WO2021261969A1 - Méthode de préparation d'un nouveau composé - Google Patents

Méthode de préparation d'un nouveau composé Download PDF

Info

Publication number
WO2021261969A1
WO2021261969A1 PCT/KR2021/008050 KR2021008050W WO2021261969A1 WO 2021261969 A1 WO2021261969 A1 WO 2021261969A1 KR 2021008050 W KR2021008050 W KR 2021008050W WO 2021261969 A1 WO2021261969 A1 WO 2021261969A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
acid
alkyl
pyrazine
dione
Prior art date
Application number
PCT/KR2021/008050
Other languages
English (en)
Korean (ko)
Inventor
윤여진
김형남
이인혜
Original Assignee
홀로스메딕 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020210083509A external-priority patent/KR20220000853A/ko
Application filed by 홀로스메딕 주식회사 filed Critical 홀로스메딕 주식회사
Publication of WO2021261969A1 publication Critical patent/WO2021261969A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present application relates to a method for preparing a novel compound.
  • Cancer is one of the most common causes of death worldwide, accounting for about 12% of deaths.
  • Chemotherapy which is a representative anticancer therapy, is currently used as the most effective treatment for cancer, either alone or in combination with other therapies such as radiotherapy.
  • the efficacy of a cancer treatment drug in chemotherapy depends on its ability to kill cancer cells, but there is a problem that when the drug is used, it can act not only on cancer cells but also on normal cells.
  • cancer stem cells are cancer cells with unlimited regenerative capacity
  • the hypothesis that tumors originate from stem cells was hypothesized in the late 1990s to introduce cells that could become cancer stem cells in acute myeloid leukemia in immunosuppressed mice. It was confirmed when it was announced that human leukemia could be reproduced in mice by transplantation, and later, by proving cancer stem cells in breast cancer, he became convinced of the existence of stem cells in solid carcinoma.
  • Cancer stem cells are cells that have the ability to self-renew and differentiate into other cells, and act as a cause of cancer recurrence and metastasis.
  • a specific patient group exhibits strong anticancer drug resistance as cancer stem cells are activated, and is classified as intractable cancer patients that are difficult to treat with existing anticancer therapies.
  • the diverse heterogeneity of malignant tumors is consistent with the diverse differentiation characteristics of stem cells, and the drug resistance of cancer cells, which is constantly expressed despite many targeted therapies, is consistent with the basic characteristics of stem cells.
  • Cancer stem cells can become a new target therapy field, and in order to efficiently perform a treatment targeting only cancer stem cells without damaging normal stem cells, there are molecular and biological properties important for the maintenance and regulation of cancer stem cells. It requires knowledge and understanding of the regulatory pathway.
  • the present application provides a method for preparing a novel compound.
  • One embodiment of the present application provides a method for preparing a compound represented by the following formula (2), comprising reacting the compound represented by the following formula (1) in the presence of a base.
  • n and y are each independently an integer of 0 to 2
  • R 1 or R 2 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, haloC 1-6 alkyl, C 2-6 alkenyl, monocyclic or bi cyclic ring, which is C 3-10 cycloalkyl; C 6-10 aryl; oxetanyl; azetidinyl; 5 membered containing 0 to 3 heteroatoms independently selected from N, O and S or a 6 membered saturated or partially saturated heterocyclic ring; 5 containing 0 to 3 heteroatoms, independently selected from N, O and S, wherein at least two of the heteroatoms are not O or S a 6-membered or 6-membered aromatic heterocyclic ring; or a 7-15 membered saturated, partially saturated, or unsaturated heterocyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S; ;
  • the R 1 and R 2 may be connected while forming a 5- to 12-membered monocyclic or bicyclic ring.
  • the base is sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), sodium acetate (NaOAc), potassium acetate (KOAc), potassium hydrogen carbonate (KHCO 3 ), carbonate Sodium hydrogen (NaHCO 3 ), sodium hydroxide (NaOH), potassium hydroxide (NaOH), lithium hydroxide (LiOH), sodium methylate (NaOMe), potassium tert-butylate, sodium tert-butylate (Sodium tert) -butylate) cesium carbonate (Cs 2 CO 3 ), triethylamine (TEA), trimethylamine (TMA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 5-diazabicyclo[4.3.
  • non-5-ene DBN
  • 1,8-diazabicyclo [5.4.0] undec-7-ene DBU
  • diisopropylamine DIPA
  • DIEA N,N-diisopropylethylamine
  • TEDA tetramethylethylenediamine
  • TPA tripropylamine
  • TAA tributylamine
  • TeA tripentylamine
  • pyridine piperazine, piperidine and pyrrolidine. It may be one or two or more.
  • the reaction in the step of reacting in the presence of a base is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanedisulfonic acid, ethanedisulfonic acid, oxalic acid and trifluoroacetic acid
  • the reaction may be carried out by introducing at least one acid selected from the group.
  • One embodiment of the present application provides a method for preparing a compound represented by Formula 5, including reacting the compound represented by Formula 2 with a compound represented by Formula 3 or Formula 4 below.
  • n is an integer from 1 to 10
  • Y' is halogen, C 1-6 alkylsulfonate, arylsulfonate, or hydroxy;
  • L 1 is directly linked or C 1-10 alkylene
  • each Z a is independently hydrogen or Z b ;
  • each Z c is independently hydrogen, or C 1-6 alkyl, or the group CZ c Z c may form a C 3-8 cycloalkyl ring;
  • n and y are each independently an integer of 0 to 2
  • R 1 or R 2 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, haloC 1-6 alkyl, C 2-6 alkenyl, monocyclic or bi cyclic ring, which is C 3-10 cycloalkyl; C 6-10 aryl; oxetanyl; azetidinyl; 5 membered containing 0 to 3 heteroatoms independently selected from N, O and S or a 6 membered saturated or partially saturated heterocyclic ring; 5 containing 0 to 3 heteroatoms, independently selected from N, O and S, wherein at least two of the heteroatoms are not O or S a 6-membered or 6-membered aromatic heterocyclic ring; or a 7-15 membered saturated, partially saturated, or unsaturated heterocyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S; ;
  • the R 1 and R 2 may be connected while forming a 5- to 12-membered monocyclic or bicyclic ring.
  • the reaction in the step of reacting the compound represented by Formula 2 with the compound represented by Formula 3 or Formula 4, the reaction may be performed in the presence of a reducing agent and a tertiary amine.
  • the reaction is an organic acid selected from the group consisting of trifluoroacetic acid, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid It can be performed by adding more.
  • the tertiary amine is triethylamine (TEA), trimethylamine (TMA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 5-diazabicyclo[ 4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diisopropylamine (DIPA), N,N-diisopropyl It may be selected from the group consisting of ethylamine (DIEA), tetramethylethylenediamine (TMEDA), tripropylamine (TPA), tributylamine (TBA), and tripentylamine (TPeA).
  • the reducing agent may be selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a mixture of two or more thereof.
  • the solvent of the reaction is dichloromethane, dichloroethane, dimethylformamide, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, dimethylsulfoxide, Or it may be selected from the group consisting of a mixture of two or more of them.
  • the method for preparing a compound according to an embodiment of the present application has an effect of very high reaction yield and reducing reaction time.
  • One embodiment of the present application provides a method for preparing a compound represented by the following formula (2), comprising reacting the compound represented by the following formula (1) in the presence of a base.
  • One embodiment of the present application provides a method for preparing a compound represented by Formula 5, including reacting the compound represented by Formula 2 with a compound represented by Formula 3 or Formula 4 below.
  • n is an integer from 1 to 10
  • Y' is halogen, C 1-6 alkylsulfonate, arylsulfonate, or hydroxy;
  • L 1 is directly linked or C 1-10 alkylene
  • each Z a is independently hydrogen or Z b ;
  • Each Z c is independently hydrogen, or C 1-6 alkyl, or the group CZ c Z c may form a C 3-8 cycloalkyl ring.
  • Ar 1 is C 1-6 straight or branched chain alkyl, naphthyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, furanyl, indole, chromone, quinoline, carbazole or thiophenyl, These are unsubstituted or hydroxy, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, — It may be substituted with at least one of C 2-6 alkynyl, C 6-12 aryl, or C 5-12 heteroaryl.
  • the Ar 1 is, C 1-6 straight or branched chain alkyl, , , , , , , , , , , , , , , , , , , , or can be
  • Each of m and y may independently be an integer of 0 to 2. Specifically, m may be 1, and y may be 1 or 2.
  • R 1 or R 2 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, haloC 1-6 alkyl, C 2-6 alkenyl, monocyclic or bicyclic ring (which is C 3-10 cycloalkyl; C 6-10 aryl; oxetanyl; azetidinyl; 5, containing 0 to 3 heteroatoms, independently selected from N, O and S a heterocyclic ring of saturated or partially saturated, or 6-membered, containing 0 to 3 heteroatoms, independently selected from N, O and S, wherein at least two of the heteroatoms are not O or S 5 or 6 membered aromatic heterocyclic ring; or 7 to 15 membered saturated, partially saturated, or unsaturated heterocyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S) is;
  • the R 1 and R 2 may be connected while forming a 5- to 12-membered monocyclic or bicyclic
  • R 1 or R 2 are each independently hydrogen, C 1-6 alkyl, benzyl, naphthylalkyl, benzofuranylalkyl, quinolinylalkyl, pyridinylalkyl, cyclohexylalkyl, thiophenylalkyl, pyrrolylalkyl, furanylalkyl or benzothiophenylalkyl, which are unsubstituted or each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 6-12 aryl, hydroxy, halogen, C 1 - may be substituted with at least one of 6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • the R 1 and R 2 may be connected while forming a 5- to 12-membered monocyclic or bicyclic ring.
  • R 1 or R 2 are each independently hydrogen, C 1-6 straight or branched chain alkyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • One embodiment of the present application provides a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof prepared by the above preparation method.
  • the term "independently” means that a variable applied independently changes independently from application to application.
  • R a XYR a if R a is “independently carbon or nitrogen” then both R a can be carbon, both R a can be nitrogen, or one R a is carbon, Another R a may be nitrogen.
  • alkyl means a saturated straight or branched hydrocarbon chain, typically C 1 to C 10 , specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl; include The term includes both substituted and unsubstituted alkyl groups.
  • the alkyl group may be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate.
  • One or more hydrogen atoms attached to the carbon atoms of the alkyl may be substituted with one or more halogen atoms such as, for example, fluorine or chlorine or both, such as trifluoromethyl, difluoromethyl, fluorochloromethyl and the like.
  • the hydrocarbon chain may also contain heteroatoms such as N, O or S in the middle.
  • cycloalkyl refers to saturated having 3-8 carbon atoms, preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. means a hydrocarbon ring.
  • the cycloalkyl group may have a ring substituted with an alkyl group such as cyclopropylmethyl.
  • alkylamino or “arylamino” refers to an amino group having one or two alkyl or aryl substituents, respectively.
  • the term "protected,” unless otherwise defined, means a group added to an oxygen, nitrogen or phosphorus atom to prevent further reaction or for other purposes.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • Non-limiting examples include C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 ,CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph,CH 2 -aryl, CH 2 O -alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldi siloxanilidene).
  • aryl refers to a C 6 -C 20 aryl group, specifically a C 6 -C 12 aryl group, and an aromatic having 6 to 20 carbon atoms that does not contain a hetero atom in the ring. contains cyclic groups.
  • Aryl group specifically means phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, chrysenyl, or picenyl, more specifically phenyl, biphenyl, naphthyl, anthracenyl, phenane threnyl or pyrenyl.
  • the term includes both substituted and unsubstituted moieties.
  • the aryl group may optionally be unprotected or one including protected hydroxyl, halogen, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate It may be substituted with the above substituents, but is not limited thereto.
  • alkaryl or “alkylaryl” refers to an alkyl group having an aryl substituent.
  • aralkyl or arylalkyl refers to an aryl group having an alkyl substituent such as benzyl.
  • halo includes chloro, bromo, iodo and fluoro.
  • acyl ester or "O-linked ester” means a carboxylic acid ester of the formula C(O)R', wherein the non-carbonyl moiety of the ester group, R', is a straight-chain or branched alkyl, or cyclo Alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen (F, Cl, Br, I) , sulfonate esters such as alkyl or aralkyl sulfonyl, including C 1 to C 4 alkyl or C 1 to C 4 alkoxy, methanesulfonyl, mono-, di- or triphosphate esters, trityl or monomethoxytri tyl, substituted benzyl, trialkylsilyl (eg dimethyl-t-butylsilyl (
  • acyl means a group of the formula R"C(O)-, wherein R" is straight or branched alkyl, or cycloalkyl, amino acid, aryl including phenyl, alkylaryl, aralkyl including benzyl , alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chlorine, bromine, fluorine, iodine, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, alkyl including methanesulfonyl or sulfonate esters such as aralkyl sulfonyl, the mono-, di- or triphosphate esters, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, aralkyl including benzyl, methoxymethyl and aryloxyal
  • the aryl group in the ester optimally includes a phenyl group.
  • the acyl group is acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropyl carboxy, propionyl, butyryl, isobutyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2 -acetoxy-2-phenylacetyl, diphenylacetyl, ⁇ -methoxy- ⁇ trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2 ,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, per
  • acyl When the term acyl is used, acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, isobutyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, di Phenylacetyl, ct-trifluoromethyl-phenylacetyl, bromoacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodi Fluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiophenacetyl, tert-butylacetyl, trichloroacety
  • C 1 -C 6 alkyl refers to straight-chain or branched alkyl having 1 to 6 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl ( sec-butyl), tert-butyl, amyl and hexyl, and the like, but are not limited thereto, and are preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C 1 ⁇ C 6 alkoxy refers to straight-chain or branched alkoxy having 1 to 6 carbon atoms, methoxy, ethoxy, propoxy, iso Propoxy (isopropoxy) and butoxy group (butoxy), including but not limited thereto.
  • C 2 ⁇ C 6 alkenyl refers to straight-chain or branched alkenyl containing one double bond having 2 to 6 carbon atoms, vinyl (vinyl), propenyl (propenyl) ), butenyl, isobutenyl, pentenyl, hexenyl, and the like, but is not limited thereto.
  • C 2 -C 6 alkynyl refers to straight-chain or branched alkynyl containing one triple bond having 2 to 6 carbon atoms, ethynyl, propynyl, butynyl, iso butynyl, pentynyl and hexynyl, and the like.
  • C 3 ⁇ C 10 cycloalkyl means a cyclic alkyl having 3 to 10 carbon atoms in the ring, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Includes cyclooctyl and cyclodecyl.
  • C 3 -C 8 cycloalkyl “C 3 -C 7 cycloalkyl” and “C3 -C 6 cycloalkyl” have similar connotations
  • C 3 ⁇ C 10 cycloalkenyl means a cyclic alkenyl having 3 to 10 carbon atoms in a ring, cyclopropenyl, cyclobutenyl, cyclophene tenyl, cyclohexenyl, cycloheptene, cyclooctene and cyclodecene, and the like.
  • C 3 -C 7 cycloalkenyl has a similar connotation.
  • 3-12 membered heterocyclic refers to a saturated or unsaturated 3 to 12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, for example, It is dioxol.
  • 3-7 membered heterocyclic has a similar connotation.
  • Alkylene in this application refers to a divalent hydrocarbyl group; This is because it is bivalent and thus can be linked with two other groups. In general, it is -(CH2)n-, where n is 1-8 and preferably n is 1-4, but in certain instances the alkylene may be substituted by other groups and may be of different lengths, The open atoms do not necessarily have to be on opposite sides of the chain.
  • any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group contained within a substituent may itself be optionally substituted by other additional substituents.
  • the nature of these substituents is similar to that recited for the primary substituents themselves, unless the substituents are otherwise stated.
  • heteroatom refers to an atom other than carbon or hydrogen, such as nitrogen, oxygen or sulfur. If it is part of the backbone or backbone of a chain or ring, the heteroatom must be at least divalent and will generally be selected from N, O, P, and S.
  • the term "which may be substituted" means that the particular group or groups said to be optionally substituted does not have non-hydrogen substituents, or that said group or groups is consistent with the chemical and pharmacological activity of the resulting molecule. Indicates that it may have non-hydrogen substituents. Unless otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present in the unsubstituted form of the group being described; Less than the maximum number of such substituents may be present.
  • -NZ c Z c is intended to include, but is not limited to, -NH2, -NH-alkyl, -N-pyrrolidinyl, and -N-morpholinyl, and is not limited to specific substitutes, Other known substitutes are also included.
  • substituted alkyl is -alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroaryl, -alkylene-C(O)OZ b , -alkylene-C (O)NZ b Z b , and -CH 2 -CH 2 -C(O)-CH 3 , but are not limited to these specific alternatives, including other alternatives known in the art.
  • One or more substituents, together with the atoms to which they are attached, may form a cyclic ring including, but not limited to, cycloalkyl and cycloheteroalkyl.
  • substituents useful for substituting an unsaturated carbon atom in a particular group, moiety or radical include -Z a , halo, -O-, -OZ b , -SZ b , -S-, -NZ c Z c , trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -S(O)2Z b , -S(O 2 )O-, - S(O 2 )OZ b , -OS(O 2 )OZ b , -OS(O 2 )O-, -P(O)(O-) 2 , -P(O)(OZ b )(O-) , -P(O)(OZ b )(O-) , -P(O)(OZ b )(O-) , -P(O)(O
  • substituents useful for replacing nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include -Z a , halo, -O-, -OZ b , -SZ b , -S-, -NZ c Z c , trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -S(O)2Z b , -S(O 2 )O-, -S( O 2 )OZ b , -OS(O 2 )OZ b , -OS(O 2 )O-, -P(O)(O-) 2 , -P(O)(OZ b )(O-), - P(O)(OZ b )(OZ b ), -C(O)Z b , -C(S)Z c , trihalomethyl
  • the compounds described in this application may contain one or more chiral centers and/or double bonds and therefore, as stereoisomers, such as double-bond isomers (i.e. geometric isomers such as E and Z), enantiomers or diastereomers. may exist.
  • stereoisomers such as double-bond isomers (i.e. geometric isomers such as E and Z), enantiomers or diastereomers.
  • the present application also encompasses mixtures of stereoisomers that differ in the percentages of E and Z with different stereoisomeric forms (such as enantiomerically pure isomers, E and Z isomers, and other replacements of stereoisomers), respectively, and differing percentages of E and Z, respectively. unless limited to a specific stereoisomer).
  • stereoisomerically pure forms such as geometrically pure, enantiomerically pure, or diastereomerically pure
  • enantiomer mixtures and stereoisomeric mixtures It encompasses all possible enantiomers and stereoisomers of the specified compounds. Mixtures of enantiomers and mixtures of stereoisomers can be resolved into their corresponding enantiomeric or stereoisomeric components using separation techniques or chiral synthesis techniques well known in the art.
  • This application includes mixtures of stereoisomers of varying chiral purity, including racemic mixtures as well as individual isolated stereoisomeric forms. This application also encompasses the various diastereomers.
  • One embodiment of the present application provides a method for preparing a compound represented by Formula 2, comprising reacting the compound represented by Formula 1 in the presence of a base.
  • the base is sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), sodium acetate (NaOAc), potassium acetate (KOAc), potassium hydrogen carbonate (KHCO 3 ), carbonate Sodium hydrogen (NaHCO 3 ), sodium hydroxide (NaOH), potassium hydroxide (NaOH), lithium hydroxide (LiOH), sodium methylate (NaOMe), potassium tert-butylate, sodium tert-butylate (Sodium tert) -butylate) cesium carbonate (Cs 2 CO 3 ), triethylamine (TEA), trimethylamine (TMA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 5-diazabicyclo[4.3.
  • non-5-ene DBN
  • 1,8-diazabicyclo [5.4.0] undec-7-ene DBU
  • diisopropylamine DIPA
  • DIEA N,N-diisopropylethylamine
  • TEDA tetramethylethylenediamine
  • TPA tripropylamine
  • TAA tributylamine
  • TeA tripentylamine
  • pyridine piperazine, piperidine and pyrrolidine. It may be one or two or more.
  • the reaction in the step of reacting in the presence of a base is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanedisulfonic acid, ethanedisulfonic acid, oxalic acid and trifluoroacetic acid
  • the reaction may be carried out by introducing at least one acid selected from the group.
  • the present application generally uses a well-known base and does not use an ion exchange resin, etc., so that the compound of Formula 2 is industrially convenient and has high safety.
  • the compound of Formula 2 may be prepared by reacting the compound of Formula 1 under basic conditions at a temperature of 0° C. to 100° C., preferably at room temperature.
  • a product in the process of making Formula 2 into a salt form, a product can be obtained by simple filtration, thereby avoiding the use of an ion exchange resin, etc., and also obtaining a purification effect.
  • a method for preparing a compound represented by Formula 5 is provided, further comprising reacting the prepared compound represented by Formula 2 with a compound represented by Formula 3 or Formula 4 do.
  • Chemical Formula 5 may be the following Chemical Formula 6, and Chemical Formula 3 may be at least one selected from the following Chemical Formulas 3a to 3k.
  • a 1 , A 2 , A 3 , or A 4 are each independently hydrogen, N, or CR, R is C 1-6 straight or branched chain alkyl, C 6-10 aryl, C 5-10 heteroaryl, hydroxy, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • Y is NR, CRR' , O or S, R or R' is C 1-6 straight or branched chain alkyl, C 6-10 aryl, C 5-10 heteroaryl, hydroxy, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • R 3 to R 6 are each independently hydrogen, C 1-6 straight or branched chain alkyl, C 6-12 aryl, C 5-12 heteroaryl, hydroxy, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • Z is C 2-6 straight or branched chain alkyl.
  • Chemical Formula 4 may be at least one selected from the following Chemical Formulas 4a to 4k.
  • n is an integer from 1 to 10
  • a 1 , A 2 , A 3 , or A 4 is N, or CR, and R is C 1-6 straight or branched chain alkyl, C 6-10 aryl, C 5-10 heteroaryl, hydroxy, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • Y is NR, CRR' , O or S, R or R' is C 1-6 straight or branched chain alkyl, C 6-10 aryl, C 5-10 heteroaryl, hydroxy, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • Y' is halogen, C 1-6 alkylsulfonate, arylsulfonate, or hydroxy;
  • R 3 To R 6 are each independently hydrogen, C 1-6 straight or branched chain alkyl, C 6- 12 aryl, C 5- 12 heteroaryl, hydroxy, halogen, C 1- 6 alkoxy, C 1- 6 haloalkyl, or halo C 1- 6 alkoxy;
  • Z is C 2-6 straight-chain or branched alkyl.
  • reaction of the compound of Formula 2 with the compound of Formula 3 or Formula 4 may be performed in the presence of a reducing agent and a tertiary amine.
  • a novel hexahydropyrazino[1,2-a]pyrazine-1,4-dione derivative represented by Formula 5 can be prepared by reacting a compound of Formula 2 with a compound of Formula 3 or 4 at room temperature in the presence of a reducing agent.
  • a reducing agent can be used to promote the generation of Chemical Formula 5 to promote the generation of Chemical Formula 5 and the generation of by-products can be controlled.
  • the production of Chemical Formula 5 can be monitored in a short reaction time using Chemical Formula 3 as much as the reaction equivalent.
  • the yield is less than 50%, but according to the embodiment of the present application, when the tertiary amine is added and reacted, the yield is 90 to 95%.
  • the reaction is an organic acid selected from the group consisting of trifluoroacetic acid, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid It can be performed by adding more.
  • the tertiary amine is triethylamine (TEA), trimethylamine (TMA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 5-diazabicyclo[ 4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diisopropylamine (DIPA), N,N-diisopropyl It may be selected from the group consisting of ethylamine (DIEA), tetramethylethylenediamine (TMEDA), tripropylamine (TPA), tributylamine (TBA), and tripentylamine (TPeA).
  • the reducing agent may be selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a mixture of two or more thereof.
  • the solvent of the reaction is dichloromethane, dichloroethane, dimethylformamide, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, dimethylsulfoxide, Or it may be selected from the group consisting of a mixture of two or more of them.
  • One embodiment of the present application provides a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof prepared by the above preparation method.
  • One embodiment of the present application provides a pharmaceutical composition for preventing or treating cancer comprising a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing or treating cancer comprising a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 5 or a pharmaceutically acceptable salt thereof is administered alone, there is an effect of inhibiting cancer activity.
  • One embodiment of the present application provides a pharmaceutical composition for preventing or treating resistant cancer comprising a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing or treating resistant cancer comprising a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 5 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiation therapy to resistant cancer, there is an effect of inhibiting cancer activity.
  • the cancer or resistant cancer is ovarian cancer, colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, Biliary tract cancer, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, brain cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, Endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, hematological cancer, leukemia, central nervous system (CNS) tumor, spinal cord tumor, brainstem glioma and pituitary gland It may be at least one selected from the group consisting of
  • a pharmaceutical composition according to an embodiment of the present application contains a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and an anticancer agent from 1:0.001 to 1:1000, 1:0.01 to 1:100, 1:0.1 to 1 It may be included in a molar concentration ratio of :50 or 1:0.1 to 1:20.
  • the pharmaceutical composition according to one embodiment of the present application may be in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and may be formulated and used in the form of oral dosage forms, external preparations, suppositories and injections.
  • the dosage form of the pharmaceutical composition of the present application may be prepared in various ways by mixing with a pharmaceutically acceptable carrier, and may be administered orally or parenterally.
  • Pharmaceutically acceptable carriers may be binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc., for oral administration, and in the case of injections, buffering agents, preservatives, analgesic agents, Solubilizers, isotonic agents, stabilizers, etc. can be mixed and used.
  • bases, excipients, lubricants, preservatives, etc. can be used for topical administration.
  • formulations for oral administration may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, pills, powders, granules, capsules, and the like.
  • at least one excipient for example, starch, calcium carbonate, sucrose, lactose gelatin, etc. may be mixed and prepared.
  • a lubricant such as magnesium stearate or talc may be used.
  • a liquid formulation in addition to water and liquid paraffin, which are simple diluents, a wetting agent, a sweetener, a fragrance, a preservative, etc. may be used, but the present invention is not limited thereto.
  • preparations for parenteral administration may be non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • preparations for parenteral administration may be non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • it may be prepared in the form of unit dosage ampoules or multiple dosages, and intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection injection method may be selected.
  • Carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, filler, anticoagulant, lubricant, wetting agent, flavoring, emulsifying agent or preservative and the like.
  • the route of administration of the pharmaceutical composition of the present application is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or work is included.
  • an adjuvant As an adjuvant (adjuvant) that can be additionally used, an adjuvant commonly used in the art may be used without limitation.
  • an adjuvant refers to any substance capable of producing, exacerbating or modifying a specific response to the active ingredient of the present application if administered simultaneously, at the same time or sequentially.
  • Known adjuvants for injectable solutions include, for example, aluminum compositions, for example aluminum hydroxide or aluminum phosphate, saponins, for example QS21, muramyldipeptide or muramyltripeptide, proteins, for example gamma-interferon or TNF, M59, squalene or polyol.
  • the dosage of the pharmaceutical composition of the present application varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present application may be administered at 0.0001 to 1000 mg/kg or 0.001 to 500 mg/kg per day.
  • Administration of the pharmaceutical composition of the present application may be administered once a day, may be administered in divided several times.
  • the above dosage does not limit the scope of the present application in any way.
  • the present application provides the use of the compound represented by Formula 5 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • the present application provides the use of a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof for use in the treatment of resistant cancer.
  • Resistant cancer the compound represented by Formula 5, or a pharmaceutically acceptable salt thereof is the same as described above, and detailed descriptions thereof will be omitted.
  • the present application relates to a subject having cancer or resistant cancer, the compound represented by Formula 5 or a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof; It provides a method for treating cancer comprising administering a therapeutically effective amount of The administration may be simultaneous, separate, or sequential administration of a chemotherapeutic agent useful for the treatment of cancer or proliferative disease.
  • terapéuticaally effective amount refers to (i) treating or preventing a particular disease, condition, or disorder, (ii) one or more symptoms of the particular disease, condition, or disorder. means an amount of a compound of formula 5 when administered to a mammal in need thereof sufficient to attenuate, ameliorate or alleviate, or (iii) prevent or delay the onset of one or more symptoms of a particular disease or condition.
  • the amount of compound equivalent to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (eg weight) of the mammal in need of treatment, but nevertheless is within the skill of the artisan. can be determined routinely.
  • administration means introducing a given substance into a subject by an appropriate method.
  • Resistant cancer the compound represented by Formula 5, or a pharmaceutically acceptable salt thereof is the same as described above, and detailed descriptions thereof will be omitted.
  • Subject with resistant cancer refers to an individual in need of appropriate treatment due to the onset or high probability of developing resistant cancer cancer, and as an anticancer therapy, for example, surgical excision therapy, chemical therapy using an anticancer agent, It may be an individual who has received radiation therapy or immunotherapy, but has developed resistance to it and has relapsed.
  • Subjects with resistant cancer may include humans, cattle, dogs, guinea pigs, rabbits, chickens, or insects.
  • the present application provides a method comprising: administering a compound represented by Formula 5 or a pharmaceutically acceptable salt thereof to a subject with resistant cancer; And irradiating radiation; provides a radiation treatment method comprising a.
  • Resistant cancer a subject with resistant cancer, the compound represented by Formula 5 or a pharmaceutically acceptable salt thereof are the same as those described above, and detailed descriptions thereof will be omitted.
  • Radiation irradiation can be applied to any radiation method conventionally used for radiation treatment of cancer or radiation method for cancer to be developed later.
  • the compound represented by Formula 5 or a pharmaceutically acceptable salt thereof prepared by the manufacturing method of the present application When the compound represented by Formula 5 or a pharmaceutically acceptable salt thereof prepared by the manufacturing method of the present application is administered in combination with irradiation, it gives a synergistic effect on growth inhibition and/or death induction of cancer cells or cancer stem cells. Thus, it is possible not only to effectively prevent or treat cancer, but also to prevent radiation resistance, cancer metastasis, or cancer recurrence.
  • the compound represented by Formula 5 of the present application or a pharmaceutically acceptable salt thereof has the effect of acting as an inhibitor targeting the SERCA protein.
  • the compound represented by Formula 5 of the present application or a pharmaceutically acceptable salt thereof has the effect of acting as an inhibitor targeting the SERCA protein, which is the cause of the anticancer drug resistance of cancer stem cells. Therefore, it is possible to increase the efficacy of chemotherapy by an anticancer drug so that an excellent anticancer effect can be exhibited even with a lower dose of the drug.
  • step 5 Through the process of step 5 described below was prepared in a tetrahydro-2 H -pyrazino represents the skeleton of the formula 8 [1,2- a] pyrazine-1,4 (3 H, 6 H) -dione (PPD).
  • PPD pyrazine-1,4
  • Piperazine-2-carboxylic acid 30g (231mmol), tetrahydrofuran 150ml, and purified water 150ml were added.
  • the reaction mass was cooled, and 26.8 g (254 mmol) of sodium carbonate was added thereto.
  • the reactant was cooled, 110.6 g (506 mmol) of di-tert-butyl decarbonate was added, and the mixture was stirred at room temperature and then the reactant was concentrated under reduced pressure. 500 ml of dichloromethane was added to the concentrated residue.
  • the reaction mass was cooled, 4M hydrochloric acid was added dropwise, and the organic layer was extracted. The aqueous layer was extracted with 60 ml of dichloromethane.
  • the reaction solution was washed with an aqueous sodium hydrogen carbonate solution and 10 ml of purified water in that order.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered, and the reaction solution was concentrated.
  • 6 ml of dichloromethane was added to the concentrated residue, and the reaction solution was dissolved.
  • 6 ml of n-heptane was slowly added dropwise to form crystals, and after stirring at room temperature for 2 hours, the reaction product was filtered.
  • the solid was dried with hot air at 60°C to obtain the title compound as a white solid. (0.95 g, yield 87%)
  • reaction solution was washed with an aqueous sodium hydrogen carbonate solution and 10 ml of purified water in that order. The organic layer was dried over anhydrous magnesium sulfate and filtered. The reaction solution was concentrated. 2 ml of dichloromethane was added to the concentrated residue, and the reaction solution was dissolved. 6 ml of n-heptane was slowly added dropwise to form crystals, and the reaction product was filtered. After drying a solid, 2 - ((9-benzyl -9 H -carbazol-3-yl) methyl) hexahydro-2 H -pyrazino [1,2-a] to give the pyrazine-6,9-dione. (0.126g, yield 54%)
  • reaction solution was washed with 100 ml of an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and filtered.
  • the reaction solution was concentrated and purified by silica chromatography to obtain 2-((3-chloroquinolin-2-yl)methyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. (0.04 g, yield 3%)
  • Tetrahydro-2 H -pyrazino at room temperature [1,2- a] pyrazine-1,4 ( 3 H, 6 H) -dione ⁇ (1.06mmol) acetate 0.3g of trifluoroacetic, dichloromethane 3ml, triethylamine 0.3 ml, 0.24 g (1.17 mmol) of 6-chloro-2-methylquinoline-3-carboxaldehyde was added. 0.449 g (2.12 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid was added to adjust the pH to 4-5 and stirred at room temperature for 5 hours.
  • reaction solution was washed with 24 ml of purified water.
  • the reaction solution was washed with 24 ml of an aqueous sodium hydrogen carbonate solution, and then with 24 ml of purified water.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered.
  • the reaction solution was concentrated and purified by silica chromatography to obtain 2-((2-chloro-6-mrthylquinolin-3-yl)methyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. got it (0.234 g, yield 56%)
  • reaction solution was washed with 16 ml of aqueous sodium bicarbonate solution and 16 ml of purified water in that order.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered.
  • the reaction solution was concentrated and purified by silica chromatography to obtain 2-(quinoline-6-ylmethyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. (0.114 g, yield 52%)
  • reaction solution was washed with 24 ml of an aqueous sodium hydrogen carbonate solution, and then with 24 ml of purified water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The reaction solution was concentrated and purified by silica chromatography to obtain 2-(quinoline-8-ylmethyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. (0.141 g, yield 43%)
  • reaction solution was concentrated and purified by silica chromatography to obtain 8-benzyl-2-(quinolin-3-ylmethyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. (0.106 g, yield 41%)
  • reaction solution was washed with 65 ml of aqueous sodium hydrogen carbonate solution and then with 65 ml of purified water in that order.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered.
  • the reaction solution was concentrated and purified by silica chromatography to obtain 2-(quinolin-2-ylmethyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. (5.8 g, yield 65%)
  • a compound of the following formula N411 was prepared by using the compound of the formula N401 of Preparation 26.
  • a compound of the following formula N412 was prepared by using the compound of the formula N401 of Preparation 26.
  • a compound of the following formula N413 was prepared by using the compound of the formula N401 of Preparation 26.
  • a compound of the following formula N414 was prepared by using the compound of the formula N401 of Preparation 26.
  • a compound of the following formula N422 was prepared by using the compound of the formula N401 of Preparation 26.
  • a compound of the following formula N423 was prepared by using the compound of the formula N401 of Preparation 26.
  • a compound of the following formula N424 was prepared by using the compound of the formula N401 of Preparation 26.
  • N611 compound was prepared by using the N601 compound of Preparation 43.
  • N612 compound was prepared using the N601 compound of Preparation 43.
  • N613 compound was prepared using the N601 compound of Preparation 43.
  • N614 compound was prepared by using the N601 compound of Preparation 43.
  • N622 compound was prepared using the N601 compound of Preparation 43.
  • reaction solution was washed with 24 ml of an aqueous sodium hydrogen carbonate solution and again washed with 24 ml of purified water.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered.
  • the reaction solution was concentrated and purified by silica chromatography to obtain 2-([1,1'-biphenyl]-4-ylmethyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. (0.249g, yield 70%)
  • reaction solution was washed with an aqueous sodium hydrogen carbonate solution and 10 ml of purified water in that order.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered.
  • the reaction solution was concentrated and purified by silica chromatography to obtain 2-(anthracen-9-ylmethyl)hexahydro- 2H- pyrazino[1,2- a ]pyrazine-6,9-dione. (0.497g, yield 78%)
  • reaction solution was concentrated and purified by silica chromatography, followed by 8-(naphthalen-1-yl)-2-(pyren-1-ylmethyl)hexahydro- 2H- pyrazino[1,2-a]pyrazine-6,9-dione got (0.344 g, yield 99%)
  • reaction solution was concentrated and purified by silica chromatography, followed by 8-(naphthalen-2-yl)-2-(pyren-1-ylmethyl)hexahydro- 2H- pyrazino[1,2-a]pyrazine-6,9-dione got (0.321 g, yield 94%)
  • reaction solution was concentrated and purified by silica chromatography to obtain 8-benzyl-2-(pyren-1-ylmethyl)hexahydro- 2H- pyrazino[1,2-a]pyrazine-6,9-dione. (0.323 g, yield 99%)
  • reaction solution was concentrated and purified by silica chromatography to 8-([1,1'-biphenyl]-4-ylmethyl)-2-(pyren-1-ylmethyl)hexahydro- 2H- pyrazino[1,2-a] Pyrazine-6,9-dione was obtained. (0.314 g, yield 87%)

Abstract

La présente invention concerne une méthode de préparation d'un nouveau composé, dans laquelle il existe des avantages tels que, lorsqu'un composé est préparé à l'aide de la méthode de préparation de la présente invention, le rendement est élevé et le temps de réaction est réduit.
PCT/KR2021/008050 2020-06-26 2021-06-26 Méthode de préparation d'un nouveau composé WO2021261969A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2020-0078242 2020-06-26
KR20200078242 2020-06-26
KR1020210083509A KR20220000853A (ko) 2020-06-26 2021-06-25 신규한 화합물의 제조방법
KR10-2021-0083509 2021-06-25

Publications (1)

Publication Number Publication Date
WO2021261969A1 true WO2021261969A1 (fr) 2021-12-30

Family

ID=79281568

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/008050 WO2021261969A1 (fr) 2020-06-26 2021-06-26 Méthode de préparation d'un nouveau composé

Country Status (1)

Country Link
WO (1) WO2021261969A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003002834A (ja) * 2001-04-19 2003-01-08 Tanabe Seiyaku Co Ltd 医薬組成物
WO2003030907A1 (fr) * 2001-10-09 2003-04-17 Myriad Genetics, Inc. Mimetiques de coudes inverses et composition et procedes afferents
KR20080046232A (ko) * 2005-09-09 2008-05-26 스미스클라인 비참 코포레이션 피리딘 유도체 및 그의 정신병적 장애의 치료에 있어서의용도
WO2010023480A1 (fr) * 2008-08-29 2010-03-04 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Dérivés hétérocycliques bicycliques saturés en tant qu’antagonistes de smo

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003002834A (ja) * 2001-04-19 2003-01-08 Tanabe Seiyaku Co Ltd 医薬組成物
WO2003030907A1 (fr) * 2001-10-09 2003-04-17 Myriad Genetics, Inc. Mimetiques de coudes inverses et composition et procedes afferents
KR20080046232A (ko) * 2005-09-09 2008-05-26 스미스클라인 비참 코포레이션 피리딘 유도체 및 그의 정신병적 장애의 치료에 있어서의용도
WO2010023480A1 (fr) * 2008-08-29 2010-03-04 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Dérivés hétérocycliques bicycliques saturés en tant qu’antagonistes de smo

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OLAF KINZEL; ANNA ALFIERI; SERGIO ALTAMURA; MIRKO BRUNETTI; SIMONE BUFALI; FABRIZIO COLACECI; FEDERICA FERRIGNO; GESSICA FILOCAMO;: "Identification of MK-5710 ((8)-8-methyl-1,3-dioxo-2-[(1,2)-2-phenylcyclo- propyl]--(1-phenyl-1-pyrazol-5-yl)hexahydro-imidazo[1,5-]pyrazine-7(1)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 21, no. 15, 1 August 2011 (2011-08-01), AMSTERDAM, NL , pages 4429 - 4435, XP028237567, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2011.06.023 *

Similar Documents

Publication Publication Date Title
EP4069686A1 (fr) Agoniste du récepteur glp-1
WO2021096284A1 (fr) Agoniste du récepteur glp-1 et son utilisation
WO2013073875A1 (fr) Dérivé antiviral inédit de pyrrolopyridine et son procédé de production
WO2021194318A1 (fr) Composé induisant une dégradation sélective de plk1
WO2015030514A1 (fr) Dérivé de tétrahydrocyclopentapyrrole et son procédé de préparation
WO2021040356A1 (fr) C-nucléosides, c-nucléotides et leurs analogues, équivalents et promédicaments de ceux-ci pour l'inhibition de l'ectonucléotidase
WO2017188694A1 (fr) Composé hétéroaryle comprenant de l'azote et son utilisation
WO2020149723A1 (fr) Dérivé de pyrrolopyrimidine et composition pharmaceutique pour la prévention ou le traitement d'une maladie liée à la protéine kinase le comprenant en tant que principe actif
WO2016032209A2 (fr) N-(pyrrolidin-3-yl)-7h-pyrrolo[2,3-d]pyrimidine-4-amine substituée utilisée en tant qu'inhibiteur de la janus kinase
WO2022035303A1 (fr) Nouveaux dérivés de dioxoloisoquinolinone et leur utilisation
WO2019054766A1 (fr) Composé dérivé de pyrazole et son utilisation
WO2011162562A2 (fr) Bicycles fusionnés [6+5] en tant qu'antagonistes de la thrombine, procédé de préparation de ceux-ci et compositions pharmaceutiques contenant les bicycles
WO2021261970A1 (fr) Nouveau composé et composition pharmaceutique le comprenant pour prévenir ou traiter un cancer résistant
WO2023017442A1 (fr) Nouveau composé induisant la dégradation de plk1
AU2021327622B2 (en) Novel compounds having inhibitory activity on prostaglandin E2 receptor and uses thereof
WO2021261969A1 (fr) Méthode de préparation d'un nouveau composé
WO2021086038A1 (fr) Nouveau composé et composition pharmaceutique le comprenant pour prévenir ou traiter un cancer
WO2022177302A1 (fr) Composé cyclique fusionné à la pyrimidine avec une activité d'inhibition de l'adn-pk et son utilisation
WO2021246781A1 (fr) Dérivés de pyridine en tant qu'immunomodulateurs
WO2020190073A1 (fr) Composition pharmaceutique comprenant un nouveau composé hétérocyclique azolopyrimidine en tant que principe actif
WO2023128708A1 (fr) Dérivé de pyrazolopyrimidine et composition pharmaceutique anticancéreuse le contenant en tant que principe actif
WO2023090829A1 (fr) Composé de faible poids moléculaire pour la régulation de l'interaction mll1-wdr5 et son utilisation
WO2022231377A1 (fr) Nouveau composé et composition pharmaceutique le comprenant pour la prévention ou le traitement du cancer, et utilisation associée
WO2024019562A1 (fr) Composé hétérobicyclique et composition pharmaceutique le comprenant
WO2023211256A1 (fr) Nouveaux inhibiteurs de pim kinase et leurs utilisations

Legal Events

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

Ref document number: 21828667

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21828667

Country of ref document: EP

Kind code of ref document: A1