62-4.56 (m, 1H), 3.99 (s, 3H), 3.93 (s, 1H), 3.85 (s, 1H), 2.91-2.62 (m, 2H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 9.79 (s, 1H), 7.79 (s, 1H), 7.46-7.26 (m, 5H), 6.87 (s, 1H), 5.22 (s, 2H ), 5.06-4.96 (m, 1H), 4.93-4.90 (m, 1H), 4.78 (br s, 1H), 4.62-4.56 (m, 1H), 3.99 (s, 3H), 3.93 (s, 1H) , 3.85 (s, 1 H), 2.91-2.62 (m, 2 H).
화합물 160의 제조Preparation of Compound 160
화합물 159 (2.7 g, 6.8 mmol)를 테트라하이드로퓨란/증류수 (60 mL/40 mL)에 녹인 후 소듐 다이싸이오나이트 (Na2S2O4, 11.2 g, 64.4 mmol)를 첨가 하였다. 질소 대기 하에서 20 시간 동안 교반하였다. 반응 용액에 메탄올 (60 ml)을 첨가하여 희석하고 6 N 염산 수용액을 첨가하여 산성화 (pH 2)하고 1 시간 동안 교반하였다. 반응 용액을 감압 농축하여 메탄올을 제거 하였다. 6 N 염산 수용액을 첨가하여 산성화(pH 2)하고 에틸 아세테이트 (5 x 100 mL)로 추출하였다. 모인 유기층을 무수 황산나트륨으로 건조하였다. 여과 후 감압 농축하고 컬럼 크로마토그래피로 정제하여 화합물 160 (1.8 g, 77%)을 수득하였다. Compound 159 (2.7 g, 6.8 mmol) was dissolved in tetrahydrofuran / distilled water (60 mL / 40 mL), followed by addition of sodium disionite (Na 2 S 2 O 4 , 11.2 g, 64.4 mmol). Stir for 20 hours under a nitrogen atmosphere. Methanol (60 ml) was added to the reaction solution to dilute, acidified by adding 6N aqueous hydrochloric acid (pH 2) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to remove methanol. 6N hydrochloric acid solution was added to acidify (pH 2) and extracted with ethyl acetate (5 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, purified by column chromatography Compound 160 (1.8 g, 77%) was obtained.
EI-MS m/z : [M+H]+ 349.3, [M+H2O]+ 367.3.EI-MS m / z: [M + H] + 349.3, [M + H 2 O] + 367.3.
화합물 161의 제조Preparation of Compound 161
화합물 160 (1.8 g, 5.3 mmol)을 다이클로로메테인/N,N-다이메틸폼아마이드 (20 mL/8 mL)에 녹인 후 0 ℃, 질소 대기 하에서 소듐 트라이아세톡시 보로하이드라이드(1.2 g, 5.8 mmol)를 첨가한 후 2 시간 동안 교반하였다. 증류수 (40 mL)를 반응 용액에 첨가한 후 다이클로로메테인 (2 x 50 mL)으로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 161 (1.2 g, 64%)을 수득하였다. Compound 160 (1.8 g, 5.3 mmol) was dissolved in dichloromethane / N , N -dimethylformamide (20 mL / 8 mL) and then sodium triacetoxy borohydride (1.2 g, 5.8 mmol) at 0 ° C. under nitrogen atmosphere. ) Was added and stirred for 2 hours. Distilled water (40 mL) was added to the reaction solution and extracted with dichloromethane (2 x 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give a compound 161. (1.2 g, 64%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.41-7.30 (m, 5H), 6.05 (s, 1H), 5.12 (s, 2H), 5.06 (s, 1H), 5.02 (s, 1H), 4.38 (d, J = 18 Hz, 1H), 4.27 (d, J = 16.4 Hz, 1H), 4.04-3.96 (m, 1H), 3.86 (s, 3H), 3.49 (d, J = 11 Hz, 1H), 3.29 (dd, J = 9.2 Hz, 1H), 2.91-2.85 (m, 1H), 2.40 (dd, J = 10 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.61 (s, 1H), 7.41-7.30 (m, 5H), 6.05 (s, 1H), 5.12 (s, 2H), 5.06 (s, 1H), 5.02 (s, 1H), 4.38 (d, J = 18 Hz, 1H), 4.27 (d, J = 16.4 Hz, 1H), 4.04-3.96 (m, 1H), 3.86 (s, 3H), 3.49 (d, J = 11 Hz, 1H), 3.29 (dd, J = 9.2 Hz, 1H), 2.91-2.85 (m, 1H), 2.40 (dd, J = 10 Hz, 1H).
화합물 162의 제조Preparation of Compound 162
화합물 161 (1.3 g, 3.7 mmol)을 다이클로로메테인 (70 mL)에 녹인 후 메테인썰폰 산 (25 mL)을 첨가하고 질소 대기 하에서 2 시간 동안 교반하였다. 증류수 (20 mL)를 반응 용액에 첨가한 후 탄산 나트륨을 첨가하여 중화하였다. 반응 용액에 물 (200 mL)을 첨가하여 희석하고 다이클로로메테인 (3 x 50 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 162 (620 mg, 64%)를 수득하였다. Compound 161 (1.3 g, 3.7 mmol) was dissolved in dichloromethane (70 mL), then methanesulfonic acid (25 mL) was added and stirred under a nitrogen atmosphere for 2 hours. Distilled water (20 mL) was added to the reaction solution, followed by neutralization by addition of sodium carbonate. To the reaction solution was diluted by addition of water (200 mL) and extracted with dichloromethane (3 x 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give 162 (620 mg, 64%) was obtained.
1H-NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 6.17 (s, 1H), 5.88 (br s, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 4.41 (d, J = 16.4 Hz, 1H), 4.31 (d, J = 16.4 Hz, 1H), 4.08-3.99 (m, 1H), 3.88 (s, 3H), 3.54 (d, J = 12.4 Hz, 1H), 3.49 (d, J = 11 Hz, 1H), 3.34 (dd, J = 9.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.43 (dd, J = 6.4 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 6.17 (s, 1H), 5.88 (br s, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 4.41 ( d, J = 16.4 Hz, 1H), 4.31 (d, J = 16.4 Hz, 1H), 4.08-3.99 (m, 1H), 3.88 (s, 3H), 3.54 (d, J = 12.4 Hz, 1H), 3.49 (d, J = 11 Hz, 1H), 3.34 (dd, J = 9.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.43 (dd, J = 6.4 Hz, 1H).
<실시예 54> 화합물 164의 제조Example 54 Preparation of Compound 164
Figure PCTKR2018003744-appb-I000107
Figure PCTKR2018003744-appb-I000107
화합물 163의 제조Preparation of Compound 163
화합물 162 (374 mg, 1.4 mmol)와 화합물 155 (1.0 g, 1.5 mmol)를 아세톤/N,N-다이메틸폼아마이드 (20 mL/20 mL)에 녹인 후, 질소 대기 하에서 탄산 칼륨 (258 mg, 1.8 mmol)을 첨가하고 80 ℃에서 12 시간 동안 가열 교반하였다. 반응 용액을 여과한 후 감압 농축하고, 증류수 (20 mL)를 반응 용액에 첨가한 후 에틸 아세테이트 (3 x 30 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 163 (620 mg, 53%)을 수득하였다. Compound 162 (374 mg, 1.4 mmol) and Compound 155 (1.0 g, 1.5 mmol) were dissolved in acetone / N , N -dimethylformamide (20 mL / 20 mL) and then potassium carbonate (258 mg, 1.8 mmol) under nitrogen atmosphere. ) Was added and stirred at 80 ° C. for 12 h. The reaction solution was filtered, concentrated under reduced pressure, distilled water (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (3 × 30 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 163 (620 mg, 53%) was obtained.
1H-NMR (400 MHz, CDCl3) (rotamers) δ 8.86 (br s, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 6.82 (s, 1H), 6.06 (s, 1H), 6.01-5.91 (m, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 5.08 (s, 1H), 5.05 (s, 1H), 5.00 (s, 1H), 4.92 (br s, 1H), 4.63 (d, J = 4.8 Hz, 2H), 4.41 (d, J = 16.4 Hz, 1H), 4.30 (d, J = 16.4 Hz, 1H), 4.20 (d J = 14 Hz, 1H), 4.13-4.10 (m, 3H), 4.05-3.98 (m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.66 (bs, 1H), 3.55 (d, J = 12.8 Hz, 1H), 3.32 (dd, J = 9.2 Hz, 1H), 2.91 (dd, J = 8.8 Hz, 1H), 2.70 (br s, 2H), 2.43 (dd, J = 7.2 Hz, 1H), 1.97-1.91 (m, 4H), 1.69-1.64 (m, 2H), 0.89 (s, 9H), 0.04 (br s, 6H). 1 H-NMR (400 MHz, CDCl 3 ) (rotamers) δ 8.86 (br s, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 6.82 (s, 1H), 6.06 (s, 1H) , 6.01-5.91 (m, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 5.08 (s, 1H), 5.05 (s, 1H), 5.00 ( s, 1H), 4.92 (br s, 1H), 4.63 (d, J = 4.8 Hz, 2H), 4.41 (d, J = 16.4 Hz, 1H), 4.30 (d, J = 16.4 Hz, 1H), 4.20 (d J = 14 Hz, 1H), 4.13-4.10 (m, 3H), 4.05-3.98 (m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.66 (bs, 1H), 3.55 (d, J = 12.8 Hz, 1H), 3.32 (dd, J = 9.2 Hz, 1H), 2.91 (dd, J = 8.8 Hz, 1H), 2.70 (br s, 2H), 2.43 (dd, J = 7.2 Hz, 1H), 1.97-1.91 (m, 4H), 1.69-1.64 (m, 2H), 0.89 (s, 9H), 0.04 (br s, 6H).
화합물 164의 제조Preparation of Compound 164
화합물 164는 화합물 163으로부터 화합물 28의 합성과 유사한 방법으로 제조하였다. EI-MS m/z : [M+H]+ 1548, 1/2[M+H]+ 775.Compound 164 was prepared by a method similar to the synthesis of compound 28 from compound 163. EI-MS m / z: [M + H] + 1548, 1/2 [M + H] + 775.
<실시예 55> 화합물 167의 제조Example 55 Preparation of Compound 167
Figure PCTKR2018003744-appb-I000108
Figure PCTKR2018003744-appb-I000108
화합물 165의 제조Preparation of Compound 165
L-히스티딘 (5.0 g, 32.22 mmol)을 다이클로로메테인 (45 mL)에 녹인 후 상온에서 다이클로로다이메틸실란 (3.9 mL, 32.22 mmol)과 트라이에틸아민 (9.0 mL, 64.44 mmol)을 첨가하고, 질소 대기 하에서 반응 용액을 4 시간 동안 가열 환류시켰다. 트리틸 클로라이드 (8.9 g, 32.22 mmol)와 트라이에틸아민 (4.5 mL, 32.22 mmol)을 첨가하고 질소 대기 하에서 2 시간 동안 교반하였다. 메탄올 (50 mL)을 반응 용액에 첨가한 후 감압 농축하고, 증류수 (50 mL)와 트라이에틸아민을 첨가하여 pH를 8-8.5 정도로 맞춘 후 녹지 않는 슬러리를 여과한 후 클로로폼 (50 mL), 다이에틸이써 (50 mL), 그리고 증류수 (50 mL)로 차례대로 씻어 주었다. 형성된 흰 고체 화합물 건조하여 화합물 165 (트라이에틸아민 염, 12.4 g, 95%)를 수득하였다. L-histidine (5.0 g, 32.22 mmol) was dissolved in dichloromethane (45 mL), followed by addition of dichlorodimethylsilane (3.9 mL, 32.22 mmol) and triethylamine (9.0 mL, 64.44 mmol) at room temperature. The reaction solution was heated to reflux for 4 hours under a nitrogen atmosphere. Trityl chloride (8.9 g, 32.22 mmol) and triethylamine (4.5 mL, 32.22 mmol) were added and stirred for 2 hours under a nitrogen atmosphere. Methanol (50 mL) was added to the reaction solution, concentrated under reduced pressure, distilled water (50 mL) and triethylamine were added to adjust the pH to about 8-8.5, and the insoluble slurry was filtered and then chloroform (50 mL), Diethyl ether (50 mL) and distilled water (50 mL) were washed sequentially. The white solid compound formed was dried to give compound 165 (triethylamine salt, 12.4 g, 95%).
1H-NMR (400 MHz, CD3OD) δ 7.45-7.32 (m, 10H), 7.21-7.15 (m, 5H), 3.75-3.77 (m, 1H), 3.20 (q, 2H), 3.00-2.97 (m,1H), 1.32 (t, 3H). 1 H-NMR (400 MHz, CD 3 OD) δ 7.45-7.32 (m, 10H), 7.21-7.15 (m, 5H), 3.75-3.77 (m, 1H), 3.20 (q, 2H), 3.00-2.97 (m, 1 H), 1.32 (t, 3 H).
화합물 166의 제조Preparation of Compound 166
화합물 165 (1.0 g, 2.52 mmol)와 N-메톡시카보닐말레이마이드 (429 mg, 2.77 mmol)을 1,4-다이옥세인/증류수 (5 mL/2.5 mL)에 녹인 후 탄산 나트륨 (267 mg, 2.52 mmol)을 첨가하고, 질소 대기 하에서 12 시간 동안 가열 환류시켰다. 반응 용액을 감압 농축하고 N,N-다이메틸폼아마이드 (3 mL)에 녹인 후 트라이에틸아민 (0.16 mL, 1.12 mmol)을 반응 용액에 첨가하고 질소 대기 하에서 10 시간 동안 교반하였다. 증류수 (5 ml)를 반응 용액에 첨가한 후, 0.5 N 염산 수용액을 첨가하여 산성화 (pH 4)하고 다이클로로메테인 (3 X 10 mL)을 넣어 추출한 후 무수 황산나트륨으로 건조하였다. 여과 및 감압 농축하여 화합물 166 (504 mg, 32%)을 수득하였다. Compound 165 (1.0 g, 2.52 mmol) and N-methoxycarbonylmaleimide (429 mg, 2.77 mmol) were dissolved in 1,4-dioxane / distilled water (5 mL / 2.5 mL) followed by sodium carbonate (267 mg, 2.52 mmol) was added and heated to reflux for 12 h under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, dissolved in N , N -dimethylformamide (3 mL), triethylamine (0.16 mL, 1.12 mmol) was added to the reaction solution, and the mixture was stirred for 10 hours under a nitrogen atmosphere. Distilled water (5 ml) was added to the reaction solution, followed by acidification (pH 4) with 0.5 N aqueous hydrochloric acid solution, extraction with dichloromethane (3 × 10 mL), and drying over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave compound 166 (504 mg, 32%).
EI-MS m/z : [M+H]+ 478.4, [M+Na]+ 500.4.EI-MS m / z: [M + H] + 478.4, [M + Na] + 500.4.
화합물 167의 제조Preparation of Compound 167
화합물 166 (252 mg, 0.53 mmol)을 N,N-다이아이소프로필에틸아민 (4 mL)에 녹인 후 N-(3-다이메틸아미노프로필)-N’-에틸카보다이이마이드 염산염 (132 mg, 0.69 mmol)과 N-하이드록시석신이마이드 (85 mg, 0.74 mmol)를 첨가하였다. 반응 용액을 상온 하에서 12 시간 동안 교반하였다. 증류수 (30 mL)를 반응 용액에 첨가한 후 에틸 아세테이트 (2 X 30 mL)로 추출하였다. 추출된 유기층을 무수 황산 나트륨으로 건조하고 여과 및 감압 농축한 후 컬럼 크로마토그래피로 정제하여 화합물 167 (274 mg, 90%)을 수득하였다. Compound 166 (252 mg, 0.53 mmol) of N, N - diisopropylethylamine were dissolved in (4 mL) N - (3- dimethylaminopropyl) - N '- ethyl carbonyl dayiyi polyimide hydrochloride (132 mg, 0.69 mmol) and N -hydroxysuccinimide (85 mg, 0.74 mmol) were added. The reaction solution was stirred at room temperature for 12 hours. Distilled water (30 mL) was added to the reaction solution and extracted with ethyl acetate (2 X 30 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 167. (274 mg, 90%) was obtained.
EI-MS m/z : [M+H]+ 575.3.EI-MS m / z: [M + H] + 575.3.
<실시예 56> 화합물 169의 제조Example 56 Preparation of Compound 169
Figure PCTKR2018003744-appb-I000109
Figure PCTKR2018003744-appb-I000109
화합물 168의 제조Preparation of Compound 168
화합물 103 (50 mg, 0.03 mmol)과 화합물 167 (27.4 mg, 0.05 mmol)을 N,N-다이메틸폼아마이드 (1 mL)에 녹인 후 N,N-다이아이소프로필에틸아민 (0.01 mL, 0.05 mmol)을 첨가하고, 질소 대기, 상온 하에서 12 시간 동안 상온 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 168 (11 mg, 18%)을 수득하였다. Compound 103 (50 mg, 0.03 mmol) and compound 167 (27.4 mg, 0.05 mmol) were dissolved in N , N -dimethylformamide (1 mL), and then N , N -diisopropylethylamine (0.01 mL, 0.05 mmol). ) Was added and stirred at room temperature for 12 hours under a nitrogen atmosphere and room temperature. The reaction solution was concentrated under reduced pressure, purified by HPLC and freeze dried to give 168 (11 mg, 18%) was obtained.
EI-MS m/z : [M+H]+ 1934.8, 1/2[M+H]+ 968.0.EI-MS m / z: [M + H] + 1934.8, 1/2 [M + H] + 968.0.
화합물 169의 제조Preparation of Compound 169
화합물 168 (11 mg, 6 μmol)과 아니솔 (6 μL, 60 μmol)을 다이클로로메테인 (0.75 mL)으로 묽힌 후 트라이플루오로아세트산 (0.25 mL)을 0 ℃에서 첨가하고 3 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 169 (2 mg, 21%)를 흰색의 고체로 수득하였다. Compound 168 (11 mg, 6 μmol) and anisole (6 μL, 60 μmol) were diluted with dichloromethane (0.75 mL), then trifluoroacetic acid (0.25 mL) was added at 0 ° C. and stirred for 3 hours. . The reaction solution was concentrated under reduced pressure, purified by HPLC, and freeze-dried to give compound 169 (2 mg, 21%) as a white solid.
EI-MS m/z : [M+H]+ 1692.7, 1/2[M+H]+ 846.9.EI-MS m / z: [M + H] + 1692.7, 1/2 [M + H] + 846.9.
<실시예 57> 화합물 171의 제조Example 57 Preparation of Compound 171
Figure PCTKR2018003744-appb-I000110
Figure PCTKR2018003744-appb-I000110
화합물 170의 제조Preparation of Compound 170
DBCO-PEG4-acid (50 mg, 91 μmol)를 다이클로로메테인 (1 mL)에 녹인 후 N-(3-다이메틸아미노프로필)-N'-에틸카보다이이마이드 염산염 (19 mg, 99 μmol)과 N-하이드록시석신이마이드 (11 mg, 99 μmol)를 첨가하고, 질소 대기, 상온 하에서 3 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 화합물 170 (59 mg)을 수득하였다. Was dissolved DBCO-PEG4-acid (50 mg , 91 μmol) in dichloromethane (1 mL) N - (3- dimethylaminopropyl) - N '- ethyl carbonyl dayiyi polyimide hydrochloride (19 mg, 99 μmol) And N -hydroxysuccinimide (11 mg, 99 μmol) were added and stirred under nitrogen atmosphere at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and then Compound 170 (59 mg) was obtained.
EI-MS m/z : [M+H]+650.7.EI-MS m / z: [M + H] + 650.7.
화합물 171의 제조Preparation of Compound 171
화합물 103 (47 mg, 32 μmol)과 화합물 170 (24 mg, 38 μmol)을 N,N-다이메틸폼아마이드/다이클로로메테인 (1 mL/0.25 mL)에 녹인 후 N,N-다이아이소프로필에틸아민 (51 μL, 38 μmol)을 첨가하고, 질소 대기, 상온 하에서 3 시간 동안 교반하였다. 반응 용액을 감압 농축한 후 HPLC로 정제하고 동결 건조하여 화합물 171 (8.1 mg, 14%)을 수득하였다. It was dissolved in dimethylformamide / dichloromethane (1 mL / 0.25 mL) N , N - - Compound 103 (47 mg, 32 μmol) and Compound 170 (24 mg, 38 μmol) of N, N-diisopropyl Ethylamine (51 μL, 38 μmol) was added and stirred under nitrogen atmosphere at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, purified by HPLC and freeze dried to give 171 (8.1 mg, 14%) was obtained.
EI-MS m/z : [M+H]+ 2010.1, 1/2[M+H]+ 1005.6.EI-MS m / z: [M + H] + 2010.1, 1/2 [M + H] + 1005.6.
화합물 172 내지 178의 제조Preparation of Compounds 172 to 178
다음 표 1에 나타낸 바와 같은 구조의 피롤로벤조디아제핀 이량체 화합물 172 내지 178을 참고문헌을 참조하여 제조하였다.The pyrrolobenzodiazepine dimer compounds 172 to 178 having the structure as shown in the following Table 1 were prepared with reference to the references.
Figure PCTKR2018003744-appb-T000001
Figure PCTKR2018003744-appb-T000001
< < 실시예Example 58 >  58>
ADC의 제조Manufacture of ADC
ADC의 제조는 다음의 두 단계를 거처 제조되었으며, 공통적으로 사용한 LCB14-0511, LCB14-0512 및 LCB14-0606는 한국공개특허 제10-2014-0035393호에 기재된 방법으로 제조하였다. LCB14-0606, LCB14-0511 및 LCB14-0512의 구조식은 다음과 같다:The preparation of the ADC was made through the following two steps, and commonly used LCB14-0511, LCB14-0512 and LCB14-0606 were prepared by the method described in Korean Patent Publication No. 10-2014-0035393. The structural formulas of LCB14-0606, LCB14-0511 and LCB14-0512 are as follows:
Figure PCTKR2018003744-appb-I000111
Figure PCTKR2018003744-appb-I000111
1단계 : prenylated antibody의 제조 Step 1: Preparation of Prenylated Antibody
항체의 프레닐레이션 반응 혼합물을 제조하여 30 ℃에서 16 시간 반응하였다. 반응혼합물은 24 μM 항체, 200 nM FTase (Calbiochem #344145)와 0.144 mM LCB14-0511 또는 LCB14-0512 또는 LCB14-0606을 포함하는 완충용액 (50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM ZnCl2, 0.5 mM DTT)으로 구성하였다. 반응 종료 후 프레닐레이션된 항체는 PBS 완충용액으로 평형화된 G25 Sepharose 컬럼 (AKTA purifier, GE healthcare)으로 제염시켰다. The prenylation reaction mixture of the antibody was prepared and reacted at 30 ° C. for 16 hours. The reaction mixture was a buffer containing 24 μM antibody, 200 nM FTase (Calbiochem # 344145) and 0.144 mM LCB14-0511 or LCB14-0512 or LCB14-0606 (50 mM Tris-HCl, pH 7.4), 5 mM MgCl 2 , 10 μM ZnCl 2 , 0.5 mM DTT). After completion of the reaction, the prenylated antibody was desalted on a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with PBS buffer.
2단계 : drug-conjugation 방법Step 2: drug-conjugation method
<옥심 결합 반응 (conjugation by oxime bond formation)><Conjugation by oxime bond formation>
프레닐레이션된 항체와 링커-약물간의 옥심본드 생성반응 혼합물은 100 mM Na-아세테이트 완충용액 pH 4.5, 10% DMSO, 24 μM 항체와 240 μM 링커-약물(in house, 실시예 8-10 및 비교예 1의 최종 산물로 표 1의 화합물)을 섞어 제조하였으며 30 ℃에서 약하게 교반하였다. 24시간 반응 후에 FPLC (AKTA purifier, GE healthcare) 과정을 거쳐 사용된 과량의 저분자 화합물들을 제거하였으며 단백질 분획은 수집하여 농축하였다.The oxime bond formation reaction mixture between the prenylated antibody and the linker-drug was 100 mM Na-acetate buffer pH 4.5, 10% DMSO, 24 μM antibody and 240 μM linker-drug (in house, Examples 8-10 and comparison). The final product of Example 1 was prepared by mixing the compound of Table 1) and stirred slightly at 30 ℃. After 24 hours, the excess low molecular weight compounds were removed by FPLC (AKTA purifier, GE healthcare) and the protein fractions were collected and concentrated.
<클릭 결합 반응 (conjugation by click reaction)> <Conjugation by click reaction>
프레닐레이션된 항체와 링커-약물간의 click 반응 혼합물은 10% DMSO, 24 μM 항체와 240 μM 링커-약물 (in house, 실시예 20, 21, 22, 26, 27, 28, 46의 최종 산물로 표 1의 화합물), 1 mM 카퍼(II) 설페이트 펜타하이드레이트, 2 mM (BimC4A)3 (Sigma-Aldrich 696854), 10 mM 소듐 아스코르베이트 (sodium ascorbate) 및 10 mM 아미노구아니딘 염산염을 섞어 제조하였으며 25 ℃ 에서 3 시간 반응 후에 2.0 mM EDTA를 처리하여 30 분 동안 반응하였다. 반응 종료 후, FPLC (AKTA purifier, GE healthcare) 과정을 거쳐 사용된 과량의 저분자 화합물들을 제거하였으며 단백질 분획은 수집하여 농축하였다.The click reaction mixture between the prenylated antibody and the linker-drug is a final product of 10% DMSO, 24 μM antibody and 240 μM linker-drug (in house, Examples 20, 21, 22, 26, 27, 28, 46). Compound 1), 1 mM Copper (II) Sulfate Pentahydrate, 2 mM (BimC 4 A) 3 (Sigma-Aldrich 696854), 10 mM sodium ascorbate and 10 mM aminoguanidine hydrochloride prepared After 3 hours of reaction at 25 ° C., 2.0 mM EDTA was reacted for 30 minutes. After completion of the reaction, the excess low molecular weight compounds were removed through FPLC (AKTA purifier, GE healthcare) and protein fractions were collected and concentrated.
Figure PCTKR2018003744-appb-T000002
Figure PCTKR2018003744-appb-T000002
< < 실험예Experimental Example 1 >  1> In vitroIn vitro 세포 독성 평가 Cytotoxicity Assessment
하기 표 2에 기재된 약물 및 ADC의 암세포주에 대한 세포증식억제 활성을 측정하였다. 암세포주로 시판 중인 사람 유방암 세포주 MCF-7 (HER2 음성 내지 정상) 및 SK-BR3 (HER2 양성), JIMT-1 (HER2 양성)을 사용하였다. 약물로서, MMAF-OMe를 ADC로서, 표 1의 ADC를 사용하였다. 96-웰 플레이트에 각 암세포주를 72시간 처리군은 웰 (well)당 5,000~13,000 개씩 168 시간 처리군은 웹당 1,500~3,000 개씩 접종 (seeding)하여 24 시간 동안 배양한 뒤에 항체와 ADC 는 0.0051~33.33 nM 혹은 0.0015~10.0 nM (3 배 연속 희석), 약물은 0.023~50 nM (3 배 연속 희석) 농도로 처리하였다. 72/168 시간 뒤에 살아있는 세포수를 SRB (Sulforhodamine B) 염료를 사용하여 정량하였다.Inhibition of cell proliferation activity against cancer cell lines of the drugs and ADC described in Table 2 below was measured. Commercial human breast cancer cell lines MCF-7 (HER2 negative to normal) and SK-BR3 (HER2 positive), JIMT-1 (HER2 positive) were used as cancer cell lines. As the drug, MMAF-OMe was used as the ADC and the ADC of Table 1 was used. Each cancer cell line in a 96-well plate was incubated for 24 hours by inoculating 1,500 to 3,000 cells per web for the 168-hour treatment group and 5,000 to 13,000 per well for the 72-hour treatment group. 33.33 nM or 0.0015-10.0 nM (3-fold serial dilution), drug was treated at 0.023-50 nM (3-fold serial dilution) concentration. After 72/168 hours live cells were quantified using SRB (Sulforhodamine B) dye.
Figure PCTKR2018003744-appb-T000003
Figure PCTKR2018003744-appb-T000003
SK-BR3와 JIMT-1 유방암 세포주에서 항체-약물 접합체 중 피롤로벤조디아제핀의 N10 위치 2개 모두 카바메이트 구조로 이루어진 전구체 링커-약물 28, 29, 30이 도입된 ADC1, 2, 3의 세포 독성이 ADC22, 23, 24 시료 대비 매우 뛰어남을 확인하였다. Cytotoxicity of ADC1, 2, 3 with the introduction of precursor linker-drugs 28, 29, 30, which consisted of carbamate structures, in both N10 positions of pyrrolobenzodiazepine in antibody-drug conjugates in SK-BR3 and JIMT-1 breast cancer cell lines It was confirmed that the ADC22, 23, 24 samples are very excellent.
본 발명에 따른 전구체 형태로 투여하는 경우, 혈중 노출 시 추가적인 반응에 의해 유효한 약물로 전환되어야 할 필요가 있기 때문에 예상치 못한 링커의 분해 시에 생길 수 있는 부작용의 발생가능성을 미연에 방지할 수 있고, 정상세포에 대한 독성이 감소하며, 약물이 보다 안정적이라는 점에서 기존 PBD 약물에 비해 유리한 점이 있다. When administered in the form of a precursor according to the present invention, it is necessary to be converted into a valid drug by an additional reaction upon exposure to blood, thereby preventing the possibility of side effects that may occur during unexpected decomposition of the linker, Toxicity to normal cells is reduced, and the drug is more stable than conventional PBD drugs in that the drug is more stable.
또한 항체-약물 접합체 제조 시, 기존 방법으로 제조한 항체-약물 접합체의 경우 불순물의 함량이 높고 노출된 이민 그룹이 뉴클레오필(nucleophile)의 공격을 받아 원치 않는 구조의 약물이 생성될 우려가 있는 반면, 본 발명에 따른 방법으로 제조된 항체-약물 접합체는 PBD 이량체의 이민 그룹이 프로드럭 형태로 뉴클레오필의 공격으로부터 보호되어 있고, 순도가 높아 분리가 용이하다는 장점이 있으며, 기존 PBD 또는 PBD 이량체에 비하여 물성이 보다 향상되는 것으로 나타났다.In addition, the antibody-drug conjugate prepared by the conventional method in the production of the antibody-drug conjugate has a high impurity content and exposed imine groups may be attacked by nucleophiles, resulting in the formation of a drug having an unwanted structure. On the other hand, the antibody-drug conjugate prepared by the method according to the present invention has the advantage that the imine group of the PBD dimer is protected from the attack of nucleophiles in the form of a prodrug, and the purity is easy to separate, and the existing PBD or It was shown that the physical properties are more improved compared to the PBD dimer.
본 발명에 따른 피롤로벤조디아제핀 이량체 전구체(prodrug), 피롤로벤조디아제핀 이량체 전구체(prodrug)-링커, 또는 피롤로벤조디아제핀 이량체 전구체(prodrug)-링커-리간드 접합체는, 암과 같은 증식성 질환의 표적화, 특이적 치료에 이용될 수 있다.The pyrrolobenzodiazepine dimer precursor (prodrug), pyrrolobenzodiazepine dimer precursor (prodrug) -linker, or pyrrolobenzodiazepine dimer precursor (prodrug) -linker-ligand conjugate according to the present invention can be used for proliferative diseases such as cancer. It can be used for targeting, specific treatment.

Claims (28)

  1. 피롤로벤조디아제핀 이량체 전구체(pyrrolobenzodiazepine dimer prodrug), 이의 약학적으로 허용되는 염 또는 용매화물이고,Pyrrolobenzodiazepine dimer prodrug, a pharmaceutically acceptable salt or solvate thereof,
    여기에서, 피롤로벤조디아제핀 이량체의 N10 및 N'10 위치에 각각 독립적으로 -C(O)O*, -S(O)O*, -C(O)*, -C(O)NR*, -S(O)2NR*, -P(O)R'NR*, -S(O)NR*, 및 -PO2NR*기로 이루어진 그룹으로부터 선택되는 어느 하나가 부착되며,Wherein, independently at the N10 and N'10 positions of the pyrrolobenzodiazepine dimer, -C (O) O *, -S (O) O *, -C (O) *, -C (O) NR *, Any one selected from the group consisting of —S (O) 2 NR *, —P (O) R′NR *, —S (O) NR *, and —PO 2 NR * is attached,
    여기에서 *은 링커가 부착되는 부분이고,Where * is where the linker is attached,
    여기에서, R, 및 R'은 각각 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, 치환되거나 비치환된 C1- 8알킬, 치환되거나 비치환된 C3- 8사이클로알킬, 치환되거나 비치환된 C1- 8알콕시, 치환되거나 비치환된 C1- 8알킬티오, 치환되거나 비치환된 C3-20헤테로아릴, 치환되거나 비치환된 C5-20아릴 또는 모노- 또는 다이-C1-8알킬아미노이고, Here, R, and R 'are each independently H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NHNH 2, halo, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 3- 8 cycloalkyl, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 1- 8 alkylthio, substituted or unsubstituted C 3-20 heteroaryl, substituted or unsubstituted C 5-20 aryl or mono- or di-C 1-8 alkylamino,
    여기에서 C1-8알킬, C3-8사이클로알킬, C1-8알콕시, C1-8알킬티오, C3-20헤테로아릴, C5-20아릴이 치환되는 경우, H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 할로, C1-6알킬, C1-6알콕시 및 C6-12아릴로 이루어진 그룹으로부터 선택되는 치환기로 치환되는,Where C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl is substituted, H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy and C 6-12 aryl, substituted with a substituent selected from the group consisting of
    피롤로벤조디아제핀 이량체 전구체(pyrrolobenzodiazepine dimer prodrug), 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer prodrug, pharmaceutically acceptable salts or solvates thereof.
  2. 제1항에 있어서,The method of claim 1,
    피롤로벤조디아제핀 이량체 전구체는 하기 화학식 Ia 또는 Ia'의 구조를 갖는 것을 특징으로 하는, The pyrrolobenzodiazepine dimer precursor has the structure of formula (Ia) or (Ia '),
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물:Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof:
    [화학식 Ia]Formula Ia
    Figure PCTKR2018003744-appb-I000112
    Figure PCTKR2018003744-appb-I000112
    상기 식에서,Where
    점선은 C1 및 C2, 또는 C2 및 C3 사이의 이중결합의 임의의 존재를 나타내고, Dashed lines indicate any presence of a double bond between C1 and C2, or C2 and C3,
    R1은 H, OH, =O, =CH2, CN, Rm, ORm, =CH-Rm' =C(Rm')2, O-SO2-Rm, CO2Rm, CORm, 할로 및 디할로(dihalo)로 이루어진 그룹으로부터 선택되고,R 1 is H, OH, = O, = CH 2 , CN, R m , OR m , = CH-R m ' = C (R m' ) 2 , O-SO 2 -R m , CO 2 R m , COR m , halo and dihalo, and
    여기에서, Rm '는 Rm, CO2Rm, CORm, CHO, CO2H, 및 할로로 이루어진 그룹으로부터 선택되며,Wherein R m ′ is selected from the group consisting of R m , CO 2 R m , COR m , CHO, CO 2 H, and halo,
    여기에서, Rm은 치환되거나 비치환된 C1-12알킬, 치환되거나 비치환된 C2-12알케닐, 치환되거나 비치환된 C2-12알키닐, 치환되거나 비치환된 C5-20아릴, 치환되거나 비치환된 C5-20헤테로아릴, 치환되거나 비치환된 C3-6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클릴, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 및 치환되거나 비치환된 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되고, Wherein R m is substituted or unsubstituted C 1-12 alkyl, substituted or unsubstituted C 2-12 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 5-20 Aryl, substituted or unsubstituted C 5-20 heteroaryl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3 to 7-membered heterocyclyl, substituted or unsubstituted 3 to 7-membered Heterocycloalkyl, and substituted or unsubstituted 5 to 7-membered heteroaryl;
    여기에서 C1-12알킬, C2-12알케닐, C2-12알키닐, C5-20아릴, C5-20헤테로아릴, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 또는 5 내지 7-원 헤테로아릴이 치환되는 경우, Wherein C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl , When 3 to 7-membered heterocycloalkyl, or 5 to 7-membered heteroaryl is substituted,
    C1-12알킬, C1-12알콕시, C2-12알케닐, C2-12알키닐, C5-20아릴, C5-20헤테로아릴, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 또는 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로 C1-12알킬, C2-12알케닐, C2-12알키닐, C5-20아릴, C5-20헤테로아릴, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되는 어느 하나 이상으로 치환되고;C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3 to 7- Each hydrogen atom of a membered heterocyclyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heteroaryl is each independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, From the group consisting of C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl Substituted with any one or more selected;
    R2, R3 및 R5는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRmRm', NO2, Me3Sn 및 할로로 이루어진 그룹으로부터 선택되며,R 2, R 3 and R 5 are each independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m ' , NO 2 , Me 3 Sn And halo,
    여기에서 Rm 및 Rm '은 상기에서 정의한 바와 같고;Wherein R m and R m ′ are as defined above;
    R4는 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRmRm', NO2, Me3Sn, 할로, 치환되거나 비치환된 C1-6알킬, 치환되거나 비치환된 C1-6알콕시, 치환되거나 비치환된 C2-6알케닐, 치환되거나 비치환된 C2-6알키닐, 치환되거나 비치환된 C3-6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C5-12아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -CN, -NCO, -ORn, -OC(O)Rn, -OC(O)NRnRn', -OS(O)Rn, -OS(O)2Rn, -SRn, -S(O)Rn, -S(O)2Rn, -S(O)NRnRn ', -S(O)2NRnRn', -OS(O)NRnRn ', -OS(O)2NRnRn ', -NRnRn ', -NRnC(O)Ro, -NRnC(O)ORo, -NRnC(O)NRoRo', -NRnS(O)Ro, -NRnS(O)2Ro, -NRnS(O)NRoRo ', -NRnS(O)2NRoRo ', -C(O)Rn, -C(O)ORn 및 -C(O)NRnRn'로 이루어진 그룹으로부터 선택되고,R 4 is H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m ' , NO 2 , Me 3 Sn, halo, substituted or unsubstituted C 1-6 alkyl, Substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted Substituted 3 to 7-membered heterocycloalkyl, substituted or unsubstituted C 5-12 aryl, substituted or unsubstituted 5 to 7-membered heteroaryl, -CN, -NCO, -OR n , -OC (O) R n , -OC (O) NR n R n ' , -OS (O) R n , -OS (O) 2 R n , -SR n , -S (O) R n , -S (O) 2 R n , -S (O) NR n R n ' , -S (O) 2 NR n R n' , -OS (O) NR n R n ' , -OS (O) 2 NR n R n ' , -NR n R n ' , -NR n C (O) R o , -NR n C (O) OR o , -NR n C (O) NR o R o' , -NR n S (O) R o , -NR n S (O) 2 R o , -NR n S (O) NR o R o ' , -NR n S (O) 2 NR o R o ' , -C (O) R n , -C (O) OR n and -C (O) NR n R n ' ;
    여기에서 C1-6알킬, C1-6알콕시, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-12아릴, 5 내지 7-원 헤테로아릴이 치환되는 경우, C1-6알킬, C1-6알콕시, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-12아릴, 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로C1-6알킬, C1-6알콕시, C2-6알케닐, C2-6알키닐, C3-C6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 5 내지 7-원 헤테로아릴, -ORp, -OC(O)Rp, -OC(O)NRpRp ', -OS(O)Rp, -OS(O)2Rp, -SRp, -S(O)Rp, -S(O)2Rp, -S(O)NRpRp ', -S(O)2NRpRp ', -OS(O)NRpRp', -OS(O)2NRpRp ', -NRpRp ', -NRpC(O)Rq, -NRpC(O)ORq, -NRpC(O)NRqRq ', -NRpS(O)Rq, -NRpS(O)2Rq, -NRpS(O)NRqRq ', -NRpS(O)2NRqRq ', -C(O)Rp, -C(O)ORp 또는 -C(O)NRpRp로 치환될 수 있으며, Wherein C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-12 aryl, When 5- to 7-membered heteroaryl is substituted, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-12 aryl, 5- to 7-membered each of the hydrogen atoms of the heteroaryl are each independently a C 1 - 6 alkyl, C 1-6 alkoxy, C 2 - 6 alkenyl, C 2-6 alkynyl, , C 3- C 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5 - 10 aryl, 5- to 7-membered heteroaryl group, -OR p, -OC (O) R p, -OC (O) NR p R p ' , -OS (O) R p , -OS (O) 2 R p , -SR p , -S (O) R p , -S (O) 2 R p , -S (O) NR p R p ' , -S (O) 2 NR p R p ' , -OS (O) NR p R p ' , -OS (O) 2 NR p R p ' , -NR p R p ' , -NR p C (O) R q , -NR p C (O) OR q , -NR p C (O) NR q R q ' , -NR p S (O) R q , -NR p S (O) 2 R q , -NR p S (O) NR q R q ' , -NR p S (O) 2 NR q R q ' , -C (O) R p , -C (O) OR p or -C (O) NR p R p , and
    여기에서, Rn, Ro, Rp, 및 Rq는 각각 독립적으로 H, C1-7알킬, C2-7알케닐, C2-7알키닐, C3-13사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되고; Here, R n, R o, R p, and R q is independently H, C 1 - 7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10, selected from aryl, and a 5- to 7-membered group consisting of heteroaryl, and;
    X 및 X'은 각각 독립적으로 -C(O)O*, -S(O)O*, -C(O)*, -C(O)NR*, -S(O)2NR*, -P(O)R'NR*, -S(O)NR*, 및 -PO2NR*기로 이루어진 그룹으로부터 선택되는 어느 하나가 부착되며,X and X 'are each independently -C (O) O *, -S (O) O *, -C (O) *, -C (O) NR *, -S (O) 2 NR *, -P Any one selected from the group consisting of (O) R'NR *, -S (O) NR *, and -PO 2 NR * is attached,
    여기에서 *은 링커가 부착되는 부분이고,Where * is where the linker is attached,
    여기에서, R, 및 R'은 각각 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, 치환되거나 비치환된 C1-8알킬, 치환되거나 비치환된 C3-8사이클로알킬, 치환되거나 비치환된 C1-8알콕시, 치환되거나 비치환된 C1-8알킬티오, 치환되거나 비치환된 C3-20헤테로아릴, 치환되거나 비치환된 C5-20아릴 또는 모노- 또는 다이-C1-8알킬아미노이고, Wherein R, and R 'are each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, substituted or unsubstituted C 1-8 alkyl, substituted Unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3-20 heteroaryl, substituted or unsubstituted C 5-20 aryl or mono- or di-C 1-8 alkylamino,
    여기에서 C1-8알킬, C3-8사이클로알킬, C1-8알콕시, C1-8알킬티오, C3-20헤테로아릴, C5-20아릴이 치환되는 경우, H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 할로, C1-6알킬, C1-6알콕시 및 C5-12아릴로 이루어진 그룹으로부터 선택되는 치환기로 치환되며;Where C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl is substituted, H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy and C 5-12 aryl;
    Y 및 Y'은 각각 독립적으로 O, S, 및 N(H)로 이루어진 그룹으로부터 선택되며;Y and Y 'are each independently selected from the group consisting of O, S, and N (H);
    R6은 치환되거나 비치환된 포화 또는 불포화 C3-12탄화수소 쇄이고,R 6 is a substituted or unsubstituted saturated or unsaturated C 3-12 hydrocarbon chain,
    여기에서 이의 쇄(chain)는 하나 이상의 헤테로원자, NMe 또는 치환되거나 비치환된 방향족 고리에 의해 차단(interrupt)될 수 있고, Wherein the chain thereof may be interrupted by one or more heteroatoms, NMe or substituted or unsubstituted aromatic rings,
    여기에서 이의 쇄(chain) 또는 방향족 고리는 이의 쇄 또는 방향족 고리 상의 수소원자 중 어느 하나 이상의 위치가 -NH, -NRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-R, 또는 -[CH2CH2O]n-R로 치환되거나 비치환될 수 있고,Wherein a chain or aromatic ring thereof has at least one position of hydrogen atom on its chain or aromatic ring, -NH, -NR m , -NHC (O) R m , -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or -May be unsubstituted or substituted with [CH 2 CH 2 O] n -R,
    여기에서 Rm 및 R은 각각 상기 Rm 및 R의 정의와 같으며, Where R m and R are the same as defined above for R m and R,
    여기에서 n은 1 내지 12의 정수이고;Where n is an integer from 1 to 12;
    R7은 H, 치환되거나 비치환된 C1-6알킬, 치환되거나 비치환된 C2-6알케닐, 치환되거나 비치환된 C2-6알키닐, 치환되거나 비치환된 C3-6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C6-10아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -ORr, -OC(O)Rr, -OC(O)NRrRr ', -OS(O)Rr, -OS(O)2Rr, -SRr, -S(O)Rr, -S(O)2Rr, -S(O)NRrRr ', -S(O)2NRrRr ', -OS(O)NRrRr ', -OS(O)2NRrRr', -NRrRr ', -NRrC(O)Rs, -NRrC(O)ORs, -NRrC(O)NRsRs ', -NRrS(O)Rs, -NRrS(O)2Rs, -NRrS(O)NRsRs', -NRrS(O)2NRsRs, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'이고,R 7 is H, substituted or unsubstituted C 1 - 6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl alkyl, substituted or unsubstituted 3 to 7-membered optionally substituted heterocycloalkyl, unsubstituted or unsubstituted C 6 - 10 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -OR r, -OC (O) r r , -OC (O) NR r R r ' , -OS (O) R r , -OS (O) 2 R r , -SR r , -S (O) R r , -S (O) 2 R r , -S (O) NR r R r ' , -S (O) 2 NR r R r ' , -OS (O) NR r R r ' , -OS (O) 2 NR r R r' , -NR r R r ' , -NR r C (O) R s , -NR r C (O) OR s , -NR r C (O) NR s R s ' , -NR r S (O) R s , -NR r S (O) 2 R s , -NR r S (O) NR s R s' , -NR r S (O) 2 NR s R s , -C (O) R r , -C (O) OR s or -C (O) NR r R r ' ,
    여기에서 C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 5 내지 7-원 헤테로아릴이 치환되는 경우, C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로 C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10아릴, 5 내지 7-원 헤테로아릴, -ORt, -OC(O)Rt, -OC(O)NRtRt ', -OS(O)Rt, -OS(O)2Rt, -SRt, -S(O)Rt, -S(O)2Rt, -S(O)NRtRt ', -S(O)2NRtRt ', -OS(O)NRtRt ', -OS(O)2NRtRt ', -NRtRt ', -NRtC(O)Ru, -NRtC(O)ORu, -NRtC(O)NRuRu ', -NRtS(O)Ru, -NRtS(O)2Ru, -NRtS(O)NRuRu ', -NRtS(O)2NRuRu', -C(O)Rt, -C(O)ORt 또는 -C(O)NRtRt'로 치환되며,Here, C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5- to 7-membered heterocyclic when the aryl is substituted, C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5 to 7-membered each hydrogen atom of the heteroaryl are each independently a C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5-7 membered heteroaryl, -OR t, -OC (O) R t, -OC (O) NR t R t ', -OS (O) R t, -OS (O) 2 R t , -SR t , -S (O) R t , -S (O) 2 R t , -S (O) NR t R t ' , -S (O) 2 NR t R t ' , -OS ( O) NR t R t ' , -OS (O) 2 NR t R t ' , -NR t R t ' , -NR t C (O) R u , -NR t C (O) OR u , -NR t C (O) NR u R u ' , -NR t S (O) R u , -NR t S (O) 2 R u , -NR t S (O) NR u R u ' , -NR t S (O ) 2 NR u R u ' , -C (O) R t , -C (O) OR t or -C (O) NR t R t' ,
    여기에서, Rr, Rr ', Rs, Rs ', Rt, Rt ', Ru 및 Ru '은 각각 독립적으로 H, C1- 7알킬, C2-7알케닐, C2- 7알키닐, C3- 13사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되고; Here, R r, R r ', R s, R s', R t, R t ', R u and R u' are each independently H, C 1- 7 alkyl, C 2-7 alkenyl, C 1-7 alkynyl, C 3- 13 is selected from cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5- to 7-membered group consisting of-heteroaryl;
    [화학식 Ia']Formula Ia '
    상기 식에서,Where
    R1, R2, R3, R4, R6, R7, 및 X는 상기 화학식 Ia에서의 정의와 같고,R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and X are as defined above in Formula Ia,
    R8은 H, 할로, 치환되거나 비치환된 C1- 6알킬, 치환되거나 비치환된 C2- 6알케닐, 치환되거나 비치환된 C2- 6알키닐, 치환되거나 비치환된 C3- 6헤테로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C5-10아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -CN, -NO2, -NCO, -OH, ORm, -OC(O)Rm, -OC(O)NRmRm', -OS(O)Rm, -OS(O)2Rm, -SRm, -S(O)Rm, -S(O)2Rm, -S(O)NRmRm ', -S(O)2NRmRm', -OS(O)NRmRm ', -OS(O)2NRmRm ', -NRmRm ', -NRmC(O)Rm, -NRmC(O)ORn, -NRmC(O)NRnRn', -NRmS(O)Rn, -NRmS(O)2Rn, -NRmS(O)NRnRn ', -NRmS(O)2NRnRn ', -C(O)Rm, -C(O)ORm 및 -C(O)NRmRm'로 이루어진 그룹으로부터 선택되며,R 8 is H, halo, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2- 6-alkynyl, substituted or unsubstituted C 3- 6 heteroalkyl, substituted or unsubstituted 3 to 7-membered heterocycloalkyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5 to 7-membered heteroaryl, -CN, -NO 2 ,- NCO, -OH, OR m , -OC (O) R m , -OC (O) NR m R m ' , -OS (O) R m , -OS (O) 2 R m , -SR m , -S (O) R m , -S (O) 2 R m , -S (O) NR m R m ' , -S (O) 2 NR m R m' , -OS (O) NR m R m ' ,- OS (O) 2 NR m R m ' , -NR m R m ' , -NR m C (O) R m , -NR m C (O) OR n , -NR m C (O) NR n R n ' , -NR m S (O) R n , -NR m S (O) 2 R n , -NR m S (O) NR n R n ' , -NR m S (O) 2 NR n R n ' ,- C (O) R m , -C (O) OR m and -C (O) NR m R m ' ,
    여기에서 C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6헤테로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 또는 5 내지 7-원 헤테로아릴이 치환되는 경우, C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6헤테로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 또는 5 내지 7-원 헤테로아릴의 각 수소원자는 각각 독립적으로 C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6헤테로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 5 내지 7-원 헤테로아릴, -ORm, -OC(O)Rm, -OC(O)NRmRm ', -OS(O)Rm, -OS(O)2Rm, -SRm, -S(O)Rm, -S(O)2Rm, -S(O)NRmRm ', -S(O)2NRmRm ', -OS(O)NRmRm ', -OS(O)2NRmRm ', -NRmRm ', -NRmC(O)Rn, -NRmC(O)ORn, -NRmC(O)NRnRn ', -NRmS(O)Rn, -NRmS(O)2Rn, -NRmS(O)NRnRn ', -NRmS(O)2NRnRn', -C(O)Rm, -C(O)ORm 또는-C(O)NRmRm'로 치환되고, Wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 heteroalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, or 5 to 7-membered When heteroaryl is substituted, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 heteroalkyl, 3 to 7 membered heterocycloalkyl, C 5-10 aryl, or Each hydrogen atom of a 5 to 7 membered heteroaryl is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 heteroalkyl, 3 to 7 membered heterocycloalkyl , C 5-10 aryl, 5-7 membered heteroaryl, -OR m , -OC (O) R m , -OC (O) NR m R m ' , -OS (O) R m , -OS (O ) 2 R m , -SR m , -S (O) R m , -S (O) 2 R m , -S (O) NR m R m ' , -S (O) 2 NR m R m ' ,- OS (O) NR m R m ' , -OS (O) 2 NR m R m ' , -NR m R m ' , -NR m C (O) R n , -NR m C (O) OR n ,- NR m C (O) NR n R n ' , -NR m S (O) R n , -NR m S (O) 2 R n , -NR m S (O) NR n R n ' , -NR m S (O) 2 NR n R n ' , -C (O) R m , -C (O) OR m or -C (O) NR m R m' ,
    Rm, Rm ', Rn 및 Rn '은 상기 화학식 Ia에서의 정의와 같으며, R m , R m ' , R n and R n ' are as defined in Formula Ia,
    Za 및 Zb는 각각 독립적으로 O, N, 또는 S이고,Z a and Z b are each independently O, N, or S,
    R12a, R13a, 및 R14a는 각각 독립적으로 H, 치환되거나 비치환된 C1-6알킬, 치환되거나 비치환된 C2-6알케닐, 치환되거나 비치환된 C2-6알키닐, 치환되거나 비치환된 C3-6사이클로알킬, 치환되거나 비치환된 3 내지 7-원 헤테로사이클로알킬, 치환되거나 비치환된 C5-10아릴, 치환되거나 비치환된 5 내지 7-원 헤테로아릴, -C(O)R15a, -C(O)OR15a 및 -C(O)NR15aR15a'이고, 여기에서 R15a 및 R15a'은 Rm의 정의와 같고,R 12a , R 13a , and R 14a are each independently H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, Substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3 to 7-membered heterocycloalkyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5 to 7-membered heteroaryl, -C (O) R 15a , -C (O) OR 15a and -C (O) NR 15a R 15a ' , wherein R 15a and R 15a' are as defined in R m ,
    여기에서 C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 5 내지 7-원 헤테로아릴이 치환되는 경우 각 수소원자는 C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 5 내지 7-원 헤테로아릴, -ORo, -OC(O)Ro, -OC(O)NRoRo ', -OS(O)Ro, -OS(O)2Ro, -SRo, -S(O)Ro, -S(O)2Ro, -S(O)NRoRo ', -S(O)2NRoRo', -OS(O)NRoRo ', -OS(O)2NRoRo ', -NRoRo ', -NRoC(O)Rp, -NRoC(O)ORp, -NRoC(O)NRpRp', -NRoS(O)Rp, -NRoS(O)2Rp, -NRoS(O)NRpRp ', -NRoS(O)2NRpRp ', -C(O)Ro, -C(O)ORo 또는 -C(O)NRoRo'로 치환되고; Wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 5-10 aryl, 5 to 7 membered hetero When aryl is substituted each hydrogen atom is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered Heterocycloalkyl, C 5-10 aryl, 5 to 7-membered heteroaryl, -OR o , -OC (O) R o , -OC (O) NR o R o ' , -OS (O) R o ,- OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o ' , -S (O) 2 NR o R o ' , -OS (O) NR o R o ' , -OS (O) 2 NR o R o ' , -NR o R o ' , -NR o C (O) R p , -NR o C (O) OR p , -NR o C (O) NR p R p ' , -NR o S (O) R p , -NR o S (O) 2 R p , -NR o S (O) NR p R p ' ,- NR o S (O) 2 NR p R p ' , -C (O) R o , -C (O) OR o or -C (O) NR o R o' ;
    여기에서, R13a 및 R14a는 이들이 부착된 원자와 함께 결합하여 3 내지 7-원 헤테로사이클릴, 또는 3 내지 7-원 헤테로사이클로알킬을 형성하거나, 또는 R13a 및 R14a는 이들이 부착되는 원자와 함께 결합하여 3 내지 7-원 헤테로아릴을 형성할 수 있고, Wherein R 13a and R 14a combine with the atoms to which they are attached to form a 3 to 7-membered heterocyclyl, or 3 to 7-membered heterocycloalkyl, or R 13a and R 14a to which they are attached Can be combined together to form a 3 to 7 membered heteroaryl,
    여기에서 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬 또는 3 내지 7-원 헤테로아릴에 존재하는 각 수소원자는 각각 독립적으로 C1-6알킬, C2-6알케닐, C2-6알키닐, C3-6사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10아릴, 5 내지 7-원 헤테로아릴, -ORo, -OC(O)Ro, -OC(O)NRoRo ', -OS(O)Ro, -OS(O)2Ro, -SRo, -S(O)Ro, -S(O)2Ro, -S(O)NRoRo ', -S(O)2NRoRo ', -OS(O)NRoRo ', -OS(O)2NRoRo ', -NRoRo ', -NRoC(O)Rp, -NRoC(O)ORp, -NRoC(O)NRpRp ', -NRoS(O)Rp, -NRoS(O)2Rp, -NRoS(O)NRpRp ', -NRoS(O)2NRpRp', -C(O)Ro, -C(O)ORo 또는 -C(O)NRoRo'로 치환되고; Wherein each hydrogen atom present in 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl or 3 to 7-membered heteroaryl is each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 5-10 aryl, 5 to 7 membered heteroaryl, -OR o , -OC (O) R o ,- OC (O) NR o R o ' , -OS (O) R o , -OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o ' , -S (O) 2 NR o R o ' , -OS (O) NR o R o ' , -OS (O) 2 NR o R o ' , -NR o R o ' , -NR o C (O) R p , -NR o C (O) OR p , -NR o C (O) NR p R p ' , -NR o S (O) R p , -NR o S (O ) 2 R p , -NR o S (O) NR p R p ' , -NR o S (O) 2 NR p R p' , -C (O) R o , -C (O) OR o or -C (O) NR o R o ' ;
    여기에서, Rn, Rn ', Ro, Ro ', Rp, 및 Rp '은 각각 독립적으로 H, C1- 7알킬, C2- 7알케닐, C2- 7알키닐, C3- 13사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5- 10아릴, 및 5 내지 7-원 헤테로아릴로 이루어진 그룹으로부터 선택되며;Here, R n, R n ', R o, R o', R p, and R p 'are each independently H, C 1- 7 alkyl, 2- C 7 alkenyl, C 2- 7 alkynyl, C 3- 13 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, and a 5- to 7-membered heteroaryl is selected from the group consisting of;
    R1', R2', R3', R4', R5', R7' 및 R8'은 각각 R1, R2, R3, R4, R5, R7 및 R8에 대해서 정의한 바와 같다.R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′, R 7 ′, and R 8 ′ are R 1 , R 2 , R 3 , R 4, R 5 , It is as defined about R <7> and R <8> .
  3. 제2항에 있어서,The method of claim 2,
    점선은 C2 및 C3 사이의 이중결합의 존재를 나타내는,The dotted line indicates the presence of a double bond between C2 and C3,
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  4. 제2항에 있어서,The method of claim 2,
    R1은 치환되거나 비치환된 C1-6알킬, 치환되거나 비치환된 C2-6알케닐, 치환되거나 비치환된 C5-7아릴 및 치환되거나 비치환된 C3-6헤테로아릴로 이루어진 그룹으로부터 선택되는,R 1 is composed of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 5-7 aryl and substituted or unsubstituted C 3-6 heteroaryl Selected from the group,
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  5. 제2항에 있어서,The method of claim 2,
    R2, R3 및 R5는 각각 독립적으로 H 또는 OH인,R 2 , R 3 and R 5 are each independently H or OH,
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  6. 제2항에 있어서,The method of claim 2,
    R4는 C1-6알콕시인,R 4 is C 1-6 alkoxy,
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  7. 제2항에 있어서,The method of claim 2,
    R4는 메톡시, 에톡시 또는 부톡시인,R 4 is methoxy, ethoxy or butoxy
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  8. 제1항에 있어서,The method of claim 1,
    X 및 X'은 각각 독립적으로 -C(O)O*, -C(O)* 및 -C(O)NR*로 이루어진 그룹으로부터 선택되고,X and X 'are each independently selected from the group consisting of -C (O) O *, -C (O) * and -C (O) NR *,
    여기서 R은 각각 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 할로, 치환되거나 비치환된 C1-8알킬 또는 치환되거나 비치환된 C1-8알콕시이며, 여기에서 C1-8알킬 또는 C1-8알콕시가 치환되는 경우, H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 또는 할로로 치환되는,Wherein R is each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, substituted or unsubstituted C 1-8 alkyl or substituted or unsubstituted C 1- 8 alkoxy, where C 1-8 alkyl or C 1-8 alkoxy is substituted, is substituted with H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , or halo ,
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  9. 제2항에 있어서,The method of claim 2,
    Y 및 Y'은 O인,Y and Y 'are O,
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  10. 제2항에 있어서,The method of claim 2,
    R6는 치환되거나 비치환된 포화 또는 불포화 C3-8탄화수소 쇄이고, R 6 is a substituted or unsubstituted saturated or unsaturated C 3-8 hydrocarbon chain,
    이의 쇄(chain)는 하나 이상의 헤테로원자 또는 치환되거나 비치환된 방향족 고리에 의해 차단(interrupt)될 수 있으며,Its chain may be interrupted by one or more heteroatoms or substituted or unsubstituted aromatic rings,
    여기에서 헤테로원자는 O, S 또는 N(H)이고, 방향족 고리는 벤젠, 피리딘, 이미다졸 또는 피라졸이며,Wherein the heteroatom is O, S or N (H), the aromatic ring is benzene, pyridine, imidazole or pyrazole,
    여기에서 이의 쇄(chain) 또는 방향족 고리는, 이의 쇄 또는 방향족 고리 상의 수소원자 중 어느 하나 이상의 위치가 -NHC(O)CH2-[OCH2CH2]n-R, 또는 -[CH2CH2O]n-R로 치환될 수 있고,Wherein in the chain or aromatic ring thereof, at least one position of a hydrogen atom on the chain or aromatic ring is -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or -[CH 2 CH 2 O] n -R can be substituted,
    여기에서 R의 정의는 제2항의 R의 정의와 같으며,Wherein the definition of R is the same as the definition of R in claim 2,
    n은 1 내지 6의 정수인,n is an integer from 1 to 6,
    피롤로벤조디아제핀 이량체 전구체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursors, pharmaceutically acceptable salts or solvates thereof.
  11. 하기 화학식 IIa의 구조를 갖는 접합체 또는 이의 약학적으로 허용되는 염 또는 용매화물:Conjugates having the structure of Formula IIa or a pharmaceutically acceptable salt or solvate thereof:
    [화학식 IIa]Formula IIa]
    Ligand - (L - D)n Ligand-(L-D) n
    상기 식에서,Where
    Ligand는 리간드이고,Ligand is a ligand,
    L은 링커이며,L is a linker,
    D는 제1항 내지 제10항 중 어느 한 항에 따른 피롤로벤조디아제핀 이량체 전구체이고, D is a pyrrolobenzodiazepine dimer precursor according to any one of claims 1 to 10,
    여기에서 링커는 제1항에 따른 D의 N10 위치, N10' 위치, 또는 N10 및 N10' 위치; 또는 Wherein the linker is selected from the N10, N10 ', or N10 and N10' positions of D according to claim 1; or
    제2항 내지 제10항 중 어느 한 항에 따른 D의 X, X' 또는 X 및 X'을 통해,Through X, X 'or X and X' of D according to any one of claims 2 to 10,
    D와 결합되며,Combined with D,
    n은 1 내지 20의 정수이다.n is an integer from 1 to 20.
  12. 제11항에 있어서,The method of claim 11,
    링커는,The linker is
    제1항에 따른 D의 N10 및 N10' 위치; 또는 N10 and N10 'positions of D according to claim 1; or
    제2항 내지 제10항 중 어느 한 항에 따른 D의 X 및 X'을 통해,Through X and X 'of D according to any one of claims 2 to 10,
    D와 결합되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 용매화물.A conjugate or a pharmaceutically acceptable salt or solvate thereof, combined with D.
  13. 제11항에 있어서,The method of claim 11,
    n은 1 내지 10의 정수인, 접합체 또는 이의 약학적으로 허용되는 염 또는 용매화물.n is an integer from 1 to 10, wherein the conjugate or a pharmaceutically acceptable salt or solvate thereof.
  14. 하기 화학식 IIb 또는 화학식 IIb'의 구조를 갖는 피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물:A pyrrolobenzodiazepine dimer precursor-linker compound having the structure of Formula (IIb) or (IIb '), a pharmaceutically acceptable salt or solvate thereof:
    [화학식 IIb]Formula IIb]
    Figure PCTKR2018003744-appb-I000114
    Figure PCTKR2018003744-appb-I000114
    [화학식 IIb']Formula IIb '
    Figure PCTKR2018003744-appb-I000115
    Figure PCTKR2018003744-appb-I000115
    상기 식에서,Where
    점선, R1, R2, R3, R4, R5, R6, R7, X, Y, R1', R2', R3', R4', R5', R7', X', Y', R8, Za, Zb, R12a, R13a, R14a, R8', Za', Zb', R12a', R13a', 및 R14a'은 각각 제2항에서 화학식 Ia 및 화학식 Ia'의 화합물에 대해 정의한 바와 동일하고,Dashed line, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
    Xa 및 Xa'은 각각 독립적으로 결합(bond), 또는 치환되거나 비치환된 C1-6알킬렌이며, 여기에서 C1-6알킬렌이 치환되는 경우, 수소, C1-8알킬 또는 C3-8사이클로알킬로 치환되고,Xa and Xa 'are each independently a bond, or a substituted or unsubstituted C 1-6 alkylene, wherein, when C 1-6 alkylene is substituted, hydrogen, C 1-8 alkyl or C 3 Substituted with -8 cycloalkyl,
    G 및 G'은 글루쿠로나이드(glucuronide)기, 갈락토사이드기 또는 이의 유도체이고,G and G 'are glucuronide groups, galactoside groups or derivatives thereof,
    Z는 H, C1- 8알킬, 할로, NO2, CN,
    Figure PCTKR2018003744-appb-I000116
    ,
    Figure PCTKR2018003744-appb-I000117
    및 -(CH2)m-OCH3로 이루어진 그룹으로부터 선택되며,     Z is H, C 1- 8 alkyl, halo, NO 2, CN,
    Figure PCTKR2018003744-appb-I000116
    ,
    Figure PCTKR2018003744-appb-I000117
    And-(CH 2 ) m -OCH 3 ,
    R8, R9 및 R10은 각각 독립적으로 H, C1-8알킬, C2-6알케닐, 및 C1-6알콕시로 이루어진 그룹으로부터 선택되고, m은 0 내지 12이며,R 8 , R 9 and R 10 are each independently selected from the group consisting of H, C 1-8 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy, m is 0-12,
    n은 1 내지 3의 정수이고, n이 2 이상의 정수인 경우 각각의 Z는 서로 동일하거나 상이할 수 있으며,n is an integer of 1 to 3, when n is an integer of 2 or more, each Z may be the same or different from each other,
    W는 -C(O)-, -C(O)NR''-, -C(O)O-, -S(O)2NR''-, -P(O)R'''NR''-, -S(O)NR''-, 또는 -PO2NR''-이고, 상기 R'' 및 R'''은 각각 독립적으로 H, C1-8알킬, C3-8사이클로알킬, C1-8알콕시, C1-8알킬티오, 모노- 또는 다이-C1-8알킬아미노, C3-20헤테로아릴, 또는 C6-20아릴이며,W is -C (O)-, -C (O) NR ''-, -C (O) O-, -S (O) 2 NR ''-, -P (O) R '''NR'' -, -S (O) NR ''-, or -PO 2 NR ''-, wherein R '' and R '''are each independently H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl,
    L은 브랜칭 유닛(branching unit), 연결 유닛(connection unit) 및 결합 유닛(binding unit)으로 이루어진 그룹으로부터 선택되는 하나 이상의 유닛, 또는 이들 유닛의 조합이며, L is one or more units selected from the group consisting of branching units, connection units and binding units, or a combination of these units,
    여기에서 연결 유닛은 W와 결합 유닛을, W와 브랜칭 유닛을, 브랜칭 유닛과 브랜칭 유닛을, 또는 브랜칭 유닛과 결합 유닛을 연결하고, 여기에서 브랜칭 유닛은 연결 유닛과 W를, 또는 연결 유닛과 또 다른 연결 유닛을 연결하며,Wherein the connecting unit connects W with a coupling unit, W with a branching unit, a branching unit with a branching unit, or a branching unit with a coupling unit, wherein the branching unit is connected with the connecting unit and W, or To connect other connecting units,
    브랜칭 유닛은 C2-100알케닐(여기서, 알케닐의 탄소 원자는 하나 또는 그 이상의 N, O 및 S로 이루어진 그룹으로부터 선택되는 헤테로원자로 치환될 수 있으며, 알케닐은 하나 또는 그 이상의 C1-20알킬로 더 치환될 수 있다), 친수성(hydrophilic) 아미노산, -C(O)-, -C(O)NR''''-, -C(O)O-, -(CH2)s-NHC(O)-(CH2)t-, -(CH2)u-C(O)NH-(CH2)v-, -(CH2)s-NHC(O)-(CH2)t-C(O)-, -(CH2)u-C(O)NH-(CH2)v-C(O)-, -S(O)2NR''''-, -P(O)R'''''NR''''-, -S(O)NR''''-, 또는 -PO2NR''''- (여기서, R'''' 및 R'''''는 각각 독립적으로 H, C1-8알킬, C3-8사이클로알킬, C1-8알콕시, C1-8알킬티오, 모노- 또는 다이-C1-8알킬아미노, C3-20헤테로아릴 또는 C5-20아릴이며, s, t, u 및 v는 각각 독립적으로 0 내지 10의 정수이고),The branching unit may be substituted with C 2-100 alkenyl, wherein the alkenyl carbon atom is substituted with one or more heteroatoms selected from the group consisting of N, O and S, alkenyl being one or more C 1- 20 may be further substituted with alkyl), hydrophilic amino acid, -C (O)-, -C (O) NR ''''-, -C (O) O-,-(CH 2 ) s- NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t- C (O)-,-(CH 2 ) u -C (O) NH- (CH 2 ) v -C (O)-, -S (O) 2 NR ''''-, -P (O) R '''''NR''''-, -S (O) NR''''-, or -PO 2 NR''''-(whereR''''andR''''' are Each independently H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 5-20 aryl, s, t, u and v are each independently an integer from 0 to 10),
    연결 유닛은 -(CH2)r(V(CH2)p)q-이고, 여기에서, r은 0 내지 10의 정수이고, p는 0 내지 12의 정수이며, q는 1 내지 20의 정수이고, V는 단일결합, -O-, 또는 S-이며,The connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, -O-, or S-,
    결합 유닛은
    Figure PCTKR2018003744-appb-I000118
    ,
    Figure PCTKR2018003744-appb-I000119
    ,
    Figure PCTKR2018003744-appb-I000120
    또는
    Figure PCTKR2018003744-appb-I000121
    이고, 여기에서 L1은 단일결합 또는 C2- 30알케닐이며, R11은 H 또는 C1-10알킬이고, L2는 C2-30알케닐이며;    Coupling unit
    Figure PCTKR2018003744-appb-I000118
    ,
    Figure PCTKR2018003744-appb-I000119
    ,
    Figure PCTKR2018003744-appb-I000120
    or
    Figure PCTKR2018003744-appb-I000121
    And, in which L 1 is a single bond or a C 2- 30 alkenyl Al, R 11 is H or C 1-10 alkyl, L 2 is C 2-30 alkenyl;
    Rv는 -NH2, N3, 치환되거나 비치환된 C1-12알킬, C1-12알키닐, C1-3알콕시, 치환되거나 비치환된 C3-20헤테로아릴, C3-20헤테로사이클릴 또는 치환되거나 비치환된 C5-20아릴이고, R v is —NH 2 , N 3 , substituted or unsubstituted C 1-12 alkyl, C 1-12 alkynyl, C 1-3 alkoxy, substituted or unsubstituted C 3-20 heteroaryl, C 3-20 Heterocyclyl or substituted or unsubstituted C 5-20 aryl,
    여기에서 C1-12알킬, C3-20헤테로아릴, C3-20헤테로사이클릴 또는 C5-20아릴이 치환되는 경우, C3-20헤테로아릴, C3-20헤테로사이클릴 또는 C5-20아릴에 존재하는 하나 이상의 수소원자는 각각 독립적으로 OH, =O, 할로, C1-6알킬, C1-6알콕시, C2-6알케닐옥시, 카르복시, C1-6알콕시카르보닐, C1-6알킬카르보닐, 포르밀, C3-8아릴, C5-12아릴옥시, C5-12아릴카르보닐, 또는 C3-6헤테로아릴로 치환된다.Where C 1-12 alkyl, C 3-20 heteroaryl, C 3-20 heterocyclyl or C 5-20 aryl is substituted, C 3-20 heteroaryl, C 3-20 heterocyclyl or C 5 One or more hydrogen atoms present at -20 aryl are each independently OH, = 0, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, carboxy, C 1-6 alkoxycarbonyl , C 1-6 alkylcarbonyl, formyl, C 3-8 aryl, C 5-12 aryloxy, C 5-12 arylcarbonyl, or C 3-6 heteroaryl.
  15. 제14항에 있어서,The method of claim 14,
    Xa 및 Xa'은 각각 독립적으로 결합(bond) 또는 C1-3알킬인,Xa and Xa 'are each independently a bond or C 1-3 alkyl,
    피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursor-linker compound, pharmaceutically acceptable salt or solvate thereof.
  16. 제14항에 있어서,The method of claim 14,
    Z는 H,
    Figure PCTKR2018003744-appb-I000122
    ,
    Figure PCTKR2018003744-appb-I000123
    및 -(CH2)m-OCH3로 이루어진 그룹으로부터 선택되며,     Z is H,
    Figure PCTKR2018003744-appb-I000122
    ,
    Figure PCTKR2018003744-appb-I000123
    And-(CH 2 ) m -OCH 3 ,
    R8, R9 및 R10은 각각 독립적으로 H, C1-3알킬, 및 C1-3알콕시로 이루어진 그룹으로부터 선택되고, m은 1 내지 6인,R 8 , R 9 and R 10 are each independently selected from the group consisting of H, C 1-3 alkyl, and C 1-3 alkoxy, m is 1 to 6,
    피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursor-linker compound, pharmaceutically acceptable salt or solvate thereof.
  17. 제14항에 있어서,The method of claim 14,
    W는 -C(O)-, -C(O)NR'''- 또는 -C(O)O-이고, 여기서 R'''은 H 또는 C1-8알킬이며,W is -C (O)-, -C (O) NR '''-or -C (O) O-, where R''' is H or C 1-8 alkyl,
    L은 브랜칭 유닛(branching unit), 연결 유닛(connection unit) 및 결합 유닛(binding unit)으로 이루어진 그룹으로부터 선택되는 하나 이상의 유닛, 또는 이들 유닛의 조합이며, 여기에서 연결 유닛은 W와 결합 유닛을, W와 브랜칭 유닛을, 브랜칭 유닛과 브랜칭 유닛을, 또는 브랜칭 유닛과 결합 유닛을 연결하고, 여기에서 브랜칭 유닛은 연결 유닛과 W를, 또는 연결 유닛과 또 다른 연결 유닛을 연결하며,L is one or more units selected from the group consisting of a branching unit, a connection unit and a binding unit, or a combination of these units, wherein the connection unit is a combination of W, Connecting the W and the branching unit, the branching unit and the branching unit, or the branching unit and the coupling unit, wherein the branching unit connects the connection unit and the W, or the connection unit and another connection unit,
    브랜칭 유닛은 C2-8알케닐(여기서, 알케닐의 탄소 원자는 하나 또는 그 이상의 N, O 및 S로 이루어진 그룹으로부터 선택되는 헤테로원자로 치환될 수 있으며, 알케닐은 하나 또는 그 이상의 C1-6알킬로 더 치환될 수 있다), 친수성(hydrophilic) 아미노산, -C(O)-, -C(O)NR''''-, -C(O)O-, -(CH2)s-NHC(O)-(CH2)t-, -(CH2)u-C(O)NH-(CH2)v-, -(CH2)s-NHC(O)-(CH2)t-C(O)-, -(CH2)u-C(O)NH-(CH2)v-C(O)-,이고(여기서, R''''는 H, C1-8알킬, C3-8사이클로알킬, C1-8알콕시, C1-8알킬티오, 모노- 또는 다이-C1-8알킬아미노, C3-20헤테로아릴 또는 C5-20아릴이며, s, t, u 및 v는 각각 독립적으로 0 내지 5의 정수이고),The branching unit may be substituted with C 2-8 alkenyl, wherein the alkenyl carbon atom is substituted with one or more heteroatoms selected from the group consisting of N, O and S, alkenyl being one or more C 1- 6 may be substituted with alkyl), hydrophilic amino acid, -C (O)-, -C (O) NR ''''-, -C (O) O-,-(CH 2 ) s- NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t- C (O)-,-(CH 2 ) u -C (O) NH- (CH 2 ) v -C (O)-, wherein R '''' is H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 5-20 aryl, s, t, u And v are each independently an integer from 0 to 5),
    연결 유닛은 -(CH2)r(V(CH2)p)q-이며, 여기에서, r은 0 내지 10의 정수이고, p는 0 내지 12의 정수이며, q는 1 내지 20의 정수이고, V는 단일결합, 또는 -O-이며,The connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, or -O-,
    결합 유닛은
    Figure PCTKR2018003744-appb-I000124
    ,
    Figure PCTKR2018003744-appb-I000125
    ,
    Figure PCTKR2018003744-appb-I000126
    또는
    Figure PCTKR2018003744-appb-I000127
    이고, 여기에서 L1은 단일결합 또는 C2- 8알케닐이며, R11은 H 또는 C1- 6알킬이고, L2는 C2- 8알케닐이며;    Coupling unit
    Figure PCTKR2018003744-appb-I000124
    ,
    Figure PCTKR2018003744-appb-I000125
    ,
    Figure PCTKR2018003744-appb-I000126
    or
    Figure PCTKR2018003744-appb-I000127
    And, in which L 1 is a single bond or a C 2- 8 alkenyl Al, R 11 is H or C 1- 6 alkyl, L 2 is C 2- 8 alkenyl, and;
    여기서, 연결 유닛은 -(CH2)r(V(CH2)p)q-이며, Wherein the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- ,
    여기서, r은 0 내지 8의 정수이고, p는 1 내지 12의 정수이며, q는 1 내지 10의 정수이고, V는 단일결합 또는 -O-인,Wherein r is an integer from 0 to 8, p is an integer from 1 to 12, q is an integer from 1 to 10, and V is a single bond or -O-,
    피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursor-linker compound, pharmaceutically acceptable salt or solvate thereof.
  18. 제14항에 있어서,The method of claim 14,
    하기 화학구조를 갖는, 피롤로벤조디아제핀 이량체 전구체-링커 화합물, 이의 약학적으로 허용되는 염 또는 용매화물:Pyrrolobenzodiazepine dimer precursor-linker compounds having the following chemical structure, pharmaceutically acceptable salts or solvates thereof:
    Figure PCTKR2018003744-appb-I000128
    Figure PCTKR2018003744-appb-I000128
    Figure PCTKR2018003744-appb-I000129
    Figure PCTKR2018003744-appb-I000129
    Figure PCTKR2018003744-appb-I000130
    Figure PCTKR2018003744-appb-I000130
    Figure PCTKR2018003744-appb-I000131
    Figure PCTKR2018003744-appb-I000131
    Figure PCTKR2018003744-appb-I000132
    Figure PCTKR2018003744-appb-I000132
    Figure PCTKR2018003744-appb-I000133
    Figure PCTKR2018003744-appb-I000133
    Figure PCTKR2018003744-appb-I000134
    Figure PCTKR2018003744-appb-I000134
    Figure PCTKR2018003744-appb-I000135
    Figure PCTKR2018003744-appb-I000135
    Figure PCTKR2018003744-appb-I000136
    Figure PCTKR2018003744-appb-I000136
    Figure PCTKR2018003744-appb-I000137
    Figure PCTKR2018003744-appb-I000137
    Figure PCTKR2018003744-appb-I000138
    Figure PCTKR2018003744-appb-I000138
    Figure PCTKR2018003744-appb-I000139
    Figure PCTKR2018003744-appb-I000139
    Figure PCTKR2018003744-appb-I000140
    Figure PCTKR2018003744-appb-I000140
    Figure PCTKR2018003744-appb-I000141
    Figure PCTKR2018003744-appb-I000141
    Figure PCTKR2018003744-appb-I000142
    Figure PCTKR2018003744-appb-I000142
    Figure PCTKR2018003744-appb-I000143
    Figure PCTKR2018003744-appb-I000143
    Figure PCTKR2018003744-appb-I000144
    Figure PCTKR2018003744-appb-I000144
    Figure PCTKR2018003744-appb-I000145
    Figure PCTKR2018003744-appb-I000145
    Figure PCTKR2018003744-appb-I000146
    Figure PCTKR2018003744-appb-I000146
    Figure PCTKR2018003744-appb-I000147
    Figure PCTKR2018003744-appb-I000147
    Figure PCTKR2018003744-appb-I000148
    Figure PCTKR2018003744-appb-I000148
    Figure PCTKR2018003744-appb-I000149
    Figure PCTKR2018003744-appb-I000149
    Figure PCTKR2018003744-appb-I000150
    Figure PCTKR2018003744-appb-I000150
    Figure PCTKR2018003744-appb-I000151
    Figure PCTKR2018003744-appb-I000151
    Figure PCTKR2018003744-appb-I000152
    및
    Figure PCTKR2018003744-appb-I000152
    And
    Figure PCTKR2018003744-appb-I000153
    .
    Figure PCTKR2018003744-appb-I000153
    .
  19. 하기 화학식 IIIa 또는 IIIb의 구조를 갖는 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물:A pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate having the structure of Formula IIIa or IIIb, a pharmaceutically acceptable salt or solvate thereof:
    [화학식 IIIa][Formula IIIa]
    Figure PCTKR2018003744-appb-I000154
    Figure PCTKR2018003744-appb-I000154
    [화학식 IIIb][Formula IIIb]
    Figure PCTKR2018003744-appb-I000155
    Figure PCTKR2018003744-appb-I000155
    상기 식에서,Where
    점선, R1, R2, R3, R4, R5, R6, R7, X, Y, R1', R2', R3', R4', R5', R7', X', Y', R8, Za, Zb, R12a, R13a, R14a, R8', Za', Zb', R12a', R13a', 및 R14a'은 각각 제2항에서 화학식 Ia 및 화학식 Ia'의 화합물에 대해 정의한 바와 동일하고,Dashed line, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
    Xa, G, Z, W, L, Xa', G', Z'은 각각 제11항에서 화학식 IIb의 화합물에 대해 정의한 바와 동일하며;Xa, G, Z, W, L, Xa ', G', Z 'are the same as defined for the compound of formula IIb in claim 11, respectively;
    Ligand는 항원 결합 모이어티이다.Ligand is an antigen binding moiety.
  20. 제19항에 있어서,The method of claim 19,
    Ligand는 단백질인, Ligand is a protein,
    피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, pharmaceutically acceptable salts or solvates thereof.
  21. 제20항에 있어서,The method of claim 20,
    상기 단백질은 이소프레노이드 트랜스퍼라아제에 의하여 인식될 수 있는 하나 이상의 아미노산 모티프를 갖는 것인, Wherein the protein has one or more amino acid motifs that can be recognized by isoprenoid transferases,
    피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, pharmaceutically acceptable salts or solvates thereof.
  22. 제21항에 있어서,The method of claim 21,
    상기 이소프레노이드 트랜스퍼라아제는 FTase(farnesyl protein transferase) 또는 GGTase(geranylgeranyl transferase)인,The isoprenoid transferase is FTase (farnesyl protein transferase) or GGTase (geranylgeranyl transferase),
    피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, pharmaceutically acceptable salts or solvates thereof.
  23. 제21항에 있어서,The method of claim 21,
    상기 아미노산 모티프가 CYYX, XXCC, XCXC 또는 CXX이고,The amino acid motif is CYYX, XXCC, XCXC or CXX,
    여기에서 C는 시스테인, Y는 지방족 아미노산, X는 이소프레노이드 트랜스퍼라아제의 기질 특이성을 결정하는 아미노산인,Where C is cysteine, Y is an aliphatic amino acid, X is an amino acid that determines the substrate specificity of the isoprenoid transferase,
    피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물.Pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, pharmaceutically acceptable salts or solvates thereof.
  24. 제19항 내지 제23항 중 어느 한 항의 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물을 포함하는, A pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate of any one of claims 19 to 23, comprising a pharmaceutically acceptable salt or solvate thereof,
    증식성 질환의 예방 또는 치료용 약학 조성물.Pharmaceutical compositions for the prevention or treatment of proliferative diseases.
  25. 제24항에 있어서,The method of claim 24,
    상기 증식성 질환은 신생물, 종양, 암, 백혈병, 건선, 뼈 질환, 섬유증식성 장애, 및 죽상동맥경화증으로 이루어진 그룹으로부터 선택되는 것인, 증식성 질환의 예방 또는 치료용 약학 조성물.The proliferative disease is selected from the group consisting of neoplasia, tumor, cancer, leukemia, psoriasis, bone disease, fibrotic disorder, and atherosclerosis, pharmaceutical composition for preventing or treating proliferative disease.
  26. 제25항에 있어서,The method of claim 25,
    상기 암은 폐암, 소세포성 폐암, 위장관암, 대장암, 장암, 유방암, 난소암, 전립선암, 고환암, 간암, 신장암, 방광암, 췌장암, 뇌암, 육종, 골육종, 카포시 육종 및 흑색종으로 이루어진 그룹으로부터 선택되는 것인, 증식성 질환의 예방 또는 치료용 약학 조성물.The cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma The pharmaceutical composition for preventing or treating proliferative diseases, which is selected from.
  27. 제19항 내지 제23항 중 어느 한 항의 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물; 및 The pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate of any one of claims 19-23, a pharmaceutically acceptable salt or solvate thereof; And
    약학적으로 허용되는 부형제를 포함하는, Comprising pharmaceutically acceptable excipients,
    증식성 질환의 예방 또는 치료용 약학 조성물.Pharmaceutical compositions for the prevention or treatment of proliferative diseases.
  28. 제19항 내지 제23항 중 어느 한 항의 피롤로벤조디아제핀 이량체 전구체-링커-리간드 접합체, 이의 약학적으로 허용되는 염 또는 용매화물;The pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate of any one of claims 19-23, a pharmaceutically acceptable salt or solvate thereof;
    1종 이상의 치료적 공동-작용제(therapeutic co-agent); 및 One or more therapeutic co-agents; And
    약학적으로 허용되는 부형제를 포함하는,Comprising pharmaceutically acceptable excipients,
    증식성 질환의 예방 또는 치료용 약학 조성물.Pharmaceutical compositions for the prevention or treatment of proliferative diseases.
PCT/KR2018/003744 2017-03-29 2018-03-29 Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof WO2018182341A1 (en)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109535035A (en) * 2019-01-08 2019-03-29 吉尔生化（上海）有限公司 A kind of preparation method of the N- benzyloxycarbonyl group -3- amino-alanine tert-butyl ester
WO2019166615A1 (en) * 2018-03-01 2019-09-06 Medimmune Limited Methods
CN112135638A (en) * 2019-03-06 2020-12-25 乐高化学生物科学股份有限公司 Antibody-drug conjugates comprising anti-human DLK1 antibodies and uses thereof
CN113260621A (en) * 2019-01-03 2021-08-13 乐高化学生物科学股份有限公司 Pyrrolobenzodiazepine dimer compound with improved safety and use thereof
WO2022015656A1 (en) 2020-07-13 2022-01-20 Regeneron Pharmaceuticals, Inc. Camptothecin analogs conjugated to a glutamine residue in a protein, and their use
JP2022516911A (en) * 2019-01-03 2022-03-03 レゴケム バイオサイエンシズ， インク． Pyrrolobenzodiazepine dimer compounds with improved stability and their uses
JP2022530482A (en) * 2019-05-02 2022-06-29 レゴケム バイオサイエンシズ， インク． Ligand-drug complex containing a linker with a Tris structure
WO2022187591A1 (en) 2021-03-05 2022-09-09 Go Therapeutics, Inc. Anti-glyco-cd44 antibodies and their uses
US11524969B2 (en) 2018-04-12 2022-12-13 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
WO2023014863A1 (en) 2021-08-05 2023-02-09 Go Therapeutics, Inc. Anti-glyco-muc4 antibodies and their uses
EP3936150A4 (en) * 2019-03-06 2023-03-29 LegoChem Biosciences, Inc. Antibody-drug conjugates including antibody against human dlk1, and use thereof
WO2023166322A1 (en) 2022-03-04 2023-09-07 Iksuda Therapeutics Limited Anti-canag antibody conjugate
US11827703B2 (en) 2018-05-09 2023-11-28 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
US11975076B2 (en) 2015-11-25 2024-05-07 Legochem Biosciences, Inc. Antibody-drug conjugates comprising branched linkers and methods related thereto

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016647A1 (en) * 2007-08-01 2009-02-05 Council Of Scientific & Industrial Research Pyrrolo [2,1-c][1, 4] benzodiazepine-glycoside prodrugs useful as a selective anti tumor agent
KR20150137015A (en) * 2014-05-28 2015-12-08 주식회사 레고켐 바이오사이언스 Compounds comprising self-immolative group
US20160256561A1 (en) * 2013-10-11 2016-09-08 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016647A1 (en) * 2007-08-01 2009-02-05 Council Of Scientific & Industrial Research Pyrrolo [2,1-c][1, 4] benzodiazepine-glycoside prodrugs useful as a selective anti tumor agent
US20160256561A1 (en) * 2013-10-11 2016-09-08 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
KR20150137015A (en) * 2014-05-28 2015-12-08 주식회사 레고켐 바이오사이언스 Compounds comprising self-immolative group

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SAGNOU, M. J. ET AL.: "Design and Synthesis of Novel Pyrrolobenzodiazepine (PBD) Prodrugs for ADEPT and GDEPT", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 10, 2000, pages 2083 - 2086, XP002323711 *
VARVOUNIS, G.: "An Update on the Synthesis of Pyrrolo[1,4]benzodiazepines", MOLECULES, vol. 21, no. 2, 28 January 2016 (2016-01-28), pages 154, XP055558979 *

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WO2019166615A1 (en) * 2018-03-01 2019-09-06 Medimmune Limited Methods
US11352324B2 (en) 2018-03-01 2022-06-07 Medimmune Limited Methods
US11524969B2 (en) 2018-04-12 2022-12-13 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
US11827703B2 (en) 2018-05-09 2023-11-28 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
JP7542266B2 (en) 2019-01-03 2024-08-30 リガケム バイオサイエンシズ， インク． Pyrrolobenzodiazepine dimer compounds with improved stability and uses thereof
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EP3936150A4 (en) * 2019-03-06 2023-03-29 LegoChem Biosciences, Inc. Antibody-drug conjugates including antibody against human dlk1, and use thereof
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JP2022530482A (en) * 2019-05-02 2022-06-29 レゴケム バイオサイエンシズ， インク． Ligand-drug complex containing a linker with a Tris structure
WO2022015656A1 (en) 2020-07-13 2022-01-20 Regeneron Pharmaceuticals, Inc. Camptothecin analogs conjugated to a glutamine residue in a protein, and their use
WO2022187591A1 (en) 2021-03-05 2022-09-09 Go Therapeutics, Inc. Anti-glyco-cd44 antibodies and their uses
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