WO2020055192A2 - Procédé de préparation d'un dérivé de quinoléine-5,8-dione qui est un inhibiteur de la tgase 2 - Google Patents

Procédé de préparation d'un dérivé de quinoléine-5,8-dione qui est un inhibiteur de la tgase 2 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 (fr
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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 .

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Abstract

La présente invention concerne un procédé de préparation d'un dérivé de quinoléine-5,8-dione représenté par la formule chimique I, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci. Un composé représenté par la formule chimique I de la présente invention présente un effet inhibiteur de la TGase 2, et une composition pharmaceutique le comprenant peut être utilisée utilement dans la prévention ou le traitement de troubles ou de maladies qui sont médiés par la TGase 2 ou réagissent à l'inhibition de la TGase 2.
PCT/KR2019/011876 2018-09-13 2019-09-11 Procédé de préparation d'un dérivé de quinoléine-5,8-dione qui est un inhibiteur de la tgase 2 WO2020055192A2 (fr)

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