WO2020055192A2 - Preparation method for quinoline-5, 8-dione derivative which is tgase 2 inhibitor - Google Patents

Preparation method for quinoline-5, 8-dione derivative which is tgase 2 inhibitor Download PDF

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WO2020055192A2
WO2020055192A2 PCT/KR2019/011876 KR2019011876W WO2020055192A2 WO 2020055192 A2 WO2020055192 A2 WO 2020055192A2 KR 2019011876 W KR2019011876 W KR 2019011876W WO 2020055192 A2 WO2020055192 A2 WO 2020055192A2
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alkyl
compound
alkenyl
cycloalkyl
heteroaryl
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WO2020055192A3 (en
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송민수
임춘영
박가영
고은비
강지희
우서연
김숭현
황희종
이은혜
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재단법인 대구경북첨단의료산업진흥재단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a quinoline-5,8-dione derivative compound having a transglutaminase 2 (Tglutaseminase 2) inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • Tglutaseminase 2 transglutaminase 2
  • Transglutaminase is a group of enzymes that form a covalent bond between the free amine group and the gamma-carboxamide group of glutamine inside the protein.It was first discovered in 1959, and its specific biochemical role was blood coagulation in 1968. It was found in the protein fibrin stabilizing factor (factor III).
  • TGase 2 type 2 transglutaminase
  • TGase 2 type 2 transglutaminase
  • TGase 2 It has been reported that abnormally excessive expression of TGase 2 plays a major role in the development of diseases such as inflammatory diseases or autoimmune diseases. In addition, it is known that excessive expression of TGase 2 induces neurodegenerative diseases, and recently, studies showing that tissue transglutaminase may have abnormally high levels in people with neurological diseases such as Huntington's disease and Parkinson's disease. Came out
  • TGase 2 plays a major role in experimental kidney and liver fibrosis, and the degree of fibrosis decreases when its activity is inhibited using an inhibitor.
  • Amine compounds are known as substances that inhibit TGase 2 activity, and examples thereof include cystamine and putrescine.
  • chemical inhibitors such as monodansylcarbaverine, w-dibenzylaminoalkylamine, 3-halo-4,5-dihydroisooxazole, and 2-[(2-oxopropyl) thio] imidazolium derivatives have been developed. However, all of them are known to be non-specific in vivo and cause inhibition of other enzymes.
  • TGase 2 inhibitory activity such as glucosamine derivative, chlorogenic acid, epigallocatechin gallate, curcumin, sulparem, etacrynic acid, etc., but it is still clear whether significant activity will appear in the treatment of TGase 2 related diseases in animals. It is in an unknown state.
  • Patent Document 1 U.S. Patent Application No. 2009-462554
  • Patent Document 2 Korean Patent Application No. 2008-0118688
  • Patent Document 3 Korean Patent Application No. 2009-0018388
  • Patent Document 4 Korean Patent Application No. 2014-0090500
  • Non-Patent Document 1 Karpuj, Marcela V. et al., "Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine.” Nature medicine 8.2 (2002): 143-149.
  • Non-Patent Document 2 Soo-Youl Kim, “Transglutaminase 2 in inflammation.” Frontier Bioscience 11 (2006): 3026-3035.
  • An object of the present invention is to provide a novel quinoline-5,8-dione derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for preparing a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, halogen, C 1-6 alkyl or -OC 1-6 alkyl
  • R 2 is hydrogen, halogen or -NH 2 , wherein one or more hydrogens of -NH 2 may be optionally substituted with R 4 ,
  • R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
  • the C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  • the production method of the present application comprises the steps of preparing a compound IMC2 by coupling a compound IMC1 according to the following reaction scheme 1; And reacting compound IMC2 to prepare compound Q1.
  • Xa represents halogen
  • Y, Y 1 and Y 2 are each independently C 1-6 alkyl
  • R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
  • the C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  • a compound ammonium nitrate (CAN) aqueous solution may be added dropwise to compound IMC2 to prepare compound Q1.
  • a method for preparing a quinoline-5,8-dione derivative comprises the steps of preparing a compound IMC2 by coupling a compound IMC1 according to the following scheme 2; Reacting compound IMC2 to prepare compound IMC3; And reacting compound IMC3 to produce compound Q2.
  • Xa represents halogen
  • Y, Y 1 and Y 2 are each independently C 1-6 alkyl
  • the coupling reaction of each of Reaction Schemes 1 and 2 includes (HO) 2 -B- (A 1 ), , K + (BF 3 (A 1 )) - , (A 1 ) -Sn (n-Bu) 3 , NH 2- (A 1 ) or Can be used.
  • (HO) 2 -B- (A 1 ), , K + (BF 3 (A 1)) -, (A 1) -Sn (n-Bu) 3 or NH 2 - A 1 in (A 1) are the same as defined in scheme 1 or scheme 2, respectively,
  • In A 1 represents C 3-12 heteroaryl unsubstituted or substituted with R 5 .
  • the preparation method of the present invention may further include the step of preparing compound Q3 by halogenating compound Q1 according to the following scheme 3.
  • Y is C 1-6 alkyl
  • a 1 is the same as defined in Scheme 1.
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q4 with compound Q3 according to the following scheme 4.
  • Y is C 1-6 alkyl
  • the method for producing the quinoline-5,8-dione derivative may further include preparing compound Q5 from compound Q3 according to the following scheme 5.
  • Y is C 1-6 alkyl
  • a 1 is the same as defined in Scheme 1.
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q6 with compound Q5 according to the following scheme 6.
  • Y is C 1-6 alkyl
  • a 1 is the same as defined in Scheme 1,
  • the method for preparing the quinoline-5,8-dione derivative comprises the steps of preparing compound IMC3 with compound Q3 according to scheme 7 below; And preparing a compound Q7 through a reduction reaction of the compound IMC3.
  • Y is C 1-6 alkyl
  • the method for preparing the quinoline-5,8-dione derivative may include preparing compound Q8 with compound Q7 according to the following scheme 8.
  • Y is C 1-6 alkyl
  • a 6 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3-
  • a hydrogen group in any one of 10 heterocycloalkyl represents a functional group substituted with -C (OH) (C 1-6 alkyl) or -NH 2 ,
  • a 7 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10
  • the method for preparing the quinoline-5,8-dione derivative herein includes preparing compound Q9 according to the following scheme 9.
  • Xb represents halogen
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q10 using compound Q9 according to the following scheme 10.
  • Xb represents halogen
  • Z 1 represents halogen, C 1-3 alkyl or -O- (C 1-3 alkyl).
  • the method for preparing the quinoline-5,8-dione derivative herein includes preparing compound Q11 according to the following scheme 11.
  • Xc and Xd each independently represent halogen
  • R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
  • the C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  • the method for preparing the quinoline-5,8-dione derivative may prepare compound Q13 using compound Q11 according to the following scheme 12.
  • compound Q12 can be prepared by sequentially adding NaN 3 and NaBH 4 to compound Q11.
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q13 by reacting compound Q12 according to the following scheme 13.
  • a 8 is the same as in Scheme 12,
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q14 by reacting compound Q11 according to the following scheme 14.
  • Z 2 represents halogen, C 1-3 alkyl or -OC 1-3 alkyl.
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q15 using compound Q14 according to the following reaction formula 15. At this time, NaN 3 and NaBH 4 may be sequentially added dropwise to compound 14 to prepare compound Q15.
  • the method for preparing the quinoline-5,8-dione derivative herein includes the step of preparing compound Q17 by reacting compound Q16 according to the following scheme 16.
  • Xf represents halogen
  • Z 3 represents halogen, C 1-3 alkyl or -OC 1-3 alkyl.
  • the method for preparing the quinoline-5,8-dione derivative may include preparing compound Q18 according to scheme 17 below. At this time, a premi salt can be used to prepare compound Q18.
  • Xg represents halogen
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q19 by reacting compound Q18 according to the following scheme 18.
  • Xg represents halogen
  • R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
  • the C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  • the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q20 by reacting compound Q19 according to the following reaction formula 19.
  • a 13 is the same as defined in Scheme 18 above.
  • the quinoline-5,8-dione derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof prepared according to the preparation method of the present invention has little side effects and effectively inhibits TGase 2.
  • a quinoline-5,8-dione derivative compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof prepared according to the preparation method of the present invention is a disorder or disease mediated by TGase 2 or reacting to an inhibitor of TGase 2 It can be useful for therapeutic or preventive purposes.
  • 1 is a graph showing the tumor volume of the control group (CT) identified in Experimental Example 3, 5 mg / kg administered group of the compound of Formula I, 10 mg / kg administered group of the compound of Formula I, and 20 mg / kg administered group of the compound of Formula I.
  • FIG. 2 is a graph showing tumor weight of the control group (CT) identified in Experimental Example 3, 5 mg / kg administered group of compound of formula I, 10 mg / kg administered group of compound of formula I, and 20 mg / kg administered group of compound of formula I.
  • FIG. 3 is a photograph showing the appearance of tumors of the control group identified in Experimental Example 3, 5 mg / kg compound of formula I, 10 mg / kg compound of compound of formula I, and 20 mg / kg compound of compound of formula I.
  • Figure 4 is a graph showing the weight of the control group and the compound of formula I 100 mg / kg group identified in Experimental Example 3.
  • Figure 5 is a graph showing the plasma concentration of the control group and the compound of formula I 10 mg / kg group identified in Experimental Example 4.
  • the term “combination (s)” included in the expression of the marki form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the marki form, It means to include one or more selected from the group consisting of the above components.
  • halo may be, but is not limited to, F, Cl, Br, or I.
  • alkyl or “alkyl group” may be a linear or branched, saturated or unsaturated, alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl, etc. , Hexyl, hexyl, octyl, nonyl, decyl, or isomers thereof, but is not limited thereto.
  • aryl or “aryl group”, alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring, such as phenyl, substituted phenyl, as well as fused groups, Examples include, but are not limited to, naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl, and indanyl.
  • the "aryl” or “aryl group” contains one or more rings having 5 or more atoms, and 5 or fewer rings containing 22 or fewer atoms may be present, adjacent carbon atoms or Double bonds may alternately (resonant) between suitable heteroatoms.
  • the "aryl” or “aryl group” may be phenyl, phenyl substituted as described above, phenyl, naphthyl, or naphthyl substituted as described above, but is not limited thereto.
  • heteroaryl or “heteroaryl group”, alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring comprising one or more atoms other than carbon atoms, eg For example, furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzodioxynyl, andazolyl, isoindolinyl, indenyl, quinolinyl and benzothiophenyl And the like, but is not limited thereto.
  • Heteroaryl or “heteroaryl group” contains one or more rings having 5 or more atoms, and may be 5 or fewer rings containing 22 or fewer atoms, adjacent carbon atoms or suitable heteroatoms There may be alternating (resonant) double bonds between them.
  • heteroaryl or “heteroaryl group” may be substituted in the same manner as described in the "aryl” or “aryl group” above.
  • alkoxy or “alkoxy group” may include, but is not limited to, an “alkoxy group” and an oxygen atom-bonded alkoxy group as defined above.
  • amine or “amine group”, alone or as part of another group, refers to -NH 2 , and also, the “amine group” is one or two substituents that may be the same or different.
  • substituents such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl , Carbonyl or carboxyl.
  • R 1 is hydrogen, halogen, C 1-6 alkyl or -OC 1-6 alkyl
  • R 2 is hydrogen, halogen or -NH 2 , wherein one or more hydrogens of -NH 2 may be optionally substituted with R 4 ,
  • R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
  • the C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  • R 1 may specifically be hydrogen, C 1-3 alkyl or -OC 1-3 alkyl, preferably hydrogen, -CH 3 or -O-CH 3 , more preferably Is hydrogen or -O-CH 3 .
  • R 2 may specifically be hydrogen, Br or -NH 2 .
  • R 3 is specifically furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzodioxynyl, indazolyl, Isoindolinyl, quinolinyl, pyridazinylamino, pyridinylamino, phenyl, indenyl, naphthalenyl, phenylamino, piperidinyl or cyclopropyl, more specifically furan-3-yl, thi Offen-2-yl, pyrazole-4-yl, pyrazine-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, benzo [d] thiazole -5-yl, benzothiophen-2-yl, dihydro
  • R a may specifically be C 1-3 alkyl, phenyl or morpholinyl.
  • R b can be specifically hydrogen, -NH 2 , -NH (CH 3 ), C 1-3 alkyl or C 2-3 alkenyl.
  • R e may specifically be C 1-3 alkyl, -OH, -OC 1-3 alkyl, -COOH, -COOCH 3 or morpholinyl.
  • R 1 is -OC 1-3 alkyl
  • R 2 is hydrogen
  • R 1 is -O-CH 3 ,
  • R 2 is hydrogen
  • R 3 is pyrimidinyl, the pyrimidinyl may be unsubstituted or one or more hydrogens may be substituted with R 5 ,
  • R 5 is -OR a
  • R a is phenyl, and the phenyl may be unsubstituted or one or more hydrogens may be substituted with -O-CF 3 .
  • R 1 is hydrogen, C 1-3 alkyl or -OC 1-3 alkyl
  • R 2 is Br
  • R 1 is hydrogen, halogen, C 1-3 alkyl or -OC 1-3 alkyl
  • R 2 is -NH 2 , wherein one or more hydrogens of -NH 2 can be optionally substituted with R 4 ,
  • R 1 is hydrogen
  • R 2 is -NH 2
  • R 3 is phenyl, the phenyl may be unsubstituted or substituted with R 5 ,
  • R 5 is -OR a or C 1-6 alkyl, wherein C 1-6 alkyl may be substituted with one or more hydrogen R e ,
  • R a is phenyl or piperidinyl, and the phenyl or piperidinyl may be unsubstituted or one or more hydrogens may be substituted with C 1-3 alkyl,
  • R e is morpholine.
  • R 1 is -O-CH 3 ,
  • R 2 is -NH 2
  • R 3 is pyrimidinyl or pyridinyl, the pyrimidinyl or pyrinidyl may be unsubstituted or substituted with R 5 ,
  • R 5 is halogen or C 1-3 alkyl, and C 1-3 alkyl may be substituted with R e ,
  • R e is halogen
  • R 1 is hydrogen, C 1-3 alkyl or -OC 1-3 alkyl
  • R 2 is hydrogen, Br or -NH 2 ,
  • R a is C 1-6 alkyl, C 1-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, wherein R a is unsubstituted or one or more hydrogens may be substituted with C 1-6 alkyl, C 1-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d , C 1-6 alkyl, C 1-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
  • the C 3-12 heteroaryl and C 3-10 heterocycloalkyl may include 1 to 3 heteroatoms selected from O, N or S.
  • R 1 is hydrogen or -O-CH 3 ,
  • R 2 is hydrogen or -NH 2 ,
  • R 3 is phenyl, pyrimidinyl or pyridinyl, the phenyl, pyrimidinyl and pyridinyl may be unsubstituted or one or more hydrogens may be substituted with R 5 ,
  • R 5 is halogen, C 1-3 alkyl, -OR a , and C 1-3 alkyl may be unsubstituted or one or more hydrogens may be substituted with R e ,
  • R a is phenyl or piperidinyl, the phenyl or piperidinyl may be unsubstituted or one or more hydrogens may be substituted with C 1-3 alkyl or O-CF 3 ,
  • R e is halogen or morpholinyl.
  • the compound represented by the formula (I) is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula represented in the following [Table 1] It may be a salt thereof, but is not limited thereto.
  • the compound represented by Formula (I) is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula shown in Table 2 below. It may be a salt thereof.
  • pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts made of calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodine Inorganic acid salts made from acids, perchloric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid Organic acid, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid made of, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid
  • the compounds of formula (I) may contain one or more asymmetric carbons, and thus may exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. These isomers can be separated by prior art techniques, for example, the compound of formula I can be separated by tube chromatography or HPLC. Alternatively, the stereoisomers of each of the compounds of formula I can be stereospecifically synthesized using known arrays of optically pure starting materials and / or reagents.
  • composition comprising a quinoline-5,8-dione derivative compound, use thereof and treatment method using same
  • the compound of the formula (I) is as described above, and overlapping parts are omitted.
  • the carrier may be, for example, a commonly used one, sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, phosphoric anhydride Calcium hydrogen, or mixtures thereof may be used, but is not limited thereto.
  • the composition may include, for example, an additive such as a binder, a disintegrant, a lubricant, a pH adjusting agent, and an antioxidant, but is not limited thereto.
  • an additive such as a binder, a disintegrant, a lubricant, a pH adjusting agent, and an antioxidant, but is not limited thereto.
  • the binder is, for example, starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone) , Hypromellose, hydroxypropylcellulose, natural gums, synthetic gums, copovidone, gelatin, or mixtures thereof may be used, but is not limited thereto.
  • the disintegrating agent may be, for example, starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clays such as bentonite, montmorillonite, or veegum; Cellulose such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Cross-linked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate and citric acid, or mixtures thereof may be used, but are not limited thereto.
  • starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch
  • Clays such as bentonite, montmorillonite, or veegum
  • Cellulose such as microcrystalline cellulose, hydroxyprop
  • the lubricant is, for example, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostea Rate, glyceryl palmitostearate, colloidal silicon dioxide, or mixtures thereof, but is not limited thereto.
  • the pH adjusting agent is, for example, acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), precipitated calcium carbonate, ammonia water, Basic agents such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, and tribasic calcium phosphate may be used, but are not limited thereto.
  • acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), precipitated calcium carbonate, ammonia water
  • Basic agents such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, and tribasic calcium phosphate may be used, but are not limited thereto.
  • the antioxidant may be, for example, dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, and the like.
  • the solubilizing aid may be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, docusate sodium, poloxamer, and the like, but is not limited thereto.
  • the composition herein can be used for the prevention or treatment of disorders or diseases mediated by TGase 2 or responding to the inhibition of TGase 2 have.
  • the use of the compounds of formula I herein is not limited thereto.
  • a pharmaceutical composition for the prevention or treatment of a disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 comprising a compound of Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • the compound of the formula (I) is as described above, and the description of the overlapping part is omitted.
  • the disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 is in the group consisting of inflammatory disease, nervous system disease, cancer, renal parenchymal disease, fibrosis or combinations thereof. It may be selected, but is not limited thereto.
  • the inflammatory diseases include, for example, degenerative arthritis, diabetes, autoimmune myositis, arteriosclerosis, Crohn's disease, inflammatory gastric ulcer, stroke, cirrhosis, meningitis, rhinitis, conjunctivitis, asthma, inflammatory skin disease, inflammatory bowel disease, rheumatoid inflammatory disease Or glomerulonephritis, but is not limited thereto.
  • the nervous system disease may be, for example, Alzheimer's disease, dementia, Parkinson's disease, or Huntington's disease, but is not limited thereto.
  • the cancer is, for example, colon cancer, small intestine cancer, rectal cancer, colon cancer, anal cancer, esophageal cancer, stomach cancer, pancreatic cancer, gallbladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, lung cancer, lymphatic cancer, thyroid cancer, prostate cancer, blood cancer , Skin cancer, brain tumor, kidney cancer or bladder cancer, but is not limited thereto.
  • the fibrosis may be, for example, lung fibrosis or liver fibrosis, but is not limited thereto.
  • the disorder or disease mediated by TGase 2 or responding to the inhibition of TGase 2 is cancer, more preferably kidney cancer, brain cancer or gastric cancer.
  • a method of inhibiting TGase 2 activity in a subject comprising administering a compound of Formula I to the subject in a therapeutically effective amount.
  • the subject includes, but is not limited to, mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice.
  • a compound of formula (I) herein for the manufacture of a medicament for the treatment of a disorder or condition mediated by TGase 2 or in response to inhibition of TGase 2 in a subject.
  • the present application provides a method for preparing the compound of Formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof.
  • the above-described compounds of the formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof are not limited to those prepared by the preparation method herein.
  • the method for preparing a quinoline-5,8-dione derivative compound represented by the formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is the same as [Scheme a], and apparent to those skilled in the art This also includes manufacturing methods modified at a level.
  • the compound of Formula 1-1 is reacted with nitric acid to synthesize the compound of Formula 1-2, and then, the compound of Formula 1-3 is synthesized by the Pd / CH 2 reduction reaction. .
  • the compound of Formula 1-3 is reacted with (E) -3-ethoxyacryloyl chloride to synthesize the compound of Formula 1-4, and the compound of Formula 1-4 is added dropwise to the sulfuric acid solution to react to formula 1-5. Synthesize the compound.
  • a compound of Formula 1-5 is dissolved in a solution of pyridine and dimethylformamide (DMF), and phosphorus oxychloride (POCl 3 ) is added dropwise to synthesize a compound of Formula 1-6.
  • DMF dimethylformamide
  • POCl 3 phosphorus oxychloride
  • a compound of Formula 1-9 can be synthesized by reacting bromine with a compound of Formula 1-8.
  • the method for preparing a quinoline-5,8-dione derivative compound represented by the formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is the same as [Scheme b], and is apparent to those skilled in the art This also includes manufacturing methods modified at a level.
  • a compound of Formula 10-2 is synthesized by reacting a compound of Formula 10-1 with nitric acid, and then a compound of Formula 10-3 is synthesized by a Pd / CH 2 reduction reaction. .
  • the compound of Formula 10-3 is reacted with acetyl chloride to synthesize the compound of Formula 10-4, and the compound of Formula 10-4 is reacted with H 2 O to synthesize the compound of Formula 10-5.
  • the compound of Formula 10-5 is reacted with benzyl bromide (BnBr) to synthesize the compound of Formula 10-6, mCPBA is added dropwise to the compound of Formula 10-6 to synthesize the compound of Formula 10-7, and POCl 3 is added.
  • BnBr benzyl bromide
  • the compound of Formula 10-8 is synthesized by dropwise addition. Then, trichloroborane and dimethyl sulfanate are added dropwise to synthesize the compound of Formula 10-9, and premi salt is added dropwise to synthesize the compound of Formula 10-10. Finally, R-boronic acid pinacol ester ( ) Or R-borate ( ) Can be used to synthesize the compound of Formula 10-11 using microwaves as a Suzuki reaction.
  • the compound of Formula 10-11 can be synthesized by desarretylating the compound of Formula 10-11.
  • Step 2 N- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclopropanecarboxamide (Formula 2-3 Preparation of compounds)
  • N- (3-bromophenyl) cyclopropanecarboxamide synthesized in Step 1 (Formula 2-2 , 2.1 g, 8.73 mmol), potassium acetate (2.57 g, 26.2 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.713 g, 0.873 mmol, 0.1 eq) and B 2 Pin 2 (6.65 g, 26.2 mmol, 3 eq) were dissolved in dimethyl sulfoxide (DMSO) (20 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 80 ° C. After completion of the reaction, the reaction mixture was filtered through celite, and extracted with ethyl acetate.
  • DMSO dimethyl sulfoxide
  • Step 2 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindolin-1-one (Formula 5-3 Preparation of compounds)
  • Preparation 8 Preparation of cyclopropyl (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (compound of formula 8-2)
  • Step 2 2- (3 ', 4'-dimethoxybiphenyl-3-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Formula 9-3 Preparation of compounds)
  • Step 1 Preparation of 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine (compound of formula 10-2 )
  • tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate (Formula 10-1 , 2 g, 5.16 mmol) was dissolved in dichloromethane (20 ml), and trifluoroacetic acid (TFA) (7.96 ml, 103 mmol, 20 eq) was added dropwise at room temperature and stirred at the same temperature for 2 hours. The reaction of the reaction mixture was terminated with H 2 O, and extracted with ethyl acetate. The organic layer was washed with H 2 O, dried over anhydrous MgSO 4 , and the organic layer was reduced in pressure to remove the solvent to obtain a target compound (Formula 10-2 ).
  • TFA trifluoroacetic acid
  • Step 2 1-cyclopropyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine (formula 10-3 Preparation of compounds)
  • Step 2 Potassium trifluoro (2- (4- (trifluoromethoxy) phenoxy) pyrimidin-5-yl) borate (Formula 11-4 Preparation of compounds)
  • 2-Bromoquinoline (Formula 14-1 , 1 g, 4.81 mmol) was dissolved in THF (20 ml), cooled to -78 ° C, and 1.6M n-butyllithium (5.41 ml, 8.65 mmol, 1.8 eq) ) was slowly added dropwise. Then, after stirring at the same temperature for 1 hour, triisopropyl borate (2.23 ml, 9.61 mmol, 2 eq) was added dropwise at the same temperature.
  • N- (8-hydroxyquinolin-7-yl) acetamide synthesized in step 4 (Formula 17-5 , 14 g, 68 mmol) was dissolved in DMF (200 ml), and then potassium carbonate (14 g, 102) mmol, 1.5 eq), benzyl bromide (12 ml, 102 mmol, 1.5 eq) was added dropwise and stirred at 50 ° C for 8 hours. After completion of the reaction, it was dissolved in dichloromethane, filtered through celite, and the solvent was dried under reduced pressure. Then, it was separated and purified by MPLC (hexane / ethyl acetate) to obtain the target compound (Formula 17-6 ).
  • Step 8 N- (2-Chloro-8-hydroxyquinolin-7-yl) acetamide (Formula 17-9 Preparation of compounds)
  • Step 9 N- (2-Chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 Preparation of compounds)
  • N- (2-chloro-8-hydroxyquinolin-7-yl) acetamide synthesized in step 8 (Formula 17-9 , 3 g, 13 mmol) was dissolved in acetone (200 ml), and then NaH 2 PO Premi salt (potassium nitrosodisulfonate) (5.57 g, 21 mmol, 1.6 eq) dissolved in 4 buffers (0.3M, 200 ml) was added dropwise and stirred at room temperature for 8 hours. After removing acetone under reduced pressure, it was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Subsequently, it was purified by solidify using ethyl acetate and hexane to obtain a solid compound (Formula 17-10 ).
  • Step 1 Synthesized 1- (4- (4-bromophenoxy) piperidin-1-yl) -2,2-dimethylpropan-1-one (Formula 19-1 Preparation of compounds)
  • the reaction mixture was dissolved in ethyl acetate, washed sequentially with saturated aqueous NaHCO 3 and brine, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to obtain the target compound (Formula 19-2 ).
  • Preparation 20 Preparation of 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) pyridine (compound of formula 20-2)
  • Step 1 4- (4-bromophenoxy) pyridine (formula 20-1 Preparation of compounds)
  • Step 2 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) pyridine (formula 20-2 Preparation of compounds)
  • Step 2 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine (formula 21-2 Preparation of compounds)
  • Step 1 4- (4-Bromophenoxy) -1-ethylpiperidine (Formula 22-1 Preparation of compounds)
  • Step 1 Preparation of methyl 1- (3- (5,6,8-trimethoxyquinolin-2yl) phenyl) ethanone
  • Step 2 Preparation of 2- (3-acetylphenyl) -6-methoxyquinoline-5,8-dione
  • Step 1 Preparation of 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-en-1-one
  • reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30), and 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-ene 1-one was obtained.
  • Step 2 Preparation of 2- (3-acryloylphenyl) -6-methoxyquinoline-5,8-dione
  • Step 2 of Example 1 The same method as described in Step 2 of Example 1 was used, but instead of 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone, synthesized in Step 1 of this Example.
  • the title compound was synthesized using 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-en-1-one.
  • Step 3 Preparation of 7-bromo-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
  • 6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione synthesized in step 2 (1 eq) was dissolved in chloroform, then bromine (1.1 eq) was added dropwise at 0 ° C and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
  • Step 1 Preparation of methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydro quinolin-2-yl) benzoate
  • Step 2 Preparation of 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzamide
  • Methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoate synthesized in Step 1 is a methanol solution in which 7 M ammonia is dissolved After dissolving in, sodium cyanide (0.1 eq) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 days. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by PTLC (dichloromethane / methanol; 98: 2) to obtain the title compound.
  • PTLC dichloromethane / methanol; 98: 2
  • Step 1 Preparation of a compound of 5,7-dibromoquinoline-8-ol
  • step 1 The 5,7-dibromoquinoline-8-ol synthesized in step 1 was slowly added dropwise to a sulfuric acid (20 eq) solution in which nitric acid (6 eq) was dissolved at 0 ° C. After stirring at the same temperature for 30 minutes, the reaction was terminated with ice water. Thereafter, the mixture was extracted with dichloromethane, and the organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 7-bromoquinoline-5,8-dione.
  • Example 73 After the 7-bromo-2-phenylquinoline-5,8-dione (1 eq) synthesized in Example 73 was dissolved in ACN, acetic acid (1.5 eq) and AgNO 3 (0.5 eq) were added dropwise. An aqueous ammonium persulfate (1.4 eq) solution was slowly added dropwise to the reaction mixture, followed by heating and stirring at 80 ° C for 4 hours. After completion of the reaction, extraction was performed with ethyl acetate, and then dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
  • acetic acid 1.5 eq
  • AgNO 3 0.5 eq
  • An aqueous ammonium persulfate (1.4 eq) solution was slowly added dropwise to the reaction mixture, followed by heating and stirring at 80 ° C for 4 hours. After completion of the reaction, extraction was performed with ethyl
  • Step 1 Preparation of 5,6,8-trimethoxy-2- (3- (trifluoromethoxy) phenyl) quinoline
  • Step 2 Preparation of 6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
  • Step 3 Preparation of 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
  • 6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione synthesized in step 2 (1 eq) was dissolved in chloroform, then bromine (1.1 eq) was added dropwise to 0 ° C and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione.
  • Step 4 Preparation of 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
  • Step 5 Preparation of 7-amino-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
  • Step 1 Preparation of 7-azido-2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione
  • Step 2 Preparation of 7-amino-2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione
  • Step 2 Preparation of 6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
  • Step 3 Preparation of 7-bromo-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
  • Step 4 Preparation of 7-azido-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
  • Step 5 Preparation of 7-amino-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
  • Step 1 Preparation of 7-azido-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
  • Step 2 Preparation of 7-amino-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
  • Step 1 Preparation of (E) -methyl 3- (3- (7-azido-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) acrylate
  • Step 2 Preparation of methyl 3- (3- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) propanoate
  • Step 1 Preparation of 2- (3-acetylphenyl) -7-azido-6-methoxyquinoline-5,8-dione
  • Step 2 Preparation of 7-amino-2- (3- (1-hydroxyethyl) phenyl) -6-methoxyquinoline-5,8-dione
  • Step 1 Preparation of 7-azido-6-methoxy-2- (3-nitrophenyl) quinoline-5,8-dione
  • Step 2 Preparation of 7-amino-2- (3-aminophenyl) -6-methoxyquinoline-5,8-dione
  • Step 1 Preparation of 2- (3-acetylphenyl) -7-amino-6-methoxyquinoline-5,8-dione
  • Step 2 Preparation of 2- (3-acryloylphenyl) -7-amino-6-methoxyquinoline-5,8-dione
  • Example 74 7-bromo-6-methyl-2-phenyl synthesized in Example 74 instead of 7-bromo-2-phenylquinoline-5,8-dione in Step 1, using the same method as described in Example 120.
  • the title compound was obtained using quinoline-5,8-dione (1 eq).
  • Step 1 Preparation of 7-bromo-2- (2-chloropyridin-4-yl) quinoline-5,8-dione
  • Step 2 Preparation of 7-bromo-2- (2-chloropyridin-4-yl) -6-methylquinoline-5,8-dione
  • Step 3 Preparation of 7-amino-2- (2-chloropyridin-4-yl) -6-methylquinoline-5,8-dione
  • Step 1 Preparation of 7-bromo-2- (3- (triflooromethoxy) phenyl) quinoline-5,8-dione
  • Step 2 Preparation of 7-amino-2- (3- (triflooromethoxy) phenyl) quinoline-5,8-dione
  • Example 120 The same method as described in Example 120 was used, but instead of 7-bromo-2-phenylquinoline-5,8-dione, 7-bromo-2- (3- (Triflo) synthesized in this Example Step 1 was used. Oromethoxy) phenyl) quinoline-5,8-dione was used to give the title compound.
  • Example 140 using the same method as described in Example 1, using R listed in Table 11 below instead of 3-acetylphenylboronic acid, and 1,4-dioxane instead of dimethyl ether (DME). The compound of Example 144 was obtained.
  • Step 2 Preparation of 6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
  • reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. It was extracted with ethyl acetate, washed with water, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline.
  • Step 2 Preparation of 6-methoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline-5,8-dione
  • Example 206 Using the same method as described in Example 75, using R listed in Table 17 instead of 3- (trifluoromethoxy) phenylboronic acid in Step 1, 1,4-di instead of dimethyl ether (DME)
  • DME dimethyl ether
  • the methyl 2-amino-4- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoic acid (1 eq) synthesized in Example 210 was MeOH / After dissolving in H 2 O (1: 1), an aqueous potassium hydroxide (35 eq) solution was added dropwise and reacted at 50 ° C. for 2.5 hours. After completion of the reaction, neutralized with 1M aqueous hydrochloric acid, extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound as an orange solid.
  • Step 1 Preparation of 7-bromo-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
  • Step 2 Preparation of 7-azido-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
  • Step 3 Preparation of 7-amino-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
  • Example 240 Preparation of 6- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) -2-methoxynicotinic acid
  • Step 1 Preparation of N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide
  • Step 2 Preparation of 7-amino-2- (4-chloro-3-fluorophenyl) quinoline-5,8-dione
  • N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in step 1 was added to methanol. After dissolving, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
  • N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 50 mg, 0.2 mmol) and Pd (Ph) synthesized in Preparation Example 17 3 ) 4 (23 mg, 0.02 mmol, 0.1 eq) was dissolved in 1,4-dioxane (4 ml), followed by 2- (tributylstannyl) pyrazine (110 mg, 0.3 mmol, 2 eq) at room temperature. Dropped in. The reaction mixture was reacted in a Biotage microwave at 130 ° C for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
  • Step 1 Preparation of N- (2- (5-methoxypyrazin-2-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide
  • Step 2 Preparation of 7-amino-2- (5-methoxypyrazin-2-yl) quinoline-5,8-dione
  • N- (5,8-dioxo-2- (4- (trifluoromethyl) phenyl) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in Example 266 was methanol. After dissolving in, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
  • Step 1 Preparation of N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide
  • N- (2-Chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 10 mg, 0.04 mmol) and aniline (4.4 synthesized in Preparation Example 17) ul, 0.048 mmol, 1.2 eq) was dissolved in 1,4-dioxane (1 ml), then Pd (dppf) Cl 2 -CH 2 Cl 2 (1 mg, 1.2 umol, 0.01 eq) and sodium tert-butox Seed (4.6 mg, 0.048 mmol, 1.2 eq) was added dropwise at room temperature. The reaction mixture was reacted in a Biotage microwave at 120 ° C for 1 hour.
  • reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide.
  • Step 2 Preparation of 7-amino-2- (phenylamino) quinoline-5,8-dione
  • Step 1 Preparation of N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide
  • N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 50 mg, 0.20 mmol) and pyridine-2 synthesized in Preparation Example 17 -Amine (23 mg, 0.24 mmol, 1.2 eq) was dissolved in 1,4-dioxane (5 ml), followed by Pd (dba) 3 (27 mg, 0.03 mmol, 0.15 eq), Cs 2 CO 3 (162 mg, 0.50 mmol, 2.5 eq) and xantphos (23 mg, 0.04m mmol, 0.2 eq) were added dropwise at room temperature.
  • reaction mixture was reacted in a Biotage microwave at 140 ° C for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by prep HPLC to obtain N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide. .
  • Step 2 Preparation of 7-amino-2- (pyridin-2-ylamino) quinoline-5,8-dione
  • step 1 N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) was dissolved in methanol, followed by 4M. Potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
  • the anti-tumor activity of the compounds of formula I herein was tested using the sulforhodamine B (SRB) assay.
  • Kidney cancer cell line ACHN cells (100 ⁇ l, containing 5,000 to 40,000 cells / well, adjusted according to the doubling time of each cell line) were incubated in a 96-well microquantitative plate. After 24 hours, 100 ⁇ l of the compound of formula I herein was added to each well, and the cultures were incubated at 37 ° C for 48 hours. Cells were fixed with trichloroacetic acid (50 ⁇ l per well). Plates were incubated at 4 ° C for a minimum of 1 hour and a maximum of 3 hours. The liquid was removed from the plate, washed 5 times with water and then dried at room temperature for 12 to 24 hours.
  • the fixed cells were stained with 100 ⁇ l SRB for 5 minutes at room temperature, and the plates were washed 3 times with 1% glacial acetic acid. And dried at room temperature for about 12 to 24 hours. SRB stained cells were lysed in 10 mM Trizma base and absorbance was measured at 515 nm.
  • GI 50 Greeneth Inhibition of 50% showing 50% growth inhibition was calculated from the following formula, and this value means a value that reduces the number of control cells to 50%.
  • Tz is the average number of cells (cells / ml) at the start of culture
  • Ti is the average number of cells (cells / ml) after 48 hours of drug treatment
  • C is the average number of cells (cells / ml) after 48 hours of the control group.
  • Transglutaminase I [1,4, - 14 C] Fu tray measures incorporating demi succinyl federated casein, and observed that NDGA inhibits its reaction in competition with God Fu tray of the compounds of the present formula (I) TGase 2 inhibitory activity was measured.
  • succinylated casein (Calbiochem, Cat. No. 573464) was dissolved in a 2% concentration in 0.1 M tris-acetic acid buffer (pH 8.0) containing 10 mM CaCl 2 , 0.15 M NaCl, 1.0 mM EDTA.
  • 5 mM DTT (1,4-disthiothreitol) was added immediately before use of the solution.
  • the reaction was terminated by adding 2 ml of cold 5% trichloroacetic acid (TCA).
  • TCA cold 5% trichloroacetic acid
  • the assay vial was set at 4 ° C for at least 1 hour to fix.
  • the assay mixture was filtered through a glass-fiber filter paper disc (Whatman GF / A) and washed with cold 5% TCA.
  • the filter was placed in a counting vial, and a scintillation cocktail solution was added.
  • the counting vial was vortexed for 5 seconds and placed in a shaker for 30 minutes before counting.
  • Kidney cancer cells are xenografted to induce kidney cancer in mice, and the compound synthesized in Example 120 is added to a solution consisting of 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water, and 5% soybean oil. / kg, 10 mg / kg or 20 mg / kg was administered once a day, 6 days per week for 7 weeks, and negative controls consisted of 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water and 5% soybean oil. The solution was administered. The results are shown in [FIG. 1] to [FIG. 4] and [Table 26].
  • mice administered with the compound of formula (I) have much smaller tumor size and weight compared to the control group.
  • the weight of the mouse does not change significantly by administration of the compound of formula (I), so it can be seen that the compound of formula (I) is less toxic.
  • mice were orally administered the compound synthesized in Example 120 at a dose of 10 mg / kg, and blood was collected through the tail vein for up to 4 hours, and the concentration in the blood was analyzed by LC-MS / MS. Quantitative results in blood are shown in Figure 5, and pharmacokinetic parameters are shown in Table 27.
  • the plasma concentration of the compound of Formula I synthesized in Example 120 was rapidly decreased, and as shown in [Table 27], T max was 8.1 minutes, and the average half-life was 79.9 minutes, so in vivo It can be expected to disappear quickly .

Abstract

The present invention relates to a preparation method for a quinoline-5, 8-dione derivative compound represented by chemical formula I, a stereoisomer of same or a pharmaceutically acceptable salt of same. A compound represented by chemical formula I of the present application has a TGase 2-inhibiting effect, and a pharmaceutical composition comprising same can be usefully employed in the prevention or treatment of disorders or diseases that are mediated by TGase 2 or react to the inhibition of TGase 2.

Description

TGASE 2 억제제로서의 퀴놀린-5,8-디온 유도체의 제조 방법Method for preparing quinoline-5,8-dione derivatives as TGASE 2 inhibitors
본 발명은 트랜스글루타미나아제 2(Transglutaminase 2, TGase 2) 억제 활성을 갖는 퀴놀린-5,8-디온 유도체 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용되는 염의 제조 방법에 관한 것이다.The present invention relates to a method for producing a quinoline-5,8-dione derivative compound having a transglutaminase 2 (Tglutaseminase 2) inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
트랜스글루타미나아제 (Transglutaminase)는 자유 아민기와 단백질 내부 글루타민의 감마-카복사미드기 사이에 공유결합을 형성하는 효소의 집단으로, 1959년에 처음 발견되었으며, 구체적인 생화학적 역할은 1968년 혈액응고 단백질인 섬유소안정인자 (fibrin stabilizing factor, factor ⅩⅢ)에서 밝혀졌다.Transglutaminase (Transglutaminase) is a group of enzymes that form a covalent bond between the free amine group and the gamma-carboxamide group of glutamine inside the protein.It was first discovered in 1959, and its specific biochemical role was blood coagulation in 1968. It was found in the protein fibrin stabilizing factor (factor III).
이 중 제2형 트랜스글루타미나아제 (TGase 2)는 리신 이소-디펩타이드 결합의 형성을 촉진함으로써 단백질 가교 효소로서 주로 기능하는 것으로 알려졌으나, 최근의 연구결과에 의하면 TGase 2의 발현이 정상적으로 조절되지 않는 것이 많은 질병의 병리적 기전에서 중요한 역할을 하는 것으로 밝혀졌다.Among them, type 2 transglutaminase (TGase 2) is known to function primarily as a protein crosslinking enzyme by promoting the formation of lysine iso-dipeptide bonds, but recent studies have shown that TGase 2 expression is normally regulated. It has been found that not being played an important role in the pathological mechanisms of many diseases.
TGase 2의 비정상적으로 과도한 발현이 염증성 질환 또는 자가면역 질환 등과 같은 질병의 발생에 주요한 역할을 하는 것으로 보고되고 있다. 또한, TGase 2의 과도한 발현은 신경퇴행성 질환을 유도하는 것으로 알려져 있으며, 최근에는 헌팅턴병과 파킨슨병과 같은 신경계질환을 앓고 있는 사람은 조직 트랜스글루타미나아제가 비정상적으로 높은 수치를 가지고 있을 수 있다는 연구결과가 나왔다.It has been reported that abnormally excessive expression of TGase 2 plays a major role in the development of diseases such as inflammatory diseases or autoimmune diseases. In addition, it is known that excessive expression of TGase 2 induces neurodegenerative diseases, and recently, studies showing that tissue transglutaminase may have abnormally high levels in people with neurological diseases such as Huntington's disease and Parkinson's disease. Came out
또한 콜라겐, 섬유결합소 (fibronectin), 라미니아 (laminia), 니도겐 (nidogen) 또는 프로테오글리칸 (proteoglycan) 등의 기질단백질 (matrix protein)들과 비가역적으로 결합하거나, 세포 외 기질의 단백질분해효소 (proteolytic enzyme)에 대한 저항성을 증가시켜, 심한 세포외 기질의 침착을 유도하여 조직의 섬유화에 관여하는 것으로 제시되고 있다. 실제로 실험적인 신장 및 간 섬유화에 있어서 TGase 2가 주요한 역할을 하고, 억제제를 이용하여 그 활성을 억제하였을 경우 섬유화의 정도가 감소하는 것으로 보고된 바 있다.It also irreversibly binds matrix proteins such as collagen, fibronectin, laminia, nidogen, or proteoglycan, or proteolytic enzymes of extracellular matrix ( It has been suggested that it increases resistance to proteolytic enzymes, induces the deposition of severe extracellular matrix, and is involved in tissue fibrosis. In fact, it has been reported that TGase 2 plays a major role in experimental kidney and liver fibrosis, and the degree of fibrosis decreases when its activity is inhibited using an inhibitor.
TGase 2 활성을 억제하는 물질로는 아민 화합물이 알려져 있으며, 대표적으로 시스타민과 푸트레신을 들 수 있다. 또한, 모노단실카다베린, w-디벤질아미노알킬아민, 3-할로-4,5-디하이드로이소옥사졸, 2-[(2-옥소프로필)티오]이미다졸리움 유도체 등의 화학적 억제제들이 개발되어 있으나, 모두 생체에서 비특이적으로 다른 효소의 억제를 유발하는 독성이 알려져 있다. 또한, 최근에는 글루코사민 유도체, 클로로겐산, 에피갈로카테친 갈레이트, 커큐민, 썰파렘, 에타크리닉 산 등의 TGase 2 억제 활성이 알려져 있으나, 동물의 TGase 2 관련 질환 치료에 유의한 활성이 나타날지는 아직 명확히 밝혀지지 않은 상태이다.Amine compounds are known as substances that inhibit TGase 2 activity, and examples thereof include cystamine and putrescine. In addition, chemical inhibitors such as monodansylcarbaverine, w-dibenzylaminoalkylamine, 3-halo-4,5-dihydroisooxazole, and 2-[(2-oxopropyl) thio] imidazolium derivatives have been developed. However, all of them are known to be non-specific in vivo and cause inhibition of other enzymes. In addition, recently, it has been known that TGase 2 inhibitory activity such as glucosamine derivative, chlorogenic acid, epigallocatechin gallate, curcumin, sulparem, etacrynic acid, etc., but it is still clear whether significant activity will appear in the treatment of TGase 2 related diseases in animals. It is in an unknown state.
따라서, 안전하고 효과적인 트랜스글루타미나제 억제제의 계속적인 개발이 요구되고 있다.　Therefore, there is a need for continued development of safe and effective transglutaminase inhibitors.
[선행기술문헌][Advanced technical literature]
(특허문헌 1) 미국특허출원 제2009-462554호(Patent Document 1) U.S. Patent Application No. 2009-462554
(특허문헌 2) 대한민국특허출원 제2008-0118688호(Patent Document 2) Korean Patent Application No. 2008-0118688
(특허문헌 3) 대한민국특허출원 제2009-0018388호(Patent Document 3) Korean Patent Application No. 2009-0018388
(특허문헌 4) 대한민국특허출원 제2014-0090500호(Patent Document 4) Korean Patent Application No. 2014-0090500
(비특허문헌 1) Karpuj, Marcela V. 등, "Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine." Nature medicine 8.2 (2002): 143-149.(Non-Patent Document 1) Karpuj, Marcela V. et al., "Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine." Nature medicine 8.2 (2002): 143-149.
(비특허문헌 2) Soo-Youl Kim, "Transglutaminase 2 in inflammation."　Frontier　Bioscience　11(2006): 3026-3035.(Non-Patent Document 2) Soo-Youl Kim, "Transglutaminase 2 in inflammation." Frontier Bioscience 11 (2006): 3026-3035.
본 발명의 목적은 신규한 퀴놀린-5,8-디온 유도체 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용되는 염의 제조방법을 제공하는 것이다.An object of the present invention is to provide a novel quinoline-5,8-dione derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
본원은 하기 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염의 제조방법을 제공한다:The present application provides a method for preparing a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 I][Formula I]
Figure PCTKR2019011876-appb-img-000001
Figure PCTKR2019011876-appb-img-000001
상기 식에서,In the above formula,
R 1은 수소, 할로겐, C 1-6알킬 또는 -O-C 1-6알킬이고,R 1 is hydrogen, halogen, C 1-6 alkyl or -OC 1-6 alkyl,
R 2는 수소, 할로겐 또는 -NH 2이고, 여기서, -NH 2의 하나 이상의 수소는 선택적으로 R 4로 치환될 수 있으며,R 2 is hydrogen, halogen or -NH 2 , wherein one or more hydrogens of -NH 2 may be optionally substituted with R 4 ,
R 3는 수소, 할로겐, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 여기서, 상기 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있으며,R 3 is hydrogen, halogen, C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocycloalkyl, wherein the C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3- 10 cycloalkenyl, and C 3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R 5 or = O,
R 4는 할로겐, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬) 또는 -(C=O)-(C 2-6알케닐)이고,R 4 is halogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl) or-(C = O)-(C 2-6 alkenyl),
R 5는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or one or more hydrogens may be substituted with R e ,
R a는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
R b는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
R c 및 R d는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
R e는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -(C=O)-R b, -(C=O)O-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬는 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl,-(C = O) -R b ,-(C = O) OR b , C 6- 12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6 -12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2-6 Alkenyl, -OH or halogen,
상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
본원의 제조 방법은, 하기 반응식 1에 따라, 화합물 IMC1을 커플링 반응시켜 화합물 IMC2를 제조하는 단계; 및 화합물 IMC2을 반응시켜 화합물 Q1을 제조하는 단계를 포함한다.The production method of the present application comprises the steps of preparing a compound IMC2 by coupling a compound IMC1 according to the following reaction scheme 1; And reacting compound IMC2 to prepare compound Q1.
[반응식 1][Scheme 1]
Figure PCTKR2019011876-appb-img-000002
Figure PCTKR2019011876-appb-img-000002
상기 반응식 1에서, In Reaction Scheme 1,
Xa 는 할로겐을 나타내고,Xa represents halogen,
Y, Y 1 및 Y 2 는 각각 독립적으로 C 1-6알킬이고,Y, Y 1 and Y 2 are each independently C 1-6 alkyl,
A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 이때, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 Heterocycloalkyl, wherein C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl may be unsubstituted or substituted with one or more hydrogens R 5 or = O,
R 5 는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b,C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or one or more hydrogens may be substituted with R e ,
R a 는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
R b 는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
R c 및 R d 는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
R e 는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -(C=O)-R b, -(C=O)O-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH,-(C = O) -R b ,-(C = O) OR b , C 6-12 aryl, C 3-12 Heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3- 12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2-6 alkenyl, -OH or Can be substituted with halogen,
상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
상기 화합물 IMC2에서 화합물 Q1을 제조하는 단계에서는, 화합물 IMC2에 질산세륨암모늄(Ceric ammonium nitrate, CAN) 수용액을 적가하여 화합물 Q1을 제조할 수 있다.In the step of preparing compound Q1 in the compound IMC2, a compound ammonium nitrate (CAN) aqueous solution may be added dropwise to compound IMC2 to prepare compound Q1.
본원에서 퀴놀린-5,8-디온 유도체의 제조 방법은, 하기 반응식 2에 따라, 화합물 IMC1을 커플링 반응시켜 화합물 IMC2를 제조하는 단계; 화합물 IMC2를 반응시켜 화합물 IMC3을 제조하는 단계; 및 화합물 IMC3을 반응시켜 화합물 Q2를 제조하는 단계를 포함한다.In the present application, a method for preparing a quinoline-5,8-dione derivative comprises the steps of preparing a compound IMC2 by coupling a compound IMC1 according to the following scheme 2; Reacting compound IMC2 to prepare compound IMC3; And reacting compound IMC3 to produce compound Q2.
[반응식 2][Scheme 2]
Figure PCTKR2019011876-appb-img-000003
Figure PCTKR2019011876-appb-img-000003
상기 반응식 2에서,In Reaction Scheme 2,
Xa는 할로겐을 나타내고,Xa represents halogen,
Y, Y 1 및 Y 2 는 각각 독립적으로 C 1-6알킬이고,Y, Y 1 and Y 2 are each independently C 1-6 alkyl,
A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나의 수소가 -(C=O)-(C 1-6알킬)로 치환된 작용기를 나타내고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- 10 represents a functional group in which any one hydrogen of heterocycloalkyl is substituted with- (C = O)-(C 1-6 alkyl),
A 2 는 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나의 수소가 -(C=O)-(C 2-6알케닐)로 치환된 작용기를 나타낸다.A 2 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- Hydrogen of any one of 10 heterocycloalkyl represents a functional group substituted with- (C = O)-(C 2-6 alkenyl).
본 발명의 일 구체예에서, 상기 반응식 1과 2 각각의 커플링 반응에는 (HO) 2-B-(A 1),
Figure PCTKR2019011876-appb-img-000004
, K +(BF 3(A 1)) -, (A 1)-Sn(n-Bu) 3, NH 2-(A 1) 또는
Figure PCTKR2019011876-appb-img-000005
를 이용할 수 있다. 이때, (HO) 2-B-(A 1),
Figure PCTKR2019011876-appb-img-000006
, K +(BF 3(A 1)) -, (A 1)-Sn(n-Bu) 3 또는 NH 2-(A 1)에서의 A 1은 반응식 1 또는 반응식 2 각각에서 정의한 것과 동일하고,
Figure PCTKR2019011876-appb-img-000007
에서 A 1은 R 5로 치환 또는 비치환된 C 3-12헤테로아릴을 나타낸다.In one embodiment of the present invention, the coupling reaction of each of Reaction Schemes 1 and 2 includes (HO) 2 -B- (A 1 ),
Figure PCTKR2019011876-appb-img-000004
, K + (BF 3 (A 1 )) - , (A 1 ) -Sn (n-Bu) 3 , NH 2- (A 1 ) or
Figure PCTKR2019011876-appb-img-000005
Can be used. At this time, (HO) 2 -B- (A 1 ),
Figure PCTKR2019011876-appb-img-000006
, K + (BF 3 (A 1)) -, (A 1) -Sn (n-Bu) 3 or NH 2 - A 1 in (A 1) are the same as defined in scheme 1 or scheme 2, respectively,
Figure PCTKR2019011876-appb-img-000007
In A 1 represents C 3-12 heteroaryl unsubstituted or substituted with R 5 .
본 발명의 제조 방법은 하기 반응식 3에 따라 화합물 Q1을 할로겐화하여 화합물 Q3을 제조하는 단계를 더 포함할 수 있다.The preparation method of the present invention may further include the step of preparing compound Q3 by halogenating compound Q1 according to the following scheme 3.
[반응식 3][Scheme 3]
Figure PCTKR2019011876-appb-img-000008
Figure PCTKR2019011876-appb-img-000008
상기 반응식 3에서,In Reaction Scheme 3,
Y 는 C 1-6 알킬이고,Y is C 1-6 alkyl,
B 1 은 할로겐이고,B 1 is halogen,
A 1 은 반응식 1에서 정의한 것과 동일하다.A 1 is the same as defined in Scheme 1.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 4에 따라 화합물 Q3으로 화합물 Q4를 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q4 with compound Q3 according to the following scheme 4.
[반응식 4][Reaction Scheme 4]
Figure PCTKR2019011876-appb-img-000009
Figure PCTKR2019011876-appb-img-000009
상기 반응식 4에서,In Reaction Scheme 4,
Y 는 C 1-6 알킬이고,Y is C 1-6 alkyl,
B 1 은 할로겐이고,B 1 is halogen,
A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -(C=O)-O(C 1-6알킬)로 치환된 작용기를 나타내고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 Represents a functional group in which one hydrogen in any one of heterocycloalkyl is substituted with-(C = O) -O (C 1-6 alkyl),
A 3 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -(C=O)-NH 2로 치환된 작용기를 나타낸다. A 3 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- It represents a functional group in which one hydrogen in any one of 10 heterocycloalkyl is substituted with-(C = O) -NH 2 .
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 5에 따라 화합물 Q3로부터 화합물 Q5를 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for producing the quinoline-5,8-dione derivative may further include preparing compound Q5 from compound Q3 according to the following scheme 5.
[반응식 5][Scheme 5]
Figure PCTKR2019011876-appb-img-000010
Figure PCTKR2019011876-appb-img-000010
상기 반응식 5에서,In Reaction Scheme 5,
Y 는 C 1-6 알킬이고,Y is C 1-6 alkyl,
B 1 은 할로겐이고,B 1 is halogen,
A 1 은 반응식 1에서 정의한 것과 동일하다.A 1 is the same as defined in Scheme 1.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 6에 따라 화합물 Q5로 화합물 Q6을 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q6 with compound Q5 according to the following scheme 6.
[반응식 6][Scheme 6]
Figure PCTKR2019011876-appb-img-000011
Figure PCTKR2019011876-appb-img-000011
상기 반응식 6에서,In Reaction Scheme 6,
Y는 C 1-6 알킬이고, Y is C 1-6 alkyl,
A 1 은 반응식 1에서 정의한 것과 동일하고, A 1 is the same as defined in Scheme 1,
A 4 및 A 5 는 각각 독립적으로 수소, 할로겐, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬) 또는 -(C=O)-(C 2-6알케닐)이되 A 4와 A 5가 동시에 수소인 경우는 제외한다.A 4 and A 5 are each independently hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl) or-(C = O)-(C 2-6 alkenyl), except when A 4 and A 5 are hydrogen at the same time.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 7에 따라 화합물 Q3으로 화합물 IMC3을 제조하는 단계; 및 화합물 IMC3의 환원반응을 통해 화합물 Q7을 제조하는 단계를 더 포함할 수 있다.In one embodiment of the invention, the method for preparing the quinoline-5,8-dione derivative comprises the steps of preparing compound IMC3 with compound Q3 according to scheme 7 below; And preparing a compound Q7 through a reduction reaction of the compound IMC3.
[반응식 7][Scheme 7]
Figure PCTKR2019011876-appb-img-000012
Figure PCTKR2019011876-appb-img-000012
상기 반응식 7에서,In Reaction Scheme 7,
Y는 C 1-6 알킬이고,Y is C 1-6 alkyl,
A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 적어도 하나의 수소가 -(C=O)(C 1-6알킬), -NO 2 또는 -(C=O)-O(C 1-6알킬)로 치환된 작용기를 나타내고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- A functional group in which at least one hydrogen in any one of 10 heterocycloalkyl is substituted with-(C = O) (C 1-6 alkyl), -NO 2 or-(C = O) -O (C 1-6 alkyl) And
A 6 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 적어도 하나의 수소가 -C(OH)(C 1-6알킬), -NH 2 또는 -(C=O)-OH로 치환된 작용기를 나타낸다.A 6 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- At least one hydrogen in any one of 10 heterocycloalkyl represents a functional group substituted with -C (OH) (C 1-6 alkyl), -NH 2 or-(C = O) -OH.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 8에 따라 화합물 Q7로 화합물 Q8을 제조하는 단계를 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may include preparing compound Q8 with compound Q7 according to the following scheme 8.
[반응식 8][Scheme 8]
Figure PCTKR2019011876-appb-img-000013
Figure PCTKR2019011876-appb-img-000013
상기 반응식 8에서, In Reaction Scheme 8,
Y는 C 1-6 알킬이고,Y is C 1-6 alkyl,
A 6 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -C(OH)(C 1-6알킬) 또는 -NH 2로 치환된 작용기를 나타내고,A 6 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- A hydrogen group in any one of 10 heterocycloalkyl represents a functional group substituted with -C (OH) (C 1-6 alkyl) or -NH 2 ,
A 7 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -(C=O)(C 1-6알킬), -(C=O)(C 2-6알케닐) 또는 -NH(C=O)-CH=CH 2로 치환된 작용기를 나타낸다.A 7 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 One hydrogen in any one of the heterocycloalkyl is-(C = O) (C 1-6 alkyl),-(C = O) (C 2-6 alkenyl) or -NH (C = O) -CH = It represents a functional group substituted with CH 2 .
본원의 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 9에 따라 화합물 Q9를 제조하는 단계를 포함한다.The method for preparing the quinoline-5,8-dione derivative herein includes preparing compound Q9 according to the following scheme 9.
[반응식 9][Scheme 9]
Figure PCTKR2019011876-appb-img-000014
Figure PCTKR2019011876-appb-img-000014
상기 반응식 9에서,In Reaction Scheme 9,
Xb 는 할로겐을 나타낸다.Xb represents halogen.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 10에 따라 화합물 Q9를 이용하여 화합물 Q10을 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q10 using compound Q9 according to the following scheme 10.
[반응식 10][Scheme 10]
Figure PCTKR2019011876-appb-img-000015
Figure PCTKR2019011876-appb-img-000015
상기 반응식 10에서,In Reaction Scheme 10,
Xb 는 할로겐을 나타내고,Xb represents halogen,
Z 1 은 할로겐, C 1-3알킬 또는 -O-(C 1-3알킬)을 나타낸다.Z 1 represents halogen, C 1-3 alkyl or -O- (C 1-3 alkyl).
본원의 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 11에 따라 화합물 Q11을 제조하는 단계를 포함한다.The method for preparing the quinoline-5,8-dione derivative herein includes preparing compound Q11 according to the following scheme 11.
[반응식 11][Scheme 11]
Figure PCTKR2019011876-appb-img-000016
Figure PCTKR2019011876-appb-img-000016
상기 반응식 11에서,In Reaction Scheme 11,
Xc 및 Xd는 각각 독립적으로 할로겐을 나타내고,Xc and Xd each independently represent halogen,
A 8 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 이때, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있고,A 8 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 Heterocycloalkyl, wherein C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl may be unsubstituted or substituted with one or more hydrogens R 5 or = O,
R 5 는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or one or more hydrogens may be substituted with R e ,
R a 는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
R b 는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
R c 및 R d 는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
R e 는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -(C=O)-R b, -(C=O)O-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH,-(C = O) -R b ,-(C = O) OR b , C 6-12 aryl, C 3-12 Heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3- 12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2-6 alkenyl, -OH or Can be substituted with halogen,
상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 12에 따라 화합물 Q11을 이용하여 화합물 Q13을 제조할 수 있다. 예를 들어, 반응식 12에서는 화합물 Q11에 NaN 3 및 NaBH 4를 순차적으로 적가하여 화합물 Q12를 제조할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may prepare compound Q13 using compound Q11 according to the following scheme 12. For example, in Scheme 12, compound Q12 can be prepared by sequentially adding NaN 3 and NaBH 4 to compound Q11.
[반응식 12][Scheme 12]
Figure PCTKR2019011876-appb-img-000017
Figure PCTKR2019011876-appb-img-000017
상기 반응식 12에서 Xd 및 A 8은 각각 상기 반응식 11에서 정의한 것과 동일하다.In Reaction Scheme 12, Xd and A 8 are the same as defined in Reaction Scheme 11, respectively.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 13에 따라 화합물 Q12를 반응시켜 화합물 Q13을 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q13 by reacting compound Q12 according to the following scheme 13.
[반응식 13][Scheme 13]
Figure PCTKR2019011876-appb-img-000018
Figure PCTKR2019011876-appb-img-000018
상기 반응식 13에서,In Reaction Scheme 13,
A 8 은 반응식 12에서와 동일하고,A 8 is the same as in Scheme 12,
A 9 및 A 10 은 각각 독립적으로 수소, 할로겐, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬) 또는 -(C=O)-(C 2-6알케닐)이되 A 9와 A 10이 동시에 수소인 경우는 제외한다.A 9 and A 10 are each independently hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl) or-(C = O)-(C 2-6 alkenyl), except when A 9 and A 10 are hydrogen at the same time.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 14에 따라 화합물 Q11를 반응시켜 화합물 Q14를 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q14 by reacting compound Q11 according to the following scheme 14.
[반응식 14][Scheme 14]
Figure PCTKR2019011876-appb-img-000019
Figure PCTKR2019011876-appb-img-000019
상기 반응식 14에서,In Reaction Scheme 14,
Xd 및 A 8은 각각 상기 반응식 11에서 정의한 것과 동일하고, Xd and A 8 are the same as defined in Reaction Scheme 11, respectively,
Z 2 는 할로겐, C 1-3알킬 또는 -O-C 1-3알킬을 나타낸다.Z 2 represents halogen, C 1-3 alkyl or -OC 1-3 alkyl.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 15에 따라 화합물 Q14를 이용하여 화합물 Q15를 제조하는 단계를 더 포함할 수 있다. 이때, 화합물 14에 NaN 3 및 NaBH 4를 순차적으로 적가하여 화합물 Q15를 제조할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q15 using compound Q14 according to the following reaction formula 15. At this time, NaN 3 and NaBH 4 may be sequentially added dropwise to compound 14 to prepare compound Q15.
[반응식 15][Scheme 15]
Figure PCTKR2019011876-appb-img-000020
Figure PCTKR2019011876-appb-img-000020
상기 반응식 15에서, In Reaction Scheme 15,
Z 2, Xd 및 A 8 은 각각 상기 반응식 14에서 정의한 것과 동일하다.Z 2 , Xd and A 8 are the same as defined in Scheme 14, respectively.
본 발명의 일 구체예에서, 본원의 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 16에 따라 화합물 Q16을 반응시켜 화합물 Q17을 제조하는 단계를 포함한다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative herein includes the step of preparing compound Q17 by reacting compound Q16 according to the following scheme 16.
[반응식 16][Scheme 16]
Figure PCTKR2019011876-appb-img-000021
Figure PCTKR2019011876-appb-img-000021
상기 반응식 16에서, In Reaction Scheme 16,
Xf는 할로겐을 나타내고,Xf represents halogen,
Z 3은 할로겐, C 1-3알킬 또는 -O-C 1-3알킬을 나타낸다.Z 3 represents halogen, C 1-3 alkyl or -OC 1-3 alkyl.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 17에 따라 화합물 Q18을 제조하는 단계를 포함할 수 있다. 이때, 화합물 Q18을 제조하는 데에는 프레미염을 이용할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may include preparing compound Q18 according to scheme 17 below. At this time, a premi salt can be used to prepare compound Q18.
[반응식 17][Scheme 17]
Figure PCTKR2019011876-appb-img-000022
Figure PCTKR2019011876-appb-img-000022
상기 반응식 17에서, In Reaction Scheme 17,
Xg는 할로겐을 나타낸다.Xg represents halogen.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 18에 따라 화합물 Q18을 반응시켜 화합물 Q19를 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q19 by reacting compound Q18 according to the following scheme 18.
[반응식 18][Reaction Scheme 18]
Figure PCTKR2019011876-appb-img-000023
Figure PCTKR2019011876-appb-img-000023
상기 반응식 18에서, In Reaction Scheme 18,
Xg는 할로겐을 나타내고,Xg represents halogen,
A 13 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 이때, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있고,A 13 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 Heterocycloalkyl, wherein C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl may be unsubstituted or substituted with one or more hydrogens R 5 or = O,
R 5는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or one or more hydrogens may be substituted with R e ,
R a 는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
R b 는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
R c 및 R d 는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
R e 는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -(C=O)-R b, -(C=O)O-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH,-(C = O) -R b ,-(C = O) OR b , C 6-12 aryl, C 3-12 Heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3- 12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2-6 alkenyl, -OH or Can be substituted with halogen,
상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
본 발명의 일 구체예에서, 상기 퀴놀린-5,8-디온 유도체의 제조 방법은 하기 반응식 19에 따라 화합물 Q19를 반응시켜 화합물 Q20을 제조하는 단계를 더 포함할 수 있다.In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q20 by reacting compound Q19 according to the following reaction formula 19.
[반응식 19][Scheme 19]
Figure PCTKR2019011876-appb-img-000024
Figure PCTKR2019011876-appb-img-000024
상기 반응식 19에서, In Reaction Scheme 19,
A 13은 상기 반응식 18에서 정의한 것과 동일하다.A 13 is the same as defined in Scheme 18 above.
본 발명의 제조방법에 따라 제조된 퀴놀린-5,8-디온 유도체, 이의 입체 이성질체 또는 이의 약제학적으로 허용되는 염은, 부작용이 적고 효과적으로 TGase 2를 저해시키는 작용 효과를 나타낸다.The quinoline-5,8-dione derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof prepared according to the preparation method of the present invention has little side effects and effectively inhibits TGase 2.
본 발명의 제조방법에 따라 제조된 퀴놀린-5,8-디온 유도체 화합물, 이의 입체이성질체 또는 약제학적으로 허용되는 이의 염은, TGase 2에 의해 매개되거나 TGase 2의 억제제에 대해 반응하는 장애 또는 질환의 치료 또는 예방 용도로 유용하게 사용할 수 있다.A quinoline-5,8-dione derivative compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof prepared according to the preparation method of the present invention is a disorder or disease mediated by TGase 2 or reacting to an inhibitor of TGase 2 It can be useful for therapeutic or preventive purposes.
도 1은 실험예 3에서 확인한 대조군(CT), 화학식 I의 화합물 5 mg/kg 투여군, 화학식 I의 화합물 10 mg/kg 투여군 및 화학식 I의 화합물 20 mg/kg 투여군의 종양 부피를 나타낸 그래프이다.1 is a graph showing the tumor volume of the control group (CT) identified in Experimental Example 3, 5 mg / kg administered group of the compound of Formula I, 10 mg / kg administered group of the compound of Formula I, and 20 mg / kg administered group of the compound of Formula I.
도 2는 실험예 3에서 확인한 대조군(CT), 화학식 I의 화합물 5 mg/kg 투여군, 화학식 I의 화합물 10 mg/kg 투여군 및 화학식 I의 화합물 20 mg/kg 투여군의 종양 무게를 나타낸 그래프이다.FIG. 2 is a graph showing tumor weight of the control group (CT) identified in Experimental Example 3, 5 mg / kg administered group of compound of formula I, 10 mg / kg administered group of compound of formula I, and 20 mg / kg administered group of compound of formula I.
도 3은 실험예 3에서 확인한 대조군, 화학식 I의 화합물 5 mg/kg 투여군, 화학식 I의 화합물 10 mg/kg 투여군 및 화학식 I의 화합물 20 mg/kg 투여군의 종양의 모습을 나타낸 사진이다.3 is a photograph showing the appearance of tumors of the control group identified in Experimental Example 3, 5 mg / kg compound of formula I, 10 mg / kg compound of compound of formula I, and 20 mg / kg compound of compound of formula I.
도 4는 실험예 3에서 확인한 대조군 및 화학식 I의 화합물 100 mg/kg 투여군 의 체중을 나타낸 그래프이다.Figure 4 is a graph showing the weight of the control group and the compound of formula I 100 mg / kg group identified in Experimental Example 3.
도 5는 실험예 4에서 확인한 대조군 및 화학식 I의 화합물 10 mg/kg 투여군의 혈장 농도를 나타낸 그래프이다.Figure 5 is a graph showing the plasma concentration of the control group and the compound of formula I 10 mg / kg group identified in Experimental Example 4.
이하, 본원이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원을 상세히 설명한다. 그러나 본원은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 구체적인 실시양태에 한정되지 않는다. 그리고 명세서 전체를 통하여 유사한 부분에 대해서는 설명을 생략하였다.Hereinafter, the present application will be described in detail so that those skilled in the art to which the present application pertains can easily practice. However, the present application can be implemented in many different forms and is not limited to the specific embodiments described herein. And, similar parts are omitted throughout the specification.
본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout this specification, when a part “includes” a certain component, it means that the component may further include other components, not to exclude other components, unless specifically stated to the contrary.
본원 명세서 전체에서 사용되는 정도의 용어 "약", "실질적으로" 등은 언급된 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본원의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다.The terms "about", "substantially", and the like, as used throughout this specification, are used in or at a value close to that value when manufacturing and material tolerances specific to the stated meaning are given, and are understood herein. To aid, accurate or absolute figures are used to prevent unconscionable abusers from unduly using the disclosed disclosure.
본원 명세서 전체에서 사용되는 정도의 용어 "~(하는) 단계" 또는 "~의 단계"는 "~를 위한 단계"를 의미하지 않는다.The terms "~ (steps)" or "steps of" of the degree used throughout this specification do not mean "steps for".
본원 명세서 전체에서, 마쿠시 형식의 표현에 포함된 "이들의 조합(들)"의 용어는 마쿠시 형식의 표현에 기재된 구성 요소들로 이루어진 군에서 선택되는 하나 이상의 혼합 또는 조합을 의미하는 것으로서, 상기 구성 요소들로 이루어진 군에서 선택되는 하나 이상을 포함하는 것을 의미한다.Throughout the present specification, the term “combination (s)” included in the expression of the marki form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the marki form, It means to include one or more selected from the group consisting of the above components.
본원 명세서 전체에서, "A 및/또는 B"의 기재는, "A 또는 B, 또는 A 및 B"를 의미한다.Throughout this specification, the description of “A and / or B” means “A or B, or A and B”.
본원 명세서 전체에서, "할로", "할로겐"또는 "할로기"는, F, Cl, Br, 또는 I일 수 있으나, 이에 제한되지 않는다.Throughout this specification, “halo”, “halogen” or “halo group” may be, but is not limited to, F, Cl, Br, or I.
본원 명세서 전체에서, "알킬" 또는 "알킬기"는, 각각, 선형 또는 분지형의, 포화 또는 불포화의, 탄소수 1 내지 10 의 알킬기일 수 있으며, 예를 들어, 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵실, 옥틸, 노닐, 데실, 또는 이들의 이성질체를 포함하는 것일 수 있으나, 이에 제한되지 않는다. Throughout this specification, “alkyl” or “alkyl group” may be a linear or branched, saturated or unsaturated, alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl, etc. , Hexyl, hexyl, octyl, nonyl, decyl, or isomers thereof, but is not limited thereto.
본원 명세서 전체에서, 단독으로 또는 또 다른 기의 일부분으로서 용어 "아릴" 또는 "아릴기"는 모노사이클릭 또는 바이사이클릭 방향족 고리, 예를 들어, 페닐, 치환된 페닐뿐만 아니라, 접합된 기, 예를 들어 나프틸, 페난트레닐, 인데닐, 테트라히드로나프틸, 및 인다닐 등을 포함하나, 이에 제한지 않는다. 예를 들어, 상기 "아릴" 또는 "아릴기"는 5개 이상의 원자를 갖는 1개 이상의 고리를 함유하며, 22개 이하의 원자를 함유하는 5개 이하의 고리가 존재할 수 있고, 인접 탄소 원자 또는 적합한 헤테로원자 사이에 이중 결합이 교대로(공명) 존재할 수 있다. 상기 "아릴" 또는 "아릴기"는 임의로 할로겐, 예컨대 F, Br, Cl 또는 I, 알킬, 예컨대 메틸, 에틸, 프로필, 알콕시, 예컨대 메톡시 또는 에톡시, 히드록시, 카복시, 카바모일, 알킬옥시카보닐, 니트로, 알케닐옥시, 트리플루오로메틸, 아미노, 시클로알킬, 아릴, 헤테로아릴, 시아노, 알킬 S(O) m (m=O, 1, 2) 또는 티올을 비롯한, 그러나 이에 한정되지 않는 1개 이상의 기로 치환될 수 있다. 예를 들어, 상기 "아릴" 또는"아릴기"는 페닐, 상기한 바와 같이 치환된 페닐, 페닐, 나프틸, 또는 상기한 바와 같이 치환된 나프틸일 수 있으나, 이에 제한되지 않는다.Throughout this specification, the term “aryl” or “aryl group”, alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring, such as phenyl, substituted phenyl, as well as fused groups, Examples include, but are not limited to, naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl, and indanyl. For example, the "aryl" or "aryl group" contains one or more rings having 5 or more atoms, and 5 or fewer rings containing 22 or fewer atoms may be present, adjacent carbon atoms or Double bonds may alternately (resonant) between suitable heteroatoms. The "aryl" or "aryl group" is optionally halogen, such as F, Br, Cl or I, alkyl such as methyl, ethyl, propyl, alkoxy such as methoxy or ethoxy, hydroxy, carboxy, carbamoyl, alkyloxy Including, but not limited to, carbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S (O) m (m = O, 1, 2) or thiol Can be substituted with one or more groups. For example, the "aryl" or "aryl group" may be phenyl, phenyl substituted as described above, phenyl, naphthyl, or naphthyl substituted as described above, but is not limited thereto.
본원 명세서 전체에서, 단독으로 또는 또 다른 기의 일부분으로서 용어 "헤테로아릴" 또는 "헤테로아릴기"는 탄소 원자가 아닌 원자를 하나 이상 포함하는 모노사이클릭 또는 바이사이클릭 방향족 고리를 의미하며, 예를 들어, 퓨란일, 티오펜일, 피라졸릴, 피라지닐, 피리디닐, 피리미디닐, 벤조티아졸릴, 벤조디옥시닐, 안다졸릴, 이소인돌리닐, 인덴일, 퀴놀리닐 및 벤조티오펜일 등을 포함하나, 이에 제한되지 않는다. "헤테로아릴" 또는 "헤테로아릴기"는 5개 이상의 원자를 갖는 1개 이상의 고리를 함유하며, 22개 이하의 원자를 함유하는 5개 이하의 고리가 존재할 수 있고, 인접 탄소 원자 또는 적합한 헤테로원자 사이에 이중 결합이 교대로(공명) 존재할 수 있다. 또한, "헤테로아릴" 또는 "헤테로아릴기"는 상기 "아릴" 또는 "아릴기"에서 설명한 바와 동일하게 치환될 수 있다.Throughout this specification, the term “heteroaryl” or “heteroaryl group”, alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring comprising one or more atoms other than carbon atoms, eg For example, furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzodioxynyl, andazolyl, isoindolinyl, indenyl, quinolinyl and benzothiophenyl And the like, but is not limited thereto. “Heteroaryl” or “heteroaryl group” contains one or more rings having 5 or more atoms, and may be 5 or fewer rings containing 22 or fewer atoms, adjacent carbon atoms or suitable heteroatoms There may be alternating (resonant) double bonds between them. In addition, "heteroaryl" or "heteroaryl group" may be substituted in the same manner as described in the "aryl" or "aryl group" above.
본원 명세서 전체에서, "알콕시" 또는 "알콕시기"는 상기 정의된 "알킬기"와 산소 원자가 결합된 알콕시기를 포함하는 것일 수 있으나, 이에 제한되지 않는다.Throughout the present specification, “alkoxy” or “alkoxy group” may include, but is not limited to, an “alkoxy group” and an oxygen atom-bonded alkoxy group as defined above.
본원 명세서 전체에서, 단독으로 또는 또 다른 기의 일부분으로서 용어 "아민" 또는 "아민기"는 -NH 2를 의미하며, 또한, 상기 "아민기"는 동일하거나 상이할 수 있는 1 또는 2개의 치환체, 예컨대 알킬, 아릴, 아릴알킬, 알케닐, 알키닐, 헤테로아릴, 헤테로아릴알킬, 시클로헤테로알킬, 시클로헤테로알킬알킬, 시클로알킬, 시클로알킬알킬, 할로알킬, 히드록시알킬, 알콕시알킬, 티오알킬, 카보닐 또는 카복실로 임의로 치환될 수 있다. Throughout this specification, the term "amine" or "amine group", alone or as part of another group, refers to -NH 2 , and also, the "amine group" is one or two substituents that may be the same or different. , Such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl , Carbonyl or carboxyl.
퀴놀린-5,8-디온 유도체 화합물Quinoline-5,8-dione derivative compound
본원은 하기 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염을 제공한다:Provided herein is a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 I][Formula I]
Figure PCTKR2019011876-appb-img-000025
Figure PCTKR2019011876-appb-img-000025
상기 식에서,In the above formula,
R 1은 수소, 할로겐, C 1-6알킬 또는 -O-C 1-6알킬이고,R 1 is hydrogen, halogen, C 1-6 alkyl or -OC 1-6 alkyl,
R 2는 수소, 할로겐 또는 -NH 2이고, 여기서, -NH 2의 하나 이상의 수소는 선택적으로 R 4로 치환될 수 있으며,R 2 is hydrogen, halogen or -NH 2 , wherein one or more hydrogens of -NH 2 may be optionally substituted with R 4 ,
R 3는 수소, 할로겐, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 여기서, 상기 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬 C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있으며,R 3 is hydrogen, halogen, C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocycloalkyl, wherein the C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl C 3-10 Cycloalkenyl, and C 3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R 5 or = O,
R 4는 할로겐, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬) 또는 -(C=O)-(C 2-6알케닐)이고,R 4 is halogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl) or-(C = O)-(C 2-6 alkenyl),
R 5는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b, C 6-12 아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12 아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or substituted with one or more hydrogen R e ,
R a는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
R b는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
R c 및 R d는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
R e는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -(C=O)-R b, -(C=O)O-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl,-(C = O) -R b ,-(C = O) OR b , C 6- 12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6 -12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2- 6 alkenyl, -OH or halogen,
상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
본원의 화학식 I의 화합물에서, R 1은 구체적으로 수소, C 1-3알킬 또는 -O-C 1-3알킬일 수 있고, 바람직하게는 수소, -CH 3 또는 -O-CH 3이고, 더 바람직하게는 수소 또는 -O-CH 3이다.In the compounds of the formula (I) herein, R 1 may specifically be hydrogen, C 1-3 alkyl or -OC 1-3 alkyl, preferably hydrogen, -CH 3 or -O-CH 3 , more preferably Is hydrogen or -O-CH 3 .
본원의 화학식 I의 화합물에서, R 2는 구체적으로 수소, Br 또는 -NH 2일 수 있다.In the compounds of formula I herein, R 2 may specifically be hydrogen, Br or -NH 2 .
본원의 화학식 I의 화합물에서, R 3는 구체적으로 퓨란일, 티오펜일, 피라졸릴, 피라지닐, 피리디닐, 피리미디닐, 벤조티아졸릴, 벤조티오펜일, 벤조디옥시닐, 인다졸릴, 이소인돌리닐, 퀴놀리닐, 피리다지닐아미노, 피리디닐아미노, 페닐, 인덴일, 나프탈렌일, 페닐아미노, 피페리디닐 또는 시클로프로필일 수 있고, 더 구체적으로는 퓨란-3-일, 티오펜-2-일, 피라졸-4-일, 피라진-2-일, 피리딘-2-일, 피리딘-3-일, 피리딘-4-일, 피리미딘-5-일, 벤조[d]티아졸-5-일, 벤조티오펜-2-일, 디히드로벤조[1,4]디옥신-6-일, 인다졸-6-일, 이소인돌린-5-일, 2-퀴놀리닐, 3-퀴놀리닐, 6-퀴놀리닐, 피리다진-3-일아미노, 페닐, 인덴-5-일, 나프탈렌-2-일, 페닐아미노, 피페리딘-1-일, 피페리딘-2-일 또는 시클로프로필일 수 있고, 바람직하게는 페닐, 피리미디닐 또는 피리디닐이다.In the compounds of formula I herein, R 3 is specifically furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzodioxynyl, indazolyl, Isoindolinyl, quinolinyl, pyridazinylamino, pyridinylamino, phenyl, indenyl, naphthalenyl, phenylamino, piperidinyl or cyclopropyl, more specifically furan-3-yl, thi Offen-2-yl, pyrazole-4-yl, pyrazine-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, benzo [d] thiazole -5-yl, benzothiophen-2-yl, dihydrobenzo [1,4] dioxine-6-yl, indazol-6-yl, isoindoline-5-yl, 2-quinolinyl, 3 -Quinolinyl, 6-quinolinyl, pyridazine-3-ylamino, phenyl, inden-5-yl, naphthalen-2-yl, phenylamino, piperidin-1-yl, piperidine-2- It may be one or cyclopropyl, preferably phenyl, pyrimidinyl or pyridinyl.
본원의 화학식 I의 화합물에서, R 4는 구체적으로 -(C=O)-(C 1-3알킬) 또는 -(C=O)-(C 2-3알케닐)일 수 있다.In the compounds of formula (I) herein, R 4 can be specifically-(C = O)-(C 1-3 alkyl) or-(C = O)-(C 2-3 alkenyl).
본원의 화학식 I의 화합물에서, R a는 구체적으로 C 1-3알킬, 페닐 또는 몰폴리닐일 수 있다.In the compounds of formula I herein, R a may specifically be C 1-3 alkyl, phenyl or morpholinyl.
본원의 화학식 I의 화합물에서, R b는 구체적으로 수소, -NH 2, -NH(CH 3), C 1-3알킬 또는 C 2-3알케닐일 수 있다.In the compounds of formula (I) herein, R b can be specifically hydrogen, -NH 2 , -NH (CH 3 ), C 1-3 alkyl or C 2-3 alkenyl.
본원의 화학식 I의 화합물에서, R c는 구체적으로 수소, C 1-3알킬, -(C=O)-(C 1-3알케닐), -(C=O)-(C 3-6시클로알킬) 또는 -SO 2-(C 1-3알킬)이고, R d는 구체적으로 수소 또는 C 1-3알킬일 수 있다.In the compounds of formula I herein, R c is specifically hydrogen, C 1-3 alkyl,-(C = O)-(C 1-3 alkenyl),-(C = O)-(C 3-6 cyclo Alkyl) or -SO 2- (C 1-3 alkyl), R d may specifically be hydrogen or C 1-3 alkyl.
본원의 화학식 I의 화합물에서, R e는 구체적으로 C 1-3알킬, -OH, -O-C 1-3알킬, -COOH, -COOCH 3 또는 몰폴리닐일 수 있다.In the compounds of formula I herein, R e may specifically be C 1-3 alkyl, -OH, -OC 1-3 alkyl, -COOH, -COOCH 3 or morpholinyl.
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염에 있어서, According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 -O-C 1-3알킬이고,R 1 is -OC 1-3 alkyl,
R 2는 수소이고,R 2 is hydrogen,
R 3는 퓨란일, 피라졸릴, 피라지닐, 피리미디닐, 벤조티아졸릴, 벤조티오펜일, 인다졸릴, 이소인돌리닐, 퀴놀리닐 또는 피페리디닐이고, 상기 퓨란일, 피라졸릴, 피라지닐, 피리미디닐, 벤조티아졸릴, 벤조티오펜일, 인다졸릴, 이소인돌리닐, 퀴놀리닐 또는 피페리디닐은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있다.R 3 is furanyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, indazolyl, isoindolinyl, quinolinyl or piperidinyl, the furanyl, pyrazolyl, pyra Genyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, indazolyl, isoindolinyl, quinolinyl or piperidinyl may be unsubstituted or one or more hydrogens may be substituted with R 5 or = O.
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염에 있어서, According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 -O-CH 3이고,R 1 is -O-CH 3 ,
R 2는 수소이고,R 2 is hydrogen,
R 3는 피리미디닐이고, 상기 피리미디닐은 비치환되거나 하나 이상의 수소가 R 5 로 치환될 수 있고,R 3 is pyrimidinyl, the pyrimidinyl may be unsubstituted or one or more hydrogens may be substituted with R 5 ,
R 5는 -O-R a 이고,R 5 is -OR a ,
R a는 페닐이고, 상기 페닐은 비치환되거나 하나 이상의 수소가 -O-CF 3로 치환될 수 있다.R a is phenyl, and the phenyl may be unsubstituted or one or more hydrogens may be substituted with -O-CF 3 .
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염에 있어서, According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 수소, C 1-3알킬 또는 -O-C 1-3알킬이고,R 1 is hydrogen, C 1-3 alkyl or -OC 1-3 alkyl,
R 2는 Br이고,R 2 is Br,
R 3는 퓨란일, 티오펜일, 피라졸릴, 피리미디닐, 벤조티아졸릴, 인다졸릴, 퀴놀리닐, 페닐, 나프탈렌일 또는 시클로프로필이고, 상기 퓨란일, 티오펜일, 피라졸릴, 피리미디닐, 벤조티아졸릴, 인다졸릴, 퀴놀리닐, 페닐, 나프탈렌일 또는 시클로프로필은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있다.R 3 is furanyl, thiophenyl, pyrazolyl, pyrimidinyl, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl, and the furanyl, thiophenyl, pyrazolyl, pyrimidi Neil, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl may be unsubstituted or one or more hydrogens may be substituted with R 5 or = O.
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약학적으로 허용되는 이의 염에 있어서,According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 수소, 할로겐, C 1-3알킬 또는 -O-C 1-3알킬이고,R 1 is hydrogen, halogen, C 1-3 alkyl or -OC 1-3 alkyl,
R 2는 -NH 2이고, 여기서, -NH 2의 하나 이상의 수소는 선택적으로 R 4로 치환될 수 있으며,R 2 is -NH 2 , wherein one or more hydrogens of -NH 2 can be optionally substituted with R 4 ,
R 3는 퀴놀리닐, 나프탈렌일, 벤조디옥신일, 벤조티아졸릴, 벤조티오펜일, 시클로프로필, 이소인돌린일, 인덴일, 인다졸릴, 페닐, 페닐아미노, 피라진, 피리다진, 피리딘, 피리디닐아미노, 피리미딘 또는 피페리딘이고, 상기 퀴놀리닐, 나프탈렌일, 벤조디옥신일, 벤조티아졸릴, 벤조티오펜일, 시클로프로필, 이소인돌린일, 인덴일, 인다졸릴, 페닐, 페닐아미노, 피라진, 피리다진, 피리딘, 피리디닐아미노, 피리미딘 및 피페리딘은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있다.R 3 is quinolinyl, naphthalenyl, benzodioxinyl, benzothiazolyl, benzothiophenyl, cyclopropyl, isoindolinyl, indenyl, indazolyl, phenyl, phenylamino, pyrazine, pyridazine, pyridine, Pyridinylamino, pyrimidine or piperidine, the quinolinyl, naphthalenyl, benzodioxinyl, benzothiazolyl, benzothiophenyl, cyclopropyl, isoindolinyl, indenyl, indazolyl, phenyl, Phenylamino, pyrazine, pyridazine, pyridine, pyridinylamino, pyrimidine and piperidine may be unsubstituted or one or more hydrogens may be substituted with R 5 or = O.
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염에 있어서, According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 수소이고,R 1 is hydrogen,
R 2는 -NH 2이고,R 2 is -NH 2 ,
R 3는 페닐이고, 상기 페닐은 비치환되거나 R 5로 치환될 수 있고,R 3 is phenyl, the phenyl may be unsubstituted or substituted with R 5 ,
R 5는 -O-R a 또는 C 1-6알킬이고, 상기 C 1-6알킬은 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -OR a or C 1-6 alkyl, wherein C 1-6 alkyl may be substituted with one or more hydrogen R e ,
R a는 페닐 또는 피페리디닐이고, 상기 페닐 또는 피페리디닐은 비치환되거나 하나 이상의 수소가 C 1-3알킬로 치환될 수 있으며,R a is phenyl or piperidinyl, and the phenyl or piperidinyl may be unsubstituted or one or more hydrogens may be substituted with C 1-3 alkyl,
R e는 몰폴린이다.R e is morpholine.
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염에 있어서, According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 -O-CH 3이고,R 1 is -O-CH 3 ,
R 2는 -NH 2이고,R 2 is -NH 2 ,
R 3는 피리미디닐 또는 피리디닐이고, 상기 피리미디닐 또는 피리니딜은 비치환되거나 R 5로 치환될 수 있고,R 3 is pyrimidinyl or pyridinyl, the pyrimidinyl or pyrinidyl may be unsubstituted or substituted with R 5 ,
R 5는 할로겐 또는 C 1-3알킬 이고, 상기 C 1-3알킬은 R e로 치환될 수 있으며,R 5 is halogen or C 1-3 alkyl, and C 1-3 alkyl may be substituted with R e ,
상기 R e는 할로겐이다.R e is halogen.
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염에 있어서, According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 수소, C 1-3알킬 또는 -O-C 1-3알킬이고,R 1 is hydrogen, C 1-3 alkyl or -OC 1-3 alkyl,
R 2는 수소, Br 또는 -NH 2이고,R 2 is hydrogen, Br or -NH 2 ,
R 3는 퀴놀리닐, 나프탈렌일, 인덴일, 벤조디옥시닐, 벤조티아졸릴, 벤조티오펜일, 이소인돌린일, 인다졸릴, 페닐아미노, 피라지닐, 피리다지닐아미노, 피페리디닐 또는 시클로프로필이고, 상기 퀴놀리닐, 나프탈렌일, 인덴일, 벤조디옥시닐, 벤조티아졸릴, 벤조티오펜일, 이소인돌린일, 인다졸릴, 페닐아미노, 피라지닐, 피리다지닐아미노, 피페리디닐 및 시클로프로필은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있다.R 3 is quinolinyl, naphthalenyl, indenyl, benzodioxynyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperidinyl or Cyclopropyl, the quinolinyl, naphthalenyl, indenyl, benzodioxynyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperidi Neil and cyclopropyl may be unsubstituted or one or more hydrogens may be substituted with R 5 or = O.
R 4는 -(C=O)-(C 1-3알킬) 또는 -(C=O)-(C 1-3알케닐)이고,R 4 is-(C = O)-(C 1-3 alkyl) or-(C = O)-(C 1-3 alkenyl),
R 5는 -CN, -NO 2, 할로겐, C 1-6알킬, C 1-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 1-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 1-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 1-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or one or more hydrogens may be substituted with R e ,
R a는 C 1-6알킬, C 1-6알케닐, C 6-12아릴, C 3-12 헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 R a는 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 1-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 1-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, wherein R a is unsubstituted or one or more hydrogens may be substituted with C 1-6 alkyl, C 1-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
R b는 수소, -NR cR d, C 1-6알킬, C 1-6알케닐, C 6-12아릴, C 3-12 헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12 헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 1-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
R c 및 R d는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
R e는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -(C=O)-R b, -(C=O)O-R b, C 6-12아릴, C 3-12 헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬는 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl,-(C = O) -R b ,-(C = O) OR b , C 6- 12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6 -12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2-6 Alkenyl, -OH or halogen,
상기 C 3-12헤테로아릴 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함할 수 있다.The C 3-12 heteroaryl and C 3-10 heterocycloalkyl may include 1 to 3 heteroatoms selected from O, N or S.
본원의 바람직한 일 실시양태에 따르면, 화학식 I로 표시되는 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염에 있어서, According to a preferred embodiment of the present application, in the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
R 1은 수소 또는 -O-CH 3이고,R 1 is hydrogen or -O-CH 3 ,
R 2는 수소 또는 -NH 2이고,R 2 is hydrogen or -NH 2 ,
R 3는 페닐, 피리미디닐 또는 피리디닐이고, 상기 페닐, 피리미디닐 및 피리디닐은 비치환되거나 하나 이상의 수소가 R 5로 치환될 수 있고, R 3 is phenyl, pyrimidinyl or pyridinyl, the phenyl, pyrimidinyl and pyridinyl may be unsubstituted or one or more hydrogens may be substituted with R 5 ,
R 5는 할로겐, C 1-3알킬, -O-R a이고, 상기 C 1-3알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is halogen, C 1-3 alkyl, -OR a , and C 1-3 alkyl may be unsubstituted or one or more hydrogens may be substituted with R e ,
R a는 페닐 또는 피페리디닐이고, 상기 페닐 또는 피페리디닐은 비치환되거나 하나 이상의 수소가 C 1-3알킬 또는 O-CF 3로 치환될 수 있으며,R a is phenyl or piperidinyl, the phenyl or piperidinyl may be unsubstituted or one or more hydrogens may be substituted with C 1-3 alkyl or O-CF 3 ,
R e는 할로겐 또는 몰폴리닐이다.R e is halogen or morpholinyl.
본원의 구체적인 실시양태에 있어서, 상기 화학식 I로 표시되는 화합물은 하기 [표 1]에 표시된 화학식의 화합물들로 이루어진 군으로부터 선택된 것인 퀴놀린-5,8-디온 유도체 화합물, 이의 입체이성질체 또는 약제학적으로 허용되는 이의 염일 수 있으나, 이에 제한되지 않는다. In a specific embodiment of the present application, the compound represented by the formula (I) is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula represented in the following [Table 1] It may be a salt thereof, but is not limited thereto.
[표 1][Table 1]
Figure PCTKR2019011876-appb-img-000026
Figure PCTKR2019011876-appb-img-000026
Figure PCTKR2019011876-appb-img-000027
Figure PCTKR2019011876-appb-img-000027
Figure PCTKR2019011876-appb-img-000028
Figure PCTKR2019011876-appb-img-000028
Figure PCTKR2019011876-appb-img-000029
Figure PCTKR2019011876-appb-img-000029
Figure PCTKR2019011876-appb-img-000030
Figure PCTKR2019011876-appb-img-000030
Figure PCTKR2019011876-appb-img-000031
Figure PCTKR2019011876-appb-img-000031
Figure PCTKR2019011876-appb-img-000032
Figure PCTKR2019011876-appb-img-000032
Figure PCTKR2019011876-appb-img-000033
Figure PCTKR2019011876-appb-img-000033
Figure PCTKR2019011876-appb-img-000034
Figure PCTKR2019011876-appb-img-000034
Figure PCTKR2019011876-appb-img-000035
Figure PCTKR2019011876-appb-img-000035
Figure PCTKR2019011876-appb-img-000036
Figure PCTKR2019011876-appb-img-000036
Figure PCTKR2019011876-appb-img-000037
Figure PCTKR2019011876-appb-img-000037
Figure PCTKR2019011876-appb-img-000038
Figure PCTKR2019011876-appb-img-000038
Figure PCTKR2019011876-appb-img-000039
Figure PCTKR2019011876-appb-img-000039
Figure PCTKR2019011876-appb-img-000040
Figure PCTKR2019011876-appb-img-000040
Figure PCTKR2019011876-appb-img-000041
Figure PCTKR2019011876-appb-img-000041
Figure PCTKR2019011876-appb-img-000042
Figure PCTKR2019011876-appb-img-000042
Figure PCTKR2019011876-appb-img-000043
Figure PCTKR2019011876-appb-img-000043
본원의 바람직한 실시양태에 있어서, 상기 화학식 I로 표시되는 화합물은 하기 [표 2]에 표시된 화학식의 화합물들로 이루어진 군으로부터 선택된 것인 퀴놀린-5,8-디온 유도체 화합물, 이의 입체이성질체 또는 약제학적으로 허용되는 이의 염일 수 있다. In a preferred embodiment of the present application, the compound represented by Formula (I) is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula shown in Table 2 below. It may be a salt thereof.
[표 2][Table 2]
Figure PCTKR2019011876-appb-img-000044
Figure PCTKR2019011876-appb-img-000044
본원에서, 약제학적으로 허용 가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 포타슘, 소듐 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 및 황산 등으로 제조된 무기산염, 아세트산, 트라이플루오로아세트산, 시트르산, 말레산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만델산, 프로피온산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트라이메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다.As used herein, pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts made of calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodine Inorganic acid salts made from acids, perchloric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid Organic acid, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid made of, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, etc. And amino acid salts made of sulfonates made of naphthalenesulfonic acid, etc., glycine, arginine, lysine, and trimethylamine, triethylamine, ammonia, pyridine, There are amine salts and the like made of picoline, but the types of salts in the present invention are not limited by the salts listed.
상기 화학식 I의 화합물은 1 개 이상의 비대칭 탄소를 함유할 수 있으며, 이에 따라 라세미체, 라세믹 혼합물, 단일의 에난티오머, 부분입체이성체 혼합물 및 각각의 부분입체이성체로서 존재할 수 있다. 이러한 이성질체는 종래기술, 예를 들어 화학식 I의 화합물은 관 크로마토그래피 또는 HPLC 등의 분할에 의해 분리가 가능하다. 또는, 화학식 I의 화합물 각각의 입체 이성질체는 공지된 배열의 광학적으로 순수한 출발 물질 및/또는 시약을 사용하여 입체 특이적으로 합성할 수 있다. The compounds of formula (I) may contain one or more asymmetric carbons, and thus may exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. These isomers can be separated by prior art techniques, for example, the compound of formula I can be separated by tube chromatography or HPLC. Alternatively, the stereoisomers of each of the compounds of formula I can be stereospecifically synthesized using known arrays of optically pure starting materials and / or reagents.
퀴놀린-5,8-디온 유도체 화합물을 포함하는 조성물, 이의 용도 및 이를 이용한 치료방법Composition comprising a quinoline-5,8-dione derivative compound, use thereof and treatment method using same
본원은 화학식 I의 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염; 및 1 종 이상의 약제학적으로 허용되는 담체를 포함하는 조성물을 제공한다.Herein is a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; And one or more pharmaceutically acceptable carriers.
상기 화학식 I의 화합물은 앞서 기술한 바와 같으며, 중복되는 부분은 상세한 설명을 생략한다.The compound of the formula (I) is as described above, and overlapping parts are omitted.
상기 담체는 예를 들어, 통상적으로 사용되는 것을 사용할 수 있으며, 슈가, 전분, 미결정셀룰로오스, 유당(유당수화물), 포도당, 디-만니톨, 알기네이트, 알칼리토금속류염, 클레이, 폴리에틸렌글리콜, 무수인산수소칼슘, 또는 이들의 혼합물 등을 사용할 수 있으나, 이에 제한되지 않는다.The carrier may be, for example, a commonly used one, sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, phosphoric anhydride Calcium hydrogen, or mixtures thereof may be used, but is not limited thereto.
상기 조성물은 예를 들어, 결합제, 붕해제, 윤활제, pH 조절제, 산화방지제 등의 첨가제를 포함할 수 있으나, 이에 제한되지 않는다.The composition may include, for example, an additive such as a binder, a disintegrant, a lubricant, a pH adjusting agent, and an antioxidant, but is not limited thereto.
상기 결합제는 예를 들어, 전분, 미결정셀룰로오스, 고분산성 실리카, 만니톨, 디-만니톨, 자당, 유당수화물, 폴리에틸렌글리콜, 폴리비닐피롤리돈(포비돈), 폴리비닐피롤리돈 공중합체(코포비돈), 히프로멜로오스, 히드록시프로필셀룰로오스, 천연검, 합성검, 코포비돈, 젤라틴, 또는 이들의 혼합물 등을 사용할 수 있으나, 이에 제한되지 않는다.The binder is, for example, starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone) , Hypromellose, hydroxypropylcellulose, natural gums, synthetic gums, copovidone, gelatin, or mixtures thereof may be used, but is not limited thereto.
상기 붕해제는 예를 들어, 전분글리콘산나트륨, 옥수수전분, 감자전분 또는 전호화전분 등의 전분 또는 변성전분; 벤토나이트, 몬모릴로나이트, 또는 비검(veegum) 등의 클레이; 미결정셀룰로오스, 히드록시프로필셀룰로오스 또는 카르복시메틸셀룰로오스 등의 셀룰로오스류; 알긴산나트륨 또는 알긴산 등의 알긴류; 크로스카멜로스(croscarmellose)나트륨 등의 가교 셀룰로오스류; 구아검, 잔탄검 등의 검류; 가교 폴리비닐피롤리돈(crospovidone) 등의 가교 중합체; 중탄산나트륨, 시트르산 등의 비등성 제제, 또는 이들의 혼합물을 사용할 수 있으나, 이에 제한되지 않는다.The disintegrating agent may be, for example, starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clays such as bentonite, montmorillonite, or veegum; Cellulose such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Cross-linked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate and citric acid, or mixtures thereof may be used, but are not limited thereto.
상기 윤활제는 예를 들어, 탈크, 스테아린산, 스테아린산 마그네슘, 스테아린산 칼슘, 라우릴설페이트나트륨, 수소화식물성오일, 나트륨벤조에이트, 나트륨스테아릴푸마레이트, 글리세릴 베헤네이트, 글리세릴 모노레이트, 글리세릴모노스테아레이트, 글리세릴 팔미토스테아레이트, 콜로이드성 이산화규소 또는 이들의 혼합물 등을 사용할 수 있으나, 이에 제한되지 않는다.The lubricant is, for example, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostea Rate, glyceryl palmitostearate, colloidal silicon dioxide, or mixtures thereof, but is not limited thereto.
상기 pH 조절제는 예를 들어, 초산, 아디프산, 아스코르빈산, 아스코르빈산 나트륨, 에테르산 나트륨, 사과산, 숙신산, 주석산, 푸마르산, 구연산(시트르산)과 같은 산성화제와 침강 탄산 칼슘, 암모니아수, 메글루민, 탄산 나트륨, 산화 마그네슘, 탄산 마그네슘, 구연산 나트륨, 삼염기칼슘인산염과 같은 염기성화제 등을 사용할 수 있으나, 이에 제한되지 않는다.The pH adjusting agent is, for example, acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), precipitated calcium carbonate, ammonia water, Basic agents such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, and tribasic calcium phosphate may be used, but are not limited thereto.
상기 산화방지제는 예를 들어, 디부틸 히드록시 톨루엔, 부틸레이티드 히드록시아니솔, 초산 토코페롤, 토코페롤, 프로필갈레이트, 아황산수소나트륨, 피로아황산나트륨 등을 사용할 수 있다. 용해보조제는 라우릴황산나트륨, 폴리소르베이트 등의 폴리옥시에틸렌 소르비탄 지방산 에스테류, 도큐세이트 나트륨, 폴록사머(poloxamer) 등을 사용할 수 있으나, 이에 제한되지 않는다.The antioxidant may be, for example, dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, and the like. The solubilizing aid may be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, docusate sodium, poloxamer, and the like, but is not limited thereto.
화학식 I의 화합물은 부작용이 적고 효과적으로 TGase2를 저해시키는 작용 효과를 나타내므로, 이에 따라 본원의 조성물은 TGase 2에 의해 매개되거나 TGase 2의 억제에 대해 반응하는 장애 또는 질환의 예방 또는 치료용도로 사용될 수 있다. 그러나 본원 화학식 I의 화합물의 용도가 이에 제한되지는 않는다.Since the compound of formula (I) has few side effects and exhibits an effect of effectively inhibiting TGase2, the composition herein can be used for the prevention or treatment of disorders or diseases mediated by TGase 2 or responding to the inhibition of TGase 2 have. However, the use of the compounds of formula I herein is not limited thereto.
본원은 화학식 I의 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하는 TGase 2에 의해 매개되거나 TGase 2의 억제에 대해 반응하는 장애 또는 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.Disclosed herein is a pharmaceutical composition for the prevention or treatment of a disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 comprising a compound of Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
상기 화학식 I의 화합물은 앞서 기술한 바와 같으며, 중복되는 부분의 기재는 상세한 설명을 생략한다.The compound of the formula (I) is as described above, and the description of the overlapping part is omitted.
본원의 구체적인 일 실시양태에 있어서, TGase 2에 의해 매개되거나 TGase 2의 억제에 대해 반응하는 상기 장애 또는 질환은 염증성 질환, 신경계 질환, 암, 신장실질 질환, 섬유화증 또는 이들의 조합으로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In one specific embodiment herein, the disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 is in the group consisting of inflammatory disease, nervous system disease, cancer, renal parenchymal disease, fibrosis or combinations thereof. It may be selected, but is not limited thereto.
상기 염증성 질환은 예를 들어, 퇴행성 관절염, 당뇨병, 자가면역 근육염, 동맥경화, 크론병, 염증성 위궤양, 뇌졸증, 간경과, 뇌막염, 비염, 결막염, 천식, 염증성 피부질환, 염증성 장질환, 류마티스 염증성 질환 또는 사구체신염일 수 있으나, 이에 제한되지 않는다.The inflammatory diseases include, for example, degenerative arthritis, diabetes, autoimmune myositis, arteriosclerosis, Crohn's disease, inflammatory gastric ulcer, stroke, cirrhosis, meningitis, rhinitis, conjunctivitis, asthma, inflammatory skin disease, inflammatory bowel disease, rheumatoid inflammatory disease Or glomerulonephritis, but is not limited thereto.
상기 신경계 질환은 예를 들어, 알츠하이머 질환, 치매, 파킨슨병 또는 헌팅턴병일 수 있으나, 이에 제한되지 않는다.The nervous system disease may be, for example, Alzheimer's disease, dementia, Parkinson's disease, or Huntington's disease, but is not limited thereto.
상기 암은 예를 들어, 대장암, 소장암, 직장암, 결장암, 항문암, 식도암, 위암, 췌장암, 담낭암, 자궁암, 자궁경부암, 유방암, 난소암, 폐암, 임파선암, 갑상선암, 전립선암, 혈액암, 피부암, 뇌종양, 신장암 또는 방광암일 수 있으나, 이에 제한되지 않는다. The cancer is, for example, colon cancer, small intestine cancer, rectal cancer, colon cancer, anal cancer, esophageal cancer, stomach cancer, pancreatic cancer, gallbladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, lung cancer, lymphatic cancer, thyroid cancer, prostate cancer, blood cancer , Skin cancer, brain tumor, kidney cancer or bladder cancer, but is not limited thereto.
상기 섬유화증은 예를 들어 폐 섬유화증 또는 간 섬유화증일 수 있으나, 이에 제한되지 않는다.The fibrosis may be, for example, lung fibrosis or liver fibrosis, but is not limited thereto.
본원의 바람직한 일 실시양태에 있어서, TGase 2에 의해 매개되거나 TGase 2의 억제에 대해 반응하는 장애 또는 질환은 암이며, 보다 바람직하게는 신장암, 뇌암 또는 위암이다.In one preferred embodiment of the present application, the disorder or disease mediated by TGase 2 or responding to the inhibition of TGase 2 is cancer, more preferably kidney cancer, brain cancer or gastric cancer.
본원의 일 양태에서, 화학식 I의 화합물을 치료학적 유효량으로 대상체에게 투여하는 것을 포함하는, 대상체의 TGase 2 활성 억제 방법을 제공한다. 상기 대상체는 예를 들어, 인간, 원숭이, 소, 말, 개, 고양이, 토끼, 레트, 마우스 등의 포유류를 포함하나 이에 제한되지 않는다.In one aspect of the present application, there is provided a method of inhibiting TGase 2 activity in a subject, comprising administering a compound of Formula I to the subject in a therapeutically effective amount. The subject includes, but is not limited to, mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice.
본원의 일 양태에서, 대상체에서 TGase 2에 의해 매개되거나 TGase 2의 억제에 대해 반응하는 장애 또는 질환의 치료용 약제를 제조하기 위한, 본원의 화학식 I의 화합물의 용도를 제공한다.In one aspect of the present application, there is provided the use of a compound of formula (I) herein for the manufacture of a medicament for the treatment of a disorder or condition mediated by TGase 2 or in response to inhibition of TGase 2 in a subject.
퀴놀린-5,8-디온 유도체 화합물의 제조방법Method for preparing quinoline-5,8-dione derivative compound
본원은 상기 화학식 I의 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용되는 염의 제조방법을 제공한다. 그러나 상기 기술한 화학식 I의 화합물, 이의 입체 이성질체 또는 약제학적으로 허용되는 이의 염이 본원의 제조방법으로 제조된 것에 한정되는 것은 아니다.The present application provides a method for preparing the compound of Formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof. However, the above-described compounds of the formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof are not limited to those prepared by the preparation method herein.
본원의 구체적인 일 실시양태에서, 화학식 I로 표시되는 퀴놀린-5,8-디온 유도체 화합물, 이의 이성질체 또는 약제학적으로 허용가능한 이의 염의 제조방법은 [반응식 a]와 같으며, 통상의 기술자에게 자명한 수준으로 변형된 제조방법도 이에 포함된다.In one specific embodiment of the present application, the method for preparing a quinoline-5,8-dione derivative compound represented by the formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is the same as [Scheme a], and apparent to those skilled in the art This also includes manufacturing methods modified at a level.
[반응식 a][Scheme a]
Figure PCTKR2019011876-appb-img-000045
Figure PCTKR2019011876-appb-img-000045
상기 [반응식 a]에 도시된 바와 같이, 화학식 1-1의 화합물을 질산과 반응시켜 화학식 1-2의 화합물을 합성하고, 이후, Pd/C H 2 환원반응으로 화학식 1-3의 화합물을 합성한다. 화학식 1-3의 화합물을 (E)-3-에톡시아크릴로일 클로라이드와 반응시켜 화학식 1-4의 화합물을 합성하고, 황산 용액에 화학식 1-4의 화합물을 적가하여 반응시켜 화학식 1-5의 화합물을 합성한다. 피리딘 및 디메틸포름아마이드(DMF) 용액에 화학식 1-5의 화합물을 용해시키고, 포스포러스 옥시클로라이드(POCl 3)를 적가하여 화학식 1-6의 화합물을 합성한다. 그리고 R-보론산 피나콜 에스터(
Figure PCTKR2019011876-appb-img-000046
) 또는 R-보레이트(
Figure PCTKR2019011876-appb-img-000047
)를 사용하여 스즈키 반응(Suzuki reaction)으로 마이크로웨이브를 사용하여 화학식 1-7의 화합물을 합성한다. 최종적으로, 화학식 1-7의 화합물을 아세토니트릴(ACN)에 용해시킨 후, 질산세륨암모늄(Ceric ammonium nitrate, CAN) 수용액을 적가하여 화합식 1-8의 화합물을 합성할 수 있다.As shown in [Reaction Scheme a], the compound of Formula 1-1 is reacted with nitric acid to synthesize the compound of Formula 1-2, and then, the compound of Formula 1-3 is synthesized by the Pd / CH 2 reduction reaction. . The compound of Formula 1-3 is reacted with (E) -3-ethoxyacryloyl chloride to synthesize the compound of Formula 1-4, and the compound of Formula 1-4 is added dropwise to the sulfuric acid solution to react to formula 1-5. Synthesize the compound. A compound of Formula 1-5 is dissolved in a solution of pyridine and dimethylformamide (DMF), and phosphorus oxychloride (POCl 3 ) is added dropwise to synthesize a compound of Formula 1-6. And R-boronic acid pinacol ester (
Figure PCTKR2019011876-appb-img-000046
) Or R-borate (
Figure PCTKR2019011876-appb-img-000047
) To synthesize a compound of Formula 1-7 using microwaves as a Suzuki reaction. Finally, after dissolving the compound of Formula 1-7 in acetonitrile (ACN), a compound of Formula 1-8 can be synthesized by dropwise addition of an aqueous solution of Ceric ammonium nitrate (CAN).
또한, 상기 반응식 a에 도시된 바와 같이, 화학식 1-8의 화합물에 브롬을 반응시켜 화학식 1-9의 화합물을 합성할 수 있다.In addition, as shown in Reaction Scheme a, a compound of Formula 1-9 can be synthesized by reacting bromine with a compound of Formula 1-8.
또한, 상기 반응식 a에 도시된 바와 같이, 화학식 1-9의 화합물에 소듐 아자이드(NaN 3)를 적가하여 화학식 1-10의 화합물을 합성한 후, 화학식 1-10의 화합물을 Pd/C, H 2 환원반응하거나, 소듐보로하이드라이드(NaBH 4)로 환원하여 화학식 1-11의 화합물을 합성할 수 있다.In addition, as shown in Reaction Scheme a, sodium azide (NaN 3 ) is added dropwise to the compound of Formula 1-9 to synthesize the compound of Formula 1-10, and then the compound of Formula 1-10 is Pd / C, Reduction of H 2 or reduction with sodium borohydride (NaBH 4 ) can be used to synthesize compounds of Formula 1-11.
본원의 구체적인 일 실시양태에서, 화학식 I 로 표시되는 퀴놀린-5,8-디온 유도체 화합물, 이의 이성질체 또는 약제학적으로 허용가능한 이의 염의 제조방법은 [반응식 b]와 같으며, 통상의 기술자에게 자명한 수준으로 변형된 제조방법도 이에 포함된다.In one specific embodiment of the present application, the method for preparing a quinoline-5,8-dione derivative compound represented by the formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is the same as [Scheme b], and is apparent to those skilled in the art This also includes manufacturing methods modified at a level.
[반응식 b][Scheme b]
Figure PCTKR2019011876-appb-img-000048
Figure PCTKR2019011876-appb-img-000048
상기 [반응식 b]에 도시된 바와 같이, 화학식 10-1의 화합물을 질산과 반응시켜 화학식 10-2의 화합물을 합성하고, 이후, Pd/C H 2 환원반응으로 화학식 10-3의 화합물을 합성한다. 화학식 10-3의 화합물을 아세틸클로라이드와 반응시켜 화학식 10-4의 화합물을 합성하고, 화학식 10-4의 화합물을 H 2O과 반응시켜 화학식 10-5의 화합물을 합성한다. 화학식 10-5의 화합물을 벤질브로마이드(BnBr)와 반응시켜 화학식 10-6의 화합물을 합성하고, 화학식 10-6의 화합물에 mCPBA를 적가하여 화학식 10-7의 화합물을 합성한 후, POCl 3를 적가하여 화학식 10-8의 화합물을 합성한다. 그리고 트리클로로보란 및 디메틸 설판염을 적가하여 화학식 10-9의 화합물을 합성하고, 프레미염을 적가하여 화학식 10-10의 화합물을 합성한다. 최종적으로 R-보론산 피나콜 에스터(
Figure PCTKR2019011876-appb-img-000049
) 또는 R-보레이트(
Figure PCTKR2019011876-appb-img-000050
)를 사용하여 스즈키 반응(Suzuki reaction)으로 마이크로웨이브를 사용하여 화학식 10-11의 화합물을 합성할 수 있다. As shown in [Reaction Scheme b], a compound of Formula 10-2 is synthesized by reacting a compound of Formula 10-1 with nitric acid, and then a compound of Formula 10-3 is synthesized by a Pd / CH 2 reduction reaction. . The compound of Formula 10-3 is reacted with acetyl chloride to synthesize the compound of Formula 10-4, and the compound of Formula 10-4 is reacted with H 2 O to synthesize the compound of Formula 10-5. The compound of Formula 10-5 is reacted with benzyl bromide (BnBr) to synthesize the compound of Formula 10-6, mCPBA is added dropwise to the compound of Formula 10-6 to synthesize the compound of Formula 10-7, and POCl 3 is added. The compound of Formula 10-8 is synthesized by dropwise addition. Then, trichloroborane and dimethyl sulfanate are added dropwise to synthesize the compound of Formula 10-9, and premi salt is added dropwise to synthesize the compound of Formula 10-10. Finally, R-boronic acid pinacol ester (
Figure PCTKR2019011876-appb-img-000049
) Or R-borate (
Figure PCTKR2019011876-appb-img-000050
) Can be used to synthesize the compound of Formula 10-11 using microwaves as a Suzuki reaction.
또한, 상기 반응식 b에 도시된 바와 같이, 화학식 10-11의 화합물을 탈사레틸화하여 화학식 10-12의 화합물을 합성할 수 있다.In addition, as shown in Reaction Scheme b, the compound of Formula 10-11 can be synthesized by desarretylating the compound of Formula 10-11.
이하, 본원에 대하여 아래에서 제조예, 실시예 및 실험예를 이용하여 좀더 구체적으로 설명한다. 그러나 하기 제조예, 실시예 및 실험예는 본원의 이해를 돕기 위하여 예시하는 것일 뿐, 본원의 내용이 하기 제조예, 실시예 및 실험예에 한정되는 것은 아니다.Hereinafter, the present application will be described in more detail by using Preparation Examples, Examples, and Experimental Examples below. However, the following Preparation Examples, Examples and Experimental Examples are only illustrative to aid understanding of the present application, and the contents of the present application are not limited to the following Preparation Examples, Examples and Experimental Examples.
[제조예] 중간체 화합물의 제조[Production Example] Preparation of intermediate compound
제조예 1: 2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6의 화합물)의 제조Preparation Example 1 Preparation of 2-chloro-5,6,8-trimethoxyquinoline (compound of Formula 1-6)
단계 1: 1,2,4-트리메톡시-5-니트로벤젠 (화학식 Step 1: 1,2,4-trimethoxy-5-nitrobenzene (Formula 1-21-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000051
Figure PCTKR2019011876-appb-img-000051
60 % 질산 (100 ml)이 용해되어 있는 물 (300 ml)을 0 °C로 냉각시킨 후, 2,4,5-트리메톡시벤즈알데히드 (5 g, 25.5 mmol)를 천천히 적가하여 녹이고, 동일 온도에서 1시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 여과하고 물로 세정한 다음, 건조하여 노란색 고체 화합물 (화학식 1-2)을 수득하였다.After cooling the water (300 ml) in which 60% nitric acid (100 ml) is dissolved to 0 ° C, 2,4,5-trimethoxybenzaldehyde (5 g, 25.5 mmol) is slowly added dropwise to dissolve, and at the same temperature. It was stirred for 1 hour. After completion of the reaction, the reaction mixture was filtered, washed with water, and then dried to obtain a yellow solid compound (Formula 1-2 ).
단계 2: 2,4,5-트리메톡시아닐린 (화학식 Step 2: 2,4,5-trimethoxyaniline (Formula 1-31-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000052
Figure PCTKR2019011876-appb-img-000052
단계 1에서 합성된1,2,4-트리메톡시-5-니트로벤젠 (화학식 1-2, 3.75 g, 17.6 mmol)을 에틸아세테이트(EtOAc)/메탄올(MeOH) (5/1)에 용해시킨 후, Pd/C (0.2 eq)를 적가하고 수소풍선기류 하에 상온에서 8시간 동안 교반시켰다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 감압 하에서 용매를 건조시켜 베이지색 고체 화합물 (화학식 1-3)을 수득하였다.The 1,2,4-trimethoxy-5-nitrobenzene synthesized in Step 1 (Formula 1-2 , 3.75 g, 17.6 mmol) was dissolved in ethyl acetate (EtOAc) / methanol (MeOH) (5/1). Then, Pd / C (0.2 eq) was added dropwise and stirred at room temperature for 8 hours under a hydrogen balloon stream. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was dried under reduced pressure to obtain a beige solid compound (Formula 1-3 ).
단계 3: 3-에톡시-N-(2,4,5-트리메톡시페닐)아크릴아미드 (화학식 Step 3: 3-ethoxy-N- (2,4,5-trimethoxyphenyl) acrylamide (Formula 1-41-4 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000053
Figure PCTKR2019011876-appb-img-000053
단계 2에서 합성된2,4,5-트리메톡시아닐린 (화학식 1-3, 3.22 g, 17.6 mmol)과 피리딘 (4.26 ml, 52.7 mmol)을 상온에서 디클로로메탄 (300 ml)에 녹이고 0 °C로 냉각시켰다. 이후, 디클로로메탄 (3 ml)에 용해된 (E)-3-에톡시아크릴로일클로라이드 (2.84 g, 21.1 mmol)를 천천히 적가하였다. 반응 혼합물을 상온에서 1시간 동안 교반하고, 감압하여 용매를 제거하였다. MPLC (헥산/에틸아세테이트) (5/1)로 분리 및 정제하여 고체 화합물 (화학식 1-4)을 수득하였다.The 2,4,5-trimethoxyaniline synthesized in Step 2 (Formula 1-3 , 3.22 g, 17.6 mmol) and pyridine (4.26 ml, 52.7 mmol) were dissolved in dichloromethane (300 ml) at room temperature and 0 ° C. Cooled to. Then, (E) -3-ethoxyacryloyl chloride (2.84 g, 21.1 mmol) dissolved in dichloromethane (3 ml) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. Separated and purified by MPLC (hexane / ethyl acetate) (5/1) to give a solid compound (Formula 1-4 ).
단계 4: 5,6,8-트리메톡시퀴놀린-2(1H)-온 (화학식 Step 4: 5,6,8-Trimethoxyquinoline-2 (1H) -one (Formula 1-51-5 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000054
Figure PCTKR2019011876-appb-img-000054
황산 (33.7 ml, 633 mmol)에 단계 3에서 합성된 3-에톡시-N-(2,4,5-트리메톡시페닐)아크릴아미드 (화학식 1-4, 3.55 g, 12.65 mmol)를 천천히 적가하여 녹인 후, 상온에서 2시간 동안 교반하였다. 얼음물을 넣어 반응을 종결시킨 후, 디클로로메탄을 이용하여 3 차례에 걸쳐 추출하였다. 이후, 유기층을 NaHCO 3 포화 수용액으로 세정하고, 유기층을 무수 MgSO 4로 건조한 다음, 감압 하에서 용매를 제거하였다. 반응 혼합물을 에틸아세테이트와 헥산을 이용하여 재결정으로 정제하여 고체 화합물 (화학식 1-5)를 수득하였다.3-Ethoxy-N- (2,4,5-trimethoxyphenyl) acrylamide (Formula 1-4 , 3.55 g, 12.65 mmol) synthesized in Step 3 was slowly added dropwise to sulfuric acid (33.7 ml, 633 mmol). After melting, the mixture was stirred at room temperature for 2 hours. After adding the ice water to terminate the reaction, extraction was performed three times using dichloromethane. Thereafter, the organic layer was washed with a saturated aqueous NaHCO 3 solution, and the organic layer was dried over anhydrous MgSO 4, and then the solvent was removed under reduced pressure. The reaction mixture was purified by recrystallization using ethyl acetate and hexane to obtain a solid compound (Formula 1-5 ).
단계 5: 2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 Step 5: 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-61-6 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000055
Figure PCTKR2019011876-appb-img-000055
단계4에서 합성된 5,6,8-트리메톡시퀴놀린-2(1H)-온 (화학식 1-5, 2.3 g, 9.78 mmol), 피리딘 (0.791 ml, 9.78 mmol) 및 디메틸포름아미드 (DMF) (40 ml)를 클로로벤젠 (100 ml)에 용해시킨 후, 포스포러스 옥시클로라이드 (5.47 ml, 58.7 mmol)를 적가하고 반응 혼합액을 3시간 동안 환류교반하였다. 반응 종결 후, 에틸아세테이트로 3차례 추출하였다. 유기층을 브라인 및 포화 NaHCO 3수용액으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 에틸아세테이트와 헥산을 이용하여 재결정으로 정제하여 고체 화합물 (화학식 1-6)을 수득하였다.5,6,8-Trimethoxyquinoline-2 (1H) -one synthesized in step 4 (Formula 1-5 , 2.3 g, 9.78 mmol), pyridine (0.791 ml, 9.78 mmol) and dimethylformamide (DMF) (40 ml) was dissolved in chlorobenzene (100 ml), then phosphorus oxychloride (5.47 ml, 58.7 mmol) was added dropwise and the reaction mixture was stirred under reflux for 3 hours. After completion of the reaction, extraction was performed three times with ethyl acetate. The organic layer was washed sequentially with brine and saturated aqueous NaHCO 3 , then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Purified by recrystallization using ethyl acetate and hexane to obtain a solid compound (Formula 1-6 ).
제조예 2: N-(3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)시클로프로판카복사미드 (화학식 2-3의 화합물)의 제조 Preparation Example 2: N- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclopropanecarboxamide (Compound of Formula 2-3 )
단계 1: N-(3-브로모페닐)시클로프로판카복사미드 (화학식 Step 1: N- (3-Bromophenyl) cyclopropanecarboxamide (Formula 2-22-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000056
Figure PCTKR2019011876-appb-img-000056
3-브로모아닐린 (화학식 2-1, 1.5 g, 8.72 mmol)을 디클로로메탄 (20 ml)에 녹인 후, N,N-디이소프로필에틸아민(DIPEA) (3.05 ml, 17.44 mmol, 2 eq)을 0 °C에서 적가하고 동일 온도에서 5분간 교반하였다. 이후, 사이클로프로판카보닐클로라이드 (0.912 g, 8.72 mmol, 1 eq)를 0 °C에서 적가하였다. 반응 혼합물을 동일 온도에서 20분간 교반한 후, H 2O로 반응을 종결하고, 유기층을 감압하여 용매를 제거하여 고체 화합물 (화학식 2-2)를 수득하였다. After 3-bromoaniline (Formula 2-1 , 1.5 g, 8.72 mmol) was dissolved in dichloromethane (20 ml), N, N-diisopropylethylamine (DIPEA) (3.05 ml, 17.44 mmol, 2 eq) Was added dropwise at 0 ° C and stirred at the same temperature for 5 minutes. Then, cyclopropanecarbonyl chloride (0.912 g, 8.72 mmol, 1 eq) was added dropwise at 0 ° C. After the reaction mixture was stirred at the same temperature for 20 minutes, the reaction was terminated with H 2 O, and the organic layer was reduced in pressure to remove the solvent to obtain a solid compound (Formula 2-2 ).
단계 2: N-(3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)시클로프로판카복사미드 (화학식 Step 2: N- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclopropanecarboxamide (Formula 2-32-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000057
Figure PCTKR2019011876-appb-img-000057
단계 1에서 합성된 N-(3-브로모페닐)시클로프로판카복사미드 (화학식 2-2, 2.1 g, 8.73 mmol), 포타슘 아세테이트 (2.57 g, 26.2 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (0.713 g, 0.873 mmol, 0.1 eq) 및 B 2Pin 2 (6.65 g, 26.2 mmol, 3 eq)를 디메틸 설폭시드 (DMSO)(20 ml)에 용해시켰다. 80 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 고체 화합물 (화학식 2-3)을 수득하였다.N- (3-bromophenyl) cyclopropanecarboxamide synthesized in Step 1 (Formula 2-2 , 2.1 g, 8.73 mmol), potassium acetate (2.57 g, 26.2 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.713 g, 0.873 mmol, 0.1 eq) and B 2 Pin 2 (6.65 g, 26.2 mmol, 3 eq) were dissolved in dimethyl sulfoxide (DMSO) (20 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 80 ° C. After completion of the reaction, the reaction mixture was filtered through celite, and extracted with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a solid compound (Formula 2-3 ).
제조예 3: 5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-2,3-디하이드로-1H-인덴-1-온 (화학식 3-2의 화합물)의 제조 Preparation Example 3: 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1H-inden-1-one (Formula Preparation of 3-2)
Figure PCTKR2019011876-appb-img-000058
Figure PCTKR2019011876-appb-img-000058
5-브로모-2,3-디히드로-1H-인덴-1-온 (화학식 3-1, 1 g, 4.74 mmol), 포타슘 아세테이트 (1.37 g, 14.22 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (0.384 g, 0.47 mmol, 0.1 eq) 및 B 2Pin 2 (2.41 g, 9.48 mmol, 3 eq)를 DMF (25 ml)에 용해시켰다. 80 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 에틸아세테이트로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 고체 화합물 (화학식 3-2)을 수득하였다.5-bromo-2,3-dihydro-1H-inden-1-one (Formula 3-1 , 1 g, 4.74 mmol), potassium acetate (1.37 g, 14.22 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.384 g, 0.47 mmol, 0.1 eq) and B 2 Pin 2 (2.41 g, 9.48 mmol, 3 eq) were dissolved in DMF (25 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 80 ° C. After completion of the reaction, extraction was performed with ethyl acetate. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a solid compound (Formula 3-2 ).
제조예 4: 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-2,3-디하이드로-1H-인덴-1-온 (화학식 4-2의 화합물)의 제조Preparation Example 4: 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1H-inden-1-one (Formula Preparation of 4-2)
Figure PCTKR2019011876-appb-img-000059
Figure PCTKR2019011876-appb-img-000059
4-브로모-2,3-디히드로-1H-인덴-1-온 (화학식 4-1, 1 g, 4.74 mmol), 포타슘 아세테이트 (1.37 g, 14.22 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (0.384 g, 0.47 mmol, 0.1 eq), B 2Pin 2 (2.41 g, 9.48 mmol, 3 eq)를 DMF (25 ml)에 용해시켰다. 80 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 Na 2SO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/디에틸아세테이트; 70:30)로 분리 및 정제하여 고체 화합물 (화학식 4-2)을 수득하였다.4-Bromo-2,3-dihydro-1H-inden-1-one (Formula 4-1 , 1 g, 4.74 mmol), potassium acetate (1.37 g, 14.22 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.384 g, 0.47 mmol, 0.1 eq), B 2 Pin 2 (2.41 g, 9.48 mmol, 3 eq) was dissolved in DMF (25 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 80 ° C. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / diethyl acetate; 70:30) to obtain a solid compound (Formula 4-2 ).
제조예 5: 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)이소인돌린-1-온 (화학식 5-3의 화합물)의 제조 Preparation Example 5: 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindoline-1-one (Formula 5-3 Compound)
단계 1: 5-브로모-2-메틸이소인돌린-1-온 (화학식 Step 1: 5-bromo-2-methylisoindolin-1-one (Formula 5-25-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000060
Figure PCTKR2019011876-appb-img-000060
메틸 4-브로모-2-(브로모메틸)벤조에이트 (화학식 5-1, 2.5 g, 8.12 mmol)를 2M 메탄아민 (122 ml, 244 mmol, 30 eq)에 용해시킨 후, 18시간 동안 환류교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O으로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 목표 화합물 (화학식 5-2)을 수득하였다.Methyl 4-bromo-2- (bromomethyl) benzoate (Formula 5-1 , 2.5 g, 8.12 mmol) was dissolved in 2M methaneamine (122 ml, 244 mmol, 30 eq) and refluxed for 18 hours. It was stirred. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain the target compound (Formula 5-2 ).
단계 2: 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)이소인돌린-1-온 (화학식 Step 2: 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindolin-1-one (Formula 5-35-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000061
Figure PCTKR2019011876-appb-img-000061
단계 1에서 합성된 5-브로모-2-메틸이소인돌린-1-온 (화학식 5-2, 2.1 g, 9.20 mmol), 포타슘 아세테이트 (2.26 g, 23 mmol, 2.5 eq), Pd(dppf)Cl 2-CH 2Cl 2 (0.225 g, 0.28 mmol, 0.03 eq) 및 B 2Pin 2 (2.34 g, 9.20 mmol, 1 eq)를 1,4-디옥산 (20 ml)에 용해시켰다. 100 °C로 온도를 높여 반응 혼합물을 5시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 목표 화합물 (화학식 5-3)을 수득하였다.5-bromo-2-methylisoindolin-1-one synthesized in step 1 (Formula 5-2 , 2.1 g, 9.20 mmol), potassium acetate (2.26 g, 23 mmol, 2.5 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.225 g, 0.28 mmol, 0.03 eq) and B 2 Pin 2 (2.34 g, 9.20 mmol, 1 eq) were dissolved in 1,4-dioxane (20 ml). The reaction mixture was stirred for 5 hours by raising the temperature to 100 ° C. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain the target compound (Formula 5-3 ).
제조예 6: 1-이소프로필-6-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-인다졸 (화학식 6-2의 화합물) 및 2-이소프로필-6-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-2H-인다졸 (화학식 6-3의 화합물)의 제조 Preparation 6: 1-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (compound of formula 6-2 ) And 2-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (compound of formula 6-3) Produce
Figure PCTKR2019011876-appb-img-000062
Figure PCTKR2019011876-appb-img-000062
6-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-인다졸 (화학식 6-1, 2 g, 8.19 mmol)을 DMF (20 ml)에 용해시킨 후, 2-브로모프로판 (2.3 ml, 24.58 mmol, 3 eq) 및 포타슘카보네이트(3.4 g, 24.58 mmol, 3 eq)를 적가하여 85 °C에서 교반하였다. 반응 종결 후, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 Na 2SO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 목표 화합물 (화학식 6-2, 6- 3)을 각각 수득하였다.6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (Formula 6-1 , 2 g, 8.19 mmol) was added to DMF (20 After dissolving in ml), 2-bromopropane (2.3 ml, 24.58 mmol, 3 eq) and potassium carbonate (3.4 g, 24.58 mmol, 3 eq) were added dropwise and stirred at 85 ° C. After completion of the reaction, extraction was performed with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 70: 30) target compound (formula 6-2, 6-3) to afford respectively.
제조예 7: 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)벤조[d]티아졸 (화학식 7-2의 화합물)의 제조 Preparation Example 7: 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] thiazole (compound of formula 7-2 )
Figure PCTKR2019011876-appb-img-000063
Figure PCTKR2019011876-appb-img-000063
5-브로모-2-메틸벤조[d]티아졸 (화학식 7-1, 0.5 g, 2.19 mmol), 포타슘 아세테이트 (0.753 g, 7.67 mmol, 3.5 eq), Pd(dppf)Cl 2-CH 2Cl 2 (0.179 g, 0.22 mmol, 0.1 eq), B 2Pin 2 (0.612 g, 2.41 mmol, 1.1 eq)를 1,4-디옥산 (15 ml)에 용해시켰다. 100 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 목표 화합물 (화학식 7-2)을 수득하였다.5-bromo-2-methylbenzo [d] thiazole (Formula 7-1 , 0.5 g, 2.19 mmol), potassium acetate (0.753 g, 7.67 mmol, 3.5 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.179 g, 0.22 mmol, 0.1 eq), B 2 Pin 2 (0.612 g, 2.41 mmol, 1.1 eq) was dissolved in 1,4-dioxane (15 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 100 ° C. After completion of the reaction, extraction was performed with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain the target compound (Formula 7-2 ).
제조예 8: 시클로프로필(3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)메탄온 (화학식 8-2의 화합물)의 제조 Preparation 8: Preparation of cyclopropyl (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (compound of formula 8-2)
Figure PCTKR2019011876-appb-img-000064
Figure PCTKR2019011876-appb-img-000064
(3-브로모페닐)(시클로프로필)메탄온 (화학식 8-1, 0.5 g, 2.22 mmol), 포타슘 아세테이트 (0.654 g, 6.66 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (91 mg, 0.11 mmol, 0.05 eq) 및 B 2Pin 2 (0.621 g, 2.44 mmol, 1.1 eq)를 1,4-디옥산 (10 ml)에 용해시켰다. 80 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하여, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 90:10)로 분리 및 정제하여 목표 화합물 (화학식 8-2)을 수득하였다.(3-Bromophenyl) (cyclopropyl) methanone (Formula 8-1 , 0.5 g, 2.22 mmol), potassium acetate (0.654 g, 6.66 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (91 mg, 0.11 mmol, 0.05 eq) and B 2 Pin 2 (0.621 g, 2.44 mmol, 1.1 eq) were dissolved in 1,4-dioxane (10 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 80 ° C. After completion of the reaction, extraction was performed with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 90:10) to obtain the target compound (Formula 8-2 ).
제조예 9: 2-(3',4'-디메톡시비페닐-3-일)-4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 (화학식 9-3의 화합물)의 제조 Preparation Example 9: 2- (3 ', 4'-dimethoxybiphenyl-3-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Formula 9-3 Compound)
단계 1: 3'-브로모-3,4-디메톡시-1,1'-비페닐 (화학식 Step 1: 3'-bromo-3,4-dimethoxy-1,1'-biphenyl (Formula 9-29-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000065
Figure PCTKR2019011876-appb-img-000065
1-브로모-3-아이오도벤젠 (화학식 9-1, 1 g, 3.53 mmol)을 톨루엔 (10 ml)에 녹인 후, 에탄올 (3 ml)에 녹인 (3,4-디메톡시페닐)보론산 (1.29 g, 7.07 mmol, 2 eq)과 2M Na 2CO 3 수용액 (3 eq)을 적가하여 10분간 질소기류 하에서 교반하였다. 이후, Pd(dppf)Cl 2-CH 2Cl 2 (144 g, 0.18 mmol, 0.05 eq)를 용해시켰다. 반응 혼합물을 12시간 동안 환류교반하였다. 반응 종결 후, 에틸아세테이트로 추출하였다. 유기층을 브라인으로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 90:10)로 분리 및 정제하여 목표 화합물 (화학식 9-2)을 수득하였다.1-bromo-3-iodobenzene (Formula 9-1 , 1 g, 3.53 mmol) was dissolved in toluene (10 ml), followed by (3,4-dimethoxyphenyl) boronic acid in ethanol (3 ml). (1.29 g, 7.07 mmol, 2 eq) and 2M Na 2 CO 3 aqueous solution (3 eq) were added dropwise and stirred under a nitrogen stream for 10 minutes. Then, Pd (dppf) Cl 2 -CH 2 Cl 2 (144 g, 0.18 mmol, 0.05 eq) was dissolved. The reaction mixture was stirred at reflux for 12 hours. After completion of the reaction, extraction was performed with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 90:10) to obtain the target compound (Formula 9-2 ).
단계 2: 2-(3',4'-디메톡시비페닐-3-일)-4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 (화학식 Step 2: 2- (3 ', 4'-dimethoxybiphenyl-3-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Formula 9-39-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000066
Figure PCTKR2019011876-appb-img-000066
단계 1에서 합성된 3'-브로모-3,4-디메톡시-1,1'-비페닐 (화학식 9-2, 0.538 g, 1.84 mmol), 포타슘 아세테이트 (0.54 g, 5.51 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (15 mg, 0.018 mmol, 0.01 eq), B 2Pin 2 (0.699 g, 2.75 mmol, 1.5 eq)를 DMSO (10 ml)에 용해시켰다. 80 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 목표 화합물 (화학식 9-3)을 수득하였다.3'-bromo-3,4-dimethoxy-1,1'-biphenyl synthesized in step 1 (Formula 9-2 , 0.538 g, 1.84 mmol), potassium acetate (0.54 g, 5.51 mmol, 3 eq) , Pd (dppf) Cl 2 -CH 2 Cl 2 (15 mg, 0.018 mmol, 0.01 eq), B 2 Pin 2 (0.699 g, 2.75 mmol, 1.5 eq) was dissolved in DMSO (10 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 80 ° C. After completion of the reaction, extraction was performed with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a target compound (Formula 9-3 ).
제조예 10: 1-시클로프로필-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)피페리딘 (화학식 10-3의 화합물)의 제조 Preparation Example 10: 1-cyclopropyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine (Formula 10- Preparation of 3)
단계 1: 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)피페리딘 (화학식 10-2 의 화합물)의 제조
Figure PCTKR2019011876-appb-img-000067
 Step 1: Preparation of 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine (compound of formula 10-2 )
Figure PCTKR2019011876-appb-img-000067
tert-부틸 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)피페리 딘-1-카복실레이트 (화학식 10-1, 2 g, 5.16 mmol)를 디클로로메탄 (20 ml)에 녹인 후, 트리플로오로아세트산 (TFA)(7.96 ml, 103 mmol, 20 eq)을 상온에서 적가하고, 동일 온도에서 2시간 동안 교반하였다. H 2O로 반응 혼합물의 반응을 종결하고, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 유기층을 감압하여 용매를 제거하여 목표 화합물 (화학식 10-2)을 수득하였다. tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate (Formula 10-1 , 2 g, 5.16 mmol) was dissolved in dichloromethane (20 ml), and trifluoroacetic acid (TFA) (7.96 ml, 103 mmol, 20 eq) was added dropwise at room temperature and stirred at the same temperature for 2 hours. The reaction of the reaction mixture was terminated with H 2 O, and extracted with ethyl acetate. The organic layer was washed with H 2 O, dried over anhydrous MgSO 4 , and the organic layer was reduced in pressure to remove the solvent to obtain a target compound (Formula 10-2 ).
단계 2: 1-시클로프로필-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)피페리딘 (화학식 Step 2: 1-cyclopropyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine (formula 10-310-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000068
Figure PCTKR2019011876-appb-img-000068
단계 1에서 합성된 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)피페리딘 (화학식 10-2, 953 mg, 3.28 mmol)을 테트라하이드로퓨란 (THF) (20 ml) 및 메탄올 (20 ml)에 녹인 후, (1-에톡시시클로프로폭시)트리메틸실란 (3.3 ml, 16.42 mmol, 5 eq) 및 아세트산 (0.376 ml, 26.2 mmol, 3 eq)을 실온에서 적가하였다. 반응 혼합물을 10분간 교반한 후, 소듐시아노보로하이드리드 (0.516 g, 8.21 mmol, 2.5 eq)를 적가하고 교반하였다. NaHCO 3 포화 수용액으로 반응 종결 후, 에틸아세테이트로 추출하였다. 무수 MgSO 4로 건조한 다음, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 고체 화합물 (화학식 10-3)을 수득하였다.4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine synthesized in Step 1 (Formula 10-2 , 953 mg , 3.28 mmol) in tetrahydrofuran (THF) (20 ml) and methanol (20 ml), followed by (1-ethoxycyclopropoxy) trimethylsilane (3.3 ml, 16.42 mmol, 5 eq) and acetic acid (0.376). ml, 26.2 mmol, 3 eq) was added dropwise at room temperature. After the reaction mixture was stirred for 10 minutes, sodium cyanoborohydride (0.516 g, 8.21 mmol, 2.5 eq) was added dropwise and stirred. After completion of the reaction with saturated aqueous NaHCO 3 solution, extraction was performed with ethyl acetate. After drying over anhydrous MgSO 4 , the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a solid compound (Formula 10-3 ).
제조예 11: 포타슘 트리플루오로(2-(4-(트리플루오로메톡시)페녹시)피리미딘-5-일)보레이트 (화학식 11-4의 화합물)의 제조 Preparation Example 11: Preparation of potassium trifluoro (2- (4- (trifluoromethoxy) phenoxy) pyrimidin-5-yl) borate (compound of formula 11-4)
단계 1: 5-브로모-2-(4-(트리플루오로메톡시)페녹시)피리미딘 (화학식 Step 1: 5-bromo-2- (4- (trifluoromethoxy) phenoxy) pyrimidine (Formula 11-311-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000069
Figure PCTKR2019011876-appb-img-000069
5-브로모-2-아이오도피리미딘(화학식 11-1, 0.5 g, 1.76 mmol)을 DMSO (23 ml)에 녹인 후, 4-(트리플루오로메톡시)페놀 (화학식 11-2, 0.341 ml, 2.63 mmol, 1.5 eq) 및 K 2CO 3 (485 mg, 3.51 mmol, 2 eq)을 상온에서 적가하였다. 반응 혼합물을 120 °C에서 1시간 동안 교반한 후, 상온까지 냉각하였다. H 2O로 반응 혼합물의 반응을 종결하고, 에틸아세테이트로 추출하였다. 유기층을 브라인으로 세정한 다음, 무수 MgSO 4로 건조하고, 유기층을 감압하여 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 90:10)로 분리 및 정제하여 목표 화합물 (화학식 11-3)을 수득하였다.5-Bromo-2-iodopyrimidine (Formula 11-1 , 0.5 g, 1.76 mmol) was dissolved in DMSO (23 ml), followed by 4- (trifluoromethoxy) phenol (Formula 11-2 , 0.341 ml). , 2.63 mmol, 1.5 eq) and K 2 CO 3 (485 mg, 3.51 mmol, 2 eq) were added dropwise at room temperature. The reaction mixture was stirred at 120 ° C for 1 hour, and then cooled to room temperature. The reaction of the reaction mixture was terminated with H 2 O, and extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous MgSO 4 , and the organic layer was reduced in pressure to remove the solvent. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 90:10) to obtain the target compound (Formula 11-3 ).
단계 2: 포타슘 트리플루오로(2-(4-(트리플루오로메톡시)페녹시)피리미딘-5-일)보레이트 (화학식 Step 2: Potassium trifluoro (2- (4- (trifluoromethoxy) phenoxy) pyrimidin-5-yl) borate (Formula 11-411-4 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000070
Figure PCTKR2019011876-appb-img-000070
단계 1에서 합성된 5-브로모-2-(4-(트리플루오로메톡시)페녹시)피리미딘 (화학식 11-3, 386 mg, 1.15 mmol)을 THF (10 ml)에 녹인 후, -78 °C로 냉각시키고, 1.6M n-부틸리튬 (1.30 ml, 2.07 mmol, 1.8 eq)을 적가하였다. 이후, 동일 온도에서 1시간 동안 교반한 후, 트리이소프로필보레이트 (0.535 ml, 2.30 mmol, 2 eq)를 동일 온도에서 적가하였다. 반응 혼합물을 1시간 동안 동일 온도에서 교반한 후, 0 °C까지 온도를 올리고 4.5M 포타슘 수소디플루오라이드 수용액 (0.768 ml, 3.46 mmol, 3 eq)을 적가하였다. 반응 혼합물을 상온에서 1시간 동안 교반하였다. 반응 종결 후, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 메탄올에 녹인 후 여과하고, 여액을 감압하여 목표 화합물 (화학식 11-4)을 수득하였다.5-Bromo-2- (4- (trifluoromethoxy) phenoxy) pyrimidine (Formula 11-3 , 386 mg, 1.15 mmol) synthesized in Step 1 was dissolved in THF (10 ml), and -78 Cooled to ° C, and 1.6M n-butyllithium (1.30 ml, 2.07 mmol, 1.8 eq) was added dropwise. Then, after stirring at the same temperature for 1 hour, triisopropyl borate (0.535 ml, 2.30 mmol, 2 eq) was added dropwise at the same temperature. After the reaction mixture was stirred at the same temperature for 1 hour, the temperature was raised to 0 ° C and a 4.5M aqueous potassium hydrogen difluoride solution (0.768 ml, 3.46 mmol, 3 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, the reaction mixture was dissolved in methanol, filtered, and the filtrate was reduced in pressure to obtain a target compound (Formula 11-4 ).
제조예 12: 포타슘 트리플루오로(2-페녹시피리미딘-5-일)보레이트 (화학식 12-3의 화합물)의 제조Preparation 12: Preparation of potassium trifluoro (2-phenoxypyrimidin-5-yl) borate (compound of formula 12-3)
단계 1: 5-브로모-2-페녹시피리미딘 (화학식 Step 1: 5-bromo-2-phenoxypyrimidine (Formula 12-212-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000071
Figure PCTKR2019011876-appb-img-000071
5-브로모-2-아이오도피리미딘 (화학식 4-1, 0.5 g, 1.76 mmol)을 DMSO (25 ml)에 녹인 후, 페놀 (화학식 12-1, 0.232 ml, 2.63 mmol, 1.5 eq) 및 K 2CO 3 (485 mg, 3.51 mmol, 2 eq)을 상온에서 적가하였다. 반응 혼합물을 120 °C에서 1시간 동안 교반한 후 상온까지 냉각하였다. H 2O로 반응 혼합물의 반응을 종결하고 에틸아세테이트로 추출하였다. 유기층을 브라인으로 세정한 다음, 무수 MgSO 4로 건조하고, 유기층을 감압하여 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 90:10)로 분리 및 정제하여 목표 화합물 (화학식 12-2)을 수득하였다.5-Bromo-2-iodopyrimidine (Formula 4-1 , 0.5 g, 1.76 mmol) was dissolved in DMSO (25 ml), followed by phenol (Formula 12-1 , 0.232 ml, 2.63 mmol, 1.5 eq) and K 2 CO 3 (485 mg, 3.51 mmol, 2 eq) was added dropwise at room temperature. The reaction mixture was stirred at 120 ° C for 1 hour and then cooled to room temperature. The reaction of the reaction mixture was terminated with H 2 O and extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous MgSO 4 , and the organic layer was reduced in pressure to remove the solvent. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 90:10) to obtain the target compound (Formula 12-2 ).
단계 2: 포타슘 트리플루오로(2-페녹시피리미딘-5-일)보레이트 (화학식 Step 2: Potassium trifluoro (2-phenoxypyrimidin-5-yl) borate (Formula 12-312-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000072
Figure PCTKR2019011876-appb-img-000072
단계 1에서 합성된 5-브로모-2-페녹시피리미딘 (화학식 12-2, 412 mg, 1.64 mmol)을 THF (10 ml)에 녹인 후, -78 °C로 냉각시키고, 1.6M n-부틸 리튬 (1.85 ml, 2.95 mmol, 1.8 eq)을 적가하였다. 이후, 동일 온도에서 1시간 동안 교반한 후, 트리이소프로필보레이트 (0.762 ml, 3.28 mmol, 2 eq)를 동일 온도에서 적가하였다. 반응 혼합물을 1시간 동안 동일 온도에서 교반한 후, 0 °C까지 온도를 올리고 4.5M 포타슘수소디플루오라이드 수용액 (1.1 ml, 4.92 mmol, 3 eq)을 적가하였다. 반응 혼합물을 상온에서 1시간 동안 교반하였다. 반응 종결 후, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 메탄올에 녹인 후 여과하고, 여액을 감압하여 목표 화합물 (화학식 12-3)을 수득하였다.The 5-bromo-2-phenoxypyrimidine synthesized in Step 1 (Formula 12-2 , 412 mg, 1.64 mmol) was dissolved in THF (10 ml), cooled to -78 ° C, and 1.6M n- Butyl lithium (1.85 ml, 2.95 mmol, 1.8 eq) was added dropwise. Then, after stirring at the same temperature for 1 hour, triisopropyl borate (0.762 ml, 3.28 mmol, 2 eq) was added dropwise at the same temperature. After the reaction mixture was stirred at the same temperature for 1 hour, the temperature was raised to 0 ° C and a 4.5M aqueous potassium hydrogen difluoride solution (1.1 ml, 4.92 mmol, 3 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, the reaction mixture was dissolved in methanol, filtered, and the filtrate was reduced in pressure to obtain a target compound (Formula 12-3 ).
제조예 13: 포타슘 트리플루오로(2-(트리플루오로메틸)피리딘-3-일)보레이트 (화학식 13-2의 화합물)의 제조Preparation 13: Preparation of potassium trifluoro (2- (trifluoromethyl) pyridin-3-yl) borate (compound of formula 13-2)
Figure PCTKR2019011876-appb-img-000073
Figure PCTKR2019011876-appb-img-000073
제조예 12의 단계 2에 기재된 방법과 동일한 방법을 사용하되, 5-브로모-2-페녹시피리미딘 (화학식 12-2) 대신 3-브로모-2-(트리플루오로메틸)피리딘 (화학식 13-1)을 사용하여 목표 화합물 (화학식 13-2)을 수득하였다.The same method as described in Step 2 of Preparation Example 12 was used, but 3-bromo-2- (trifluoromethyl) pyridine (Formula 12-2 ) instead of 5-bromo-2-phenoxypyrimidine (Formula 12-2 ) 13-1 ) to obtain the target compound (Formula 13-2 ).
제조예 14: 포타슘 트리플루오로(퀴놀린-2-일)보레이트 (화학식 14-2의 화합물)의 제조Preparation 14: Preparation of potassium trifluoro (quinolin-2-yl) borate (compound of formula 14-2)
Figure PCTKR2019011876-appb-img-000074
Figure PCTKR2019011876-appb-img-000074
2-브로모퀴놀린 (화학식 14-1, 1 g, 4.81 mmol)을 THF (20 ml)에 녹인 후, -78 °C로 냉각시키고, 1.6M n-부틸리튬 (5.41 ml, 8.65 mmol, 1.8 eq)을 천천히 적가하였다. 이후, 동일 온도에서 1시간 동안 교반한 후, 트리이소프로필보레이트 (2.23 ml, 9.61 mmol, 2 eq)를 동일 온도에서 적가하였다. 반응 혼합물을 1시간 동안 동일 온도에서 교반한 후, 0 °C까지 온도를 올리고 1M 포타슘수소디플루오라이드 수용액 (14.42 ml, 14.42 mmol, 3 eq)을 적가하였다. 반응 혼합물을 상온에서 1시간 동안 교반하였다. 반응 종결 후, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 메탄올에 녹인 후 여과하고, 여액을 감압하여 목표 화합물 (화학식 14-2)을 수득하였다.2-Bromoquinoline (Formula 14-1 , 1 g, 4.81 mmol) was dissolved in THF (20 ml), cooled to -78 ° C, and 1.6M n-butyllithium (5.41 ml, 8.65 mmol, 1.8 eq) ) Was slowly added dropwise. Then, after stirring at the same temperature for 1 hour, triisopropyl borate (2.23 ml, 9.61 mmol, 2 eq) was added dropwise at the same temperature. After the reaction mixture was stirred at the same temperature for 1 hour, the temperature was raised to 0 ° C and 1M aqueous potassium hydrogen difluoride solution (14.42 ml, 14.42 mmol, 3 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, the reaction mixture was dissolved in methanol, filtered, and the filtrate was reduced in pressure to obtain a target compound (Formula 14-2 ).
제조예 15: 포타슘 트리플루오로(5-메톡시피리딘-2-일)보레이트 (화학식 15-2의 화합물)의 제조Preparation 15: Preparation of potassium trifluoro (5-methoxypyridin-2-yl) borate (compound of formula 15-2)
Figure PCTKR2019011876-appb-img-000075
Figure PCTKR2019011876-appb-img-000075
제조예 14에 기재된 방법과 동일한 방법을 사용하되, 2-브로모퀴놀린 (화학식 14-1)대신 2-브로모-5-메톡시피리딘 (화학식 15-1)을 사용하여 목표 화합물 (화학식 15-2)을 수득하였다.Using the same method as described in Production Example 14, 2-bromoquinoline (Formula 14-1 ) instead of 2-bromo-5-methoxypyridine (Formula 15-1 ) using the target compound (Formula 15- 2 ) was obtained.
제조예 16: 2-메톡시-6-(트리부틸스태닐)피라진 (화학식 16-2의 화합물)의 제조Preparation Example 16: Preparation of 2-methoxy-6- (tributylstannyl) pyrazine (compound of formula 16-2)
Figure PCTKR2019011876-appb-img-000076
Figure PCTKR2019011876-appb-img-000076
2-브로모-6-메톡시피라진 (화학식 16-1, 50 mg, 0.27 mmol) 및 Pd(Ph 3) 4 (15 mg, 0.013 mmol, 0.05 eq)을 톨루엔 (1 ml)에 용해시킨 후, 헥사부틸디티안산 (153 mg, 0.27 mmol, 1.0 eq)을 적가하여 110 °C에서 8시간 동안 교반시켰다. 반응 혼합물을 실온까지 냉각시켜 셀라이트로 여과한 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 목표 화합물 (화학식 16-2)을 수득하였다.After 2-bromo-6-methoxypyrazine (Formula 16-1 , 50 mg, 0.27 mmol) and Pd (Ph 3 ) 4 (15 mg, 0.013 mmol, 0.05 eq) were dissolved in toluene (1 ml), Hexabutylditian acid (153 mg, 0.27 mmol, 1.0 eq) was added dropwise and stirred at 110 ° C for 8 hours. The reaction mixture was cooled to room temperature, filtered through celite, and then extracted with dichloromethane. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 16-2 ).
제조예 17: N-(2-(2-플루오로페닐)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (화학식 17-10의 화합물)의 제조Preparation 17: Preparation of N- (2- (2-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (compound of formula 17-10)
단계 1: 5-클로로-7-니트로퀴놀린-8-올 (화학식 Step 1: 5-chloro-7-nitroquinoline-8-ol (Formula 17-217-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000077
Figure PCTKR2019011876-appb-img-000077
5-클로로퀴놀린-8-올 (화학식 17-1, 20g, 111mmol)을 황산 (100 ml)에 용해시킨 혼합물을 0 °C로 냉각시킨 후, 70 % 질산 (8.53 ml, 134 mmol, 1.2 eq)을 천천히 내부온도가 2 °C 이상이 되지않도록 적가하였다. 동일 온도에서 1 시간 동안 교반한 후, 얼음물을 제거하여 실온까지 온도를 올려 4 시간 더 교반하였다. 반응종결 후, 얼음물 적가하고 4시간 동안 교반하였다. 생성된 노란색 고체를 여과하고 물로 세정한 다음, 건조하여 목표 화합물 (화학식 17-2)을 수득하였다.After the mixture of 5-chloroquinoline-8-ol (Formula 17-1 , 20g, 111mmol) dissolved in sulfuric acid (100 ml) was cooled to 0 ° C, 70% nitric acid (8.53 ml, 134 mmol, 1.2 eq) Was slowly added dropwise so that the internal temperature did not exceed 2 ° C. After stirring at the same temperature for 1 hour, the ice water was removed and the temperature was raised to room temperature and stirred for 4 hours. After completion of the reaction, ice water was added dropwise and stirred for 4 hours. The resulting yellow solid was filtered, washed with water, and then dried to obtain the target compound (Formula 17-2 ).
단계 2: 7-아미노퀴놀린-8-올 (화학식 Step 2: 7-aminoquinoline-8-ol (Formula 17-317-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000078
Figure PCTKR2019011876-appb-img-000078
단계1에서 합성된 5-클로로-7-니트로퀴놀린-8-올 (화학식 17-2, 15 g, 68 mmol)을 메탄올 (400 ml)에 용해시킨 후, Pd/C (0.1 eq)를 적가하고 수소풍선기류 하에 상온에서 3 일간 교반시켰다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 감압 하에서 용매를 건조시켜 고체 화합물 (화학식 17-3)을 수득하였다.The 5-chloro-7-nitroquinoline-8-ol synthesized in Step 1 (Formula 17-2 , 15 g, 68 mmol) was dissolved in methanol (400 ml), and Pd / C (0.1 eq) was added dropwise. The mixture was stirred for 3 days at room temperature under a hydrogen balloon. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was dried under reduced pressure to obtain a solid compound (Formula 17-3 ).
단계 3: 7-아세트아미도퀴놀린-8-일 아세테이트 (화학식 Step 3: 7-acetamidoquinolin-8-yl acetate (Formula 17-417-4 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000079
Figure PCTKR2019011876-appb-img-000079
단계 2에서 합성된 7-아미노퀴놀린-8-올 (화학식 17-3, 11 g, 68.7 mmol, 1 eq)을 THF (300 ml)에 용해시킨 후, N,N-디이소프로필에틸아민 (48 ml, 275 mmol, 4 eq)을 적가하고, 반응 혼합물을 0 °C 로 냉각시켰다. 그 후, THF (43 ml)에 용해시킨 아세틸클로라이드 (12 ml, 172 mmol, 2.5 eq)를 동일 온도에서 천천히 적가하였다. 반응 혼합물을 실온에서 8시간 동안 교반하고, 감압 하에서 용매를 건조한 다음, 디클로로메탄에 녹인 후 물로 세정하였다. 유기층을 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 목표 화합물 (화학식 17-4)을 수득하였다.Synthesized in step 2 7-aminoquinoline-8-ol (Formula 17-3 , 11 g, 68.7 mmol, 1 eq) was dissolved in THF (300 ml), followed by N, N-diisopropylethylamine (48 ml, 275 mmol, 4 eq) was added dropwise and the reaction mixture was cooled to 0 ° C. Then, acetyl chloride (12 ml, 172 mmol, 2.5 eq) dissolved in THF (43 ml) was slowly added dropwise at the same temperature. The reaction mixture was stirred at room temperature for 8 hours, the solvent was dried under reduced pressure, dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to obtain the target compound (Formula 17-4 ).
단계 4: N-(8-하이드록시퀴놀린-7-일)아세트아마이드 (화학식 Step 4: N- (8-hydroxyquinolin-7-yl) acetamide (Formula 17-517-5 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000080
Figure PCTKR2019011876-appb-img-000080
단계 3에서 합성된 7-아세트아미도퀴놀린-8-일 아세테이트 (화학식 17-4, 15 g, 62 mmol)를 메탄올 (400 ml)에 용해시킨 후, H 2O (40 ml)을 적가하여 1시간 동안 환류교반하였다. 반응 종결 후, 반응 혼합물을 감압 하에서 건조하여 목표 화합물 (화학식 17-5)을 수득하였다.The 7-acetamidoquinolin-8-yl acetate synthesized in Step 3 (Formula 17-4 , 15 g, 62 mmol) was dissolved in methanol (400 ml), and H 2 O (40 ml) was added dropwise to 1 The mixture was refluxed for an hour. After completion of the reaction, the reaction mixture was dried under reduced pressure to obtain the target compound (Formula 17-5 ).
단계 5: N-(8-(벤질옥시)퀴놀린-7-일)아세트아미드 (화학식 Step 5: N- (8- (benzyloxy) quinolin-7-yl) acetamide (Formula 17-617-6 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000081
Figure PCTKR2019011876-appb-img-000081
단계 4에서 합성된 N-(8-하이드록시퀴놀린-7-일)아세트아미드 (화학식 17-5, 14 g, 68 mmol)를 DMF (200 ml)에 용해 시킨 후, 포타슘카보네이트 (14 g, 102 mmol, 1.5 eq), 벤질브로마이드 (12 ml, 102 mmol, 1.5 eq)를 적가하고, 50 °C에서 8시간 동안 교반하였다. 반응 종결 후, 디클로로메탄에 녹여 셀라이트로 여과하고, 감압 하에서 용매를 건조시켰다. 그 후, MPLC (헥산/에틸아세테이트)로 분리 및 정제하여 목표 화합물 (화학식 17-6)을 수득하였다.N- (8-hydroxyquinolin-7-yl) acetamide synthesized in step 4 (Formula 17-5 , 14 g, 68 mmol) was dissolved in DMF (200 ml), and then potassium carbonate (14 g, 102) mmol, 1.5 eq), benzyl bromide (12 ml, 102 mmol, 1.5 eq) was added dropwise and stirred at 50 ° C for 8 hours. After completion of the reaction, it was dissolved in dichloromethane, filtered through celite, and the solvent was dried under reduced pressure. Then, it was separated and purified by MPLC (hexane / ethyl acetate) to obtain the target compound (Formula 17-6 ).
단계 6: 7-아세트아미도-8-(벤질옥시)퀴놀린 1-옥사이드 (화학식 Step 6: 7-acetamido-8- (benzyloxy) quinoline 1-oxide (Formula 17-717-7 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000082
Figure PCTKR2019011876-appb-img-000082
단계 5에서 합성된 N-(8 -(벤질옥시)퀴놀린-7-일)아세트아미드 (화학식 17-6, 14 g, 47 mmol)를 1,2-디클로로에탄 (140 ml)에 용해 시킨 후, 메타-클로로퍼옥시벤조산 (mCPBA)(16 g, 95 mmol, 2 eq)을 적가하고, 실온에서 48시간 동안 교반하였다. 반응 종결 후, 셀라이트로 여과하고, 감압 하에서 용매를 건조시켰다. 이후, MPLC(디클로로메탄/메탄올)로 분리 및 정제하여 목표 화합물 (화학식 17-7)을 수득하였다.Was dissolved in a - ((benzyloxy) quinolin-7-one 8) acetamide (Formula 17-6, 14 g, 47 mmol) in 1,2-dichloroethane (140 ml), the synthesis in step 5, N- Meta -chloroperoxybenzoic acid (mCPBA) (16 g, 95 mmol, 2 eq) was added dropwise and stirred at room temperature for 48 hours. After completion of the reaction, it was filtered through celite, and the solvent was dried under reduced pressure. Then, it was separated and purified by MPLC (dichloromethane / methanol) to obtain a target compound (Formula 17-7 ).
단계 7: N-(8-(벤질옥시)-2-클로로 퀴놀린-7-일)아세트아미드 (화학식 Step 7: N- (8- (benzyloxy) -2-chloro quinoline-7-yl) acetamide (Formula 17-817-8 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000083
Figure PCTKR2019011876-appb-img-000083
단계 6에서 합성된 7-아세트아미도-8-(벤질옥시)퀴놀린 1-옥사이드 (화학식 17-7, 13 g, 42 mmol)를 클로로포름 (300 ml)에 용해시킨 후, 클로로포름 (3 ml)에 녹아있는 POCl 3 (4.7 ml, 50 mmol, 1.2 eq)를 적가하여 15분간 교반하였다. 반응 혼합물을 2시간 동안 환류교반하고 냉각시킨 후, 얼음을 투입하고 pH가 12정도가 될 때까지 6 N NaOH을 천천히 적가하였다. 디클로로메탄으로 추출하고 물로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 목표 화합물 (화학식 17-8)을 수득하였다.7-acetamido-8- (benzyloxy) quinoline 1-oxide (Formula 17-7 , 13 g, 42 mmol) synthesized in step 6 was dissolved in chloroform (300 ml), and then chloroform (3 ml). The dissolved POCl 3 (4.7 ml, 50 mmol, 1.2 eq) was added dropwise and stirred for 15 minutes. The reaction mixture was stirred at reflux for 2 hours and cooled, then ice was added and 6 N NaOH was slowly added dropwise until the pH reached 12. Extracted with dichloromethane, washed with water, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to obtain the target compound (Formula 17-8 ).
단계 8: N-(2-클로로-8-하이드록시퀴놀린-7-일)아세트아미드 (화학식 Step 8: N- (2-Chloro-8-hydroxyquinolin-7-yl) acetamide (Formula 17-917-9 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000084
Figure PCTKR2019011876-appb-img-000084
단계 7에서 합성된 N-(8-(벤질옥시)-2-클로로 퀴놀린-7-일)아세트아미드 (화학식 17-8, 6 g, 17 mmol)를 디클로로메탄 (100 ml)에 용해시킨 후, 2M 트리클로로보란 디메틸설파이드 (85 ml, 170 mmol, 10 eq)를 적가하고 실온에서 8시간 동안 교반하였다. NaHCO 3 포화 수용액으로 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 물로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트)로 분리 및 정제하여 목표 화합물(화학식 17-9)을 수득하였다.N- (8- (benzyloxy) -2-chloro quinolin-7-yl) acetamide synthesized in step 7 (Formula 17-8 , 6 g, 17 mmol) was dissolved in dichloromethane (100 ml), 2M trichloroborane dimethylsulfide (85 ml, 170 mmol, 10 eq) was added dropwise and stirred at room temperature for 8 hours. After completion of the reaction with saturated aqueous NaHCO 3 solution, extraction was performed with dichloromethane. The organic layer was washed with water, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate) to obtain a target compound (Formula 17-9 ).
단계 9: N-(2-클로로-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (화학식 Step 9: N- (2-Chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-1017-10 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000085
Figure PCTKR2019011876-appb-img-000085
단계 8에서 합성된 N-(2-클로로-8-하이드록시퀴놀린-7-일)아세트아미드 (화학식 17-9, 3 g, 13 mmol)를 아세톤 (200 ml)에 용해시킨 후, NaH 2PO 4 완충액 (0.3M, 200 ml)에 녹인 프레미염 (포타슘 니트로소디술포네이트)(5.57 g, 21 mmol, 1.6 eq)을 적가하고 실온에서 8시간 동안 교반하였다. 감압 하에서 아세톤을 제거한 후, 디클로로메탄으로 추출하였다. 유기층을 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 에틸아세테이트와 헥산을 이용하여 솔리디파이로 정제하여 고체 화합물 (화학식 17-10)을 수득하였다.N- (2-chloro-8-hydroxyquinolin-7-yl) acetamide synthesized in step 8 (Formula 17-9 , 3 g, 13 mmol) was dissolved in acetone (200 ml), and then NaH 2 PO Premi salt (potassium nitrosodisulfonate) (5.57 g, 21 mmol, 1.6 eq) dissolved in 4 buffers (0.3M, 200 ml) was added dropwise and stirred at room temperature for 8 hours. After removing acetone under reduced pressure, it was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Subsequently, it was purified by solidify using ethyl acetate and hexane to obtain a solid compound (Formula 17-10 ).
제조예 18: 4,4,5,5-테트라메틸-2-(4-(테트라히드로-2H-피란-4-일옥시)페닐)-1,3,2-디옥사보롤란 (화학식 18-3의 화합물)의 제조Preparation Example 18: 4,4,5,5-tetramethyl-2- (4- (tetrahydro-2H-pyran-4-yloxy) phenyl) -1,3,2-dioxaborolane (Formula 18- Preparation of 3)
단계 1: 4-(4-브로모페녹시)테트라하이드로-2H-피란 (화학식 Step 1: 4- (4-Bromophenoxy) tetrahydro-2H-pyran (Formula 18-218-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000086
Figure PCTKR2019011876-appb-img-000086
4-브로모페놀 (화학식 18-1, 500 mg, 2.89 mmol), 4-하이드록시테트라히드로피란 (0.4 ml, 4.34 mmol, 1.5 eq) 및 트리페닐포스핀(PPh 3) (1.1 g, 4.34 mmol, 1.5 eq)을 톨루엔 (8 ml)에 용해시킨 후, 디에틸 아조디카복실레이트 (DEAD)(1.4 ml, 3.18 mmol, 1.1 eq)를 0 °C에서 적가하였다. 반응 혼합물을 상온에서 45분간 교반시켰다. 반응 종결 후, 감압 하에서 용매를 제거하고 디에틸에테르에 녹인 후, 생성된 고체를 여과하여 제거하였다. 여액에 에틸아세테이트를 넣고 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 목표 화합물 (화학식 18-2)을 수득하였다.4-Bromophenol (Formula 18-1 , 500 mg, 2.89 mmol), 4-hydroxytetrahydropyran (0.4 ml, 4.34 mmol, 1.5 eq) and triphenylphosphine (PPh 3 ) (1.1 g, 4.34 mmol) , 1.5 eq) was dissolved in toluene (8 ml), then diethyl azodicarboxylate (DEAD) (1.4 ml, 3.18 mmol, 1.1 eq) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 45 minutes. After completion of the reaction, the solvent was removed under reduced pressure, dissolved in diethyl ether, and the resulting solid was filtered off. Ethyl acetate was added to the filtrate, washed with H 2 O, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 18-2 ).
단계 2: 4,4,5,5-테트라메틸-2-(4-(테트라히드로-2H-피란-4-일옥시)페닐)-1,3,2-디옥사보롤란 (화학식 Step 2: 4,4,5,5-tetramethyl-2- (4- (tetrahydro-2H-pyran-4-yloxy) phenyl) -1,3,2-dioxaborolane (Formula 18-318-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000087
Figure PCTKR2019011876-appb-img-000087
단계 1에서 합성된 4-(4-브로모페녹시)테트라하이드로-2H-피란 (화학식 18-2, 638 mg, 2.48 mmol), 포타슘 아세테이트 (731 mg, 7.44 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (203 mg, 0.25 mmol, 0.1 eq) 및 B 2Pin 2 (756 mg, 2.98 mmol, 1.2 eq)를 1,4-디옥산 (15 ml)에 용해시켰다. 100 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트)로 분리 및 정제하여 목표 화합물 (화학식 18-3)을 수득하였다.4- (4-Bromophenoxy) tetrahydro-2H-pyran synthesized in Step 1 (Formula 18-2 , 638 mg, 2.48 mmol), potassium acetate (731 mg, 7.44 mmol, 3 eq), Pd (dppf ) Cl 2 -CH 2 Cl 2 (203 mg, 0.25 mmol, 0.1 eq) and B 2 Pin 2 (756 mg, 2.98 mmol, 1.2 eq) were dissolved in 1,4-dioxane (15 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 100 ° C. After completion of the reaction, the reaction mixture was filtered through celite, and extracted with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate) to obtain the target compound (Formula 18-3 ).
제조예 19: 1-이소프로필-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피페리딘 (화학식 19-4의 화합물)의 제조Preparation 19: 1-isopropyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine (Formula 19 -4 compound)
단계 1: 합성된 1-(4-(4-브로모페녹시)피페리딘-1-일)-2,2-디메틸프로판-1-온 (화학식 Step 1: Synthesized 1- (4- (4-bromophenoxy) piperidin-1-yl) -2,2-dimethylpropan-1-one (Formula 19-119-1 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000088
Figure PCTKR2019011876-appb-img-000088
4-브로모페놀 (화학식 18-1, 500 mg, 2.89 mmol), 4-하이드록시피페리딘-1-카복실레이트 (0.87 g, 4.34 mmol, 1.5 eq) 및 트리페닐포스핀 (1.1 g, 4.34 mmol, 1.5 eq)을 무수 THF (8 ml)에 용해시킨 후, DEAD (1.4 ml, 3.18 mmol, 1.1 eq)를 0 °C에서 적가하였다. 반응 혼합물을 상온에서 8시간 동안 교반시켰다. 반응 종결 후, 감압 하에서 용매를 제거하고 디에틸에테르에 녹인 후, 생성된 고체를 여과하여 제거하였다. 여액에 에틸아세테이트를 넣고 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 목표 화합물 (화학식 19-1)을 수득하였다.4-bromophenol (Formula 18-1 , 500 mg, 2.89 mmol), 4-hydroxypiperidine-1-carboxylate (0.87 g, 4.34 mmol, 1.5 eq) and triphenylphosphine (1.1 g, 4.34 mmol, 1.5 eq) was dissolved in anhydrous THF (8 ml), then DEAD (1.4 ml, 3.18 mmol, 1.1 eq) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the solvent was removed under reduced pressure, dissolved in diethyl ether, and the resulting solid was filtered off. Ethyl acetate was added to the filtrate, washed with H 2 O, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 19-1 ).
단계 2: 4-(4-브로모페녹시)피페리딘 (화학식 Step 2: 4- (4-Bromophenoxy) piperidine (Formula 19-219-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000089
Figure PCTKR2019011876-appb-img-000089
단계 1에서 합성된 1-(4-(4-브로모페녹시)피페리딘-1-일)-2,2-디메틸프로판-1-온 (화학식 19-1, 913 mg, 2.68 mmol)을 디클로로메탄 (DCM)(10 ml)에 용해시킨 후, TFA (5.1 ml, 67.1 mmol, 25 eq)를 0 °C에서 천천히 적가하였다. 반응 혼합물을 상온에서 2.5시간 동안 교반하고, 감압 하에서 용매를 제거하였다. 반응 혼합물을 에틸아세테이트에 녹여 NaHCO 3 포화 수용액과 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 목표 화합물 (화학식 19-2)을 수득하였다.1- (4- (4-Bromophenoxy) piperidin-1-yl) -2,2-dimethylpropan-1-one (Formula 19-1 , 913 mg, 2.68 mmol) synthesized in Step 1 was prepared. After dissolving in dichloromethane (DCM) (10 ml), TFA (5.1 ml, 67.1 mmol, 25 eq) was slowly added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 2.5 hours, and the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, washed sequentially with saturated aqueous NaHCO 3 and brine, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to obtain the target compound (Formula 19-2 ).
단계 3: 4-(4-브로모페녹시)-1-이소프로필피페리딘 (화학식 Step 3: 4- (4-Bromophenoxy) -1-isopropylpiperidine (Formula 19-319-3 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000090
Figure PCTKR2019011876-appb-img-000090
단계 2에서 합성된 4-(4-브로모페녹시)피페리딘 (화학식 19-2, 200 mg, 0.78 mmol)을 THF (1 ml)/1,2-디클로로에탄 (2 ml)에 용해시킨 후, AcOH (3 방울), 아세톤 (0.25 ml, 3.36 mmol, 4.3 eq) 및 소듐 트리아세톡시보로하이드리드 (331 mg, 1.56 mmol, 2 eq)를 상온에서 적가하였다. 반응 혼합물을 40 °C에서 24시간 교반하고 NaHCO 3 포화 수용액으로 반응을 종결시켰다. 에틸아세테이트로 추출하고, 물과 브라인으로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 목표 화합물 (화학식 19-3)을 수득하였다.4- (4-Bromophenoxy) piperidine synthesized in Step 2 (Formula 19-2 , 200 mg, 0.78 mmol) was dissolved in THF (1 ml) / 1,2-dichloroethane (2 ml). Then, AcOH (3 drops), acetone (0.25 ml, 3.36 mmol, 4.3 eq) and sodium triacetoxyborohydride (331 mg, 1.56 mmol, 2 eq) were added dropwise at room temperature. The reaction mixture was stirred at 40 ° C for 24 hours and the reaction was terminated with saturated aqueous NaHCO 3 solution. Extracted with ethyl acetate, washed with water and brine, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 19-3 ).
단계 4: 1-이소프로필-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피페리딘 (화학식 Step 4: 1-isopropyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine (formula 19-419-4 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000091
Figure PCTKR2019011876-appb-img-000091
단계 3에서 합성된 4-(4-브로모페녹시)-1-이소프로필피페리딘 (화학식 19-3, 145 mg, 0.49 mmol), 포타슘 아세테이트 (143 mg, 1.46 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (20 mg, 0.024 mmol, 0.05 eq) 및 B 2Pin 2 (148 mg, 0.58 mmol, 1.2 eq)를 DMSO (3 ml)에 용해시켰다. 반응 혼합물을 바이오타지 마이크로웨이브에서 85 °C로 2시간 동안 반응시켰다. 물로 반응을 종결시킨 후, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (디클로로메탄/메탄올)로 분리 및 정제하여 고체 화합물 (화학식 19-4)을 수득하였다.4- (4-Bromophenoxy) -1-isopropylpiperidine synthesized in Step 3 (Formula 19-3 , 145 mg, 0.49 mmol), potassium acetate (143 mg, 1.46 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (20 mg, 0.024 mmol, 0.05 eq) and B 2 Pin 2 (148 mg, 0.58 mmol, 1.2 eq) were dissolved in DMSO (3 ml). The reaction mixture was reacted in a Biotage microwave at 85 ° C for 2 hours. After completion of the reaction with water, extraction was performed with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (dichloromethane / methanol) to obtain a solid compound (Formula 19-4 ).
제조예 20: 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피리딘 (화학식 20-2의 화합물)의 제조Preparation 20: Preparation of 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) pyridine (compound of formula 20-2)
단계 1: 4-(4-브로모페녹시)피리딘 (화학식 Step 1: 4- (4-bromophenoxy) pyridine (formula 20-120-1 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000092
Figure PCTKR2019011876-appb-img-000092
NaH (42 mg, 1 mmol, 1.2 eq)를 용해시킨 DMF (3 ml)에 4-브로모페놀 (화학식 18-1, 150 mg, 0.87 mmol)을 0 °C에서 천천히 적가하였다. 동일 온도에서 5분간 교반시킨 후, 180 °C에서 45분간 환류교반하였다. 반응 종결 후, 상온까지 냉각시켜 셀라이트로 여과하고, 에틸아세테이트로 추출하였다. 유기층을 물로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 목표 화합물 (화학식 20-1)을 수득하였다.4-Bromophenol (Formula 18-1 , 150 mg, 0.87 mmol) was slowly added dropwise at 0 ° C to DMF (3 ml) in which NaH (42 mg, 1 mmol, 1.2 eq) was dissolved. After stirring at the same temperature for 5 minutes, the mixture was refluxed at 180 ° C for 45 minutes. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a target compound (Formula 20-1 ).
단계 2: 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피리딘 (화학식 Step 2: 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) pyridine (formula 20-220-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000093
Figure PCTKR2019011876-appb-img-000093
단계 1에서 합성된 4-(4-브로모페녹시)피리딘 (화학식 20-1, 109 mg, 0.44 mmol), 포타슘 아세테이트 (128 mg, 1.31 mmol, 3 eq), Pd(dppf)Cl 2-CH 2Cl 2 (11 mg, 0.013 mmol, 0.03 eq) 및 B 2Pin 2 (133 mg, 0.52 mmol, 1.2 eq)를 DMSO (3 ml)에 용해시켰다. 120 °C로 온도를 높여 반응 혼합물을 12시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 에틸아세테이트로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트)로 분리 및 정제하여 목표 화합물 (화학식 20-2)을 수득하였다.4- (4-bromophenoxy) pyridine synthesized in Step 1 (Formula 20-1 , 109 mg, 0.44 mmol), potassium acetate (128 mg, 1.31 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (11 mg, 0.013 mmol, 0.03 eq) and B 2 Pin 2 (133 mg, 0.52 mmol, 1.2 eq) were dissolved in DMSO (3 ml). The reaction mixture was stirred for 12 hours by raising the temperature to 120 ° C. After completion of the reaction, the reaction mixture was filtered through celite, and extracted with ethyl acetate. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate) to obtain the target compound (Formula 20-2 ).
제조예 21: 1-메틸-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피페리딘 (화학식 21-2의 화합물)의 제조Preparation Example 21: 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine (Formula 21- Preparation of 2)
단계 1: 4-(4-브로모페녹시)-1-메틸피페리딘 (화학식 Step 1: 4- (4-Bromophenoxy) -1-methylpiperidine (Formula 21-121-1 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000094
Figure PCTKR2019011876-appb-img-000094
제조예 19의 단계 2에서 합성된 4-(4-브로모페녹시)피페리딘 (화학식 19-2, 150 mg, 0.59 mmol)을 포름산 (3 ml)에 용해시킨 후, 포름알데하이드 (69 ul, 1.87 mmol, 3.2 eq)를 상온에서 적가하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 150 °C로 5분간 반응시켰다. 반응 종결 후, 감압 하에서 용매를 제거하고, 에틸아세테이트에 용해시켰다. NaHCO 3 포화 수용액과 브라인으로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 목표 화합물 (화학식 21-1)을 수득하였다.After dissolving 4- (4-bromophenoxy) piperidine (Formula 19-2 , 150 mg, 0.59 mmol) synthesized in Step 2 of Preparation Example 19 in formic acid (3 ml), formaldehyde (69 ul) , 1.87 mmol, 3.2 eq) was added dropwise at room temperature. The reaction mixture was reacted in a Biotage microwave at 150 ° C for 5 minutes. After completion of the reaction, the solvent was removed under reduced pressure and dissolved in ethyl acetate. After washing with saturated aqueous NaHCO 3 and brine, dried over anhydrous MgSO 4 and removing the solvent under reduced pressure to obtain the target compound (Formula 21-1 ).
단계 2: 1-메틸-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피페리딘 (화학식 Step 2: 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine (formula 21-221-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000095
Figure PCTKR2019011876-appb-img-000095
제조예 19의 단계 4에 기재된 방법과 동일한 방법을 사용하되, 4-(4-브로모페녹시)-1-이소프로필피페리딘 (화학식 19-3) 대신 4-(4-브로모페녹시)-1-메틸피페리딘 (화학식 21-1)을 사용하여 목표 화합물 (화학식 21-2)을 수득하였다.Using the same method as described in Step 4 of Preparation Example 19, 4- (4-bromophenoxy) instead of 4- (4-bromophenoxy) -1-isopropylpiperidine (Formula 19-3 ). ) -1-methylpiperidine (Formula 21-1 ) to give the target compound (Formula 21-2 ).
제조예 22: 1-에틸-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피페리딘 (화학식 22-2의 화합물)의 제조Preparation Example 22: 1-ethyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine (Formula 22- Preparation of 2)
단계 1: 4-(4-브로모페녹시)-1-에틸피페리딘 (화학식 Step 1: 4- (4-Bromophenoxy) -1-ethylpiperidine (Formula 22-122-1 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000096
Figure PCTKR2019011876-appb-img-000096
제조예 19의 단계 2에서 합성된 4-(4-브로모페녹시)피페리딘 (화학식 19-2, 150 mg, 0.59 mmol)을 THF (0.5 ml)/1,2-디클로로에탄(1 ml)에 용해시킨 후, AcOH (3 방울), 아세트알데하이드 (0.16 ml, 2.93 mmol, 5 eq), 소듐 트리아 세톡시보로하이드리드 (248 mg, 1.17 mmol, 2 eq)를 상온에서 적가하였다. 반응 혼합물을 40 °C에서 12시간 동안 교반하고, NaHCO 3 포화 수용액으로 반응을 종결시켰다. 에틸아세테이트로 추출하고, 물과 브라인으로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 목표 화합물 (화학식 22-1)을 수득하였다.4-F4- (4-bromophenoxy) piperidine (Formula 19-2 , 150 mg, 0.59 mmol) synthesized in Step 2 of Preparation Example 19 was THF (0.5 ml) / 1,2-dichloroethane (1 ml). ), AcOH (3 drops), acetaldehyde (0.16 ml, 2.93 mmol, 5 eq), sodium triacetoxyborohydride (248 mg, 1.17 mmol, 2 eq) was added dropwise at room temperature. The reaction mixture was stirred at 40 ° C for 12 hours, and the reaction was terminated with saturated aqueous NaHCO 3 solution. Extracted with ethyl acetate, washed with water and brine, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 22-1 ).
단계 2: 1-에틸-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페녹시)피페리딘 (화학식 Step 2: 1-ethyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine (formula 22-222-2 의 화합물)의 제조Preparation of compounds)
Figure PCTKR2019011876-appb-img-000097
Figure PCTKR2019011876-appb-img-000097
제조예 19의 단계 4에 기재된 방법과 동일한 방법을 사용하되, 4-(4-브로모페녹시)-1-이소프로필피페리딘 (화학식 19-3) 대신 4-(4-브로모페녹시)-1-메틸피페리딘 (화학식 22-1)을 사용하여 목표 화합물 (화학식 22-2)을 수득하였다.Using the same method as described in Step 4 of Preparation Example 19, 4- (4-bromophenoxy) instead of 4- (4-bromophenoxy) -1-isopropylpiperidine (Formula 19-3 ). ) -1-methylpiperidine (Formula 22-1 ) to give the target compound (Formula 22-2 ).
[실시예] 퀴놀린-5,8-디온 유도체 화합물의 제조[Example] Preparation of quinoline-5,8-dione derivative compound
실시예 1: Example 1: 2-(3-아세틸페닐)-6-메톡시퀴놀린-5,8-디온2- (3-acetylphenyl) -6-methoxyquinoline-5,8-dione 의 제조Manufacturing
단계 1: 메틸 1-(3-(5,6,8-트리메톡시퀴놀린-2일)페닐)에탄온의 제조Step 1: Preparation of methyl 1- (3- (5,6,8-trimethoxyquinolin-2yl) phenyl) ethanone
Figure PCTKR2019011876-appb-img-000098
Figure PCTKR2019011876-appb-img-000098
제조예 1에서 합성된 2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6, 1eq)을 디메틸에테르(DME)에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 3-아세틸페닐보론산 (1.1eq) 및 2M Na 2CO 3 수용액 (4 eq)을 실온에서 적가하고 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브로 160 °C에서 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 1-(3-(5,6,8-트리메톡시퀴놀린-2일)페닐)에탄온를 수득하였다. After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in dimethyl ether (DME), Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol%), 3-acetylphenylboronic acid (1.1 eq) and 2M Na 2 CO 3 aqueous solution (4 eq) was added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted with biotage microwaves at 160 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 1- (3- (5,6,8-trimethoxyquinolin-2yl) phenyl) ethanone.
단계 2: 2-(3-아세틸페닐)-6-메톡시퀴놀린-5,8-디온의 제조Step 2: Preparation of 2- (3-acetylphenyl) -6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000099
Figure PCTKR2019011876-appb-img-000099
단계1에서 합성된 1-(3-(5,6,8-트리메톡시퀴놀린-2-일)페닐)에탄온 (1 eq)를 소량의 아세토니트릴 (ACN)에 용해시킨 후, 어두운곳에서 0 °C로 0.6 M의 세륨 암모늄 니트레이트(CAN) (3 eq) 수용액을 천천히 적가하였다. 반응 혼합물을 실온에서 12시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone (1 eq) synthesized in step 1 in a small amount of acetonitrile (ACN), in a dark place An aqueous solution of 0.6 M cerium ammonium nitrate (CAN) (3 eq) was slowly added dropwise to 0 ° C. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400MHz, CDCl3) δ 8.68 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.48 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.1 (d, J = 7.8 Hz, 1H), 8.48 (t, J = 7.7 Hz, 1H), 6.40 (s, 1H), 3.97 (s, 3H), 2.71 (s, 3H). MS 308 (M+1).1H NMR (400MHz, CDCl3) δ 8.68 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.48 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H) , 8.1 (d, J = 7.8 Hz, 1H), 8.48 (t, J = 7.7 Hz, 1H), 6.40 (s, 1H), 3.97 (s, 3H), 2.71 (s, 3H). MS 308 (M + 1).
실시예 2 내지 실시예 35Examples 2 to 35
실시예 1에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 3-아세틸페닐보론산 대신 하기 [표 3]에 나열된 R을 사용하여 실시예 2 내지 실시예 35의 화합물을 수득하였다.Compounds of Examples 2 to 35 were obtained using the same method as described in Example 1, but using R listed in Table 3 below instead of 3-acetylphenylboronic acid in Step 1.
[표 3][Table 3]
Figure PCTKR2019011876-appb-img-000100
Figure PCTKR2019011876-appb-img-000100
Figure PCTKR2019011876-appb-img-000101
Figure PCTKR2019011876-appb-img-000101
Figure PCTKR2019011876-appb-img-000102
Figure PCTKR2019011876-appb-img-000102
Figure PCTKR2019011876-appb-img-000103
Figure PCTKR2019011876-appb-img-000103
Figure PCTKR2019011876-appb-img-000104
Figure PCTKR2019011876-appb-img-000104
Figure PCTKR2019011876-appb-img-000105
Figure PCTKR2019011876-appb-img-000105
Figure PCTKR2019011876-appb-img-000106
Figure PCTKR2019011876-appb-img-000106
Figure PCTKR2019011876-appb-img-000107
Figure PCTKR2019011876-appb-img-000107
실시예 36: 6-메톡시-2-(2-메틸피리미딘-5-일)퀴놀린-5,8-디온의 제조Example 36: Preparation of 6-methoxy-2- (2-methylpyrimidin-5-yl) quinoline-5,8-dione
단계 1: 5,6,8-트리메톡시-2-(2-메틸피리미딘-5-일)퀴놀린의 제조Step 1: Preparation of 5,6,8-trimethoxy-2- (2-methylpyrimidin-5-yl) quinoline
Figure PCTKR2019011876-appb-img-000108
Figure PCTKR2019011876-appb-img-000108
제조예 1에서 합성된 2-클로로-5,6,8-트리 메톡시퀴놀린 (화학식 1-6, 1eq)을 THF:H 2O (4:1)에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)피리미딘 및 K 2CO 3 (3 eq)를 실온에서 적가하고 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브로 70 °C에서 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 5,6,8-트리메톡시-2-(2-메틸피리미딘-5-일)퀴놀린을 수득하였다.After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in THF: H 2 O (4: 1), Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol%), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine and K 2 CO 3 (3 eq) was added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted with biotage microwaves at 70 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2- (2-methylpyrimidin-5-yl) quinoline.
단계 2: 6-메톡시-2-(2-메틸피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 6-methoxy-2- (2-methylpyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000109
Figure PCTKR2019011876-appb-img-000109
단계 1에서 합성된 5,6,8-트리메톡시-2-(2-메틸피리미딘-5-일)퀴놀린 (1 eq)을 소량의 ACN에 용해시킨 후, 어두운곳에서0 °C로 0.6 M의 CAN (3 eq) 수용액을 천천히 적가하였다. 반응 혼합물을 실온에서 12시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.The 5,6,8-trimethoxy-2- (2-methylpyrimidin-5-yl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN, and then 0.6 at 0 ° C in a dark place. M CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.49 (s, 2H), 9.36 (s, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 6.44 (s, 1H), 3.99 (s, 3H). MS 267.95 (M).1H NMR (400 MHz, CDCl3) δ 9.49 (s, 2H), 9.36 (s, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 6.44 (s , 1H), 3.99 (s, 3H). MS 267.95 (M).
실시예 37 내지 실시예 39Examples 37-39
실시예 36에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)피리미딘 대신 하기 [표 4]에 나열된 R을 사용하여 실시예 37 내지 실시예 39의 화합물을 수득하였다.The same method as described in Example 36 was used, but in step 1, 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyri Compounds of Examples 37 to 39 were obtained using R listed in Table 4 below instead of midine.
[표 4][Table 4]
Figure PCTKR2019011876-appb-img-000110
Figure PCTKR2019011876-appb-img-000110
실시예 40: 2-(3-아크릴로일페닐)-6-메톡시퀴놀린-5,8-디온의 제조Example 40: Preparation of 2- (3-acryloylphenyl) -6-methoxyquinoline-5,8-dione
단계 1: 1-(3-(5,6,8-트리메톡시퀴놀린-2-일) 페닐)프로프-2-엔-1-온의 제조Step 1: Preparation of 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-en-1-one
Figure PCTKR2019011876-appb-img-000111
Figure PCTKR2019011876-appb-img-000111
실시예 1의 단계1에서 합성된 1-(3-(5,6,8-트리메톡시퀴놀린-2-일)페닐)에탄온 (1 eq)을 테트라하이드로퓨란 (THF)에 용해시킨 후, 파라포름알데하이드 (2 eq), 디이소프필아민, 2,2,2-트리플루오로아세트산 염 (1 eq) 및 트리플로오로아세트산(TFA) (0.1 eq)을 실온에서 적가하였다. 반응 혼합물을 3일간 환류교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 1-(3-(5,6,8-트리메톡시퀴놀린-2-일) 페닐)프로프-2-엔-1-온을 수득하였다.After dissolving 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone (1 eq) synthesized in Step 1 of Example 1 in tetrahydrofuran (THF), Paraformaldehyde (2 eq), diisopropylamine, 2,2,2-trifluoroacetic acid salt (1 eq) and trifluoroacetic acid (TFA) (0.1 eq) were added dropwise at room temperature. The reaction mixture was stirred at reflux for 3 days. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30), and 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-ene 1-one was obtained.
단계 2: 2-(3-아크릴로일페닐)-6-메톡시퀴놀린-5,8-디온의 제조Step 2: Preparation of 2- (3-acryloylphenyl) -6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000112
Figure PCTKR2019011876-appb-img-000112
실시예 1의 단계 2에 기재된 방법과 동일한 방법을 사용하되, 1-(3-(5,6,8-트리메톡시퀴놀린-2-일)페닐)에탄온 대신 본 실시예 단계1에서 합성된 1-(3-(5,6,8-트리메톡시퀴놀린-2-일)페닐)프로프-2-엔-1-온을 사용하여 표제 화합물을 합성하였다.The same method as described in Step 2 of Example 1 was used, but instead of 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone, synthesized in Step 1 of this Example. The title compound was synthesized using 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-en-1-one.
1H NMR (400MHz, CDCl3) δ 8.67 (t, J = 1.6 Hz, 1H), 8.57 (d, J = 8.1 Hz, 1H), 8.50 (m, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.10 (m, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.24 (m, 1H), 6.52 (dd, J = 17.1, 1.4 Hz, 1H), 6.41 (s, 1H), 6.02 (dd, J = 10.6, 1.6 Hz, 1H), 3.98 (s, 3H). MS 320 (M+1).1H NMR (400MHz, CDCl3) δ 8.67 (t, J = 1.6 Hz, 1H), 8.57 (d, J = 8.1 Hz, 1H), 8.50 (m, 1H), 8.17 (d, J = 8.3 Hz, 1H) , 8.10 (m, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.24 (m, 1H), 6.52 (dd, J = 17.1, 1.4 Hz, 1H), 6.41 (s, 1H), 6.02 ( dd, J = 10.6, 1.6 Hz, 1H), 3.98 (s, 3H). MS 320 (M + 1).
실시예 41: 7-브로모-6-메톡시-2-페닐퀴놀린-5,8-디온의 제조Example 41: Preparation of 7-bromo-6-methoxy-2-phenylquinoline-5,8-dione
단계 1: 5,6,8-트리메톡시-2-페닐퀴놀린의 제조Step 1: Preparation of 5,6,8-trimethoxy-2-phenylquinoline
Figure PCTKR2019011876-appb-img-000113
Figure PCTKR2019011876-appb-img-000113
제조예 1에서 합성된 2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6, 1eq)을 DME에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 4,4,5,5-테트라메틸-2-페닐-1,3,2-디옥사보롤레인 (1.1eq) 및 2M Na 2CO 3 수용액 (4 eq)을 실온에서 적가한 다음 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브로 160 °C에서 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 5,6,8-트리메톡시-2-페닐퀴놀린을 수득하였다. After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in DME, Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol% ), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (1.1eq) and 2M Na 2 CO 3 aqueous solution (4 eq) were added dropwise at room temperature, followed by 10 min. It was stirred. The reaction mixture was reacted with biotage microwaves at 160 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2-phenylquinoline.
단계 2: 6-메톡시-2-페닐퀴놀린-5,8-디온의 제조Step 2: Preparation of 6-methoxy-2-phenylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000114
Figure PCTKR2019011876-appb-img-000114
단계1에서 합성된 5,6,8-트리메톡시-2-페닐퀴놀린 (1 eq)을 소량의 ACN에 용해시킨 후, 어두운곳에서 0 °C로 0.6 M의 CAN (3 eq)수용액을 천천히 적가하였다. 반응 혼합물을 실온에서 12시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 6-메톡시-2-페닐퀴놀린-5,8-디온을 수득하였다.After dissolving the 5,6,8-trimethoxy-2-phenylquinoline (1 eq) synthesized in step 1 in a small amount of ACN, slowly dissolve a 0.6 M CAN (3 eq) aqueous solution at 0 ° C in a dark place. Dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 6-methoxy-2-phenylquinoline-5,8-dione.
1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.51 (d, J = 6.8 Hz, 1H), 8.48 (s, 2H), 8.14 (d, J = 5.2 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 6.55 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H)1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.51 (d, J = 6.8 Hz, 1H), 8.48 (s, 2H), 8.14 (d, J = 5.2 Hz, 1H), 7.75 (t , J = 7.8 Hz, 1H), 6.55 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H)
단계 3: 7-브로모-6-메톡시-2-페닐퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-bromo-6-methoxy-2-phenylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000115
Figure PCTKR2019011876-appb-img-000115
단계 2에서 합성된 6-메톡시-2-페닐퀴놀린-5,8-디온 (1 eq)을 클로로포름에 용해시킨 후, 0 °C에서 브로민(Br 2) (1.1 eq)을 적가하고, 반응 혼합물을 실온에서 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.6-methoxy-2-phenylquinoline-5,8-dione synthesized in step 2 (1 eq) was dissolved in chloroform, then bromine (Br 2 ) (1.1 eq) was added dropwise at 0 ° C, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.3 Hz, 1H), 8.19 (m, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.53 (m, 3H), 4.36 (s, 3H). MS 345.60 (M+1).1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.3 Hz, 1H), 8.19 (m, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.53 (m, 3H), 4.36 (s , 3H). MS 345.60 (M + 1).
실시예 42 내지 실시예 67Examples 42-67
실시예 45에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 4,4,5,5-테트라메틸-2-페닐-1,3,2-디옥사보롤레인 대신 하기 [표 5]에 나열된 R을 사용하여 실시예 42 내지 실시예 67의 화합물을 수득하였다.R, which is the same as the method described in Example 45, is used in Step 1 instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane, listed in Table 5 below. The compounds of Examples 42 to 67 were obtained.
[표 5][Table 5]
Figure PCTKR2019011876-appb-img-000116
Figure PCTKR2019011876-appb-img-000116
Figure PCTKR2019011876-appb-img-000117
Figure PCTKR2019011876-appb-img-000117
Figure PCTKR2019011876-appb-img-000118
Figure PCTKR2019011876-appb-img-000118
Figure PCTKR2019011876-appb-img-000119
Figure PCTKR2019011876-appb-img-000119
Figure PCTKR2019011876-appb-img-000120
Figure PCTKR2019011876-appb-img-000120
Figure PCTKR2019011876-appb-img-000121
Figure PCTKR2019011876-appb-img-000121
실시예 68: 7-브로모-6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온의 제조Example 68: Preparation of 7-bromo-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
단계 1: 5,6,8-트리메톡시-2-(피리미딘-5-일)퀴놀린의 제조Step 1: Preparation of 5,6,8-trimethoxy-2- (pyrimidin-5-yl) quinoline
Figure PCTKR2019011876-appb-img-000122
Figure PCTKR2019011876-appb-img-000122
제조예 1에서 합성된 2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6, 1eq)을 THF:H 2O (4:1)에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 피리미딘-5-일보론산 및 K 2CO 3 (3 eq)을 실온에서 적가하고, 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브로 70 °C에서 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 5,6,8-트리메톡시-2-(피리미딘-5-일)퀴놀린을 수득하였다.After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in THF: H 2 O (4: 1), Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol%), pyrimidine-5-ylboronic acid and K 2 CO 3 (3 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted with biotage microwaves at 70 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2- (pyrimidin-5-yl) quinoline.
단계 2: 6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000123
Figure PCTKR2019011876-appb-img-000123
단계 1에서 합성된 5,6,8-트리메톡시-2-(피리미딘-5-일)퀴놀린 (1 eq)을 소량의 ACN에 용해시킨 후 어두운곳에서 0 °C로 0.6 M의 CAN (3 eq) 수용액을 천천히 적가하였다. 반응 혼합물을 실온에서 12시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온을 수득하였다.The 5,6,8-trimethoxy-2- (pyrimidin-5-yl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN and then 0.6 M CAN (0 ° C) in a dark place ( 3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione.
단계 3: 7-브로모-6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-bromo-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000124
Figure PCTKR2019011876-appb-img-000124
단계 2에서 합성된 6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온 (1 eq)을 클로로포름에 용해시킨 후, 0 °C에서 브로민 (1.1 eq)을 적가하고 반응 혼합물을 실온에서 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione synthesized in step 2 (1 eq) was dissolved in chloroform, then bromine (1.1 eq) was added dropwise at 0 ° C and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.50 (s, 2H), 9.37 (s, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 4.39 (s, 3H). MS 347.95 (M+1).1H NMR (400 MHz, CDCl3) δ 9.50 (s, 2H), 9.37 (s, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 4.39 (s , 3H). MS 347.95 (M + 1).
실시예 69 및 실시예 70Example 69 and Example 70
실시예 68에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 피리미딘-5-일보론산 대신 하기 [표 6]에 나열된 R을 사용하여 실시예 69 및 실시예 70의 화합물을 수득하였다.Compounds of Examples 69 and 70 were obtained using the same method as described in Example 68, but using R listed in Table 6 below instead of pyrimidine-5-ylboronic acid in Step 1.
[표 6][Table 6]
Figure PCTKR2019011876-appb-img-000125
Figure PCTKR2019011876-appb-img-000125
실시예 71: 3-(7-브로모-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)벤즈아미드의 제조Example 71: Preparation of 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzamide
단계 1: 메틸 3-(7-브로모-6-메톡시-5,8-디옥소-5,8-디히드로 퀴놀린-2-일)벤조에이트의 제조Step 1: Preparation of methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydro quinolin-2-yl) benzoate
실시예 41에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 4,4,5,5-테트라메틸-2-페닐-1,3,2-디옥사보롤레인 대신 3-(메톡시카보닐)페닐보론산을 사용하여 메틸 3-(7-브로모-6-메톡시-5,8-디옥소-5,8-디히드로 퀴놀린-2-일)벤조에이트를 수득하였다.The same method as that described in Example 41 was used, but in step 1, instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolein 3- (methoxycarbonyl) Phenylboronic acid was used to obtain methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydro quinolin-2-yl) benzoate.
단계 2: 3-(7-브로모-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)벤즈아미드의 제조Step 2: Preparation of 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzamide
Figure PCTKR2019011876-appb-img-000126
Figure PCTKR2019011876-appb-img-000126
단계 1에서 합성된 메틸 3-(7-브로모-6-메톡시-5,8-디옥소-5,8-디히드로 퀴놀린-2-일)벤조에이트를 7 M의 암모니아가 녹아있는 메탄올 용액에 용해시킨 후, 소듐시아나이드 (0.1 eq)를 실온에서 적가하였다. 반응 혼합물을 실온에서 3 일간 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 PTLC (디클로로메탄/메탄올; 98:2)로 분리 및 정제하여 표제 화합물을 수득하였다.Methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoate synthesized in Step 1 is a methanol solution in which 7 M ammonia is dissolved After dissolving in, sodium cyanide (0.1 eq) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 days. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by PTLC (dichloromethane / methanol; 98: 2) to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 3.98 (s, 3H). MS 388.80 (M+1).1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H ), 8.10 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 3.98 (s, 3H). MS 388.80 (M + 1).
실시예 72: 7-브로모-6-에톡시퀴놀린-5,8-디온의 제조Example 72: Preparation of 7-bromo-6-ethoxyquinoline-5,8-dione
단계 1: 5,7-디브로모퀴놀린-8-올의 화합물의 제조Step 1: Preparation of a compound of 5,7-dibromoquinoline-8-ol
Figure PCTKR2019011876-appb-img-000127
Figure PCTKR2019011876-appb-img-000127
퀴놀린-8-올 (1 eq)을 브로민 (3 eq)이 용해되어 있는 메탄올 용액에 적가하였다. 이 혼합물에 NaHCO 3 (2 eq)가 용해되어 있는 메탄올 용액을 적가하고 실온(RT)에서 5분간 교반하였다. 이후, Na 2SO 3 (0.63 eq)를 반응 혼합물에 적가하고 10분간 실온에서 교반하였다. 반응 종결 후, 반응 고체를 여과하고 H 2O로 세정한 다음, 건조하여 5,7-디브로모퀴놀린-8-올을 수득하였다.Quinoline-8-ol (1 eq) was added dropwise to the methanol solution in which bromine (3 eq) was dissolved. To this mixture, a methanol solution in which NaHCO 3 (2 eq) was dissolved was added dropwise and stirred at room temperature (RT) for 5 minutes. Then, Na 2 SO 3 (0.63 eq) was added dropwise to the reaction mixture and stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solid was filtered, washed with H 2 O, and then dried to obtain 5,7-dibromoquinoline-8-ol.
단계 2: 7-브로모퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-bromoquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000128
Figure PCTKR2019011876-appb-img-000128
단계 1에서 합성된 5,7-디브로모퀴놀린-8-올을 0 °C에서 질산 (6 eq)이 용해되어있는 황산 (20 eq) 용액에 천천히 적가하였다. 동일 온도에서 30분간 교반한 후, 얼음물로 반응을 종결 시켰다. 이후, 디클로로메탄으로 추출하고, 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 7-브로모퀴놀린-5,8-디온을 수득하였다. The 5,7-dibromoquinoline-8-ol synthesized in step 1 was slowly added dropwise to a sulfuric acid (20 eq) solution in which nitric acid (6 eq) was dissolved at 0 ° C. After stirring at the same temperature for 30 minutes, the reaction was terminated with ice water. Thereafter, the mixture was extracted with dichloromethane, and the organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 7-bromoquinoline-5,8-dione.
단계 3: 7-브로모-6-에톡시퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-bromo-6-ethoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000129
Figure PCTKR2019011876-appb-img-000129
단계 2에서 합성된 7-브로모퀴놀린-5,8-디온 (1 eq)을 메탄올에 용해시키고 세슘클로라이드 (1.1 eq)와 소듐에톡시드 (2 eq)를 0 °C에서 적가하였다. 이 반응 혼합물을 실온에서 30분간 교반하였다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.The 7-bromoquinoline-5,8-dione (1 eq) synthesized in Step 2 was dissolved in methanol and cesium chloride (1.1 eq) and sodium ethoxide (2 eq) were added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.05 (dd, J = 4.7, 1.72 Hz, 1H), 8.44 (dd, J = 7.9, 1.8 Hz, 1H), 7.71 (dd, J = 7.9, 4.7 Hz, 1H), 4.68 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H). MS 283.50 (M+1).1H NMR (400 MHz, CDCl3) δ 9.05 (dd, J = 4.7, 1.72 Hz, 1H), 8.44 (dd, J = 7.9, 1.8 Hz, 1H), 7.71 (dd, J = 7.9, 4.7 Hz, 1H) , 4.68 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H). MS 283.50 (M + 1).
실시예 73: 7-브로모-2-페닐퀴놀린-5,8-디온 의 화합물의 제조Example 73: Preparation of a compound of 7-bromo-2-phenylquinoline-5,8-dione
단계 1: 2-페닐퀴놀린-8-올의 제조Step 1: Preparation of 2-phenylquinoline-8-ol
Figure PCTKR2019011876-appb-img-000130
Figure PCTKR2019011876-appb-img-000130
-브로모퀴놀린-8-올을 디메톡시에탄에 용해시킨 후, 페닐보론산 (1.5 eq) 및 2M Na 2CO 3 수용액 (3 eq)을 실온에서 적가하고 10분간 교반하였다. 반응 혼합물에 Pd(PPh 3) 4 (0.1 eq)를 적가한 후, 바이오타지 마이크로웨이브로 160 °C에서 30분간 반응시켰다. 반응 종결 후, 셀라이트로 여과하고 1M HCl수용액으로 중화시켰다. 이 혼합물을 에틸 아세테이트로 추출하고, 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 2-페닐퀴놀린-8-올을 수득하였다.-After dissolving bromoquinoline-8-ol in dimethoxyethane, phenylboronic acid (1.5 eq) and 2M Na 2 CO 3 aqueous solution (3 eq) were added dropwise at room temperature and stirred for 10 minutes. After adding Pd (PPh 3 ) 4 (0.1 eq) dropwise to the reaction mixture, it was reacted for 30 minutes at 160 ° C. with biotage microwave. After completion of the reaction, it was filtered through celite and neutralized with 1M HCl aqueous solution. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 2-phenylquinoline-8-ol.
단계 2: 5,7-디브로모-2-페닐퀴놀린-8-올의 제조Step 2: Preparation of 5,7-dibromo-2-phenylquinoline-8-ol
Figure PCTKR2019011876-appb-img-000131
Figure PCTKR2019011876-appb-img-000131
단계 1에서 합성된 2-페닐퀴놀린-8-올 (1 eq)을 아세트산에 용해시킨 후, 브로민 (2.2 eq)이 용해된 아세트산 용액을 천천히 적가하였다. 이 반응 혼합물을 실온에서 30분간 교반 후, 얼음물과 Na 2S 2O 3를 적가하고 10분간 교반하였다. 반응 종결 후, 여과하고 에탄올로 재결정하여 5,7-디브로모-2-페닐퀴놀린-8-올을 수득하였다.After dissolving 2-phenylquinoline-8-ol (1 eq) synthesized in step 1 in acetic acid, an acetic acid solution in which bromine (2.2 eq) was dissolved was slowly added dropwise. After stirring the reaction mixture at room temperature for 30 minutes, ice water and Na 2 S 2 O 3 were added dropwise and stirred for 10 minutes. After completion of the reaction, it was filtered and recrystallized from ethanol to obtain 5,7-dibromo-2-phenylquinoline-8-ol.
단계 3: 7-브로모-2-페닐퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-bromo-2-phenylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000132
Figure PCTKR2019011876-appb-img-000132
단계 2에서 합성된 5,7-디브로모-2-페닐퀴놀린-8-올 (1 eq)을 ACN에 용해시킨후, H 2O에 용해시킨 CAN (2.2 eq)을 천천히 적가하였다. 이 반응 혼합물을 실온에서 2시간 동안 교반한 후, H 2O로 반응을 종결시켰다. 에틸아세테이트(EtOAc)로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After the 5,7-dibromo-2-phenylquinoline-8-ol (1 eq) synthesized in Step 2 was dissolved in ACN, CAN (2.2 eq) dissolved in H 2 O was slowly added dropwise. After the reaction mixture was stirred at room temperature for 2 hours, the reaction was terminated with H 2 O. After extraction with ethyl acetate (EtOAc), it was dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.3 Hz, 1H), 8.22 - 8.17 (m, 2H), 8.13 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.57 - 7.51 (m, 3H). MS 316 (M+2).1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.3 Hz, 1H), 8.22-8.17 (m, 2H), 8.13 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.57 -7.51 (m, 3H). MS 316 (M + 2).
실시예 74: 7-브로모-6-메틸-2-페닐퀴놀린-5,8-디온의 제조Example 74: Preparation of 7-bromo-6-methyl-2-phenylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000133
Figure PCTKR2019011876-appb-img-000133
실시예 73에서 합성된 7-브로모-2-페닐퀴놀린-5,8-디온 (1 eq)을 ACN에 용해시킨 후, 아세트산 (1.5 eq) 및 AgNO 3 (0.5 eq)를 적가하였다. 이 반응 혼합물에 과황산암모늄 (1.4 eq) 수용액을 천천히 적가하고 80 °C에서 4시간 동안 가열교반하였다. 반응 종결 후, 에틸아세테이트로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다. After the 7-bromo-2-phenylquinoline-5,8-dione (1 eq) synthesized in Example 73 was dissolved in ACN, acetic acid (1.5 eq) and AgNO 3 (0.5 eq) were added dropwise. An aqueous ammonium persulfate (1.4 eq) solution was slowly added dropwise to the reaction mixture, followed by heating and stirring at 80 ° C for 4 hours. After completion of the reaction, extraction was performed with ethyl acetate, and then dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.3 Hz, 1H), 8.21 - 8.16 (m, 2H), 8.11 (d, J = 8.3 Hz, 1H), 7.56 - 7.51 (m, 3H), 2.43 (s, 3H). MS 330.05 (M+1).1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.3 Hz, 1H), 8.21-8.16 (m, 2H), 8.11 (d, J = 8.3 Hz, 1H), 7.56-7.51 (m, 3H) , 2.43 (s, 3H). MS 330.05 (M + 1).
실시예 75: 7-아미노-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온의 제조Example 75: Preparation of 7-amino-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
단계 1: 5,6,8-트리메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린의 제조Step 1: Preparation of 5,6,8-trimethoxy-2- (3- (trifluoromethoxy) phenyl) quinoline
Figure PCTKR2019011876-appb-img-000134
Figure PCTKR2019011876-appb-img-000134
제조예 1에서 합성된 2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6, 1eq)을 DME에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 3-(트리플루오로메톡시)페닐보론산 (1.1eq) 및 2 M Na 2CO 3 수용액 (4 eq)을 실온에서 적가하고 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브로 160 °C에서 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 5,6,8-트리메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린을 수득하였다. After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6, 1eq) synthesized in Preparation Example 1 in DME, Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol% ), 3- (trifluoromethoxy) phenylboronic acid (1.1 eq) and 2 M Na 2 CO 3 aqueous solution (4 eq) was added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted with biotage microwaves at 160 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2- (3- (trifluoromethoxy) phenyl) quinoline.
단계 2: 6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온의 제조Step 2: Preparation of 6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000135
Figure PCTKR2019011876-appb-img-000135
단계 1에서 합성된 5,6,8-트리메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린 (1 eq)를 소량의 ACN에 용해시킨 후, 어두운곳에서 0 °C에 0.6 M의 CAN (3 eq) 수용액을 천천히 적가하였다. 반응 혼합물을 실온에서 12시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온을 수득하였다.The 5,6,8-trimethoxy-2- (3- (trifluoromethoxy) phenyl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN, and then 0.6 at 0 ° C in a dark place. M CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione.
단계 3: 7-브로모-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000136
Figure PCTKR2019011876-appb-img-000136
단계 2에서 합성된 6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온 (1 eq)를 클로로포름에 용해시킨 후, 0 °C에 브로민 (1.1 eq)을 적가하고 반응 혼합물을 실온에서 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 7-브로모-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온을 수득하였다.6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione synthesized in step 2 (1 eq) was dissolved in chloroform, then bromine (1.1 eq) was added dropwise to 0 ° C and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione.
단계 4: 7-아지도-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온의 제조Step 4: Preparation of 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000137
Figure PCTKR2019011876-appb-img-000137
단계 3에서 합성된 7-브로모-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온 (1 eq)를 DMF/MeOH (1/1)에 용해시킨 후, 소듐 아자이드 (1.5 eq)를 적가하고 실온에서 1시간 내지 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 7-아지도-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온을 수득하였다.7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione synthesized in step 3 (1 eq) was dissolved in DMF / MeOH (1/1), then sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 to 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to give 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl). Quinoline-5,8-dione was obtained.
단계 5: 7-아미노-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온의 제조Step 5: Preparation of 7-amino-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000138
Figure PCTKR2019011876-appb-img-000138
단계 4에서 합성된 7-아지도-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온 (1 eq)를 EtOAc/MeOH (1/1)에 용해시킨 후, Pd/C (1 eq)를 적가하고 수소기류하에서 12시간 동안 교반하였다. 반응 종결 후, 셀라이트로 여과하고 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.The 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione (1 eq) synthesized in step 4 was dissolved in EtOAc / MeOH (1/1). After the addition, Pd / C (1 eq) was added dropwise and stirred under a hydrogen stream for 12 hours. After completion of the reaction, it was filtered through celite and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CD 3OD) δ 8.79 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H). MS 338.75 (M).1H NMR (400 MHz, CD 3 OD) δ 8.79 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz , 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H). MS 338.75 (M).
실시예 76 내지 실시예 108Examples 76-108
실시예 75에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 3-(트리플루오로메톡시)페닐보론산 대신 하기 [표 7]에 나열된 R을 사용하여 실시예 76 내지 실시예 108의 화합물을 수득하였다.Using the same method as described in Example 75, but using R listed in Table 7 below instead of 3- (trifluoromethoxy) phenylboronic acid in Step 1 to obtain the compounds of Examples 76-108 Did.
[표 7][Table 7]
Figure PCTKR2019011876-appb-img-000139
Figure PCTKR2019011876-appb-img-000139
Figure PCTKR2019011876-appb-img-000140
Figure PCTKR2019011876-appb-img-000140
Figure PCTKR2019011876-appb-img-000141
Figure PCTKR2019011876-appb-img-000141
Figure PCTKR2019011876-appb-img-000142
Figure PCTKR2019011876-appb-img-000142
Figure PCTKR2019011876-appb-img-000143
Figure PCTKR2019011876-appb-img-000143
Figure PCTKR2019011876-appb-img-000144
Figure PCTKR2019011876-appb-img-000144
Figure PCTKR2019011876-appb-img-000145
Figure PCTKR2019011876-appb-img-000145
Figure PCTKR2019011876-appb-img-000146
Figure PCTKR2019011876-appb-img-000146
실시예 109: 7-아미노-2-(4-클로로-3-플로오로페닐)-6-메톡시퀴놀린-5,8-디온의 제조Example 109: Preparation of 7-amino-2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione
단계 1: 7-아지도-2-(4-클로로-3-플로오로페닐)-6-메톡시퀴놀린-5,8-디온의 제조Step 1: Preparation of 7-azido-2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000147
Figure PCTKR2019011876-appb-img-000147
실시예 75의 단계 1 내지 단계 4에 기재된 방법과 동일한 방법을 사용하되, 3-(트리플루오로메톡시)페닐보론산 대신 4-클로로-3-플로오로페닐보론산을 사용하여 7-아지도-2-(4-클로로-3-플로오로페닐)-6-메톡시퀴놀린-5,8-디온을 수득하였다.Using the same method as that described in Step 1 to Step 4 of Example 75, using 4-chloro-3-fluorophenylboronic acid instead of 3- (trifluoromethoxy) phenylboronic acid 7-azido- 2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione was obtained.
단계 2: 7-아미노-2-(4-클로로-3-플로오로페닐)-6-메톡시퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000148
Figure PCTKR2019011876-appb-img-000148
단계 1에서 합성된7-아지도-2-(4-클로로-3-플로오로페닐)-6-메톡시퀴놀린-5,8-디온 (1 eq)을 THF/MeOH (5/1)에 용해시킨 후, 소듐보로하이드리드 (10 eq)를 적가하고 실온에서 3시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다. The 7-azido-2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione (1 eq) synthesized in step 1 was dissolved in THF / MeOH (5/1). After the addition, sodium borohydride (10 eq) was added dropwise and stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.2 Hz, 1H), 7.99 (m, 2H), 7.86 (m, 1H), 7.54 (m, 1H), 5.22 (s, NH2), 4.10 (s, 3H). MS 332.70 (M).1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.2 Hz, 1H), 7.99 (m, 2H), 7.86 (m, 1H), 7.54 (m, 1H), 5.22 (s, NH2), 4.10 (s, 3H). MS 332.70 (M).
실시예 110: 7-아미노-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온의 제조Example 110: Preparation of 7-amino-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
단계 1: 5,6,8-트리메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린의 제조Step 1: Preparation of 5,6,8-trimethoxy-2- (2-methoxypyrimidin-5-yl) quinoline
Figure PCTKR2019011876-appb-img-000149
Figure PCTKR2019011876-appb-img-000149
제조예 1에서 합성된 2-클로로-5,6,8-트리 메톡시퀴놀린 (화학식 1-6, 1eq)을 THF:H 2O (4:1)에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 2-메톡시피리미딘-5-일보론산 및 K 2CO 3 (3 eq)를 실온에서 적가하고 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브로 70 °C에서 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 5,6,8-트리메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린을 수득하였다.After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in THF: H 2 O (4: 1), Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol%), 2-methoxypyrimidin-5-ylboronic acid and K 2 CO 3 (3 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted with biotage microwaves at 70 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2- (2-methoxypyrimidin-5-yl) quinoline.
단계 2: 6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000150
Figure PCTKR2019011876-appb-img-000150
단계 1에서 합성된 5,6,8-트리메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린 (1 eq)을 소량의 ACN에 용해시킨 후, 어두운곳에서 0 °C로 0.6 M의 CAN (3 eq) 수용액을 천천히 적가하였다. 반응 혼합물을 실온에서 12시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온을 수득하였다.The 5,6,8-trimethoxy-2- (2-methoxypyrimidin-5-yl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN, and then turned to 0 ° C in a dark place. A solution of 0.6 M CAN (3 eq) was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione.
단계 3: 7-브로모-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-bromo-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000151
Figure PCTKR2019011876-appb-img-000151
단계 2에서 합성된 6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온 (1 eq)을 클로로포름에 용해시킨 후, 0 °C에서 브로민 (1.1 eq)을 적가하고 반응 혼합물을 실온에서 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 7-브로모-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온을 수득하였다.After dissolving 6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione (1 eq) synthesized in Step 2 in chloroform, bromine (1.1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 7-bromo-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione.
단계 4: 7-아지도-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 4: Preparation of 7-azido-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000152
Figure PCTKR2019011876-appb-img-000152
단계 3에서 합성된 7-브로모-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온 (1 eq)을 DMF/MeOH (1/1)에 용해시킨 후, 소듐아자이드 (1.5 eq)를 적가하고 실온에서 1시간 내지 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 7-아지도-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온을 수득하였다.7-bromo-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione synthesized in step 3 (1 eq) was dissolved in DMF / MeOH (1/1), sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 to 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to give 7-azido-6-methoxy-2- (2-methoxypyrimidin-5-yl. ) Quinoline-5,8-dione was obtained.
단계 5: 7-아미노-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 5: Preparation of 7-amino-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000153
Figure PCTKR2019011876-appb-img-000153
단계 4에서 합성된 7-아지도-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온 (1 eq)을 EtOAc/MeOH (1/1)에 용해시킨 후, Pd/C (1 eq)를 적가하고, 수소기류 하에서 12시간 동안 교반하였다. 반응 종결 후, 셀라이트로 여과하고 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다. 7-azido-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione (1 eq) synthesized in step 4 was added to EtOAc / MeOH (1/1). After dissolution, Pd / C (1 eq) was added dropwise and stirred under a hydrogen stream for 12 hours. After completion of the reaction, it was filtered through celite and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.25 (s, 2H), 8.46 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 4.11 (s, 3H), 4.10 (s, 3H). MS 312.95 (M).1H NMR (400 MHz, CDCl3) δ 9.25 (s, 2H), 8.46 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 4.11 (s, 3H), 4.10 (s , 3H). MS 312.95 (M).
실시예 111: 7-아미노-6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온의 제조Example 111: Preparation of 7-amino-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
단계 1: 7-아지도-6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 1: Preparation of 7-azido-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000154
Figure PCTKR2019011876-appb-img-000154
실시예 110의 단계 1 내지 단계 4에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 2-메톡시피리미딘-5-일보론산 대신 피리미딘-5-일보론산을 사용하여 7-아지도-6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온을 수득하였다.7-azido-6 using the same method as that described in steps 1 to 4 of Example 110, using pyrimidine-5-ylboronic acid in step 1 instead of 2-methoxypyrimidine-5-ylboronic acid. -Methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione was obtained.
단계 2: 7-아미노-6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000155
Figure PCTKR2019011876-appb-img-000155
단계 1에서 합성된 7-아지도-6-메톡시-2-(피리미딘-5-일)퀴놀린-5,8-디온 (1 eq)을 THF/MeOH (5/1)에 용해시킨 후, 소듐보로하이드리드 (10 eq)를 적가하고 실온에서 3시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다. After dissolving the 7-azido-6-methoxy-2- (pyrimidin-5-yl) quinoline-5,8-dione (1 eq) synthesized in step 1 in THF / MeOH (5/1), Sodium borohydride (10 eq) was added dropwise and stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.45 (s, 2H), 9.33 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 4.12 (s, 3H). MS 282.95 (M).1H NMR (400 MHz, CDCl3) δ 9.45 (s, 2H), 9.33 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 4.12 (s , 3H). MS 282.95 (M).
실시예 112 내지 실시예 114Examples 112-114
실시예 118에 기재된 방법과 동일한 방법을 사용하되, 피리미딘-5-일보론산대신 하기 [표 8]에 나열된 R을 사용하여 실시예 112 내지 실시예 114의 화합물을 수득하였다.Using the same method as described in Example 118, but using R listed in Table 8 below instead of pyrimidine-5-ylboronic acid, compounds of Examples 112 to 114 were obtained.
[표 8][Table 8]
Figure PCTKR2019011876-appb-img-000156
Figure PCTKR2019011876-appb-img-000156
실시예 115: 메틸 3-(3-(7-아미노-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)페닐)프로파노에이트의 제조Example 115: Preparation of methyl 3- (3- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) propanoate
단계 1: (E)-메틸 3-(3-(7-아지도-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)페닐)아크릴레이트의 제조Step 1: Preparation of (E) -methyl 3- (3- (7-azido-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) acrylate
Figure PCTKR2019011876-appb-img-000157
Figure PCTKR2019011876-appb-img-000157
실시예 75의 단계 1 내지 단계 4에 기재된 방법과 동일한 방법을 사용하되, 3-(트리플루오로메톡시)페닐보론산 (1.1eq) 대신 (E)-3-(3-메톡시-3-옥소프로프-1-엔일)페닐보론산을 사용하여 (E)-3-(3-(7-아지도-6-메톡시-5,8-디옥소-5,8-디히드로퀴놀린-2-일)페닐)아크릴레이트를 수득하였다.The same method as that described in Step 1 to Step 4 of Example 75 was used, but instead of 3- (trifluoromethoxy) phenylboronic acid (1.1eq), (E) -3- (3-methoxy-3-oxo (E) -3- (3- (7-azido-6-methoxy-5,8-dioxo-5,8-dihydroquinoline-2- using prop-1-enyl) phenylboronic acid 1) phenyl) acrylate.
단계 2: 메틸 3-(3-(7-아미노-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)페닐)프로파노에이트의 제조Step 2: Preparation of methyl 3- (3- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) propanoate
Figure PCTKR2019011876-appb-img-000158
Figure PCTKR2019011876-appb-img-000158
단계 1에서 합성된 메틸 (E)-3-(3-(7-아지도-6-메톡시-5,8-디옥소-5,8-디히드로퀴놀린-2-일)페닐)아크릴레이트 (1 eq)를 EtOAc/MeOH (1/1)에 용해시킨 후, Pd/C (1 eq)를 적가하고 수소기류 하에서 12시간 동안 교반하였다. 반응 종결 후, 셀라이트로 여과하고 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.Methyl (E) -3- (3- (7-azido-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) acrylate synthesized in step 1 ( 1 eq) was dissolved in EtOAc / MeOH (1/1), then Pd / C (1 eq) was added dropwise and stirred for 12 hours under a hydrogen stream. After completion of the reaction, it was filtered through celite and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400MHz, CDCl3) δ 8.41 (d, J = 7.8 Hz, 1H), 8.00 (m, 2H), 7.95 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 5.21 (brs, 2H, NH2), 4.09 (s, 3H), 3.70 (m, 3H) 3.07 (t, J = 7.8 Hz, 1H), 2.71 (t, J = 7.8 Hz, 1H). MS 366.80 (M).1H NMR (400MHz, CDCl3) δ 8.41 (d, J = 7.8 Hz, 1H), 8.00 (m, 2H), 7.95 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H) , 7.33 (d, J = 7.5 Hz, 1H), 5.21 (brs, 2H, NH2), 4.09 (s, 3H), 3.70 (m, 3H) 3.07 (t, J = 7.8 Hz, 1H), 2.71 (t , J = 7.8 Hz, 1H). MS 366.80 (M).
실시예 116: 7-아미노-2-(3-(1-하이드록시에틸)페닐)-6-메톡시퀴놀린-5,8-디온의 제조Example 116: Preparation of 7-amino-2- (3- (1-hydroxyethyl) phenyl) -6-methoxyquinoline-5,8-dione
단계 1: 2-(3-아세틸페닐)-7-아지도-6-메톡시퀴놀린-5,8-디온의 제조Step 1: Preparation of 2- (3-acetylphenyl) -7-azido-6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000159
Figure PCTKR2019011876-appb-img-000159
실시예 75의 단계 1 내지 단계 4에 기재된 방법과 동일한 방법을 사용하되, 3-(트리플루오로메톡시)페닐보론산 (1.1 eq) 대신 3-아세틸페닐보론산을 사용하여 2-(3-아세틸페닐)-7-아지도-6-메톡시퀴놀린-5,8-디온을 수득하였다.Using 2- (3-acetyl) using 3-acetylphenylboronic acid instead of 3- (trifluoromethoxy) phenylboronic acid (1.1 eq), using the same method as described in steps 1 to 4 of Example 75. Phenyl) -7-azido-6-methoxyquinoline-5,8-dione was obtained.
단계 2: 7-아미노-2-(3-(1-하이드록시에틸)페닐)-6-메톡시퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (3- (1-hydroxyethyl) phenyl) -6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000160
Figure PCTKR2019011876-appb-img-000160
단계 1에서 합성된 메틸 2-(3-아세틸페닐)-7-아지도-6-메톡시퀴놀린-5,8-디온 (1 eq)를 EtOAc/MeOH (1/1)에 용해시킨 후, Pd/C (1 eq)를 적가하고 수소기류 하에서 12시간 동안 교반하였다. 반응 종결 후, 셀라이트로 여과하고 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving methyl 2- (3-acetylphenyl) -7-azido-6-methoxyquinoline-5,8-dione (1 eq) synthesized in Step 1 in EtOAc / MeOH (1/1), Pd / C (1 eq) was added dropwise and stirred under a hydrogen stream for 12 hours. After completion of the reaction, it was filtered through celite and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400MHz, CDCl3) δ 8.42 (d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 8.04 (m, 2H), 7.50 (m, 2H), 5.21 (brs, 2H, NH2), 4.09 (s, 3H), 1.56 (s, 3H). MS 325.00 (M+1). 1 H NMR (400MHz, CDCl3) δ 8.42 (d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 8.04 (m, 2H), 7.50 (m, 2H), 5.21 (brs, 2H, NH2) , 4.09 (s, 3H), 1.56 (s, 3H). MS 325.00 (M + 1).
실시예 117: 7-아미노-2-(3-아미노페닐)-6-메톡시퀴놀린-5,8-디온의 제조Example 117: Preparation of 7-amino-2- (3-aminophenyl) -6-methoxyquinoline-5,8-dione
단계 1: 7-아지도-6-메톡시-2-(3-니트로페닐)퀴놀린-5,8-디온의 제조Step 1: Preparation of 7-azido-6-methoxy-2- (3-nitrophenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000161
Figure PCTKR2019011876-appb-img-000161
실시예 75의 단계 4에 기재된 방법과 동일한 방법을 사용하되, 7-브로모-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온 대신 실시예 44에서 합성된 7-브로모-6-메톡시-2-(3-니트로페닐)퀴놀린-5,8-디온 (1 eq)을 사용하여 7-아지도-6-메톡시-2-(3-니트로페닐)퀴놀린-5,8-디온을 수득하였다.Using the same method as described for Step 4 of Example 75, but instead of 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione Example 44 7-azido-6-methoxy-2- (3- using 7-bromo-6-methoxy-2- (3-nitrophenyl) quinoline-5,8-dione (1 eq) synthesized from Nitrophenyl) quinoline-5,8-dione was obtained.
단계 2: 7-아미노-2-(3-아미노페닐)-6-메톡시퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (3-aminophenyl) -6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000162
Figure PCTKR2019011876-appb-img-000162
실시예 75의 단계 5에 기재된 방법과 동일한 방법을 사용하되, 7-아지도-6-메톡시-2-(3-(트리플루오로메톡시)페닐)퀴놀린-5,8-디온 대신 본 실시예 단계 1에서 합성된 7-아지도-6-메톡시-2-(3-니트로페닐)퀴놀린-5,8-디온 (1 eq)을 사용하여 표제 화합물을 수득하였다.The same method as that described in Step 5 of Example 75 was used, but instead of 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione The title compound was obtained using 7-azido-6-methoxy-2- (3-nitrophenyl) quinoline-5,8-dione (1 eq) synthesized in step 1.
1H NMR (400MHz, CDCl3) δ 8.39 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.57 (m, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.30 (m, 1H), 6.81 (dd, J = 7.9, 16 Hz, 1H), 5.21 (brs, 2H, NH2), 4.09 (s, 3H), 3.85 (s, 2H). MS 296.05 (M+1).1H NMR (400MHz, CDCl3) δ 8.39 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.57 (m, 1H), 7.42 (d, J = 7.8 Hz, 1H) , 7.30 (m, 1H), 6.81 (dd, J = 7.9, 16 Hz, 1H), 5.21 (brs, 2H, NH2), 4.09 (s, 3H), 3.85 (s, 2H). MS 296.05 (M + 1).
실시예 118: 2-(3-아크릴로일페닐)-7-아미노-6-메톡시퀴놀린-5,8-디온의 제조Example 118: Preparation of 2- (3-acryloylphenyl) -7-amino-6-methoxyquinoline-5,8-dione
단계 1: 2-(3-아세틸페닐)-7-아미노-6-메톡시퀴놀린-5,8-디온의 제조Step 1: Preparation of 2- (3-acetylphenyl) -7-amino-6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000163
Figure PCTKR2019011876-appb-img-000163
실시예 116에서 합성된 7-아미노-2-(3-(1-하이드록시에틸)페닐)-6-메톡시퀴놀린-5,8-디온을 디클로로메탄에 용해시킨 후, 데스-마틴 퍼아이오디난 (Dess-Martin Periodinane)(2 eq)를 0 °C에서 적가하고 실온에서 4시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 2-(3-아세틸페닐)-7-아미노-6-메톡시퀴놀린-5,8-디온을 수득하였다.After dissolving 7-amino-2- (3- (1-hydroxyethyl) phenyl) -6-methoxyquinoline-5,8-dione synthesized in Example 116 in dichloromethane, des-Martin periodic Egg (Dess-Martin Periodinane) (2 eq) was added dropwise at 0 ° C and stirred at room temperature for 4 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed with H 2 O, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to obtain 2- (3-acetylphenyl) -7-amino-6-methoxyquinoline-5,8-dione. .
단계 2: 2-(3-아크릴로일페닐)-7-아미노-6-메톡시퀴놀린-5,8-디온의 제조Step 2: Preparation of 2- (3-acryloylphenyl) -7-amino-6-methoxyquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000164
Figure PCTKR2019011876-appb-img-000164
실시예 40의 단계 1에 기재된 방법과 동일한 방법을 사용하되, 1-(3-(5,6,8-트리메톡시퀴놀린-2-일)페닐)에탄온 대신 본 실시예 단계 1에서 합성된 2-(3-아세틸페닐)-7-아미노-6-메톡시퀴놀린-5,8-디온을 사용하여 표제 화합물을 수득하였다.The same method as that described in Step 1 of Example 40 was used, but instead of 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone, synthesized in Step 1 of this Example. The title compound was obtained using 2- (3-acetylphenyl) -7-amino-6-methoxyquinoline-5,8-dione.
1H NMR (400MHz, CDCl3) δ 8.63 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.66 (t, J = 7.7 Hz, 1H), 6.49 (d, J = 1.5 Hz, 1H), 6.00 (dd, J = 1.9, 1.5 Hz, 1H), 5.23 (brs, 2H, NH2). MS 334.98 (M).1H NMR (400MHz, CDCl3) δ 8.63 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.66 (t, J = 7.7 Hz, 1H), 6.49 (d, J = 1.5 Hz, 1H), 6.00 (dd, J = 1.9, 1.5 Hz, 1H), 5.23 (brs, 2H, NH2). MS 334.98 (M).
실시예 119: N-(3-(7-아미노-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)페닐)아크릴아미드의 제조Example 119: Preparation of N- (3- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) acrylamide
Figure PCTKR2019011876-appb-img-000165
Figure PCTKR2019011876-appb-img-000165
실시예 117에서 합성된 7-아미노-2-(3-아미노페닐)-6-메톡시퀴놀린-5,8-디온 (1 eq)을 디클로로메탄에 용해시킨 후, 아크릴로일클로라이드 (1.2 eq), 트리에틸아민 (1.2 eq)을 0 °C에서 적가하고, 실온에서 8시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 포화 NaHCO 3수용액으로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 PTLC (헥산/에틸아세테이트; 40:60)로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving the 7-amino-2- (3-aminophenyl) -6-methoxyquinoline-5,8-dione (1 eq) synthesized in Example 117 in dichloromethane, acryloyl chloride (1.2 eq) , Triethylamine (1.2 eq) was added dropwise at 0 ° C and stirred at room temperature for 8 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed with a saturated NaHCO 3 aqueous solution, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by PTLC (hexane / ethyl acetate; 40:60) to obtain the title compound.
1H NMR (400MHz, CDCl3) δ 8.40 (d, J = 8.1 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.48 (dd, J = 16.8, 1.2 Hz, 1H), 6.32 (dd, J = 16.8 10.2 Hz, 1H), 5.81 (dd, J = 10.3, 1.2 Hz, 1H), 5.21(brs, 2H, NH2), 4.09 (s, 3H). MS 350.20 (M+1).1H NMR (400MHz, CDCl3) δ 8.40 (d, J = 8.1 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H) , 7.81 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.48 (dd, J = 16.8, 1.2 Hz, 1H), 6.32 (dd, J = 16.8 10.2 Hz, 1H), 5.81 (dd, J = 10.3, 1.2 Hz, 1H), 5.21 (brs, 2H, NH2), 4.09 (s, 3H). MS 350.20 (M + 1).
실시예 120: 7-아미노-2-페닐퀴놀린-5,8-디온의 제조Example 120: Preparation of 7-amino-2-phenylquinoline-5,8-dione
단계 1: 7-아지도-2-페닐퀴놀린-5,8-디온의 제조Step 1: Preparation of 7-azido-2-phenylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000166
Figure PCTKR2019011876-appb-img-000166
실시예 73에서 합성된 7-브로모-2-페닐퀴놀린-5,8-디온을 THF에 용해시킨 후, 소듐아자이드 (1.2 eq) 수용액을 적가하고 실온에서 30분간 교반하였다. 반응 종결 후, 에틸아세테이트로 추출하였다. 무수 MgSO 4로 건조한 다음, 감압 하에서 용매를 제거하여 7-아지도-2-페닐퀴놀린-5,8-디온을 수득하였다.After dissolving the 7-bromo-2-phenylquinoline-5,8-dione synthesized in Example 73 in THF, an aqueous sodium azide (1.2 eq) solution was added dropwise and stirred at room temperature for 30 minutes. After completion of the reaction, extraction was performed with ethyl acetate. After drying over anhydrous MgSO 4 , the solvent was removed under reduced pressure to obtain 7-azido-2-phenylquinoline-5,8-dione.
단계 2: 7-아미노-2-페닐퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2-phenylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000167
Figure PCTKR2019011876-appb-img-000167
단계 1에서 합성된 7-아지도-2-페닐퀴놀린-5,8-디온 (1 eq)을 THF/H 2O (5/1)에 용해시킨 후, 소듐보로하이드리드 (10 eq)를 적가하고 1시간 동안 실온에서 교반하였다. 반응 종결 후, 에틸 아세테이트로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 표제 화합물을 수득하였다.After dissolving the 7-azido-2-phenylquinoline-5,8-dione (1 eq) synthesized in step 1 in THF / H 2 O (5/1), sodium borohydride (10 eq) was added. It was added dropwise and stirred at room temperature for 1 hour. After completion of the reaction, extraction was performed with ethyl acetate, and then dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.2 Hz, 1H), 8.14 (dd, J = 8.2, 1.9 Hz, 2H), 8.07 (d, J = 8.2 Hz, 1H), 7.55 - 7.48 (m, 3H), 6.07 (s, 1H), 5.30 (bs, 2H). MS 251 (M+1).1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.2 Hz, 1H), 8.14 (dd, J = 8.2, 1.9 Hz, 2H), 8.07 (d, J = 8.2 Hz, 1H), 7.55-7.48 (m, 3H), 6.07 (s, 1H), 5.30 (bs, 2H). MS 251 (M + 1).
실시예 121: 7-아미노-6-메틸-2-페닐퀴놀린-5,8-디온의 제조Example 121: Preparation of 7-amino-6-methyl-2-phenylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000168
Figure PCTKR2019011876-appb-img-000168
실시예 120에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 7-브로모-2-페닐퀴놀린-5,8-디온 대신 실시예 74에서 합성된 7-브로모-6-메틸-2-페닐퀴놀린-5,8-디온 (1 eq)을 사용하여 표제 화합물을 수득하였다.7-bromo-6-methyl-2-phenyl synthesized in Example 74 instead of 7-bromo-2-phenylquinoline-5,8-dione in Step 1, using the same method as described in Example 120. The title compound was obtained using quinoline-5,8-dione (1 eq).
1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.2 Hz, 1H), 8.15 - 8.13 (m, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.53 - 7.46 (m, 3H), 5.15 (bs, 2H), 2.06 (s, 3H). MS 265.20 (M+1).1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.2 Hz, 1H), 8.15-8.13 (m, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.53-7.46 (m, 3H) , 5.15 (bs, 2H), 2.06 (s, 3H). MS 265.20 (M + 1).
실시예 122: 7-아미노-2-(2-클로로피리딘-4-일)-6-메틸퀴놀린-5,8-디온의 제조Example 122: Preparation of 7-amino-2- (2-chloropyridin-4-yl) -6-methylquinoline-5,8-dione
단계 1: 7-브로모-2-(2-클로로피리딘-4-일)퀴놀린-5,8-디온의 제조Step 1: Preparation of 7-bromo-2- (2-chloropyridin-4-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000169
Figure PCTKR2019011876-appb-img-000169
실시예 73에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 페닐보론산 대신 2-클로로피리딘-4-일보론산 (1.5 eq)을 사용하여 7-브로모-2-(2-클로로피리딘-4-일)퀴놀린-5,8-디온을 수득하였다.7-bromo-2- (2-chloropyridin-4 using 2-chloropyridin-4-ylboronic acid (1.5 eq) instead of phenylboronic acid in step 1 using the same method as described in Example 73 -Yl) quinoline-5,8-dione.
단계 2: 7-브로모-2-(2-클로로피리딘-4-일)-6-메틸퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-bromo-2- (2-chloropyridin-4-yl) -6-methylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000170
Figure PCTKR2019011876-appb-img-000170
실시예 74에 기재된 방법과 동일한 방법을 사용하되, 7-브로모-2-페닐퀴놀린-5,8-디온 (1 eq) 대신 단계 1에서 합성된 7-브로모-2-(2-클로로피리딘-4-일)퀴놀린-5,8-디온을 사용하여 7-브로모-2-(2-클로로피리딘-4-일)-6-메틸퀴놀린-5,8-디온을 수득하였다.Using the same method as described in Example 74, 7-bromo-2- (2-chloropyridine synthesized in Step 1 instead of 7-bromo-2-phenylquinoline-5,8-dione (1 eq) 4-yl) quinoline-5,8-dione was used to obtain 7-bromo-2- (2-chloropyridin-4-yl) -6-methylquinoline-5,8-dione.
단계 3: 7-아미노-2-(2-클로로피리딘-4-일)-6-메틸퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-amino-2- (2-chloropyridin-4-yl) -6-methylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000171
Figure PCTKR2019011876-appb-img-000171
실시예 120에 기재된 방법과 동일한 방법을 사용하되, 7-브로모-2-페닐퀴놀린-5,8-디온 대신 단계 2에서 합성된 7-브로모-2-(2-클로로피리딘-4-일)-6-메틸퀴놀린-5,8-디온을 사용하여 표제 화합물을 수득하였다.7-bromo-2- (2-chloropyridin-4-yl synthesized in Step 2 instead of 7-bromo-2-phenylquinoline-5,8-dione, using the same method as described in Example 120. ) -6-Methylquinoline-5,8-dione to give the title compound.
1H NMR (400 MHz, CDCl3) δ 8.57 - 8.53 (m, 2H), 8.10 - 8.07 (m, 2H), 7.94 (dd, J = 5.2, 1.5 Hz, 1H), 5.22 (bs, 2H), 2.08 (s, 3H). MS 300.15 (M+1)1H NMR (400 MHz, CDCl3) δ 8.57-8.53 (m, 2H), 8.10-8.07 (m, 2H), 7.94 (dd, J = 5.2, 1.5 Hz, 1H), 5.22 (bs, 2H), 2.08 ( s, 3H). MS 300.15 (M + 1)
실시예 123: 7-아미노-2-(3-(트리플로오로메톡시)페닐)퀴놀린-5,8-디온의 제조Example 123: Preparation of 7-amino-2- (3- (triflooromethoxy) phenyl) quinoline-5,8-dione
단계 1: 7-브로모-2-(3-(트리플로오로메톡시)페닐)퀴놀린-5,8-디온의 제조Step 1: Preparation of 7-bromo-2- (3- (triflooromethoxy) phenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000172
Figure PCTKR2019011876-appb-img-000172
실시예 73에 기재된 방법과 동일한 방법을 사용하되, 페닐보론산 대신 3-(트리플로오로메톡시)페닐보론산 (1.5 eq)을 사용하여 7-브로모-2-(3-(트리플로오로메톡시)페닐)퀴놀린-5,8-디온을 수득하였다.Using the same method as described in Example 73, using 3- (triflooromethoxy) phenylboronic acid (1.5 eq) instead of phenylboronic acid to 7-bromo-2- (3- (triflouro) Methoxy) phenyl) quinoline-5,8-dione was obtained.
단계 2: 7-아미노-2-(3-(트리플로오로메톡시)페닐)퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (3- (triflooromethoxy) phenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000173
Figure PCTKR2019011876-appb-img-000173
실시예 120에 기재된 방법과 동일한 방법을 사용하되, 7-브로모-2-페닐퀴놀린-5,8-디온 대신 본 실시예 단계 1에서 합성된 7-브로모-2-(3-(트리플로오로메톡시)페닐)퀴놀린-5,8-디온 을 사용하여 표제 화합물을 수득하였다.The same method as described in Example 120 was used, but instead of 7-bromo-2-phenylquinoline-5,8-dione, 7-bromo-2- (3- (Triflo) synthesized in this Example Step 1 was used. Oromethoxy) phenyl) quinoline-5,8-dione was used to give the title compound.
1H NMR (400MHz, CDCl3) δ 8.49 (d, J = 8.3 Hz, 1H), 8.07 (m, 2H), 8.00 (s, 1H), 7.55 (t, J = 7.9, 2H), 7.35 (d, J = 8.3, 1H), 6.09 (s, 2H), 5.34 (brs, 2H, NH2). MS 334.70 (M)1H NMR (400MHz, CDCl3) δ 8.49 (d, J = 8.3 Hz, 1H), 8.07 (m, 2H), 8.00 (s, 1H), 7.55 (t, J = 7.9, 2H), 7.35 (d, J = 8.3, 1H), 6.09 (s, 2H), 5.34 (brs, 2H, NH2). MS 334.70 (M)
실시예 124 내지 실시예 127Examples 124 to 127
실시예 123에 기재된 방법과 동일한 방법을 사용하되, 3-(트리플로오로메톡시)페닐보론산 대신 하기 [표 9]에 나열된 R을 사용하여 실시예 124 내지 실시예 127의 화합물을 수득하였다.Compounds of Examples 124 to 127 were obtained using the same method as described in Example 123, but using R listed in Table 9 below instead of 3- (triflooromethoxy) phenylboronic acid.
[표 9][Table 9]
Figure PCTKR2019011876-appb-img-000174
Figure PCTKR2019011876-appb-img-000174
실시예 128: N-(6-메톡시-2-(2-메톡시피리미딘-5-일)-5,8-디옥소-5,8-디하이드로퀴놀린-7-일)아세트아미드의 제조Example 128: Preparation of N- (6-methoxy-2- (2-methoxypyrimidin-5-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000175
Figure PCTKR2019011876-appb-img-000175
실시예 90에서 합성된7-아미노-2-(2-플루오로피리딘-4-일)-6-메톡시퀴놀린-5,8-디온 (1 eq)을 클로로포름에 용해시킨 후, 아크릴로일클로라이드 (9 eq)와 트리에틸아민 (2 eq)을 적가하고 2일 동안 환류교반하였다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 PTLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving 7-amino-2- (2-fluoropyridin-4-yl) -6-methoxyquinoline-5,8-dione (1 eq) synthesized in Example 90 in chloroform, acryloyl chloride (9 eq) and triethylamine (2 eq) were added dropwise and stirred under reflux for 2 days. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by PTLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.1 Hz, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 6.43 (m, 2H), 5.91 (d, J = 9.36 Hz, 1H), 4.27 (s, 3H). MS 354.20 (M+1).1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.1 Hz, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 6.43 (m, 2H), 5.91 (d, J = 9.36 Hz, 1H), 4.27 (s, 3H). MS 354.20 (M + 1).
실시예 129: N-(5,8-디옥소-2-페닐-5,8-디하이드로퀴놀린-7-일)아세트아미드의 제조Example 129: Preparation of N- (5,8-dioxo-2-phenyl-5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000176
Figure PCTKR2019011876-appb-img-000176
실시예 120에서 합성된 7-아미노-2-페닐퀴놀린-5,8-디온 (1 eq)을 THF/CH 2Cl 2 (1/1)에 용해시킨 후, 아세틸클로라이드 (2.5 eq), 피리딘 (3 eq) 및 N, N-디메틸피리딘-4-아민 (0.1 eq)을 적가하고 7일간 교반하였다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving the 7-amino-2-phenylquinoline-5,8-dione (1 eq) synthesized in Example 120 in THF / CH 2 Cl 2 (1/1), acetylchloride (2.5 eq), pyridine ( 3 eq) and N, N-dimethylpyridin-4-amine (0.1 eq) were added dropwise and stirred for 7 days. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.3 Hz, 1H), 8.43 (bs, 1H), 8.17 - 8.12 (m, 2H), 7.96 (s, 1H), 7.56 - 7.51 (m, 3H), 2.34 (s, 3H). MS 293.20 (M+1).1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.3 Hz, 1H), 8.43 (bs, 1H), 8.17-8.12 (m, 2H), 7.96 (s, 1H), 7.56-7.51 (m, 3H), 2.34 (s, 3H). MS 293.20 (M + 1).
실시예 130: N-(2-(2-플로오로피리딘-4-일)-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-7-일)아크릴아미드의 제조Example 130: Preparation of N- (2- (2-flooropyridin-4-yl) -6-methoxy-5,8-dioxo-5,8-dihydroquinolin-7-yl) acrylamide
Figure PCTKR2019011876-appb-img-000177
Figure PCTKR2019011876-appb-img-000177
실시예 110에서 합성된 7-아미노-6-메톡시-2-(2-메톡시피리미딘-5-일)퀴놀린-5,8-디온 (1 eq)을 클로로포름에 용해시킨 후, 아세틸클로라이드 (10 eq) 및 트리에틸아민 (1 eq)을 적가하고 12시간 동안 환류교반하였다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 PTLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving the 7-amino-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinoline-5,8-dione (1 eq) synthesized in Example 110 in chloroform, acetylchloride ( 10 eq) and triethylamine (1 eq) were added dropwise and stirred under reflux for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by PTLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.28 (s, 2H), 8.49 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 4.25 (s, 3H), 4.12 (s, 3H). MS 355.15 (M+1).1H NMR (400 MHz, CDCl3) δ 9.28 (s, 2H), 8.49 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 4.25 (s, 3H), 4.12 (s , 3H). MS 355.15 (M + 1).
실시예 131 내지 실시예 139Examples 131 to 139
실시예 1에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 3-아세틸페닐보론산 대신 하기 [표 10]에 나열된 R을 사용하여 실시예 131 내지 실시예 139의 화합물을 수득하였다.Compounds of Examples 131 to 139 were obtained using the same method as described in Example 1, but using R listed in Table 10 below instead of 3-acetylphenylboronic acid in Step 1.
[표 10]Table 10
Figure PCTKR2019011876-appb-img-000178
Figure PCTKR2019011876-appb-img-000178
Figure PCTKR2019011876-appb-img-000179
Figure PCTKR2019011876-appb-img-000179
Figure PCTKR2019011876-appb-img-000180
Figure PCTKR2019011876-appb-img-000180
실시예 140 내지 실시예 144Examples 140-144
실시예 1에 기재된 방법과 동일한 방법을 사용하되, 3-아세틸페닐보론산 대신 하기 [표 11]에 나열된 R을 사용하고, 디메틸에테르(DME) 대신 1,4-디옥산을 사용하여 실시예 140 내지 실시예 144의 화합물을 수득하였다.Example 140 using the same method as described in Example 1, using R listed in Table 11 below instead of 3-acetylphenylboronic acid, and 1,4-dioxane instead of dimethyl ether (DME). The compound of Example 144 was obtained.
[표 11][Table 11]
Figure PCTKR2019011876-appb-img-000181
Figure PCTKR2019011876-appb-img-000181
실시예 145 내지 실시예 170Examples 145 to 170
실시예 36에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)피리미딘 대신 하기 [표 12]에 나열된 R을 사용하여 실시예 145 내지 실시예 170의 화합물을 수득하였다.The same method as described in Example 36 was used, but in step 1, 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyri Compounds of Examples 145 to 170 were obtained using R listed in Table 12 below instead of midine.
[표 12]Table 12
Figure PCTKR2019011876-appb-img-000182
Figure PCTKR2019011876-appb-img-000182
Figure PCTKR2019011876-appb-img-000183
Figure PCTKR2019011876-appb-img-000183
Figure PCTKR2019011876-appb-img-000184
Figure PCTKR2019011876-appb-img-000184
Figure PCTKR2019011876-appb-img-000185
Figure PCTKR2019011876-appb-img-000185
Figure PCTKR2019011876-appb-img-000186
Figure PCTKR2019011876-appb-img-000186
Figure PCTKR2019011876-appb-img-000187
Figure PCTKR2019011876-appb-img-000187
실시예 171: 6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온의 제조Example 171: Preparation of 6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
단계 1: 5,6,8-트리메톡시-2-(피라진-2-일)퀴놀린의 제조Step 1: Preparation of 5,6,8-trimethoxy-2- (pyrazin-2-yl) quinoline
Figure PCTKR2019011876-appb-img-000188
Figure PCTKR2019011876-appb-img-000188
2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6, 90 mg, 0.3 mmol)과 Pd(Ph 3) 4 (46 mg, 0.039 mmol, 0.1 eq)을 1,4-디옥산 (8 ml)에 용해시킨 후, 2-(트리부틸스태닐)피라진 (218 mg, 0.59 mmol, 2 eq)을 상온에서 적가하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 130 °C로 2시간 반응시켰다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 5,6,8-트리메톡시-2-(피라진-2-일)퀴놀린을 수득하였다.2-Chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 90 mg, 0.3 mmol) and Pd (Ph 3 ) 4 (46 mg, 0.039 mmol, 0.1 eq) with 1,4-dioxane After dissolving in (8 ml), 2- (tributylstannyl) pyrazine (218 mg, 0.59 mmol, 2 eq) was added dropwise at room temperature. The reaction mixture was reacted in a Biotage microwave at 130 ° C for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2- (pyrazin-2-yl) quinoline.
단계 2: 6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000189
Figure PCTKR2019011876-appb-img-000189
단계1에서 합성된 5,6,8-트리메톡시-2-(피라진-2-일)퀴놀린 (1 eq)을 소량의 ACN에 용해시킨 후, 어두운곳에서 0 °C로 0.6 M의 CAN (3 eq) 수용액을 천천히 적가하였다. 반응 혼합물을 실온에서 12시간 동안 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving 5,6,8-trimethoxy-2- (pyrazin-2-yl) quinoline (1 eq) synthesized in step 1 in a small amount of ACN, 0.6 M CAN (0 ° C) in a dark place ( 3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 8.72-8.68 (m, 2H), 8.62 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H), 3.98 (s, 3H). MS 268.2 (M+1).1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 8.72-8.68 (m, 2H), 8.62 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H), 3.98 (s, 3H). MS 268.2 (M + 1).
실시예 172: 6-메톡시-2-(6-메톡시피라진-2-일)퀴놀린-5,8-디온의 제조Example 172: Preparation of 6-methoxy-2- (6-methoxypyrazin-2-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000190
Figure PCTKR2019011876-appb-img-000190
실시예 171에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 2-(트리부틸스태닐)피라진 대신 2-메톡시-6-(트리부틸스태닐)피라진 (화학식 16-2)을 사용하여 표제 화합물을 수득하였다.Using the same method as described in Example 171, but using 2-methoxy-6- (tributylstannyl) pyrazine (Formula 16-2 ) in Step 1 instead of 2- (tributylstannyl) pyrazine The compound was obtained.
1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 8.2 Hz, 1H), 8.37 (s, 1H), 6.42 (s, 1H), 4.11 (s, 3H), 3.98 (s, 3H). MS 298.04 (M+1).1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 8.2 Hz, 1H), 8.37 (s, 1H), 6.42 (s , 1H), 4.11 (s, 3H), 3.98 (s, 3H). MS 298.04 (M + 1).
실시예 173: 메틸 2-메톡시-6-(5,6,8-트리메톡시퀴놀린-2-일)니코티네이트의 제조Example 173: Preparation of methyl 2-methoxy-6- (5,6,8-trimethoxyquinolin-2-yl) nicotinate
Figure PCTKR2019011876-appb-img-000191
Figure PCTKR2019011876-appb-img-000191
2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6, 0.3 g, 1.18 mmol)을 THF (4 ml)/ H 2O (1 ml)에 녹인 후, PdCl 2(dtbpf) (116 mg, 0.18 mmol, 0.15 eq) 및 K 2CO 3 (490 mg, 3.55 mmol, 3 eq)을 상온에서 적가하였다. 반응 혼합물을 70 °C에서 8시간 동안 교반한 후 상온까지 냉각하였다. 반응 혼합물을 셀라이트로 여과한 후, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (헥산/에틸아세테이트; 70:30)로 분리 및 정제하여 표제 화합물을 수득하였다.2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 0.3 g, 1.18 mmol) was dissolved in THF (4 ml) / H 2 O (1 ml), followed by PdCl 2 (dtbpf) ( 116 mg, 0.18 mmol, 0.15 eq) and K 2 CO 3 (490 mg, 3.55 mmol, 3 eq) were added dropwise at room temperature. The reaction mixture was stirred at 70 ° C for 8 hours and then cooled to room temperature. After the reaction mixture was filtered through celite, the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain the title compound.
1H NMR (400 MHz, DMSO) δ 8.77 (d, J = 8.2 Hz, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 4.10 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H). MS 355.20 (M+1).1H NMR (400 MHz, DMSO) δ 8.77 (d, J = 8.2 Hz, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 4.10 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H). MS 355.20 (M + 1).
실시예 174: 6-메톡시-2-(4-(트리플루오로메틸)피페리딘-1-일)퀴놀린-5,8-디온의 제조Example 174: Preparation of 6-methoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline-5,8-dione
단계 1: 5,6,8-트리메톡시-2-(4-(트리플루오로메틸)피페리딘-1-일)퀴놀린 의 제조Step 1: Preparation of 5,6,8-trimethoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline
Figure PCTKR2019011876-appb-img-000192
Figure PCTKR2019011876-appb-img-000192
2-클로로-5,6,8-트리메톡시퀴놀린 (화학식 1-6, 0.4 g, 1.58 mmol)을 톨루엔 (2 ml)에 용해시킨 후, 4-(트리플루오로메틸)피페리딘(1 eq), Pd 2(dba) 3 (0.05 eq), 2,2'-비스(디페닐포스피노)-1,1'-바이나프틸(BINAP)(0.1 eq) 및 소듐 tert-부톡시드(2.5 eq)를 실온에서 적가하고 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 125 °C로 1시간 동안 반응시켰다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 감압 하에서 용매를 제거하였다. 에틸아세테이트로 추출하고 물로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 5,6,8-트리메톡시-2-(4-(트리플루오로메틸)피페리딘-1-일)퀴놀린을 수득하였다.2-Chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 0.4 g, 1.58 mmol) was dissolved in toluene (2 ml), followed by 4- (trifluoromethyl) piperidine (1 eq), Pd 2 (dba) 3 (0.05 eq), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) (0.1 eq) and sodium tert-butoxide (2.5 eq) was added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted in a Biotage microwave at 125 ° C for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. It was extracted with ethyl acetate, washed with water, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline.
단계 2: 6-메톡시-2-(4-(트리플루오로메틸)피페리딘-1-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 6-methoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000193
Figure PCTKR2019011876-appb-img-000193
단계 1에서 합성된 5,6,8-트리메톡시-2-(4-(트리플루오로메틸)피페리딘-1-일)퀴놀린 (0.098 g, 0.27 mmol)을 아세톤 (8 ml)에 용해시킨 후, NaH 2PO 4 완충액(0.3 M /8 ml, 2.4 mmol)에 녹인 프레미염(포타슘 니트로소디술포네이트)(0.114 g, 0.42 mmol, 1.6 eq)을 적가하였다. 반응 혼합물을 실온에서 8시간 동안 교반한 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O로 세정한 다음, 무수 MgSO 4로 건조하고, 유기층을 감압하여 용매를 제거하였다. 이후, 반응 혼합물을 PTLC로 분리 및 정제하여 표제 화합물을 수득하였다.The 5,6,8-trimethoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline (0.098 g, 0.27 mmol) synthesized in step 1 was dissolved in acetone (8 ml). After the addition, premi salt (potassium nitrosodisulfonate) (0.114 g, 0.42 mmol, 1.6 eq) dissolved in NaH 2 PO 4 buffer (0.3 M / 8 ml, 2.4 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 8 hours, and then extracted with dichloromethane. The organic layer was washed with H 2 O, then dried over anhydrous MgSO 4 , and the organic layer was reduced in pressure to remove the solvent. Then, the reaction mixture was separated and purified by PTLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.15 (s, 1H), 4.77 (d, J = 12.4 Hz, 2H), 3.90 (s, 3H), 3.03 (t, J = 12.1 Hz, 1H), 2.37 (dd, J = 8.0, 4.0 Hz, 1H), 2.03 (d, J = 8.3 Hz, 2H), 1.65 (td, J = 12.7, 3.8 Hz, 1H). MS 341.20 (M+1).1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.15 (s, 1H), 4.77 (d, J = 12.4 Hz, 2H ), 3.90 (s, 3H), 3.03 (t, J = 12.1 Hz, 1H), 2.37 (dd, J = 8.0, 4.0 Hz, 1H), 2.03 (d, J = 8.3 Hz, 2H), 1.65 (td , J = 12.7, 3.8 Hz, 1H). MS 341.20 (M + 1).
실시예 175: 2-(4,4-디플루오로피페리딘-1-일)-6-메톡시퀴놀린-5,8-디온의 제조Example 175: Preparation of 2- (4,4-difluoropiperidin-1-yl) -6-methoxyquinoline-5,8-dione
실시예 174에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 4-(트리플루오로메틸)피페리딘 대신 4,4-디플루오로피페리딘을 사용하여 표제 화합물을 수득하였다.Using the same method as described for Example 174, using 4,4-difluoropiperidine instead of 4- (trifluoromethyl) piperidine in Step 1 to give the title compound.
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.16 (s, 1H), 3.98 (d, J = 5.1 Hz, 4H), 3.90 (s, 3H), 2.19 - 1.93 (m, 4H). MS 309.20 (M+1).1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.16 (s, 1H), 3.98 (d, J = 5.1 Hz, 4H ), 3.90 (s, 3H), 2.19-1.93 (m, 4H). MS 309.20 (M + 1).
실시예 176: 2,7-디브로모-6-이소프로필퀴놀린-5,8-디온의 제조Example 176: Preparation of 2,7-dibromo-6-isopropylquinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000194
Figure PCTKR2019011876-appb-img-000194
2,7-디브로모퀴놀린-5,8-디온 (200 mg, 0.63 mmol, 1 eq)과 이소부틸산 (167 mg, 1.89 mmol, 3 eq)을 아세토니트릴(4 ml)에 용해시킨 후, 질산은 (54 mg, 0.32 mmol, 0.5 eq) 및 과산화황산 2암모니아염(403 mg, 1.77 mmol, 2.8 eq)을 적가하여 80 °C에서 8시간 동안 반응시켰다. H 2O로 반응을 종결시킨 후, 에틸아세테이트로 추출하고 무수 MgSO 4로 건조한 다음, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 2,7-디브로모-6-이소프로필퀴놀린-5,8-디온을 수득하였다.After dissolving 2,7-dibromoquinoline-5,8-dione (200 mg, 0.63 mmol, 1 eq) and isobutyl acid (167 mg, 1.89 mmol, 3 eq) in acetonitrile (4 ml), Silver nitrate (54 mg, 0.32 mmol, 0.5 eq) and dibasic ammonia salt (403 mg, 1.77 mmol, 2.8 eq) were added dropwise and reacted at 80 ° C for 8 hours. After completion of the reaction with H 2 O, extraction was performed with ethyl acetate, dried over anhydrous MgSO 4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 2,7-dibromo-6-isopropylquinoline-5,8-dione.
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 3.64-3.57 (m, 1H), 1.40 (d, J = 7.0 Hz, 6H). MS 359.85(M).1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 3.64-3.57 (m, 1H), 1.40 (d, J = 7.0 Hz , 6H). MS 359.85 (M).
실시예 177 내지 실시예 180Examples 177 to 180
실시예 41에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 4,4,5,5-테트라메틸-2-페닐-1,3,2-디옥사보롤레인 대신 하기 [표 13]에 나열된 R을 사용하여 실시예 177 내지 실시예 180의 화합물을 수득하였다.R, which is the same as the method described in Example 41, but is listed in Table 13 below instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane in Step 1 The compounds of Examples 177 to 180 were obtained using.
[표 13][Table 13]
Figure PCTKR2019011876-appb-img-000195
Figure PCTKR2019011876-appb-img-000195
실시예 181 내지 실시예 183Examples 181 to 183
실시예 41에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 4,4,5,5-테트라메틸-2-페닐-1,3,2-디옥사보롤레인 대신 하기 [표 14]에 나열된 R을 사용하고, 디메틸에테르(DME) 대신 1,4-디옥산을 사용하여 실시예 181 내지 실시예 183의 화합물을 수득하였다.R, listed in Table 14 below, using the same method as described in Example 41, instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane in step 1 Using 1,4-dioxane in place of dimethyl ether (DME), the compounds of Examples 181 to 183 were obtained.
[표 14]Table 14
Figure PCTKR2019011876-appb-img-000196
Figure PCTKR2019011876-appb-img-000196
실시예 184 내지 실시예 196Examples 184 to 196
실시예 68에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 피리미딘-5-일보론산 대신 하기 [표 15]에 나열된 R을 사용하여 실시예 184 내지 실시예 196의 화합물을 수득하였다.Compounds of Examples 184 to 196 were obtained using the same method as that described in Example 68, but using R listed in Table 15 below instead of pyrimidine-5-ylboronic acid in Step 1.
[표 15]Table 15
Figure PCTKR2019011876-appb-img-000197
Figure PCTKR2019011876-appb-img-000197
Figure PCTKR2019011876-appb-img-000198
Figure PCTKR2019011876-appb-img-000198
Figure PCTKR2019011876-appb-img-000199
Figure PCTKR2019011876-appb-img-000199
Figure PCTKR2019011876-appb-img-000200
Figure PCTKR2019011876-appb-img-000200
실시예 197 내지 203Examples 197 to 203
실시예 75에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 3-(트리플루오로메톡시)페닐보론산 대신 하기 [표 16]에 나열된 R을 사용하여 실시예 197 내지 실시예 203의 화합물을 수득하였다.Using the same method as described in Example 75, but using R listed in Table 16 below instead of 3- (trifluoromethoxy) phenylboronic acid in Step 1 to obtain the compounds of Examples 197 to 203 Did.
[표 16]Table 16
Figure PCTKR2019011876-appb-img-000201
Figure PCTKR2019011876-appb-img-000201
Figure PCTKR2019011876-appb-img-000202
Figure PCTKR2019011876-appb-img-000202
실시예 204: 7-아미노-6-메톡시-2-(2-니트로페닐)퀴놀린-5,8-디온의 제조Example 204: Preparation of 7-amino-6-methoxy-2- (2-nitrophenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000203
Figure PCTKR2019011876-appb-img-000203
실시예 109에 기재된 것과 동일한 방법을 사용하되, 4-클로로-3-플로오로페닐보론산 대신 2-메톡시-6-(트리부틸스태닐)피라진 ( 화학식 16-2)을 사용하여 표제 화합물을 수득하였다.Using the same method as described for Example 109, using 2-methoxy-6- (tributylstannyl) pyrazine ( Formula 16-2 ) instead of 4-chloro-3-fluorophenylboronic acid to give the title compound. Obtained.
1H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.63 (d, J = 8.1 Hz, 1H), 8.46-8.43 (m, 2H), 7.01 (s, 2H), 4.07 (s, 3H), 3.83 (s, 3H). MS 313.2 (M+1).1H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.63 (d, J = 8.1 Hz, 1H), 8.46-8.43 (m, 2H), 7.01 (s, 2H), 4.07 (s, 3H) , 3.83 (s, 3 H). MS 313.2 (M + 1).
실시예 205: 7-아미노-6-메톡시-2-(6-메톡시피라진-2-일)퀴놀린-5,8-디온의 제조Example 205: Preparation of 7-amino-6-methoxy-2- (6-methoxypyrazin-2-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000204
Figure PCTKR2019011876-appb-img-000204
실시예 109에 기재된 것과 동일한 방법을 사용하되, 4-클로로-3-플로오로페닐보론산 대신 4,4,5,5-테트라메틸-2-(2-니트로페닐)-1,3,2-디옥사보롤레인을 사용하여 표제 화합물을 수득하였다.The same method as described in Example 109 was used, but 4,4,5,5-tetramethyl-2- (2-nitrophenyl) -1,3,2- instead of 4-chloro-3-fluorophenylboronic acid. Dioxaborolein was used to give the title compound.
1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.0 Hz, 1H), 8.04 (dd, J = 7.8, 0.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.65-7.60 (m, 2H), 4.10 (s, 3H). MS 326.2 (M+1).1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.0 Hz, 1H), 8.04 (dd, J = 7.8, 0.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.65-7.60 (m, 2H), 4.10 (s, 3H). MS 326.2 (M + 1).
실시예 206 및 실시예 207Example 206 and Example 207
실시예 75에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 3-(트리플루오로메톡시)페닐보론산 대신 [표 17]에 나열된 R을 사용하고, 디메틸에테르(DME) 대신 1,4-디옥산을 사용하여 실시예 206 및 실시예 207의 화합물을 수득하였다.Using the same method as described in Example 75, using R listed in Table 17 instead of 3- (trifluoromethoxy) phenylboronic acid in Step 1, 1,4-di instead of dimethyl ether (DME) The compounds of Example 206 and Example 207 were obtained using Oxane.
[표 17]Table 17
Figure PCTKR2019011876-appb-img-000205
Figure PCTKR2019011876-appb-img-000205
실시예 208 및 실시예 209Example 208 and Example 209
실시예 109에 기재된 것과 동일한 방법을 사용하되, 4-클로로-3-플로오로페닐보론산 대신 [표 18]의 R을 사용하고, 디메틸에테르(DME) 대신 1,4-디옥산을 사용하여, 실시예 208 및 209의 화합물을 수득하였다.Using the same method as described in Example 109, using R of [Table 18] instead of 4-chloro-3-floorophenylboronic acid and 1,4-dioxane instead of dimethyl ether (DME), The compounds of Examples 208 and 209 were obtained.
[표 18]Table 18
Figure PCTKR2019011876-appb-img-000206
Figure PCTKR2019011876-appb-img-000206
실시예 210 내지 실시예 214Examples 210 to 214
실시예 110에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 2-메톡시피리미딘-5-일보론산 대신 [표 19]에 나열된 R을 사용하여 실시예 210 내지 실시예 214의 화합물을 수득하였다.Using the same method as that described in Example 110, but using R listed in Table 19 instead of 2-methoxypyrimidine-5-ylboronic acid in Step 1, the compounds of Examples 210 to 214 were obtained. .
[표 19]Table 19
Figure PCTKR2019011876-appb-img-000207
Figure PCTKR2019011876-appb-img-000207
실시예 215 내지 실시예 237Examples 215 to 237
실시예 111에 기재된 것과 동일한 방법을 사용하되, 피리미딘-5-일보론산 대신 [표 20]의 R을 사용하여, 실시예 215 내지 실시예 237의 화합물을 수득하였다.Using the same method as described in Example 111, but using R in [Table 20] instead of pyrimidine-5-ylboronic acid, compounds of Examples 215 to 237 were obtained.
[표 20]Table 20
Figure PCTKR2019011876-appb-img-000208
Figure PCTKR2019011876-appb-img-000208
Figure PCTKR2019011876-appb-img-000209
Figure PCTKR2019011876-appb-img-000209
Figure PCTKR2019011876-appb-img-000210
Figure PCTKR2019011876-appb-img-000210
Figure PCTKR2019011876-appb-img-000211
Figure PCTKR2019011876-appb-img-000211
Figure PCTKR2019011876-appb-img-000212
Figure PCTKR2019011876-appb-img-000212
실시예 238: 2-아미노-4-(7-아미노-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)벤조산의 제조Example 238: Preparation of 2-amino-4- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoic acid
Figure PCTKR2019011876-appb-img-000213
Figure PCTKR2019011876-appb-img-000213
실시예 210에서 합성된 메틸 2-아미노-4-(7-아미노-6-메톡시-5,8-디옥소-5,8-디히드로퀴놀린-2-일)벤조산 (1 eq)을 MeOH/H 2O (1:1)에 용해시킨 후, 포타슘 하이드록시드 (35 eq) 수용액을 적가하여 50 °C에서 2.5시간 동안 반응시켰다. 반응 종결 후, 1M 염산수용액으로 중화시키고, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 오렌지색 고체의 표제 화합물을 수득하였다.The methyl 2-amino-4- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoic acid (1 eq) synthesized in Example 210 was MeOH / After dissolving in H 2 O (1: 1), an aqueous potassium hydroxide (35 eq) solution was added dropwise and reacted at 50 ° C. for 2.5 hours. After completion of the reaction, neutralized with 1M aqueous hydrochloric acid, extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound as an orange solid.
1H NMR (400 MHz, MeOD) δ 8.37 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.3, 1.7 Hz, 1H), 3.81 (s, 3H). MS 341.10 (M+2).1H NMR (400 MHz, MeOD) δ 8.37 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.3, 1.7 Hz, 1H), 3.81 (s, 3H). MS 341.10 (M + 2).
실시예 239: 7-아미노-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온의 제조Example 239: Preparation of 7-amino-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
단계 1: 7-브로모-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온의 제조Step 1: Preparation of 7-bromo-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000214
Figure PCTKR2019011876-appb-img-000214
실시예 171에서 합성된 6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온 (1 eq)을 클로로포름에 용해시킨 후, 0 °C에 브로민 (1.1 eq)을 적가하고 반응 혼합물을 실온에서 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 7-브로모-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온을 수득하였다.After dissolving 6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione (1 eq) synthesized in Example 171 in chloroform, bromine (1.1 eq) was added dropwise at 0 ° C. And the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 7-bromo-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione.
단계 2: 7-아지도-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-azido-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000215
Figure PCTKR2019011876-appb-img-000215
단계 1에서 합성된 7-브로모-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온 (1 eq)을 DMF/MeOH (1/1)에 용해시킨 후, 소듐 아자이드 (1.5 eq)를 적가하고 실온에서 1시간 내지 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하여 7-아지도-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온을 수득하였다.7-bromo-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione synthesized in step 1 (1 eq) was dissolved in DMF / MeOH (1/1), sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 to 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to give 7-azido-6-methoxy-2- (pyrazin-2-yl) quinoline-5, 8-dione was obtained.
단계 3: 7-아미노-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온의 제조Step 3: Preparation of 7-amino-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000216
Figure PCTKR2019011876-appb-img-000216
단계 2에서 합성된 7-아지도-6-메톡시-2-(피라진-2-일)퀴놀린-5,8-디온 (1 eq)을 THF/MeOH (5/1)에 용해시킨 후, 소듐보로하이드리드 (10 eq)를 적가하고 실온에서 3시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다. After dissolving the 7 -azido-6-methoxy-2- (pyrazin-2-yl) quinoline-5,8-dione (1 eq) synthesized in step 2 in THF / MeOH (5/1), sodium Borohydride (10 eq) was added dropwise and stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 8.71-8.66 (m, 3H), 8.52 (d, J = 8.2 Hz, 1H), 4.20 (s, 3H). MS 283.2 (M+1).1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 8.71-8.66 (m, 3H), 8.52 (d, J = 8.2 Hz, 1H), 4.20 (s, 3H). MS 283.2 (M + 1).
실시예 240: 6-(7-아미노-6-메톡시-5,8-디옥소-5,8-디하이드로퀴놀린-2-일)-2-메톡시니코틴산의 제조Example 240: Preparation of 6- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) -2-methoxynicotinic acid
Figure PCTKR2019011876-appb-img-000217
Figure PCTKR2019011876-appb-img-000217
실시예 214에서 합성된 메틸 6-(7-아미노-6-메톡시-5,8-디옥소-5,8-디히드로퀴놀린-2-일)-2-메톡시니코틴산 (1 eq)을 MeOH/H 2O (5/1)에 용해시키고, NaOH (5 eq)을 적가하여 70 °C에서 3시간 동안 교반한 후, 상온까지 냉각하였다. 반응 종결 후, 1M 염산수용액으로 중화시켰다. 유기층을 에틸아세테이트로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC (디클로로메탄/메탄올; 90:10)로 분리 및 정제하여 표제 화합물을 수득하였다.The methyl 6- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) -2-methoxynicotinic acid (1 eq) synthesized in Example 214 was MeOH. It was dissolved in / H 2 O (5/1), NaOH (5 eq) was added dropwise and stirred at 70 ° C for 3 hours, and then cooled to room temperature. After completion of the reaction, neutralization was performed with a 1M aqueous hydrochloric acid solution. The organic layer was extracted with ethyl acetate, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (dichloromethane / methanol; 90:10) to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.1 Hz, 1H), 8.58 (d, J = 7.9 Hz, 1H), 8.50 - 8.37 (m, 2H), 5.19 (s, 2H), 4.28 (s, 3H), 4.05 (s, 3H). MS 356.20 (M+1).1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.1 Hz, 1H), 8.58 (d, J = 7.9 Hz, 1H), 8.50-8.37 (m, 2H), 5.19 (s, 2H), 4.28 (s, 3H), 4.05 (s, 3H). MS 356.20 (M + 1).
실시예 241: 7-아미노-2-(4-클로로-3-플루오로페닐)퀴놀린-5,8-디온의 제조Example 241: Preparation of 7-amino-2- (4-chloro-3-fluorophenyl) quinoline-5,8-dione
단계 1: N-(2-(4-클로로-3-플루오로페닐)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Step 1: Preparation of N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000218
Figure PCTKR2019011876-appb-img-000218
제조예 17에서 합성된 N-(2-클로로-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (화학식 17-10, 1 eq)를 DME에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 4-클로로-3-플루오로페닐보론산(1.1 eq) 및 2M Na 2CO 3 수용액 (4 eq)을 실온에서 적가하고 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 130 °C로 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조시하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 N-(2-(4-클로로-3-플루오로페닐)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드를 수득하였다.After dissolving N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 1 eq) synthesized in Preparation Example 17 in DME, Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol%), 4-chloro-3-fluorophenylboronic acid (1.1 eq) and 2M Na 2 CO 3 aqueous solution (4 eq) was added dropwise at room temperature for 10 min. It was stirred. The reaction mixture was reacted in a Biotage microwave at 130 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide. Obtained.
단계 2: 7-아미노-2-(4-클로로-3-플루오로페닐)퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (4-chloro-3-fluorophenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000219
Figure PCTKR2019011876-appb-img-000219
단계 1에서 합성된 N-(2-(4-클로로-3-플루오로페닐)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (1 eq)를 메탄올에 용해시킨 후, 4M 포타슘하이드록시드 (1.1 eq) 수용액을 적가하여 70 °C에서 30분간 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in step 1 was added to methanol. After dissolving, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 10.8, 1.9 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.82 (dd, J = 8.1 Hz, 1H), 5.89 (s, 1H). MS 303.0 (M+1).1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 10.8, 1.9 Hz, 1H), 8.14 (dd , J = 8.4, 1.7 Hz, 1H), 7.82 (dd, J = 8.1 Hz, 1H), 5.89 (s, 1H). MS 303.0 (M + 1).
실시예 242 내지 실시예 262Examples 242 to 262
실시예 241에 기재된 방법과 동일한 방법을 사용하되, 실시예 249의 단계 1에서 2-플루오로페닐보론산대신 하기 [표 21]에 나열된 R을 사용하여 실시예 242 내지 실시예 262의 화합물을 수득하였다.Using the same method as described in Example 241, but using R listed in Table 21 below instead of 2-fluorophenylboronic acid in Step 1 of Example 249 to obtain the compounds of Examples 242 to 262 Did.
[표 21]Table 21
Figure PCTKR2019011876-appb-img-000220
Figure PCTKR2019011876-appb-img-000220
Figure PCTKR2019011876-appb-img-000221
Figure PCTKR2019011876-appb-img-000221
Figure PCTKR2019011876-appb-img-000222
Figure PCTKR2019011876-appb-img-000222
Figure PCTKR2019011876-appb-img-000223
Figure PCTKR2019011876-appb-img-000223
Figure PCTKR2019011876-appb-img-000224
Figure PCTKR2019011876-appb-img-000224
실시예 263: N-(5,8-디옥소-2-(피라진-2-일)-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Example 263: Preparation of N- (5,8-dioxo-2- (pyrazin-2-yl) -5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000225
Figure PCTKR2019011876-appb-img-000225
제조예 17에서 합성된 N-(2-클로로-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (화학식 17-10, 50 mg, 0.2 mmol) 및 Pd(Ph 3) 4 (23 mg, 0.02 mmol, 0.1 eq)를 1,4-디옥산 (4 ml)에 용해시킨 후, 2-(트리부틸스태닐)피라진 (110 mg, 0.3 mmol, 2 eq)을 상온에서 적가하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 130 °C로 2시간 동안 반응시켰다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 50 mg, 0.2 mmol) and Pd (Ph) synthesized in Preparation Example 17 3 ) 4 (23 mg, 0.02 mmol, 0.1 eq) was dissolved in 1,4-dioxane (4 ml), followed by 2- (tributylstannyl) pyrazine (110 mg, 0.3 mmol, 2 eq) at room temperature. Dropped in. The reaction mixture was reacted in a Biotage microwave at 130 ° C for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.70 (dd, J = 1.5 Hz, 1H), 8.59 (d, J = 8.2 Hz, 1H), 8.45 (Broad s, 1H), 8.01 (s, 1H), 2.35 (s, 3H). MS 295.2 (M).1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.70 (dd, J = 1.5 Hz, 1H ), 8.59 (d, J = 8.2 Hz, 1H), 8.45 (Broad s, 1H), 8.01 (s, 1H), 2.35 (s, 3H). MS 295.2 (M).
실시예 264: 7-아미노-2-(5-메톡시피라진-2-일)퀴놀린-5,8-디온의 제조Example 264: Preparation of 7-amino-2- (5-methoxypyrazin-2-yl) quinoline-5,8-dione
단계 1: N-(2-(5-메톡시피라진-2-일)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Step 1: Preparation of N- (2- (5-methoxypyrazin-2-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000226
Figure PCTKR2019011876-appb-img-000226
실시예 263에 기재된 방법과 동일한 방법을 사용하되, 2-(트리부틸스태닐)피라진 대신 2-메톡시-5-(트리부틸스태닐)피라진을 사용하여 N-(2-(5-메톡시피라진-2-일)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드를 수득하였다.Using the same method as described in Example 263, using 2-methoxy-5- (tributylstannyl) pyrazine instead of 2- (tributylstannyl) pyrazine, N- (2- (5-methoxy Pyrazin-2-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide was obtained.
단계 2: 7-아미노-2-(5-메톡시피라진-2-일)퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (5-methoxypyrazin-2-yl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000227
Figure PCTKR2019011876-appb-img-000227
단계 1에서 합성된 N-(2-(5-메톡시피라진-2-일)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드를 메탄올에 용해시킨후 4M 포타슘하이드록시드 (1.1 eq) 수용액을 적가하여 70 °C에서 30분간 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving the N- (2- (5-methoxypyrazin-2-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide synthesized in step 1 in methanol, 4M Potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 5.89 (s, 1H), 4.02 (s, 3H). MS 283.09 (M+1).1H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 5.89 (s , 1H), 4.02 (s, 3H). MS 283.09 (M + 1).
실시예 265: N-(2-(2-플루오로페닐)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Example 265: Preparation of N- (2- (2-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000228
Figure PCTKR2019011876-appb-img-000228
제조예 17에서 합성된 N-(2-클로로-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (화학식 17-10, 1 eq)를 DME에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (10 mol %), 2-플루오로페닐보론산 (1.1 eq) 및 2 M Na 2CO 3 수용액 (4 eq)을 실온에서 적가하고 10분간 교반하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 130 °C로 30분간 반응시켰다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 1 eq) synthesized in Preparation Example 17 in DME, Pd (dppf) Cl 2 -CH 2 Cl 2 (10 mol%), 2-fluorophenylboronic acid (1.1 eq) and 2 M Na 2 CO 3 aqueous solution (4 eq) was added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted in a Biotage microwave at 130 ° C for 30 minutes. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.3 Hz, 1H), 8.42 (s, 1H), 8.22-8.16 (m, 2H), 7.98 (s, 1H), 7.51-7.46 (m, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.24-7.19 (m, 1H), 2.33 (s, 3H). MS 311.04 (M+1).1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.3 Hz, 1H), 8.42 (s, 1H), 8.22-8.16 (m, 2H), 7.98 (s, 1H), 7.51-7.46 (m, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.24-7.19 (m, 1H), 2.33 (s, 3H). MS 311.04 (M + 1).
실시예 266: N-(5,8-디옥소-2-(4-(트리플루오로메틸)페닐)-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Example 266: Preparation of N- (5,8-dioxo-2- (4- (trifluoromethyl) phenyl) -5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000229
Figure PCTKR2019011876-appb-img-000229
실시예 265에 기재된 방법과 동일한 방법을 사용하되, 2-플루오로페닐보론산대신 4-(트리플루오로메틸)페닐보론산을 사용하여 표제의 화합물을 수득하였다.The same method as described in Example 265 was used, but 4- (trifluoromethyl) phenylboronic acid was used instead of 2-fluorophenylboronic acid to obtain the title compound.
1H NMR (400 MHz, CDCl 3) δ 8.54 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.27 (d, J = 8.0 Hz, 2H), 8.17 (d, J = 8.2 Hz, 1H), 7.99 (s, 1H), 7.80 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H). MS 360.93 (M).1H NMR (400 MHz, CDCl 3 ) δ 8.54 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.27 (d, J = 8.0 Hz, 2H), 8.17 (d, J = 8.2 Hz, 1H), 7.99 (s, 1H), 7.80 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H). MS 360.93 (M).
실시예 267: 7-아미노-2-(4-(트리플루오로메티)페닐)퀴놀린-5,8-디온의 제조Example 267: Preparation of 7-amino-2- (4- (trifluoromethy) phenyl) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000230
Figure PCTKR2019011876-appb-img-000230
실시예 266에서 합성된 N-(5,8-디옥소-2-(4-(트리플루오로메틸)페닐)-5,8-디히드로퀴놀린-7-일)아세트아미드 (1 eq)를 메탄올에 용해시킨 후, 4M 포타슘하이드록시드 (1.1 eq) 수용액을 적가하여 70 °C에서 30분간 교반시켰다. 반응 종결 후, 다이클로로메탄으로 추출한 다음, 무수 MgSO 4 로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC 로 분리 및 정제하여 표제 화합물을 수득하였다.N- (5,8-dioxo-2- (4- (trifluoromethyl) phenyl) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in Example 266 was methanol. After dissolving in, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 7.9 Hz, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 6.10 (s, 1H), 5.33 (s, 2H). MS 319.00 (M+1).1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 7.9 Hz, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 6.10 (s, 1H), 5.33 (s, 2H). MS 319.00 (M + 1).
실시예 268: N-(2-(4,4-디플루오로피페리딘-1-일)-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Example 268: Preparation of N- (2- (4,4-difluoropiperidin-1-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000231
Figure PCTKR2019011876-appb-img-000231
제조예 17에서 합성된 N-(2-클로로-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (화학식 17-10, 1 eq)를 DMF에용해시킨 후 4,4-디플로로피페리딘 (1.1 eq), DIPEA (1 eq)를 실온에서 적가하고 80 °C에서 3시간 동안 반응시켰다. 반응 종결 후, 에틸아세테이트로 추출하였다. 유기층을 H 2O 및 브라인으로 순서대로 세정한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 1 eq) synthesized in Preparation Example 17 was dissolved in DMF, and then 4 , 4-Difluoropiperidine (1.1 eq), DIPEA (1 eq) was added dropwise at room temperature and reacted at 80 ° C for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 3.96 (s, 4H), 2.29 (s, 32H), 2.10-2.07 (m, 4H). MS 336.03 (M+1).1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 3.96 (s , 4H), 2.29 (s, 32H), 2.10-2.07 (m, 4H). MS 336.03 (M + 1).
실시예 269: 7-아미노-2-(페닐아미노)퀴놀린-5,8-디온의 제조Example 269: Preparation of 7-amino-2- (phenylamino) quinoline-5,8-dione
단계 1: N-(5,8-디옥소-2-(페닐아미노)-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Step 1: Preparation of N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000232
Figure PCTKR2019011876-appb-img-000232
제조예 17에서 합성된 N-(2-클로로-5,8-디옥소-5,8-디히드로 퀴놀린-7-일)아세트아미드 (화학식 17-10, 10 mg, 0.04 mmol) 및 아닐린 (4.4 ul, 0.048 mmol, 1.2 eq)을 1,4-디옥산 (1 ml)에 용해시킨 후, Pd(dppf)Cl 2-CH 2Cl 2 (1 mg, 1.2 umol, 0.01 eq) 및 소듐 tert-부톡시드 (4.6 mg, 0.048 mmol, 1.2 eq)를 상온에서 적가하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 120 °C로 1시간 동안 반응시켰다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 N-(5,8-디옥소-2-(페닐아미노)-5,8-디히드로퀴놀린-7-일)아세트아미드를 수득하였다.N- (2-Chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 10 mg, 0.04 mmol) and aniline (4.4 synthesized in Preparation Example 17) ul, 0.048 mmol, 1.2 eq) was dissolved in 1,4-dioxane (1 ml), then Pd (dppf) Cl 2 -CH 2 Cl 2 (1 mg, 1.2 umol, 0.01 eq) and sodium tert-butox Seed (4.6 mg, 0.048 mmol, 1.2 eq) was added dropwise at room temperature. The reaction mixture was reacted in a Biotage microwave at 120 ° C for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide.
단계 2: 7-아미노-2-(페닐아미노)퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (phenylamino) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000233
Figure PCTKR2019011876-appb-img-000233
단계 1에서 합성된 N-(5,8-디옥소-2-(페닐아미노)-5,8-디히드로퀴놀린-7-일)아세트아미드 (1 eq)를 메탄올에 용해시킨후 4 M 포타슘하이드록시드 (1.1 eq) 수용액을 적가하여 70 °C에서 30분간 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.After dissolving N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in Step 1 in methanol, 4 M potassium hydride Aqueous (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, MeOD) δ 8.08 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.10 - 7.06 (m, 2H), 5.84 (s, 1H). MS 266.1 (M+1).1H NMR (400 MHz, MeOD) δ 8.08 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.10-7.06 (m , 2H), 5.84 (s, 1H). MS 266.1 (M + 1).
실시예 270: 7-아미노-2-(4-(트리플루오로메틸)페닐아미노)퀴놀린-5,8-디온의 제조Example 270: Preparation of 7-amino-2- (4- (trifluoromethyl) phenylamino) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000234
Figure PCTKR2019011876-appb-img-000234
실시예 269에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 아닐린 대신 4-(트리플루오로메틸)아닐린을 사용하여 표제 화합물을 수득하였다.The same method as described in Example 269 was used, but 4- (trifluoromethyl) aniline was used instead of aniline in step 1 to obtain the title compound.
1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.7 Hz, 1H), 5.97 (s, 1H), 5.17 (s, 2H). MS 333.90 (M).1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.7 Hz, 1H), 5.97 (s, 1H), 5.17 (s, 2H). MS 333.90 (M).
실시예 271: 7-아미노-2-(피리딘-2-일아미노)퀴놀린-5,8-디온 의 제조Example 271: Preparation of 7-amino-2- (pyridin-2-ylamino) quinoline-5,8-dione
단계 1: N-(5,8-디옥소-2-(피리딘-2-일아미노)-5,8-디히드로퀴놀린-7-일)아세트아미드의 제조Step 1: Preparation of N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide
Figure PCTKR2019011876-appb-img-000235
Figure PCTKR2019011876-appb-img-000235
제조예 17 에서 합성된 N-(2-클로로-5,8-디옥소-5,8-디히드로퀴놀린-7-일)아세트아미드 (화학식 17-10, 50 mg, 0.20 mmol) 및 피리딘-2-아민 (23 mg, 0.24 mmol, 1.2 eq)을 1,4-디옥산 (5 ml)에 용해시킨 후, Pd(dba) 3 (27 mg, 0.03 mmol, 0.15 eq), Cs 2CO 3 (162 mg, 0.50 mmol, 2.5 eq) 및 잔포스 (xantphos)(23 mg, 0.04m mmol, 0.2 eq)를 상온에서 적가하였다. 반응 혼합물을 바이오타지 마이크로웨이브에서 140 °C로 1시간 동안 반응시켰다. 반응 종결 후, 반응 혼합물을 셀라이트로 여과하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 prep HPLC로 분리 및 정제하여 N-(5,8-디옥소-2-(피리딘-2-일아미노)-5,8-디히드로퀴놀린-7-일)아세트아미드를 수득하였다.N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 50 mg, 0.20 mmol) and pyridine-2 synthesized in Preparation Example 17 -Amine (23 mg, 0.24 mmol, 1.2 eq) was dissolved in 1,4-dioxane (5 ml), followed by Pd (dba) 3 (27 mg, 0.03 mmol, 0.15 eq), Cs 2 CO 3 (162 mg, 0.50 mmol, 2.5 eq) and xantphos (23 mg, 0.04m mmol, 0.2 eq) were added dropwise at room temperature. The reaction mixture was reacted in a Biotage microwave at 140 ° C for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by prep HPLC to obtain N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide. .
단계 2: 7-아미노-2-(피리딘-2-일아미노)퀴놀린-5,8-디온의 제조Step 2: Preparation of 7-amino-2- (pyridin-2-ylamino) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000236
Figure PCTKR2019011876-appb-img-000236
단계 1에서 N-(5,8-디옥소-2-(피리딘-2-일아미노)-5,8-디히드로퀴놀린-7-일)아세트아미드 (1 eq)를 메탄올에 용해시킨 후, 4M 포타슘하이드록시드 (1.1 eq) 수용액을 적가하여 70 °C에서 30분간 교반시켰다. 반응 종결 후, 디클로로메탄으로 추출한 다음, 무수 MgSO 4로 건조하고, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 표제 화합물을 수득하였다.In step 1, N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) was dissolved in methanol, followed by 4M. Potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.
1H NMR (400 MHz, MeOD) δ 8.18 (d, J = 3.8 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.69 - 7.61 (m, 1H), 6.90 (dd, J = 6.8, 5.3 Hz, 2H), 5.76 (s, 1H). MS 266.97 (M).1H NMR (400 MHz, MeOD) δ 8.18 (d, J = 3.8 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.69-7.61 (m , 1H), 6.90 (dd, J = 6.8, 5.3 Hz, 2H), 5.76 (s, 1H). MS 266.97 (M).
실시예 272: 7-아미노-2-(피리다진-3-일아미노)퀴놀린-5,8-디온의 제조Example 272: Preparation of 7-amino-2- (pyridazin-3-ylamino) quinoline-5,8-dione
Figure PCTKR2019011876-appb-img-000237
Figure PCTKR2019011876-appb-img-000237
실시예 271에 기재된 방법과 동일한 방법을 사용하되, 단계 1에서 피리딘-2-아민 대신 피리다진-3-아민을 사용하여 표제 화합물을 수득하였다.The same method as described in Example 271 was used, but pyridazine-3-amine was used instead of pyridin-2-amine in step 1 to obtain the title compound.
1H NMR (400 MHz, MeOD) δ 8.87 (d, J = 4.6 Hz, 1H), 8.54 (m, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.88 (m, 1H), 7.72 (d, J = 8.6 Hz, 1H), 5.94 (s, 1H). MS 267.97 (M).1H NMR (400 MHz, MeOD) δ 8.87 (d, J = 4.6 Hz, 1H), 8.54 (m, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.88 (m, 1H), 7.72 (d , J = 8.6 Hz, 1H), 5.94 (s, 1H). MS 267.97 (M).
[실험예] [Experimental Example]
실험예 1: 화학식 I의 화합물의 세포 성장 억제 활성 시험Experimental Example 1: Cell growth inhibitory activity test of the compound of formula (I)
술포로다민 B(SRB) 검정을 사용하여 본원의 화학식 I의 화합물의 항-종양 활성을 시험하였다.The anti-tumor activity of the compounds of formula I herein was tested using the sulforhodamine B (SRB) assay.
신장암 세포주인 ACHN세포(100 μl, 5,000 내지 40,000 cells/well 함유, 각각의 세포주의 배가시간(doubling time)에 따라 조절)를 96-웰 미량정량 플레이트에서 인큐베이트 하였다. 24시간 후, 본원 화학식 I의 화합물 100 μl를 각각의 웰에 첨가하고, 배양물을 37 °C에서 48시간 동안 인큐베이트 하였다. 세포를 트리클로로아세트산(50 ㎕ per well)로 고정시켰다. 플레이트를 4 °C에서 최소 1시간에서 최대 3시간 동안 인큐베이트하였다. 플레이트에서 액체를 제거하고, 물로 5회 세척한 후 실온에서 12시간 내지 24시간 동안 건조하였다. 고정된 세포를 100 μl SRB로 실온에서 5분간 염색하고, 플레이트를 1 % 글라시알 아세트산으로 3회 세척하였다. 그리고 실온에서 약 12시간 내지 24시간 동안 건조하였다. SRB 염색된 세포를 10 mM 트리즈마 염기(Trizma base)에 용해시키고, 515 nm에서 흡광도를 측정하였다.Kidney cancer cell line ACHN cells (100 μl, containing 5,000 to 40,000 cells / well, adjusted according to the doubling time of each cell line) were incubated in a 96-well microquantitative plate. After 24 hours, 100 μl of the compound of formula I herein was added to each well, and the cultures were incubated at 37 ° C for 48 hours. Cells were fixed with trichloroacetic acid (50 μl per well). Plates were incubated at 4 ° C for a minimum of 1 hour and a maximum of 3 hours. The liquid was removed from the plate, washed 5 times with water and then dried at room temperature for 12 to 24 hours. The fixed cells were stained with 100 μl SRB for 5 minutes at room temperature, and the plates were washed 3 times with 1% glacial acetic acid. And dried at room temperature for about 12 to 24 hours. SRB stained cells were lysed in 10 mM Trizma base and absorbance was measured at 515 nm.
50% 성장 억제를 나타내는 GI 50(Growth Inhibition of 50%)는 하기 식으로부터 계산하였으며, 이 수치는 대조군 세포의 수가 50%로 줄어들도록 하는 수치를 의미한다.GI 50 (Growth Inhibition of 50%) showing 50% growth inhibition was calculated from the following formula, and this value means a value that reduces the number of control cells to 50%.
[(Ti-Tz)/(C-Tz)] × 100=50[(Ti-Tz) / (C-Tz)] × 100 = 50
상기 식에서, Tz은 배양 시작시 평균 세포수(cells/ml), Ti는 약물 처리 48시간 후 평균 세포수(cells/ml), C는 대조군의 48시간 후 평균 세포수(cells/ml)이다.In the above formula, Tz is the average number of cells (cells / ml) at the start of culture, Ti is the average number of cells (cells / ml) after 48 hours of drug treatment, and C is the average number of cells (cells / ml) after 48 hours of the control group.
그 결과, 본원의 화학식 I의 화합물이 TGase 2 억제 활성을 나타냄을 알 수 있었으며, 구체적인 결과는 아래 [표 22] 및 [표 23]과 같다.As a result, it was found that the compound of the formula (I) herein exhibits TGase 2 inhibitory activity, and specific results are shown in [Table 22] and [Table 23] below.
[표 22]Table 22
Figure PCTKR2019011876-appb-img-000238
Figure PCTKR2019011876-appb-img-000238
[표 23]Table 23
Figure PCTKR2019011876-appb-img-000239
Figure PCTKR2019011876-appb-img-000239
실험예 2: 화학식 I의 화합물의 TGase 2 억제 활성 시험Experimental Example 2: TGase 2 inhibitory activity test of the compound of formula (I)
트랜스글루타미나제가 [1,4,- 14C]푸트레신을 숙시닐레이티드 카제인에 결합시키는 것을 측정하고, NDGA가 푸트레신과 경쟁하여 그 반응을 억제하는 것을 관찰하여 본원 화학식 I의 화합물의 TGase 2 억제 활성을 측정하였다. Transglutaminase I [1,4, - 14 C] Fu tray measures incorporating demi succinyl federated casein, and observed that NDGA inhibits its reaction in competition with God Fu tray of the compounds of the present formula (I) TGase 2 inhibitory activity was measured.
구체적으로, 숙시닐화된 카제인(Calbiochem, Cat. No. 573464)을 10 mM CaCl 2, 0.15 M NaCl, 1.0 mM EDTA을 함유하는 0.1 M 트리스-아세트산 버퍼(pH 8.0)에 2 % 농도로 용해시켰다. 또한 상기 용액의 사용 직전에 5 mM DTT(1,4-디싸이오트레이톨)을 첨가하였다. Specifically, succinylated casein (Calbiochem, Cat. No. 573464) was dissolved in a 2% concentration in 0.1 M tris-acetic acid buffer (pH 8.0) containing 10 mM CaCl 2 , 0.15 M NaCl, 1.0 mM EDTA. In addition, 5 mM DTT (1,4-disthiothreitol) was added immediately before use of the solution.
250 μCi/ml의 [C- 14C]푸트레신 디하이드로클로라이드(Chemicals, Cat. No. ARC-245)를 122.5 mL 증류수에 용해시켜 2 μCi/ml로 조절하였다. 기니피그 간으로부터 수득한 트랜스글루타미나아제(gpTG2, Zedia, Pro. No. T006)를 50 mM 1 mM EDTA를 함유하는 트리스-HCl 버퍼(pH 7.5)에 용해시켰다. 1X TEN 버퍼는 100 mM 트리스-아세트산 버퍼(pH 8.0), 1 mM EDTA, 및 150 mM NaCl로 구성되며, 글래스 마이크로파이버 필터는 Whatman GF/A로부터 구입하였다(Cat. No. 1820-025)250 [mu] Ci / ml [C- 14 C] Futresin dihydrochloride (Chemicals, Cat. No. ARC-245) was dissolved in 122.5 mL distilled water and adjusted to 2 [mu] Ci / ml. Transglutaminase (gpTG2, Zedia, Pro. No. T006) obtained from guinea pig liver was dissolved in Tris-HCl buffer (pH 7.5) containing 50 mM 1 mM EDTA. 1X TEN buffer consisted of 100 mM Tris-acetic acid buffer (pH 8.0), 1 mM EDTA, and 150 mM NaCl, a glass microfiber filter was purchased from Whatman GF / A (Cat. No. 1820-025)
각각의 바이알에 TEN 버퍼 48.58 μl 및 25 ng/μl의 gpTG2 0.42 μl을 첨가하였다. 그 후, 실시예에서 제조된 화학식 I의 화합물들을 1 μl씩 서로 다른 6개의 농도(100 μM, 200 μM, 300 μM, 400 μM, 500 μM, 600 μM)로 검정 바이알에 첨가하였다. 검정 바이알을 실온에서 5분 동안 프리-인큐베이트시킨 후, 2 % 석시닐화 카제인 (5mM DTT) 140 μl 및 2 μCi/ml 푸트레신 10 μl를 각각의 검정 바이알에 첨가하하고, 온도조절믹서(thermomixer)로 37 °C에서 15분간 인큐베이트하였다. 차가운 5 % 트리클로로아세트산(TCA) 2 ml를 첨가하여 반응을 종결시켰다. 검정 바이알을 4 °C에서 1시간 이상 두어 고정시켰다. 검정 혼합물을 글래스-파이버 필터 페이퍼 디스크(Whatman GF/A)를 통해 여과하고, 차가운 5 % TCA로 세척하였다. 필터를 카운팅 바이알에 넣고, 섬광 칵테일(scintillation cocktail) 용액을 첨가하였다. 카운팅 바이알을 5초간 볼텍스하고, 계수 전 30분 동안 쉐이커에 두었다. 48.58 μl of TEN buffer and 0.42 μl of gpTG2 at 25 ng / μl were added to each vial. Thereafter, the compounds of Formula I prepared in the Examples were added to assay vials at 6 different concentrations (100 μM, 200 μM, 300 μM, 400 μM, 500 μM, 600 μM) at 1 μl. After pre-incubating the assay vials at room temperature for 5 minutes, 140 μl of 2% succinylated casein (5 mM DTT) and 10 μl of 2 μCi / ml putrescine were added to each assay vial, and the thermostatic mixer ( thermomixer) for 15 minutes at 37 ° C. The reaction was terminated by adding 2 ml of cold 5% trichloroacetic acid (TCA). The assay vial was set at 4 ° C for at least 1 hour to fix. The assay mixture was filtered through a glass-fiber filter paper disc (Whatman GF / A) and washed with cold 5% TCA. The filter was placed in a counting vial, and a scintillation cocktail solution was added. The counting vial was vortexed for 5 seconds and placed in a shaker for 30 minutes before counting.
그 결과, 본원의 화학식 I의 화합물이 TGase 2 억제 활성을 나타냄을 알 수 있었으며, 구체적인 결과는 하기 [표 24] 및 [표 25]에 나타내었다.As a result, it was found that the compound of the formula (I) herein exhibits TGase 2 inhibitory activity, and specific results are shown in the following [Table 24] and [Table 25].
[표 24]Table 24
Figure PCTKR2019011876-appb-img-000240
Figure PCTKR2019011876-appb-img-000240
[표 25]Table 25
Figure PCTKR2019011876-appb-img-000241
Figure PCTKR2019011876-appb-img-000241
실험예 3: 화학식 I의 화합물의 종양 억제 효과 확인Experimental Example 3: Confirmation of tumor suppression effect of compound of formula (I)
신장암 세포를 이종이식하여 마우스에 신장암을 유발하고, 실시예 120에서 합성한 화합물을 폴록사머 7.5%, 폴리에틸렌글리콜 30%, 증류수 57.5% 및 소이빈 오일 5%로 이루어진 용액에 첨가하여 5 mg/kg, 10 mg/kg 또는 20 mg/kg으로 7주간 주 6일 1일 1회 투여 하였으며, 음성 대조군으로는 폴록사머 7.5%, 폴리에틸렌글리콜 30%, 증류수 57.5% 및 소이빈 오일 5%로 이루어진 용액을 투여하였다. 그 결과를 [도 1] 내지 [도 4] 및 [표 26]에 나타내었다.Kidney cancer cells are xenografted to induce kidney cancer in mice, and the compound synthesized in Example 120 is added to a solution consisting of 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water, and 5% soybean oil. / kg, 10 mg / kg or 20 mg / kg was administered once a day, 6 days per week for 7 weeks, and negative controls consisted of 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water and 5% soybean oil. The solution was administered. The results are shown in [FIG. 1] to [FIG. 4] and [Table 26].
[표 26]Table 26
Figure PCTKR2019011876-appb-img-000242
Figure PCTKR2019011876-appb-img-000242
[도 1] 내지 [도 3] 및 [표 26]에 나타난 바와 같이, 화학식 I의 화합물의 투여한 마우스는 대조군과 비교하여 종양의 크기 및 무게가 훨씬 작은 것을 알 수 있다. 또한, 도 4에 나타낸 바와 같이, 화학식 I의 화합물의 투여에 의해 마우스의 체중은 크게 변화하지 않는 것을 확인할 수 있으며, 따라서 화학식 I의 화합물이 독성이 적은 것을 알 수 있다.As shown in [Fig. 1] to [Fig. 3] and [Table 26], it can be seen that the mice administered with the compound of formula (I) have much smaller tumor size and weight compared to the control group. In addition, as shown in Figure 4, it can be seen that the weight of the mouse does not change significantly by administration of the compound of formula (I), so it can be seen that the compound of formula (I) is less toxic.
실험예 4: 화학식 I의 화합물의 약동학적 프로파일 확인Experimental Example 4: Confirmation of the pharmacokinetic profile of the compound of formula (I)
8 마리의 마우스에 10 mg/kg 용량으로 실시예 120에서 합성한 화합물을 경구 투여한 후, 꼬리 정맥을 통해 4시간까지 혈액을 채취하여 혈중에서의 농도를 LC-MS/MS로 분석하였다. 혈액에서의 정량 결과를 [도 5]에 나타내었으며, 약동학적 파라미터를 [표 27]에 나타내었다.Eight mice were orally administered the compound synthesized in Example 120 at a dose of 10 mg / kg, and blood was collected through the tail vein for up to 4 hours, and the concentration in the blood was analyzed by LC-MS / MS. Quantitative results in blood are shown in Figure 5, and pharmacokinetic parameters are shown in Table 27.
[표 27]Table 27
Figure PCTKR2019011876-appb-img-000243
Figure PCTKR2019011876-appb-img-000243
[도 5]에 나타낸 바와 같이, 실시예 120에서 합성한 화학식 I의 화합물은 혈장 농도가 빠르게 감소하였으며, [표 27]에 나타낸 바와 같이, T max가 8.1분이고, 평균 반감기가 79.9분이므로 생체 중에서 빠르게 소실됨을 예상할 수 있다 . As shown in FIG. 5, the plasma concentration of the compound of Formula I synthesized in Example 120 was rapidly decreased, and as shown in [Table 27], T max was 8.1 minutes, and the average half-life was 79.9 minutes, so in vivo It can be expected to disappear quickly .

Claims (20)

  1. 하기 반응식 1에 따라, 화합물 IMC1을 커플링 반응시켜 화합물 IMC2를 제조하는 단계; 및According to Reaction Scheme 1 below, a compound IMC1 is coupled to prepare a compound IMC2; And
    화합물 IMC2를 반응시켜 화합물 Q1을 제조하는 단계를 포함하는,Reacting compound IMC2 to produce compound Q1,
    퀴놀린-5,8-디온 유도체의 제조 방법;A method for producing a quinoline-5,8-dione derivative;
    [반응식 1][Scheme 1]
    Figure PCTKR2019011876-appb-img-000244
    Figure PCTKR2019011876-appb-img-000244
    상기 반응식 1에서, In Reaction Scheme 1,
    Xa 는 할로겐이고,Xa is halogen,
    Y, Y 1 및 Y 2 는 각각 독립적으로 C 1-6알킬이고,Y, Y 1 and Y 2 are each independently C 1-6 alkyl,
    A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 여기서, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10 헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O 로 치환될 수 있고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 Heterocycloalkyl, wherein C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl may be unsubstituted or substituted with one or more hydrogens R 5 or = O,
    R 5 는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e 로 치환될 수 있고,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl may be unsubstituted or one or more hydrogens may be substituted with R e ,
    R a 는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 Heterocycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
    R b 는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl are unsubstituted or one The above hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
    R c 및 R d 는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) is unsubstituted or at least one hydrogen is C 1-6 alkyl, C 2-6 alkenyl, -OH or halogen,
    R e 는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -(C=O)-R b, -(C=O)O-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH,-(C = O) -R b ,-(C = O) OR b , C 6-12 aryl, C 3-12 Heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3 -12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl is unsubstituted or at least one hydrogen is C 1-6 alkyl, C 2-6 alkenyl, -OH Or may be substituted with halogen,
    상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  2. 하기 반응식 2에 따라, 화합물 IMC1을 커플링 반응시켜 화합물 IMC2를 제조하는 단계;According to the following scheme 2, coupling the compound IMC1 to prepare a compound IMC2;
    화합물 IMC2을 반응시켜 화합물 IMC3을 제조하는 단계; 및Reacting compound IMC2 to prepare compound IMC3; And
    화합물 IMC3을 반응시켜 화합물 Q2를 제조하는 단계를 포함하는,Reacting compound IMC3 to produce compound Q2,
    퀴놀린-5,8-디온 유도체의 제조 방법;A method for producing a quinoline-5,8-dione derivative;
    [반응식 2][Scheme 2]
    Figure PCTKR2019011876-appb-img-000245
    Figure PCTKR2019011876-appb-img-000245
    상기 반응식 2에서,In Reaction Scheme 2,
    Xa 는 할로겐을 나타내고,Xa represents halogen,
    Y, Y 1 및 Y 2 는 각각 독립적으로 C 1-6알킬이고,Y, Y 1 and Y 2 are each independently C 1-6 alkyl,
    A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나의 수소가 -(C=O)-(C 1-6알킬)로 치환된 작용기를 나타내고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- 10 represents a functional group in which any one hydrogen of heterocycloalkyl is substituted with- (C = O)-(C 1-6 alkyl),
    A 2 는 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나의 수소가 -(C=O)-(C 2-6알케닐)로 치환된 작용기를 나타낸다.A 2 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- Hydrogen of any one of 10 heterocycloalkyl represents a functional group substituted with- (C = O)-(C 2-6 alkenyl).
  3. 제1항 또는 제2항에 있어서, The method according to claim 1 or 2,
    상기 반응식 1 또는 반응식 2 의 커플링 반응은 (HO) 2-B-(A 1),
    Figure PCTKR2019011876-appb-img-000246
    , K +(BF 3(A 1)) -, (A 1)-Sn(n-Bu) 3, NH 2-(A 1) 또는
    Figure PCTKR2019011876-appb-img-000247
    를 이용하는 것이고,    The coupling reaction of Scheme 1 or Scheme 2 is (HO) 2 -B- (A 1 ),
    Figure PCTKR2019011876-appb-img-000246
    , K + (BF 3 (A 1 )) - , (A 1 ) -Sn (n-Bu) 3 , NH 2- (A 1 ) or
    Figure PCTKR2019011876-appb-img-000247
    Is to use,
    상기 (HO) 2-B-(A 1),
    Figure PCTKR2019011876-appb-img-000248
    , K +(BF 3(A 1)) -, (A 1)-Sn(n-Bu) 3 또는 NH 2-(A 1)에서의 A 1 은 제1항 또는 제2항에서 정의한 것과 동일하고,    (HO) 2 -B- (A 1 ),
    Figure PCTKR2019011876-appb-img-000248
    , K + (BF 3 (A 1)) -, (A 1) -Sn (n-Bu) 3 or NH 2 - A 1 in (A 1) are the same as defined in claim 1 or 2, wherein ,
    Figure PCTKR2019011876-appb-img-000249
    에서 A 1 은 R 5로 치환 또는 비치환된 C 3-12헤테로아릴인,
    Figure PCTKR2019011876-appb-img-000249
    In A 1 is C 3-12 heteroaryl unsubstituted or substituted with R 5 ,
    퀴놀린-5,8-디온 유도체의 제조 방법.A method for producing a quinoline-5,8-dione derivative.
  4. 하기 반응식 3에 따라, 제1항의 제조방법에 따라 제조된 화합물 Q1을 할로겐화하여 화합물 Q3를 제조하는 단계를 포함하는,According to the following scheme 3, comprising the step of halogenating compound Q1 prepared according to the method of claim 1 to prepare compound Q3,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 3][Scheme 3]
    Figure PCTKR2019011876-appb-img-000250
    Figure PCTKR2019011876-appb-img-000250
    상기 반응식 3에서,In Reaction Scheme 3,
    Y 는 C 1-6알킬이고,Y is C 1-6 alkyl,
    B 1 은 할로겐이고,B 1 is halogen,
    A 1 은 제1항에서 정의한 것과 동일하다.A 1 is the same as defined in paragraph 1.
  5. 하기 반응식 4에 따라, 제4항의 제조방법에 따라 제조된 화합물 Q3로부터 화합물 Q4를 제조하는 단계를 포함하는, According to the following scheme 4, comprising the step of preparing a compound Q4 from compound Q3 prepared according to the production method of claim 4,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 4][Reaction Scheme 4]
    Figure PCTKR2019011876-appb-img-000251
    Figure PCTKR2019011876-appb-img-000251
    상기 반응식 4에서,In Reaction Scheme 4,
    Y 는 C 1-6 알킬이고,Y is C 1-6 alkyl,
    B 1 은 할로겐이고,B 1 is halogen,
    A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -(C=O)-O(C 1-6알킬)로 치환된 작용기를 나타내고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 Represents a functional group in which one hydrogen in any one of heterocycloalkyl is substituted with-(C = O) -O (C 1-6 alkyl),
    A 3 는 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -(C=O)-NH 2로 치환된 작용기를 나타낸다.A 3 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- It represents a functional group in which one hydrogen in any one of 10 heterocycloalkyl is substituted with-(C = O) -NH 2 .
  6. 하기 반응식 5에 따라, 제4항의 제조방법에 따라 제조된 화합물 Q3로부터 화합물 Q5를 제조하는 단계를 포함하는,Comprising the following scheme 5, comprising the step of preparing a compound Q5 from the compound Q3 prepared according to the production method of claim 4,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 5][Scheme 5]
    Figure PCTKR2019011876-appb-img-000252
    Figure PCTKR2019011876-appb-img-000252
    상기 반응식 5에서,In Reaction Scheme 5,
    Y 는 C 1-6 알킬이고,Y is C 1-6 alkyl,
    B 1 은 할로겐이고,B 1 is halogen,
    A 1 은 제1항에서 정의한 것과 동일하다.A 1 is the same as defined in paragraph 1.
  7. 하기 반응식 6에 따라, 제6항의 제조방법에 따라 제조된 화합물 Q5로부터 화합물 Q6을 제조하는 단계를 포함하는,Comprising the following scheme 6, comprising the step of preparing a compound Q6 from compound Q5 prepared according to the production method of claim 6,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 6][Scheme 6]
    Figure PCTKR2019011876-appb-img-000253
    Figure PCTKR2019011876-appb-img-000253
    상기 반응식 6에서,In Reaction Scheme 6,
    Y 는 C 1-6 알킬이고, Y is C 1-6 alkyl,
    A 1 은 제1항에서 정의한 것과 동일하고, A 1 is the same as defined in paragraph 1,
    A 4 및 A 5 는 각각 독립적으로 수소, 할로겐, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬) 또는 -(C=O)-(C 2-6알케닐)이되 A 4와 A 5가 동시에 수소인 경우는 제외한다.A 4 and A 5 are each independently hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl) or-(C = O)-(C 2-6 alkenyl), except when A 4 and A 5 are hydrogen at the same time.
  8. 하기 반응식 7에 따라, 제4항의 제조방법에 따라 제조된 화합물 Q3로부터 화합물 IMC3을 제조하는 단계; 및According to the following scheme 7, preparing a compound IMC3 from compound Q3 prepared according to the preparation method of claim 4; And
    화합물 IMC3의 환원 반응을 통해 화합물 Q7을 제조하는 단계를 포함하는,Comprising the step of preparing a compound Q7 through the reduction reaction of the compound IMC3,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 7][Scheme 7]
    Figure PCTKR2019011876-appb-img-000254
    Figure PCTKR2019011876-appb-img-000254
    상기 반응식 7에서,In Reaction Scheme 7,
    Y 는 C 1-6알킬이고,Y is C 1-6 alkyl,
    A 1 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 적어도 하나의 수소가 -(C=O)(C 1-6알킬), -NO 2 또는 -(C=O)-O(C 1-6알킬)로 치환된 작용기를 나타내고,A 1 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- A functional group in which at least one hydrogen in any one of 10 heterocycloalkyl is substituted with-(C = O) (C 1-6 alkyl), -NO 2 or-(C = O) -O (C 1-6 alkyl) And
    A 6 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 적어도 하나의 수소가 -C(OH)(C 1-6알킬), -NH 2 또는 -(C=O)-OH로 치환된 작용기를 나타낸다.A 6 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- At least one hydrogen in any one of 10 heterocycloalkyl represents a functional group substituted with -C (OH) (C 1-6 alkyl), -NH 2 or-(C = O) -OH.
  9. 하기 반응식 8에 따라, 제8항의 제조방법에 따라 제조된 화합물 Q7로부터 화합물 Q8을 제조하는 단계를 포함하는,Comprising the following scheme 8, comprising the step of preparing a compound Q8 from compound Q7 prepared according to the production method of claim 8,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 8][Scheme 8]
    Figure PCTKR2019011876-appb-img-000255
    Figure PCTKR2019011876-appb-img-000255
    상기 반응식 8에서,In Reaction Scheme 8,
    Y 는 C 1-6 알킬이고,Y is C 1-6 alkyl,
    A 6 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -C(OH)(C 1-6알킬) 또는 -NH 2로 치환된 작용기를 나타내고,A 6 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- A hydrogen group in any one of 10 heterocycloalkyl represents a functional group substituted with -C (OH) (C 1-6 alkyl) or -NH 2 ,
    A 7 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, 및 C 3-10헤테로시클로알킬 중 어느 하나에서 하나의 수소가 -(C=O)(C 1-6알킬), -(C=O)(C 2-6알케닐) 또는 -NH(C=O)-CH=CH 2로 치환된 작용기를 나타낸다.A 7 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, and C 3- One hydrogen in any one of 10 heterocycloalkyl is-(C = O) (C 1-6 alkyl),-(C = O) (C 2-6 alkenyl) or -NH (C = O) -CH = CH 2 represents the functional group substituted.
  10. 하기 반응식 9에 따라, 화합물 Q9를 제조하는 단계를 포함하는,According to Scheme 9, comprising the step of preparing a compound Q9,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 9][Scheme 9]
    Figure PCTKR2019011876-appb-img-000256
    Figure PCTKR2019011876-appb-img-000256
    상기 반응식 9에서,In Reaction Scheme 9,
    Xb 는 할로겐을 나타낸다.Xb represents halogen.
  11. 하기 반응식 10에 따라, 제10항의 제조방법에 따라 제조된 화합물 Q9로부터 화합물 Q10을 제조하는 단계를 포함하는,Comprising the following scheme 10, comprising the step of preparing a compound Q10 from compound Q9 prepared according to the production method of claim 10,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 10][Scheme 10]
    Figure PCTKR2019011876-appb-img-000257
    Figure PCTKR2019011876-appb-img-000257
    상기 반응식 10에서,In Reaction Scheme 10,
    Xb 는 할로겐을 나타내고,Xb represents halogen,
    Z 1 은 할로겐, C 1-3알킬 또는 -O-(C 1-3알킬)을 나타낸다.Z 1 represents halogen, C 1-3 alkyl or -O- (C 1-3 alkyl).
  12. 하기 반응식 11에 따라, 화합물 Q11을 제조하는 단계를 포함하는,According to Reaction Scheme 11, comprising the step of preparing a compound Q11,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 11][Scheme 11]
    Figure PCTKR2019011876-appb-img-000258
    Figure PCTKR2019011876-appb-img-000258
    상기 반응식 11에서, In Reaction Scheme 11,
    Xc 및 Xd는 각각 독립적으로 할로겐을 나타내고,Xc and Xd each independently represent halogen,
    A 8 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 이때, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있고,A 8 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 Heterocycloalkyl, wherein C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl may be unsubstituted or substituted with one or more hydrogens R 5 or = O,
    R 5 는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a,-(C=O)-R b, -(C=O)O-R b,-NR cR d, -SO 2-R b,C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or one or more hydrogens may be substituted with R e ,
    R a 는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
    R b 는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
    R c 및 R d 는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
    R e 는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -(C=O)-R b, -(C=O)O-R b,C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH,-(C = O) -R b ,-(C = O) OR b , C 6-12 aryl, C 3-12 Heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3- 12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2-6 alkenyl, -OH or Can be substituted with halogen,
    상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  13. 하기 반응식 12에 따라, 제12항의 제조방법에 따라 제조된 화합물 Q11을 이용하여 화합물 Q12를 제조하는 단계를 포함하는,According to the following Reaction Scheme 12, comprising the step of preparing a compound Q12 using the compound Q11 prepared according to the production method of claim 12,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 12][Scheme 12]
    Figure PCTKR2019011876-appb-img-000259
    Figure PCTKR2019011876-appb-img-000259
    상기 반응식 12에서,In Reaction Scheme 12,
    Xd 및 A 8 은 각각 제12항에서 정의한 것과 동일하다.Xd and A 8 are the same as defined in claim 12, respectively.
  14. 하기 반응식 13에 따라, 제13항의 제조방법에 따라 제조된 화합물 Q12를 반응시켜 화합물 Q13을 제조하는 단계를 포함하는,According to the following scheme 13, comprising the step of reacting compound Q12 prepared according to the preparation method of claim 13 to prepare a compound Q13,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 13][Scheme 13]
    Figure PCTKR2019011876-appb-img-000260
    Figure PCTKR2019011876-appb-img-000260
    상기 반응식 13에서,In Reaction Scheme 13,
    A 8 은 제13항에서 정의된 것과 동일하고,A 8 is the same as defined in paragraph 13,
    A 9 및 A 10 은 각각 독립적으로 수소, 할로겐, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬) 또는 -(C=O)-(C 2-6알케닐)이되 A 9와 A 10이 동시에 수소인 경우는 제외한다.A 9 and A 10 are each independently hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl) or-(C = O)-(C 2-6 alkenyl), except when A 9 and A 10 are hydrogen at the same time.
  15. 하기 반응식 14에 따라, 제12항의 제조방법에 따라 제조된 화합물 Q11를 반응시켜 화합물 Q14를 제조하는 단계를 포함하는,According to the following reaction formula 14, comprising the step of reacting compound Q11 prepared according to the preparation method of claim 12 to prepare a compound Q14,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 14][Scheme 14]
    Figure PCTKR2019011876-appb-img-000261
    Figure PCTKR2019011876-appb-img-000261
    상기 반응식 14에서,In Reaction Scheme 14,
    Xd 및 A 8 은 각각 제12항에서 정의된 것과 동일하고,Xd and A 8 are the same as defined in claim 12, respectively,
    Z 2 는 할로겐(F, Cl, Br, I), C 1-3알킬 또는 -O-C 1-3알킬을 나타낸다.Z 2 represents halogen (F, Cl, Br, I), C 1-3 alkyl or -OC 1-3 alkyl.
  16. 하기 반응식 15에 따라, 제15항의 제조방법에 따라 제조된 화합물 Q14를 이용하여 화합물 Q15를 제조하는 단계를 포함하는,According to the following reaction formula 15, comprising the step of preparing a compound Q15 using the compound Q14 prepared according to the production method of claim 15,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 15][Scheme 15]
    Figure PCTKR2019011876-appb-img-000262
    Figure PCTKR2019011876-appb-img-000262
    상기 반응식 15에서,In Reaction Scheme 15,
    Z 2, Xd 및 A 8 은 각각 제15항에서 정의한 것과 동일하다.Z 2 , Xd and A 8 are the same as defined in claim 15, respectively.
  17. 하기 반응식 16에 따라, 화합물 Q16을 반응시켜 화합물 Q17을 제조하는 단계를 포함하는,According to Reaction Scheme 16, comprising reacting compound Q16 to prepare compound Q17,
    퀴놀린-5,8-디온 유도체의 제조 방법;A method for producing a quinoline-5,8-dione derivative;
    [반응식 16][Scheme 16]
    Figure PCTKR2019011876-appb-img-000263
    Figure PCTKR2019011876-appb-img-000263
    상기 반응식 16에서,In Reaction Scheme 16,
    Xf 는 할로겐을 나타내고,Xf represents halogen,
    Z 3 은 할로겐, C 1-3알킬 또는 -O-C 1-3알킬을 나타낸다.Z 3 represents halogen, C 1-3 alkyl or -OC 1-3 alkyl.
  18. 하기 반응식 17에 따라, 화합물 Q18을 제조하는 단계를 포함하는,According to Scheme 17 below, comprising the step of preparing a compound Q18,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 17][Scheme 17]
    Figure PCTKR2019011876-appb-img-000264
    Figure PCTKR2019011876-appb-img-000264
    상기 반응식 17에서,In Reaction Scheme 17,
    Xg는 할로겐을 나타낸다.Xg represents halogen.
  19. 하기 반응식 18에 따라, 제18항의 제조방법에 따라 제조된 화합물 Q18을 반응시켜 화합물 Q19를 제조하는 단계를 포함하는,According to the following reaction scheme 18, comprising the step of preparing a compound Q19 by reacting the compound Q18 prepared according to the production method of claim 18,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 18][Reaction Scheme 18]
    Figure PCTKR2019011876-appb-img-000265
    Figure PCTKR2019011876-appb-img-000265
    상기 반응식 18에서,In Reaction Scheme 18,
    Xg 는 할로겐을 나타내고,Xg represents halogen,
    A 13 은 C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬, C 3-10시클로알케닐, C 3-10헤테로시클로알킬이고, 이때, C 6-12아릴, C 3-12헤테로아릴, C 6-12아릴아미노, C 3-12헤테로아릴아미노, C 3-10시클로알킬 C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R 5 또는 =O로 치환될 수 있고,A 13 is C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 Heterocycloalkyl, wherein C 6-12 aryl, C 3-12 heteroaryl, C 6-12 arylamino, C 3-12 heteroarylamino, C 3-10 cycloalkyl C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R 5 or = O,
    R 5 는 -CN, -NO 2, 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -O-R a, -(C=O)-R b, -(C=O)O-R b, -NR cR d, -SO 2-R b, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 R e로 치환될 수 있으며,R 5 is -CN, -NO 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH, -OR a ,-(C = O) -R b ,-(C = O) OR b , -NR c R d , -SO 2 -R b , C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl , Where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl Silver may be unsubstituted or substituted with one or more hydrogen R e ,
    R a 는 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH, -O-C 1-6알킬, -O-CF 3 또는 할로겐으로 치환될 수 있으며,R a is C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocyclo Alkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 hetero Cycloalkyl may be unsubstituted or substituted with one or more hydrogens of C 1-6 alkyl, C 2-6 alkenyl, -OH, -OC 1-6 alkyl, -O-CF 3 or halogen,
    R b 는 수소, -NR cR d, C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, -OH 또는 할로겐으로 치환될 수 있으며,R b is hydrogen, -NR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocyclo Alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3-12 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl are unsubstituted or one or more Hydrogen may be substituted with C 1-6 alkyl, -OH or halogen,
    R c 및 R d 는 각각 독립적으로 수소, C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 또는 -SO 2-(C 2-6알킬)이고, 여기서 C 1-6알킬, C 2-6알케닐, -(C=O)-(C 1-6알킬), -(C=O)-(C 2-6알케닐), -(C=O)-(C 3-10시클로알킬), -(C=O)-(C 3-10헤테로시클로알킬) 및 -SO 2-(C 2-6알킬)은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R c and R d are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2- 6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) or -SO 2- (C 2-6 alkyl) , Where C 1-6 alkyl, C 2-6 alkenyl,-(C = O)-(C 1-6 alkyl),-(C = O)-(C 2-6 alkenyl),-(C = O)-(C 3-10 cycloalkyl),-(C = O)-(C 3-10 heterocycloalkyl) and -SO 2- (C 2-6 alkyl) are unsubstituted or one or more hydrogens are C 1 -6 alkyl, C 2-6 alkenyl, -OH or halogen,
    R e 는 할로겐, C 1-6알킬, C 2-6알케닐, -OH, -(C=O)-R b, -(C=O)O-R b,C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 또는 C 3-10헤테로시클로알킬이고, 여기서 C 1-6알킬, C 2-6알케닐, C 6-12아릴, C 3-12헤테로아릴, C 3-10시클로알킬, C 3-10시클로알케닐 및 C 3-10헤테로시클로알킬은 비치환되거나 하나 이상의 수소가 C 1-6알킬, C 2-6알케닐, -OH 또는 할로겐으로 치환될 수 있으며,R e is halogen, C 1-6 alkyl, C 2-6 alkenyl, -OH,-(C = O) -R b ,-(C = O) OR b , C 6-12 aryl, C 3-12 Heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl or C 3-10 heterocycloalkyl, where C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl, C 3- 12 heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C 1-6 alkyl, C 2-6 alkenyl, -OH or Can be substituted with halogen,
    상기 C 3-12헤테로아릴, C 3-12헤테로아릴아미노 및 C 3-10헤테로시클로알킬은 O, N 또는 S에서 선택되는 1 내지 3의 헤테로원자를 포함한다.The C 3-12 heteroaryl, C 3-12 heteroarylamino and C 3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.
  20. 하기 반응식 19에 따라, 제19항의 제조방법에 따라 제조된 화합물 Q19를 반응시켜 화합물 Q20을 제조하는 단계를 포함하는, According to the following reaction formula 19, comprising the step of preparing a compound Q20 by reacting the compound Q19 prepared according to the production method of claim 19,
    퀴놀린-5,8-디온 유도체의 제조 방법:Method for preparing quinoline-5,8-dione derivatives:
    [반응식 19][Scheme 19]
    Figure PCTKR2019011876-appb-img-000266
    Figure PCTKR2019011876-appb-img-000266
    상기 반응식 19에서,In Reaction Scheme 19,
    A 13 은 제19항에서 정의한 것과 동일하다.A 13 is the same as defined in paragraph 19.
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