WO2022249120A1 - Novel benzoindolone compounds and pharmaceutical composition comprising same - Google Patents
Novel benzoindolone compounds and pharmaceutical composition comprising same Download PDFInfo
- Publication number
- WO2022249120A1 WO2022249120A1 PCT/IB2022/054947 IB2022054947W WO2022249120A1 WO 2022249120 A1 WO2022249120 A1 WO 2022249120A1 IB 2022054947 W IB2022054947 W IB 2022054947W WO 2022249120 A1 WO2022249120 A1 WO 2022249120A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- benzoindolone
- compound
- pharmaceutically acceptable
- stereoisomer
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- KXBTULMIMYFPGV-UHFFFAOYSA-N benzo[g]indol-2-one Chemical class C1=CC=C2C3=NC(=O)C=C3C=CC2=C1 KXBTULMIMYFPGV-UHFFFAOYSA-N 0.000 title description 3
- -1 benzoindolone compound Chemical class 0.000 claims abstract description 55
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- 125000000217 alkyl group Chemical group 0.000 claims description 28
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- 238000000034 method Methods 0.000 claims description 19
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- 239000003814 drug Substances 0.000 claims description 11
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
- C07D209/92—Naphthostyrils
Definitions
- the present invention is a novel benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and It relates to a pharmaceutical composition comprising the same.
- the Hippo signaling pathway is a major signaling pathway that regulates the proliferation of normal cells in the human body and the growth and size of tissues and organs such as skin, muscle, lung, and liver.
- the Hippo signaling system is known as a tumor suppressor in normal cells or tissues, it has been reported that it is involved in diseases such as tumors, revealing that the Hippo signaling system plays an important role in cancer development and growth.
- the Hippo signal transduction system interacts (cross talk) with other signal transduction systems involved in previously known tumors, such as ffnt, EGFR or TGF-beta signal transduction system, and Hippo signal transduction in various cancer types in the human body It has been reported that systems may be involved.
- the Hippo signaling system starts from a kinase cascade composed of MST-1/2 and LATS-1/2 and is activated by phosphorylating YAP or TAZ protein, which is a transcriptional activator.
- the show protein is not phosphorylated.
- 2022/249120 1» that 1'/182022/054947
- moves from the cytoplasm to the nucleus and binds to TEA domain (TEAD) proteins (TEAD1, 2, 3, 4) present in the nucleus to form CTGF, Cyr61, and FGF It acts as a transcription factor for genes involved in cell proliferation, such as 1, and induces their expression.
- the YAP protein is phosphorylated, and the phosphorylated YAP protein is ubiquitinated in the cytoplasm and degraded in the proteasome, or binds to the VGLL4 protein, a tumor suppressor, and does not move into the nucleus. As a result, it is unable to bind with TEAD proteins, and the expression of genes involved in cell growth is suppressed.
- Inhibiting the binding of YAP and TEAD proteins in the cell nucleus is known to be the only way to suppress the overexpression of genes involved in cell proliferation due to abnormal regulation of the Hippo signaling system. This is because MST-1/2 kinase and LATS-1/2 kinase, which are upper proteins of the Hippo signaling pathway, phosphorylate the YAP protein and inhibit its migration into the nucleus. is not done YAP 2022/249120 1»(That 1'/182022/054947 This is because proteins can move into the nucleus and combine with TEAD proteins to further promote overexpression of genes. In addition, since YAP proteins have a very flexible structure without a specific tertiary structure, they are difficult to target for therapeutic substances.
- TEAD proteins are currently the only targets that can inhibit the Hippo signaling system.
- S- palmitoylation of TEAD protein itself has been found to be a very essential factor for the stability and function of TEAD protein (Cel l Rep. 2020 Jun 23; 31(12): 107809. ). Accordingly, various methods for interfering with the binding between the YAP protein and the TEAD proteins or inhibiting the function of the TEAD proteins by binding to the TEAD proteins have been attempted.
- TEAD proteins composed of TEAD1, 2, 3, and 4 have a very high amino acid composition similarity of about 70%. All TEAD proteins undergo a post-translational modification process called palmitoylation by binding a fatty acid called palmitate to a specific cysteine group. This process is known to improve the structural stability of TEAD protein or to promote binding to YAP or TAZ proteins to express genes (Chan, P. et al. Nat. Chem. Biol. (2016) 12 : 282-289; No 1 and , CL et al. Structure (2016) 24: 179-186; Mesrouze, Y. et al. Protein Sci.
- the Hippo signaling system is involved in cancer and It is a signal transduction system that is critically involved in diseases caused by excessive cell proliferation.
- the hippo signaling system 2022/249120 1» That 1'/182022/054947 TEAD proteins located at the bottom of the signal transduction system are suggested as the only therapeutic targets to suppress gene overexpression. Accordingly, recently, small-molecular compounds that inhibit palmitoylation of TEAD proteins to inhibit gene overexpression by the Hippo signaling pathway have been developed.
- Non-Patent Document 1 Cell 2011 Nov 11; 147(4):759-72 (Non-Patent Document 2) Folia Histochem Cytobiol.2015; 53(2):105-119 (Non-Patent Document 3) Translung Cancer Res.2014 ;3:75-83 (Non-Patent Document 4) Cancer Res.1995; 55: 1227-31 (Non-Patent Document 5) CellRep.2020 Jun 23; 31(12):107809 (Non-Patent Document 6) Chan,P. et al.Nat.Chem.Biol. (2016) 12: 282-289 (Non-Patent Document 7) Noland, C.L.
- Non-Patent Document 8 Mesrouze, Y. et al .Protein Sci. (2017) 26: 2399-2409 (Non-Patent Document 9) Furet, P. et al.Bioorg.Med.Chem.Lett. (2019) 29: 2316-2319
- Non-Patent Document 10 Zhou,ff.et al.Anal.Biochem.(2019) 586: 113413
- Non-Patent Document 11 Pobbati, A.V. et al. Structure (2015) 23: 2076-2086
- Non-Patent Document 12 Holden, J.K. et al. Cell Rep. (2020) 31: 107809
- Non-Patent Document 13 Kaneda, A. et al. Am. J. Cancer Res. (2020) 10:4399-
- the present invention proposes a novel myosho inhibitory substance that inhibits palmitoylation while structurally completely different from the myosho palmitoylation inhibitors reported so far, and the object of the present invention is to use this novel substance as an anticancer agent, etc.
- the goal is to develop treatments for diseases involving the hippo signaling system.
- One object of the present invention is to provide a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
- Another object of the present invention is to provide a pharmaceutical composition comprising a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof as an active ingredient.
- Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer, including a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. That is, by binding to Myosho protein, which is located at the bottom of the signal transduction system of Hippo signaling, which is one of the very important signal systems for cell development and growth, and acts as a switch to regulate the expression of genes involved in cell development and growth, protein Benzoindolone compounds, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, for the prevention or treatment of cancer, which are caused by excessive proliferation of cells by inhibiting the function of and suppressing the expression of genes.
- Another object of the present invention is to provide a use of a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the preparation of a drug for preventing or treating cancer.
- One or more II of 3 ⁇ 4 are each independently halogen, -3alkyl, (1) -0 1 - 3alkylene-eg, -3alkylene-ganeunseong (wherein, mother 4 and 3 ⁇ 4 are each independently -3alkyl It can be substituted with) or - ⁇ (alkyl),
- 13 ⁇ 4 is II, -6 alkyl or * ⁇ 2-3 ⁇ 4,
- * ⁇ 2 - is a single bond or *_ - 6 alkylene-
- 3 ⁇ 4 is - 6 alkynx, 3 ⁇ 4- 1 () cycloalkyl, 3 ⁇ 4- 6 cycloalkenyl, 0 4 -
- One or more II of 3 ⁇ 4 is each independently -3 alkyl, (1) - -3 alkylene- 011, - -3 alkylene- liver function (wherein, the mother 4 and 3 ⁇ 4 each independently represent -3 alkyl) or ⁇ -( ⁇ - 3 alkyl) may be substituted,
- 3 ⁇ 4 is II, - 6 alkyl or 3 ⁇ 4,
- *- - is a single bond or *- - 6 alkylene-, 2022/249120 1»(That 1'/182022/054947
- 3 ⁇ 4 is 01-6 alkynx - cycloalkyl, 3 ⁇ 4- 6 cycloalkenyl, 0
- One or more II of 3 ⁇ 4 is each independently - 6 alkyl, - 6 alkoxy, phenoxy, ?
- R3 in the above formula 1b is the same as defined in formula 1.
- the expression "C x " of the functional group represents the number of carbons (C), and " ⁇ -/" means an integer of more than X and less than y of carbon atoms.
- the term n substituted " represents a moiety having a substituent replacing hydrogen on one or more carbons of the main chain. Substitution n ” or “substituted with ” depends on whether such substitution is allowed by the substituted atom and substituent, and is a compound that is stable by substitution, for example, a compound that is not naturally transformed by rearrangement, cyclization, elimination, etc.
- n single bond means a case in which adjacent atoms or atomic groups are directly bonded.
- ''alkyl'' is a linear (or straight-chain, linear) saturated hydrocarbon group unless otherwise specified. Or a branched (or side chain, branched) saturated hydrocarbon group, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl And it may be one or more selected from n- pentyl, etc., but is not limited thereto.
- alkylene means a divalent functional group derived from alkyl as defined above unless otherwise specified.
- alkenyl refers to an unsaturated hydrocarbon group containing at least one double bond between carbons unless otherwise specified.
- alkynyl refers to at least one triple bond between carbons unless otherwise specified. It means an unsaturated hydrocarbon group containing.
- halogen means 01 , mya, or I unless otherwise specified.
- aryl includes monoaromatic or polycyclic aromatics, phenyl, biphenyl, naphthalenyl, etc., unless otherwise specified. It may be one or more selected from, but is not limited thereto.
- heteroaryl refers to a monocyclic or polycyclic heterocyclic ring in which at least one carbon atom in the aryl group is substituted with nitrogen ), oxygen (0) or sulfur.
- Heteroaryl is pyridinyl, t Ofenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrroyl, furanyl, pyrroleyl, thiazolyl, isothiazolyl, already Dazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzooxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl And it may be one or more selected from chromenyl, etc., but is not limited thereto.
- cycloalkyl means a saturated hydrocarbon ring having 3 or more specified carbon atoms including a ring, and the saturated hydrocarbon ring is a monocyclic and 2022/249120 1» (that 1'/182022/054947 means including all polycyclic ring structures, and may be one or more selected from cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, but is not limited thereto.
- bicycloalkyl means a ring structure in which two or more rings of a saturated hydrocarbon ring, usually having at least three specified carbon atoms containing the ring, share at least one pair of carbon atoms, and It may be one or more selected from, but is not limited thereto.
- cycloalkenyl means a structure having at least one double bond between cycloalkyl ring vertices, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl It may be one or more selected from, but is not limited to, etc.
- heterocycloalkyl is a saturated containing 1 to 4 heteroatoms independently selected from nitrogen), oxygen (0) and sulfur) monocyclic and polycyclic heterocycles or ring structures in which two or more rings share at least one pair of carbon atoms.
- Heterocycloalkyl is oxiranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl and tetrahydrothiopyranyl, etc. It may be one or more selected from, but is not limited thereto.
- the benzoindolone compound represented by Formula 1 according to (1), (2) or (3) is one selected from the group consisting of compounds shown in Table 1 below. 2022/249120 1» (the 1'/182022/054947 or higher benzoindolone compound represented by Formula 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate:
- n stereoisomer includes diastereomers and optical isomers, and optical isomers are enantiomers
- the "hydrate” of the present invention is a benzoindolone compound, its stereoisomer or its pharmaceutically acceptable salt and water are bound by non-covalent intermolecular forces, containing a stoichiometric or non-stoichiometric amount of water.
- the hydrate may include water in a ratio of about 0.25 to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, 2022/249120 1 » (that 1'/182022/054947 about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc.).
- the "solvate" of the present invention is a benzoindolone compound, its stereoisomer or its pharmaceutically acceptable salt and a solvent other than water are bound by intermolecular forces
- the solvent in a stoichiometric or non-stoichiometric amount can include Specifically, the solvate may include solvent molecules in a ratio of about 0.25 to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, and about 2 mole. , about 2.5 moles, about 3 moles, about 5 moles, etc.
- a pharmaceutical composition containing a benzoindolone compound and its use is a pharmaceutical composition comprising a benzoindolone compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof as an active ingredient. It provides an enemy composition.
- the benzoindolone compound represented by Formula 1 of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate can prevent or treat cancer. That is, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a benzoindolone compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof as an active ingredient.
- the cancers include lung cancer, stomach cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, head and neck cancer, blood cancer, bone cancer, liver cancer, and thyroid cancer.
- parathyroid cancer skin cancer, lymphoma, mesothelioma, leukemia, myeloma, sarcoma, and one or more selected from virus-related cancers, etc. 2022/249120 1»(That 1'/182022/054947 but not limited thereto.
- the virus-related cancer may be at least one selected from nasopharyngeal cancer, vaginal cancer, vulvar cancer, penile cancer, Kaposi's sarcoma, Burkitt's lymphoma, cellular lymphoma, and Merkel cell cancer, but is not limited thereto.
- the present invention provides the use of the benzoindolone compound, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate for the prevention or treatment of cancer.
- the present invention provides a method for preventing or treating cancer, comprising administering to a subject a therapeutically effective amount of a benzoindolone compound, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate. .
- prevention refers to any activity that suppresses or delays the onset of Myosho protein-related diseases by administration of the compound according to the present invention.
- treatment refers to all activities that improve or beneficially change the symptoms of Myosho protein-related diseases by administration of the compound according to the present invention.
- composition of the present invention is pharmaceutically acceptable
- pharmaceutically acceptable carriers are commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, Gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, stearic acid 2022/249120 1» (the 1'/182022/054947 includes magnesium and mineral oil, etc., but is not limited thereto.
- the pharmaceutical composition of the present invention includes cell signal transduction inhibitors, mitosis inhibitors, alkylat ing agents, ant metabolites, antibiotics (ant ibiot ics) ) , growth factor inhibitors , cell cycle inhibitors , topoisomerase inhibitors , biological reaction ion modifiers , anti hormonal agents), anti-androgen, cell differentiation/proliferation/survival inhibitors (cel l di fferent iat ion/prol i ferat ion/survival inhibitors), and apoptosis inducer 1 selected from the group consisting of It may additionally include more than one kind of drug, and when formulating the pharmaceutical composition of the present invention, it may be used in combination or combined formulation with the additionally included drugs.
- the pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) according to the desired method, and the dosage is dependent on the patient's condition and weight, disease It varies depending on the degree, drug form, administration route and time, but can be appropriately selected by those skilled in the art.
- the pharmaceutical composition of the present invention in addition to the benzoindolone compound represented by Formula 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate, exhibits the same or similar effect, or is used in combination to improve the medicinal effect. 2022/249120 1»(That 1'/182022/054947 It is also possible to further include one or more ingredients that can bring about synergy.
- the pharmaceutical composition of the present invention can be administered in a therapeutically effective amount.
- therapeutically effective amount means a moderate amount to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and severity of the patient's disease It may be determined according to activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, factors including concurrently used drugs, and other factors well known in the medical field. It can be administered as or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered single or multiple times. It is important to administer an amount that can be administered, which can be easily determined by those skilled in the art.
- the effective amount of the pharmaceutical composition of the present invention depends on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, and inactivity. It may vary depending on the rate and excretion rate, disease type, and concomitant drugs, generally about 0.01 to 3001 per 113 ⁇ 4 of body weight, more specifically about 0.1 to 1001 administered daily or every other day, or divided into 1 to 3 times a day However, since the dosage may increase or decrease depending on the route of administration, severity of obesity, sex, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
- the present invention provides the use of a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the preparation of a drug for preventing or treating cancer. Matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applied unless contradictory to each other, and other terms and abbreviations used herein have their original meanings unless otherwise defined.
- the present invention can provide a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
- the benzoindolone compound of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate can be usefully used for the prevention or treatment of cancer by inhibiting Myosho protein activity.
- Figure 1 is a view showing the experimental results confirming the palmitoylation inhibitory effect of the compounds according to an embodiment of the present invention.
- Step 2 Synthesis of Compound 1-1: Alkylation 1_iodobutane (1.27 mL, 1.12 mL , 1.12 mmol) was added dropwise at room temperature (10-35 ° C), and stirred at 80 ° C for 12 hours. Then, distilled water was added to the reaction mixture and the obtained solid was filtered. After washing the filtered solid twice with distilled water (50mL) and twice with nucleic acid (50mL), it was dried overnight in a vacuum oven at 60 °C. Thereafter, the target compound bll (1.76 g, 61%) was obtained as a yellow solid without further purification. 2022/249120 1»(That 1'/182022/054947 obtained.
- Step 3 Synthesis of Compound 0-1-1 3 ⁇ 401 to a mixture of dioxane/distilled water (4: 1 V8, 121111) and the 13-1-1 compound (30011 degree, 1.111—01) synthesized in step 2 above and zinc powder (3 ⁇ 4 ⁇ ) After adding dropwise, the mixture was stirred at room temperature for 3 hours. Thereafter, Celite A was spread and the reaction mixture was filtered while washing with distilled water (301) and ethyl acetate (301 series).
- Step 1 Compound Alkylation reaction via Suzuki (3 ⁇ 4) reaction
- Compound 3-1 (500113 ⁇ 4, 1.5311111101), 4 - (trifluoromethyl) phenylboric acid (4_ ( 1 or 0 6 1) 613 ⁇ 4, 11) 01, 0118 synthesized in step 1 of the synthesis example show_1: 301(1) (500!1degree, 3.05 1()1) ⁇ &g(0) 2 (278!!degree, 1 - 53
- a mixture of reel solvent (201 degree) was stirred for 2 hours at room temperature under argon ( ).
- Step 2 Synthesis of Compound 3 Using Compound 2-1 obtained above, Compound 3 was synthesized through substantially the same reactions as in Steps 3 and 4 described in Synthesis Example / 1.
- Compounds of Table 5 below in substantially the same manner as described in Synthesis Example Show-2, except that the compound of Table 4 was used instead of 4-(trifluoromethyl)phenylboric acid in step 1 of Synthesis Example Show-2. was synthesized.
- Step 2 Synthesis of Compound 42 Using Compound 3-1 obtained above, Compound 42 was synthesized through substantially the same reactions as in Steps 3 and 4 described in Synthesis Example Show-1.
- step 1 of Synthesis Example 3 3 ⁇ 4-) in Table 6 below was used as a compound corresponding to each target compound instead of cyclohexane bromide, in the same manner as described in Synthesis Example Show-3, except that Compounds of 7 were synthesized.
- the compounds in Table 9 were prepared in substantially the same manner as described in Synthesis Example / 4, except that 3 ⁇ 4-E in Table 8 was used instead of methacrylic acid in the production process of Synthesis Example Show-4.
- Step 4 is the Synthesis Example Compounds in Table 11 were synthesized in substantially the same manner as described above. However, when synthesizing compound 17, 46 3 ⁇ 4 or more of vinylsulfonyl chloride was added.
- Step 1 Synthesis of 1-butyl- 6- (piperazin- 1 -yl) benzo [0 (1] indol- 2 (13 ⁇ 4-one) After dissolving in 0.4, bis (2-chloroethyl) amine hydrochloride (0.081 ⁇ 4, 0.45 ⁇ 101) was added. Thereafter, the mixture was refluxed at 1501 and reacted for 24 hours. After completion of the reaction, the solution was cooled to room temperature, distilled water was added, and extraction was performed using methylene chloride.
- Step 2 Synthesis of Compound 81
- the 1-butyl-6-(piperazin-1-yl)benzo[0(1]indol-2(13 ⁇ 4-one synthesized in Step 1) was prepared in the same manner as in Step 4 of Synthesis Example 3.
- the final compound 81 was synthesized.
- the analysis results of the compounds of each example are shown in Table 12.
- the MCF-7 cell line injected to stably express the TEAD reporter gene that expresses firefly luciferase according to the activation of the TEAD response element (TRE) was developed by BPS bioscience 2022/249120 1»(G1'/182022/054947
- luciferase assay working solution ONE-Ste Georg Luciferase assay reagent; BPS bioscience
- a luciferase substrate was added to each well.
- Each was treated and placed on a shaker for 15 minutes to mix well. Thereafter, the degree of luminescence generated by the luciferase expressed upon activation of TEAD was measured using a microplate reader (TECAN).
- the relative activity of luciferase was calculated based on the luminescence level of the vehicle group (solvent treatment control group) as 100%, and the results are shown in Table 13 below.
- HEK-293T cells were transfected with pUAS-Luc, pCMV-SP0RT6_YAPl, and pCMX-Gal4_TEAI)l using OPTI-MEM (Gibco) medium and Lipofectamine® (Invitrogen), respectively, and then incubated at 37 ° C for 24 hours. It was cultured in a cell culture incubator maintained with 5% C3 ⁇ 4. After that, over 24 hours, 1% of DMS0 or each compound was added in an amount corresponding to lOuM, and after 24 hours of incubation, the cells were lysed, followed by a microplate reader (TECAN) using the Promega Luciferase® system. Luciferase activity was measured. Based on the luminescence level of the vehicle group (solvent treatment control group) as 100%, the relative activity of luciferase was calculated, and the results are shown in Table 14 below.
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Abstract
The present invention relates to a benzoindolone compound represented by chemical formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition comprising same.
Description
2022/249120 1»（그1’/182022/054947 2022/249120 1»（That 1’/182022/054947
【명세서】 【Specification】
【발명의 명칭】 신규한 벤조인돌론 화합물 및 이를 포함하는 약학적 조성물 【기술분야】 본 발명은 신규한 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물 및 이를 포함하는 약학적 조성물에 관한 것이다. [Title of the invention] Novel benzoindolone compound and pharmaceutical composition containing the same [Technical field] The present invention is a novel benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and It relates to a pharmaceutical composition comprising the same.
【배경기술】 히포 신호전달체계 (Hippo signal ing pathway)는 인체에서 정상 세포의 증식 및 피부， 근육， 폐， 간 등의 조직 및 장기들의 성장과 크기 등을 조절하는 주요 신호전달체계이다. 히포 신호전달체계는 정상 세포 또는 조직에서 종양억제인자 (tumor suppressor)로 알려져 있지만， 종양과 같은 질병에 관여하는 것으로 보고됨으로써 히포 신호전달체계가 암 발생과 성장에 중요한 역할을 한다는 것이 밝혀졌다. 또한 히포 신호전달체계는 ffnt , EGFR 또는 TGF-beta 신호전달체계 등과 같이 기존에 알려진 종양에 관여하는 다른 신호전달체계들과도 상호작용 (cross talk)하여， 인체 내 다양한 암종들에 있어서 히포 신호전달체계가 관여할 수 있다는 것이 보고되고 있다. 히포 신호전달체계는 MST-1/2, LATS-1/2로 구성된 키나아제 캐스케이드 (cascade)로부터 시작되어 전사활성 인자인 YAP 또는 TAZ 단백질을 인산화시켜 활성화된다. 히포 신호전달체계가 활성화되어 있지 않으면， 쇼 단백질은 인산화되지
2022/249120 1»（그1’/182022/054947 않아 세포질에서 핵 내로 이동하게 되며， 핵 내에 존재하는 TEA 도메인 (TEAD) 단백질들 (TEAD1，2,3 ,4)과 결합하여 CTGF, Cyr61 , FGF 1 등과 같이 세포의 증식에 관여하는 유전자들의 전사인자로 작용하여 이들의 발현을 유도한다. 반대로 히포 신호전달체계가 활성화되면， YAP 단백질이 인산화되고 인산화된 YAP 단백질은 세포질 내에서 유비퀴틴화되어 프로테아좀 (proteasome)에서 분해되거나， 종양억제인자인 VGLL4 단백질과 결합하여 핵 내로 이동하지 못하게 되므로， 결과적으로 TEAD 단백질들과 결합하지 못하게 되어 세포 성장에 관여하는 유전자들의 발현이 억제된다. 최근 보고에 의하면 다양한 종양과 같이 비정상적인 세포 증식을 일으키는 원인이， 히포 신호전달체계에 작용하는 관련 유전자들의 비정상적 발현으로 인해 히포 신호전달체계가 정상적으로 조절되지 않음에 있는 것으로 밝혀지고 있다 (Cel l 2011 Nov 11； 147(4)： 759-72， Fol ia Histochem Cytobiol . 2015； 53(2) : 105-119) . 특히， 예후가 좋지 않은 중피종 (mesothel ioma) 환자들에서 NF-2 단백질에 대한 유전적 변이에 의해 히포 신호전달체계의 활성화가 50% 정도 저해되는 것으로 보고되었다 (Trans 1 Lung Cancer Res . 2014; 3： 75-83， Cancer Res . 1995； 55： 1227-31) . 히포 신호전달체계가 비정상적으로 조절되어 세포 증식에 관여하는 유전자들의 과발현을 억제하기 위해서는 세포 핵 내에서 YAP 단백질과 TEAD 단백질들의 결합을 억제하는 것이 유일한 방법으로 알려져 있다. 이는， 히포 신호전달경로의 상위 단백질들인 MST-1/2 키나아제와 LATS-1/2 키나아제는 YAP 단백질을 인산화시켜 핵 내로의 이동을 억제하기 때문에， 이 키나아제들의 기능을 억제한다면 오히려 YAP 단백질의 인산화가 이루어지지 않아 YAP
2022/249120 1»（그1’/182022/054947 단백질들이 핵 내로 이동 후 TEAD 단백질들과 결합하여 유전자들의 과발현을 더욱 촉진시킬 수 있기 때문이다. 그리고 YAP 단백질들은 특정한 3차 구조가 없는 매우 유연한 구조를 지닌 단백질이기 때문에 치료 물질의 타겟이 되기 어려운 점이 있어 이러한 이유로 현재 TEAD 단백질들이 히포신호전달체계를 억제할 수 있는 유일한 타겟이 되고 있다. 뿐만 아니라， 최근 연구에 따르면 TEAD 단백질의 S-팔미토일화 자체가 TEAD 단백질의 안정성과 기능에 매우 필수적인 요소로 밝혀졌다 (Cel l Rep. 2020 Jun 23； 31(12)： 107809. ) . 이에 따라， TEAD 단백질들과 결합함으로써 YAP 단백질과 TEAD 단백질들 간의 결합을 방해하거나 또는 TEAD 단백질들의 기능을 저해하기 위한 다양한 방법들이 시도되고 있다. [Background Art] The Hippo signaling pathway is a major signaling pathway that regulates the proliferation of normal cells in the human body and the growth and size of tissues and organs such as skin, muscle, lung, and liver. Although the Hippo signaling system is known as a tumor suppressor in normal cells or tissues, it has been reported that it is involved in diseases such as tumors, revealing that the Hippo signaling system plays an important role in cancer development and growth. In addition, the Hippo signal transduction system interacts (cross talk) with other signal transduction systems involved in previously known tumors, such as ffnt, EGFR or TGF-beta signal transduction system, and Hippo signal transduction in various cancer types in the human body It has been reported that systems may be involved. The Hippo signaling system starts from a kinase cascade composed of MST-1/2 and LATS-1/2 and is activated by phosphorylating YAP or TAZ protein, which is a transcriptional activator. When the Hippo signaling system is not activated, the show protein is not phosphorylated. 2022/249120 1» (that 1'/182022/054947), moves from the cytoplasm to the nucleus, and binds to TEA domain (TEAD) proteins (TEAD1, 2, 3, 4) present in the nucleus to form CTGF, Cyr61, and FGF It acts as a transcription factor for genes involved in cell proliferation, such as 1, and induces their expression. Conversely, when the Hippo signaling system is activated, the YAP protein is phosphorylated, and the phosphorylated YAP protein is ubiquitinated in the cytoplasm and degraded in the proteasome, or binds to the VGLL4 protein, a tumor suppressor, and does not move into the nucleus. As a result, it is unable to bind with TEAD proteins, and the expression of genes involved in cell growth is suppressed. According to recent reports, it has been found that the cause of abnormal cell proliferation, such as in various tumors, is that the Hippo signaling pathway is not normally regulated due to abnormal expression of related genes acting on the Hippo signaling pathway (Cel l 2011 Nov 11; 147(4): 759-72, Folia Histochem Cytobiol.2015; 53(2): 105-119). In particular, it has been reported that activation of the hippo signaling pathway is inhibited by about 50% in mesotheloma patients with poor prognosis due to genetic mutations in NF-2 protein (Trans 1 Lung Cancer Res. 2014; 3 : 75-83, Cancer Res.1995; 55: 1227-31). Inhibiting the binding of YAP and TEAD proteins in the cell nucleus is known to be the only way to suppress the overexpression of genes involved in cell proliferation due to abnormal regulation of the Hippo signaling system. This is because MST-1/2 kinase and LATS-1/2 kinase, which are upper proteins of the Hippo signaling pathway, phosphorylate the YAP protein and inhibit its migration into the nucleus. is not done YAP 2022/249120 1»（That 1'/182022/054947 This is because proteins can move into the nucleus and combine with TEAD proteins to further promote overexpression of genes. In addition, since YAP proteins have a very flexible structure without a specific tertiary structure, they are difficult to target for therapeutic substances. For this reason, TEAD proteins are currently the only targets that can inhibit the Hippo signaling system. In addition, according to recent studies, S- palmitoylation of TEAD protein itself has been found to be a very essential factor for the stability and function of TEAD protein (Cel l Rep. 2020 Jun 23; 31(12): 107809. ). Accordingly, various methods for interfering with the binding between the YAP protein and the TEAD proteins or inhibiting the function of the TEAD proteins by binding to the TEAD proteins have been attempted.
TEAD1，2,3,4로 구성된 TEAD 단백질들은 서로 간의 아미노산 구성의 유사성이 70% 정도로 매우 높다. TEAD 단백질들은 모두 특정 시스테인기에 팔미테이트라는 지방산이 결합하여 팔미토일화라는 단백질 번역 후 변경 과정을 거치게 된다. 이러한 과정은 TEAD 단백질의 구조적 안정성을 향상시켜주거나， YAP 또는 TAZ 단백질들과의 결합을 촉진하여 유전자들을 발현시키는데 필요하다고 알려져 있다 (Chan, P. et al . Nat . Chem. Biol . (2016) 12： 282-289； No 1 and , C. L. et al . Structure (2016) 24: 179-186; Mesrouze, Y. et al . Protein Sci . (2017) 26： 2399-2409. ) 최근 TEAD 단백질들과 결합하는 YAP 단백질의 일부 부위를 모방한 펩타이드들이 연구되었지만， 이러한 펩타이드 물질들은 in vitro 실험상에서는 TEAD 단백질들과 강력한 결합력을 보임에도 불구하고 (Furet， P. et al . Bioorg. Med. Chem. Lett . (2019) 29： 2316-2319) , 부족한 세포 내 투과율과 생체 내
2022/249120 1»（그1’/182022/054947 불안정성 때문에 실질적인 치료제 개발로 진행되지 못하였다. 이러한 펩타이드의 문제점들을 해결하기 위해 세포 내 투과율과 안정성이 뛰어나고， YAP단백질이 TEAD 단백질들과 상호작용하는 인터페이스(interface)에 결합하는 저분자 화합물을 개발하려는 시도들도 있었으나 (Zhou,ff.et al.Anal.Biochem.(2019) 586： 113413),이러한 저분자 화합물들은 미약한 YAP-TEAD저해 효능 때문에 히포 신호전달체계 억제 치료 물질로 개발되지 못하였다. 현재까지의 연구결과들을 보면， TEAD 단백질에서 YAP 단백질과 직접적으로 결합하는 인터페이스를 저해하는 기전의 치료물질들을 개발하기 매우 어려운 것을 볼 수 있다. 이 난관을 해결하기 위해 최근에는 TEAD단백질들에서 팔미토일화 과정의 중요성이 부각되었고， 팔미테이트 지방산이 탄소 16개의 저분자 화합물인 점， 그리고 팔미토일화 사이트가 모든 TEAD 단백질들에서 굉장히 유사하다는 점이 알려지면서 TEAD 단백질의 팔미토일화 사이트에 결합하는 저분자 화합물을 개발하는 전략이 보고되고 있다. 플루페나믹산(flufenamic acid)을 포함한 다양한 저분자 화합물들이 TEAD의 팔미토일화를 억제할 수 있다는 것이 알려지고 있으며 (Pobbati, A. V. et al. Structure (2015) 23： 2076-2086)， 이런 저분자 화합물들이 TEAD의 팔미토일화를 억제함으로써 암세포의 증식을 억제하여 앞서 언급한 기존 물질들보다 강력한 효능을 나타낼 수 있음이 보고되고 있다. (Holden, J. K. et al.Cell Rep. (2020) 31:107809;Kaneda,A.et al.Am.J.Cancer Res. (2020) 10： 4399-4415.) 결론적으로 히포 신호전달체계는 암과 같이 과다 세포증식이 원인이 되는 질병에 중요하게 관여하는 신호전달체계이다. 히포 신호전달체계에 의한
2022/249120 1»（그1’/182022/054947 유전자 과발현을 억제하기 위해서는 신호전달체계 최하단에 위치한 TEAD 단백질들이 유일한 치료 타겟으로 제시되고 있다. 이에 따라 최근 TEAD 단백질들의 팔미토일화를 억제하여 히포 신호전달체계에 의한 유전자 과발현을 저해하는 저분자 화합물들이 개발되고 있다. TEAD proteins composed of TEAD1, 2, 3, and 4 have a very high amino acid composition similarity of about 70%. All TEAD proteins undergo a post-translational modification process called palmitoylation by binding a fatty acid called palmitate to a specific cysteine group. This process is known to improve the structural stability of TEAD protein or to promote binding to YAP or TAZ proteins to express genes (Chan, P. et al. Nat. Chem. Biol. (2016) 12 : 282-289; No 1 and , CL et al. Structure (2016) 24: 179-186; Mesrouze, Y. et al. Protein Sci. (2017) 26: 2399-2409.) Peptides that mimic some parts of the YAP protein have been studied, but these peptide materials show strong binding to TEAD proteins in in vitro experiments (Furet, P. et al. Bioorg. Med. Chem. Lett. (2019 ) 29: 2316-2319) , Poor intracellular permeability and in vivo 2022/249120 1»（That 1'/182022/054947 Due to instability, development of a practical treatment could not be progressed. In order to solve the problems of these peptides, there have been attempts to develop low-molecular compounds that have excellent intracellular permeability and stability and bind to the interface where YAP proteins interact with TEAD proteins (Zhou, ff. et al. Anal. Biochem. (2019) 586: 113413), these small molecule compounds were not developed as therapeutic substances for inhibiting the Hippo signaling pathway due to weak YAP-TEAD inhibitory effects. Looking at the research results so far, it can be seen that it is very difficult to develop therapeutic substances with a mechanism that inhibits the interface that directly binds to the YAP protein in the TEAD protein. To solve this difficulty, the importance of the palmitoylation process in TEAD proteins has recently been highlighted, and it is known that palmitate fatty acid is a low-molecular compound with 16 carbon atoms, and that the palmitoylation site is very similar in all TEAD proteins. As a result, a strategy to develop a small molecule compound that binds to the palmitoylation site of the TEAD protein has been reported. It is known that various small-molecular compounds, including flufenamic acid, can inhibit palmitoylation of TEAD (Pobbati, AV et al. Structure (2015) 23: 2076-2086), and these small-molecular compounds It has been reported that by inhibiting the palmitoylation of , it can inhibit the proliferation of cancer cells and exhibit stronger efficacy than the above-mentioned existing substances. (Holden, JK et al.Cell Rep. (2020) 31:107809; Kaneda, A. et al.Am.J.Cancer Res. (2020) 10: 4399-4415.) In conclusion, the Hippo signaling system is involved in cancer and It is a signal transduction system that is critically involved in diseases caused by excessive cell proliferation. by the hippo signaling system 2022/249120 1» (That 1'/182022/054947 TEAD proteins located at the bottom of the signal transduction system are suggested as the only therapeutic targets to suppress gene overexpression. Accordingly, recently, small-molecular compounds that inhibit palmitoylation of TEAD proteins to inhibit gene overexpression by the Hippo signaling pathway have been developed.
［선행기술문헌］ [Prior art literature]
［비특허문헌］ [Non-patent literature]
（비특허문헌 1） Cell 2011 Nov 11； 147（4）:759-72 （비특허문헌 2） Folia Histochem Cytobiol.2015； 53（2）:105-119 （비특허문헌 3）TranslLung Cancer Res.2014;3:75-83 （비특허문헌 4） Cancer Res.1995； 55： 1227-31 （비특허문헌 5） CellRep.2020 Jun 23； 31（12）:107809 （비특허문헌 6） Chan,P.et al.Nat.Chem.Biol.（2016） 12： 282-289 （비특허문헌 7） Noland,C.L.et al.Structure（2016） 24： 179-186 （비특허문헌 8）Mesrouze,Y.et al.Protein Sci.（2017）26： 2399-2409 （비특허문헌 9） Furet,P.et al.Bioorg.Med.Chem.Lett.（2019） 29: 2316-2319 (Non-Patent Document 1) Cell 2011 Nov 11; 147(4):759-72 (Non-Patent Document 2) Folia Histochem Cytobiol.2015; 53(2):105-119 (Non-Patent Document 3) Translung Cancer Res.2014 ;3:75-83 (Non-Patent Document 4) Cancer Res.1995; 55: 1227-31 (Non-Patent Document 5) CellRep.2020 Jun 23; 31(12):107809 (Non-Patent Document 6) Chan,P. et al.Nat.Chem.Biol. (2016) 12: 282-289 (Non-Patent Document 7) Noland, C.L. et al.Structure (2016) 24: 179-186 (Non-Patent Document 8) Mesrouze, Y. et al .Protein Sci. (2017) 26: 2399-2409 (Non-Patent Document 9) Furet, P. et al.Bioorg.Med.Chem.Lett. (2019) 29: 2316-2319
（비특허문헌 10）Zhou,ff.et al.Anal.Biochem.（2019） 586： 113413(Non-Patent Document 10) Zhou,ff.et al.Anal.Biochem.(2019) 586: 113413
（비특허문헌 11）Pobbati,A.V.et al.Structure（2015）23： 2076-2086(Non-Patent Document 11) Pobbati, A.V. et al. Structure (2015) 23: 2076-2086
（비특허문헌 12） Holden,J.K.et al.CellRep.（2020） 31： 107809(Non-Patent Document 12) Holden, J.K. et al. Cell Rep. (2020) 31: 107809
（비특허문헌 13）Kaneda,A.et al.Am.J.CancerRes.（2020）10:4399-(Non-Patent Document 13) Kaneda, A. et al. Am. J. Cancer Res. (2020) 10:4399-
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【발명의 상세한 설명】
2022/249120 1»（그1’/182022/054947 【Detailed description of the invention】 2022/249120 1»（That 1'/182022/054947
【기술적 과제】 본 발명은 지금까지 보고된 묘쇼 팔미토일화 억제 물질들과는 구조적으로 완전히 다르면서 팔미토일화를 억제하는 신규 묘쇼 저해 물질을 제시하며， 본 발명의 목적은 이 신규 물질을 이용해 항암제 등과 같이 히포 신호전달체계가 관여하는 질병들의 치료제를 개발하는 것이다 . 본 발명의 일 목적은 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 제공하는 것이다 . 본 발명의 또 다른 목적은 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 유효성분으로 포함하는 약학적 조성물을 제공하는 것이다. 본 발명의 또 다른 목적은 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 포함하는， 암의 예방 또는 치료를 위한 약학적 조성물을 제공하는 것이다 . 즉， 세포의 발생， 성장에 매우 중요한 신호체계 중 하나인 히포 시그널링의 신호전달체계의 최하위에 위치하여 세포의 발생 및 성장에 관여하는 유전자들의 발현을 조절하는 스위치 역할을 하는 묘쇼 단백질에 결합함으로써 단백질의 기능을 저해하고 유전자들의 발현을 억제하여 세포의 과다 증식으로 유발되는， 암의 예방 또는 치료를 위한， 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 포함하는 약학적 조성물을 제공하는 것이다 . 본 발명의 또 다른 목적은 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 치료학적으로
2022/249120 1»（그1’/182022/054947 유효한 양을 개체에 투여하는 것을 포함하는， 암의 예방 또는 치료 방법을 제공하는 것이다. 본 발명의 또 다른 목적은 암의 예방 또는 치료를 위한 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 용도를 제공하는 것이다. 본 발명의 또 다른 목적은 암의 예방 또는 치료용 약제의 제조를 위한 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 용도를 제공하는 것이다. [Technical Problem] The present invention proposes a novel myosho inhibitory substance that inhibits palmitoylation while structurally completely different from the myosho palmitoylation inhibitors reported so far, and the object of the present invention is to use this novel substance as an anticancer agent, etc. The goal is to develop treatments for diseases involving the hippo signaling system. One object of the present invention is to provide a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. Another object of the present invention is to provide a pharmaceutical composition comprising a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof as an active ingredient. Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer, including a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. That is, by binding to Myosho protein, which is located at the bottom of the signal transduction system of Hippo signaling, which is one of the very important signal systems for cell development and growth, and acts as a switch to regulate the expression of genes involved in cell development and growth, protein Benzoindolone compounds, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, for the prevention or treatment of cancer, which are caused by excessive proliferation of cells by inhibiting the function of and suppressing the expression of genes. It is to provide a pharmaceutical composition comprising. Another object of the present invention is to treat the benzoindolone compound, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate 2022/249120 1» (the 1'/182022/054947 It is to provide a method for preventing or treating cancer, comprising administering an effective amount to a subject. Another object of the present invention is to provide a use of a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the prevention or treatment of cancer. Another object of the present invention is to provide a use of a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the preparation of a drug for preventing or treating cancer.
【기술적 해결방법】 이하， 본 발명을 보다 구체적으로 설명한다. 본 발명에서 개시된 다양한 요소들의 모든 조합은 본 발명의 범주에 속한다. 또한， 하기의 구체적인 서술에 의해 본 발명의 범주가 제한된다고 볼 수 없다. 화학식 1로 나타내는 화합물 본 발명은 하기 (1) 내지 (4)의 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 제공한다. [Technical Solution] Hereinafter, the present invention will be described in more detail. All combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific description below. Compounds represented by Formula 1 The present invention provides benzoindolone compounds of the following (1) to (4), stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof.
(1) 하기 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물: (1) A benzoindolone compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof:
[화학식 1]
2022/249120 1»（그1’/182022/054947
[Formula 1] 2022/249120 1 » （G1'/182022/054947
*_］ᅴ1 -은 *_3(=0)2 -， 또는 *_(〕(=0)-이고，
* _ ] ᅴ 1 - is *_3 (= 0) 2 -, or * _ (] (= 0) -,
¾ 및 ¾가 서로 연결되어 과 함께 형성하는 고리는 적어도 1개 이상의 을 포함하는 4원 내지 8원의 헤테로사이클로알킬이고 ， 이때 상기 헤테로사이클로알킬의 II는 - =0)-01=抑 2로 치환될 수 있고， ¾ and ¾ are linked to each other to form a 4- to 8-membered heterocycloalkyl containing at least one or more, wherein II of the heterocycloalkyl is substituted with - =0)-01=抑2 can be,
¾의 1개 이상의 II는 각각 독립적으로 할로겐， -3알킬， ⑴ -01- 3알킬렌-예， - -3알킬렌- 간能 (이때， 묘4 및 ¾는 각각 독립적으로 -3알킬을 나타냄) 또는 -^( 알킬)로 치환될 수 있고， One or more II of ¾ are each independently halogen, -3alkyl, ⑴ -0 1 - 3alkylene-eg, -3alkylene-ganeunseong (wherein, mother 4 and ¾ are each independently -3alkyl It can be substituted with) or -^ (alkyl),
1¾는 II， -6알킬 또는 *斗2-¾이고， 1¾ is II, -6 alkyl or *斗2-¾,
*斗2 -는 단결합 또는 *_ -6알킬렌-이고， *斗2 - is a single bond or *_ - 6 alkylene-,
¾는 -6알큭시， ¾-1()사이클로알킬， ¾-6사이클로알케닐， 04-¾ is - 6 alkynx, ¾- 1 () cycloalkyl, ¾- 6 cycloalkenyl, 0 4 -
12바이사이클로알킬， - 2아릴， 또는 0를 포함하는 5-6원 헤테로사이클로알킬，
12 bicycloalkyl, -2 aryl, or 5-6 membered heterocycloalkyl including 0,
¾의 1개 이상의 II는 각각 독립적으로 -6알킬， -6알큭시， 페녹시
2022/249120 1»（그1’/182022/054947 할로겐
치환될 수 있고， 이 0(=0) 또는 =0)2이고， ¾는 -3알킬인 경우， ¾는 II 또는 12One or more II of ¾ are each independently - 6 alkyl, - 6 alkoxy, phenoxy 2022/249120 1»（H1’/182022/054947 Halogen May be substituted, is 0 (=0) or =0) 2 , ¾ is -3 alkyl, ¾ is II or 12
¾ 이고， ¾, and
1¾이 -6알킬인 경우， ¾ 및
서로 연결되어 과 함께 고리를 형성하거나，
-抑 =대2, º抑， 또는 - =0)-01=抑 2이고， 할로겐은 01, 먀 또는 I이며， When 1¾ is -6 alkyl, ¾ and Connected to each other to form a ring with, or -抑 = large 2, º抑, or - =0) -01 = 抑 2, halogen is 01, mya or I,
¾，
동시에 II는 아니다. ¾， At the same time not II.
(2)상기 (1)에 따른 화학식 1에서，
서로 연결되어 과 함께 고리를 형성하고，
(2) In Formula 1 according to (1) above, Connected to each other to form a ring with,
¾의 1개 이상의 II는 각각 독립적으로 -3알킬， ⑴ - -3알킬렌- 011， - -3알킬렌- 간能 (이때， 묘4 및 ¾는 각각 독립적으로 -3알킬을 나타냄) 또는 ^-(^-3알킬)로 치환될 수 있고， One or more II of ¾ is each independently -3 alkyl, ⑴ - -3 alkylene- 011, - -3 alkylene- liver function (wherein, the mother 4 and ¾ each independently represent -3 alkyl) or ^ -(^- 3 alkyl) may be substituted,
¾ 및 1¾가 서로 연결되어 과 함께 형성하는 고리는 피페라진일이고， 이때 상기 피페라진일의 II는 (=0)-01=抑 2 로 치환될 수 있고， The ring formed by linking ¾ and 1¾ with is piperazinyl, wherein II of the piperazinyl may be substituted with (=0)-01=抑2 ,
¾는 II， -6알킬 또는 에 ¾이고， ¾ is II, - 6 alkyl or ¾,
*- -는 단결합 또는 *- -6알킬렌-이고，
2022/249120 1»（그1’/182022/054947 *- - is a single bond or *- - 6 alkylene-, 2022/249120 1»（That 1'/182022/054947
¾는 01-6알큭시 - 사이클로알킬， ¾-6사이클로알케닐， 0¾ is 01-6 alkynx - cycloalkyl, ¾- 6 cycloalkenyl, 0
12바이사이클로알킬， 페닐 바이페닐 테트라하이드로퓨란일， 테트라하이드로피란일， 피롤리딘일 於^
12 bicycloalkyl, phenyl biphenyl tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl 於^
¾의 1개 이상의 II는 각각 독립적으로 -6알킬， -6알큭시， 페녹시， ?One or more II of ¾ is each independently - 6 alkyl, - 6 alkoxy, phenoxy, ?
01,
치환될 수 있고 이 0(=0) 또는 =0)2이고， ¾는 -3알킬인 경우， ¾는 II 또는 斗2 -01, It can be substituted and is 0 (=0) or =0) 2 , ¾ is - 3 alkyl, ¾ is II or 斗2 -
¾ 이고 ¾ and
1¾이 -6알킬인 경우， ¾ 및
서로 연결되어 과 함께 고리 형성하거나， 또는 의 ¾는
-抑 =대2， º抑， 또는 -0(=0) 대=抑 2이고， When 1¾ is -6 alkyl, ¾ and Linked to each other to form a ring with, or ¾ of -抑 = versus 2, º抑, or -0 (=0) versus = 抑 2,
¾，
동시에 II가 아닌， 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물. ¾， At the same time, other than II, the benzoindolone compound represented by Formula 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate.
(3) 상기 (1) 또는 (2)에 따른 화학식 1에서， (3) In Formula 1 according to (1) or (2) above,
¾은 II이고，
¾ is II,
*- _은 * (=0)2 - 또는 *- =0) -이고， ¾는 -대=抑 2이고， ¾의 1개 이상의 II는 각각 독립적으로 -3알킬로 치환될 수 있고，
*斗2 -는 단결합 또는 *- -6알킬렌-이고， *- _이 * (=0)2 -인 경우， ¾는 페닐 또는 바이페닐이되， 페닐 또는
2022/249120 1»（그1’/182022/054947
6알큭시， ¾-1()사이클로알킬 또는 페닐의 1개 이상의 II는 01 , 먀 또는
치환될 수 있는 것인， 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물. 일 실시예에서， 상기 화학식 1에서， ¾ 및
연결되어 과 함께 고리를 형성하는 치환기를 포함하는 화합물은 하기 화학식 로 나타낼 수 있다. *- _ is * (=0) 2 - or *- = 0) -, ¾ is -to = 抑2 , and one or more II of ¾ can be independently substituted with -3 alkyl, *斗2 - is a single bond or *- -6alkylene-, and *- _ is * (=0) 2 -, ¾ is phenyl or biphenyl, phenyl or 2022/249120 1»（That 1'/182022/054947 6 alkoxy, ¾- 1 () cycloalkyl or one or more II of phenyl is 01, mya or A benzoindolone compound represented by Formula 1, which may be substituted, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. In one embodiment, in Formula 1, ¾ and A compound including a substituent connected to form a ring with can be represented by the following formula
［화학식 1
내지 8원의 헤테로사이클로알킬， 보다 구체적으로 2개의 을 포함하는 4원 내지 8원의 헤테로사이클로알킬일 수 있다. 예를 들어
피페라진일을 포함할 수
2022/249120 1»（그1’/182022/054947 있다. 상기 CH 의 II가 -^=0）-01=抑 2 로 치환되는 경우 하기 화학식 와 와 같이 나타낼 수 있다. [Formula 1 to 8-membered heterocycloalkyl, more specifically, it may be a 4- to 8-membered heterocycloalkyl including two. for example May contain piperazinyl 2022/249120 1»（There is that 1'/182022/054947. When II of CH is substituted with -^=0)-01=抑2 , it can be represented as shown in the following formula.
[화학식 113 ]
이 때 상기 화학식 lb에서의 R3는 화학식 1에서 정의한 바와 동일하다. 본 발명에서， 작용기의 "Cx"의 표시에서 는 탄소（C）의 개수를 나타내고， "己-/는 탄소 수 X 이상 y 이하의 정수를 의미하는 것으로 한다. 본 발명에서， 용어 n치환된"은 주쇄의 하나 이상의 탄소상의 수소를 대체하는 치환기를 갖는 부분을 나타낸다. n치환” 또는 "〜로 치환된"은 이러한 치환이 치환된 원자 및 치환체의 허용되는 가에 따르며， 치환에 의해 안정한 화합물 예를 들어， 재배열， 고리화， 제거 등에 의해 자연적으로 변형되지 않는 화합물을 유도한다는 암묵적 조건을 포함하는 것으로 정의한다. 본 발명에서， n단결합"은 인접하는 원자 또는 원자단끼리 직접 결합하고 있는 경우를 의미한다. 본 발명에서， ''알킬''은 다른 언급이 없으면 선형（또는 직쇄형， l inear） 포화탄화수소기 또는 분지형（또는 측쇄형， branched） 포화탄화수소기를 의미하는 것으로， 메틸， 에틸， n-프로필， 이소프로필， n-부틸， sec-부틸， 이소부틸， tert- 부틸， n-펜틸， n-핵실 및 n-혭틸 등으로부터 선택되는 1종 이상일 수 있으나 이에 한정하지 않는다.
2022/249120 1»（그1’/182022/054947 본 발명에서 ”알킬렌”은 다른 언급이 없으면 상기와 같이 정의된 알킬로부터 유도된 2가의 작용기를 의미하는 것이다. 본 발명에서 ”알케닐"은 다른 언급이 없으면 탄소 사이의 적어도 1개의 이중결합을 포함하는 불포화탄화수소기를 의미하는 것이다. 본 발명에서 ”알키닐"은 다른 언급이 없으면 탄소 사이의 적어도 1개의 삼중결합을 포함하는 불포화탄화수소기를 의미하는 것이다. 본 발명에서 "할로겐”은 다른 언급이 없으면 01 , 먀 또는 I를 의미하는 것이다. 본 발명에서 ”아릴"은 다른 언급이 없으면 일환 방향족 또는 다환 방향족을 포함하는 것으로， 페닐， 바이페닐 및 나프탈렌일 등으로부터 선택되는 1종 이상일 수 있으나， 이에 한정하지 않는다. 본 발명에서 ”헤테로아릴"은 상기 아릴기에서 적어도 1개 이상의 탄소원자가 질소 )， 산소 (0) 또는 황比)으로 치환된 일환 또는 다환의 헤테로 고리를 의미하는 것이다. 헤테로아릴은 피리딘일， 티오펜일， 트리아졸일， 테트라졸일， 벤조티아졸일， 벤조티오펜일， 퀴놀린일， 인돌일， 이소인돌일， 벤조퓨란일， 벤조피롤일， 퓨란일， 피롤일， 티아졸일， 이소티아졸일， 이미다졸일， 피라졸일， 옥사졸일， 이소옥사졸일， 피라진일， 피리다진일， 피리미딘일， 이소퀴놀린일， 벤조옥사졸일， 벤조이미다졸일， 디하이드로벤조티오펜일， 퓨린일， 인돌리진일 및 크로멘일 등으로부터 선택되는 1종 이상일 수 있으나， 이에 한정하지 않는다 . 본 발명에서 "사이클로알킬 ”은 고리를 포함하는 3개 이상의 명시된 탄소원자를 갖는 포화탄화수소 고리를 의미하며 포화탄화수소 고리는 일환 및
2022/249120 1»（그1’/182022/054947 다환 고리 구조를 모두 포함하는 의미이며， 사이클로펜틸， 사이클로핵실， 사이클로헵틸 및 사이클로옥틸 등으로부터 선택되는 1종 이상일 수 있으나， 이에 한정하지 않는다 . 본 발명에서 "바이사이클로알킬 ”은 고리를 포함하는 3개 이상의 명시된 탄소원자를 일반적으로 갖는 포화탄화수소 고리의 2개 이상의 고리가 한쌍 이상의 탄소원자를 공유하고 있는 고리 구조를 의미하며
로부터 선택되는 1종 이상일 수 있으나， 이에 한정하지 않는다. 본 발명에서 ”사이클로알케닐"은 사이클로알킬 고리 정점 사이에 적어도 하나의 이중 결합을 지닌 구조를 의미하며， 사이클로프로페닐， 사이클로부테닐， 사이클로펜테닐， 사이클로핵세닐， 사이클로헵테닐 및 사이클로옥테닐 등으로부터 선택되는 1종 이상일 수 있으나， 이에 한정하지 않는다. 본 발명에서， ”헤테로사이클로알킬"은 질소 )， 산소 (0) 및 황比)으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 함유하는 포화된 일환 및 다환의 헤테로 고리 또는 2개 이상의 고리가 한쌍 이상의 탄소원자를 공유하고 있는 고리 구조를 의미한다. 헤테로사이클로알킬은 옥시란일， 옥세탄일， 모포린일， 피롤리딘일， 피페리딘일， 피페라진일， 테트라하이드로퓨란일， 테트라하이드로티오펜일， 테트라하이드로피란일 및 테트라하이드로티오피란일 등으로부터 선택되는 1종 이상일 수 있으나， 이에 한정하지 않는다. [Formula 113] In this case, R3 in the above formula 1b is the same as defined in formula 1. In the present invention, the expression "C x " of the functional group represents the number of carbons (C), and "己-/" means an integer of more than X and less than y of carbon atoms. In the present invention, the term n substituted " represents a moiety having a substituent replacing hydrogen on one or more carbons of the main chain. Substitution n ” or “substituted with ” depends on whether such substitution is allowed by the substituted atom and substituent, and is a compound that is stable by substitution, for example, a compound that is not naturally transformed by rearrangement, cyclization, elimination, etc. It is defined as including the implicit condition that induces In the present invention, "n single bond" means a case in which adjacent atoms or atomic groups are directly bonded. In the present invention, ''alkyl'' is a linear (or straight-chain, linear) saturated hydrocarbon group unless otherwise specified. Or a branched (or side chain, branched) saturated hydrocarbon group, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl And it may be one or more selected from n- pentyl, etc., but is not limited thereto. 2022/249120 1» (That 1'/182022/054947 In the present invention, "alkylene" means a divalent functional group derived from alkyl as defined above unless otherwise specified. In the present invention, "alkenyl" refers to an unsaturated hydrocarbon group containing at least one double bond between carbons unless otherwise specified. In the present invention, "alkynyl" refers to at least one triple bond between carbons unless otherwise specified. It means an unsaturated hydrocarbon group containing. In the present invention, "halogen" means 01 , mya, or I unless otherwise specified. In the present invention, "aryl" includes monoaromatic or polycyclic aromatics, phenyl, biphenyl, naphthalenyl, etc., unless otherwise specified. It may be one or more selected from, but is not limited thereto. In the present invention, "heteroaryl" refers to a monocyclic or polycyclic heterocyclic ring in which at least one carbon atom in the aryl group is substituted with nitrogen ), oxygen (0) or sulfur. Heteroaryl is pyridinyl, t Ofenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrroyl, furanyl, pyrroleyl, thiazolyl, isothiazolyl, already Dazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzooxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl And it may be one or more selected from chromenyl, etc., but is not limited thereto. In the present invention, "cycloalkyl" means a saturated hydrocarbon ring having 3 or more specified carbon atoms including a ring, and the saturated hydrocarbon ring is a monocyclic and 2022/249120 1» (that 1'/182022/054947 means including all polycyclic ring structures, and may be one or more selected from cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, but is not limited thereto. In the present invention, "bicycloalkyl" means a ring structure in which two or more rings of a saturated hydrocarbon ring, usually having at least three specified carbon atoms containing the ring, share at least one pair of carbon atoms, and It may be one or more selected from, but is not limited thereto. In the present invention, "cycloalkenyl" means a structure having at least one double bond between cycloalkyl ring vertices, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl It may be one or more selected from, but is not limited to, etc. In the present invention, "heterocycloalkyl" is a saturated containing 1 to 4 heteroatoms independently selected from nitrogen), oxygen (0) and sulfur) monocyclic and polycyclic heterocycles or ring structures in which two or more rings share at least one pair of carbon atoms. Heterocycloalkyl is oxiranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl and tetrahydrothiopyranyl, etc. It may be one or more selected from, but is not limited thereto.
(4) 상기 (1)， (2) 또는 (3)에 따른 화학식 1로 나타내는 벤조인돌론 화합물은 하기 표 1에 나타낸 화합물들로 이루어진 군으로부터 선택되는 1종
2022/249120 1»（그1’/182022/054947 이상인 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물: (4) The benzoindolone compound represented by Formula 1 according to (1), (2) or (3) is one selected from the group consisting of compounds shown in Table 1 below. 2022/249120 1» (the 1'/182022/054947 or higher benzoindolone compound represented by Formula 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate:
【표 1】
2022/249120 1^(:1^ 2022/054947
2022/249120 1^(:1^ 2022/054947
2022/249120 1^(:1^2022/054947
2022/249120 1^(:1^2022/054947
2022/249120 1^(:1^2022/054947
2022/249120 1^(:1^ 2022/054947
2022/249120 1^(:1^2022/054947
2022/249120 1^(:1^ 2022/054947
2022/249120 1^(:1^ 2022/054947
2022/249120 1^(:1^2022/054947
2022/249120 1^(:1^2022/054947
2022/249120 1^(:1^2022/054947
2022/249120 1»（그1’/182022/054947 본 발명에서， n입체 이성질체"는 부분입체 이성질체 (diastereomer) 및 광학 이성질체 (opt ical isomer)를 포함하는 것으로， 광학이성질체는 거울상 이성질체 (enant iomer)뿐만 아니라 거울상 이성질체의 혼합물 및 라세미체까지 모두 포함한다. 본 발명에서， "약학적으로 허용가능한 염 ”은 의약업계에서 통상적으로 사용되는 염을 의미하며， 예를 들어 칼슘， 포타슘， 소듐 또는 마그네슘 등으로 제조된 무기이온염 ; 염산， 질산， 인산， 브롬산， 요오드산， 과염소산 또는 황산 등으로 제조된 무기산염 ; 아세트산， 트라이플루오로아세트산， 시트르산， 말레인산， 숙신산， 옥살산， 벤조산， 타르타르산， 푸마르산， 만데르산， 프로피온산， 젖산， 글리콜산， 글루콘산， 갈락투론산， 글루탐산， 글루타르산， 글루쿠론산， 아스파르트산， 아스코르브산， 카본산 또는 바닐릭산 등으로 제조된 유기산염 ; 메탄설폰산， 에탄설폰산， 벤젠설폰산， p_톨루엔설폰산 또는 나프탈렌설폰산 등으로 제조된 설폰산염 ; 글리신， 아르기닌 또는 라이신 등으로 제조된 아미노산염 ; 및 트라이메틸아민， 트라이에틸아민， 암모니아， 피리딘 또는 피콜린 등으로 제조된 아민염 등이 있으나， 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. 본 발명의 "수화물”은 벤조인돌론 화합물， 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염과 물이 비공유적 분자간 힘으로 결합되어 있는 것으로 화학양론적 또는 비화학양론적의 양의 물을 포함하는 것일 수 있다. 구체적으로는， 상기 수화물은 활성성분 1몰을 기준으로 물을 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며， 보다 구체적으로는 약 0.5몰， 약 1몰， 약 1.5몰，
2022/249120 1»（그1’/182022/054947 약 2몰， 약 2.5몰， 약 3몰， 약 5몰 등으로 포함할 수 있다. 본 발명의 ”용매화물 ”은 벤조인돌론 화합물， 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염과 물이 아닌 용매가 분자간 힘으로 결합되어 있는 것으로， 용매를 화학양론적 또는 비화학양론적 양으로 포함할 수 있다. 구체적으로는， 상기 용매화물은 활성성분 1몰을 기준으로 용매분자를 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며， 보다 구체적으로는 약 0.5몰， 약 1몰， 약 1.5몰， 약 2몰， 약 2.5몰， 약 3몰， 약 5몰 등으로 포함할 수 있다. 벤조인돌론 화합물을 포함하는 약학적 조성물 및 이의 용도 본 발명은 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 유효성분으로 포함하는， 약학적 조성물을 제공한다. 본 발명의 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물은 암을 예방 또는 치료할 수 있다. 즉， 본 발명은 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다. 상기 암은 폐암， 위암， 난소암， 전립선암， 식도암， 위장암， 췌장암， 결장직장암， 결장암， 신장암， 고환암， 방광암， 유방암， 자궁암， 자궁경부암， 두경부암， 혈액암， 뼈암， 간암， 갑상선암， 부갑상선암， 피부암， 림프종， 중피종， 백혈병， 골수종， 육종 및 바이러스 관련 암 등으로부터 선택되는 1종 이상일 수
2022/249120 1»（그1’/182022/054947 있으나 이에 한정하지 않는다. 상기 바이러스 관련 암은 비인두암， 질암， 외음부암， 음경암， 카포시육종， 버킷 림프종， 세포 림프종 및 메르켈 세포암 등으로부터 선택되는 1종 이상일 수 있으나 이에 한정하지 않는다. 본 발명은 암의 예방 또는 치료를 위한 본 발명의 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 용도를 제공한다. 또한 본 발명은 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 치료학적으로 유효한 양을 개체에게 투여하는 것을 포함하는， 암의 예방 또는 치료 방법을 제공한다. 본 발명에서 사용되는 용어 ”예방”이란 본 발명에 따른 화합물의 투여에 의해 묘쇼 단백질 관련 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다. 본 발명에서 사용되는 용어 ”치료"란 본 발명에 따른 화합물의 투여에 의해 묘쇼 단백질 관련 질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다. 본 발명의 약학적 조성물은 약학적으로 허용되는 담체를 추가로 포함할 수 있다. 이때， 약학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서， 락토오스， 텍스트로오스， 수크로오스， 솔비톨， 만니톨， 전분， 아카시아고무， 인산 칼슘， 알기네이트， 젤라틴， 규산 칼슘， 미세 결정성 셀룰로오스， 폴리비닐피롤리돈， 셀룰로오스， 물， 시럽， 메틸 셀룰로오스， 메틸히드록시벤조에이트， 프로필 히드록시벤조에이트 ， 활석， 스테아르산
2022/249120 1»（그1’/182022/054947 마그네슘 및 미네랄 오일 등을 포함하나， 이에 한정되는 것은 아니다. 또한， 상기 성분들 이외에 윤활제， 습윤제， 감미제， 향미제， 유화제， 현탁제， 보존제 등을 추가로 포함할 수 있다. 또한， 본 발병의 약학적 조성물은 세포신호전달 억제제 (cel l signal transduct ion inhibitors) , 유사분열 저해제 (mitosis inhibitors) , 알킬화제 (alkylat ing agents) , 대사길항제 (ant metabol ites) , 항생제 (ant ibiot ics) , 성장인자 저해제 (growth factor inhibitors) , 세포주기 저해제 (cel l cycle inhibitors) , 토포이소머라아제 저해제 (topoisomerase inhibitors) , 생물학적 반응조절제 (biological react ion modi f iers) , 항호르몬제 (ant i hormonal agents) , 항안드로겐제 (ant i androgen) , 세포 분화/증식/생존 저해제 (cel l di fferent iat ion/prol i ferat ion/survival inhibitors) 및 세포자살 유도제 (apoptosis inducer)로 이루어진 군으로부터 선택되는 1종 이상의 약제를 추가적으로 포함할 수 있으며， 본 발명의 약학적 조성물을 제제화 하는 경우에는 상기 추가적으로 포함되는 약제와 병용하거나 또는 복합 제제화할 수 있다. 본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여 (예를 들어， 정맥 내， 피하， 복강 내 또는 국소에 적용)할 수 있으며， 투여량은 환자의 상태 및 체중， 질병의 정도， 약물형태， 투여경로 및 시간에 따라 다르지만， 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 상기 약학적 조성물은 상기 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물 외에 동일 또는 유사한 효과를 나타내거나 병용하여 약효에
2022/249120 1»（그1’/182022/054947 시너지를 가져올 수 있는 성분을 1종 이상 더 포함하는 것도 가능하다. 본 발명의 약학적 조성물은 치료학적으로 유효한 양으로 투여할 수 있다. 본 발명에 있어서， ”치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 중분한 양을 의미하며， 유효용량 수준은 환자의 질환의 종류， 중증도， 약물의 활성， 약물에 대한 민감도， 투여 시간， 투여 경로 및 배출 비율， 치료 기간， 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며， 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며， 이는 당업자에 의해 용이하게 결정될 수 있다. 구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령， 성별， 상태， 체중， 체내에 활성 성분의 흡수도， 불활성률 및 배설속도， 질병 종류， 병용되는 약물에 따라 달라질 수 있으며， 일반적으로는 체중 11¾ 당 약 0.01 내지 3001 ， 보다 구체적으로는 약 0.1 내지 1001 을 매일 또는 격일 투여하거나， 1일 1 내지 3 회로 나누어 투여할 수 있다. 그러나 투여 경로， 비만의 중증도， 성별， 체중， 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다. 본 발명에서 "개체"란 질병의 예방 또는 치료가 있어야 하는 대상을 의미하고， 보다 구체적으로는， 인간， 원숭이， 생쥐細0배6）， 개， 고양이， 말， 소
2022/249120 1»（그1’/182022/054947 등의 포유류를 의미할 수 있으나， 여기에 한정되는 것은 아니다. 또한 본 발명은 암의 예방 또는 치료용 약제의 제조를 위한 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 용도를 제공한다. 본 발명의 용도， 조성물， 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용되며， 이 밖에 본 명세서에서 사용된 용어들과 약어들은 달리 정의되지 않는 한 그 본래의 의미를 갖는다. 【Table 1】 2022/249120 1^(:1^ 2022/054947 2022/249120 1^(:1^ 2022/054947 2022/249120 1^(:1^2022/054947 2022/249120 1^(:1^2022/054947 2022/249120 1^(:1^2022/054947 2022/249120 1^(:1^ 2022/054947 2022/249120 1^(:1^2022/054947 2022/249120 1^(:1^ 2022/054947 2022/249120 1^(:1^ 2022/054947 2022/249120 1^(:1^2022/054947 2022/249120 1^(:1^2022/054947 2022/249120 1^(:1^2022/054947 2022/249120 1 » (that 1'/182022/054947 In the present invention, " n stereoisomer" includes diastereomers and optical isomers, and optical isomers are enantiomers) In addition, it includes both mixtures and racemates of enantiomers.In the present invention, "pharmaceutically acceptable salt" means a salt commonly used in the pharmaceutical industry, for example, calcium, potassium, sodium or magnesium Inorganic ion salts prepared with the like; Inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid or sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid organic acid salts made of acid, ascorbic acid, carbonic acid or vanillic acid; sulfonic acid salts made of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p_toluenesulfonic acid or naphthalenesulfonic acid; Amino acid salts made of glycine, arginine or lysine; and amine salts made of trimethylamine, triethylamine, ammonia, pyridine or picoline, etc., but the types of salts meant in the present invention are not limited by these listed salts. The "hydrate" of the present invention is a benzoindolone compound, its stereoisomer or its pharmaceutically acceptable salt and water are bound by non-covalent intermolecular forces, containing a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may include water in a ratio of about 0.25 to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, 2022/249120 1 » (that 1'/182022/054947 about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc.). The "solvate" of the present invention is a benzoindolone compound, its stereoisomer or its pharmaceutically acceptable salt and a solvent other than water are bound by intermolecular forces, the solvent in a stoichiometric or non-stoichiometric amount can include Specifically, the solvate may include solvent molecules in a ratio of about 0.25 to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, and about 2 mole. , about 2.5 moles, about 3 moles, about 5 moles, etc. A pharmaceutical composition containing a benzoindolone compound and its use The present invention is a pharmaceutical composition comprising a benzoindolone compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof as an active ingredient. It provides an enemy composition. The benzoindolone compound represented by Formula 1 of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate can prevent or treat cancer. That is, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a benzoindolone compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof as an active ingredient. The cancers include lung cancer, stomach cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, head and neck cancer, blood cancer, bone cancer, liver cancer, and thyroid cancer. , parathyroid cancer, skin cancer, lymphoma, mesothelioma, leukemia, myeloma, sarcoma, and one or more selected from virus-related cancers, etc. 2022/249120 1»（That 1'/182022/054947 but not limited thereto. The virus-related cancer may be at least one selected from nasopharyngeal cancer, vaginal cancer, vulvar cancer, penile cancer, Kaposi's sarcoma, Burkitt's lymphoma, cellular lymphoma, and Merkel cell cancer, but is not limited thereto. The present invention provides the use of the benzoindolone compound, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate for the prevention or treatment of cancer. In addition, the present invention provides a method for preventing or treating cancer, comprising administering to a subject a therapeutically effective amount of a benzoindolone compound, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate. . The term "prevention" as used herein refers to any activity that suppresses or delays the onset of Myosho protein-related diseases by administration of the compound according to the present invention. As used herein, the term "treatment" refers to all activities that improve or beneficially change the symptoms of Myosho protein-related diseases by administration of the compound according to the present invention. The pharmaceutical composition of the present invention is pharmaceutically acceptable In this case, pharmaceutically acceptable carriers are commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, Gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, stearic acid 2022/249120 1» (the 1'/182022/054947 includes magnesium and mineral oil, etc., but is not limited thereto. In addition to the above components, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like may be further included. In addition, the pharmaceutical composition of the present invention includes cell signal transduction inhibitors, mitosis inhibitors, alkylat ing agents, ant metabolites, antibiotics (ant ibiot ics) ) , growth factor inhibitors , cell cycle inhibitors , topoisomerase inhibitors , biological reaction ion modifiers , anti hormonal agents), anti-androgen, cell differentiation/proliferation/survival inhibitors (cel l di fferent iat ion/prol i ferat ion/survival inhibitors), and apoptosis inducer 1 selected from the group consisting of It may additionally include more than one kind of drug, and when formulating the pharmaceutical composition of the present invention, it may be used in combination or combined formulation with the additionally included drugs. The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) according to the desired method, and the dosage is dependent on the patient's condition and weight, disease It varies depending on the degree, drug form, administration route and time, but can be appropriately selected by those skilled in the art. The pharmaceutical composition of the present invention, in addition to the benzoindolone compound represented by Formula 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate, exhibits the same or similar effect, or is used in combination to improve the medicinal effect. 2022/249120 1»（That 1'/182022/054947 It is also possible to further include one or more ingredients that can bring about synergy. The pharmaceutical composition of the present invention can be administered in a therapeutically effective amount. In the present invention, "therapeutically effective amount" means a moderate amount to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and severity of the patient's disease It may be determined according to activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, factors including concurrently used drugs, and other factors well known in the medical field. It can be administered as or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered single or multiple times. It is important to administer an amount that can be administered, which can be easily determined by those skilled in the art. Specifically, the effective amount of the pharmaceutical composition of the present invention depends on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, and inactivity. It may vary depending on the rate and excretion rate, disease type, and concomitant drugs, generally about 0.01 to 3001 per 11¾ of body weight, more specifically about 0.1 to 1001 administered daily or every other day, or divided into 1 to 3 times a day However, since the dosage may increase or decrease depending on the route of administration, severity of obesity, sex, weight, age, etc., the dosage is not limited to the scope of the present invention in any way. It means a subject that needs to be prevented or treated, and more specifically, humans, monkeys, mice 0x6), dogs, cats, horses, cows 2022/249120 1» (That 1'/182022/054947 may mean mammals such as, but is not limited thereto. In addition, the present invention provides the use of a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the preparation of a drug for preventing or treating cancer. Matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applied unless contradictory to each other, and other terms and abbreviations used herein have their original meanings unless otherwise defined.
【발명의 효과】 본 발명은 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 제공할 수 있다. 본 발명의 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물은 묘쇼 단백질 활성을 억제함으로써 암의 예방 또는 치료에 유용하게 이용될 수 있다. [Effects of the Invention] The present invention can provide a benzoindolone compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The benzoindolone compound of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate can be usefully used for the prevention or treatment of cancer by inhibiting Myosho protein activity.
【도면의 간단한 설명】 도 1은 본 발명의 실시예에 따른 화합물들의 팔미토일화 억제 효과를 확인한 실험 결과를 나타낸 도면이다. [Brief description of the drawings] Figure 1 is a view showing the experimental results confirming the palmitoylation inhibitory effect of the compounds according to an embodiment of the present invention.
【발명의 실시를 위한 최선의 형태】 이하， 본 발명을 제조예 및 실시예를 이용하여 더욱 상세하게 설명한다. 그러나 하기 제조예 및 실시예는 본 발명을 예시하기 위한 것으로서 본 발명은 하기 제조예 및 실시예에 의해 한정되는 것은 아니다. [Best Mode for Carrying Out the Invention] Hereinafter, the present invention will be described in more detail using manufacturing examples and examples. However, the following Preparation Examples and Examples are intended to illustrate the present invention, and the present invention is not limited by the following Preparation Examples and Examples.
＜제조예＞
2022/249120 1»（그1’/182022/054947 본 발명에 따른 화합물들 각각을 후술하는 방법으로 합성하였으며， 이하의 구체적인 합성방법을 조합하여 도출되는 당업자에게 통상적인 방법을 이용할 수 있다. 합성에 사용한 각각의 화합물들은 외부업체에서 구입하거나 당업자에게 자명한 유기합성방법을 이용하여 합성하였으며， 별도의 정제 과정 없이 사용하였다. 각 실시예의 화합물은 40（ ¾ ¾ -·묘 （쇼 삵사， 400^） , 10-1388라 사， 3 2） 분석을 통하여 확인하였다. <Production example> 2022/249120 1» (that 1'/182022/054947 Each of the compounds according to the present invention was synthesized by the method described below, and a method common to those skilled in the art derived by combining the following specific synthesis methods can be used. Each compound used in the synthesis was purchased from an outside company or synthesized using an organic synthesis method obvious to those skilled in the art, and was used without a separate purification process. The compound of each example was confirmed through 40 ( ¾ ¾ -·myo (Shoyangsa, 400^) , 10-1388rasa, 3 2) analysis.
『합성 예 시
『Synthesis Example
[단계 1] 화합물 3-1 합성
2022/249120 1^(:1^ 2022/054947
a-^ 벤조 [05]인돌- 2(111)-론 (8.4요, 49.65—101 )을 아세트산 (1001111>)에 녹인 용액에 ■¾ (60%, 3.631111, 2. 13^101 )를 0° (:에서 천천히 적가하고， 이 반응 혼합물은 50° (:에서 15시간 동안 교반하였다 . 이 반응물을 아이스 ( 에 넣어 냉각하고， 여과 (filtration)를 통해 고체를 분리하였다 . 여과된 고체를 차가운 증류수 (50mL)로 3번 세척한 뒤， 60°C진공 오븐에서 밤새(overnight ) 건조하였다 . 이후 별도의 정제 없이 목적 화합물 3-1(8.74§, 92.9%)을 노란색 고체로 얻었다 . [Step 1] Synthesis of Compound 3-1 2022/249120 1^(:1^ 2022/054947 a-^ Benzo[05]indole-2(111)-lone (8.4yo, 49.65—101 ) in acetic acid (1001111 > ) ¾ (60%, 3.631111, 2. 13^101 ) was added to 0° ( : was slowly added dropwise, and the reaction mixture was stirred at 50 ° ( : for 15 hours. The reaction was cooled by putting it in ice ( ), and the solid was separated through filtration. The filtered solid was cold distilled water ( 50 mL), and then dried overnight in a vacuum oven at 60 ° C. After that, the target compound 3-1 (8.74 § , 92.9%) was obtained as a yellow solid without additional purification.
[단계 2] 화합물 1-1 합성 : 알킬화반응
상기 단계 1에서 합성된 a-1 화합물 (2g, 9.34mmo 1 ) , CS2CO3 (4.56g, U.Olmmol) 및 다이메틸포름아마이드 (45mL) 혼합물에 1_아이오도부탄 (1.27mL, 1.12mmol)을 실온 (10~35°C)에서 적가한 뒤， 80°C에서 12시간 동안 교반하였다 . 이후 반응 혼합물에 증류수를 첨가하고 얻어진 고체를 여과하였다 . 여과된 고체를 증류수 (50mL)로 2번， 핵산 (50mL)으로 2번 세척한 뒤， 60°C진공 오븐에서 밤새(overnight ) 건조하였다 . 이후 별도의 정제 없이 목적 화합물 b-l-l(1.76g, 61%)을 노란색 고체로
2022/249120 1»（그1’/182022/054947 얻었다. [Step 2] Synthesis of Compound 1-1: Alkylation 1_iodobutane (1.27 mL, 1.12 mL , 1.12 mmol) was added dropwise at room temperature (10-35 ° C), and stirred at 80 ° C for 12 hours. Then, distilled water was added to the reaction mixture and the obtained solid was filtered. After washing the filtered solid twice with distilled water (50mL) and twice with nucleic acid (50mL), it was dried overnight in a vacuum oven at 60 °C. Thereafter, the target compound bll (1.76 g, 61%) was obtained as a yellow solid without further purification. 2022/249120 1»（That 1'/182022/054947 obtained.
[단계 3] 화합물 0-1-1 합성
다이옥산/증류수 （4: 1 V八， 121111） 및 상기 단계 2에서 합성된 13-1-1 화합물 （30011度， 1 .111—01）의 혼합물에 ¾01
및 아연 분말（¾ 加 ）
적가한 뒤， 실온에서 3시간 동안 교반하였다. 이후 셀라이트 ᄄ 를 깔고 반응 혼합물을 증류수（301）와 에틸아세테이트（301此）로 세척하면서 여과하였다. 여과된 여 액 중 유기층을 분리하여 마그네슘설페이트어§ 4）로 건조하고， 농축된 혼합물은 컬럼 크로마토그래피（에틸아세테이트 : 핵산 = 1： 1）로 정제하여 목적 화합물 0-1 - 1（90%）을 붉은색 고체로 얻었다. [Step 3] Synthesis of Compound 0-1-1 ¾01 to a mixture of dioxane/distilled water (4: 1 V8, 121111) and the 13-1-1 compound (30011 degree, 1.111—01) synthesized in step 2 above and zinc powder (¾ 加 ) After adding dropwise, the mixture was stirred at room temperature for 3 hours. Thereafter, Celite A was spread and the reaction mixture was filtered while washing with distilled water (301) and ethyl acetate (301 series). The organic layer was separated from the filtered filtrate, dried over magnesium sulfate § 4 ), and the concentrated mixture was purified by column chromatography (ethyl acetate: nucleic acid = 1: 1) to obtain the target compound 0-1 - 1 (90%) was obtained as a red solid.
[단계 4] 화합물 6 （（1-1-1） 합성
다이클로로메탄（21此）을 0°（:， 질소（¾） 하에서 교반하면서 트리에틸아민 （0.17½ᄂ[Step 4] Synthesis of Compound 6 ((1-1-1) Triethylamine (0.17½ᄂ) while stirring dichloromethane (21°) under 0° (:, nitrogen (¾)
1.248 101）과 아크릴로일클로라이드 （0.0371此， 0.458 101）를 차례로 첨가한 뒤， 이 반응 혼합물을 실온에서 1시간 동안 교반하였다. 농축된 혼합물은 컬럼
2022/249120 1»（그1’/182022/054947 크로마토그래피（핵산: 에틸아세테이트 = 2： 1）로 정제하여 목적 화합물 6（3¾ ， 29%）을 노란색 고체로 얻었다. 상기 합성 예 /ᅡ1에서， 단계 2의 1 -아이오도부탄 대신 각각의 목적 화합물에 상응하는 화합물로서 하기 표 2의 !¾_）（를 사용한 것을 제외하고 동일한 방법으로 하기 표 3의 화합물들을 합성하였다. 단， 화합물 68은 아크릴로일클로라이드 대신 4-（다이메틸아미노）부트- 2 -에노일클로라이드를 사용하였다. 1.248 101) and acryloyl chloride (0.0371 此, 0.458 1 0 1) were sequentially added, and the reaction mixture was stirred at room temperature for 1 hour. The concentrated mixture is column 2022/249120 1» (H1'/182022/054947 Purification by chromatography (nucleic acid: ethyl acetate = 2: 1) to obtain the target compound 6 (3¾, 29%) as a yellow solid. In the synthesis example / ᅡ1, the compounds in Table 3 were synthesized in the same manner except for using !¾ _ ) in Table 2 as a compound corresponding to each target compound instead of 1-iodobutane in step 2. did However, for compound 68, 4-(dimethylamino)but-2-enoyl chloride was used instead of acryloyl chloride.
【표 2]
2022/249120 1^(:1^ 2022/054947
[Table 2] 2022/249120 1^(:1^ 2022/054947
【표 3]
2022/249120 1»（그1’/182022/054947
[Table 3] 2022/249120 1»（That 1'/182022/054947
[합성예 쇼-2] 화합물 3 합성 상기 합성예 쇼-1에서 설명한 단계 1 내지 단계 4 중에서 단계 2의 알킬화 반응 대신， 스즈키 (¾ ) 반응을 통한 알킬화를 통하여 중간체 화합물 13-2-1을 얻은 후에 이를 이용한 것을 제외하고는 상기 합성예 /ᅡ1에서 설명한 것과 실질적으로 동일하게 반응을 진행하여 목적 화합물인 화합물 3 ((1-2-1)을 합성하였다.
2022/249120 1»（그1’/182022/054947
[Synthesis Example Show-2] Synthesis of Compound 3 Among steps 1 to 4 described in Synthesis Example Show-1, intermediate compound 13-2-1 was obtained through alkylation through Suzuki (¾) reaction instead of the alkylation reaction of step 2. Except for using it later, the reaction proceeded in substantially the same manner as described in Synthesis Example / 1 to synthesize the target compound, Compound 3 ((1-2-1). 2022/249120 1»（That 1'/182022/054947
［단계 1］ 화합물
스즈키（¾ ） 반응을 통한 알킬화 반응
상기 합성예 쇼_1의 단계 1에서 합성된 화합물 3-1（50011¾， 1.5311111101）， 4 - （트리플루오로메틸）페닐붕산 （4_（ 1나0 6 1） 61¾，11）01，011八: 301（1） （500!1度， 3.05 1（）1）， &그（0 ）2 （278!!度， 1 - 53|·。 1） , 묘쇼 （0.6½］시 4.29 101） 및 아세토나이트릴 용매（201此）의 혼합물을 아르곤（ ） 하에서， 실온에서 2시간 동안 교반하였다. 이후 셀라이트를 깔고 반응 혼합물을 증류수（101此）와 다이클로로메탄（201此）으로 세척하면서 여과하였다. 여과된 여액 중 유기층을 분리하여 증류수（201）로 2번， 포화 소금물（加比 로 세척하였다. 모아진 유기층은 마그네슘설페이트로 건조하고， 진공에서 농축된 혼합물은 컬럼 크로마토그래피（에틸아세테이트: 핵산 = 1： 2 내지 1： 1）로 정제하여 목적 화합물 2-1 （37¾ ， 55%）을 얻었다.
2022/249120 1»（그1’/182022/054947 [Step 1] Compound Alkylation reaction via Suzuki (¾) reaction Compound 3-1 (50011¾, 1.5311111101), 4 - (trifluoromethyl) phenylboric acid (4_ ( 1 or 0 6 1) 61¾, 11) 01, 0118 synthesized in step 1 of the synthesis example show_1: 301（1） （500!1degree， 3.05 1（）1）、 &g（0） 2 （278!!degree， 1 - 53|·。 1） , Myosho（0.6½】shi 4.29 101） and acetonite A mixture of reel solvent (201 degree) was stirred for 2 hours at room temperature under argon ( ). Thereafter, Celite was spread and the reaction mixture was filtered while washing with distilled water (101 levels) and dichloromethane (201 levels). The organic layer was separated from the filtered filtrate and washed twice with distilled water (201) and saturated brine (加比). The collected organic layers were dried over magnesium sulfate, and the mixture concentrated in vacuo was purified by column chromatography (ethyl acetate: nucleic acid = 1: 2 to 1: 1) to obtain the target compound 2-1 (37¾, 55%). 2022/249120 1»（That 1'/182022/054947
[단계 2] 화합물 3 합성 상기에서 얻은 화합물 2-1을 이용해 상기 합성 예 /ᅡ1에서 설명한 단계 3 및 단계 4와 실질적으로 동일한 반응을 통해 화합물 3을 합성하였다. 상기 합성 예 쇼-2의 단계 1에서 4-（트리플루오로메틸）페닐붕산 대신 하기 표 4의 화합물을 사용한 것을 제외하고 상기 합성 예 쇼-2에서 설명한 것과 실질적으로 동일한 방법으로 하기 표 5의 화합물을 합성하였다. [Step 2] Synthesis of Compound 3 Using Compound 2-1 obtained above, Compound 3 was synthesized through substantially the same reactions as in Steps 3 and 4 described in Synthesis Example / 1. Compounds of Table 5 below in substantially the same manner as described in Synthesis Example Show-2, except that the compound of Table 4 was used instead of 4-(trifluoromethyl)phenylboric acid in step 1 of Synthesis Example Show-2. was synthesized.
【표 4]
[Table 4]
【표 5]
[Table 5]
[합성예 쇼-3 ] 화합물 42 합성 상기 합성 예 쇼-1에서 설명한 단계 1 내지 단계 4 중에서 단계 2의
2022/249120 1»（그1’/182022/054947 알킬화 반응 대신， 마이크로웨이브 반응을 통한 알킬화를 통하여 중간체 3-1을 얻은 후 이를 이용한 것을 제외하고는， 상기 합성 예 /ᅡ1에서 설명 한 것과 실질적으로 동일하게 반응시 켜 목적 화합물인 화합물 42 （（1-3-1）를 합성하였다 .
상기 합성 예 쇼_1의 단계 1에서 합성된 화합물 a-l （50011¾， 2.23311111101）， 사이클로핵산브로마이드 （7611 ， 4.669_01） 및 082003 （ 2.28§, 7.003 101）를 마이크로웨이브 바이 알（1 （：1'0¥ 6 크1）에 넣고 혼합하였다 . 상기 바이 알에 아르곤을 주입（ 하며 다이 메틸포름아마이드（¾此）를 첨가한 뒤， 150 마이크로웨이브 반응기 에서 30분간 반응을 진행하였다 . 이후 반응 혼합물에 수용액을 처 리하고， 에틸아세테이트 （501）로 추출하였다 . 유기층은 마그네슘설페이트로 건조하고， 농축된 혼합물은 컬럼 크로마토그래피 （핵산 : 에틸아세테이트 = 1： 1）로 정제하여 목적 화합물（2771 ， 40%）을 어두운 노란색 고체로 얻었다 .
2022/249120 1»（그1’/182022/054947 [Synthesis Example Show-3] Synthesis of Compound 42 Step 2 of Steps 1 to 4 described in Synthesis Example Show-1 2022/249120 1» (That 1'/182022/054947 Substantially the same as described in Synthesis Example / 1 above, except for using intermediate 3-1 obtained through alkylation through microwave reaction instead of alkylation reaction. was reacted in the same way to synthesize the target compound, Compound 42 ((1-3-1)). The compound al (50011¾, 2.23311111101), cyclonucleic acid bromide (7611, 4.669_01) and 08 2 00 3 (2.28 § , 7.003 1 0 1) synthesized in step 1 of the above synthesis example show_1 were mixed in a microwave vial (1 (: 1'0¥ 6 K 1) and mixed. After injecting argon into the vial and adding dimethylformamide (¾), the reaction proceeded for 30 minutes in a 150 microwave reactor. Then, the reaction mixture was treated with an aqueous solution and extracted with ethyl acetate (501). The organic layer was dried over magnesium sulfate, and the concentrated mixture was purified by column chromatography (nucleic acid: ethyl acetate = 1: 1) to obtain the target compound (2771, 40%) as a dark yellow solid. 2022/249120 1»（That 1'/182022/054947
[단계 2] 화합물 42 합성 상기에서 얻은 화합물 3-1을 이용해 상기 합성 예 쇼-1에서 설명한 단계 3 및 단계 4와 실질적으로 동일한 반응을 통해 화합물 42를 합성하였다. 상기 합성 예 3의 단계 1에서 사이클로핵산브로마이드 대신 각각의 목적 화합물에 상응하는 화합물로서 하기 표 6의 ¾-）（를 사용한 것을 제외하고 상기 합성 예 쇼-3에서 설명한 것과 실질적으로 동일한 방법으로 하기 표 7의 화합물들을 합성하였다. [Step 2] Synthesis of Compound 42 Using Compound 3-1 obtained above, Compound 42 was synthesized through substantially the same reactions as in Steps 3 and 4 described in Synthesis Example Show-1. In step 1 of Synthesis Example 3, ¾-) in Table 6 below was used as a compound corresponding to each target compound instead of cyclohexane bromide, in the same manner as described in Synthesis Example Show-3, except that Compounds of 7 were synthesized.
【표 6]
[Table 6]
【표 7]
[Table 7]
[합성예 쇼-4] 화합물 78 합성
2022/249120 1»（그1’/182022/054947
구체적으로， 상기 합성예 /ᅡ1의 단계 3에서 합성한 아민 화합물 0-1-1 （1001 ， 0.416 101）， ä （47¾度， 1.245 101） 및 다이이소프로필에틸아민 ①比시 （2161111, 1.245_01）를 다이메틸포름아마이드 （21）에 넣고， 여기에 메타크릴산（71.621 ， 8.319_101）을 적가한 뒤， 실온에서 3시간 동안 교반하였다. 농축된 혼합물은 컬럼 크로마토그래피（핵산: 에틸아세테이트 = 2： 1）로 정제하여 목적 화합물인 화합물 78（10¾度， 80%）을 노란색 고체로 얻었다. 상기 합성예 쇼-4의 제조 공정에서 메타크릴산 대신 하기 표 8의 ¾- 에를 사용한 것을 제외하고 상기 합성예 /ᅡ4에서 설명한 것과 실질적으로 동일한 방법으로 하기 표 9의 화합물들을 제조하였다. [Synthesis Example Show-4] Synthesis of Compound 78 2022/249120 1»（That 1'/182022/054947 Specifically, the amine compound 0-1-1 (1001, 0.416 101), ä (47¾ degree, 1.245 1 0 1) and diisopropylethylamine ① synthesized in step 3 of Synthesis Example / ᅡ1 (2161111 , 1.245_01) into dimethylformamide (21), methacrylic acid (71.621, 8.319_101) was added dropwise thereto, and stirred at room temperature for 3 hours. The concentrated mixture was purified by column chromatography (nucleic acid: ethyl acetate = 2: 1) to obtain the target compound, Compound 78 (10¾ degree, 80%) as a yellow solid. The compounds in Table 9 were prepared in substantially the same manner as described in Synthesis Example / 4, except that ¾-E in Table 8 was used instead of methacrylic acid in the production process of Synthesis Example Show-4.
【표 8]
2022/249120 1^(:1^2022/054947
[Table 8] 2022/249120 1^(:1^2022/054947
【표 9]
2022/249120 1»（그1’/182022/054947
[Table 9] 2022/249120 1»（That 1'/182022/054947
[합성 예 쇼-5] 화합물 61（6-1-1）합성 상기 합성예 쇼-1에서 합성한 화합물 （1-1-1을 메틸화 반응시켜 목적 화합물인 화합물 61 （6-1-1）을 합성하였다.
상기 합성예 쇼_1에서 합성한 화합물 （1-1-1（4911¾, 0.1611111101） 및 다이메틸포름아마이드（111 ）의 실온 혼합물에
0.2111111101）를 첨가한 뒤 （15.51111, 0.25 101）를 천천히 적가하고， 실온에서 3시간 동안 교반하였다. 반응 혼합물에 증류수（101此）를 넣어 반응을 종료하고， 에틸아세테이트 （101此）를 이용해 2번 추출하였다. 모아진 유기층은 증류수（201）와 포화 소금물（101此）로 세척하고， 마그네슘설페이트로 건조 및 농축하였다. 농축된 혼합물은 컬럼 크로마토그래피（에틸아세테이트: 핵산 = 1： 1）로 정제하여 목적 화합물인 화합물 61 （2¾度， 45%）을 노란색 고체로 얻었다. [Synthesis Example Show-5] Synthesis of Compound 61 (6-1-1) Compound 61 (6-1-1) as the target compound was obtained by methylation of the compound (1-1-1 synthesized in Synthesis Example Show-1) synthesized. In a room temperature mixture of the compound (1-1-1 (4911¾, 0.1611111101) synthesized in Synthesis Example Show_1 and dimethylformamide (111) 0.2111111101) was added, (15.51111, 0.25 101) was slowly added dropwise, and stirred at room temperature for 3 hours. Distilled water (101 此) was added to the reaction mixture to terminate the reaction, and extraction was performed twice using ethyl acetate (101 此). The collected organic layers were washed with distilled water (201) and saturated brine (101°), dried over magnesium sulfate, and concentrated. The concentrated mixture was purified by column chromatography (ethyl acetate: nucleic acid = 1: 1) to obtain the target compound, Compound 61 (2¾ degree, 45%) as a yellow solid.
『합성 예 미
2022/249120 1»（그1’/182022/054947
『Synthesis Example 2022/249120 1»（That 1'/182022/054947
(상기 합성예 B의 묘에서 Me은 메틸기를， Et은 에틸기를， 은 비닐 (vinyl)을 의미한다) (In the seed of Synthesis Example B, Me is a methyl group, Et is an ethyl group, and means a vinyl)
[합성예 B-l] 화합물 25 (f-l-l) 합성 상기 합성예 세의 단계 4에서 사용한 아크릴로일클로라이드 대신 바이닐 설포닐 클로라이드 (vinyl sulfonyl chloride)를 이용하여 화합물 c_l_l을 설포닐화 (sulfonylat ion)한 것을 제외하고는 합성예 A_1에서 설명한 것과 실질적으로 동일한 공정을 통해 목적 화합물 25 (f-1-l)를 합성하였다.
구체적으로， 상기 합성예 세의 단계 3에서 얻은 화합물 0-1-1 (2001 ， 0.832_01) 및 용매로서 테트라하이드로퓨란奸 )/다이클로로메탄 (11») (1/1, V八， ¾ ) 혼합물에 트리에틸아민 (0.0581， 0.416 101)과 바이닐설포닐클로라이드 (0.1581 ， 1.6611111101)를 차례로 첨가한 뒤， 실온에서[Synthesis Example Bl] Synthesis of Compound 25 (fll) Except for sulfonylation of compound c_l_l using vinyl sulfonyl chloride instead of acryloyl chloride used in step 4 of Synthesis Example 3, synthesized the target compound 25 (f-1-l) through substantially the same process as described in Synthesis Example A_1. Specifically, the compound 0-1-1 (2001, 0.832_ 0 1) obtained in step 3 of Synthesis Example 3 and tetrahydrofuran as a solvent) / dichloromethane (11 ») (1/1, V八, ¾) After adding triethylamine (0.0581, 0.416 101) and vinylsulfonyl chloride (0.1581, 1.6611111101) to the mixture in turn,
3시간 동안 교반하였다. 이후 진공에서 농축하여 얻어진 비정제 화합물 ((^(뇨 product)을 다이클로로메탄 (5mL)으로 희석하고， IN HC1 수용액을 이용하여
2022/249120 1»（그1’/182022/054947 산성화한 뒤 다이클로로메탄（¾此）으로 2차례 추출하였다. 모아진 유기층은 마그네슘설페이트로 건조하고， 농축된 혼합물은 컬럼 크로마토그래피（핵산: 에틸아세테이트 = 1： 1）로 정제하여 목적 화합물 25（1301 ， 47%）를 노란색 고체로 얻었다. 상기 합성 예 쇼-1과 동일하게 진행하되， 단계 2의 1 -아이오도부탄 대신 각각의 목적 화합물에 상응하는 화합물로서 하기 표 10의 ¾-）（를 사용하고， 단계 4는 상기 합성 예
설명한 방법과 실질적으로 동일한 방법으로 진행하여 하기 표 11의 화합물들을 합성하였다. 단， 화합물 17 합성 시에는 바이닐설포닐클로라이드를 46¾ 이상 첨가하였다 . Stir for 3 hours. Then, the crude compound ((^ (urine product) obtained by concentration in vacuo was diluted with dichloromethane (5mL), using IN HC1 aqueous solution 2022/249120 1» (That 1'/182022/054947 After acidification, it was extracted twice with dichloromethane (¾). The collected organic layers were dried over magnesium sulfate, and the concentrated mixture was purified by column chromatography (nucleic acid: ethyl acetate = 1: 1) to obtain the target compound 25 (1301, 47%) as a yellow solid. Proceed in the same manner as in the Synthesis Example Show-1, but using ¾-) in Table 10 as a compound corresponding to each target compound instead of 1-iodobutane in Step 2, and Step 4 is the Synthesis Example Compounds in Table 11 were synthesized in substantially the same manner as described above. However, when synthesizing compound 17, 46 ¾ or more of vinylsulfonyl chloride was added.
【표 10]
2022/249120 1^(:1^ 2022/054947 [Table 10] 2022/249120 1^(:1^ 2022/054947
【표 111
2022/249120 1»（그1’/182022/054947
【Table 111 2022/249120 1»（That 1'/182022/054947
[합성예 6-2] 화합물 12 및 13 합성 합성예 8에 따라， 화합물 12 및 13 은 상기 합성예
단계 1에서 사용한 바이닐 설포닐 클로라이드 대신 각각의 목적화합물에 상응하는 메탄설포닐클로라이드 및 에탄설포닐클로라이드를 각각 사용하여 화합물
설포닐화（ 1比11기 1011） 함으로써 목적 화합물 화합물 12 및 13을 합성하였다. 화합물 12의 합성 구체적으로， 상기 합성예 /ᅡ2에서 합성된 화합물 0-2-1 （1001 ，[Synthesis Example 6-2] Synthesis of Compounds 12 and 13 According to Synthesis Example 8, Compounds 12 and 13 are the above Synthesis Example Instead of vinyl sulfonyl chloride used in step 1, methanesulfonyl chloride and ethanesulfonyl chloride corresponding to each target compound were used to obtain compounds Compounds 12 and 13 of the target compound were synthesized by sulfonylation (1% 11 group 1011). Synthesis of Compound 12 Specifically, Compound 0-2-1 (1001,
0.305 101） 및 용매로서 다이클로로메탄/피리딘 （1/1， V八， 21111） 혼합물에 트리에틸아민 （0.1271此， 0.914_101）과 메탄설포닐클로라이드 （41.^, 0.36611111101）를 첨가한 뒤， 반응 혼합물은 실온에서 1시간 동안 교반하였다. 진공 농축된 혼합물에
수용액을 처리하고， 에틸아세테이트（101此）로 두차례 추출하였다. 유기층은 마그네슘설페이트로 건조하고， 농축된 혼합물은 컬럼 크로마토그래피（핵산: 에틸아세테이트 = 2: 1）로 정제하여 목적 화합물 12（60%）를 연노란색 고체로 수득하였다.
2022/249120 1»（그1’/182022/054947 화합물 13의 합성 메탄설포닐클로라이드 대신 에탄설포닐클로라이드를 사용한 것을 제외하고는 상기 화합물 12의 제조방법에서 설명한 것과 실질적으로 동일한 방법으로 목적 화합물 13을 수득하였다. 0.305 101) and dichloromethane / pyridine (1/1, V八, 21111) as a solvent, triethylamine (0.1271 degree, 0.914_101) and methanesulfonyl chloride (41.^, 0.36611111101) were added to the mixture, The reaction mixture was stirred at room temperature for 1 hour. in a vacuum concentrated mixture The aqueous solution was treated and extracted twice with ethyl acetate (101 degrees). The organic layer was dried over magnesium sulfate, and the concentrated mixture was purified by column chromatography (nucleic acid: ethyl acetate = 2: 1) to obtain the target compound 12 (60%) as a pale yellow solid. 2022/249120 1» (That 1'/182022/054947 Synthesis of Compound 13 Compound 13 was prepared by substantially the same method as described in the method for preparing Compound 12, except that ethanesulfonyl chloride was used instead of methanesulfonyl chloride. obtained.
［합성예 0］ 화합물 81 합성 [Synthesis Example 0] Synthesis of Compound 81
［단계 1］ 1 -부틸- 6-(피페라진- 1 -일 )벤조［0(1］인돌- 2(1¾-온의 합성
0.4 에 녹인 후， 비스 (2 -클로로에틸 )아민하이드로클로라이드 (0.08¼， 0.45^101 )를 첨가하였다. 이후 1501에서 환류하며 24시간 동안 반응시켰다. 반응 종결 후 용액이 실온이 될 때까지 식혀주고 증류수를 넣은 뒤， 메틸렌클로라이드를 이용해 추출하였다 . 분별깔대기를 이용해 모은 유기층을 마그네슘설페이트로 건조하고 감압 증류하여 얻어진 비정제 화합물 ((^(뇨 0(111(:1 )을 컬럼 크로마토그래피 (다이클로로메탄: 메탄올 = 9： 1)로 정제하여 목적 화합물인 화합물 1 -부틸- 6-(피페라진- 1 -일 )벤조［0(1］인돌- 2(1 -온 (5¾ ，[Step 1] Synthesis of 1-butyl- 6- (piperazin- 1 -yl) benzo [0 (1] indol- 2 (1¾-one) After dissolving in 0.4, bis (2-chloroethyl) amine hydrochloride (0.08¼, 0.45^101) was added. Thereafter, the mixture was refluxed at 1501 and reacted for 24 hours. After completion of the reaction, the solution was cooled to room temperature, distilled water was added, and extraction was performed using methylene chloride. The organic layer collected using a separatory funnel was dried over magnesium sulfate, and the crude compound ((^(urine 0(111(:1)) obtained by distillation under reduced pressure was purified by column chromatography (dichloromethane: methanol = 9: 1) to obtain The compound compound 1-butyl- 6- (piperazin- 1 -yl) benzo [0 ( 1] indol- 2 (1 -one (5¾,
48.3%)을 얻었다.
2022/249120 1»（그1’/182022/054947 48.3%) was obtained. 2022/249120 1»（That 1'/182022/054947
［단계 2］ 화합물 81 합성 상기 단계 1에서 합성된 1 -부틸- 6-(피페라진- 1 -일)벤조［0(1］인돌- 2(1¾- 온을 상기 합성예 세의 단계 4와 동일한 방법을 사용하여， 최종화합물 81을 합성하였다. 각 실시예의 화합물의 분석 결과는 표 12와 같다. [Step 2] Synthesis of Compound 81 The 1-butyl-6-(piperazin-1-yl)benzo[0(1]indol-2(1¾-one synthesized in Step 1) was prepared in the same manner as in Step 4 of Synthesis Example 3. Using the method, the final compound 81 was synthesized. The analysis results of the compounds of each example are shown in Table 12.
【표 12】
2022/249120 1^（:1^2022/054947
【Table 12】 2022/249120 1^（:1^2022/054947
＜실험예 ñ TEAD활성 평가 실험예 1. TEAD반응 요소 (TRE) reporter assay <Experimental Example ñ TEAD activity evaluation Experimental Example 1. TEAD response element (TRE) reporter assay
TEAD 반응 요소 (TEAD Response Element, TRE) 활성화에 따라 반딧불의 루시퍼라아제 (firefly luciferase)를 발현하는 TEAD 보고 유전자 (reporter gene)가 안정적으로 발현되도록 주입된 MCF-7 세포주를 BPS bioscience
2022/249120 1»(그1’/182022/054947 The MCF-7 cell line injected to stably express the TEAD reporter gene that expresses firefly luciferase according to the activation of the TEAD response element (TRE) was developed by BPS bioscience 2022/249120 1»(G1'/182022/054947
(將 0618)로부터 입수하였다 . 이를 10 u g/mL 인슐린 (Sigma)이 첨가된 세포 전용 배양액 (BPS bioscience)으로 37 °C , 5% C¾ 조건에서 배양하였다. 상기 세포를 96 웰 플레이트에 분주하고 24시간 뒤， 최종 농도가 0.2 ii M 이 되도록 (최종 농도가 다른 경우 표에 별도로 서술) 실시예 화합물들 혹은 용매 (vehicle) (f inal 1% DMS0)를 무-혈청 (serum-free) 배양액으로 희석하여 처치하였다. 상기 처치 후 24시간 경과 뒤 루시퍼라아제 (luciferase)의 기질이 포함되어 있는 루시퍼라아제 분석 사용 용액 ( luci ferase assay working solution) (ONE-Stepä Luciferase assay reagent ; BPS bioscience)을 각 웰에 100 y L씩 처치하고， 잘 섞이도록 15분간 쉐이커 (shaker)에 놓아두었다. 이후 TEAD 활성화에 따라 발현된 루시퍼라아제가 발생시키는 발광 ( luminescence) 정도를 마이크로플레이트 리더기 (microplate reader) (TECAN)로 측정하였다.(將 0618). This was cultured at 37 ° C and 5% C¾ with a cell-only culture medium (BPS bioscience) to which 10 ug/mL insulin (Sigma) was added. After 24 hours of dispensing the cells into a 96-well plate, the final concentration is 0.2 ii M (if the final concentration is different, it is separately described in the table) Example compounds or a solvent (vehicle) (final 1% DMS0) - It was treated by diluting with a serum-free culture medium. 24 hours after the treatment, 100 y L of luciferase assay working solution (ONE-Stepä Luciferase assay reagent; BPS bioscience) containing a luciferase substrate was added to each well. Each was treated and placed on a shaker for 15 minutes to mix well. Thereafter, the degree of luminescence generated by the luciferase expressed upon activation of TEAD was measured using a microplate reader (TECAN).
Vehicle군 (용매 처리 대조군)의 발광 수준을 100%로 기준하여 상대적인 루시퍼라아제의 활성 ( 을 계산하였고 그 결과를 하기 표 13에 나타내었다. The relative activity of luciferase was calculated based on the luminescence level of the vehicle group (solvent treatment control group) as 100%, and the results are shown in Table 13 below.
【표 13]
2022/249120 1»(그1’/182022/054947
주） 쇼: > 60% 저해 (1!1]111) 1011) 표: 30 내지 60% 저해（比11比 1011） [Table 13] 2022/249120 1»(G1'/182022/054947 Note) Show: > 60% inhibition (1!1]111) 1011) Table: 30 to 60% inhibition (比11比 1011)
C < 30% 저해 (1!1]111) 1011) 상기 표 13을 참조하면， 본 발명에 따른 벤조인돌론 화합물은 묘쇼 에 의한 루시퍼라아제의 전사를 효과적으로 억제하는 것을 확인하였으며， 이를 통해 ¬묘쇼 활성에 의존적인 유전자들의 발현을 효과적으로 저해할 수 있음을 확인하였다.
2022/249120 1»（그1’/182022/054947 실험예 2. YAP-TEAD reporter assay C < 30% inhibition (1!1] 111) 1011) Referring to Table 13 above, it was confirmed that the benzoindolone compound according to the present invention effectively inhibits the transcription of luciferase by Myosho, through which ¬Myosho It was confirmed that the expression of activity-dependent genes can be effectively inhibited. 2022/249120 1» (That 1'/182022/054947 Experimental Example 2. YAP-TEAD reporter assay
HEK-293T 세포에 OPTI-MEM (Gibco) 배지와 Lipofectamine® (Invitrogen)을 이용하여 pUAS-Luc, pCMV-SP0RT6_YAPl, pCMX-Gal4_TEAI)l을 각각 형질 주입 (transfection)시킨 뒤 24시간 동안 37°C및 5% C¾가 유지되는 세포 배양 인큐베이터에서 배양하였다. 그 이후， 24시간에 걸쳐 1%의 DMS0또는 각각의 화합물을 lOuM에 해당하는 양만큼 첨가하여 24시간 배양 후 세포를 용해 (lysis)시킨 뒤 Promega Luciferase® 시스템을 이용하여 마이크로플레이트 리더기 (TECAN)로 루시퍼라아제 활성을 측정하였다. Vehicle군 (용매 처리 대조군)의 발광 수준을 100%로 기준하여 상대적인 루시퍼라아제의 활성 ( 을 계산하였고 그 결과를 하기 표 14에 나타내었다. HEK-293T cells were transfected with pUAS-Luc, pCMV-SP0RT6_YAPl, and pCMX-Gal4_TEAI)l using OPTI-MEM (Gibco) medium and Lipofectamine® (Invitrogen), respectively, and then incubated at 37 ° C for 24 hours. It was cultured in a cell culture incubator maintained with 5% C¾. After that, over 24 hours, 1% of DMS0 or each compound was added in an amount corresponding to lOuM, and after 24 hours of incubation, the cells were lysed, followed by a microplate reader (TECAN) using the Promega Luciferase® system. Luciferase activity was measured. Based on the luminescence level of the vehicle group (solvent treatment control group) as 100%, the relative activity of luciferase was calculated, and the results are shown in Table 14 below.
【표 14]
2022/249120 1»(그1’/182022/054947
주) 쇼: > 60% 저해 (1!1]111) 1011) 표: 30 내지 60% 저해 (比11比 1011) [Table 14] 2022/249120 1»(G1'/182022/054947 Note) Show: > 60% inhibition (1!1]111) 1011) Table: 30 to 60% inhibition (比11比 1011)
C < 30% 저해 (1!1]111) 1011) 상기 표 14를 참조하면， 본 발명에 따른 벤조인돌론 화합물은 YAP1과 TEAD1에 의한 루시퍼라아제의 전사를 우수하게 억제하는 것을 확인하였으며， 이를 통해 본 발명에 따른 벤조인돌론 화합물이 TEAD 활성에 의존적인 유전자들의 발현을 효과적으로 억제할 수 있음을 확인하였다. 실험예 3. Cell-free palmitoylation assay 재조합 (recombinant) GST-TEAD1 단백질 (209-426 a.a.)에 1, 5 또는 10 liM의 농도에 해당되는 각각의 실시예 화합물 (화합물 1, 2, 20, 30, 32, 38, 39)을 각각 첨가하고 30분간 배양하였다. 배양 후 단백질의 자동 팔미토일화 (autopalmitoylation) 반응을 위해 알카인-팔미토일-CoA(alkyne palmitoyl-CoA) (Cayman chemical)와 50 mM MES버퍼 (pH 6.4)를 넣고 2시간 동안 배양해 준 뒤 1%에 해당되는 소듐 도데실 설페이트 (SDS)를 첨가하여 반응을 중단하였다. 그 이후， 클릭 (Click) 반응을 통하여 비오틴화 (biotinylation) 시켜준 뒤 단백질 용액을 농축하여 샘플을 제조하였다. 샘플의 분석은 SDS- PAGE와 스트렙트아비딘 (streptavidin) HRP (Thermo scientific)를 이용하여
2022/249120 1»（그1’/182022/054947 실시하였으며 결과의 정규화 (normal izat ion)는 글루타티온 S-전이효소C < 30% inhibition (1!1] 111) 1011) Referring to Table 14 above, it was confirmed that the benzoindolone compound according to the present invention excellently inhibits the transcription of luciferase by YAP1 and TEAD1, which Through this, it was confirmed that the benzoindolone compound according to the present invention can effectively inhibit the expression of genes dependent on TEAD activity. Experimental Example 3. Cell-free palmitoylation assay Each Example compound (Compound 1, 2 , 20, 30 , 32, 38, 39) were added and incubated for 30 minutes. After incubation, add alkyne palmitoyl-CoA (Cayman chemical) and 50 mM MES buffer (pH 6.4) for autopalmitoylation of proteins and incubate for 2 hours. The reaction was stopped by adding % sodium dodecyl sulfate (SDS). After that, biotinylation was performed through a click reaction, and the protein solution was concentrated to prepare a sample. Analysis of the sample was performed using SDS-PAGE and streptavidin HRP (Thermo scientific). 2022/249120 1»（That 1′/182022/054947 was carried out, and the normalization of the result (normal izat ion) is glutathione S-transferase
(Glutathione S-Transf erase, GST)에 대한 웨스턴블롯 (western blot ) (Ant i -GST 토끼 단일클론항체 (91G1) , 세포신호 (Cel l signal ing)을 통해 분석하였다. 팔미토일화 (palmitoylat ion) 실험 결과는 도 1에 나타내었다. 도 1을 통해 확인할 수 있는 바와 같이， 본 발명에 따른 벤조인돌론 화합물이 묘쇼이의 팔미토일화를 효과적으로 억제하는 것으로 보아， TEAD1 단백질의 팔미토일화 되는 부분에 결합하는 것으로 판단할 수 있다. 그 결과， 본 발명에 따른 벤조인돌론 화합물이 TEAD1의 팔미토일화를 억제하여 상술한 표 13 및 표 14에 나타낸 것과 같이 TEAD1 활성에 따른 유전자 발현을 효과적으로 억제할 수 있음을 확인하였다. 상기에서는 본 발명의 일 실시예를 참조하여 설명하였지만， 해당 기술 분야의 숙련된 당업자는 하기의 특허 청구 범위에 기재된 본 발명의 사상 및 영역으로부터 벗어나지 않는 범위 내에서 본 발명을 다양하게 수정 및 변경시킬 수 있음을 이해할 수 있을 것이다.
Western blot for (Glutathione S-Transf erase, GST), (Ant i -GST rabbit monoclonal antibody (91G1), cell signal ing) were analyzed. Palmitoylation (palmitoylat ion) The experimental results are shown in Figure 1. As can be seen in Figure 1, the benzoindolone compound according to the present invention effectively inhibits the palmitoylation of Myoshoi, so that the palmitoylated portion of the TEAD1 protein As a result, the benzoindolone compound according to the present invention inhibits palmitoylation of TEAD1 and can effectively inhibit gene expression according to TEAD1 activity, as shown in Tables 13 and 14 above. Although the above has been described with reference to one embodiment of the present invention, those skilled in the art can vary the present invention within the scope not departing from the spirit and scope of the present invention described in the claims below. It will be understood that it can be modified and changed accordingly.
Claims
[화학식 1]
알킬이고，[Formula 1] is an alkyl,
¾ 및 ¾가 서로 연결되어 과 함께 형성하는 고리는 적어도 1개 이상의 을 포함하는 4원 내지 8원의 헤테로사이클로알킬이고 ， 이때 상기 헤테로사이클로알킬의 II는 (=0)-01=抑 2 로 치환될 수 있고， A ring formed by linking ¾ and ¾ with is a 4- to 8-membered heterocycloalkyl containing at least one or more, wherein II of the heterocycloalkyl is substituted with (=0)-01=抑2 can be,
¾의 1개 이상의 II는 각각 독립적으로 할로겐， -3알킬， ⑴ -01- 3알킬렌-예， - -3알킬렌- 간能 (이때， 묘4 및 ¾는 각각 독립적으로 -3알킬을 나타냄) 또는 -^( 알킬)로 치환될 수 있고， One or more II of ¾ are each independently halogen, -3alkyl, ⑴ -0 1 - 3alkylene-eg, -3alkylene-ganeunseong (wherein, mother 4 and ¾ are each independently -3alkyl It can be substituted with) or -^ (alkyl),
1¾는 II， -6알킬 또는 *斗2-¾이고， 1¾ is II, -6 alkyl or *斗2-¾,
*斗2 -는 단결합 또는 *_ -6알킬렌-이고，
2022/249120 1»（그1’/182022/054947 *斗2 - is a single bond or *_ - 6 alkylene-, 2022/249120 1»（That 1'/182022/054947
¾는 -6알큭시， ¾-1()사이클로알킬， ¾-6사이클로알케닐 0¾ is - 6 alkynyl, ¾- 1 () cycloalkyl, ¾- 6 cycloalkenyl 0
12바이사이클로알킬， - 2아릴， 또는 0를 포함하는 5-6원 헤테로사이클로알킬
이 0(=0) 또는 =0)2이고， ¾는 -3알킬인 경우， ¾는 II 또는 1 12 bicycloalkyl, -2 aryl, or 5-6 membered heterocycloalkyl including 0 is 0 (=0) or =0) 2 , and ¾ is -3 alkyl, ¾ is II or 1
¾ 이고， ¾, and
1¾이 -6알킬인 경우， ¾ 및
서로 연결되어 과 함께 고리를 형성하거나，
-抑 =대2, º抑， 또는 - =0)-01=抑 2이고， 할로겐은 01, 먀 또는 I이며， When 1¾ is -6 alkyl, ¾ and Connected to each other to form a ring with, or -抑 = large 2, º抑, or - =0) -01 = 抑 2, halogen is 01, mya or I,
¾，
동시에 II는 아니다. ¾, At the same time not II.
【청구항 2] 제 1항에 있어서， 상기 화학식 1에서
서로 연결되어 과 함께 고리를 형성하고，
2022/249120 1»（그1’/182022/054947
[Claim 2] The method of claim 1, in Formula 1 Connected to each other to form a ring with, 2022/249120 1»（That 1'/182022/054947
¾의 1개 이상의 II는 각각 독립적으로 -3알킬， ⑴ - -3알킬렌- 011， - -3알킬렌- 간能 (이때， 묘4 및 ¾는 각각 독립적으로 -3알킬을 나타냄) 또는 ^-(^-3알킬)로 치환될 수 있고， One or more II of ¾ are each independently -3 alkyl, ⑴ - -3 alkylene- 011, - -3 alkylene- liver function (wherein, mother 4 and ¾ each independently represent -3 alkyl) or ^ -(^- 3 alkyl) may be substituted,
¾ 및 ¾가 서로 연결되어 과 함께 형성하는 고리는 피페라진일이고， 이때 상기 피페라진일의 II는 (=0)-01=抑 2 로 치환될 수 있고， The ring formed by linking ¾ and ¾ with is piperazinyl, wherein II of the piperazinyl may be substituted with (=0)-01=抑2 ,
1¾는 II， -6알킬 또는 *斗2-¾이고， 1¾ is II, -6 alkyl or *斗2-¾,
*斗2 -는 단결합 또는 *_ -6알킬렌-이고， *斗2 - is a single bond or *_ - 6 alkylene-,
¾는 -6알큭시， ¾-1()사이클로알킬， ¾-6사이클로알케닐， 04- ¾ is - 6 alkynyl, ¾- 1 () cycloalkyl, ¾- 6 cycloalkenyl, 0 4-
12바이사이클로알킬， 페닐， 바이페닐， 테트라하이드로퓨란일， 테트라하이드로피란일， 피롤리딘일 社^
12 bicycloalkyl, phenyl, biphenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl company^
¾의 1개 이상의 II는 각각 독립적으로 -6알킬， -6알큭시， 페녹시， ?One or more II of ¾ is each independently - 6 alkyl, - 6 alkoxy, phenoxy, ?
01,
치환될 수 있고 이 0(=0) 또는 =0)2이고， ¾는 -3알킬인 경우， ¾는 II 또는 1201, It can be substituted and is 0 (=0) or =0) 2 , ¾ is -3 alkyl, ¾ is II or 12
¾ 이고 ¾ and
1¾이 -6알킬인 경우， ¾ 및
서로 연결되어 과 함께 고리를 형성하거나， 또는 1¾의 ¾는
-抑 =대2， -［：º抑， 또는 - =0)_ 대=抑 2이고 When 1¾ is -6 alkyl, ¾ and Connected to each other to form a ring with, or ¾ of 1¾ is -抑 = vs 2 ， -［：º抑， or - =0)_ vs=抑2
¾， ¾ 및 1¾가 동시에 II가 아닌， 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의
2022/249120 1^(:1^ 2022/054947 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물. ¾, ¾ and 1¾ are not II at the same time, a benzoindolone compound represented by Formula 1, its stereoisomer, its 2022/249120 1^(:1^ 2022/054947 Pharmaceutically acceptable salts, hydrates or solvates thereof.
【청구항 3] 제 1항에 있어서， 상기 화학식 1에서， [Claim 3] The method of claim 1, in Formula 1,
¾은 II이고，
¾ is II,
*- _은 * (=0)2 - 또는 *- =0) -이고， ¾는 -대=抑 2이고， ¾의 1개 이상의 II는 각각 독립적으로 -3알킬로 치환될 수 있고，
*斗2 -는 단결합 또는 *- -6알킬렌-이고， *- _이 * (=0)2 -인 경우， ¾는 페닐 또는 바이페닐이되， 페닐 또는
6알큭시， ¾-10사이클로알킬 또는 페닐의 1개 이상의 II는 01, 먀 또는
치환될 수 있는 것인， 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물. *- _ is * (=0) 2 - or *- = 0) -, ¾ is -to = 抑2 , and one or more II of ¾ can be independently substituted with -3 alkyl, *斗2 - is a single bond or *- -6alkylene-, and *- _ is * (=0) 2 -, ¾ is phenyl or biphenyl, phenyl or 6 alkoxy, ¾- 10 cycloalkyl or one or more II of phenyl is 01, mya or Which may be substituted, a benzoindolone compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof.
【청구항 4] 제 1항에 있어서
2022/249120 1»（그1’/182022/054947 상기 화학식 1로 나타내는 화합물은 하기 표에 나타낸 화합물들로 이루어진 군으로부터 선택되는 1종 이상인， 화학식 1로 나타내는 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물:
2022/249120 1»（그1’/182022/054947
[Claim 4] The method of claim 1 2022/249120 1» (the 1'/182022/054947 The compound represented by Formula 1 is at least one selected from the group consisting of compounds shown in the table below, a benzoindolone compound represented by Formula 1, its stereoisomer, its Pharmaceutically acceptable salts, hydrates or solvates thereof: 2022/249120 1»（That 1'/182022/054947
【청구항 5] 제 1항 내지 제 4항 중 어느 한 항에 따른 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물을 유효성분으로 포함하는， 약학적 조성물 . [Claim 5] A pharmaceutical composition comprising the benzoindolone compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
【청구항 6]
2022/249120 1»（그1’/182022/054947 제 5항에 있어서 상기 약학적 조성물은 암의 예방 또는 치료용인 것인， 약학적 조성물. [Claim 6] 2022/249120 1» (the 1'/182022/054947 The pharmaceutical composition according to claim 5, which is for preventing or treating cancer.
【청구항 7] 제 1항 내지 제 4항 중 어느 한 항에 따른 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 치료학적으로 유효한 양을 개체에 투여하는 것을 포함하는， 암의 예방 또는 치료 방법 . [Claim 7] Administering a therapeutically effective amount of the benzoindolone compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, to a subject Including, a method for preventing or treating cancer.
【청구항 8] 암의 예방 또는 치료를 위한 제 1항 내지 제 4항 중 어느 한 항에 따른 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 용도. [Claim 8] Use of the benzoindolone compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the prevention or treatment of cancer.
【청구항 9] 암의 예방 또는 치료용 약제의 제조를 위한 제 1항 내지 제 4항 중 어느 한 항에 따른 벤조인돌론 화합물， 이의 입체 이성질체， 이의 약학적으로 허용 가능한 염， 이의 수화물 또는 용매화물의 용도.
[Claim 9] The benzoindolone compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof for the production of a drug for preventing or treating cancer use of.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210069519A KR20220161077A (en) | 2021-05-28 | 2021-05-28 | Novel benzoindolone compounds and pharmaceutical composition comprising the same |
| KR10-2021-0069519 | 2021-05-28 |
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| Publication Number | Publication Date |
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| WO2022249120A1 true WO2022249120A1 (en) | 2022-12-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IB2022/054947 WO2022249120A1 (en) | 2021-05-28 | 2022-05-26 | Novel benzoindolone compounds and pharmaceutical composition comprising same |
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| KR (1) | KR20220161077A (en) |
| WO (1) | WO2022249120A1 (en) |
Citations (3)
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| US6667303B1 (en) * | 2001-07-30 | 2003-12-23 | Wyeth | Aryl substituted 1,4-diazepanes and method of use thereof |
| US10183010B2 (en) * | 2015-01-28 | 2019-01-22 | Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences | 2-oxo-1,2-dihydrobenzo[cd]indole compound and use thereof |
| KR20200054096A (en) * | 2018-11-09 | 2020-05-19 | 한국화학연구원 | Compound inhibiting YAP-TEAD interaction and pharmaceutical composition for treating or preventing cancer comprising the same as an active ingredient |
-
2021
- 2021-05-28 KR KR1020210069519A patent/KR20220161077A/en active Search and Examination
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2022
- 2022-05-26 WO PCT/IB2022/054947 patent/WO2022249120A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6667303B1 (en) * | 2001-07-30 | 2003-12-23 | Wyeth | Aryl substituted 1,4-diazepanes and method of use thereof |
| US10183010B2 (en) * | 2015-01-28 | 2019-01-22 | Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences | 2-oxo-1,2-dihydrobenzo[cd]indole compound and use thereof |
| KR20200054096A (en) * | 2018-11-09 | 2020-05-19 | 한국화학연구원 | Compound inhibiting YAP-TEAD interaction and pharmaceutical composition for treating or preventing cancer comprising the same as an active ingredient |
Non-Patent Citations (2)
| Title |
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| GRYSHCHENKO ANDRII, KOSTIANTYN VASYLIOVYCH LEVCHENKO, VOLODYMYR GRYGOROVICH BDZHOLA, TATIANA PANASIVNA RUBAN, LYUBOV LEONIDOVNA LU: "Design, synthesis and biological evaluation of naphthostyril derivatives as novel protein kinase FGFR1 inhibitors", JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 30, no. 1, 18 June 2014 (2014-06-18), pages 126 - 132, XP093008469, DOI: 10.3109/14756366.2014.895718 * |
| XIAOQIAN XUE, YAN ZHANG, ZHAOXUAN LIU, MING SONG, YANLI XING, QIUPING XIANG, ZHEN WANG, ZHENGCHAO TU, YULAI ZHOU, KE DING, YONG XU: "Discovery of Benzo[ cd ]indol-2(1 H )-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 59, no. 4, 25 February 2016 (2016-02-25), US , pages 1565 - 1579, XP055273700, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.5b01511 * |
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| KR20220161077A (en) | 2022-12-06 |
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