WO2021112626A1 - Novel indirubin derivative and use thereof - Google Patents

Novel indirubin derivative and use thereof Download PDF

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Publication number
WO2021112626A1
WO2021112626A1 PCT/KR2020/017666 KR2020017666W WO2021112626A1 WO 2021112626 A1 WO2021112626 A1 WO 2021112626A1 KR 2020017666 W KR2020017666 W KR 2020017666W WO 2021112626 A1 WO2021112626 A1 WO 2021112626A1
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Prior art keywords
biindolinylidene
oxo
imino
amino
acetamide
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PCT/KR2020/017666
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French (fr)
Korean (ko)
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김용철
이제헌
김우찬
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주식회사 펠레메드
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Publication of WO2021112626A1 publication Critical patent/WO2021112626A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to novel indirubin derivatives and their use as inhibitors of fms-like tyrosine kinase 3 (FLT3).
  • FLT3 fms-like tyrosine kinase 3
  • Fms-like tyrosine kinase 3 (fms-like tyrosine kinase 3; FLT3) is a protein belonging to class III of receptor-type tyrosine kinases, has five immnunoglobulin-like motifs in the N-terminal extracellular domain, and two kinases at the C-terminus. have a domain FLT3 is expressed on normal CD34-positive human bone marrow progenitor cells and dendritic progenitor cells, and plays an important role in proliferation and differentiation of these cells (Brown P et al., European Journal of Cancer, 40th, pp.707-721). , 2004).
  • the ligand (FL) of FLT3 is expressed in bone marrow stromal cells and T cells, affects the cell development of a number of hematopoietic lines, and interacts with other growth factors such as hepatocytes, progenitor cells, dendritic cells and natural killer cells.
  • FL ligand
  • FLT3 is also known to be an acute myeloid leukemia (AML) target antigen, is overexpressed in blasts of AML patients when compared to healthy cells, and is expressed in the majority of patient cells (Carow et al, Feb 2, 1996 Blood: 87(3); Birg et al Nov 1992 Blood: 80(10))
  • FLT3 is a frequently mutated gene in AML patients, and the mutation is associated with a poor prognosis (Abu-Duhier et al Br J Haematol 2000 Oct;111(1):190).
  • Yamamoto et al April 15, 2001;Blood: 97 (8) small molecule FLT3 inhibitors showed activity in clinical trials; The response is usually transient due to the acquisition of resistance.
  • kinase inhibitors are only effective in a subset of patients expressing a mutated form of FLT3, so there is still a need for improved therapeutic agents.
  • novel indirubin derivative compounds can effectively inhibit FLT3, in particular, mutant FLT3, the present invention has been completed.
  • An object of the present invention is to provide a novel indirubin derivative compound having FLT3 inhibitory ability, and a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for preventing or treating FLT3-related diseases, including a novel indirubin derivative compound, use of the novel compound for preventing or treating FLT3-related diseases, and administering the novel compound to a subject in need thereof It is intended to provide a method for preventing or treating FLT3-related diseases, including the steps of:
  • R4 is -NRcRd
  • Rc and Rd are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, provided that Rc and Rd is not hydrogen at the same time; or
  • Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl;
  • R5 and R6 are each independently hydrogen or C1-C6 alkyl
  • Re and Rf is each independently hydrogen or C1-C6 alkyl.
  • the compounds disclosed herein have high inhibitory activity against FLT3, particularly mutant FLT3.
  • the compounds and pharmaceutical compositions disclosed herein are useful, for example, in preventing or treating FLT3-related diseases by administering the compounds or compositions to a subject.
  • the indirubin derivative compound of the present invention is a novel compound that has not been previously known, and effectively inhibits the activity of FLT3, in particular, mutant FLT3, and thus can be usefully used for the prevention or treatment of mutant FLT3-associated diseases, particularly acute myeloid leukemia. .
  • n-member typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n.
  • pyridine is an example of a 6-membered heteroaryl ring
  • thiophene is an example of a 5-membered heteroaryl ring.
  • substituents are intended to include both substituted and unsubstituted instances.
  • halo refers to bromo, chloro, fluoro, or iodo.
  • alkyl is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms and includes saturated aliphatic groups, which may be straight chain, branched, or cyclic, or combinations thereof. do.
  • an alkyl group may have 1 to 20 carbon atoms (ie, C1-C20 alkyl), 1 to 10 carbon atoms (ie, C1-C10 alkyl), or 1 to 6 carbon atoms (ie, C1-C6 alkyl).
  • alkyl can have examples of suitable alkyl include methyl (Me, —CH 3 ), ethyl (Et, —C 2 H 5 ), 1-propyl (n-Pr, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, -CH 2 CH(CH 3 ) 2 ) , 2-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl- 2-Butyl (-CH(CH
  • alkoxy refers to a group having -OR, wherein an alkyl group as defined above is attached to the parent compound through an oxygen atom.
  • Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula -R-O-R'. wherein R and R' are each independently an alkyl group as defined above.
  • the oxygen atom may be bonded to any carbon atom in the alkyl radical.
  • amine refers to a substituted or unsubstituted group represented by the form -NRR'.
  • Substituted amino wherein R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heterocyclyl groups.
  • amino also includes the corresponding quaternary ammonium salts of any amino group, for example -[N(Rl)(Rm)(Rn)]+.
  • amino groups include aminoalkyl groups in which at least one of Rl, Rm, or Rn is an alkyl group. In certain embodiments, R1 and Rm are hydrogen or alkyl.
  • aryl includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic, or polycyclic.
  • the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring.
  • An aryl group can be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein one or more of the rings are aromatic, e.g., the other cyclic rings are cycloalkyl , cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.
  • heteroaryl refers to a monocyclic, bicyclic or polycyclic, substituted or unsubstituted monovalent or divalent aromatic group containing one or more heteroatoms in the ring.
  • suitable heteroatoms include oxygen, sulfur and nitrogen.
  • the ring system has at least two cyclic rings in which at least two carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
  • a heteroaryl group is, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like, each of which may be substituted or unsubstituted.
  • cycloalkyl refers to a non-aromatic saturated or unsaturated, monovalent or divalent ring, which may be monocyclic, bicyclic or polycyclic and wherein each atom of the ring is carbon.
  • a cycloalkyl group can have 3 to 7 carbon atoms as a monocyclo, 7 to 12 carbon atoms as a bicyclo, and up to about 20 carbon atoms as a polycyclo.
  • Maternalcyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms.
  • Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be fused ring systems, spirocyclic ring systems or bridged ring systems.
  • the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], [6,6] system.
  • the cycloalkyl contains 3 to 20 atoms, or 3 to 10 atoms, or more preferably 3 to 7 atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • heterocycloalkyl As used herein, the terms “heterocycloalkyl”, “heterocyclyl”, “heterocycle” and “heterocyclic” are used interchangeably and the ring structure contains one or more heteroatoms, preferably 1 to 4 A monovalent or divalent, saturated or partially saturated non-aromatic ring structure comprising two heteroatoms, more preferably 1 to 2 heteroatoms, preferably a 3- to 10-membered ring, more preferably 3- to 7-membered ring.
  • suitable heteroatoms include oxygen, sulfur and nitrogen.
  • heterocycloalkyl also refers to polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings. wherein at least one of the rings is heterocyclic, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
  • Bicyclic and polycyclic heterocyclic ring systems may be fused, bridged, or spiro ring systems.
  • heterocycloalkyls include azetidinyl, dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidi nyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroiso Quinolinyl, 6H-1,2,5-thiadiazinyl, pyranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, a
  • ester refers to —C(O)R 9 , wherein R 9 represents a hydrocarbyl group.
  • cyano refers to the —CN radical.
  • hydroxy refers to the —OH radical.
  • substituted as used herein for alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, etc. means alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heteroaryl , heterocycloalkyl, or one or more hydrogen atoms of cycloalkyl are each independently replaced by a non-hydrogen substituent.
  • Substituents are any of the substituents described herein, for example halogen, hydroxyl, amino, nitro, alkyl, alkoxy, carbonyl (eg, carboxyl, alkoxycarbonyl, formyl, or acyl), phosphoryl, phosphate , phosphonate, phosphinate, amido, amidine, imine, cyano, azido, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or hetero aromatic moieties. It will be understood by those skilled in the art that a substituted moiety on the hydrocarbon chain may itself be optionally substituted.
  • pyridinyl is 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl) ) can be
  • adjacent groups combine with each other to form a ring means to form a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or condensed ring thereof by combining adjacent groups with each other do.
  • phrases “pharmaceutically acceptable” is an art-used expression that indicates that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal to be treated therewith. indicates.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient.
  • exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid acids, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid.
  • Monoacid or diacid salts may be formed, and such salts may exist in hydrated, solvated or substantially anhydrous form.
  • acid addition salts of compounds of the present invention are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base form.
  • the selection of an appropriate salt is known to the person skilled in the art.
  • Other non-pharmaceutically acceptable salts, such as oxalates, can be used in the isolation of compounds of the present invention, for example, for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.
  • Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Exemplary organic bases that form suitable salts include aliphatic, cycloaliphatic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia.
  • contemplated salts of the present invention include alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, theanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol; Ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • Pharmaceutically acceptable acid addition salts may also exist in various solvates, such as solvates with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared.
  • the source of such a solvate may be from the solvent of crystallization, native to the solvent of manufacture or crystallization, or adventitious to such solvent.
  • IC 50 refers to the concentration of an inhibitor or compound that produces 50% inhibition.
  • GI 50 refers to a concentration of an inhibitor or compound that produces 50% inhibition to maximal inhibition of cell proliferation.
  • the terms “subject”, “subject”, “patient” refer to warm-blooded animals such as, for example, pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.
  • the terms “treat”, “treating”, “treatment” in addition to “ameliorate” and “ameliorate” refer to any objective or subjective parameter, eg, reduction; driveway; reduce symptoms or make the symptoms, injury, pathology or condition better tolerated by the patient; reduce the frequency or duration of a symptom or condition; In some contexts, refers to any indication of success in the treatment or amelioration of an injury, pathology, condition, or symptom (eg, pain), including preventing the onset of the symptom or condition. Treatment or amelioration of symptoms may be based on any objective or subjective parameter, including, for example, the results of a physical examination.
  • the present invention provides novel indirubin derivative compounds.
  • the present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R4 is -NRcRd
  • Rc and Rd are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, provided that Rc and Rd are not simultaneously hydrogen; or
  • Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a heteroaryl or heterocycloalkyl
  • R5 and R6 are each independently hydrogen or alkyl
  • Re and Rf is each independently hydrogen or alkyl.
  • R4 is -NRcRd
  • Rc and Rd are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, provided that Rc and Rd is not hydrogen at the same time; or
  • Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl;
  • R5 and R6 are each independently hydrogen or C1-C6 alkyl
  • Re and Rf is each independently hydrogen or C1-C6 alkyl.
  • the heteroaryl or heterocycloalkyl includes one or more of N, O, or S atoms.
  • R1 and R3 can each independently be hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy.
  • R4 is -NRcRd
  • Rc and Rd are each independently hydrogen, C1-C6 alkyl, 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl, provided that Rc and Rd are not simultaneously hydrogen; or
  • Rc and Rd may be taken together with the nitrogen atom to which they are attached at -NRcRd to form a 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl.
  • R4 is -NRcRd
  • Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
  • Rc and Rd may be such that together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
  • R5 and R6 can each independently be hydrogen or methyl.
  • R2 is
  • the present invention provides a compound represented by Formula 1a or a pharmaceutically acceptable salt thereof.
  • R1, R2, and R3 are as defined above.
  • R 1 is halogen; or C1-C6 alkoxy unsubstituted or substituted with halogen.
  • R 3 may be hydrogen
  • R2 is or ego
  • R4 is -NRcRd
  • Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
  • Rc and Rd may be such that together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
  • Representative compounds of Formula 1 or 1a include, but are not limited to, compounds selected from compounds 1) to 35).
  • novel indirubin derivative compound or a pharmaceutically acceptable salt thereof according to the present invention inhibits the activity of FLT3, particularly mutant FLT3, and exhibits a preventive or therapeutic effect on diseases related to these activities.
  • the mutant FLT3 may have a mutation in a tyrosine kinase domain (TKD) (FLT3-TKD) of the FLT3 amino acid sequence.
  • the mutant FLT3 may further include an internal tandem duplication (ITD).
  • ITD internal tandem duplication
  • Examples of the mutant FLT3 include, but are not limited to, one or more of FLT3-ITD, FLT3-D835Y, FLT3-F691L, FLT3-F691L/D835Y, FLT3-ITD/D835Y, or FLT3-ITD/F691L.
  • the compounds of the present invention may be used to treat FLT3-related diseases.
  • the FLT3-associated disease comprises malignant cells expressing FLT3, eg, cancer.
  • the cancer is a cancer of hematopoietic origin, such as lymphoma or leukemia.
  • the cancer is multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte-predominant Hodgkin's lymphoma, Caller's disease and myeloma, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia , Hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), follicular lymphoma, Burkitt Lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, progenitor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphom
  • AML acute myeloid leukemia
  • the compound of the present invention has a mutant FLT3 inhibitory ability, and it was confirmed that it can be used as an AML therapeutic agent by confirming strong antiproliferative activity in the FLT3-ITD-expressing MV4-11 cell line, the FLT3/D835Y-expressing MOLM14-FLT3/D835Y cell line, and the like.
  • the present invention provides a pharmaceutical composition for inhibiting FLT3 comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition is for preventing or treating a FLT3-associated disease, more specifically, for preventing or treating AML.
  • the present invention provides a method for preventing or treating FLT3-associated diseases, comprising administering a compound according to the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject in need thereof.
  • the present invention comprises the step of administering the compound according to the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in a pharmaceutically effective amount to a subject having AML or a subject at risk of developing, Methods for inhibiting FLT3 are provided.
  • the present invention provides a method for inhibiting FLT3, wherein the pharmaceutical composition has potent antiproliferative activity in FLT3-ITD expressing MV4-11 cell line and FLT3/D835Y expressing MOLM14-FLT3/D835Y cell line.
  • the present invention provides the use of the compound according to the present invention or a pharmaceutically acceptable salt thereof for inhibiting FLT3 or preventing or treating FLT3-associated diseases.
  • the present invention also provides the use of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of AML.
  • the indirubin derivative compound of the present invention may have an IC 50 value of 100 nM or less for FLT3 inhibition. More specifically, the compound represented by Formula 1 may have an IC 50 value for FLT3 inhibition of 50 nM or less, more specifically 40 nM or less, still more specifically 35 nM or less, and even more specifically may be 30 nM or less, more specifically 25 nM or less, still more specifically 20 nM or less, still more specifically 15 nM or less, and even more specifically 10 nM or less.
  • Intermediate 3 of a compound of the present invention can be prepared according to Scheme 1 below.
  • the compound of the present invention can be prepared according to Scheme 2 below.
  • a suitable compound eg, 1-Boc-piperazine, etc.
  • glycolic acid 4 is added, stirred, and the product 5 is obtained through neutralization, extraction, concentration and purification.
  • the obtained product 5 is dissolved in an appropriate solvent, MsCl and TEA are added and stirred, followed by neutralization, extraction, concentration and purification to obtain product 6 .
  • stirring, adding TEA and stirring again the mixture is cooled, neutralized, extracted and concentrated.
  • TFA is added, followed by stirring, followed by neutralization, extraction, concentration and purification to obtain product 7 .
  • the compounds of the present invention may be prepared according to Scheme 3 below.
  • Diiodomethane is dissolved in an appropriate solvent, refluxed by adding Na 2 SO 3 , and the mixture is concentrated and recrystallized to obtain product 10.
  • the obtained product 10 was dissolved in a solvent, refluxed and neutralized, followed by extraction and concentration again. It is dissolved in a solvent, an appropriate reagent (eg 1-Boc-piperazine) and TEA are added, stirred, and then neutralized, extracted, concentrated and purified to obtain the product 11 .
  • the obtained product 11 is added to product 3 dissolved in a suitable solvent and stirred, followed by addition of K 2 CO 3 and stirring again.
  • the mixture is cooled, neutralized, extracted and concentrated.
  • the resulting mixture is dissolved in an appropriate solvent, stirred with TFA, and then subjected to neutralization, extraction, concentration and purification to obtain product 12.
  • the compounds of the present invention can be prepared according to Scheme 4 below.
  • the product 14 After dissolving 2-chloroacetyl chloride 13 in an appropriate solvent and stirring, the product 14 is obtained through neutralization, extraction, concentration, and purification processes.
  • the obtained product 14 is dissolved in a suitable solvent, NaOAc is added and stirred, then cooled and neutralized.
  • KOH is added, stirred, and concentrated and neutralized, and this is again extracted, concentrated and purified to obtain product 15.
  • the obtained product 15 is dissolved in a solvent, and MsCl and TEA are added thereto and stirred, followed by neutralization, extraction, concentration, and purification to obtain product 16.
  • the obtained product 16 was added to the product 3 dissolved in a solvent, stirred, and K 2 CO 3 was It is added and stirred again, then cooled and neutralized.
  • the neutralized product is extracted and concentrated, and the resulting mixture is dissolved in a solvent, stirred by adding TFA, and then subjected to neutralization, extraction, concentration and purification to obtain product 17.
  • the obtained product 5 was dissolved in DCM, and MsCl (1.5eq) and TEA (1.5eq) were added thereto and stirred for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain product 6 .
  • the obtained product 6 was added to Indirubin-3'-oxime 3a-g dissolved in DMF and stirred for 5 minutes. TEA (2eq) was then added and stirred at 60° C. overnight. The mixture was cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain products 7a-g .
  • the obtained product 10 was dissolved in DCM and PCl 5 was added and refluxed for 1 hour. Then, the mixture was cooled , neutralized with an aqueous NaHCO 3 solution, extracted using EA, and concentrated by rotary evaporation. The obtained extract was dissolved in DCM, 1-Boc-piperazine (1.5eq) and TEA (2eq) were added and stirred at -20°C for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain product 11 .
  • the obtained product 11 was added to Indirubin-3'-oxime 3a-b dissolved in DMF and stirred for 5 minutes. Then K 2 CO 3 (5eq) was added and stirred at 60° C. overnight. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product is extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 12a-b .
  • the obtained product 14a-d was dissolved in DMF, and NaOAc (2eq) was added and stirred at 80° C. for 1 hour. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The obtained extract was dissolved in MeOH, and 10% KOH was added and stirred for 1 hour. Then, MeOH in the mixture was removed by rotary evaporation and neutralized with 1N HCl aqueous solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain products 15a-d .
  • the obtained product 15a-d was dissolved in DCM, MsCl (1.5eq) and TEA (1.5eq) were added and stirred for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 16a-d .
  • the FLT3 inhibitory effect of the compound of the present invention was confirmed through the FLT enzyme inhibition test and the leukemia cell proliferation inhibition test in cancer cell lines.
  • Inhibition of FLT3 activity was measured using a homogeneous, time-resolved fluorescence (HTRF) assay.
  • HTRF time-resolved fluorescence
  • Recombinant protein containing the FLT3 domain was purchased from Carna biosciences (Japan). Optimal enzyme, ATP and substrate concentrations were established using the HTRF KinEASE kit (Cisbio, France) according to the manufacturer's instructions.
  • FLT3 enzyme or FLT3/D835Y enzyme in kinase reaction buffer 50 mM HEPES (pH 7.0), 500 ⁇ M ATP, 0.1 mM sodium orthovanadate, 5 mM MgCl 2 , 1 mM DTT, 0.01% bovine serum albumin (BSA), 0.02% NaN3 ), the diluted compounds of the present invention and peptide substrates were mixed in sequence.
  • IC 50 was calculated by nonlinear regression using Prism version 5.01 (GraphPad).
  • MV4-11 is an FLT3-ITD expressing AML cell line
  • MOLM-14/D835Y is an FLT3/D835Y expressing AML cell line
  • MOLM-14 is a FLT3-ITD expressing AML cell line.
  • MV4-11 human AML cells were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA, CRL-9591) and cells were cultured with 10% fetal bovine serum, 1% penicillin/streptomycin and 4 mM L-glutamine (Life Technology). , Grand Island, NY) supplemented with IMDM medium (Sigma Co., St. Louis, MO, USA).
  • MOLM14-FLT3/D835Y is produced by transfecting MOLM14 with the pLKO.1 blast lentiviral expression vector containing the genetic information of FLT3-ITD-D835Y. MOLM14 expressing FLT3-ITD-D835Y was selected and maintained through puromycin selection.
  • EZ-Cytox Cell Viability Assay kit (DaeilLab, Korea). Specifically, 2,000 - 15,000 cells were plated in a 96-well plate in 100 ⁇ l of medium. The next day, cells were treated with compounds with dimethyl sulfoxide (DMSO) as a negative control. 3 days (72 hours) after compound addition, 10 ⁇ l of EZ-Cytox kit reagent was placed in each well of a 96-well plate and incubated at 37° C. in a humidified CO 2 incubator for 4 hours.
  • DMSO dimethyl sulfoxide
  • GI 50 was calculated by nonlinear regression using Prism version 5.01 (GraphPad, LaJolla, CA, USA).
  • the compounds of the present invention exhibited FLT3 or FLT3 mutagenesis inhibitory activity, and in particular FLT3/D835Y mutation inhibitory activity was excellent*.
  • the compound of the present invention exhibits potent antiproliferative activity in acute leukemia cell lines.
  • FLT3-ITD expressing MV4-11 and MOLM14 cell lines expressing mutant kinases
  • FLT3/D835Y expressing MOLM14-FLT3/D835Y cell lines expressing potent antiproliferative activity It was confirmed that the proliferation activity was shown.
  • the compound of the present invention has excellent FTL3, particularly FLT3 mutation inhibitory activity.

Abstract

The present invention relates to a novel indirubin derivative and a use thereof as an fms-like tyrosine kinase 3 (FLT3) inhibitor.

Description

신규한 인디루빈 유도체 및 이의 용도Novel indirubin derivatives and uses thereof
본 발명은 신규한 인디루빈 유도체 및 FLT3(fms-like tyrosine kinase 3) 억제제로서의 이의 용도에 관한 것이다.The present invention relates to novel indirubin derivatives and their use as inhibitors of fms-like tyrosine kinase 3 (FLT3).
Fms-유사 티로신 키나제 3(fms-like tyrosine kinase 3; FLT3)은 수용체형 티로신 키나제의 클래스 III에 속하는 단백질이며, N-말단 세포외 도메인에 5개의 immnunoglobulin-like motif, C-말단에 2개의 kinase domain을 갖는다. FLT3은 정상인 CD34 양성 인간 골수전구세포 및 수상 조세포 상에 발현이 확인되며, 이들 세포의 증식·분화 등에 중요한 역활을 한다(Brown P et al., European Journal of Cancer, 40th, pp.707-721, 2004). 또한 FLT3의 리간드(FL)는 골수간질세포 및 T세포에 발현되고, 다수의 조혈계통의 세포발생에 영향을 주며, 다른 성장인자와의 상호작용에 의해 간세포, 전구세포, 수상세포 및 자연살해 세포의 증식을 자극하는 사이토카인의 하나이다.Fms-like tyrosine kinase 3 (fms-like tyrosine kinase 3; FLT3) is a protein belonging to class III of receptor-type tyrosine kinases, has five immnunoglobulin-like motifs in the N-terminal extracellular domain, and two kinases at the C-terminus. have a domain FLT3 is expressed on normal CD34-positive human bone marrow progenitor cells and dendritic progenitor cells, and plays an important role in proliferation and differentiation of these cells (Brown P et al., European Journal of Cancer, 40th, pp.707-721). , 2004). In addition, the ligand (FL) of FLT3 is expressed in bone marrow stromal cells and T cells, affects the cell development of a number of hematopoietic lines, and interacts with other growth factors such as hepatocytes, progenitor cells, dendritic cells and natural killer cells. One of the cytokines that stimulates the proliferation of
FLT3은 또한 급성 골수성 백혈병(AML) 표적 항원이며, 건강한 세포와 비교할 때 AML 환자 블라스트에서 과발현되고, 환자 세포 대부분에서 발현됨이 알려져있다(Carow et al, Feb 2, 1996 Blood: 87(3); Birg et al Nov 1992 Blood: 80(10)) 특히 FLT3은 AML 환자에서 빈번하게 돌연변이되는 유전자이며, 돌연변이는 불량한 예후와 연관된다(Abu-Duhier et al Br J Haematol 2000 Oct;111(1):190-5, Yamamoto et al April 15, 2001; Blood: 97 (8)) 소분자 FLT3 저해제가 임상 시험에서 활성을 나타내었지만; 그 반응은 내성 획득으로 인해서 통상적으로 일시적이다. 추가로 키나제 저해제는 FLT3의 돌연변이된 형태를 발현하는 환자의 일부에만 효과를 나타내어, 개선된 치료제에 대한 요구가 여전히 존재한다.FLT3 is also known to be an acute myeloid leukemia (AML) target antigen, is overexpressed in blasts of AML patients when compared to healthy cells, and is expressed in the majority of patient cells (Carow et al, Feb 2, 1996 Blood: 87(3); Birg et al Nov 1992 Blood: 80(10)) In particular, FLT3 is a frequently mutated gene in AML patients, and the mutation is associated with a poor prognosis (Abu-Duhier et al Br J Haematol 2000 Oct;111(1):190). -5, Yamamoto et al April 15, 2001;Blood: 97 (8)) small molecule FLT3 inhibitors showed activity in clinical trials; The response is usually transient due to the acquisition of resistance. In addition, kinase inhibitors are only effective in a subset of patients expressing a mutated form of FLT3, so there is still a need for improved therapeutic agents.
본 발명자들은 FLT3 억제능을 갖는 신규 화합물을 도출하고자 예의 연구 노력하였다. 그 결과 신규한 인디루빈 유도체 화합물들이 효과적으로 FLT3, 특히 돌연변이 FLT3를 억제할 수 있음을 규명함으로써, 본 발명을 완성하게 되었다. The present inventors made intensive research efforts to derive novel compounds having FLT3 inhibitory ability. As a result, by identifying that novel indirubin derivative compounds can effectively inhibit FLT3, in particular, mutant FLT3, the present invention has been completed.
본 발명은 FLT3 억제능을 갖는 신규한 인디루빈 유도체 화합물, 이의 약학적으로 허용되는 염을 제공하고자 한다.An object of the present invention is to provide a novel indirubin derivative compound having FLT3 inhibitory ability, and a pharmaceutically acceptable salt thereof.
본 발명은 또한 신규한 인디루빈 유도체 화합물을 포함하는, FLT3 관련 질병의 예방 또는 치료용 약학 조성물, 상기 신규 화합물의 FLT3 관련 질병의 예방 또는 치료 용도, 상기 신규 화합물을, 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는, FLT3 관련 질병의 예방 또는 치료 방법을 제공하고자 한다. The present invention also provides a pharmaceutical composition for preventing or treating FLT3-related diseases, including a novel indirubin derivative compound, use of the novel compound for preventing or treating FLT3-related diseases, and administering the novel compound to a subject in need thereof It is intended to provide a method for preventing or treating FLT3-related diseases, including the steps of:
본 발명의 일 측면에 따라, 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용되는 염이 제공된다.According to one aspect of the present invention, there is provided a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2020017666-appb-I000001
Figure PCTKR2020017666-appb-I000001
상기 식에 있어서, In the above formula,
R1 및 R3은 각각 독립적으로 수소, 할로젠, 시아노, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬, -N(Ra)(Rb), -N(Ra)(C(=O)-Rb), -C(=O)N(Ra)(Rb), -O-C(=O)-N(Ra)(Rb), -C(=O)-Ra, 및 -C(=O)-ORa로 이루어진 군으로부터 선택되고; 여기에서 Ra 및 Rb는 각각 독립적으로 수소 또는 C1-C6 알킬이고,R1 and R3 are each independently hydrogen, halogen, cyano, hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl; 3- to 10-membered heterocycloalkyl, -N(Ra)(Rb), -N(Ra)(C(=O)-Rb), -C(=O)N(Ra)(Rb), -OC (=O)-N(Ra)(Rb), -C(=O)-Ra, and -C(=O)-ORa; wherein Ra and Rb are each independently hydrogen or C1-C6 alkyl;
R2는R2 is
Figure PCTKR2020017666-appb-I000002
또는
Figure PCTKR2020017666-appb-I000003
이며,
Figure PCTKR2020017666-appb-I000002
or
Figure PCTKR2020017666-appb-I000003
is,
R4는 -NRcRd이고, R4 is -NRcRd,
Rc 및 Rd는 각각 독립적으로 수소, C1-C6 알킬, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는 Rc and Rd are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, provided that Rc and Rd is not hydrogen at the same time; or
Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 5- 내지 10-원 헤테로아릴 또는 3- 내지 10-원 헤테로시클로알킬을 형성하고, Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl;
R5 및 R6는 각각 독립적으로 수소 또는 C1-C6 알킬이고, R5 and R6 are each independently hydrogen or C1-C6 alkyl;
상기 C1-C6 알킬, C1-C6 알콕시, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬은 할로젠; 비치환되거나 또는 할로젠으로 치환된 C1-C6 알킬; 비치환되거나 또는 할로젠으로 치환된 C1-C6 알콕시; 시아노; 히드록시; 니트로; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; 비치환되거나 또는 C1-C6 알킬로 치환된 C6-C10 아릴; 비치환되거나 또는 C1-C6 알킬로 치환된 5- 내지 10-원 헤테로아릴; 비치환되거나 또는 C1-C6 알킬로 치환된 C3-C10 시클로알킬; 및 비치환되거나 또는 C1-C6 알킬로 치환된 3- 내지 10-원 헤테로시클로알킬로 이루어지는 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고; wherein said C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl is halogen; C1-C6 alkyl unsubstituted or substituted with halogen; C1-C6 alkoxy unsubstituted or substituted with halogen; cyano; hydroxy; nitro; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; C6-C10 aryl unsubstituted or substituted with C1-C6 alkyl; 5- to 10-membered heteroaryl unsubstituted or substituted with C1-C6 alkyl; C3-C10 cycloalkyl unsubstituted or substituted with C1-C6 alkyl; and 3- to 10-membered heterocycloalkyl unsubstituted or substituted with C1-C6 alkyl;
Re 및 Rf는 각각 독립적으로 수소 또는 C1-C6 알킬이다.Re and Rf is each independently hydrogen or C1-C6 alkyl.
본원에 개시된 화합물은 FLT3, 특히 돌연변이 FLT3에 대한 높은 억제 활성을 갖는다.The compounds disclosed herein have high inhibitory activity against FLT3, particularly mutant FLT3.
본원에 개시된 화합물 및 약학적 조성물은, 예를 들어 상기 화합물 또는 조성물을 대상체에게 투여함으로써 FLT3-관련 질병을 예방 또는 치료하는데 있어서 유용하다.The compounds and pharmaceutical compositions disclosed herein are useful, for example, in preventing or treating FLT3-related diseases by administering the compounds or compositions to a subject.
본 발명의 인디루빈 유도체 화합물은 종래 공지되지 않은 신규한 화합물로서, FLT3의 활성, 특히 돌연변이 FLT3를 효과적으로 억제하여, 돌연변이 FLT3-연관 질병, 특히 급성 골수성 백혈병의 예방 또는 치료하는 데 유용하게 사용할 수 있다. The indirubin derivative compound of the present invention is a novel compound that has not been previously known, and effectively inhibits the activity of FLT3, in particular, mutant FLT3, and thus can be usefully used for the prevention or treatment of mutant FLT3-associated diseases, particularly acute myeloid leukemia. .
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
정의Justice
달리 정의되지 않는 한, 본원에서 사용되는 모든 기술용어는 본 발명이 속한 분야의 당업자가 일반적으로 이해하는 바와 동일한 의미를 갖는다. 더욱이, 본원에 기재된 수치는 명백히 언급되지 않는 한 "약"의 의미를 포함하는 것으로 간주한다. Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Moreover, numerical values recited herein are intended to include the meaning of “about” unless explicitly stated otherwise.
본원에서 사용되는 잔기 및 치환기의 정의를 하기 제공한다. 달리 명시하지 않는 한, 각각의 잔기는 하기 정의를 가지며, 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다.Definitions of residues and substituents as used herein are provided below. Unless otherwise specified, each residue has the following definitions and is used in the sense commonly understood by one of ordinary skill in the art.
본원에 사용된 용어 "n-원" (여기서 n은 정수임)은 전형적으로 모이어티 내 고리-형성 원자의 수를 기재하며, 여기서 고리-형성 원자의 수는 n이다. 예를 들어, 피리딘은 6-원 헤테로아릴 고리의 한 예이고, 티오펜은 5-원 헤테로아릴 고리의 한 예이다.As used herein, the term “n-member” (where n is an integer) typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl ring.
본원에 사용된 치환기는 추가로 치환되거나 치환되지 않은 경우를 모두를 포함하는 것으로 의도된다. As used herein, substituents are intended to include both substituted and unsubstituted instances.
본원에 사용된 용어 "할로", "할로젠", "할로겐"은 브로모, 클로로, 플루오로, 또는 요오도를 지칭한다.As used herein, the terms “halo”, “halogen”, “halogen” refer to bromo, chloro, fluoro, or iodo.
본원에 사용된 용어 "알킬"은 1차, 2차, 3차, 및/또는 4차 탄소 원자를 갖는 탄화수소이며, 직쇄형, 분지형, 또는 환형, 또는 이들의 조합일 수 있는 포화 지방족 기를 포함한다. 예를 들어, 알킬 기는 1 내지 20개의 탄소 원자 (즉, C1-C20 알킬), 1 내지 10개의 탄소 원자 (즉, C1-C10 알킬), 또는 1 내지 6개의 탄소 원자 (즉, C1-C6 알킬)를 가질 수 있다. 적합한 알킬의 예로는 메틸 (Me, -CH3), 에틸 (Et, -C2H5), 1-프로필 (n-Pr, -CH2CH2CH3), 2-프로필 (i-Pr, -CH(CH3)2), 1-부틸 (n-Bu, - CH2CH2CH2CH3), 2-메틸-1-프로필 (i-Bu, -CH2CH(CH3)2), 2-부틸 (s-Bu, -CH(CH3)CH2CH3), 2-메틸-2-프로필 (t-Bu, -C(CH3)3), 1-펜틸 (n-펜틸, -CH2CH2CH2CH2CH3), 2-펜틸 (-CH(CH3)CH2CH2CH3), 3-펜틸 (-CH(CH2CH3)2), 2-메틸-2-부틸 (-CH(CH3)2CH2CH3), 3-메틸-2-부틸 (-CH(CH3)CH(CH3)2), 3-메틸-1-부틸 (-CH2CH2CH(CH3)2), 2-메틸-1-부틸 (-CH2CH(CH3)CH2CH3), 1-헥실 (-CH2CH2CH2CH2CH2CH3), 2-헥실 (-CH(CH3)CH2CH2CH2CH3), 3-헥실 (-CH(CH2CH3)(CH2CH2CH3)), 2-메틸-2-펜틸 (-C(CH3)2CH2CH2CH3), 3-메틸-2-펜틸 (-CH(CH3)CH(CH3)CH2CH3), 4-메틸-2-펜틸 (-CH(CH3)CH2CH(CH3)2), 3-메틸-3-펜틸(-C(CH3)(CH2CH3)2), 2-메틸-3-펜틸 (-CH(CH2CH3)CH(CH3)2), 2,3-디메틸-2-부틸 (-C(CH3)2CH(CH3)2), 3,3-디메틸-2-부틸 (-CH(CH3)C(CH3)3), 및 옥틸 (-(CH2)7CH3)을 들 수 있으나 이로 제한되지는 않는다.The term “alkyl,” as used herein, is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms and includes saturated aliphatic groups, which may be straight chain, branched, or cyclic, or combinations thereof. do. For example, an alkyl group may have 1 to 20 carbon atoms (ie, C1-C20 alkyl), 1 to 10 carbon atoms (ie, C1-C10 alkyl), or 1 to 6 carbon atoms (ie, C1-C6 alkyl). ) can have Examples of suitable alkyl include methyl (Me, —CH 3 ), ethyl (Et, —C 2 H 5 ), 1-propyl (n-Pr, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, -CH 2 CH(CH 3 ) 2 ) , 2-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl- 2-Butyl (-CH(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 ) CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) , 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (- CH ( CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl(-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH) 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH( CH 3 )C(CH 3 ) 3 ), and octyl (-(CH 2 ) 7 CH 3 ).
본원에 사용된 용어 "알콕시"는 상기 정의된 바와 같은 알킬 기가 산소 원자를 통해 모 화합물에 부착된 것인 -OR을 갖는 기를 지칭한다. C1-6알콕시의 예는 메톡시, 에톡시, 프로폭시, 이소프로폭시, 부톡시, 이소부톡시, 펜톡시, 및 헥속시를 포함하지만, 이로 제한되지는 않는다.The term "alkoxy," as used herein, refers to a group having -OR, wherein an alkyl group as defined above is attached to the parent compound through an oxygen atom. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.
본원에 사용된 용어 "알콕시알킬"은 알콕시 기로 치환된 알킬 기를 지칭하며 일반식 -R-O-R'로 표시될 수 있다. 여기서 R 및 R'는 각각 독립적으로 상기 정의된 바와 같은 알킬 기이다. 산소 원자는 알킬 라디칼 중 임의의 탄소 원자에 결합될 수 있다.The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula -R-O-R'. wherein R and R' are each independently an alkyl group as defined above. The oxygen atom may be bonded to any carbon atom in the alkyl radical.
본원에 사용된 용어 "아민" 또는 "아미노"는 형태 -NRR'로 표시되는 치환되거나 치환되지 않은 기를 지칭한다. 여기서 "치환된 아미노"는 R 및 R'가 각각 독립적으로 수소, 알킬, 알케닐, 알키닐, 아릴, 아릴알킬, 시클로알킬, 헤테로아릴 및 헤테로시클릴 기로부터 선택된다. 용어 "아미노"는 또한 임의의 아미노 기의 상응하는 4급 암모늄 염, 예를 들어 -[N(Rl)(Rm)(Rn)]+를 포함한다. 아미노 기의 예로는 Rl, Rm, 또는 Rn 중 적어도 하나가 알킬 기인 아미노알킬 기를 포함한다. 특정 실시양태에서, Rl 및 Rm는 수소 또는 알킬이다. As used herein, the term "amine" or "amino" refers to a substituted or unsubstituted group represented by the form -NRR'. "Substituted amino" wherein R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heterocyclyl groups. The term "amino" also includes the corresponding quaternary ammonium salts of any amino group, for example -[N(Rl)(Rm)(Rn)]+. Examples of amino groups include aminoalkyl groups in which at least one of Rl, Rm, or Rn is an alkyl group. In certain embodiments, R1 and Rm are hydrogen or alkyl.
본원에 사용된 용어 "아릴"은 고리의 원자 각각이 탄소인, 모노시클릭, 바이시클릭, 또는 폴리시클릭인, 치환되거나 치환되지 않은 1가 또는 2가 방향족 탄화수소 기를 포함한다. 바람직하게는, 아릴 고리는 6- 내지 20-원 고리, 6- 내지 14-원 고리, 6- 내지 10-원 고리, 또는 보다 바람직하게는 6-원 고리이다. 아릴 기는 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 갖는 폴리시클릭 고리계일 수 있으며, 여기서 고리 중 1개 이상은 방향족이고, 예를 들어, 다른 시클릭 고리는 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클로알킬일 수 있다. 아릴 기로는 벤젠, 나프탈렌, 페난트렌, 안트라센, 인덴, 인단, 페놀, 아닐린 등을 들 수 있다.The term "aryl," as used herein, includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic, or polycyclic. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring. An aryl group can be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein one or more of the rings are aromatic, e.g., the other cyclic rings are cycloalkyl , cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. Aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.
본원에 사용된 용어 "헤테로아릴"은 고리 내에 1개 이상의 헤테로원자를 함유하는, 모노시클릭, 바이시클릭 또는 폴리시클릭인, 치환되거나 치환되지 않은 1가 또는 2가 방향족 기를 지칭한다. 방향족 고리에 함유될 수 있는 적합한 헤테로원자의 비제한적인 예로는 산소, 황 및 질소를 들 수 있다. 폴리시클릭 헤테로아릴 고리계에서, 고리계는 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 가지며, 여기서 고리 중 1개 이상은 헤테로 방향족이고, 예를 들어 다른 시클릭 고리는 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클릴일 수 있다. 헤테로아릴 기는 예를 들어, 벤조푸란, 벤조티오펜, 피롤, 푸란, 티오펜, 이미다졸, 인돌, 이소인돌, 이속사졸, 이소티아졸, 옥사졸, 티아졸, 퀴놀린, 이소퀴놀린, 피라졸, 피리딘, 피라진, 피리다진, 및 피리미딘 등 (이들 각각은 치환되거나 치환되지 않은 것일 수 있음)을 포함한다.As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic or polycyclic, substituted or unsubstituted monovalent or divalent aromatic group containing one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur and nitrogen. In polycyclic heteroaryl ring systems, the ring system has at least two cyclic rings in which at least two carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. A heteroaryl group is, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like, each of which may be substituted or unsubstituted.
본원에 사용된 용어 "시클로알킬"은 모노시클릭, 바이시클릭 또는 폴리시클릭일 수 있고 고리의 원자 각각이 탄소인 비방향족 포화 또는 불포화, 1가 또는 2가 고리를 지칭한다. 시클로알킬 기는 모노시클로서 3 내지 7개의 탄소 원자, 바이시클로서 7 내지 12개의 탄소 원자, 및 폴리시클로서 약 20개 이하의 탄소 원자를 가질 수 있다. 모뇌클릭 시클로알킬은 3 내지 7개의 고리 원자, 보다 전형적으로 5 또는 6 개의 고리 원자를 갖는다. 바이시클릭 시클로알킬은 7 내지 12개의 고리 원자를 가질 수 있고, 융합 고리계, 스피로시클릭 고리계 또는 다리 고리계일 수 있다. 예시적인 시클로알킬 기에서, 원자는 바이시클로[4,5], [5,5], [5,6], [6,6] 시스템으로 배열될 수 있다. 특정 실시양태에서 시클로알킬은 3 내지 20개의 원자, 또는 3 내지 10개의 원자, 또는 보다 바람직하게는 3 내지 7개의 원자를 함유한다. 시클로알킬의 예로는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵틸, 시클로옥틸 등을 들 수 있다. The term “cycloalkyl,” as used herein, refers to a non-aromatic saturated or unsaturated, monovalent or divalent ring, which may be monocyclic, bicyclic or polycyclic and wherein each atom of the ring is carbon. A cycloalkyl group can have 3 to 7 carbon atoms as a monocyclo, 7 to 12 carbon atoms as a bicyclo, and up to about 20 carbon atoms as a polycyclo. Maternalcyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be fused ring systems, spirocyclic ring systems or bridged ring systems. In an exemplary cycloalkyl group, the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], [6,6] system. In certain embodiments the cycloalkyl contains 3 to 20 atoms, or 3 to 10 atoms, or more preferably 3 to 7 atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
본원에 사용된 용어 "헤테로시클로알킬", "헤테로시클릴", "헤테로사이클" 및 "헤테로시클릭"은 상호교환적으로 사용되며, 고리 구조가 1개 이상의 헤테로원자, 바람직하게는 1 내기 4개의 헤테로원자, 보다 바람직하게는 1 내지 2개의 헤테로원자를 포함하는, 1가 또는 2가, 포화 또는 부분 포화 비방향족 고리 구조, 바람직하게는 3- 내지 10-원 고리, 보다 바람직하게는 3- 내지 7-원 고리를 지칭한다. 상기 적합한 헤테로원자의 비제한적인 예로는 산소, 황 및 질소를 들 수 있다. 용어 "헤테로시클로알킬", "헤테로시클릴", "헤테로사이클" 및 "헤테로시클릭"은 또한 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 갖는 폴리시클릭 고리계를 포함하며, 여기서 고리 중 1개 이상은 헤테로시클릭이고, 예를 들어 다른 시클릭 고리는 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클릴일 수 있다. 바이시클릭 및 폴리시클릭 헤테로시클릭 고리계는 융합, 다리, 또는 스피로 고리계일 수 있다. 예시적인 헤테로시클로알킬로는 아제티디닐, 디히드로피리딜, 디히드로인돌릴, 테트라히드로피리딜(피페리디닐), 테트라히드로티오페닐, 황-산화된 테트라히드로티오페닐, 인돌레닐, 피페리디닐, 4-피페리디닐, 피롤리디닐, 2-피롤리도닐, 피롤리닐, 테트라히드로푸라닐, 테트라히드로퀴놀리닐, 테트라히드로이소퀴놀리닐, 데카히드로퀴놀리닐, 옥타히드로이소퀴놀리닐, 6H-1,2,5-티아디아지닐, 피라닐, 크로메닐, 크산테닐, 페녹사티닐, 2H-피롤릴, 3H-인돌릴, 4H-퀴놀리지닐, 프탈라지닐, 나프티리디닐, 퀴녹살리닐, 퀴나졸리닐, 신놀리닐, 프테리디닐, 4aH-카르바졸릴, 카르바졸릴, 베타-카르볼리닐, 페난트리디닐, 아크리디닐, 페난트롤리닐, 페나지닐, 페노티아지닐, 푸라지닐, 페녹사지닐, 이소크로마닐, 크로마닐, 이미다졸리디닐, 이미다졸리닐, 피라졸리디닐, 피라졸리닐, 피페라지닐, 퀴누클리디닐, 모르폴리닐, 및 옥사졸리디닐 (이들 각각은 치환되거나 치환되지 않은 것일 수 있음)을 들 수 있으나 이로 제한되는 것은 아니다,As used herein, the terms "heterocycloalkyl", "heterocyclyl", "heterocycle" and "heterocyclic" are used interchangeably and the ring structure contains one or more heteroatoms, preferably 1 to 4 A monovalent or divalent, saturated or partially saturated non-aromatic ring structure comprising two heteroatoms, more preferably 1 to 2 heteroatoms, preferably a 3- to 10-membered ring, more preferably 3- to 7-membered ring. Non-limiting examples of suitable heteroatoms include oxygen, sulfur and nitrogen. The terms "heterocycloalkyl", "heterocyclyl", "heterocycle" and "heterocyclic" also refer to polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings. wherein at least one of the rings is heterocyclic, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. Bicyclic and polycyclic heterocyclic ring systems may be fused, bridged, or spiro ring systems. Exemplary heterocycloalkyls include azetidinyl, dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidi nyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroiso Quinolinyl, 6H-1,2,5-thiadiazinyl, pyranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, Naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, beta-carbolinyl, phenantridinyl, acridinyl, phenanthrolinyl, phenazinyl , phenothiazinyl, furazinyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, quinuclidinyl, morpholinyl, and oxazolidinyl, each of which may be substituted or unsubstituted, but is not limited thereto.
본원에 사용된 용어 "에스테르" 기는 -C(O)R9 (여기서, R9는 히드로카르빌 기를 나타냄)를 지칭한다.As used herein, the term “ester” group refers to —C(O)R 9 , wherein R 9 represents a hydrocarbyl group.
본원에 사용된 용어 "시아노"는 -CN 라디칼을 지칭한다.As used herein, the term “cyano” refers to the —CN radical.
본원에 사용된 용어 "히드록시"는 -OH 라디칼을 지칭한다.As used herein, the term “hydroxy” refers to the —OH radical.
본 발명에서 알킬, 알콕시, 알콕시알킬, 아미노알킬, 아릴, 헤테로아릴, 헤테로시클로알킬, 또는 시클로알킬 등에 대하여 사용된 용어 "치환된"이라는 것은 알킬, 알콕시, 알콕시알킬, 아미노알킬, 아릴, 헤테로아릴, 헤테로시클로알킬, 또는 시클로알킬의 1개 이상의 수소 원자가 각각 독립적으로 비-수소 치환기에 의해 대체된 것을 의미한다. 치환기는 본 발명에 기재된 임의의 치환기, 예를 들어 할로젠, 히드록실, 아미노, 니트로, 알킬, 알콕시, 카르보닐 (예컨대, 카르복실, 알콕시카르보닐, 포르밀, 또는 아실), 포스포릴, 포스페이트, 포스포네이트, 포스피네이트, 아미도, 아미딘, 이민, 시아노, 아지도, 술페이트, 술포네이트, 술파모일, 술폰아미도, 술포닐, 헤테로시클릴, 아르알킬, 또는 방향족 또는 헤테로방향족 잔기를 포함하나, 이로 제한되는 것은 아니다. 탄화수소 사슬 상의 치환된 잔기는 경우에 따라 그 자체가 치환될 수 있다는 것을 당업자는 이해할 것이다.The term "substituted" as used herein for alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, etc. means alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heteroaryl , heterocycloalkyl, or one or more hydrogen atoms of cycloalkyl are each independently replaced by a non-hydrogen substituent. Substituents are any of the substituents described herein, for example halogen, hydroxyl, amino, nitro, alkyl, alkoxy, carbonyl (eg, carboxyl, alkoxycarbonyl, formyl, or acyl), phosphoryl, phosphate , phosphonate, phosphinate, amido, amidine, imine, cyano, azido, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or hetero aromatic moieties. It will be understood by those skilled in the art that a substituted moiety on the hydrocarbon chain may itself be optionally substituted.
명시되지 않는 한, 본원에 사용된 치환기의 부착 지점은 치환기의 임의의 적합한 위치로부터의 것일 수 있다. 예를 들어, 피리디닐 (또는 피리딜)은 2-피리디닐 (또는 피리딘-2-일), 3-피리디닐 (또는 피리딘-3-일), 또는 4-피리디닐 (또는 피리딘-4-일)일 수 있다.Unless otherwise specified, the point of attachment of a substituent as used herein may be from any suitable position of the substituent. For example, pyridinyl (or pyridyl) is 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl) ) can be
본 발명에서 "인접하는 기와 서로 결합하여 고리를 형성한다"는 것은 인접하는 기와 서로 결합하여 치환 또는 비치환된 아릴, 헤테로아릴, 시클로알킬, 헤테로시클로알킬, 또는 이들의 축합고리를 형성하는 것을 의미한다.In the present invention, "adjacent groups combine with each other to form a ring" means to form a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or condensed ring thereof by combining adjacent groups with each other do.
어구 "약학적으로 허용되는"은 당업계에서 통용되는 표현으로, 물질 또는 조성물이, 제제를 구성하는 다른 성분 및/또는 그로 치료될 포유동물과 화학적으로 및/또는 독성학적으로 상용성이어야 함을 나타낸다.The phrase “pharmaceutically acceptable” is an art-used expression that indicates that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal to be treated therewith. indicates.
"약학적으로 허용되는 염" 또는 "염"은 본원에서 환자의 치료에 적합한 또는 상용성이 있는 산부가염 또는 염기부가염을 지칭하는데 사용된다. 적합한 염을 형성하는 예시적 무기산으로는 염산, 브롬화수소산, 황산 및 인산, 뿐만 아니라 금속 염, 예컨대 오르토인산 일수소 나트륨 및 황산수소칼륨을 들 수 있다. 적합한 염을 형성하는 예시적 유기산으로는 모노-, 디- 및 트리카르복실산, 예컨대 글리콜산, 락트산, 피루브산, 말론산, 숙신산, 글루타르산, 푸마르산, 말산, 타르타르산, 시트르산, 아스코르브산, 말레산, 벤조산, 페닐아세트산, 신남산 및 살리실산, 뿐만 아니라 술폰산, 예컨대 p-톨루엔 술폰산 및 메탄술폰산을 들 수 있다. 일산 또는 이산 염이 형성될 수 있으며, 이러한 염은 수화, 용매화 또는 실질적으로 무수 형태로 존재할 수 있다. 일반적으로, 본 발명의 화합물의 산부가염은 이의 유리 염기 형태와 비교하여 물 및 다양한 친수성 유기 용매에 더욱 가용성이고, 일반적으로 더 높은 융점을 나타낸다. 적절한 염의 선택은 당업자에게 공지되어 있다. 다른 비-약학적으로 허용되는 염, 예를 들어 옥살레이트는 예를 들어, 실험실용으로 또는 약학적으로 허용되는 산부가염으로의 후속 전환용으로 본 발명의 화합물의 단리에서 사용될 수 있다. 적합한 염을 형성하는 예시적 무기 염기로는 리튬, 나트륨, 칼륨, 칼슘, 마그네슘, 또는 바륨 히드록시드를 들 수 있다. 적합한 염을 형성하는 예시적 유기 염기로는 지방족, 지환족 또는 방향족 유기 아민, 예컨대 메틸아민, 트리메틸아민 및 피콜린 또는 암모니아를 들 수 있다. 따라서, 일부 예에서, 본 발명의 고려되는 염으로는 알킬, 디알킬, 트리알킬 또는 테트라-알킬 암모늄 염을 들 수 있다. 특정 실시양태에서, 본 발명의 고려되는 염으로는 L-아르기닌, 베넨타민, 벤자틴, 베타인, 수산화칼슘, 콜린, 데아놀, 디에탄올아민, 디에틸아민, 2-(디에틸아미노)에탄올, 에탄올아민, 에틸렌디아민, N-메틸글루카민, 히드라바민, 1H-이미다졸, 리튬, L-리신, 마그네슘, 4-(2-히드록시에틸)모르폴린, 피페라진, 칼륨, 1-(2-히드록시에틸)피롤리딘, 나트륨, 트리에탄올아민, 트로메타민, 및 아연 염을 들 수 있으나 이에 제한되는 것은 아니다. 특정 실시양태에서, 본 발명의 고려되는 염으로는 Na, Ca, K, Mg, Zn 또는 다른 금속 염을 들 수 있으나 이에 제한되는 것은 아니다."Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid acids, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid. Monoacid or diacid salts may be formed, and such salts may exist in hydrated, solvated or substantially anhydrous form. In general, acid addition salts of compounds of the present invention are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base form. The selection of an appropriate salt is known to the person skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, can be used in the isolation of compounds of the present invention, for example, for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, cycloaliphatic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. Thus, in some instances, contemplated salts of the present invention include alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, theanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol; Ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
적절한 염의 선택은 당업자에게 공지되어 있다.The selection of an appropriate salt is known to the person skilled in the art.
약학적으로 허용되는 산부가염은 또한 다양한 용매화물, 예컨대 물, 메탄올, 에탄올, 디메틸포름아미드 등과의 용매화물로 존재할 수 있다. 이러한 용매화물의 혼합물이 또한 제조될 수 있다. 이러한 용매화물의 공급원은 결정화의 용매로부터 것이거나, 제조 또는 결정화의 용매에 고유한 것이거나, 또는 이러한 용매에 우발적인 것일 수 있다.Pharmaceutically acceptable acid addition salts may also exist in various solvates, such as solvates with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared. The source of such a solvate may be from the solvent of crystallization, native to the solvent of manufacture or crystallization, or adventitious to such solvent.
본원에 사용된 용어 "IC50"은 50% 억제를 생성하는 억제제 또는 화합물의 농도를 지칭한다.As used herein, the term “IC 50 ” refers to the concentration of an inhibitor or compound that produces 50% inhibition.
본원에 사용된 용어 "GI50"은 세포 증식의 최대 억제에 대해 50% 억제를 생성하는 억제제 또는 화합물의 농도를 지칭한다.As used herein, the term “GI 50 ” refers to a concentration of an inhibitor or compound that produces 50% inhibition to maximal inhibition of cell proliferation.
본원에 사용된 용어 "대상", "대상체", "환자"는 온혈 동물 예컨대 예를 들어 돼지, 소, 닭, 말, 기니 피그, 마우스, 래트, 저빌, 고양이, 토끼, 개,원숭이, 침팬지, 및 인간을 지칭한다.As used herein, the terms “subject”, “subject”, “patient” refer to warm-blooded animals such as, for example, pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.
본원에 사용되는 바와 같이, 용어 "치료하다", "치료하는", "치료"에 더하여 "개선하다" 및 "개선하는"은, 임의의 객관적 또는 주관적 파라미터, 예를 들어 감퇴; 차도; 증상을 감소시키거나 증상, 부상, 병리 또는 병태를 환자가 더 잘 참을 수 있게 하거나; 증상 또는 병태의 빈도 또는 지속 기간을 저하시키거나; 일부 상황에서, 증상 또는 병태의 개시를 방지하는 것을 비롯하여, 부상, 병리, 병태, 또는 증상(예를 들어, 통증)의 치료 또는 개선에 있어서 임의의 성공의 징후를 지칭한다. 증상의 치료 또는 개선은, 예를 들어 신체 검사의 결과를 포함하는, 임의의 객관적 또는 주관적 파라미터에 기초할 수 있다.As used herein, the terms “treat”, “treating”, “treatment” in addition to “ameliorate” and “ameliorate” refer to any objective or subjective parameter, eg, reduction; driveway; reduce symptoms or make the symptoms, injury, pathology or condition better tolerated by the patient; reduce the frequency or duration of a symptom or condition; In some contexts, refers to any indication of success in the treatment or amelioration of an injury, pathology, condition, or symptom (eg, pain), including preventing the onset of the symptom or condition. Treatment or amelioration of symptoms may be based on any objective or subjective parameter, including, for example, the results of a physical examination.
[인디루빈 유도체 화합물][Indirubin derivative compound]
본 발명은 신규한 인디루빈 유도체 화합물을 제공한다.The present invention provides novel indirubin derivative compounds.
일 실시태양에서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용되는 염에 관한 것이다.In one embodiment, the present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2020017666-appb-I000004
Figure PCTKR2020017666-appb-I000004
상기식에 있어서, In the above formula,
R1 및 R3은 각각 독립적으로 수소, 할로젠, 시아노, 히드록시, 니트로, 알킬, 알콕시, 아릴, 헤테로아릴, 시클로알킬, 헤테로시클로알킬, -N(Ra)(Rb), -N(Ra)(C(=O)-Rb), -C(=O)N(Ra)(Rb), -O-C(=O)-N(Ra)(Rb), -C(=O)-Ra, 및 -C(=O)-ORa로 이루어진 군으로부터 선택되고; 여기에서 Ra 및 Rb는 각각 독립적으로 수소 또는 알킬이고,R1 and R3 are each independently hydrogen, halogen, cyano, hydroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -N(Ra)(Rb), -N(Ra) (C(=O)-Rb), -C(=O)N(Ra)(Rb), -OC(=O)-N(Ra)(Rb), -C(=O)-Ra, and - selected from the group consisting of C(=O)-ORa; wherein Ra and Rb are each independently hydrogen or alkyl,
R2는R2 is
Figure PCTKR2020017666-appb-I000005
또는
Figure PCTKR2020017666-appb-I000006
이며,
Figure PCTKR2020017666-appb-I000005
or
Figure PCTKR2020017666-appb-I000006
is,
R4는 -NRcRd이고, R4 is -NRcRd,
Rc 및 Rd는 각각 독립적으로 수소, 알킬, 아릴, 헤테로아릴, 시클로알킬, 헤테로시클로알킬이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는 Rc and Rd are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, provided that Rc and Rd are not simultaneously hydrogen; or
Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 헤테로아릴 또는 헤테로시클로알킬을 형성하고, Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a heteroaryl or heterocycloalkyl;
R5 및 R6는 각각 독립적으로 수소 또는 알킬이고, R5 and R6 are each independently hydrogen or alkyl,
상기 알킬, 알콕시, 아릴, 헤테로아릴, 시클로알킬, 헤테로시클로알킬은 추가로 치환될 수 있고, 예컨대, 할로젠; 알킬; C1-C6 알콕시; 시아노; 히드록시; 니트로; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; 아릴; 헤테로아릴; 시클로알킬; 및 헤테로시클로알킬로 이루어지는 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고; The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl may be further substituted, for example, halogen; alkyl; C1-C6 alkoxy; cyano; hydroxy; nitro; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; aryl; heteroaryl; cycloalkyl; and one or more substituents selected from the group consisting of heterocycloalkyl;
Re 및 Rf는 각각 독립적으로 수소 또는 알킬이다. Re and Rf is each independently hydrogen or alkyl.
일 구체적 실시태양에서, In one specific embodiment,
R1 및 R3은 각각 독립적으로 수소, 할로젠, 시아노, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬, -N(Ra)(Rb), -N(Ra)(C(=O)-Rb), -C(=O)N(Ra)(Rb), -O-C(=O)-N(Ra)(Rb), -C(=O)-Ra, 및 -C(=O)-ORa로 이루어진 군으로부터 선택되고; 여기에서 Ra 및 Rb는 각각 독립적으로 수소 또는 C1-C6 알킬이고,R1 and R3 are each independently hydrogen, halogen, cyano, hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl; 3- to 10-membered heterocycloalkyl, -N(Ra)(Rb), -N(Ra)(C(=O)-Rb), -C(=O)N(Ra)(Rb), -OC (=O)-N(Ra)(Rb), -C(=O)-Ra, and -C(=O)-ORa; wherein Ra and Rb are each independently hydrogen or C1-C6 alkyl;
R2는R2 is
Figure PCTKR2020017666-appb-I000007
또는
Figure PCTKR2020017666-appb-I000008
이며,
Figure PCTKR2020017666-appb-I000007
or
Figure PCTKR2020017666-appb-I000008
is,
R4는 -NRcRd이고, R4 is -NRcRd,
Rc 및 Rd는 각각 독립적으로 수소, C1-C6 알킬, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는 Rc and Rd are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, provided that Rc and Rd is not hydrogen at the same time; or
Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 5- 내지 10-원 헤테로아릴 또는 3- 내지 10-원 헤테로시클로알킬을 형성하고, Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl;
R5 및 R6는 각각 독립적으로 수소 또는 C1-C6 알킬이고, R5 and R6 are each independently hydrogen or C1-C6 alkyl;
상기 C1-C6 알킬, C1-C6 알콕시, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬은 할로젠; C1-C6 알킬; C1-C6 알콕시; 시아노; 히드록시; 니트로; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; C6-C10 아릴; 5- 내지 10-원 헤테로아릴; C3-C10 시클로알킬; 및 3- 내지 10-원 헤테로시클로알킬로 이루어지는 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고; wherein said C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl is halogen; C1-C6 alkyl; C1-C6 alkoxy; cyano; hydroxy; nitro; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; C6-C10 aryl; 5- to 10-membered heteroaryl; C3-C10 cycloalkyl; and one or more substituents selected from the group consisting of 3- to 10-membered heterocycloalkyl;
Re 및 Rf는 각각 독립적으로 수소 또는 C1-C6 알킬이다. Re and Rf is each independently hydrogen or C1-C6 alkyl.
보다 구체적 실시태양에서, 상기 C1-C6 알킬, C1-C6 알콕시, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬은 할로젠; 비치환되거나 또는 치환된 C1-C6 알킬; 비치환되거나 또는 할로젠으로 치환된 C1-C6 알콕시; 시아노; 히드록시; 니트로; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; 비치환되거나 또는 C1-C6 알킬로 치환된 C6-C10 아릴; 비치환되거나 또는 C1-C6 알킬로 치환된 5- 내지 10-원 헤테로아릴; 비치환되거나 또는 C1-C6 알킬로 치환된 C3-C10 시클로알킬; 및 비치환되거나 또는 C1-C6 알킬로 치환된 3- 내지 10-원 헤테로시클로알킬로 이루어지는 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있다.In a more specific embodiment, the C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl is halogen; unsubstituted or substituted C1-C6 alkyl; C1-C6 alkoxy unsubstituted or substituted with halogen; cyano; hydroxy; nitro; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; C6-C10 aryl unsubstituted or substituted with C1-C6 alkyl; 5- to 10-membered heteroaryl unsubstituted or substituted with C1-C6 alkyl; C3-C10 cycloalkyl unsubstituted or substituted with C1-C6 alkyl; and 3- to 10-membered heterocycloalkyl unsubstituted or substituted with C1-C6 alkyl.
상기 헤테로아릴 또는 헤테로시클로알킬은, N, O, 또는 S 원자 중 하나 이상을 포함한다.The heteroaryl or heterocycloalkyl includes one or more of N, O, or S atoms.
바람직한 실시태양에서, R1 및 R3은 각각 독립적으로 수소, 할로젠, C1-C6 알킬, 또는 C1-C6 알콕시일 수 있다.In a preferred embodiment, R1 and R3 can each independently be hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy.
바람직한 실시태양에서, In a preferred embodiment,
R4는 -NRcRd이고, R4 is -NRcRd,
Rc 및 Rd는 각각 독립적으로 수소, C1-C6 알킬, 5- 내지 6-원 헤테로아릴 또는 3- 내지 7-원 헤테로시클로알킬이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는 Rc and Rd are each independently hydrogen, C1-C6 alkyl, 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl, provided that Rc and Rd are not simultaneously hydrogen; or
Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 5- 내지 6-원 헤테로아릴 또는 3- 내지 7-원 헤테로시클로알킬을 형성하는 것일 수 있다.Rc and Rd may be taken together with the nitrogen atom to which they are attached at -NRcRd to form a 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl.
보다 바람직한 실시태양에서, In a more preferred embodiment,
R4는 -NRcRd이고, R4 is -NRcRd,
Rc 및 Rd는 각각 독립적으로 수소, 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐을 형성하는 것일 수 있다.Rc and Rd may be such that together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
바람직한 실시태양에서, R5 및 R6은 각각 독립적으로 수소 또는 메틸일 수 있다.In a preferred embodiment, R5 and R6 can each independently be hydrogen or methyl.
바람직한 실시태양에서, R2는 In a preferred embodiment, R2 is
Figure PCTKR2020017666-appb-I000009
Figure PCTKR2020017666-appb-I000009
Figure PCTKR2020017666-appb-I000010
Figure PCTKR2020017666-appb-I000010
Figure PCTKR2020017666-appb-I000011
Figure PCTKR2020017666-appb-I000011
Figure PCTKR2020017666-appb-I000012
Figure PCTKR2020017666-appb-I000012
Figure PCTKR2020017666-appb-I000013
Figure PCTKR2020017666-appb-I000013
Figure PCTKR2020017666-appb-I000014
Figure PCTKR2020017666-appb-I000014
또는
Figure PCTKR2020017666-appb-I000015
일 수 있다. or
Figure PCTKR2020017666-appb-I000015
can be
또다른 실시태양에서, 본 발명은 화학식 1a로 표시되는 화합물 또는 이의 약학적으로 허용되는 염을 제공한다.In another embodiment, the present invention provides a compound represented by Formula 1a or a pharmaceutically acceptable salt thereof.
[화학식 1a][Formula 1a]
Figure PCTKR2020017666-appb-I000016
Figure PCTKR2020017666-appb-I000016
R1, R2, 및 R3는 상기 정의된 바와 같다.R1, R2, and R3 are as defined above.
바람직한 실시태양에서, R1은 할로젠; 또는 비치환되거나 또는 할로젠으로 치환된 C1-C6 알콕시일 수 있다.In a preferred embodiment, R 1 is halogen; or C1-C6 alkoxy unsubstituted or substituted with halogen.
바람직한 실시태양에서, R3은 수소일 수 있다.In a preferred embodiment, R 3 may be hydrogen.
바람직한 실시태양에서, In a preferred embodiment,
R2는
Figure PCTKR2020017666-appb-I000017
또는
Figure PCTKR2020017666-appb-I000018
이고, R2 is
Figure PCTKR2020017666-appb-I000017
or
Figure PCTKR2020017666-appb-I000018
ego,
R4는 -NRcRd이고, R4 is -NRcRd,
Rc 및 Rd는 각각 독립적으로 수소, 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는 Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐을 형성하는 것일 수 있다.Rc and Rd may be such that together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
바람직한 실시태양에서, In a preferred embodiment,
R2는 R2 is
Figure PCTKR2020017666-appb-I000019
Figure PCTKR2020017666-appb-I000019
Figure PCTKR2020017666-appb-I000020
Figure PCTKR2020017666-appb-I000020
Figure PCTKR2020017666-appb-I000021
Figure PCTKR2020017666-appb-I000021
Figure PCTKR2020017666-appb-I000022
또는
Figure PCTKR2020017666-appb-I000023
일 수 있다.
Figure PCTKR2020017666-appb-I000022
or
Figure PCTKR2020017666-appb-I000023
can be
상기 화학식 1 또는 1a의 대표적인 화합물은 화합물 1) 내지 35)로부터 선택된 화합물을 포함하나 이에 제한되는 것은 아니다.Representative compounds of Formula 1 or 1a include, but are not limited to, compounds selected from compounds 1) to 35).
1) (2Z,3E)-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;1) (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one ;
2) (2Z,3E)-5'-플루오로-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;2) (2Z,3E)-5'-fluoro-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-one;
3) (2Z,3E)-5'-클로로-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;3) (2Z,3E)-5'-chloro-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene] -2'-one;
4) (2Z,3E)-5'-브로모-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;4) (2Z,3E)-5'-bromo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-one;
5) (2Z,3E)-5'-아이오도-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온5) (2Z,3E)-5'-iodo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-on
6) (2Z,3E)-5'-메톡시-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;6) (2Z,3E)-5'-methoxy-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-one;
7) (2Z,3E)-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-2'-온; 7) (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-5′-(trifluoromethoxy)-[2,3′-bi indolinylidene]-2'-one;
8) (2Z,3E)-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;8) (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2 '-On;
9) (2Z,3E)-5'-플루오로-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;9) (2Z,3E)-5′-fluoro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3′-biyne dolinylidene]-2'-one;
10) (2Z,3E)-5'-클로로-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;10) (2Z,3E)-5'-chloro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindoli nylidene]-2'-one;
11) (2Z,3E)-5'-메톡시-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;11) (2Z,3E)-5'-methoxy-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biyne dolinylidene]-2'-one;
12) (2Z,3E)-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-2'-온;12) (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-5′-(trifluoromethoxy)-[2,3 '-Biindolinylidene]-2'-one;
13) (2Z,3E)-3-(((피페라진-1-일술포닐)메톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;13) (2Z,3E)-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3′-biindolinylidene]-2′-one;
14) (2Z,3E)-5'-플루오로-3-(((피페라진-1-일술포닐)메톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온; 14) (2Z,3E)-5'-fluoro-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3'-biindolinylidene]-2'- On;
15) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;15) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]- 2'-on;
16) 2-((((2Z,3E)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드; 16) 2-((((2Z,3E)-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidine-4- 1) acetamide;
17) N-(아제티딘-3-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;17) N-(azetidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino )oxy)acetamide;
18) 2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피롤리딘-3-일)아세트아미드; 18) 2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(pyrrolidine- 3-yl)acetamide;
19) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-플루오로-[2,3'-바이인돌리닐리덴]-2'-온; 19) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-fluoro-[2,3′-bi indolinylidene]-2'-one;
20) 2-((((2Z,3E)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드; 20) 2-((((2Z,3E)-5′-fluoro-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)-N-( piperidin-4-yl)acetamide;
21) N-(아제티딘-3-일)-2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;21) N-(azetidin-3-yl)-2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]- 3-ylidene)amino)oxy)acetamide;
22) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피롤리딘-3-일)아세트아미드;22) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(pyrrolidin-3-yl)acetamide;
23) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-클로로-[2,3'-바이인돌리닐리덴]-2'-온;23) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-chloro-[2,3′-biyne dolinylidene]-2'-one;
24) 2-((((2Z,3E)-5'-클로로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드;24) 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(p peridin-4-yl)acetamide;
25) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-메톡시-[2,3'-바이인돌리닐리덴]-2'-온; 25) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-methoxy-[2,3′-bi indolinylidene]-2'-one;
26) 2-((((2Z,3E)-5'-메톡시-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드; 26) 2-((((2Z,3E)-5'-methoxy-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-( piperidin-4-yl)acetamide;
27) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-2'-온;27) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-(trifluoromethoxy)-[2, 3'-biindolinylidene]-2'-one;
28) 2-((((2Z,3E)-2'-옥소-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드;28) 2-((((2Z,3E)-2′-oxo-5′-(trifluoromethoxy)-[2,3′-biindolinylidene]-3-ylidene)amino)oxy) -N-(piperidin-4-yl)acetamide;
29) N-(1-메틸피페리딘-4-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;29) N-(1-methylpiperidin-4-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3- ylidene)amino)oxy)acetamide;
30) N-(1-메틸아제티딘-3-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;30) N-(1-methylazetidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-yl) den)amino)oxy)acetamide;
31) N-(1-메틸피롤리딘-3-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;31) N-(1-methylpyrrolidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3- ylidene)amino)oxy)acetamide;
32) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸피페리딘-4-일)아세트아미드;32) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(1-methylpiperidin-4-yl)acetamide;
33) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸아제티딘-3-일)아세트아미드;33) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(1-methylazetidin-3-yl)acetamide;
34) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸피롤리딘-3-일)아세트아미드; 및 34) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(1-methylpyrrolidin-3-yl)acetamide; and
35) 2-((((2Z,3E)-5'-클로로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸피페리딘-4-일)아세트아미드. 35) 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1 -Methylpiperidin-4-yl)acetamide.
[치료 용도][therapeutic use]
본 발명에 따른 신규한 인디루빈 유도체 화합물 또는 이의 약학적으로 허용되는 염은 FLT3, 특히 돌연변이 FLT3의 활성을 억제하며, 이들 활성과 관련된 질병에 예방 또는 치료 효과를 나타낸다.The novel indirubin derivative compound or a pharmaceutically acceptable salt thereof according to the present invention inhibits the activity of FLT3, particularly mutant FLT3, and exhibits a preventive or therapeutic effect on diseases related to these activities.
돌연변이 FLT3은 FLT3 아미노산 서열의 티로신 키나아제 도메인(tyrosine kinase domain:TKD)(FLT3-TKD)에 돌연변이를 갖는 것일 수 있다. 상기 돌연변이 FLT3은 유전자내 종렬 중복(internal tandem duplication; ITD)을 추가로 포함하는 것일 수 있다. 상기 돌연변이 FLT3의 예로는, FLT3-ITD, FLT3-D835Y, FLT3-F691L, FLT3-F691L/D835Y,　FLT3-ITD/D835Y,　또는 FLT3-ITD/F691L 중 하나 이상을 포함하나, 이로 제한되는 것은 아니다.The mutant FLT3 may have a mutation in a tyrosine kinase domain (TKD) (FLT3-TKD) of the FLT3 amino acid sequence. The mutant FLT3 may further include an internal tandem duplication (ITD). Examples of the mutant FLT3 include, but are not limited to, one or more of FLT3-ITD, FLT3-D835Y, FLT3-F691L, FLT3-F691L/D835Y, FLT3-ITD/D835Y, or FLT3-ITD/F691L.
일 실시태양에서, 본 발명의 화합물은 FLT3-관련 질환을 치료하는데 사용될 수 있다. 일부 실시태양에서, FLT3-연관 질환은 FLT3을 발현하는 악성 세포, 예를 들어, 암을 포함한다. 구체적 실시태양에서, 상기 암은 조혈 기원의 암, 예컨대, 림프종 또는 백혈병이다. 보다 구체적 실시태양에서, 상기 암은 다발성 골수종, 악성 형질 세포 신생물, 호지킨 림프종, 결절성 림프구 우세형 호지킨 림프종, 칼러병 및 골수종증, 형질 세포 백혈병, 형질세포종, B-세포 전림프구성 백혈병, 모발 세포 백혈병, B-세포 비호지킨 림프종(NHL), 급성 골수성 백혈병(AML), 만성 림프구성 백혈병(CLL), 급성 림프구성 백혈병(ALL), 만성 골수성 백혈병(CML), 소포성 림프종, 버킷 림프종, 변연부 림프종, 외투 세포 림프종, 대세포 림프종, 전구 B-림프모구 림프종, 골수성 백혈병, 발덴스트롬 거대글로불린혈증, 미만성 거대 B 세포 림프종, 소포성 림프종, 변연부 림프종, 점막 관련 림프 조직 림프종, 소세포 림프구성 림프종, 외투 세포 림프종, 버킷 림프종, 원발성 종격동(흉선) 거대 B세포 림프종, 림프형질세포성 림프종, 발덴스트롬 마크로글로불린혈증, 림프절 변연부 B 세포 림프종, 비장 변 연부 림프종, 혈관내 거대 B-세포 림프종, 원발성 삼출성 림프종, 림프종양 육아종증, T 세포/조직구-풍부 거대 B-세포 림프종, 원발성 중추 신경계 림프종, 원발성 피부 미만성 거대 B-세포 림프종(다리 유형), 노인의 EBV 양성 미만성 거대 B-세포 림프종, 염증 연관된 미만성 거대 B-세포 림프종, 혈관내 거대 B-세포 림프종, ALK-양 성 거대 B-세포 림프종, 형질세포성 림프종, HHV8-연관 다중심성 캐슬만병에서 발생하는 거대 B-세포 림프종, 미만성 거대 B-세포 림프종과 버킷 림프종 사이의 중간 특징을 갖는 미분류 B-세포 림프종, 미만성 거대 B-세포 림프종와 전통적인 호지킨 림프종 사이의 중간 특징으로 갖는 미분류 B-세포 림프종, 또는 기타 조혈 세포 관련 암이나, 이로 제한되는 것은 아니다. 바람직하게는, 상기 암은 급성 골수성 백혈병(AML)이며, 보다 바람직하게는, 돌연변이 FLT3이 발현된 AML이다.In one embodiment, the compounds of the present invention may be used to treat FLT3-related diseases. In some embodiments, the FLT3-associated disease comprises malignant cells expressing FLT3, eg, cancer. In a specific embodiment, the cancer is a cancer of hematopoietic origin, such as lymphoma or leukemia. In a more specific embodiment, the cancer is multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte-predominant Hodgkin's lymphoma, Caller's disease and myeloma, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia , Hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), follicular lymphoma, Burkitt Lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, progenitor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosal associated lymphoid tissue lymphoma, small cell lymph Constituent lymphoma, mantle cell lymphoma, Burkitt's lymphoma, primary mediastinal (thymic) giant B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, lymph node marginal zone B-cell lymphoma, splenic marginal zone lymphoma, endovascular giant B-cell lymphoma , Primary exudative lymphoma, lymphoblastic granulomatosis, T-cell/histiocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV-positive diffuse large B-cell in the elderly Lymphoma, Inflammation Associated Diffuse Large B-Cell Lymphoma, Intravascular Large B-Cell Lymphoma, ALK-positive Large B-Cell Lymphoma, Plasmacytic Lymphoma, HHV8-Associated Multicentral Large B-Cell Lymphoma arising from Castleman's Disease, Unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and traditional Hodgkin's lymphoma, or other hematopoietic cell-associated cancer or , but is not limited thereto. Preferably, the cancer is acute myeloid leukemia (AML), more preferably, AML in which a mutant FLT3 is expressed.
본원에 사용된 용어 "급성 골수성 백혈병(acute myeloid leukemia: AML)"이란 골수에서 유래한 비정상적인 혈액 세포의 급속한 성장을 특징으로 하는 정상 혈액 세포를 방해하는, 골수성 혈액 세포 라인의 암이다. AML의 주 증상은 피로감, 가쁜 호흡, 쉽게 멍이나 출혈이 일어나며 감염이 빈번하게 일어나는 것 등이다. AML의 원인으로 추정되는 여러가지 것들이 확인되었지만 확실한 AML의 원인은 밝혀지지 않은 상황이다. 본 발명의 화합물은 특히, 돌연변이 FLT3 억제능을 가지는 것으로 FLT3-ITD 발현 MV4-11 세포주, FLT3/D835Y 발현 MOLM14-FLT3/D835Y 세포주 등에서 강력한 항증식 활성을 확인함으로서 AML 치료제로서 사용가능함을 확인하였다. As used herein, the term "acute myeloid leukemia (AML)" is a cancer of a line of myeloid blood cells that interferes with normal blood cells characterized by the rapid growth of abnormal blood cells derived from the bone marrow. The main symptoms of AML are fatigue, shortness of breath, easy bruising or bleeding, and frequent infections. A number of presumed causes of AML have been identified, but the exact cause of AML has not been identified. In particular, the compound of the present invention has a mutant FLT3 inhibitory ability, and it was confirmed that it can be used as an AML therapeutic agent by confirming strong antiproliferative activity in the FLT3-ITD-expressing MV4-11 cell line, the FLT3/D835Y-expressing MOLM14-FLT3/D835Y cell line, and the like.
이에 따라 본 발명은 본 발명에 따른 화합물 또는 이의 약학적으로 허용되는 염을 활성 성분으로서 포함하는, FLT3 억제를 위한 약학적 조성물을 제공한다. 일 구체예에서, 상기 약학적 조성물은 FLT3-연관 질환의 예방 또는 치료, 보다 구체적으로는, AML의 예방 또는 치료를 위한 것이다.Accordingly, the present invention provides a pharmaceutical composition for inhibiting FLT3 comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment, the pharmaceutical composition is for preventing or treating a FLT3-associated disease, more specifically, for preventing or treating AML.
또한, 본 발명은 본 발명에 따른 화합물 또는 이의 약학적으로 허용되는 염, 또는 상기 약학 조성물을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는, FLT3-연관 질환의 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method for preventing or treating FLT3-associated diseases, comprising administering a compound according to the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject in need thereof.
또한, 본 발명은 본 발명에 따른 화합물 또는 이의 약학적으로 허용되는 염, 또는 상기 약학 조성물을 약제학적으로 유효한 양으로 AML이 발명된 개체 또는 발병될 위험이 있는 개체에 투여하는 단계를 포함하는, FLT3 억제 방법을 제공한다.In addition, the present invention comprises the step of administering the compound according to the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in a pharmaceutically effective amount to a subject having AML or a subject at risk of developing, Methods for inhibiting FLT3 are provided.
추가적으로, 본 발명은 상기 약학 조성물이 FLT3-ITD 발현 MV4-11 세포주 및 FLT3/D835Y 발현 MOLM14-FLT3/D835Y 세포주에서 강력한 항증식 활성을 갖는 것인, FLT3 억제 방법을 제공한다.Additionally, the present invention provides a method for inhibiting FLT3, wherein the pharmaceutical composition has potent antiproliferative activity in FLT3-ITD expressing MV4-11 cell line and FLT3/D835Y expressing MOLM14-FLT3/D835Y cell line.
또한, 본 발명은 FLT3 억제, 또는 FLT3-연관 질환의 예방 또는 치료를 위한, 본 발명에 따른 화합물 또는 이의 약학적으로 허용되는 염의 용도를 제공한다. 본 발명은 또한 AML의 예방 또는 치료용 의약의 제조를 위한, 본 발명에 따른 화합물 또는 이의 약학적으로 허용되는 염의 용도를 제공한다.In addition, the present invention provides the use of the compound according to the present invention or a pharmaceutically acceptable salt thereof for inhibiting FLT3 or preventing or treating FLT3-associated diseases. The present invention also provides the use of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of AML.
일 구체적 실시태양에 있어서, 본 발명의 인디루빈 유도체 화합물은 FLT3 억제에 대한 IC50 값이 100 nM 이하일 수 있다. 더욱 구체적으로 화학식 1로 표시되는 화합물은 FLT3 억제에 대한 IC50 값은 50 nM 이하일 수 있고, 더욱 더 구체적으로는 40 nM 이하일 수 있으며, 더욱 더 구체적으로는 35 nM 이하일 수 있고, 더욱 더 구체적으로는 30 nM 이하이며, 더욱 더 구체적으로는 25 nM 이하이고, 더욱 더 구체적으로는 20 nM 이하이며, 더욱 더 구체적으로는 15 nM이하이고, 더욱 더 구체적으로는 10 nM 이하일 수 있다. In one specific embodiment, the indirubin derivative compound of the present invention may have an IC 50 value of 100 nM or less for FLT3 inhibition. More specifically, the compound represented by Formula 1 may have an IC 50 value for FLT3 inhibition of 50 nM or less, more specifically 40 nM or less, still more specifically 35 nM or less, and even more specifically may be 30 nM or less, more specifically 25 nM or less, still more specifically 20 nM or less, still more specifically 15 nM or less, and even more specifically 10 nM or less.
[일반적인 합성 방법][General Synthesis Method]
본 발명에 따른 화합물은 용이하게 입수가능한 출발 물질로부터 당업자에게 익히 공지된 아래 기재된 특정 합성 프로토콜에 대한 변형을 이용해서 제조될 수 있다.The compounds according to the invention can be prepared from readily available starting materials using modifications to the specific synthetic protocols described below well known to those skilled in the art.
일 실시양태에서, 본 발명의 화합물의 중간체 3은 하기 반응식 1에 따라 제조될 수 있다. In one embodiment, Intermediate 3 of a compound of the present invention can be prepared according to Scheme 1 below.
[반응식 1][Scheme 1]
Figure PCTKR2020017666-appb-I000024
Figure PCTKR2020017666-appb-I000024
상기식에서, 치환기 R1은 상기 정의된 바와 같다. In the above formula, the substituent R1 is as defined above.
적절한 용매에 isatin analogue 1을 첨가하고 적절한 시간 하에 교반시킨다. 무수 Na2CO3을 첨가하고 교반시킨 후, 물을 첨가하여 여과시키고 세척하여, 5번 위치가 치환된 생성물 2를 침전물 형태로 수득한다. 생성물 2를 적절한 용매 하에서 hydroxylamine hydrochloride 등 아민 화합물을 첨가하여 환류시켜, 이민 형성 반응을 통해 생성물 3을 수득한다. Add isatin analogue 1 to an appropriate solvent and stir for an appropriate time. Anhydrous Na 2 CO 3 was added and stirred, followed by addition of water, filtration, and washing to obtain a product 2 substituted at the 5-position in the form of a precipitate. The product 2 is refluxed by adding an amine compound such as hydroxylamine hydrochloride in an appropriate solvent to obtain a product 3 through an imine formation reaction.
일 실시태양에서, 본 발명의 화합물은 하기 반응식 2에 따라 제조될 수 있다.In one embodiment, the compound of the present invention can be prepared according to Scheme 2 below.
[반응식 2][Scheme 2]
Figure PCTKR2020017666-appb-I000025
Figure PCTKR2020017666-appb-I000025
상기식에서, 치환기 R1 및 R4는 상기 정의된 바와 같다. wherein the substituents R1 and R4 are as defined above.
적절한 화합물(예컨대, 1-Boc-피페라진 등)을 적절한 용매 하에 용해시키고 글리콜산 4를 첨가하고 교반시키고, 중화, 추출, 농축, 정제 과정을 거쳐 생성물 5를 수득한다. 적절한 용매 에 수득한 생성물 5를 용해시키고, MsCl 및 TEA를 첨가하고 교반시킨 후, 중화, 추출, 농축, 정제 과정을 거쳐 생성물 6을 수득한다. 적절한 용매에 용해시킨 생성물 3에 수득한 생성물 6을 첨가한 후 교반시키고 TEA를 첨가하여 다시 교반시킨 후 이 혼합물을 식히고 중화, 추출, 농축시킨다. 혼합물을 다시 적절한 용매에 용해시킨 후 TFA를 첨가하고 교반시킨 후 중화, 추출, 농축, 정제 과정을 거쳐 생성물 7을 수득한다. aq 37% formaldehyde을 적절한 용매에 용해시키고 NaBH3CN을 첨가하여 교반시킨다. pH를 5로 맞추고 얻어진 생성물 7을 첨가하여 교반시킨 후 혼합물에 Na2CO3 수용액을 첨가하여 교반시킨다. 혼합물을 추출, 농축, 정제 과정을 거쳐 생성물 8을 얻는다.A suitable compound (eg, 1-Boc-piperazine, etc.) is dissolved in an appropriate solvent, glycolic acid 4 is added, stirred, and the product 5 is obtained through neutralization, extraction, concentration and purification. The obtained product 5 is dissolved in an appropriate solvent, MsCl and TEA are added and stirred, followed by neutralization, extraction, concentration and purification to obtain product 6 . After adding the obtained product 6 to the product 3 dissolved in an appropriate solvent, stirring, adding TEA and stirring again, the mixture is cooled, neutralized, extracted and concentrated. After dissolving the mixture in an appropriate solvent again, TFA is added, followed by stirring, followed by neutralization, extraction, concentration and purification to obtain product 7 . Dissolve aq 37% formaldehyde in an appropriate solvent, add NaBH 3 CN, and stir. The pH is adjusted to 5, the resulting product 7 is added and stirred, and an aqueous solution of Na 2 CO 3 is added to the mixture and stirred. The mixture is extracted, concentrated and purified to obtain product 8.
일 실시태양에서, 본 발명의 화합물은 하기 반응식 3에 따라 제조될 수 있다.In one embodiment, the compounds of the present invention may be prepared according to Scheme 3 below.
[반응식 3][Scheme 3]
Figure PCTKR2020017666-appb-I000026
Figure PCTKR2020017666-appb-I000026
상기식에서, 치환기 R1 및 R4는 상기 정의된 바와 같다. wherein the substituents R1 and R4 are as defined above.
Diiodomethane을 적절한 용매에 용해시키고 Na2SO3을 첨가하여 reflux 시킨 후 혼합물을 농축 및 recrystallization하여 생성물 10을 얻는다. 수득한 생성물 10을 용매에 용해시키고 reflux 및 중화시킨 후 다시 추출 및 농축시킨다. 이를 용매에 용해시키고 적절한 시약(예: 1-Boc-piperazine) 및 TEA를 첨가하여 교반시킨 후 중화, 추출, 농축, 정제하여 생성물 11을 얻는다. 수득한 생성물 11을 적절한 용매에 용해시킨 생성물 3에 첨가한 후 교반시키고, K2CO3를 첨가하여 다시 교반시킨다. 이 혼합물을 식히고 중화시킨 후 추출 및 농축시킨다. 얻어진 혼합물을 적절한 용매에 용해시키고 TFA를 첨가하여 교반시킨 후 중화, 추출, 농축, 정제 과정을 거쳐 생성물 12를 얻는다.Diiodomethane is dissolved in an appropriate solvent, refluxed by adding Na 2 SO 3 , and the mixture is concentrated and recrystallized to obtain product 10. The obtained product 10 was dissolved in a solvent, refluxed and neutralized, followed by extraction and concentration again. It is dissolved in a solvent, an appropriate reagent (eg 1-Boc-piperazine) and TEA are added, stirred, and then neutralized, extracted, concentrated and purified to obtain the product 11 . The obtained product 11 is added to product 3 dissolved in a suitable solvent and stirred, followed by addition of K 2 CO 3 and stirring again. The mixture is cooled, neutralized, extracted and concentrated. The resulting mixture is dissolved in an appropriate solvent, stirred with TFA, and then subjected to neutralization, extraction, concentration and purification to obtain product 12.
일 실시태양에서, 본 발명의 화합물은 하기 반응식 4에 따라 제조될 수 있다.In one embodiment, the compounds of the present invention can be prepared according to Scheme 4 below.
[반응식 4][Scheme 4]
Figure PCTKR2020017666-appb-I000027
Figure PCTKR2020017666-appb-I000027
상기식에서, 치환기 R1 및 R4는 상기 정의된 바와 같다. wherein the substituents R1 and R4 are as defined above.
2-chloroacetyl chloride 13을 적절한 용매에 용해시키고 교반시킨 후, 중화, 추출, 농축, 정제 과정을 거쳐 생성물 14를 수득한다. 수득한 생성물 14를 적절한 용매에 용해시키고 NaOAc을 첨가하고 교반시킨 후 냉각 및 중화시킨다. 중화한 생성물을 용매에 용해시킨 후 KOH를 첨가하고 교반시킨 후 농축 및 중화하고 이를 다시 추출, 농축, 정제하여 생성물 15를 얻는다. 수득한 생성물 15를 용매에 용해시키고 MsCl, TEA를 첨가하여 교반시킨 후 중화, 추출, 농축, 정제 과정을 거쳐 생성물 16을 수득한다. 얻어진 생성물 16을 용매에 용해시킨 생성물 3에 첨가하고 교반시키고 K2CO3를 첨가하고 다시 교반시킨 후 냉각 및 중화시킨다. 중화한 생성물을 추출 및 농축시켜 얻어진 혼합물을 용매에 용해시키고 TFA를 첨가하여 교반시킨 후 중화, 추출, 농축, 정제 과정을 거쳐 생성물 17을 수득한다.After dissolving 2-chloroacetyl chloride 13 in an appropriate solvent and stirring, the product 14 is obtained through neutralization, extraction, concentration, and purification processes. The obtained product 14 is dissolved in a suitable solvent, NaOAc is added and stirred, then cooled and neutralized. After the neutralized product is dissolved in a solvent, KOH is added, stirred, and concentrated and neutralized, and this is again extracted, concentrated and purified to obtain product 15. The obtained product 15 is dissolved in a solvent, and MsCl and TEA are added thereto and stirred, followed by neutralization, extraction, concentration, and purification to obtain product 16. The obtained product 16 was added to the product 3 dissolved in a solvent, stirred, and K 2 CO 3 was It is added and stirred again, then cooled and neutralized. The neutralized product is extracted and concentrated, and the resulting mixture is dissolved in a solvent, stirred by adding TFA, and then subjected to neutralization, extraction, concentration and purification to obtain product 17.
aq 37% formaldehyde를 적절한 용매에 용해시키고 생성물 17과 AcOH를 첨가하여 교반시킨다. 이후 혼합물을 중화, 추출, 농축, 정제하여 생성물 18을 수득한다.Aq 37% formaldehyde is dissolved in an appropriate solvent, the product 17 and AcOH are added and stirred. Then, the mixture is neutralized, extracted, concentrated and purified to obtain product 18.
실시예Example
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이며 본 발명의 내용을 예시하는 것일 뿐이므로 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples are provided to more completely explain the present invention to those with average knowledge in the art, and are only illustrative of the contents of the present invention, so that the scope of the present invention is limited to the following examples no.
<합성예 1: 화합물 1 내지 12의 제조><Synthesis Example 1: Preparation of compounds 1 to 12>
아래 합성모식도 1 및 2에 기초하여, 화합물 1 내지 12를 제조하였다. Based on the following synthetic schemes 1 and 2, compounds 1 to 12 were prepared.
합성모식도 1Synthesis Schematic 1
Figure PCTKR2020017666-appb-I000028
Figure PCTKR2020017666-appb-I000028
시약 및 반응조건: Reagents and Reaction Conditions:
(a) Indoxyl acetate, Na2CO3, methanol: water (2:1), RT, 3h (a) Indoxyl acetate, Na 2 CO 3 , methanol: water (2:1), RT, 3h
(b) Hydroxylamine hydrochloride, pyridine, reflux, 6h(b) Hydroxylamine hydrochloride, pyridine, reflux, 6h
Indoxyl acetate에 MeOH에 용해시킨 isatin analogue 1a-g를 첨가하고 5분 동안 교반시켰다. 이어서 무수 Na2CO3 (2.5eq)를 첨가하고 상온에서 3시간 동안 교반시켰다. 물을 첨가하여 여과시키고 찬물로 여러 번 씻겨준 후 5번 위치가 치환된 생성물 2a-g를 침전물 형태로 얻었다. 생성물 2a-g를 pyridine (0.1M)에 용해시키고 hydroxylamine hydrochloride (5eq)을 첨가하고 6시간 동안 환류시켰다. 이어서 혼합물을 식히고 1N HCl을 이용하여 산성화시킨 후, 생성된 침전물을 여과시키고 물로 여러 번 세척하였다. DCM 및 hexane을 이용한 solidification을 통해 정제하여 최종 생성물 3a-g를 수득하였다. Isatin analogue 1a-g dissolved in MeOH was added to indoxyl acetate and stirred for 5 minutes. Then, anhydrous Na 2 CO 3 (2.5eq) was added and stirred at room temperature for 3 hours. After adding water, filtration, and washing with cold water several times, the product 2a-g in which the 5-position was substituted was obtained in the form of a precipitate. The product 2a-g was dissolved in pyridine (0.1M), hydroxylamine hydrochloride (5eq) was added, and refluxed for 6 hours. The mixture was then cooled and acidified with 1N HCl, and the resulting precipitate was filtered and washed several times with water. The final product 3a-g was obtained by purification through solidification using DCM and hexane.
합성모식도 2Synthesis Schematic 2
Figure PCTKR2020017666-appb-I000029
Figure PCTKR2020017666-appb-I000029
시약 및 반응조건: Reagents and Reaction Conditions:
(a) 1-Boc-piperazine, EDC, TEA, DMF, 60℃, O/N (a) 1-Boc-piperazine, EDC, TEA, DMF, 60℃, O/N
(b) MsCl, TEA, DCM, RT, 1h (b) MsCl, TEA, DCM, RT, 1 h
(c) TEA, DMF, 60℃, O/N (c) TEA, DMF, 60℃, O/N
(d) TFA, DCM, RT, 2h (d) TFA, DCM, RT, 2h
(e) aq 37% formaldehyde, NaBH3CN, Acetic acid, MeOH, RT, 2h(e) aq 37% formaldehyde, NaBH 3 CN, Acetic acid, MeOH, RT, 2h
1-Boc-piperazine을 DMF에 용해시키고 Glycolic acid 4 (1.5eq), TEA (2eq), EDC (2.5eq)을 첨가하여 60℃에서 밤새 교반시켰다. 혼합물을 냉각시키고 NH4Cl 수용액으로 중화시켰다. 중화한 생성물을 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 이 추출물을 column chromatography로 정제하여 생성물 5를 수득하였다. 1-Boc-piperazine was dissolved in DMF, Glycolic acid 4 (1.5eq), TEA (2eq), EDC (2.5eq) were added and stirred at 60°C overnight. The mixture was cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain product 5 .
얻어진 생성물 5를 DCM에 용해시키고 MsCl (1.5eq), TEA (1.5eq)을 첨가하여 1시간 동안 교반시켰다. 이후 혼합물을 NH4Cl 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 추출물을 column chromatography로 정제하여 생성물 6을 수득하였다. The obtained product 5 was dissolved in DCM, and MsCl (1.5eq) and TEA (1.5eq) were added thereto and stirred for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain product 6 .
수득된 생성물 6을 DMF에 용해시킨 Indirubin-3'-oxime 3a-g에 첨가하고 5분 동안 교반시켰다. 이어서 TEA (2eq)를 첨가하고 60℃에서 밤새 교반시켰다. 혼합물을 냉각시키고 NH4Cl 수용액으로 중화시켰다. 중화한 생성물을 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 얻어진 혼합물을 DCM에 용해시키고 TFA를 첨가하여 2시간 동안 교반시켰다. 이후 혼합물을 1N NaOH 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 상기 추출물을 column chromatography로 정제하여 생성물 7a-g를 수득하였다.The obtained product 6 was added to Indirubin-3'-oxime 3a-g dissolved in DMF and stirred for 5 minutes. TEA (2eq) was then added and stirred at 60° C. overnight. The mixture was cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain products 7a-g .
aq 37% formaldehyde을 MeOH에 용해시키고 NaBH3CN (1.2eq)을 첨가하여 5분 동안 교반시켰다. 이후 Acetic acid으로 pH를 5로 조정한 후, 상기 수득된 생성물 7a- c,f,g를 첨가하여 2시간 동안 교반시켰다. 이후 혼합물에 Na2CO3 수용액을 첨가하여 15분 동안 교반시켰다. 혼합물 속에 MeOH을 rotary evaporation을 이용하여 제거하고 생성물을 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 이 추출물을 column chromatography로 정제하여 생성물 8a-e를 수득하였다.Aq 37% formaldehyde was dissolved in MeOH, NaBH 3 CN (1.2eq) was added and stirred for 5 minutes. After adjusting the pH to 5 with acetic acid, the obtained product 7a- c,f,g was added and stirred for 2 hours. Then, Na 2 CO 3 aqueous solution was added to the mixture and stirred for 15 minutes. MeOH in the mixture was removed by rotary evaporation, and the product was extracted using EA and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 8a-e .
NMR을 통해 화합물 1 내지 12의 생성을 다음과 같이 확인하였다.Through NMR, the production of compounds 1 to 12 was confirmed as follows.
생성물 7a: (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 1) Product 7a: (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one (Compound 1)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (s, 1H), 10.76 (s, 1H), 8.47 (d, J = 7.93 Hz, 1H), 8.23 (d, J = 7.63 Hz, 1H), 7.35 - 7.50 (m, 2H), 7.14 (dt, J = 0.90, 7.30 Hz, 1H), 7.04 (dt, J = 1.50, 6.90 Hz, 1H), 6.85 - 6.96 (m, 2H), 5.30 (s, 2H), 3.36 - 3.51 (m, 4H), 2.57 - 2.74 (m, 4H); MS (ESI): M+=403.92. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.65 (s, 1H), 10.76 (s, 1H), 8.47 (d, J = 7.93 Hz, 1H), 8.23 (d, J = 7.63 Hz, 1H) ), 7.35 - 7.50 (m, 2H), 7.14 (dt, J = 0.90, 7.30 Hz, 1H), 7.04 (dt, J = 1.50, 6.90 Hz, 1H), 6.85 - 6.96 (m, 2H), 5.30 ( s, 2H), 3.36 - 3.51 (m, 4H), 2.57 - 2.74 (m, 4H); MS (ESI): M + =403.92.
생성물 7b: (2Z,3E)-5'-fluoro-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 2) Product 7b: (2Z,3E)-5'-fluoro-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one ( compound 2)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 - 11.88 (m, 1H), 10.67 - 10.97 (m, 1H), 8.26 (dd, J = 2.40, 11.00 Hz, 1H), 8.20 (d, J = 7.60 Hz, 1H), 7.41 - 7.49 (m, 2H), 7.07 (dt, J = 2.50, 6.70 Hz, 1H), 6.94 (dt, J = 2.80, 8.80 Hz, 1H), 6.81 - 6.87 (m, 1H), 5.22 - 5.39 (m, 2H), 3.37 - 3.46 (m, 4H), 2.56 - 2.75 (m, 4H); MS (ESI): M+=422.11.. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.60 - 11.88 (m, 1H), 10.67 - 10.97 (m, 1H), 8.26 (dd, J = 2.40, 11.00 Hz, 1H), 8.20 (d, J = 7.60 Hz, 1H), 7.41 - 7.49 (m, 2H), 7.07 (dt, J = 2.50, 6.70 Hz, 1H), 6.94 (dt, J = 2.80, 8.80 Hz, 1H), 6.81 - 6.87 (m) , 1H), 5.22 - 5.39 (m, 2H), 3.37 - 3.46 (m, 4H), 2.56 - 2.75 (m, 4H); MS (ESI): M + =422.11..
생성물 7c: (Product 7c: ( 2Z,3E2Z, 3E )-5'-)-5'- chlorochloro -3-((2--3-((2- oxooxo -2-(-2-( piperazinpiperazin -1--One- ylyl )) ethoxyethoxy )) iminoimino )-[2,3'-biindolinylidene]-2'-one (화합물 3) )-[2,3'-biindolinylidene]-2'-one (Compound 3)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 - 11.84 (m, 1H), 10.74 - 11.02 (m, 1H), 8.51 (d, J = 2.44 Hz, 1H), 8.18 (d, J = 7.60 Hz, 1H), 7.42 - 7.50 (m, 2H), 7.15 (dd, J = 2.14, 8.24 Hz, 1H), 7.03 - 7.10 (m, 1H), 6.88 (d, J = 8.24 Hz, 1H), 5.33 (s, 2H), 3.35 - 3.46 (m, 4H), 2.60 - 2.77 (m, 4H); MS (ESI): M+=438.08. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.55 - 11.84 (m, 1H), 10.74 - 11.02 (m, 1H), 8.51 (d, J = 2.44 Hz, 1H), 8.18 (d, J = 7.60 Hz, 1H), 7.42 - 7.50 (m, 2H), 7.15 (dd, J = 2.14, 8.24 Hz, 1H), 7.03 - 7.10 (m, 1H), 6.88 (d, J = 8.24 Hz, 1H), 5.33 (s, 2H), 3.35 - 3.46 (m, 4H), 2.60 - 2.77 (m, 4H); MS (ESI): M + =438.08.
생성물 7d: (2Z,3E)-5'-bromo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 4) Product 7d: (2Z,3E)-5'-bromo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one ( compound 4)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 - 11.80 (m, 1H), 10.89 (br. s., 1H), 8.66 (s, 1H), 8.18 (d, J = 7.60 Hz, 1H), 7.42 - 7.50 (m, 2H), 7.28 (dd, J = 2.20, 8.20 Hz, 1H), 7.03 - 7.11 (m, 1H), 6.84 (d, J = 8.24 Hz, 1H), 5.34 (s, 2H), 3.36 - 3.48 (m, 4H), 2.63 - 2.77 (m, 4H); MS (ESI): M+=483.93. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.63 - 11.80 (m, 1H), 10.89 (br. s., 1H), 8.66 (s, 1H), 8.18 (d, J = 7.60 Hz, 1H) ), 7.42 - 7.50 (m, 2H), 7.28 (dd, J = 2.20, 8.20 Hz, 1H), 7.03 - 7.11 (m, 1H), 6.84 (d, J = 8.24 Hz, 1H), 5.34 (s, 2H), 3.36 - 3.48 (m, 4H), 2.63 - 2.77 (m, 4H); MS (ESI): M + =483.93.
생성물 7e: (2Z,3E)-5'-iodo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 5) Product 7e: (2Z,3E)-5'-iodo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one ( compound 5)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 - 11.83 (m, 1H), 10.74 - 11.03 (m, 1H), 8.85 (s, 1H), 8.19 (d, J = 7.63 Hz, 1H), 7.38 - 7.50 (m, 3H), 7.00 - 7.12 (m, 1H), 6.74 (d, J = 7.93 Hz, 1H), 5.35 (s, 2H), 3.38 - 3.52 (m, 4H), 2.63 - 2.81 (m, 4H); MS (ESI): M+=530.03. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.54 - 11.83 (m, 1H), 10.74 - 11.03 (m, 1H), 8.85 (s, 1H), 8.19 (d, J = 7.63 Hz, 1H) , 7.38 - 7.50 (m, 3H), 7.00 - 7.12 (m, 1H), 6.74 (d, J = 7.93 Hz, 1H), 5.35 (s, 2H), 3.38 - 3.52 (m, 4H), 2.63 - 2.81 (m, 4H); MS (ESI): M + =530.03.
생성물 7f: (2Z,3E)-5'-methoxy-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 6) Product 7f: (2Z,3E)-5'-methoxy-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one ( compound 6)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (br. s., 1H), 10.61 (s, 1H), 8.20 - 8.29 (m, 1H), 8.08 - 8.20 (m, 1H), 7.32 - 7.54 (m, 2H), 7.04 (dt, J = 1.40, 7.50 Hz, 1H), 6.58 - 6.82 (m, 2H), 5.35 (s, 2H), 3.76 (s, 3H), 3.36 - 3.44 (m, 4H, overlapped with water), 2.59 - 2.78 (m, 4H); MS (ESI): M+=434.00. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.76 (br. s., 1H), 10.61 (s, 1H), 8.20 - 8.29 (m, 1H), 8.08 - 8.20 (m, 1H), 7.32 - 7.54 (m, 2H), 7.04 (dt, J = 1.40, 7.50 Hz, 1H), 6.58 - 6.82 (m, 2H), 5.35 (s, 2H), 3.76 (s, 3H), 3.36 - 3.44 (m) , 4H, overlapped with water), 2.59 - 2.78 (m, 4H); MS (ESI): M + =434.00.
생성물 7g: (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2'-one (화합물 7) 7 g product: (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2'- one (compound 7)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (s, 1H), 10.96 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 7.60 Hz, 1H), 7.47 (d, J = 4.30 Hz, 2H), 7.01 - 7.16 (m, 2H), 6.94 (d, J = 8.30 Hz, 1H), 5.22 - 5.38 (m, 2H), 3.34 - 3.42 (m, 4H), 2.59 - 2.73 (m, 4H); MS (ESI): M+=488.48. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.77 (s, 1H), 10.96 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 7.60 Hz, 1H), 7.47 (d , J = 4.30 Hz, 2H), 7.01 - 7.16 (m, 2H), 6.94 (d, J = 8.30 Hz, 1H), 5.22 - 5.38 (m, 2H), 3.34 - 3.42 (m, 4H), 2.59 - 2.73 (m, 4H); MS (ESI): M + =488.48.
생성물 8a: (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 8) Product 8a: (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (compound 8)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (s, 1H), 10.76 (s, 1H), 8.46 (d, J = 7.56 Hz, 1H), 8.23 (d, J = 7.50 Hz, 1H), 7.37 - 7.49 (m, 2H), 7.14 (dt, J = 1.10, 7.60 Hz, 1H), 7.00 - 7.07 (m, 1H), 6.86 - 6.97 (m, 2H), 5.32 (s, 2H), 3.43 - 3.59 (m, 4H), 2.22 - 2.37 (m, 4H), 2.17 (s, 3H); MS (ESI): M+=418.03. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.65 (s, 1H), 10.76 (s, 1H), 8.46 (d, J = 7.56 Hz, 1H), 8.23 (d, J = 7.50 Hz, 1H) ), 7.37 - 7.49 (m, 2H), 7.14 (dt, J = 1.10, 7.60 Hz, 1H), 7.00 - 7.07 (m, 1H), 6.86 - 6.97 (m, 2H), 5.32 (s, 2H), 3.43 - 3.59 (m, 4H), 2.22 - 2.37 (m, 4H), 2.17 (s, 3H); MS (ESI): M + =418.03.
생성물 8b: (2Z,3E)-5'-fluoro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 9) Product 8b: (2Z,3E)-5'-fluoro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (Compound 9)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.62 - 11.82 (m, 1H), 10.65 - 10.88 (m, 1H), 8.17 - 8.30 (m, 2H), 7.41 - 7.53 (m, 2H), 7.03 - 7.11 (m, 1H), 6.95 (dt, J = 2.50, 8.50 Hz, 1H), 6.80 - 6.89 (m, 1H), 5.28 - 5.39 (s, 2H), 3.39 - 3.58 (m, 4H), 2.23 - 2.43 (m, 4H), 2.18 (s, 3H); MS (ESI): M+=436.02. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.62 - 11.82 (m, 1H), 10.65 - 10.88 (m, 1H), 8.17 - 8.30 (m, 2H), 7.41 - 7.53 (m, 2H), 7.03 - 7.11 (m, 1H), 6.95 (dt, J = 2.50, 8.50 Hz, 1H), 6.80 - 6.89 (m, 1H), 5.28 - 5.39 (s, 2H), 3.39 - 3.58 (m, 4H), 2.23 - 2.43 (m, 4H), 2.18 (s, 3H); MS (ESI): M + =436.02.
생성물 8c: (2Z,3E)-5'-chloro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 10) Product 8c: (2Z,3E)-5'-chloro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (Compound 10)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 - 11.88 (m, 1H), 10.63 - 11.06 (m, 1H), 8.45 - 8.53 (m, 1H), 8.18 (d, J = 7.56 Hz, 1H), 7.40 - 7.50 (m, 2H), 7.14 (dd, J = 2.00, 8.00 Hz, 1H), 7.01 - 7.10 (m, 1H), 6.87 (d, J = 8.00 Hz, 1H), 5.35 (s, 2H), 3.43 - 3.55 (m, 4H), 2.23 - 2.42 (m, 4H), 2.19 (s, 3H); MS (ESI): M+=451.91. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.55 - 11.88 (m, 1H), 10.63 - 11.06 (m, 1H), 8.45 - 8.53 (m, 1H), 8.18 (d, J = 7.56 Hz, 1H), 7.40 - 7.50 (m, 2H), 7.14 (dd, J = 2.00, 8.00 Hz, 1H), 7.01 - 7.10 (m, 1H), 6.87 (d, J = 8.00 Hz, 1H), 5.35 (s) , 2H), 3.43 - 3.55 (m, 4H), 2.23 - 2.42 (m, 4H), 2.19 (s, 3H); MS (ESI): M + =451.91.
생성물 8d: (2Z,3E)-5'-methoxy-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 11) Product 8d: (2Z,3E)-5'-methoxy-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2'-one (Compound 11)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (s, 1H), 10.59 (br. s., 1H), 8.23 (d, J = 7.56 Hz, 1H), 8.16 (d, J = 2.52 Hz, 1H), 7.40 - 7.49 (m, 2H), 7.04 (dt, J = 1.10, 7.20 Hz, 1H), 6.70 - 6.81 (m, 2H), 5.37 (s, 2H), 3.76 (s, 3H), 3.41 - 3.50 (m, 4H), 2.25 - 2.37 (m, 4H), 2.19 (s, 3H); MS (ESI): M+=447.97. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.76 (s, 1H), 10.59 (br. s., 1H), 8.23 (d, J = 7.56 Hz, 1H), 8.16 (d, J = 2.52) Hz, 1H), 7.40 - 7.49 (m, 2H), 7.04 (dt, J = 1.10, 7.20 Hz, 1H), 6.70 - 6.81 (m, 2H), 5.37 (s, 2H), 3.76 (s, 3H) , 3.41 - 3.50 (m, 4H), 2.25 - 2.37 (m, 4H), 2.19 (s, 3H); MS (ESI): M + =447.97.
생성물 8e: (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2'-one (화합물 12) Product 8e: (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2' -one (compound 12)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 - 11.89 (m, 1H), 10.88 - 11.10 (m, 1H), 8.43 - 8.51 (m, 1H), 8.20 (d, J = 7.56 Hz, 1H), 7.44 - 7.50 (m, 2H), 7.04 - 7.15 (m, 2H), 6.94 (d, J = 8.24 Hz, 1H), 5.32 (s, 2H), 3.42 - 3.53 (m, 4H), 2.25 - 2.39 (m, 4H), 2.19 (s, 3H); MS (ESI): M+=501.89. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.70 - 11.89 (m, 1H), 10.88 - 11.10 (m, 1H), 8.43 - 8.51 (m, 1H), 8.20 (d, J = 7.56 Hz, 1H), 7.44 - 7.50 (m, 2H), 7.04 - 7.15 (m, 2H), 6.94 (d, J = 8.24 Hz, 1H), 5.32 (s, 2H), 3.42 - 3.53 (m, 4H), 2.25 - 2.39 (m, 4H), 2.19 (s, 3H); MS (ESI): M + =501.89.
<합성예 2: 화합물 13 내지 14의 제조><Synthesis Example 2: Preparation of compounds 13 to 14>
아래 합성모식도 3에 기초하여, 화합물 13 내지 14를 제조하였다. Based on the following synthetic scheme 3, compounds 13 to 14 were prepared.
합성모식도 3Synthesis Schematic 3
Figure PCTKR2020017666-appb-I000030
Figure PCTKR2020017666-appb-I000030
시약 및 반응조건: Reagents and Reaction Conditions:
(a) Na2SO3, EtOH/H2O, reflux, O/N (a) Na 2 SO 3 , EtOH/H 2 O, reflux, O/N
(b) PCl5, DCM, reflux, 1h (b) PCl 5 , DCM, reflux, 1h
(c) 1-Boc-piperazine, TEA, DCM, -20℃, 1h (c) 1-Boc-piperazine, TEA, DCM, -20°C, 1 h
(d) K2CO3, DMF, 60℃, O/N (d) K 2 CO 3 , DMF, 60° C., O/N
(e) TFA, DCM, RT, 2h (e) TFA, DCM, RT, 2h
Diiodomethane을 EtOH/H2O=1:1에 용해시키고 Na2SO3을 첨가하여 밤새 환류시켰다. 이후 혼합물을 rotary evaporation하여 농축시키고 EtOH/H2O=5:1 조건에서 recrystallization하여 생성물 10을 수득하였다. Diiodomethane was dissolved in EtOH/H 2 O=1:1 and Na 2 SO 3 was added and refluxed overnight. Thereafter, the mixture was concentrated by rotary evaporation and recrystallized under EtOH/H 2 O=5:1 conditions to obtain product 10.
수득된 생성물 10을 DCM에 용해시키고 PCl5을 첨가하여 1시간 동안 환류시켰다. 이후 혼합물을 냉각시키고 NaHCO3 수용액으로 중화시킨 후, EA를 이용하여 추출하고, rotary evaporation하여 농축시켰다. 얻어진 추출물을 DCM에 용해시키고 1-Boc-piperazine (1.5eq), TEA (2eq)을 첨가하여 -20℃에서 1시간 동안 교반시켰다. 이후 혼합물을 NH4Cl 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 상기 추출물을 column chromatography로 정제하여 생성물 11를 얻었다. The obtained product 10 was dissolved in DCM and PCl 5 was added and refluxed for 1 hour. Then, the mixture was cooled , neutralized with an aqueous NaHCO 3 solution, extracted using EA, and concentrated by rotary evaporation. The obtained extract was dissolved in DCM, 1-Boc-piperazine (1.5eq) and TEA (2eq) were added and stirred at -20°C for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain product 11 .
얻어진 생성물 11을 DMF에 용해시킨 Indirubin-3'-oxime 3a-b에 첨가하고 5분 동안 교반시켰다. 이어서 K2CO3 (5eq)를 첨가하고 60℃에서 밤새 교반시켰다. 이후 혼합물을 냉각시키고 NH4Cl 수용액으로 중화시켰다. 중화한 생성물을 EA를 이용하여 추출한 후 rotary evaporation하여 농축시킨다. 얻어진 혼합물을 DCM에 용해시키고 TFA를 첨가하여 2시간 동안 교반시켰다. 이후 혼합물을 1N NaOH 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 이 추출물을 column chromatography로 정제하여 생성물 12a-b를 수득하였다.The obtained product 11 was added to Indirubin-3'-oxime 3a-b dissolved in DMF and stirred for 5 minutes. Then K 2 CO 3 (5eq) was added and stirred at 60° C. overnight. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product is extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 12a-b .
NMR을 통해 화합물 13 내지 14의 생성을 다음과 같이 확인하였다.The production of compounds 13 to 14 was confirmed through NMR as follows.
생성물 12a: (2Z,3E)-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 13) Product 12a: (2Z,3E)-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3'-biindolinylidene]-2'-one (compound 13)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 - 11.72 (m, 1H), 10.73 - 10.89 (m, 1H), 8.63 (dd, J = 0.46, 7.79 Hz, 1H), 8.18 (d, J = 7.79 Hz, 1H), 7.32 - 7.54 (m, 2H), 7.17 (dt, J = 1.30, 7.70 Hz, 1H), 6.94 - 7.10 (m, 2H), 6.89 (dd, J = 0.70, 7.80 Hz, 1H), 5.79 (s, 2H), 3.16 (s, 4H), 2.52 - 2.69 (m, 4H); MS (ESI): M+=439.97. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.60 - 11.72 (m, 1H), 10.73 - 10.89 (m, 1H), 8.63 (dd, J = 0.46, 7.79 Hz, 1H), 8.18 (d, J = 7.79 Hz, 1H), 7.32 - 7.54 (m, 2H), 7.17 (dt, J = 1.30, 7.70 Hz, 1H), 6.94 - 7.10 (m, 2H), 6.89 (dd, J = 0.70, 7.80 Hz) , 1H), 5.79 (s, 2H), 3.16 (s, 4H), 2.52 - 2.69 (m, 4H); MS (ESI): M + =439.97.
생성물 12b: (2Z,3E)-5'-fluoro-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3'-biindolinylidene]-2'-one (화합물 14) Product 12b: (2Z,3E)-5'-fluoro-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3'-biindolinylidene]-2'-one (Compound 14)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 - 11.85 (m, 1H), 10.77 - 10.94 (m, 1H), 8.46 (dd, J = 2.80, 11.00 Hz, 1H), 8.18 (d, J = 7.79 Hz, 1H), 7.45 - 7.53 (m, 2H), 7.07 - 7.13 (m, 1H), 6.99 (dt, J = 2.50, 8.50 Hz, 1H), 6.87 (d, J = 4.81 Hz, 1H), 5.73 (s, 2H), 3.14 - 3.27 (m, 4H), 2.60 - 2.69 (m, 4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.67 - 11.85 (m, 1H), 10.77 - 10.94 (m, 1H), 8.46 (dd, J = 2.80, 11.00 Hz, 1H), 8.18 (d, J = 7.79 Hz, 1H), 7.45 - 7.53 (m, 2H), 7.07 - 7.13 (m, 1H), 6.99 (dt, J = 2.50, 8.50 Hz, 1H), 6.87 (d, J = 4.81 Hz, 1H) ), 5.73 (s, 2H), 3.14 - 3.27 (m, 4H), 2.60 - 2.69 (m, 4H).
<합성예 3: 화합물 15 내지 35의 제조><Synthesis Example 3: Preparation of compounds 15 to 35>
아래 합성모식도 4에 기초하여, 화합물 15 내지 35를 제조하였다. Based on the following synthetic scheme 4, compounds 15 to 35 were prepared.
합성모식도 4Synthesis Schematic 4
Figure PCTKR2020017666-appb-I000031
Figure PCTKR2020017666-appb-I000031
시약 및 반응조건: Reagents and Reaction Conditions:
(a) i-iii, TEA, DCM, RT, 1h (a) i-iii, TEA, DCM, RT, 1h
(b) sodium acetate, DMF, 80℃, o/n (b) sodium acetate, DMF, 80℃, o/n
(c) 10% KOH, MeOH, RT, 1h (c) 10% KOH, MeOH, RT, 1 h
(d) MsCl, TEA, DCM, RT, 1h (d) MsCl, TEA, DCM, RT, 1 h
(e) TEA, DMF, 60℃, o/n (e) TEA, DMF, 60°C, o/n
(f) TFA, DCM, RT, 2h (f) TFA, DCM, RT, 2h
(g) aq 37% formaldehyde, NaBH3CN, AcOH, MeOH, RT, 2h (g) aq 37% formaldehyde, NaBH 3 CN, AcOH, MeOH, RT, 2h
2-chloroacetyl chloride 13을 DCM에 용해시키고 i-iii (1.5eq), TEA (2eq)을 첨가하여 1시간 동안 교반시켰다. 이후 혼합물을 NH4Cl 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 이 추출물을 column chromatography로 정제하여 생성물 14a-d를 수득하였다. 2-chloroacetyl chloride 13 was dissolved in DCM, and i-iii (1.5eq) and TEA (2eq) were added thereto and stirred for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 14a-d .
수득된 생성물 14a-d를 DMF에 용해시키고 NaOAc (2eq)을 첨가하여 80℃에서 1시간 동안 교반시켰다. 이후 혼합물을 냉각시키고 NH4Cl 수용액으로 중화시켰다. 중화한 생성물을 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 얻어진 추출물을 MeOH에 용해시키고 10% KOH을 첨가하여 1시간 동안 교반시켰다. 이후 혼합물 속에 MeOH을 Rotary evaporation을 이용하여 제거하고 1N HCl 수용액으로 중화시켰다. 중화한 생성물을 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 추출물을 column chromatography로 정제하여 생성물 15a-d를 얻었다.The obtained product 14a-d was dissolved in DMF, and NaOAc (2eq) was added and stirred at 80° C. for 1 hour. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The obtained extract was dissolved in MeOH, and 10% KOH was added and stirred for 1 hour. Then, MeOH in the mixture was removed by rotary evaporation and neutralized with 1N HCl aqueous solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain products 15a-d .
얻어진 생성물 15a-d를 DCM에 용해시키고 MsCl (1.5eq), TEA(1.5eq)을 첨가하여 1시간 동안 교반시켰다. 이후 혼합물을 NH4Cl 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 이 추출물을 column chromatography로 정제하여 생성물 16a-d를 수득하였다. The obtained product 15a-d was dissolved in DCM, MsCl (1.5eq) and TEA (1.5eq) were added and stirred for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 16a-d .
얻어진 생성물 16a-d을 DMF에 용해시킨 Indirubin-3'-oxime 3a-c, f, g에 첨가하고 5분 동안 교반시켰다. 이어서 K2CO3 (5eq)를 첨가하고 60℃에서 밤새 교반시켰다. 이후 혼합물을 냉각시키고 NH4Cl 수용액으로 중화시켰다. 중화한 생성물을 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 얻어진 혼합물을 DCM에 용해시키고 TFA를 첨가하여 2시간 동안 교반시켰다. 이후 혼합물을 1N NaOH 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 상기 추출물을 column chromatography로 정제하여 생성물 17a-n를 수득하였다.The obtained product 16a-d was added to Indirubin-3'-oxime 3a-c, f, g dissolved in DMF and stirred for 5 minutes. Then K 2 CO 3 (5eq) was added and stirred at 60° C. overnight. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain products 17a-n .
aq 37% formaldehyde을 MeOH에 용해시키고 얻어진 생성물 17b,c,d,f,g,h,j와 AcOH (2eq)을 첨가하여 2시간 동안 교반시켰다. 이후 혼합물을 Na2CO3 수용액으로 중화시키고 EA를 이용하여 추출한 후 rotary evaporation하여 농축시켰다. 이 추출물을 column chromatography로 정제하여 생성물 18a-g를 수득하였다.Aq 37% formaldehyde was dissolved in MeOH, and the resulting product 17b,c,d,f,g,h,j and AcOH (2eq) were added and stirred for 2 hours. Then, the mixture was neutralized with an aqueous solution of Na 2 CO 3 , extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 18a-g .
NMR을 통해 화합물 15 내지 35의 생성을 다음과 같이 확인하였다.The production of compounds 15 to 35 was confirmed through NMR as follows.
생성물 17a: (Product 17a: ( 2Z,3E2Z, 3E )-3-((2-(4-)-3-((2-(4- aminopiperidinaminopiperidin -1--One- ylyl )-2-)-2- oxoethoxyoxoethoxy )) iminoimino )-[2,3'-biindolinylidene]-2'-one (화합물 15) )-[2,3'-biindolinylidene]-2'-one (Compound 15)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 - 11.79 (m, 1H), 10.63 - 10.93 (m, 1H), 8.47 (d, J = 7.60 Hz, 1H), 8.23 (d, J = 7.56 Hz, 1H), 7.37 - 7.49 (m, 2H), 7.14 (t, J = 7.60 Hz, 1H), 7.04 (dt, J = 1.60, 7.30 Hz, 1H), 6.94 (t, J = 7.60 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 5.22 - 5.38 (m, 2H), 4.10 - 4.23 (m, 1H), 3.82 - 3.93 (m, 1H), 3.04 - 3.20 (m, 1H), 2.73 - 2.89 (m, 2H), 1.61 - 1.80 (m, 3H), 0.99 - 1.26 (m, 3H); MS (ESI): M+=417.96. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.52 - 11.79 (m, 1H), 10.63 - 10.93 (m, 1H), 8.47 (d, J = 7.60 Hz, 1H), 8.23 (d, J = 7.56 Hz, 1H), 7.37 - 7.49 (m, 2H), 7.14 (t, J = 7.60 Hz, 1H), 7.04 (dt, J = 1.60, 7.30 Hz, 1H), 6.94 (t, J = 7.60 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 5.22 - 5.38 (m, 2H), 4.10 - 4.23 (m, 1H), 3.82 - 3.93 (m, 1H), 3.04 - 3.20 (m, 1H) , 2.73 - 2.89 (m, 2H), 1.61 - 1.80 (m, 3H), 0.99 - 1.26 (m, 3H); MS (ESI): M + =417.96.
생성물 17b: 2-((((2Z,3E)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl)acetamide (화합물 16) Product 17b: 2-((((2Z,3E)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl)acetamide (compound 16 )
Figure PCTKR2020017666-appb-I000032
Figure PCTKR2020017666-appb-I000032
1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 10.79 (s, 1H), 8.57 - 8.80 (br. s., 2H), 8.45 - 8.49 (m, 2H), 8.20 (d, J = 7.33 Hz, 1H), 7.39 - 7.48 (m, 2H), 7.14 (d, J = 15.11 Hz, 1H), 7.04 (t, J = 7.21 Hz, 1H), 6.87 - 6.96 (m, 2H), 4.99 (s, 2H), 3.95 (d, J = 17.40 Hz, 1H), 3.24 (d, J = 14.65 Hz, 2H), 2.96 (t, J = 12.25 Hz, 2H), 1.89 (d, J = 11.45 Hz, 2H), 1.59 - 1.72 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66 (s, 1H), 10.79 (s, 1H), 8.57 - 8.80 (br. s., 2H), 8.45 - 8.49 (m, 2H), 8.20 (d, J = 7.33 Hz, 1H), 7.39 - 7.48 (m, 2H), 7.14 (d, J = 15.11 Hz, 1H), 7.04 (t, J = 7.21 Hz, 1H), 6.87 - 6.96 (m, 2H), 4.99 (s, 2H), 3.95 (d, J = 17.40 Hz, 1H), 3.24 (d, J = 14.65 Hz, 2H), 2.96 (t, J = 12.25 Hz, 2H), 1.89 (d, J = 11.45 Hz, 2H), 1.59 - 1.72 (m, 2H).
생성물 17c: N-(azetidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide (화합물 17) Product 17c: N-(azetidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide ( compound 17)
Figure PCTKR2020017666-appb-I000033
Figure PCTKR2020017666-appb-I000033
1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 10.81 (br. s., 1H), 9.01 (d, J = 6.41 Hz, 1H), 8.73 - 8.92 (br. s., 2H), 8.40 (d, J = 8.01 Hz, 1H), 8.21 (d, J = 7.10 Hz, 1H), 7.40 - 7.49 (m, 2H), 7.30 (s, 1H), 7.17 (s, 1H), 7.05 (br. s., 1H), 6.87 - 6.93 (m, 1H), 5.02 (s, 2H), 4.73 (br. s., 1H), 3.96 - 4.06 (m, 4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66 (s, 1H), 10.81 (br. s., 1H), 9.01 (d, J = 6.41 Hz, 1H), 8.73 - 8.92 (br. s) ., 2H), 8.40 (d, J = 8.01 Hz, 1H), 8.21 (d, J = 7.10 Hz, 1H), 7.40 - 7.49 (m, 2H), 7.30 (s, 1H), 7.17 (s, 1H) ), 7.05 (br. s., 1H), 6.87 - 6.93 (m, 1H), 5.02 (s, 2H), 4.73 (br. s., 1H), 3.96 - 4.06 (m, 4H).
생성물 17d: 2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(pyrrolidin-3-yl)acetamide (화합물 18) Product 17d: 2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(pyrrolidin-3-yl)acetamide ( compound 18)
Figure PCTKR2020017666-appb-I000034
Figure PCTKR2020017666-appb-I000034
1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 10.80 (s, 1H), 8.63 (d, J = 5.72 Hz, 1H), 8.44 (d, J = 7.56 Hz, 1H), 8.21 (d, J = 7.56 Hz, 1H), 7.39 - 7.49 (m, 2H), 7.10 - 7.20 (m, 1H), 7.01 - 7.10 (m, 1H), 6.86 - 6.96 (m, 2H), 5.00 (s, 2H), 4.36 - 4.48 (m, 1H), 3.17 (br. s., 2H), 2.99 (br. s., 1H), 2.14 (br. s., 1H), 1.84 (br. s., 1H); MS (ESI): M+=404.00. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66 (s, 1H), 10.80 (s, 1H), 8.63 (d, J = 5.72 Hz, 1H), 8.44 (d, J = 7.56 Hz, 1H) ), 8.21 (d, J = 7.56 Hz, 1H), 7.39 - 7.49 (m, 2H), 7.10 - 7.20 (m, 1H), 7.01 - 7.10 (m, 1H), 6.86 - 6.96 (m, 2H), 5.00 (s, 2H), 4.36 - 4.48 (m, 1H), 3.17 (br. s., 2H), 2.99 (br. s., 1H), 2.14 (br. s., 1H), 1.84 (br. s., 1H); MS (ESI): M + =404.00.
생성물 17e: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-fluoro-[2,3'-biindolinylidene]-2'-one (화합물 19) Product 17e: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-fluoro-[2,3'-biindolinylidene]-2'-one (Compound 19)
1H NMR (400 MHz, DMSO-d6) δ ppm 10.55 - 10.98 (m, 1H), 8.26 (dd, J = 2.52, 11.22 Hz, 1H), 8.21 (d, J = 7.60 Hz, 1H), 7.42 - 7.50 (m, 2H), 7.03 - 7.10 (m, 1H), 6.95 (dt, J = 2.80, 9.20 Hz, 1H), 6.80 - 6.87 (m, 1H), 5.25 - 5.39 (m, 2H), 4.11 - 4.24 (m, 1H), 3.72 - 3.88 (m, 1H), 3.04 - 3.21 (m, 1H), 2.72 - 2.88 (m, 2H), 1.62 - 1.84 (m, 3H), 1.00 - 1.29 (m, 3H); MS (ESI): M+=435.95. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.55 - 10.98 (m, 1H), 8.26 (dd, J = 2.52, 11.22 Hz, 1H), 8.21 (d, J = 7.60 Hz, 1H), 7.42 - 7.50 (m, 2H), 7.03 - 7.10 (m, 1H), 6.95 (dt, J = 2.80, 9.20 Hz, 1H), 6.80 - 6.87 (m, 1H), 5.25 - 5.39 (m, 2H), 4.11 - 4.24 (m, 1H), 3.72 - 3.88 (m, 1H), 3.04 - 3.21 (m, 1H), 2.72 - 2.88 (m, 2H), 1.62 - 1.84 (m, 3H), 1.00 - 1.29 (m, 3H); MS (ESI): M + =435.95.
생성물 17f: 2-((((2Z,3E)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl)acetamide (화합물 20) Product 17f: 2-((((2Z,3E)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl )acetamide (compound 20)
Figure PCTKR2020017666-appb-I000035
Figure PCTKR2020017666-appb-I000035
1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 10.82 (br. s., 1H), 8.58 - 8.83 (br. s., 2H), 8.44 (d, J = 6.87 Hz, 1H), 8.17 - 8.29 (m, 2H), 7.45 (br. s., 2H), 7.03 - 7.11 (m, 1H), 6.96 (t, J = 7.33 Hz, 1H), 6.87 (br. s., 1H), 5.01 (s, 2H), 4.81 (br. s., 1H), 3.95 (br. s., 2H), 2.90 - 3.00 (m, 2H), 1.90 (d, J = 14.65 Hz, 2H), 1.57 - 1.71 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.75 (s, 1H), 10.82 (br. s., 1H), 8.58 - 8.83 (br. s., 2H), 8.44 (d, J = 6.87) Hz, 1H), 8.17 - 8.29 (m, 2H), 7.45 (br. s., 2H), 7.03 - 7.11 (m, 1H), 6.96 (t, J = 7.33 Hz, 1H), 6.87 (br. s) ., 1H), 5.01 (s, 2H), 4.81 (br. s., 1H), 3.95 (br. s., 2H), 2.90 - 3.00 (m, 2H), 1.90 (d, J = 14.65 Hz, 2H), 1.57 - 1.71 (m, 2H).
생성물 17g: N-(azetidin-3-yl)-2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide (화합물 21) 17 g product: N-(azetidin-3-yl)-2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino )oxy)acetamide (compound 21)
Figure PCTKR2020017666-appb-I000036
Figure PCTKR2020017666-appb-I000036
1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (br. s., 1H), 10.83 (br. s., 1H), 9.01 (d, J = 4.35 Hz, 1H), 8.79 - 8.93 (br. s., 2H), 8.20 (s, 1H), 8.22 (s, 1H), 7.43 - 7.53 (m, 2H), 7.04 - 7.12 (m, 1H), 6.92 - 7.00 (m, 1H), 6.87 (br. s., 1H), 5.03 (br. s., 2H), 4.76 (br. s., 1H), 3.95 - 4.09 (m, 4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.73 (br. s., 1H), 10.83 (br. s., 1H), 9.01 (d, J = 4.35 Hz, 1H), 8.79 - 8.93 ( s., 2H), 8.20 (s, 1H), 8.22 (s, 1H), 7.43 - 7.53 (m, 2H), 7.04 - 7.12 (m, 1H), 6.92 - 7.00 (m, 1H), 6.87 (br. s., 1H), 5.03 (br. s., 2H), 4.76 (br. s., 1H), 3.95 - 4.09 (m, 4H).
생성물 17h: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(pyrrolidin-3-yl)acetamide (화합물 22) Product 17h: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(pyrrolidin-3 -yl)acetamide (compound 22)
Figure PCTKR2020017666-appb-I000037
Figure PCTKR2020017666-appb-I000037
1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (s, 1H), 10.82 (s, 1H), 8.88 - 9.03 (br. s., 1H), 8.60 (d, J = 6.41 Hz, 1H), 8.19 - 8.27 (m, 2H), 7.43 - 7.49 (m, 2H), 7.05 - 7.10 (m, 1H), 6.94 - 7.00 (m, 1H), 6.84 - 6.89 (m, 1H), 5.02 (s, 2H), 4.42 (br. s., 1H), 3.03 (br. s., 1H), 2.13 (br. s., 1H), 1.88 (br. s., 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.74 (s, 1H), 10.82 (s, 1H), 8.88 - 9.03 (br. s., 1H), 8.60 (d, J = 6.41 Hz, 1H) ), 8.19 - 8.27 (m, 2H), 7.43 - 7.49 (m, 2H), 7.05 - 7.10 (m, 1H), 6.94 - 7.00 (m, 1H), 6.84 - 6.89 (m, 1H), 5.02 (s) , 2H), 4.42 (br. s., 1H), 3.03 (br. s., 1H), 2.13 (br. s., 1H), 1.88 (br. s., 1H).
생성물 17i: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-chloro-[2,3'-biindolinylidene]-2'-one (화합물 23) Product 17i: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-chloro-[2,3'-biindolinylidene]-2'-one (Compound 23)
1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 - 11.16 (m, 1H), 8.52 (d, J = 2.30 Hz, 1H), 8.19 (d, J = 7.60 Hz, 1H), 7.37 - 7.51 (m, 2H), 7.15 (dd, J = 2.06, 8.24 Hz, 1H), 7.02 - 7.12 (m, 1H), 6.87 (d, J = 8.24 Hz, 1H), 5.34 (s, 2H), 4.10 - 4.27 (m, 1H), 3.70 - 3.87 (m, 1H), 3.02 - 3.19 (m, 1H), 2.74 - 2.90 (m, 2H), 1.63 - 1.83 (m, 2H), 1.03 - 1.33 (m, 3H); MS (ESI): M+=451.98. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.41 - 11.16 (m, 1H), 8.52 (d, J = 2.30 Hz, 1H), 8.19 (d, J = 7.60 Hz, 1H), 7.37 - 7.51 (m, 2H), 7.15 (dd, J = 2.06, 8.24 Hz, 1H), 7.02 - 7.12 (m, 1H), 6.87 (d, J = 8.24 Hz, 1H), 5.34 (s, 2H), 4.10 - 4.27 (m, 1H), 3.70 - 3.87 (m, 1H), 3.02 - 3.19 (m, 1H), 2.74 - 2.90 (m, 2H), 1.63 - 1.83 (m, 2H), 1.03 - 1.33 (m, 3H) ); MS (ESI): M + =451.98.
생성물 17j: 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl)acetamide (화합물 24) Product 17j: 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl )acetamide (Compound 24)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 - 11.80 (m, 1H), 10.85 - 10.99 (m, 1H), 8.52 - 8.57 (m, 1H), 8.21 (dd, J = 0.69, 7.33 Hz, 1H), 8.01 - 8.08 (m, 1H), 7.42 - 7.51 (m, 2H), 7.14 - 7.18 (m, 1H), 7.02 - 7.10 (m, 1H), 6.88 (d, J = 7.80 Hz, 1H), 4.98 (s, 2H), 3.66 - 3.79 (m, 1H), 2.80 - 2.93 (m, 2H), 2.37 - 2.48 (m, 2H), 1.64 - 1.70 (m, 2H), 1.24 - 1.34 (m, 3H); MS (ESI): M+=451.91. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.70 - 11.80 (m, 1H), 10.85 - 10.99 (m, 1H), 8.52 - 8.57 (m, 1H), 8.21 (dd, J = 0.69, 7.33) Hz, 1H), 8.01 - 8.08 (m, 1H), 7.42 - 7.51 (m, 2H), 7.14 - 7.18 (m, 1H), 7.02 - 7.10 (m, 1H), 6.88 (d, J = 7.80 Hz, 1H), 4.98 (s, 2H), 3.66 - 3.79 (m, 1H), 2.80 - 2.93 (m, 2H), 2.37 - 2.48 (m, 2H), 1.64 - 1.70 (m, 2H), 1.24 - 1.34 ( m, 3H); MS (ESI): M + =451.91.
생성물 17k: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-methoxy-[2,3'-biindolinylidene]-2'-one (화합물 25) Product 17k: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-methoxy-[2,3'-biindolinylidene]-2'-one (Compound 25)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 - 11.99 (m, 1H), 10.60 (br. s., 1H), 8.24 (d, J = 7.79 Hz, 1H), 8.16 (d, J = 2.52 Hz, 1H), 7.38 - 7.49 (m, 2H), 7.04 (t, J = 7.40 Hz, 1H), 6.69 - 6.82 (m, 2H), 5.36 (s, 2H), 4.14 (d, J = 13.28 Hz, 1H), 3.65 - 3.80 (m, 4H), 3.06 (t, J = 11.22 Hz, 1H), 2.74 - 2.87 (m, 2H), 1.72 (t, J = 13.97 Hz, 2H), 1.00 - 1.28 (m, 3H); MS (ESI): M+=447.90. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.55 - 11.99 (m, 1H), 10.60 (br. s., 1H), 8.24 (d, J = 7.79 Hz, 1H), 8.16 (d, J) = 2.52 Hz, 1H), 7.38 - 7.49 (m, 2H), 7.04 (t, J = 7.40 Hz, 1H), 6.69 - 6.82 (m, 2H), 5.36 (s, 2H), 4.14 (d, J = 13.28 Hz, 1H), 3.65 - 3.80 (m, 4H), 3.06 (t, J = 11.22 Hz, 1H), 2.74 - 2.87 (m, 2H), 1.72 (t, J = 13.97 Hz, 2H), 1.00 - 1.28 (m, 3H); MS (ESI): M + =447.90.
생성물 17l: 2-((((2Z,3E)-5'-methoxy-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl)acetamide (화합물 26) Product 17l: 2-((((2Z,3E)-5'-methoxy-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl )acetamide (compound 26)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (br. s., 1H), 10.57 (br. s., 1H), 8.20 (d, J = 7.56 Hz, 1H), 8.13 (d, J = 2.29 Hz, 1H), 7.98 (d, J = 8.01 Hz, 1H), 7.34 - 7.45 (m, 2H), 7.00 (t, J = 7.21 Hz, 1H), 6.65 - 6.78 (m, 2H), 4.95 (s, 2H), 3.58 - 3.77 (m, 4H), 2.84 (d, J = 12.36 Hz, 2H), 2.40 (t, J = 11.22 Hz, 2H), 1.57 - 1.67 (m, 2H), 1.13 - 1.33 (m, 3H); MS (ESI): M+=447.90. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.74 (br. s., 1H), 10.57 (br. s., 1H), 8.20 (d, J = 7.56 Hz, 1H), 8.13 (d, J = 2.29 Hz, 1H), 7.98 (d, J = 8.01 Hz, 1H), 7.34 - 7.45 (m, 2H), 7.00 (t, J = 7.21 Hz, 1H), 6.65 - 6.78 (m, 2H), 4.95 (s, 2H), 3.58 - 3.77 (m, 4H), 2.84 (d, J = 12.36 Hz, 2H), 2.40 (t, J = 11.22 Hz, 2H), 1.57 - 1.67 (m, 2H), 1.13 - 1.33 (m, 3H); MS (ESI): M + =447.90.
생성물 17m: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2'-one (화합물 27) Product 17m: (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2' -one (compound 27)
1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 - 11.51 (m, 1H), 8.48 (s, 1H), 8.22 (d, J = 7.56 Hz, 1H), 7.44 - 7.50 (m, 2H), 7.04 - 7.14 (m, 2H), 6.94 (d, J = 8.24 Hz, 1H), 5.24 - 5.37 (m, 2H), 4.16 (d, J = 13.05 Hz, 1H), 3.74 (d, J = 13.28 Hz, 1H), 3.07 (t, J = 11.33 Hz, 1H), 2.73 - 2.86 (m, 2H), 1.72 (dd, J = 13.97, 17.86 Hz, 2H), 1.01 - 1.31 (m, 3H); MS (ESI): M+=502.24 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.56 - 11.51 (m, 1H), 8.48 (s, 1H), 8.22 (d, J = 7.56 Hz, 1H), 7.44 - 7.50 (m, 2H) , 7.04 - 7.14 (m, 2H), 6.94 (d, J = 8.24 Hz, 1H), 5.24 - 5.37 (m, 2H), 4.16 (d, J = 13.05 Hz, 1H), 3.74 (d, J = 13.28) Hz, 1H), 3.07 (t, J = 11.33 Hz, 1H), 2.73 - 2.86 (m, 2H), 1.72 (dd, J = 13.97, 17.86 Hz, 2H), 1.01 - 1.31 (m, 3H); MS (ESI): M + =502.24
생성물 17n: 2-((((2Z,3E)-2'-oxo-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4-yl)acetamide (화합물 28) Product 17n: 2-((((2Z,3E)-2'-oxo-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidin-4 -yl)acetamide (compound 28)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 - 11.88 (m, 1H), 10.88 - 11.05 (m, 1H), 8.50 (s, 1H), 8.21 (d, J = 7.56 Hz, 1H), 8.00 (d, J = 7.79 Hz, 1H), 7.44 - 7.50 (m, 2H), 7.04 - 7.18 (m, 2H), 6.94 (d, J = 8.24 Hz, 1H), 4.94 (s, 2H), 3.62 - 3.75 (m, 1H), 2.87 (d, J = 12.36 Hz, 2H), 2.43 (t, J = 11.11 Hz, 2H), 1.59 - 1.70 (m, 2H), 1.24 - 1.35 (m, 3H); MS (ESI): M+=502.10. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.69 - 11.88 (m, 1H), 10.88 - 11.05 (m, 1H), 8.50 (s, 1H), 8.21 (d, J = 7.56 Hz, 1H) , 8.00 (d, J = 7.79 Hz, 1H), 7.44 - 7.50 (m, 2H), 7.04 - 7.18 (m, 2H), 6.94 (d, J = 8.24 Hz, 1H), 4.94 (s, 2H), 3.62 - 3.75 (m, 1H), 2.87 (d, J = 12.36 Hz, 2H), 2.43 (t, J = 11.11 Hz, 2H), 1.59 - 1.70 (m, 2H), 1.24 - 1.35 (m, 3H) ; MS (ESI): M + =502.10.
생성물 18a: N-(1-methylpiperidin-4-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide (화합물 29)Product 18a: N-(1-methylpiperidin-4-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy) acetamide (compound 29)
Figure PCTKR2020017666-appb-I000038
Figure PCTKR2020017666-appb-I000038
1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (s, 1H), 10.78 (s, 1H), 8.46 (d, J = 7.32 Hz, 1H), 8.16 - 8.22 (m, 2H), 7.40 - 7.48 (m, 2H), 7.15 (dt, J = 1.22, 7.63 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.86 - 6.94 (m, 2H), 4.96 (s, 2H), 3.56 - 3.67 (m, 1H), 2.63 - 2.70 (m, 2H), 2.11 (s, 3H), 1.85 - 1.95 (m, 2H), 1.66 - 1.73 (m, 2H), 1.40 - 1.52 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.67 (s, 1H), 10.78 (s, 1H), 8.46 (d, J = 7.32 Hz, 1H), 8.16 - 8.22 (m, 2H), 7.40 - 7.48 (m, 2H), 7.15 (dt, J = 1.22, 7.63 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.86 - 6.94 (m, 2H), 4.96 (s, 2H), 3.56 - 3.67 (m, 1H), 2.63 - 2.70 (m, 2H), 2.11 (s, 3H), 1.85 - 1.95 (m, 2H), 1.66 - 1.73 (m, 2H), 1.40 - 1.52 (m, 2H).
생성물 18b: N-(1-Product 18b: N-(1- methylazetidinmethylazetidin -3--3- ylyl )-2-(((E)-((Z)-2'-)-2-(((E)-((Z)-2'- oxooxo -[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide (화합물 30)-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide (Compound 30)
Figure PCTKR2020017666-appb-I000039
Figure PCTKR2020017666-appb-I000039
1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 10.78 (s, 1H), 8.75 (d, J = 7.32 Hz, 1H), 8.43 (d, J = 7.63 Hz, 1H), 8.19 (d, J = 7.63 Hz, 1H), 7.39 - 7.48 (m, 2H), 7.15 (dt, J = 1.22, 7.63 Hz, 1H), 7.04 (ddd, J = 1.53, 6.71, 7.93 Hz, 1H), 6.87 - 6.94 (m, 2H), 4.96 (s, 2H), 4.31 (sxt, J = 6.90 Hz, 1H), 3.44 - 3.50 (m, 2H), 2.83 - 2.88 (m, 2H), 2.19 (s, 3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66 (s, 1H), 10.78 (s, 1H), 8.75 (d, J = 7.32 Hz, 1H), 8.43 (d, J = 7.63 Hz, 1H) ), 8.19 (d, J = 7.63 Hz, 1H), 7.39 - 7.48 (m, 2H), 7.15 (dt, J = 1.22, 7.63 Hz, 1H), 7.04 (ddd, J = 1.53, 6.71, 7.93 Hz, 1H), 6.87 - 6.94 (m, 2H), 4.96 (s, 2H), 4.31 (sxt, J = 6.90 Hz, 1H), 3.44 - 3.50 (m, 2H), 2.83 - 2.88 (m, 2H), 2.19 (s, 3H).
생성물 18c: N-(1-Product 18c: N-(1- methylpyrrolidinmethylpyrrolidin -3--3- ylyl )-2-(((E)-((Z)-2'-)-2-(((E)-((Z)-2'- oxooxo -[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide (화합물 31)-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)acetamide (Compound 31)
Figure PCTKR2020017666-appb-I000040
Figure PCTKR2020017666-appb-I000040
1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 10.78 (s, 1H), 8.43 - 8.49 (m, 2H), 8.19 (d, J = 7.63 Hz, 1H), 7.39 - 7.47 (m, 2H), 7.12 - 7.17 (m, 1H), 7.02 - 7.07 (m, 1H), 6.93 (dt, J = 1.22, 7.78 Hz, 1H), 6.87 - 6.90 (m, 1H), 4.96 (s, 2H), 4.23 - 4.31 (m, 1H), 2.52 - 2.62 (m, 2H), 2.37 (dd, J = 4.43, 9.31 Hz, 1H), 2.24 - 2.31 (m, 1H), 2.20 (s, 3H), 2.05 - 2.17 (m, 1H), 1.61 (dddd, J = 4.58, 6.41, 8.16, 12.89 Hz, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66 (s, 1H), 10.78 (s, 1H), 8.43 - 8.49 (m, 2H), 8.19 (d, J = 7.63 Hz, 1H), 7.39 - 7.47 (m, 2H), 7.12 - 7.17 (m, 1H), 7.02 - 7.07 (m, 1H), 6.93 (dt, J = 1.22, 7.78 Hz, 1H), 6.87 - 6.90 (m, 1H), 4.96 (s, 2H), 4.23 - 4.31 (m, 1H), 2.52 - 2.62 (m, 2H), 2.37 (dd, J = 4.43, 9.31 Hz, 1H), 2.24 - 2.31 (m, 1H), 2.20 (s) , 3H), 2.05 - 2.17 (m, 1H), 1.61 (dddd, J = 4.58, 6.41, 8.16, 12.89 Hz, 1H).
생성물 18d: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylpiperidin-4-yl)acetamide (화합물 32)Product 18d: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylpiperidin -4-yl)acetamide (compound 32)
Figure PCTKR2020017666-appb-I000041
Figure PCTKR2020017666-appb-I000041
1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br. s., 1H), 10.79 (br. s., 1H), 8.19 - 8.29 (m, 2H), 8.12 (d, J = 7.79 Hz, 1H), 7.42 - 7.49 (m, 2H), 7.03 - 7.09 (m, 1H), 6.96 (dt, J = 2.75, 8.82 Hz, 1H), 6.85 (dd, J = 5.04, 8.47 Hz, 1H), 4.97 (s, 2H), 3.56 - 3.67 (m, 1H), 2.66 (d, J = 10.99 Hz, 2H), 2.11 (s, 3H), 1.86 - 1.94 (m, 2H), 1.70 (dd, J = 2.86, 12.94 Hz, 2H), 1.40 - 1.51 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.75 (br. s., 1H), 10.79 (br. s., 1H), 8.19 - 8.29 (m, 2H), 8.12 (d, J = 7.79) Hz, 1H), 7.42 - 7.49 (m, 2H), 7.03 - 7.09 (m, 1H), 6.96 (dt, J = 2.75, 8.82 Hz, 1H), 6.85 (dd, J = 5.04, 8.47 Hz, 1H) , 4.97 (s, 2H), 3.56 - 3.67 (m, 1H), 2.66 (d, J = 10.99 Hz, 2H), 2.11 (s, 3H), 1.86 - 1.94 (m, 2H), 1.70 (dd, J) = 2.86, 12.94 Hz, 2H), 1.40 - 1.51 (m, 2H).
생성물 18e: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylazetidin-3-yl)acetamide (화합물 33)Product 18e: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylazetidin -3-yl)acetamide (compound 33)
Figure PCTKR2020017666-appb-I000042
Figure PCTKR2020017666-appb-I000042
1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (br. s., 1H), 10.79 (br. s., 1H), 8.20 - 8.29 (m, 2H), 8.11 (d, J = 7.79 Hz, 1H), 7.40 - 7.49 (m, 2H), 7.02 - 7.11 (m, 1H), 7.00 (dt, J = 2.75, 8.82 Hz, 1H), 6.75 (dd, J = 5.04, 8.47 Hz, 1H), 5.00 (s, 2H), 4.33 - 4.44 (sxt, J = 6.90 Hz, 1H), 3.50 - 3.58 (m, 2H), 2.80 - 2.85 (m, 2H), 2.21 (s, 3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.76 (br. s., 1H), 10.79 (br. s., 1H), 8.20 - 8.29 (m, 2H), 8.11 (d, J = 7.79) Hz, 1H), 7.40 - 7.49 (m, 2H), 7.02 - 7.11 (m, 1H), 7.00 (dt, J = 2.75, 8.82 Hz, 1H), 6.75 (dd, J = 5.04, 8.47 Hz, 1H) , 5.00 (s, 2H), 4.33 - 4.44 (sxt, J = 6.90 Hz, 1H), 3.50 - 3.58 (m, 2H), 2.80 - 2.85 (m, 2H), 2.21 (s, 3H).
생성물 18f: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylpyrrolidin-3-yl)acetamide (화합물 34)Product 18f: 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylpyrrolidin -3-yl)acetamide (compound 34)
Figure PCTKR2020017666-appb-I000043
Figure PCTKR2020017666-appb-I000043
1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (br. s., 1H), 10.70 (br. s., 1H), 8.21 - 8.29 (m, 2H), 8.12 (d, J = 7.79 Hz, 1H), 7.40 - 7.46 (m, 2H), 6.99 - 7.04 (m, 1H), 6.96 (dt, J = 2.75, 8.82 Hz, 1H), 6.85 (dd, J = 5.04, 8.47 Hz, 1H), 4.96 (s, 2H), 4.20 - 4.31 (m, 1H), 2.55 - 2.65 (m, 2H), 2.33 (dd, J = 4.43, 9.31 Hz, 1H), 2.20 - 2.30 (m, 1H), 2.18 (s, 3H), 2.05 - 2.17 (m, 1H), 1.57 (dddd, J = 4.58, 6.41, 8.16, 12.89 Hz, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.77 (br. s., 1H), 10.70 (br. s., 1H), 8.21 - 8.29 (m, 2H), 8.12 (d, J = 7.79) Hz, 1H), 7.40 - 7.46 (m, 2H), 6.99 - 7.04 (m, 1H), 6.96 (dt, J = 2.75, 8.82 Hz, 1H), 6.85 (dd, J = 5.04, 8.47 Hz, 1H) , 4.96 (s, 2H), 4.20 - 4.31 (m, 1H), 2.55 - 2.65 (m, 2H), 2.33 (dd, J = 4.43, 9.31 Hz, 1H), 2.20 - 2.30 (m, 1H), 2.18 (s, 3H), 2.05 - 2.17 (m, 1H), 1.57 (dddd, J = 4.58, 6.41, 8.16, 12.89 Hz, 1H).
생성물 18g: 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylpiperidin-4-yl)acetamide (화합물 35) 18 g product: 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1-methylpiperidin-4 -yl)acetamide (compound 35)
Figure PCTKR2020017666-appb-I000044
Figure PCTKR2020017666-appb-I000044
1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 - 11.94 (m, 1H), 10.69 - 11.13 (m, 1H), 8.52 (s, 1H), 8.14 - 8.28 (m, 1H), 8.01 - 8.13 (m, 1H), 7.38 - 7.53 (m, 2H), 7.01 - 7.19 (m, 2H), 6.87 (d, J = 8.24 Hz, 1H), 4.97 (s, 2H), 3.56 - 3.72 (m, 1H), 2.61 - 2.71 (m, 2H), 2.11 (s, 3H), 1.83 - 1.95 (m, 2H), 1.65 - 1.76 (m, 2H), 1.38 - 1.55 (m, 2H); MS (ESI): M+=465.73 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.59 - 11.94 (m, 1H), 10.69 - 11.13 (m, 1H), 8.52 (s, 1H), 8.14 - 8.28 (m, 1H), 8.01 - 8.13 (m, 1H), 7.38 - 7.53 (m, 2H), 7.01 - 7.19 (m, 2H), 6.87 (d, J = 8.24 Hz, 1H), 4.97 (s, 2H), 3.56 - 3.72 (m, 1H), 2.61 - 2.71 (m, 2H), 2.11 (s, 3H), 1.83 - 1.95 (m, 2H), 1.65 - 1.76 (m, 2H), 1.38 - 1.55 (m, 2H); MS (ESI): M + =465.73
실시예 1. FLT3 억제 효과 확인Example 1. Confirmation of FLT3 inhibitory effect
본 실시예에서는 FLT 효소 저해 시험 및 암세포주에서의 백혈병 세포 증식 저해 시험을 통해, 본 발명의 화합물의 FLT3 억제 효과를 확인하였다.In this Example, the FLT3 inhibitory effect of the compound of the present invention was confirmed through the FLT enzyme inhibition test and the leukemia cell proliferation inhibition test in cancer cell lines.
1.1 FLT3 효소 저해 시험(in vitro kinase Assay)1.1 FLT3 enzyme inhibition assay (in vitro kinase Assay)
FLT3 활성 억제를 HTRF(homogeneous, time-resolved fluorescence) 분석을 사용하여 측정하였다. Inhibition of FLT3 activity was measured using a homogeneous, time-resolved fluorescence (HTRF) assay.
FLT3 도메인을 함유하는 재조합 단백질을 Carna biosciences (Japan)로부터 구입하였다. 최적의 효소, ATP 및 기질 농도는 제조자의 지시에 따라 HTRF KinEASE 키트(Cisbio, France)를 사용하여 확립하였다. FLT3 효소 또는 FLT3/D835Y 효소를 키나제 반응 버퍼(50 mM HEPES (pH 7.0), 500 μM ATP, 0.1 mM sodium orthovanadate, 5 mM MgCl2, 1 mM DTT, 0.01 % 소 혈청 알부민(BSA), 0.02% NaN3) 내에서, 본 발명의 희석된 화합물 및 펩타이드 기질들과 순서대로 혼합하였다. 검출용 시약을 첨가한 후, Victor multilabel reader(Perkin Elmer, Waltham, MA, USA)를 사용하여 TR-FRET 신호를 측정하여 기질 펩티드의 인산화를 측정하였다. IC50은 Prism version 5.01 (GraphPad)을 이용한 비선형 회귀 분석(nonlinear regression)에 의해 계산되었다.Recombinant protein containing the FLT3 domain was purchased from Carna biosciences (Japan). Optimal enzyme, ATP and substrate concentrations were established using the HTRF KinEASE kit (Cisbio, France) according to the manufacturer's instructions. FLT3 enzyme or FLT3/D835Y enzyme in kinase reaction buffer (50 mM HEPES (pH 7.0), 500 μM ATP, 0.1 mM sodium orthovanadate, 5 mM MgCl 2 , 1 mM DTT, 0.01% bovine serum albumin (BSA), 0.02% NaN3 ), the diluted compounds of the present invention and peptide substrates were mixed in sequence. After adding the detection reagent, the phosphorylation of the substrate peptide was measured by measuring the TR-FRET signal using a Victor multilabel reader (Perkin Elmer, Waltham, MA, USA). IC 50 was calculated by nonlinear regression using Prism version 5.01 (GraphPad).
그 결과를 표 1에 나타내었다.The results are shown in Table 1.
1.2 세포 증식 저해 시험1.2 Cell proliferation inhibition test
급성 골수성 백혈병(AML) 세포주 MV4-11, MOLM-14/D835Y, 및 MOLM-14를 이용하여 FLT3 억제 활성을 시험하였다. MV4-11은 FLT3-ITD 발현 AML 세포주이며, MOLM-14/D835Y는 FLT3/D835Y 발현 AML 세포주이며, 및 MOLM-14은 FLT3-ITD 발현 AML 세포주이다. FLT3 inhibitory activity was tested using the acute myeloid leukemia (AML) cell lines MV4-11, MOLM-14/D835Y, and MOLM-14. MV4-11 is an FLT3-ITD expressing AML cell line, MOLM-14/D835Y is an FLT3/D835Y expressing AML cell line, and MOLM-14 is a FLT3-ITD expressing AML cell line.
MV4-11 인간 AML 세포를 American Type Culture Collection (ATCC, Rockville, MD, USA, CRL-9591)에서 구입하고 세포를 10% 태아소 혈청, 1% 페니실린/스트렙토마이신 및 4 mM L-글루타민(Life Technology,Grand Island, NY)이 보충된 IMDM 배지(Sigma Co., St. Louis, MO, USA)에서 배양하였다. MV4-11 human AML cells were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA, CRL-9591) and cells were cultured with 10% fetal bovine serum, 1% penicillin/streptomycin and 4 mM L-glutamine (Life Technology). , Grand Island, NY) supplemented with IMDM medium (Sigma Co., St. Louis, MO, USA).
MOLM14-FLT3/D835Y은 MOLM14에 FLT3-ITD-D835Y의 유전정보를 담고 있는 pLKO.1 blast lentiviral expression vector를 transfection을 시켜 제작한다. FLT3-ITD-D835Y가 발현된 MOLM14은 puromycin selection을 통해서 선택되고 유지된다.MOLM14-FLT3/D835Y is produced by transfecting MOLM14 with the pLKO.1 blast lentiviral expression vector containing the genetic information of FLT3-ITD-D835Y. MOLM14 expressing FLT3-ITD-D835Y was selected and maintained through puromycin selection.
세포 생존력을 EZ-Cytox Cell Viability Assay kit(DaeilLab, Korea)를 사용하여 테트라 졸륨(tetrazolium) 기반 분석법으로 평가하였다. 구체적으로, 2,000 - 15,000개의 세포를 100 ㎕의 배지에서 96-웰 플레이트에 도말하였다. 다음날, 세포를 음성 대조군으로서 디메틸 설폭시드(DMSO)와 함께 화합물들로 처리하였다. 화합물 첨가 3일 (72시간) 후, EZ-Cytox kit 시약 10 ㎕를 96-웰 플레이트의 각 웰에 넣고 가습된 CO2 인큐베이터에서 37℃로 4시간 동안 배양하였다. 배양 후 Victor multilabel reader(Perkin Elmer, Waltham, MA, USA)를 사용하여 450 nm의 파장에서 광학 밀도 (OD)를 측정하였다. GI50은 Prism version 5.01 (GraphPad, LaJolla, CA, USA)을 사용하여 비선형 회귀(nonlinear regression)에 의해 계산하였다.Cell viability was evaluated by a tetrazolium-based assay using the EZ-Cytox Cell Viability Assay kit (DaeilLab, Korea). Specifically, 2,000 - 15,000 cells were plated in a 96-well plate in 100 μl of medium. The next day, cells were treated with compounds with dimethyl sulfoxide (DMSO) as a negative control. 3 days (72 hours) after compound addition, 10 μl of EZ-Cytox kit reagent was placed in each well of a 96-well plate and incubated at 37° C. in a humidified CO 2 incubator for 4 hours. After incubation, the optical density (OD) was measured at a wavelength of 450 nm using a Victor multilabel reader (Perkin Elmer, Waltham, MA, USA). GI 50 was calculated by nonlinear regression using Prism version 5.01 (GraphPad, LaJolla, CA, USA).
그 결과를 표 1에 나타내었다.The results are shown in Table 1.
화합물 compound R1 R 1 R2 R 2 IC50 (nM)
or %inhibition
at 100 nMIC 50 (nM)
or %inhibition
at 100 nM 		IC50 (nM)IC 50 (nM) GI50 (nM)GI 50 (nM) GI50 (nM)GI 50 (nM) GI50 (nM)GI 50 (nM)
FLT3FLT3 FLT3/
D835YFLT3/
D835Y 		MV4-11MV4-11 MOLM14
D835Y MOLM14
D835Y 		MOLM14 MOLM14
1One HH
Figure PCTKR2020017666-appb-I000045
Figure PCTKR2020017666-appb-I000045
 		2.1 nM2.1 nM 0.180.18 1.3 1.3 5.0 5.0 6.2 6.2
22 FF
Figure PCTKR2020017666-appb-I000046
Figure PCTKR2020017666-appb-I000046
 		2.8 nM2.8 nM 0.180.18 1.2 1.2 7.1 7.1 7.2 7.2
33 ClCl
Figure PCTKR2020017666-appb-I000047
Figure PCTKR2020017666-appb-I000047
 		2.5 nM2.5 nM 0.20.2 0.8 0.8 12.7 12.7 7.2 7.2
44 BrBr
Figure PCTKR2020017666-appb-I000048
Figure PCTKR2020017666-appb-I000048
 		2.5 nM2.5 nM 0.220.22 1.3 1.3 16.0 16.0 13.9 13.9
55 II
Figure PCTKR2020017666-appb-I000049
Figure PCTKR2020017666-appb-I000049
 		2.4 nM2.4 nM 0.450.45 3.6 3.6 20.9 20.9 23.7 23.7
66 OMeOMe
Figure PCTKR2020017666-appb-I000050
Figure PCTKR2020017666-appb-I000050
 		99.70%99.70% 1.611.61 8.4 8.4 36.4 36.4 n.tn.t.
77 OCF3 OCF 3
Figure PCTKR2020017666-appb-I000051
Figure PCTKR2020017666-appb-I000051
 		94.63%94.63% 1.621.62 27.4 27.4 87.5 87.5 n.tn.t.
88 HH
Figure PCTKR2020017666-appb-I000052
Figure PCTKR2020017666-appb-I000052
 		98.56%98.56% 0.520.52 12.2 12.2 23.5 23.5 27.8 27.8
99 FF
Figure PCTKR2020017666-appb-I000053
Figure PCTKR2020017666-appb-I000053
 		98.73%98.73% 0.350.35 15.2 15.2 26.1 26.1 28.0 28.0
1010 ClCl
Figure PCTKR2020017666-appb-I000054
Figure PCTKR2020017666-appb-I000054
 		99.49%99.99% 0.390.39 31.8 31.8 62.3 62.3 103.0 103.0
1111 OMeOMe
Figure PCTKR2020017666-appb-I000055
Figure PCTKR2020017666-appb-I000055
 		92.58%92.58% 5.375.37 19.8 19.8 115.0 115.0 n.tn.t.
1212 OCF3 OCF 3
Figure PCTKR2020017666-appb-I000056
Figure PCTKR2020017666-appb-I000056
 		71.40%71.40% 15.615.6 20.4 20.4 412.1 412.1 n.tn.t.
1313 HH
Figure PCTKR2020017666-appb-I000057
Figure PCTKR2020017666-appb-I000057
 		92.95%92.95% 3.783.78 8.0 8.0 24.3 24.3 26.6 26.6
1414 FF
Figure PCTKR2020017666-appb-I000058
Figure PCTKR2020017666-appb-I000058
 		96.46%96.46% 2.712.71 22.0 22.0 30.8 30.8 46.2 46.2
1515 HH
Figure PCTKR2020017666-appb-I000059
Figure PCTKR2020017666-appb-I000059
 		97.32%97.32% 3.073.07 17.3 17.3 38.9 38.9 48.6 48.6
1616 HH
Figure PCTKR2020017666-appb-I000060
Figure PCTKR2020017666-appb-I000060
 		99.15%99.15% 1.121.12 7.0 7.0 23.8 23.8 25.6 25.6
1717 HH
Figure PCTKR2020017666-appb-I000061
Figure PCTKR2020017666-appb-I000061
 		100.4%100.4%
1818 HH
Figure PCTKR2020017666-appb-I000062
Figure PCTKR2020017666-appb-I000062
 		99.01%99.01%
1919 FF
Figure PCTKR2020017666-appb-I000063
Figure PCTKR2020017666-appb-I000063
 		99.63%99.63% 3.453.45 10.9 10.9 28.1 28.1 35.7 35.7
2020 FF
Figure PCTKR2020017666-appb-I000064
Figure PCTKR2020017666-appb-I000064
 		97.02%97.02% 2.162.16 3.3 3.3 25.8 25.8 18.6 18.6
2121 FF
Figure PCTKR2020017666-appb-I000065
Figure PCTKR2020017666-appb-I000065
 		99.60%99.90%
2222 FF
Figure PCTKR2020017666-appb-I000066
Figure PCTKR2020017666-appb-I000066
 		99.08%99.08%
2323 ClCl
Figure PCTKR2020017666-appb-I000067
Figure PCTKR2020017666-appb-I000067
 		100%100% 1.341.34 22.8 22.8 28.3 28.3 41.3 41.3
2424 ClCl
Figure PCTKR2020017666-appb-I000068
Figure PCTKR2020017666-appb-I000068
 		97.04%97.04% 1.081.08 1.1 1.1 44.2 44.2 8.6 8.6
2525 OMeOMe
Figure PCTKR2020017666-appb-I000069
Figure PCTKR2020017666-appb-I000069
 		94.87%94.87% 5.025.02 22.2 22.2 55.0 55.0 n.tn.t.
2626 OMeOMe
Figure PCTKR2020017666-appb-I000070
Figure PCTKR2020017666-appb-I000070
 		96.87%96.87% 5.785.78 84.7884.78 53.7 53.7 n.tn.t.
2727 OCF3 OCF 3
Figure PCTKR2020017666-appb-I000071
Figure PCTKR2020017666-appb-I000071
 		71.40%71.40% 15.615.6 20.3820.38 412.1 412.1 n.tn.t.
2828 OCF3 OCF 3
Figure PCTKR2020017666-appb-I000072
Figure PCTKR2020017666-appb-I000072
 		88.44%88.44% 6.236.23 112.9 112.9 56.3 56.3 n.tn.t.
2929 HH
Figure PCTKR2020017666-appb-I000073
Figure PCTKR2020017666-appb-I000073
 		91.75%91.75%
3030 HH
Figure PCTKR2020017666-appb-I000074
Figure PCTKR2020017666-appb-I000074
 		97.71%97.71%
3131 HH
Figure PCTKR2020017666-appb-I000075
Figure PCTKR2020017666-appb-I000075
 		96.67%96.67%
3232 FF
Figure PCTKR2020017666-appb-I000076
Figure PCTKR2020017666-appb-I000076
 		98.73%98.73%
3535 ClCl
Figure PCTKR2020017666-appb-I000077
Figure PCTKR2020017666-appb-I000077
 		96.09%96.09% n.tn.t. 31.2 31.2 94.2 94.2 39.0 39.0
표 1로부터 확인할 수 있는 바와 같이, 본 발명의 화합물은 FLT3 또는 FLT3 돌연변이 억제 활성을 나타내었는데, 특히 FLT3/D835Y 돌연변이 억제 활성이 우수하*다.As can be seen from Table 1, the compounds of the present invention exhibited FLT3 or FLT3 mutagenesis inhibitory activity, and in particular FLT3/D835Y mutation inhibitory activity was excellent*.
본 발명의 화합물은 급성백혈병 세포주에서 강력한 항증식 활성을 나타냄이 확인되었는데, 특히, 돌연변이 키나제를 발현하는 FLT3-ITD 발현 MV4-11 및 MOLM14 세포주, FLT3/D835Y 발현 MOLM14-FLT3/D835Y 세포주에서 강력한 항증식 활성을 보임을 확인할 수 있었다. It was confirmed that the compound of the present invention exhibits potent antiproliferative activity in acute leukemia cell lines. In particular, FLT3-ITD expressing MV4-11 and MOLM14 cell lines expressing mutant kinases, and FLT3/D835Y expressing MOLM14-FLT3/D835Y cell lines expressing potent antiproliferative activity It was confirmed that the proliferation activity was shown.
이로부터 본 발명의 화합물은 FTL3, 특히 FLT3 돌연변이 억제 활성이 우수함이 확인되었다. From this, it was confirmed that the compound of the present invention has excellent FTL3, particularly FLT3 mutation inhibitory activity.

Claims (15)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용되는 염:A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2020017666-appb-I000078
    Figure PCTKR2020017666-appb-I000078
    상기식에 있어서, In the above formula,
    R1 및 R3은 각각 독립적으로 수소, 할로젠, 시아노, 히드록시, 니트로, C1-C6 알킬, C1-C6 알콕시, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬, -N(Ra)(Rb), -N(Ra)(C(=O)-Rb), -C(=O)N(Ra)(Rb), -O-C(=O)-N(Ra)(Rb), -C(=O)-Ra, 및 -C(=O)-ORa로 이루어진 군으로부터 선택되고; 여기에서 Ra 및 Rb는 각각 독립적으로 수소 또는 C1-C6 알킬이고,R1 and R3 are each independently hydrogen, halogen, cyano, hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl; 3- to 10-membered heterocycloalkyl, -N(Ra)(Rb), -N(Ra)(C(=O)-Rb), -C(=O)N(Ra)(Rb), -OC (=O)-N(Ra)(Rb), -C(=O)-Ra, and -C(=O)-ORa; wherein Ra and Rb are each independently hydrogen or C1-C6 alkyl;
    R2는R2 is
    Figure PCTKR2020017666-appb-I000079
    또는
    Figure PCTKR2020017666-appb-I000080
    이며,
    Figure PCTKR2020017666-appb-I000079
    or
    Figure PCTKR2020017666-appb-I000080
    is,
    R4는 -NRcRd이고, R4 is -NRcRd,
    Rc 및 Rd는 각각 독립적으로 수소, C1-C6 알킬, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 또는 3- 내지 10-원 헤테로시클로알킬이되, 단, Rc 및 Rd는 동시에 수소는 아니거나, 또는 Rc and Rd are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, provided that Rc and Rd is not hydrogen at the same time, or
    Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 5- 내지 10-원 헤테로아릴 또는 3- 내지 10-원 헤테로시클로알킬을 형성하고, Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl;
    R5 및 R6는 각각 독립적으로 수소 또는 C1-C6 알킬이고, R5 and R6 are each independently hydrogen or C1-C6 alkyl;
    상기 C1-C6 알킬, C1-C6 알콕시, C6-C10 아릴, 5- 내지 10-원 헤테로아릴, C3-C10 시클로알킬, 3- 내지 10-원 헤테로시클로알킬은 할로젠; 비치환되거나 또는 할로젠으로 치환된 C1-C6 알킬; 비치환되거나 또는 할로젠으로 치환된 C1-C6 알콕시; 시아노; 히드록시; 니트로; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; 비치환되거나 또는 C1-C6 알킬로 치환된 C6-C10 아릴; 비치환되거나 또는 C1-C6 알킬로 치환된 5- 내지 10-원 헤테로아릴; 비치환되거나 또는 C1-C6 알킬로 치환된 C3-C10 시클로알킬; 및 비치환되거나 또는 C1-C6 알킬로 치환된 3- 내지 10-원 헤테로시클로알킬로 이루어지는 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고; wherein said C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl is halogen; C1-C6 alkyl unsubstituted or substituted with halogen; C1-C6 alkoxy unsubstituted or substituted with halogen; cyano; hydroxy; nitro; -N(Re)(Rf) ; -N(Re)(C(=O)-Rf); -C(=O)N(Re)(Rf); -O-C(=O)-N(Re)(Rf); -C(=O)-Re; -C(=O)-ORf; C6-C10 aryl unsubstituted or substituted with C1-C6 alkyl; 5- to 10-membered heteroaryl unsubstituted or substituted with C1-C6 alkyl; C3-C10 cycloalkyl unsubstituted or substituted with C1-C6 alkyl; and 3- to 10-membered heterocycloalkyl unsubstituted or substituted with C1-C6 alkyl;
    Re 및 Rf는 각각 독립적으로 수소 또는 C1-C6 알킬이다. Re and Rf is each independently hydrogen or C1-C6 alkyl.
  2. 제1항에 있어서, R1 및 R3은 각각 독립적으로 수소, 할로젠, C1-C6 알킬, 또는 C1-C6 알콕시인 화합물 또는 이의 약학적으로 허용되는 염.The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1 and R3 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy.
  3. 제1항에 있어서, According to claim 1,
    R4는 -NRcRd이고, R4 is -NRcRd,
    Rc 및 Rd는 각각 독립적으로 수소, C1-C6 알킬, 5- 내지 6-원 헤테로아릴 또는 3- 내지 7-원 헤테로시클로알킬이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는 Rc and Rd are each independently hydrogen, C1-C6 alkyl, 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl, provided that Rc and Rd are not simultaneously hydrogen; or
    Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 5- 내지 6-원 헤테로아릴 또는 3- 내지 7-원 헤테로시클로알킬을 형성하는 것인, Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl;
    화합물 또는 이의 약학적으로 허용되는 염.A compound or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,According to claim 1,
    R4는 -NRcRd이고, R4 is -NRcRd,
    Rc 및 Rd는 각각 독립적으로 수소, 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
    Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐을 형성하는 것인, Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl;
    화합물 또는 이의 약학적으로 허용되는 염.A compound or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서, R5 및 R6은 각각 독립적으로 수소 또는 메틸인 화합물 또는 이의 약학적으로 허용되는 염.The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R5 and R6 are each independently hydrogen or methyl.
  6. 제1항에 있어서, R2는 The method of claim 1, wherein R2 is
    Figure PCTKR2020017666-appb-I000081
    Figure PCTKR2020017666-appb-I000081
    Figure PCTKR2020017666-appb-I000082
    Figure PCTKR2020017666-appb-I000082
    Figure PCTKR2020017666-appb-I000083
    Figure PCTKR2020017666-appb-I000083
    Figure PCTKR2020017666-appb-I000084
    Figure PCTKR2020017666-appb-I000084
    Figure PCTKR2020017666-appb-I000085
    Figure PCTKR2020017666-appb-I000085
    Figure PCTKR2020017666-appb-I000086
    Figure PCTKR2020017666-appb-I000086
    또는
    Figure PCTKR2020017666-appb-I000087
    인 화합물 또는 이의 약학적으로 허용되는 염.    or
    Figure PCTKR2020017666-appb-I000087
    A phosphorus compound or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서, 하기 화학식 1a로 표시되는 화합물 또는 이의 약학적으로 허용되는 염:According to claim 1, wherein the compound represented by the formula (1a) or a pharmaceutically acceptable salt thereof:
    [화학식 1a][Formula 1a]
    Figure PCTKR2020017666-appb-I000088
    Figure PCTKR2020017666-appb-I000088
    상기식에서, R1, R2, 및 R3는 제1항에 정의된 바와 같다.wherein R1, R2, and R3 are as defined in claim 1.
  8. 제7항에 있어서, R1은 할로젠; 또는 비치환되거나 또는 할로젠으로 치환된 C1-C6 알콕시인 화합물 또는 이의 약학적으로 허용되는 염.8. The method of claim 7, wherein R1 is halogen; or an unsubstituted or halogen-substituted C1-C6 alkoxy compound, or a pharmaceutically acceptable salt thereof.
  9. 제7항에 있어서, R3은 수소인 화합물 또는 이의 약학적으로 허용되는 염.The compound according to claim 7, wherein R3 is hydrogen, or a pharmaceutically acceptable salt thereof.
  10. 제7항에 있어서, 8. The method of claim 7,
    R2는
    Figure PCTKR2020017666-appb-I000089
    또는
    Figure PCTKR2020017666-appb-I000090
    이고,     R2 is
    Figure PCTKR2020017666-appb-I000089
    or
    Figure PCTKR2020017666-appb-I000090
    ego,
    R4는 -NRcRd이고, R4 is -NRcRd,
    Rc 및 Rd는 각각 독립적으로 수소, 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐이되, 단, Rc 및 Rd는 동시에 수소는 아니거나; 또는 Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
    Rc 및 Rd는 이들이 -NRcRd에서 결합되는 질소 원자와 함께 아제티디닐, 피롤리디닐, 피페리디닐, 또는 피페라지닐을 형성하는 것인, Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl;
    화합물 또는 이의 약학적으로 허용되는 염.A compound or a pharmaceutically acceptable salt thereof.
  11. 제1항에 있어서, R2는 The method of claim 1, wherein R2 is
    Figure PCTKR2020017666-appb-I000091
    Figure PCTKR2020017666-appb-I000091
    Figure PCTKR2020017666-appb-I000092
    Figure PCTKR2020017666-appb-I000092
    Figure PCTKR2020017666-appb-I000093
    Figure PCTKR2020017666-appb-I000093
    Figure PCTKR2020017666-appb-I000094
    , 또는
    Figure PCTKR2020017666-appb-I000095
    인 화합물 또는 이의 약학적으로 허용되는 염.
    Figure PCTKR2020017666-appb-I000094
    , or
    Figure PCTKR2020017666-appb-I000095
    A phosphorus compound or a pharmaceutically acceptable salt thereof.
  12. 하기 화합물로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염:A compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
    1) (2Z,3E)-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;1) (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one ;
    2) (2Z,3E)-5'-플루오로-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;2) (2Z,3E)-5'-fluoro-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-one;
    3) (2Z,3E)-5'-클로로-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;3) (2Z,3E)-5'-chloro-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene] -2'-one;
    4) (2Z,3E)-5'-브로모-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;4) (2Z,3E)-5'-bromo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-one;
    5) (2Z,3E)-5'-아이오도-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온5) (2Z,3E)-5'-iodo-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-on
    6) (2Z,3E)-5'-메톡시-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;6) (2Z,3E)-5'-methoxy-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene ]-2'-one;
    7) (2Z,3E)-3-((2-옥소-2-(피페라진-1-일)에톡시)이미노)-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-2'-온; 7) (2Z,3E)-3-((2-oxo-2-(piperazin-1-yl)ethoxy)imino)-5′-(trifluoromethoxy)-[2,3′-bi indolinylidene]-2'-one;
    8) (2Z,3E)-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;8) (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]-2 '-On;
    9) (2Z,3E)-5'-플루오로-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;9) (2Z,3E)-5′-fluoro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3′-biyne dolinylidene]-2'-one;
    10) (2Z,3E)-5'-클로로-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;10) (2Z,3E)-5'-chloro-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindoli nylidene]-2'-one;
    11) (2Z,3E)-5'-메톡시-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;11) (2Z,3E)-5'-methoxy-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-[2,3'-biyne dolinylidene]-2'-one;
    12) (2Z,3E)-3-((2-(4-메틸피페라진-1-일)-2-옥소에톡시)이미노)-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-2'-온;12) (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)imino)-5′-(trifluoromethoxy)-[2,3 '-Biindolinylidene]-2'-one;
    13) (2Z,3E)-3-(((피페라진-1-일술포닐)메톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;13) (2Z,3E)-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3′-biindolinylidene]-2′-one;
    14) (2Z,3E)-5'-플루오로-3-(((피페라진-1-일술포닐)메톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온; 14) (2Z,3E)-5'-fluoro-3-(((piperazin-1-ylsulfonyl)methoxy)imino)-[2,3'-biindolinylidene]-2'- On;
    15) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-[2,3'-바이인돌리닐리덴]-2'-온;15) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-[2,3'-biindolinylidene]- 2'-on;
    16) 2-((((2Z,3E)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드; 16) 2-((((2Z,3E)-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)-N-(piperidine-4- 1) acetamide;
    17) N-(아제티딘-3-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;17) N-(azetidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino )oxy)acetamide;
    18) 2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피롤리딘-3-일)아세트아미드; 18) 2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(pyrrolidine- 3-yl)acetamide;
    19) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-플루오로-[2,3'-바이인돌리닐리덴]-2'-온; 19) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-fluoro-[2,3′-bi indolinylidene]-2'-one;
    20) 2-((((2Z,3E)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드; 20) 2-((((2Z,3E)-5′-fluoro-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)-N-( piperidin-4-yl)acetamide;
    21) N-(아제티딘-3-일)-2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;21) N-(azetidin-3-yl)-2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]- 3-ylidene)amino)oxy)acetamide;
    22) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피롤리딘-3-일)아세트아미드;22) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(pyrrolidin-3-yl)acetamide;
    23) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-클로로-[2,3'-바이인돌리닐리덴]-2'-온;23) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-chloro-[2,3′-biyne dolinylidene]-2'-one;
    24) 2-((((2Z,3E)-5'-클로로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드;24) 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(p peridin-4-yl)acetamide;
    25) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-메톡시-[2,3'-바이인돌리닐리덴]-2'-온; 25) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-methoxy-[2,3′-bi indolinylidene]-2'-one;
    26) 2-((((2Z,3E)-5'-메톡시-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드; 26) 2-((((2Z,3E)-5'-methoxy-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-( piperidin-4-yl)acetamide;
    27) (2Z,3E)-3-((2-(4-아미노피페리딘-1-일)-2-옥소에톡시)이미노)-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-2'-온;27) (2Z,3E)-3-((2-(4-aminopiperidin-1-yl)-2-oxoethoxy)imino)-5′-(trifluoromethoxy)-[2, 3'-biindolinylidene]-2'-one;
    28) 2-((((2Z,3E)-2'-옥소-5'-(트리플루오로메톡시)-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(피페리딘-4-일)아세트아미드;28) 2-((((2Z,3E)-2′-oxo-5′-(trifluoromethoxy)-[2,3′-biindolinylidene]-3-ylidene)amino)oxy) -N-(piperidin-4-yl)acetamide;
    29) N-(1-메틸피페리딘-4-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;29) N-(1-methylpiperidin-4-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3- ylidene)amino)oxy)acetamide;
    30) N-(1-메틸아제티딘-3-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;30) N-(1-methylazetidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3-yl) den)amino)oxy)acetamide;
    31) N-(1-메틸피롤리딘-3-일)-2-(((E)-((Z)-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)아세트아미드;31) N-(1-methylpyrrolidin-3-yl)-2-(((E)-((Z)-2'-oxo-[2,3'-biindolinylidene]-3- ylidene)amino)oxy)acetamide;
    32) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸피페리딘-4-일)아세트아미드;32) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(1-methylpiperidin-4-yl)acetamide;
    33) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸아제티딘-3-일)아세트아미드;33) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(1-methylazetidin-3-yl)acetamide;
    34) 2-(((E)-((Z)-5'-플루오로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸피롤리딘-3-일)아세트아미드; 및 34) 2-(((E)-((Z)-5'-fluoro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N -(1-methylpyrrolidin-3-yl)acetamide; and
    35) 2-((((2Z,3E)-5'-클로로-2'-옥소-[2,3'-바이인돌리닐리덴]-3-일리덴)아미노)옥시)-N-(1-메틸피페리딘-4-일)아세트아미드. 35) 2-((((2Z,3E)-5'-chloro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)-N-(1 -Methylpiperidin-4-yl)acetamide.
  13. 제1항 내지 제12항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용되는 염을 포함하는, FLT3(fms-like tyrosine kinase) 억제용 약학 조성물.A pharmaceutical composition for inhibiting FLT3 (fms-like tyrosine kinase), comprising the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
  14. 제13항에 있어서, 상기 FLT3는 돌연변이 FLT3인, 약학 조성물.14. The pharmaceutical composition of claim 13, wherein the FLT3 is a mutant FLT3.
  15. 제1항 내지 제12항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용되는 염을 포함하는, 백혈병 또는 림프종의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for the prevention or treatment of leukemia or lymphoma, comprising the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
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WO2000061555A1 (en) * 1999-04-12 2000-10-19 Gerhard Eisenbrand Indigoid bisindole derivatives
WO2002100401A1 (en) * 2001-06-11 2002-12-19 Schering Aktiengesellschafat Soluble cdk-inhibitory indirubin derivatives
WO2007099402A2 (en) * 2005-12-23 2007-09-07 Centre National De La Recherche Scientifique (Cnrs) New 3’-, 7-substituted indirubins and their applications
US20140275168A1 (en) * 2013-03-14 2014-09-18 City Of Hope Indirubin derivatives, and uses thereof
KR20190049584A (en) * 2017-10-31 2019-05-09 광주과학기술원 Composition for Inhibiting or Treating for Acute Myeloid Leukemia or Metastatic Breast Cancer

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WO2000061555A1 (en) * 1999-04-12 2000-10-19 Gerhard Eisenbrand Indigoid bisindole derivatives
WO2002100401A1 (en) * 2001-06-11 2002-12-19 Schering Aktiengesellschafat Soluble cdk-inhibitory indirubin derivatives
WO2007099402A2 (en) * 2005-12-23 2007-09-07 Centre National De La Recherche Scientifique (Cnrs) New 3’-, 7-substituted indirubins and their applications
US20140275168A1 (en) * 2013-03-14 2014-09-18 City Of Hope Indirubin derivatives, and uses thereof
KR20190049584A (en) * 2017-10-31 2019-05-09 광주과학기술원 Composition for Inhibiting or Treating for Acute Myeloid Leukemia or Metastatic Breast Cancer

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