WO2024019562A1 - Heterobicyclic compound and pharmaceutical composition comprising same - Google Patents

Heterobicyclic compound and pharmaceutical composition comprising same Download PDF

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WO2024019562A1
WO2024019562A1 PCT/KR2023/010500 KR2023010500W WO2024019562A1 WO 2024019562 A1 WO2024019562 A1 WO 2024019562A1 KR 2023010500 W KR2023010500 W KR 2023010500W WO 2024019562 A1 WO2024019562 A1 WO 2024019562A1
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compound
phenyl
trifluoromethyl
prop
dihydroisoquinolin
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PCT/KR2023/010500
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French (fr)
Korean (ko)
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김진혁
김용찬
문성호
김민혜
조선연
이인상
노경태
박성일
김한성
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주식회사 바오밥에이바이오
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Publication of WO2024019562A1 publication Critical patent/WO2024019562A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterobicyclic compound and a pharmaceutical composition containing the same, and more specifically, to a heterobicyclic compound that exhibits TEAD transcriptional activation inhibitory activity through inhibiting the binding of YAP or TAZ to TEAD, and to a drug containing the same as an active ingredient. It is about academic composition.
  • 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 pathway begins with a kinase cascade consisting of MST-1/2 and LATS-1/2 and is activated by phosphorylating the transcriptional activator YAP or TAZ protein.
  • MST Mommalian Sterile20-like
  • SAV1 Small Cell Growth Factor 1
  • LATS Large tumor suppressor
  • MOB1 cofactor is its downstream targets.
  • Phosphorylated YAP binds to 14-3-3 protein and is degraded in the cytoplasm. As YAP is degraded, its binding to the TEAD family in the nucleus is inhibited.
  • YAP is suppressed, and the expression of genes that bind to YAP are suppressed, thereby limiting the growth of cells and tissues.
  • inactivation of the Hippo signaling pathway causes YAP to enter the nucleus, form a complex with the transcription factor TEAD, and cause gene expression, including connective tissue growth factor (CTGF), cysteine-rich 61 (Cry61), and fibroblast growth factor (FGF).
  • CTGF connective tissue growth factor
  • cysteine-rich 61 Cry61
  • FGF fibroblast growth factor
  • the YAP protein enters the nucleus and binds to the transcription factor TEAD protein to form a transcriptional complex, producing excessive amounts of various growth factors such as CTGF and FGF, thereby promoting the proliferation and growth of cancer cells. Therefore, it can be seen that it is very important to prevent excessive activation of the function of TEAD protein as a transcription factor (Nat Rev Cancer, 2013 Apr, 13(4), 246-57).
  • Republic of Korea Patent Publication No. 10-2022-0054307 discloses a 1,2,4-oxadiazol-5-one derivative as an inhibitor that regulates the interaction between YAP/TAZ and TEAD.
  • One object of the present invention is to provide a heterobicyclic compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof, which exhibits TEAD transcriptional activation inhibitory activity through inhibition of the binding of YAP or TAZ to TEAD.
  • Another object of the present invention is to provide a pharmaceutical composition for inhibiting the binding of YAP or TAZ and TEAD containing a heterobicyclic compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present invention relates to a heterobicyclic compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 is , , , or ego
  • R 2 and R 3 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 7 alkoxycarbonyl group, an oxo group, or a C 1 -C 6 hydroxyalkyl group,
  • R 4 is an aryl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, a C 1 -C 6 haloalkoxy group, and a C 1 -C 6 alkyl group, C It is a 3 -C 10 cycloalkenyl group or a C 3 -C 10 cycloalkyl group,
  • X, Y and Z are each independently a nitrogen atom or CR 5 ,
  • R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, a C 1 -C 6 haloalkyl group, or an aryloxy group,
  • L 1 does not exist or is an alkylene group of C 1 -C 6 ,
  • R 6 and R 7 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, or This is,
  • R 6 and R 7 are combined with each other to form a 4- to 7-membered hetero ring that may or may not be substituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group,
  • L 2 is absent or is an alkylene group or carbonyl group of C 1 -C 6 ,
  • R 8 is an aryl group substituted or unsubstituted with a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group, a C 3 -C 10 heterocycloalkyl group, or C It is a 3 -C 10 cycloalkyl group or a C 1 -C 6 alkyl group,
  • n is an integer from 0 to 2.
  • the C 1 -C 6 alkyl group used herein refers to a straight-chain or branched monovalent hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, and n-butyl. , i-butyl, t-butyl, n-pentyl, n-hexyl, etc., but are not limited thereto.
  • the C 2 -C 7 alkoxycarbonyl group used in this specification refers to a complex group formed by connecting a C 1 -C 6 alkoxy group and a carbonyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, and propaneoxycarbonyl group. It includes, but is not limited to, a nyl group, butoxycarbonyl group, etc.
  • the hydroxyalkyl group of C 1 -C 6 refers to a straight-chain or branched hydrocarbon having 1 to 6 carbon atoms substituted with a hydroxy group, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, etc. Included but not limited to this.
  • the haloalkyl group of C 1 -C 6 refers to a straight-chain or branched hydrocarbon having 1 to 6 carbon atoms substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine and iodine, for example Trifluoromethyl, trichloromethyl, trifluoroethyl, etc. are included, but are not limited thereto.
  • haloalkoxy group of C 1 -C 6 used herein refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine, and iodine, and trifluoro. It includes, but is not limited to, methoxy, trichloromethoxy, trifluoroethoxy, etc.
  • Aryl groups used herein include both aromatic groups, heteroaromatic groups, and partially reduced derivatives thereof.
  • the aromatic group is a simple or fused ring of 5 to 15 members
  • the heteroaromatic group refers to an aromatic group containing one or more oxygen, sulfur, or nitrogen.
  • Representative examples of aryl groups include phenyl, naphthyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, indolyl, quinolinyl, and Examples include imidazolinyl, oxazolyl, thiazolyl, and tetrahydronaphthyl, but are not limited thereto.
  • the cycloalkenyl group of C 3 -C 10 refers to a simple or fused cyclic unsaturated hydrocarbon consisting of 3 to 10 carbon atoms with one or more carbon-carbon double bonds, for example, cyclopropenyl, cycloalkenyl, It includes, but is not limited to, tenyl, cyclopentenyl, cyclohexenyl, etc.
  • the cycloalkyl group of C 3 -C 10 refers to a simple or fused cyclic saturated hydrocarbon consisting of 3 to 10 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It is not limited.
  • the C 1 -C 6 alkoxy group used in this specification refers to a straight-chain or branched alkoxy group consisting of 1 to 6 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propanoxy, etc.
  • an aryloxy group refers to an oxygen functional group single-bonded to an aryl group, and includes, but is not limited to, phenoxy, benzyloxy, etc.
  • the C 1 -C 6 alkylene group refers to a straight-chain or branched divalent hydrocarbon consisting of 1 to 6 carbon atoms, and examples include, but are limited to, methylene, ethylene, propylene, butylene, etc. It doesn't work.
  • the C 1 -C 6 alkylamino group used herein is a group of the formula -NR a R b (where R a and R b are each independently a hydrogen atom or a C 1 -C 6 alkyl group, provided that R a and R b is not a hydrogen atom at the same time) and includes, but is not limited to, monomethylamino group, dimethylamino group, monoethylamino group, diethylamino group, etc.
  • a 4- to 7-membered hetero ring refers to a functional group in which at least one ring carbon of a 4- to 7-membered hydrocarbon ring is substituted with oxygen, sulfur, or nitrogen, for example, piperidine, piperazine, It includes, but is not limited to, pyrrolidine, morpholine, pyrimidine, oxolein, oxane, thiazolidine, etc.
  • the heterocycloalkyl group of C 3 -C 10 refers to a functional group in which at least one ring carbon of a simple or fused cyclic hydrocarbon consisting of 3 to 10 carbon atoms is substituted with oxygen, sulfur, or nitrogen, for example It includes, but is not limited to, piperidinyl, piperazinyl, pyrrolidinyl, thiazolidinyl, oxiranyl, etc.
  • the heterobicyclic compound is,
  • R 1 is , or It is a phosphorus compound.
  • the heterobicyclic compound is,
  • R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group.
  • the heterobicyclic compound is,
  • R 4 is a compound that is an aryl group or a C 3 -C 10 cycloalkyl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, and a C 1 -C 6 haloalkoxy group. am.
  • the heterobicyclic compound is,
  • R 4 is a phenyl group, a naphthyl group, or a C 3 -C 10 cycloalkyl group that is substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group , a halogen atom, and a C 1 -C 6 haloalkoxy group. It is a phosphorus compound.
  • the heterobicyclic compound is,
  • X is a nitrogen atom or CR 5
  • Y and Z are each independently CR 5 compounds.
  • the heterobicyclic compound is,
  • R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or It is a phosphorus compound.
  • the heterobicyclic compound is,
  • R 6 is an alkyl group of C 1 -C 6
  • R 7 is an alkyl group of C 1 -C 6 or This is,
  • R 6 and R 7 are combined with each other to form a 4- to 7-membered heterocycle that may or may not be substituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group.
  • the heterobicyclic compound is,
  • R 6 is an alkyl group of C 1 -C 6
  • R 7 is an alkyl group of C 1 -C 6 or This is,
  • R 6 and R 7 are combined with each other to form a pyrrolidine that is substituted or unsubstituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group.
  • the heterobicyclic compound is,
  • L 2 is absent or is an alkylene group of C 1 -C 6 ,
  • R 8 is a compound that is an aryl group substituted or unsubstituted with a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group.
  • the heterobicyclic compound is,
  • L 2 is absent or is an alkylene group of C 1 -C 6 ,
  • R 8 is a compound that is a phenyl group substituted or unsubstituted with a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group.
  • the heterobicyclic compound is,
  • n is a compound where 1 is 1.
  • the heterobicyclic compound is,
  • R 1 is or ego
  • R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group
  • R 4 is a phenyl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, and a C 1 -C 6 haloalkoxy group,
  • X is a nitrogen atom or CR 5
  • Y and Z are each independently CR 5
  • R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or and
  • R 6 and R 7 are each independently an alkyl group of C 1 -C 6 ,
  • n is a compound where 1 is 1.
  • the heterobicyclic compound is,
  • R 1 is ego
  • R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group
  • X is a nitrogen atom or CR 5 ,
  • Y and Z are each independently CR 5 ,
  • R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or ego,
  • R 6 and R 7 are each independently an alkyl group of C 1 -C 6 ,
  • R 9 is a C 1 -C 6 haloalkyl group, a halogen atom, or a C 1 -C 6 haloalkoxy group
  • R 10 is a hydrogen atom or a halogen atom.
  • Pharmaceutically acceptable salts herein include both non-toxic inorganic salts and organic salts, and may be acid addition salts or base addition salts.
  • Acid addition salts include, for example, hydrochloride, sulfate, nitrate, phosphate, acetate, adipate, aspartate, benzoate, benzenesulfonate, citrate, camphorate, camphorsulfonate, and diphosphate.
  • Salts include ethanesulfonate, fumarate, glutamate, malate, lactate, methanesulfonate, succinate, tartrate, picrate, tosylate, etc.
  • Base addition salts include, for example, alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, magnesium and calcium, ammonium salts, quaternary ammonium salts such as tetramethylammonium and methylamine, dimethylamine, trimethylamine and triethyl. amines and amine salts such as ethylamine, etc.
  • Representative compounds among the compounds of the present invention are selected from the following groups.
  • the heterobicyclic compound represented by Formula I can be prepared by methods known in the art.
  • heterobicyclic compound represented by Formula 1 can be prepared by the method described in the Synthesis Example described later.
  • the heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention exhibits TEAD transcriptional activation inhibitory activity through inhibition of the binding of YAP or TAZ to TEAD (see Test Example 1).
  • heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent metabolic stability and pharmacokinetic properties (see Test Examples 2 and 3).
  • heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent tumor suppressive activity in a tumor mouse model (see Test Example 4).
  • the present invention provides a pharmaceutical composition for inhibiting the binding of YAP or TAZ to TEAD, comprising a heterobicyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, specifically, It relates to a pharmaceutical composition for the treatment or prevention of cancer.
  • the heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof induces an anticancer effect through inhibition of TEAD transcriptional activation by inhibiting the binding of YAP or TAZ to TEAD, thus preventing cancer. It can be useful in treatment.
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer, skin cancer, or mesothelioma.
  • the cancer is mesothelioma, eg malignant mesothelioma.
  • the cancer includes, but is not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, medium chain Diseases, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, an hematoma,
  • Carcinoma papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, testicular tumor, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma.
  • small cell lung carcinoma bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic schwannoma, oligodendroglioma, Schwann cell tumor, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).
  • GBM glioblastoma multiforme
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic schwannoma, oligodendroglioma, Schwann cell tumor, Neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • the cancer is an acoustic schwannoma, an astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - sub-grade astrocytoma, grade III - anaplastic astrocytoma, or grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma , pituitary tumor, primitive neuroectodermal (PNET) tumor, or Schwann cell tumor.
  • astrocytoma e.g., grade I - pilocytic astrocytoma, grade II - sub-grade astrocytoma,
  • the cancer is of a type more commonly found in children than in adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve.
  • JPA juvenile pilocytic astrocytoma
  • Glioma pineal tumor, primitive neuroectodermal tumor (PNET), or rod tumor.
  • the cancer includes, but is not limited to, mesothelioma, hepatobiliary (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, Rectal cancer, cancer of the anal area, stomach cancer, gastrointestinal (stomach, colorectal, and adenocarcinoma) cancer, uterine cancer, carcinoma of the uterine tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, adrenal cancer, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leuk
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, uterine tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC) , hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST) ), Waldenstrom's macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • the cancer is a solid tumor, such as sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally contain large amounts of abnormal tissue that typically do not contain cysts or areas of fluid.
  • the cancer is renal cell carcinoma, or kidney cancer; Hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; Colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; Lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); Ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or uterine tube cancer; Papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; Anaplastic thyroid cancer; Adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic a
  • the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, Uterine tubal cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatobiliary carcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreas.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colorectal carcinoma
  • colorectal cancer colon cancer
  • rectal cancer anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, Uterine tubal cancer, papillary serous cystadenocar
  • ductal carcinoma pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.
  • MPNST neurofibromatosis-1 associated malignant peripheral nerve sheath tumor
  • Waldenstrom's macroglobulinemia or medulloblastoma.
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, uterine tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous Carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve home tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer ovarian epi
  • the cancer is caused by human immunodeficiency virus (HIV)-related solid tumors, human papillomavirus (HPV)-16 benign incurable solid tumors, and human T-cell leukemia virus type I (HTLV-I).
  • HSV human immunodeficiency virus
  • HPV human papillomavirus
  • HTLV-I human T-cell leukemia virus type I
  • Adult T-cell leukemia a highly aggressive form of CD4+ T-cell leukemia caused by and characterized by clonal integration of HTLV-I in leukemic cells, as well as gastric, nasopharyngeal carcinoma, cervical, vaginal, and vulvar cancers.
  • Virus-associated cancers include virus-associated tumors in squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • the pharmaceutical composition according to the present invention can be administered orally (e.g., by ingestion or inhalation) or parenterally (e.g., by injection, deposition, implantation, suppository), and injection is, for example, intravenous. , it may be a subcutaneous injection, an intramuscular injection, or an intraperitoneal injection.
  • the pharmaceutical composition according to the present invention is available as tablets, capsules, granules, fine subtilae, powder, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc., depending on the route of administration. It can be formulated.
  • compositions according to the present invention can be prepared by known techniques using pharmaceutically acceptable carriers commonly used in each dosage form.
  • pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweeteners, solubilizers, bases, dispersants, and wetting agents. , suspending agents, stabilizers, colorants, etc.
  • the pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the specific dosage of the pharmaceutical composition of the present invention may vary depending on the type, weight, gender, degree of disease, doctor's judgment, etc. of the mammal, including humans, to be treated.
  • the total daily dosage may be administered all at once or in several divided doses depending on the degree of the disease, the doctor's judgment, etc.
  • the compounds of the present invention exhibit TEAD transcriptional activation inhibitory activity through inhibition of the binding of YAP or TAZ to TEAD. Therefore, the compounds of the present invention can be effectively used in pharmaceutical compositions for the treatment or prevention of cancer.
  • Figure 1 shows the results of evaluating the activity of the compound of Example 1 in a tumor mouse model.
  • Example 1-1 Synthesis of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 1-3 1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one synthesis
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-3,3-dimethyl-3,4- The title compound was obtained in the same manner as Example 1, except for using dihydroisoquinoline-2(1H)-carboxylate.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 3-bromo-7,8-dihydro-1,6
  • the title compound was obtained in the same manner as Example 1, except that -naphthyridine-6(5H)-carboxylate was used.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-3-methyl-3,4-dihydro
  • the title compound was obtained in the same manner as Example 1, except that isoquinoline-2(1H)-carboxylate was used.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-methyl-3,4-dihydro
  • the title compound was obtained in the same manner as Example 1, except that isoquinoline-2(1H)-carboxylate was used.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-methoxy-3,4-di
  • the title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-5-fluoro-3,4-di
  • the title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-nitro-3,4-dihydro
  • the title compound was obtained in the same manner as Example 1, except that isoquinoline-2(1H)-carboxylate was used.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-5-methoxy-3,4-di
  • the title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-fluoro-3,4-di
  • the title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
  • Example 1-1 Using tert-butyl 5-bromoisoindoline-2-carboxylate instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1.
  • the title compound was obtained in the same manner as Example 1, except that.
  • Example 1-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 2-bromo-4-(trifluoromethyl)-5
  • the title compound was obtained in the same manner as Example 1, except that ,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate was used.
  • Example 17 instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 3,3-dimethyl-7-(4-(trifluoromethyl)phenyl )-1,2,3,4-Tetrahydroisoquinoline was used in the same manner as in Example 17 to obtain the title compound.
  • Example 17 instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 3-(4-(trifluoromethyl)phenyl)-5,6, The title compound was obtained in the same manner as Example 17, except for using 7,8-tetrahydro-1,6-naphthyridine.
  • Example 17 instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 3-(4-(trifluoromethyl)phenyl)-5,6, The title compound was obtained in the same manner as Example 17, except for using 7,8-tetrahydropyrido[4,3-c]pyridazine.
  • Example 17 6-methyl-7-(4-(trifluoromethyl)phenyl)- The title compound was obtained in the same manner as Example 17, except for using 1,2,3,4-tetrahydroisoquinoline.
  • Example 17 6-methoxy-7-(4-(trifluoromethyl)phenyl) The title compound was obtained in the same manner as Example 17, except that -1,2,3,4-tetrahydroisoquinoline was used.
  • Example 17 Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 5-methoxy-7-(4-(trifluoromethyl)phenyl) The title compound was obtained in the same manner as Example 17, except that -1,2,3,4-tetrahydroisoquinoline was used.
  • Example 28-1 Synthesis of tert-butyl 7-(cyclohex-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 28-3 1-(7-(cyclohex-1-en-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one synthesis of
  • Example 28-1 The title compound was obtained in the same manner as Example 28, except that phenylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
  • Example 28-1 The title compound was obtained in the same manner as Example 28, except that (4-fluorophenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
  • Example 28-1 The title compound was prepared in the same manner as in Example 28, except that (3,4-difluorophenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. got it
  • Example 28-1 The title compound was obtained in the same manner as Example 28, except that thiophen-2-ylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
  • Example 28-1 The title compound was obtained in the same manner as Example 28, except that (3-(trifluoromethyl)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. got it
  • Example 28-1 Same as Example 28, except that (6-(trifluoromethyl)pyridin-3-yl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
  • Example 28-1 The title compound was obtained in the same manner as Example 28, except that (4-(trifluoromethoxy)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. got it
  • Example 28 The same as Example 28, except that (2-chloro-4-(trifluoromethyl)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
  • Example 28-1 Same as Example 28, except that (3-fluoro-4-(trifluoromethyl)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
  • Example 28-1 The title compound was obtained in the same manner as Example 28, except that naphthalene-2-ylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
  • Example 28 The same as Example 28, except that (5-(trifluoromethyl)pyridin-2-yl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
  • Example 28-1 The title compound was obtained in the same manner as Example 28, except that p-tolylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
  • Example 42 except that 5-bromoisoindolin-1-one was used instead of 7-bromo-1,4-dihydroisoquinolin-3(2H)-one in Example 42-1. The same procedure was performed to obtain the title compound.
  • Example 44-1 Synthesis of tert-butyl 6-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 44-2 Synthesis of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 44-3 Synthesis of tert-butyl 6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 44-4 1-(6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
  • Example 44-3 the product prepared in Example 44-3 The above examples except that tert-butyl 6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The same procedure as 1-2 and 1-3 was performed to obtain the title compound.
  • Example 1-2 tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-2, tert-butyl 6-(benzylamino) Same as Examples 1-2 and 1-3 above, except for using -7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate This was performed to obtain the title compound.
  • Example 52-1 Of tert-butyl 6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate synthesis
  • Example 52-1 the product prepared in Example 52-1 Except using tert-butyl 6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, The title compound was obtained in the same manner as Examples 1-2 and 1-3.
  • Example 52-1 Except using tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate prepared in Example 44-2. , the title compound was obtained in the same manner as Example 52.
  • Example 1-2 tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-2, tert-butyl 6-(dimethylamino) Same as Examples 1-2 and 1-3 above, except for using -7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate This was performed to obtain the title compound.
  • Example 55-2 1-(4-Bromo-3-methoxyphenyl)propan-2-amine (171 mg) prepared in Example 55-2 was dissolved in 5 ml of DCM, and then TEA (212 mg, 2.1 mmol) and TFAA (220 mg, 1.0 mg) were dissolved in 5 ml of DCM. mmol) was added and stirred at room temperature for 1 day. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (160mg, 67.4%)
  • Example 55-4 1-(7-Bromo-6-methoxy-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane Synthesis of -1-one
  • N-(1-(4-bromo-3-methoxyphenyl)propan-2-yl)-2,2,2-trifluoroacetamide 160 mg, 0.47 mmol prepared in Example 55-3. was dissolved in a mixed solution of 6ml AcOH and 2ml H 2 SO 4 . (CH 2 O) n (40 mg, 0.47 mmol) was added to the mixture and stirred at 30°C for 2 days. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white liquid. (34mg, 21%)
  • Example 56-1 Synthesis of tert-butyl 6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 56-2 1-(6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
  • Example 56-1 tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, prepared in Example 56-1 The above examples except that tert-butyl 6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The same procedure as 1-2 and 1-3 was performed to obtain the title compound.
  • Example 67-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1, tert-butyl 5-benzamido- prepared in Example 67-1 was used.
  • the title compound was obtained in the same manner as Example 1, except that 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate was used.
  • Example 67-1 The title compound was obtained in the same manner as in Example 67, except that acetic acid was used instead of benzoic acid in Example 67-1.
  • Example 67-1 The title compound was obtained in the same manner as in Example 67, except that propionic acid was used instead of benzoic acid in Example 67-1.
  • Example 72-1 Synthesis of tert-butyl 7-bromo-5-(dimethylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 72-2 1-(5-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
  • Example 72-1 tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1.
  • tert-butyl 7-bromo-5 prepared in Example 72-1 was used.
  • the title compound was obtained in the same manner as in Example 1, except that -(dimethylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used.
  • Example 73-1 Synthesis of tert-butyl 6-benzamido-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 1-2 instead of the tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, the product prepared in Example 73-1 Example 1 above, except that tert-butyl 6-benzamido-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The title compound was obtained in the same manner as -2 and 1-3.
  • Example 74-1 1-(6-hydroxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one
  • Example 74-2 1-(6-(benzyloxy)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
  • Example 75-1 Synthesis of methyl (S)-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
  • Example 75-1 methyl (S)-7-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate of Example 75-1, methyl (R)-7-bromo-1,2,3 , The title compound was obtained in the same manner as Example 75, except for using 4-tetrahydroisoquinoline-3-carboxylate.
  • Example 77-1 Synthesis of tert-butyl 5-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Example 77-2 Synthesis of tert-butyl 5-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  • Test Example 1 Evaluation of TEAD transcriptional activation inhibition
  • TEAD activity status of MCF7 cells into which the TEAD reporter gene was inserted was evaluated.
  • the prepared compound was treated at a concentration ranging from 100 pM to 1 ⁇ M for 24 hours to confirm its effect on the transcriptional activity of TEAD.
  • the activity of each compound was measured by setting the activity measurement value of the TEAD luciferase reporter treated with dimethyl sulfoxide (DMSO) alone as a dissolving agent as 100%, and half-maximal inhibition was performed using Prism software (v.9.4; GraphPad). The concentration, IC 50 , was calculated.
  • DMSO dimethyl sulfoxide
  • Example TEAD reporter inhibition IC 50 (nM) One 0.17 2 0.37 3 0.59 4 8.78 5 0.34 6 0.62 7 0.28 8 0.45 9 18 10 5.74 11 0.19 12 0.08 13 0.15 14 6.49 15 3.1 16 2.5 17 0.17 18 66 19 7.5 20 86 21 5.98 22 2.80 23 0.69 24 0.16 25 0.17 26 33.5 27 >100 28 3.12 29 3.41 30 0.92 31 2.81 32 5.36 33 0.31 34 4.91 35 0.43 36 0.94 37 0.55 38 1.54 39 3.7 40 3.3 41 0.83 42 >100 43 >100 44 23.35 45 3.65 46 2.5 47 3.7 48 14.15 49 6.6 50 6.99 51 >100 52 0.34 53 >100 54 0.17 55 0.16 56 13 57 6.16 58 35 59 25 60 3.15 61 7.9 62 4.36 63 14 64 2.8 65 29 66 15.3 67 3 68 14.67 69 10.02 70 15.81 71 61.5 72 0.62 73 9.5 74 3.7 75 8.76 76 5.87 77 >100 78 0.98
  • the heterobicyclic compound according to the present invention showed excellent TEAD transcriptional activation inhibition efficacy.
  • Rat liver microsomes (MLM) stored in the freezer were thawed, and the microsomes dispersed in NADPH (1mM) and metabolism test solution were reacted for 5 minutes and treated with the test drug. After 30 minutes, the reaction was terminated, and the supernatant was separated using a centrifuge for 15 minutes and analyzed with an LC-MS/MS system.
  • mice 7-8 week old mice (approximately 30-40 g) were fasted for approximately 18 hours.
  • Administration The test drug was dissolved in a vehicle at a concentration of 2 mg/mL and then administered at a dose of 10 mg/kg in a volume of 5 mL/kg. After administration, orbital blood was collected using a heparin-treated blood collection capillary. Blood was centrifuged at 14000 rpm for 10 minutes to separate plasma and analyzed with an LC-MS/MS system.
  • Example 1 62.7 288.8
  • Example 2 55.3 787.3
  • Example 5 N.A. 636.3
  • Example 7 72.2 478.6
  • Example 12 72.3 312.4
  • Example 13 70.2 373.7
  • Example 17 85.1 324.8
  • Example 55 74.1 513.4
  • Example 72 78.2 737.3
  • heterobicyclic compound of the present invention exhibits excellent metabolic stability and pharmacokinetic properties.
  • Test Example 4 Activity evaluation in tumor mouse model
  • Tumors were formed by injecting 1 ⁇ 10 7 NCI-H226 cell line mixed 1:1 with Matrigel subcutaneously into 10 NOD SCID mice aged 6 to 7 weeks, and then administered the test drug of Example 1 as a test drug.
  • the compounds were administered orally at concentrations of 10 mg/kg and 30 mg/kg, and size changes were measured for 28 days.

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Abstract

The present invention relates to a heterobicyclic compound that exhibits inhibitory activity against TEAD transcriptional activation by inhibiting the binding of YAP or TAZ to TEAD, and a pharmaceutical composition comprising same as an active ingredient. The heterobicyclic compound of the present invention can be advantageously used in the treatment or prevention of cancer.

Description

헤테로비시클릭 화합물 및 그를 포함하는 약제학적 조성물Heterobicyclic compounds and pharmaceutical compositions containing them
본 발명은 헤테로비시클릭 화합물 및 그를 포함하는 약제학적 조성물에 관한 것으로, 보다 구체적으로 YAP 또는 TAZ와 TEAD의 결합 저해를 통해 TEAD 전사 활성화 저해 활성을 나타내는 헤테로비시클릭 화합물 및 그를 유효성분으로 포함하는 약제학적 조성물에 관한 것이다.The present invention relates to a heterobicyclic compound and a pharmaceutical composition containing the same, and more specifically, to a heterobicyclic compound that exhibits TEAD transcriptional activation inhibitory activity through inhibiting the binding of YAP or TAZ to TEAD, and to a drug containing the same as an active ingredient. It is about academic composition.
히포 신호전달 경로(Hippo signaling pathway)는 인체에서 정상 세포의 증식 및 피부, 근육, 폐, 간 등의 조직 및 장기들의 성장과 크기 등을 조절하는 주요 신호전달 경로이다.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.
히포 신호전달 경로는 MST-1/2, LATS-1/2로 구성된 키나아제 캐스케이드(cascade)로부터 시작되어 전사활성 인자인 YAP 또는 TAZ 단백질을 인산화시켜 활성화된다.The Hippo signaling pathway begins with a kinase cascade consisting of MST-1/2 and LATS-1/2 and is activated by phosphorylating the transcriptional activator YAP or TAZ protein.
히포 신호전달 경로가 활성화되면, MST(Mammalian Sterile20-like) 키나아제는 SAV1(Salvador Family WWDomain Containing Protein 1)과 복합체를 이루어 LATS(Large tumor suppressor) 키나아제를 인산화시키고, LATS 키나아제와 MOB1 cofactor는 그 하위 표적인 YAP을 인산화시킨다. 인산화된 YAP은 14-3-3 단백질과 결합하여 세포질에서 분해된다. YAP가 분해됨에 따라 핵 내에서 TEAD family와의 결합이 저해된다. 즉, 히포 신호전달 경로가 활성화되면 YAP가 억제되고, YAP와 결합하는 유전자 발현이 억제되어 세포와 조직의 성장이 제한된다.When the Hippo signaling pathway is activated, MST (Mammalian Sterile20-like) kinase forms a complex with SAV1 (Salvador Family WWDomain Containing Protein 1) to phosphorylate LATS (Large tumor suppressor) kinase, and LATS kinase and MOB1 cofactor are its downstream targets. Phosphorylates YAP. Phosphorylated YAP binds to 14-3-3 protein and is degraded in the cytoplasm. As YAP is degraded, its binding to the TEAD family in the nucleus is inhibited. In other words, when the Hippo signaling pathway is activated, YAP is suppressed, and the expression of genes that bind to YAP are suppressed, thereby limiting the growth of cells and tissues.
반면, 히포 신호전달 경로의 비활성화는 YAP가 핵 내로 들어가 전사인자인 TEAD와 복합체를 이루고, 유전자 발현을 일으켜 CTGF(connective tissue growth factor), Cry61(cystein-rich 61), FGF(fibroblast growth factor)와 같은 성장인자의 분비를 통해 세포의 성장을 촉진하고 세포사멸을 억제하게 된다.On the other hand, inactivation of the Hippo signaling pathway causes YAP to enter the nucleus, form a complex with the transcription factor TEAD, and cause gene expression, including connective tissue growth factor (CTGF), cysteine-rich 61 (Cry61), and fibroblast growth factor (FGF). Through the secretion of the same growth factors, cell growth is promoted and cell death is suppressed.
암세포의 발생 및 성장에는 바로 YAP 단백질이 핵 내로 들어가 전사인자인 TEAD 단백질과 결합하여 전사보합체를 이루어 CTGF, FGF 등의 다양한 성장인자를 과량으로 생산하게 됨으로써 암세포의 증식, 성장을 촉진하는 것으로 보고 있어, TEAD 단백질의 전사인자로의 기능이 과하게 활성화되는 것을 막는 게 매우 중요함을 알 수 있다(Nat Rev Cancer, 2013 Apr, 13(4), 246-57).During the development and growth of cancer cells, the YAP protein enters the nucleus and binds to the transcription factor TEAD protein to form a transcriptional complex, producing excessive amounts of various growth factors such as CTGF and FGF, thereby promoting the proliferation and growth of cancer cells. Therefore, it can be seen that it is very important to prevent excessive activation of the function of TEAD protein as a transcription factor (Nat Rev Cancer, 2013 Apr, 13(4), 246-57).
Hippo 신호전달 활성화 및 YAP/TAZ를 억제하는 표적 치료의 가능성이 대두되었지만 YAP, TAZ 단백질의 구조 규명의 한계점으로 새로운 타겟의 가능성이 제시되었다. 다른 하위 조절인자인 TEAD의 PTM(Post-translational modification)을 통한 활성화 조절에 대한 연구가 진행되었고 TEAD 전사활성화의 억제를 바탕으로 한 항암 기전연구를 통해 신규 악성 종양의 치료방법으로 제안되었다(Nat Chem Biol., 2016 Apr, 12(4), 282-9).The possibility of targeted treatment that activates Hippo signaling and inhibits YAP/TAZ has emerged, but limitations in elucidating the structures of YAP and TAZ proteins have suggested the possibility of new targets. Research has been conducted on the regulation of activation through PTM (Post-translational modification) of TEAD, another downstream regulator, and it has been proposed as a treatment method for new malignant tumors through research on anticancer mechanisms based on inhibition of TEAD transcriptional activation (Nat Chem Biol., 2016 Apr, 12(4), 282-9).
최근 Hippo 신호전달 경로 조절제 중 YAP과 TAZ 단백질의 TEAD 단백질과의 상호작용 억제제로서 제안된 화합물들이 다수 있다. 예를 들어, 대한민국 공개특허 제10-2022-0054307호는 YAP/TAZ와 TEAD 간의 상호작용을 조절하는 억제제로서 1,2,4-옥사디아졸-5-온 유도체를 개시하고 있다.Recently, among Hippo signaling pathway regulators, there are a number of compounds proposed as inhibitors of the interaction of YAP and TAZ proteins with TEAD proteins. For example, Republic of Korea Patent Publication No. 10-2022-0054307 discloses a 1,2,4-oxadiazol-5-one derivative as an inhibitor that regulates the interaction between YAP/TAZ and TEAD.
그러나, 여전히 보다 효과적으로 YAP 또는 TAZ와 TEAD의 결합 저해를 통해 TEAD 전사 활성화 저해 활성을 나타내는 새로운 구조의 물질에 대한 개발이 요구되고 있는 실정이다.However, there is still a need for the development of materials with new structures that exhibit TEAD transcriptional activation inhibitory activity through more effective inhibition of the combination of YAP or TAZ with TEAD.
본 발명의 한 목적은 YAP 또는 TAZ와 TEAD의 결합 저해를 통해 TEAD 전사 활성화 저해 활성을 나타내는 하기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염을 제공하는 것이다.One object of the present invention is to provide a heterobicyclic compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof, which exhibits TEAD transcriptional activation inhibitory activity through inhibition of the binding of YAP or TAZ to TEAD.
본 발명의 다른 목적은 하기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염을 함유하는 YAP 또는 TAZ와 TEAD의 결합 저해용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for inhibiting the binding of YAP or TAZ and TEAD containing a heterobicyclic compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
본 발명의 일 실시형태는 하기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염에 관한 것이다.One embodiment of the present invention relates to a heterobicyclic compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
Figure PCTKR2023010500-appb-img-000001
Figure PCTKR2023010500-appb-img-000001
상기 식에서, In the above equation,
R1은
Figure PCTKR2023010500-appb-img-000002
,
Figure PCTKR2023010500-appb-img-000003
,
Figure PCTKR2023010500-appb-img-000004
,
Figure PCTKR2023010500-appb-img-000005
또는
Figure PCTKR2023010500-appb-img-000006
이고, R 1 is
Figure PCTKR2023010500-appb-img-000002
,
Figure PCTKR2023010500-appb-img-000003
,
Figure PCTKR2023010500-appb-img-000004
,
Figure PCTKR2023010500-appb-img-000005
or
Figure PCTKR2023010500-appb-img-000006
ego,
R2 및 R3는 각각 독립적으로 수소 원자, C1-C6의 알킬기, C2-C7의 알콕시카보닐기, 옥소기 또는 C1-C6의 히드록시알킬기이며, R 2 and R 3 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 7 alkoxycarbonyl group, an oxo group, or a C 1 -C 6 hydroxyalkyl group,
R4는 C1-C6의 할로알킬기, 할로겐 원자, C1-C6의 할로알콕시기 및 C1-C6의 알킬기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 아릴기, C3-C10의 사이클로알케닐기 또는 C3-C10의 사이클로알킬기이고, R 4 is an aryl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, a C 1 -C 6 haloalkoxy group, and a C 1 -C 6 alkyl group, C It is a 3 -C 10 cycloalkenyl group or a C 3 -C 10 cycloalkyl group,
X, Y 및 Z는 각각 독립적으로 질소 원자 또는 CR5이며, X, Y and Z are each independently a nitrogen atom or CR 5 ,
R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기, C1-C6의 할로알킬기,
Figure PCTKR2023010500-appb-img-000007
또는 아릴옥시기이고, R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, a C 1 -C 6 haloalkyl group,
Figure PCTKR2023010500-appb-img-000007
or an aryloxy group,
L1은 존재하지 않거나, C1-C6의 알킬렌기이며, L 1 does not exist or is an alkylene group of C 1 -C 6 ,
R6 및 R7은 각각 독립적으로 수소 원자, C1-C6의 알킬기 또는
Figure PCTKR2023010500-appb-img-000008
이거나, R 6 and R 7 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, or
Figure PCTKR2023010500-appb-img-000008
This is,
R6과 R7은 서로 결합하여, C1-C6의 알킬기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 4 내지 7원의 헤테로 고리를 형성하고, R 6 and R 7 are combined with each other to form a 4- to 7-membered hetero ring that may or may not be substituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group,
L2는 존재하지 않거나, C1-C6의 알킬렌기 또는 카보닐기이며, L 2 is absent or is an alkylene group or carbonyl group of C 1 -C 6 ,
R8은 C1-C6의 알콕시기, C1-C6의 알킬기, 히드록시기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 아릴기, C3-C10의 헤테로사이클로알킬기 또는 C3-C10의 사이클로알킬기이거나, C1-C6의 알킬기이고, R 8 is an aryl group substituted or unsubstituted with a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group, a C 3 -C 10 heterocycloalkyl group, or C It is a 3 -C 10 cycloalkyl group or a C 1 -C 6 alkyl group,
n은 0 내지 2의 정수이다.n is an integer from 0 to 2.
본 명세서에서 사용되는 C1-C6의 알킬기는 탄소수 1 내지 6개로 구성된 직쇄형 또는 분지형의 1가 탄화수소를 의미하며, 예를 들어 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, n-펜틸, n-헥실 등이 포함되나 이에 한정되는 것은 아니다.The C 1 -C 6 alkyl group used herein refers to a straight-chain or branched monovalent hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, and n-butyl. , i-butyl, t-butyl, n-pentyl, n-hexyl, etc., but are not limited thereto.
본 명세서에서 사용되는 C2-C7의 알콕시카보닐기는 C1-C6의 알콕시기와 카보닐기가 연결되어 형성된 복합기를 의미하며, 예를 들어 메톡시카보닐기, 에톡시카보닐기, 프로판옥시카보닐기, 부톡시카보닐기 등이 포함되나 이에 한정되는 것은 아니다.The C 2 -C 7 alkoxycarbonyl group used in this specification refers to a complex group formed by connecting a C 1 -C 6 alkoxy group and a carbonyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, and propaneoxycarbonyl group. It includes, but is not limited to, a nyl group, butoxycarbonyl group, etc.
본 명세서에서 사용되는 C1-C6의 히드록시알킬기는 히드록시기로 치환된 탄소수 1 내지 6개의 직쇄형 또는 분지형 탄화수소를 의미하며, 예를 들어 히드록시메틸, 히드록시에틸, 히드록시프로필 등이 포함되나 이에 한정되는 것은 아니다.As used herein, the hydroxyalkyl group of C 1 -C 6 refers to a straight-chain or branched hydrocarbon having 1 to 6 carbon atoms substituted with a hydroxy group, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, etc. Included but not limited to this.
본 명세서에서 사용되는 C1-C6의 할로알킬기는 불소, 염소, 브롬 및 요오드로 구성된 군으로부터 선택된 하나 이상의 할로겐으로 치환된 탄소수 1 내지 6개의 직쇄형 또는 분지형 탄화수소를 의미하며, 예를 들어 트리플로오로메틸, 트리클로로메틸, 트리플루오로에틸 등이 포함되나 이에 한정되는 것은 아니다.As used herein, the haloalkyl group of C 1 -C 6 refers to a straight-chain or branched hydrocarbon having 1 to 6 carbon atoms substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine and iodine, for example Trifluoromethyl, trichloromethyl, trifluoroethyl, etc. are included, but are not limited thereto.
본 명세서에서 사용되는 C1-C6의 할로알콕시기는 불소, 염소, 브롬 및 요오드로 구성된 군으로부터 선택된 하나 이상의 할로겐으로 치환된 탄소수 1 내지 6개의 직쇄형 또는 분지형 알콕시기를 의미하며, 트리플로오로메톡시, 트리클로로메톡시, 트리플로오로에톡시 등이 포함되나 이에 한정되는 것은 아니다.The haloalkoxy group of C 1 -C 6 used herein refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine, and iodine, and trifluoro. It includes, but is not limited to, methoxy, trichloromethoxy, trifluoroethoxy, etc.
본 명세서에서 사용되는 아릴기는 아로메틱기와 헤테로아로메틱기 및 그들의 부분적으로 환원된 유도체를 모두 포함한다. 상기 아로메틱기는 5원 내지 15원의 단순 또는 융합 고리형이며, 헤테로아로메틱기는 산소, 황 또는 질소를 하나 이상 포함하는 아로메틱기를 의미한다. 대표적인 아릴기의 예로는 페닐, 나프틸, 피리디닐(pyridinyl), 피리미디닐(pyrimidinyl), 푸라닐(furanyl), 티오페닐(thiophenyl), 인돌릴(indolyl), 퀴놀리닐(quinolinyl), 이미다졸리닐(imidazolinyl), 옥사졸릴(oxazolyl), 티아졸릴(thiazolyl), 테트라히드로나프틸 등이 있으나 이에 한정되는 것은 아니다.Aryl groups used herein include both aromatic groups, heteroaromatic groups, and partially reduced derivatives thereof. The aromatic group is a simple or fused ring of 5 to 15 members, and the heteroaromatic group refers to an aromatic group containing one or more oxygen, sulfur, or nitrogen. Representative examples of aryl groups include phenyl, naphthyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, indolyl, quinolinyl, and Examples include imidazolinyl, oxazolyl, thiazolyl, and tetrahydronaphthyl, but are not limited thereto.
본 명세서에서 사용되는 C3-C10의 사이클로알케닐기는 하나 이상의 탄소-탄소 이중결합을 갖는 탄소수 3 내지 10개로 구성된 단순 또는 융합 고리형 불포화 탄화수소를 의미하며, 예를 들어 사이클로프로펜일, 사이클로부텐일, 사이클로펜텐일, 사이클로헥센일 등이 포함되나 이에 한정되는 것은 아니다. As used herein, the cycloalkenyl group of C 3 -C 10 refers to a simple or fused cyclic unsaturated hydrocarbon consisting of 3 to 10 carbon atoms with one or more carbon-carbon double bonds, for example, cyclopropenyl, cycloalkenyl, It includes, but is not limited to, tenyl, cyclopentenyl, cyclohexenyl, etc.
본 명세서에서 사용되는 C3-C10의 사이클로알킬기는 탄소수 3 내지 10개로 구성된 단순 또는 융합 고리형 포화 탄화수소를 의미하며, 예를 들어 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 등이 포함되나 이에 한정되는 것은 아니다. As used herein, the cycloalkyl group of C 3 -C 10 refers to a simple or fused cyclic saturated hydrocarbon consisting of 3 to 10 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It is not limited.
본 명세서에서 사용되는 C1-C6의 알콕시기는 탄소수 1 내지 6개로 구성된 직쇄형 또는 분지형 알콕시기를 의미하며, 메톡시, 에톡시, n-프로판옥시 등이 포함되나 이에 한정되는 것은 아니다.The C 1 -C 6 alkoxy group used in this specification refers to a straight-chain or branched alkoxy group consisting of 1 to 6 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propanoxy, etc.
본 명세서에서 아릴옥시기는 아릴기에 단일결합된 산소 작용기를 의미하며, 페녹시, 벤질옥시 등이 포함되나 이에 한정되는 것은 아니다.In this specification, an aryloxy group refers to an oxygen functional group single-bonded to an aryl group, and includes, but is not limited to, phenoxy, benzyloxy, etc.
본 명세서에서 사용되는 C1-C6의 알킬렌기는 탄소수 1 내지 6개로 구성된 직쇄형 또는 분지형의 2가 탄화수소를 의미하며, 예를 들어 메틸렌, 에틸렌, 프로필렌, 부틸렌 등이 포함되나 이에 한정되는 것은 아니다.As used herein, the C 1 -C 6 alkylene group refers to a straight-chain or branched divalent hydrocarbon consisting of 1 to 6 carbon atoms, and examples include, but are limited to, methylene, ethylene, propylene, butylene, etc. It doesn't work.
본 명세서에서 사용되는 C1-C6의 알킬아미노기는 화학식 -NRaRb의 기(이때 Ra 및 Rb는 각각 독립적으로 수소 원자 또는 C1-C6의 알킬기이고, 단 Ra 및 Rb는 동시에 수소 원자는 아니다)를 나타내며, 모노메틸아미노기, 디메틸아미노기, 모노에틸아미노기, 디에틸아미노기 등이 포함되나 이에 한정되는 것은 아니다.The C 1 -C 6 alkylamino group used herein is a group of the formula -NR a R b (where R a and R b are each independently a hydrogen atom or a C 1 -C 6 alkyl group, provided that R a and R b is not a hydrogen atom at the same time) and includes, but is not limited to, monomethylamino group, dimethylamino group, monoethylamino group, diethylamino group, etc.
본 명세서에서 사용되는 4 내지 7원의 헤테로 고리는 4 내지 7원의 탄화수소 고리의 환 탄소 중 하나 이상이 산소, 황 또는 질소로 치환된 작용기를 의미하며, 예를 들어 피페리딘, 피페라진, 피롤리딘, 모르폴린, 피리미딘, 옥솔레인, 옥산, 티아졸리딘 등이 포함되나 이에 한정되는 것은 아니다.As used herein, a 4- to 7-membered hetero ring refers to a functional group in which at least one ring carbon of a 4- to 7-membered hydrocarbon ring is substituted with oxygen, sulfur, or nitrogen, for example, piperidine, piperazine, It includes, but is not limited to, pyrrolidine, morpholine, pyrimidine, oxolein, oxane, thiazolidine, etc.
본 명세서에서 사용되는 C3-C10의 헤테로사이클로알킬기는 탄소수 3 내지 10개로 구성된 단순 또는 융합 고리형 탄화수소의 환 탄소 중 하나 이상이 산소, 황 또는 질소로 치환된 작용기를 의미하며, 예를 들어 피페리디닐, 피페라지닐, 피롤리디닐, 티아졸리디닐, 옥시라닐 등이 포함되나 이에 한정되는 것은 아니다.As used herein, the heterocycloalkyl group of C 3 -C 10 refers to a functional group in which at least one ring carbon of a simple or fused cyclic hydrocarbon consisting of 3 to 10 carbon atoms is substituted with oxygen, sulfur, or nitrogen, for example It includes, but is not limited to, piperidinyl, piperazinyl, pyrrolidinyl, thiazolidinyl, oxiranyl, etc.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R1은
Figure PCTKR2023010500-appb-img-000009
,
Figure PCTKR2023010500-appb-img-000010
또는
Figure PCTKR2023010500-appb-img-000011
인 화합물이다.R 1 is
Figure PCTKR2023010500-appb-img-000009
,
Figure PCTKR2023010500-appb-img-000010
or
Figure PCTKR2023010500-appb-img-000011
It is a phosphorus compound.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R2 및 R3는 각각 독립적으로 수소 원자 또는 C1-C6의 알킬기인 화합물이다.R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R4는 C1-C6의 할로알킬기, 할로겐 원자 및 C1-C6의 할로알콕시기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 아릴기 또는 C3-C10의 사이클로알킬기인 화합물이다.R 4 is a compound that is an aryl group or a C 3 -C 10 cycloalkyl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, and a C 1 -C 6 haloalkoxy group. am.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R4는 C1-C6의 할로알킬기, 할로겐 원자 및 C1-C6의 할로알콕시기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 페닐기, 나프틸기 또는 C3-C10의 사이클로알킬기인 화합물이다.R 4 is a phenyl group, a naphthyl group, or a C 3 -C 10 cycloalkyl group that is substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group , a halogen atom, and a C 1 -C 6 haloalkoxy group. It is a phosphorus compound.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
X는 질소 원자 또는 CR5이고, Y 및 Z는 각각 독립적으로 CR5인 화합물이다.X is a nitrogen atom or CR 5 , and Y and Z are each independently CR 5 compounds.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기 또는
Figure PCTKR2023010500-appb-img-000012
인 화합물이다.R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or
Figure PCTKR2023010500-appb-img-000012
It is a phosphorus compound.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R6은 C1-C6의 알킬기이고, R7은 C1-C6의 알킬기 또는
Figure PCTKR2023010500-appb-img-000013
이거나, R 6 is an alkyl group of C 1 -C 6 , and R 7 is an alkyl group of C 1 -C 6 or
Figure PCTKR2023010500-appb-img-000013
This is,
R6과 R7은 서로 결합하여, C1-C6의 알킬기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 4 내지 7원의 헤테로 고리를 형성하는 화합물이다.R 6 and R 7 are combined with each other to form a 4- to 7-membered heterocycle that may or may not be substituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R6은 C1-C6의 알킬기이고, R7은 C1-C6의 알킬기 또는
Figure PCTKR2023010500-appb-img-000014
이거나, R 6 is an alkyl group of C 1 -C 6 , and R 7 is an alkyl group of C 1 -C 6 or
Figure PCTKR2023010500-appb-img-000014
This is,
R6과 R7은 서로 결합하여, C1-C6의 알킬기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 피롤리딘을 형성하는 화합물이다.R 6 and R 7 are combined with each other to form a pyrrolidine that is substituted or unsubstituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
L2는 존재하지 않거나, C1-C6의 알킬렌기이며, L 2 is absent or is an alkylene group of C 1 -C 6 ,
R8은 C1-C6의 알콕시기, C1-C6의 알킬기, 히드록시기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 아릴기인 화합물이다.R 8 is a compound that is an aryl group substituted or unsubstituted with a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
L2는 존재하지 않거나, C1-C6의 알킬렌기이며, L 2 is absent or is an alkylene group of C 1 -C 6 ,
R8은 C1-C6의 알콕시기, C1-C6의 알킬기, 히드록시기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 페닐기인 화합물이다.R 8 is a compound that is a phenyl group substituted or unsubstituted with a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
n은 1인 화합물이다.n is a compound where 1 is 1.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
R1은
Figure PCTKR2023010500-appb-img-000015
또는
Figure PCTKR2023010500-appb-img-000016
이고, R 1 is
Figure PCTKR2023010500-appb-img-000015
or
Figure PCTKR2023010500-appb-img-000016
ego,
R2 및 R3는 각각 독립적으로 수소 원자 또는 C1-C6의 알킬기이며, R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group,
R4는 C1-C6의 할로알킬기, 할로겐 원자 및 C1-C6의 할로알콕시기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 페닐기이고,R 4 is a phenyl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, and a C 1 -C 6 haloalkoxy group,
X는 질소 원자 또는 CR5이며, Y 및 Z는 각각 독립적으로 CR5이고, X is a nitrogen atom or CR 5 , Y and Z are each independently CR 5 ,
R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기 또는
Figure PCTKR2023010500-appb-img-000017
이며, R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or
Figure PCTKR2023010500-appb-img-000017
and
L1은 존재하지 않고, L 1 does not exist,
R6 및 R7은 각각 독립적으로 C1-C6의 알킬기이며, R 6 and R 7 are each independently an alkyl group of C 1 -C 6 ,
n은 1인 화합물이다.n is a compound where 1 is 1.
본 발명의 일 실시형태에서, 상기 헤테로비시클릭 화합물은, In one embodiment of the present invention, the heterobicyclic compound is,
하기 화학식 I-1로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염일 수 있다.It may be a heterobicyclic compound represented by the following formula (I-1) or a pharmaceutically acceptable salt thereof.
[화학식 I-1][Formula I-1]
Figure PCTKR2023010500-appb-img-000018
Figure PCTKR2023010500-appb-img-000018
상기 식에서, In the above equation,
R1은
Figure PCTKR2023010500-appb-img-000019
이고, R 1 is
Figure PCTKR2023010500-appb-img-000019
ego,
R2 및 R3는 각각 독립적으로 수소 원자 또는 C1-C6의 알킬기이며, R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group,
X는 질소 원자 또는 CR5이고, X is a nitrogen atom or CR 5 ,
Y 및 Z는 각각 독립적으로 CR5이며, Y and Z are each independently CR 5 ,
R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기 또는
Figure PCTKR2023010500-appb-img-000020
이고, R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or
Figure PCTKR2023010500-appb-img-000020
ego,
L1은 존재하지 않으며, L 1 does not exist,
R6 및 R7은 각각 독립적으로 C1-C6의 알킬기이고, R 6 and R 7 are each independently an alkyl group of C 1 -C 6 ,
R9은 C1-C6의 할로알킬기, 할로겐 원자 또는 C1-C6의 할로알콕시기이며,R 9 is a C 1 -C 6 haloalkyl group, a halogen atom, or a C 1 -C 6 haloalkoxy group,
R10은 수소 원자 또는 할로겐 원자이다.R 10 is a hydrogen atom or a halogen atom.
본 명세서에서 약제학적으로 허용되는 염은 무독성 무기염 및 유기염 모두를 포함하며, 산부가염 또는 염기부가염일 수 있다. 산부가염으로는 예를 들어 염산염, 황산염, 질산염, 인산염, 아세테이트산염, 아디페이트산염, 아스파테이트산염, 벤조에이트산염, 벤젠설포네이트산염, 시트레이트산염, 캄포레이트산염, 캄포설포네이트산염, 디포스페이트산염, 에탄설포네이트산염, 푸마레이트산염, 글루타메이트산염, 말레이트산염, 락테이트산염, 메탄설포네이트산염, 숙시네이트산염, 타르트레이트산염, 피크레이트산염, 토실레이트산염 등을 포함한다. 염기부가염으로는 예를 들어 리튬, 나트륨, 칼륨, 마그네슘 및 칼슘과 같은 알칼리금속 또는 알칼리토금속 염, 암모늄 염, 테트라메틸암모늄과 같은 4차 암모늄 염 및 메틸아민, 디메틸아민, 트리메틸아민, 트리에틸아민 및 에틸아민과 같은 아민 염 등을 포함한다.Pharmaceutically acceptable salts herein include both non-toxic inorganic salts and organic salts, and may be acid addition salts or base addition salts. Acid addition salts include, for example, hydrochloride, sulfate, nitrate, phosphate, acetate, adipate, aspartate, benzoate, benzenesulfonate, citrate, camphorate, camphorsulfonate, and diphosphate. Salts include ethanesulfonate, fumarate, glutamate, malate, lactate, methanesulfonate, succinate, tartrate, picrate, tosylate, etc. Base addition salts include, for example, alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, magnesium and calcium, ammonium salts, quaternary ammonium salts such as tetramethylammonium and methylamine, dimethylamine, trimethylamine and triethyl. amines and amine salts such as ethylamine, etc.
본 발명의 화합물 중 대표적인 화합물은 하기 그룹에서 선택된다.Representative compounds among the compounds of the present invention are selected from the following groups.
1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 1); 1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 1);
1-(3,3-디메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 2);1-(3,3-dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one ( Compound 2);
1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로-1,6-나프티리딘-6(5H)-일)프로프-2-엔-1-온 (화합물 3);1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en-1-one (compound 3);
1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로피리도[4,3-c]피리다진-6(5H)-일)프로프-2-엔-1-온 (화합물 4);1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrido[4,3-c]pyridazin-6(5H)-yl)prop-2-en-1 -one (compound 4);
1-(3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 5);1-(3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 5 );
1-(6-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 6);1-(6-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 6 );
1-(6-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 7);1-(6-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 7);
1-(5-플루오로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 8);1-(5-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 8);
메틸 (R)-2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트 (화합물 9);Methyl (R)-2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Compound 9);
메틸 (S)-2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트 (화합물 10);Methyl (S)-2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Compound 10);
1-(6-니트로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 11);1-(6-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 11 );
1-(5-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 12);1-(5-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 12);
1-(6-플루오로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 13);1-(6-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 13);
1-(5-(4-(트리플루오로메틸)페닐)이소인돌린-2-일)프로프-2-엔-1-온 (화합물 14);1-(5-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)prop-2-en-1-one (Compound 14);
1-(2-(4-(트리플루오로메틸)페닐)-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-일)프로프-2-엔-1-온 (화합물 15);1-(2-(4-(trifluoromethyl)phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)prop-2-en-1 -one (compound 15);
1-(4-(트리플루오로메틸)-2-(4-(트리플루오로메틸)페닐)-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-일)프로프-2-엔-1-온 (화합물 16);1-(4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl ) Prop-2-en-1-one (Compound 16);
2-플루오로-1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 17);2-Fluoro-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 17);
1-(3,3-디메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)-2-플루오로프로프-2-엔-1-온 (화합물 18);1-(3,3-dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-fluoroprop-2-en- 1-one (Compound 18);
2-플루오로-1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로-1,6-나프티리딘-6(5H)-일)프로프-2-엔-1-온 (화합물 19);2-fluoro-1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en- 1-one (Compound 19);
2-플루오로-1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로피리도[4,3-c]피리다진-6(5H)-일)프로프-2-엔-1-온 (화합물 20);2-fluoro-1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrido[4,3-c]pyridazin-6(5H)-yl)prop- 2-en-1-one (Compound 20);
2-플루오로-1-(3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 21);2-fluoro-1-(3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 -one (compound 21);
2-플루오로-1-(6-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 22);2-Fluoro-1-(6-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 -one (compound 22);
2-플루오로-1-(6-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 23);2-fluoro-1-(6-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 23);
2-플루오로-1-(5-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 24);2-fluoro-1-(5-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 24);
(E)-4-(디메틸아미노)-1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)부트-2-엔-1-온 (화합물 25);(E)-4-(dimethylamino)-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-en- 1-one (Compound 25);
1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)부트-2-인-1-온 (화합물 26);1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-yn-1-one (Compound 26);
2-(7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-2-카보닐)아크릴로니트릴 (화합물 27);2-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)acrylonitrile (Compound 27);
1-(7-(시클로헥스-1-엔-1-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 28);1-(7-(Cyclohex-1-en-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 28);
1-(7-페닐-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 29);1-(7-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 29);
1-(7-(4-플루오로페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 30);1-(7-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 30);
1-(7-(3,4-디플루오로페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 31);1-(7-(3,4-difluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 31);
1-(7-(티오펜-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 32);1-(7-(thiophen-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 32);
1-(7-(3-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 33);1-(7-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 33);
1-(7-(6-(트리플루오로메틸)피리딘-3-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 34);1-(7-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 34 );
1-(7-(4-(트리플루오로메톡시)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 35);1-(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 35);
1-(7-(2-클로로-4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 36);1-(7-(2-Chloro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 36 );
1-(7-(3-플루오로-4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 37);1-(7-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 37);
1-(7-(나프탈렌-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 38);1-(7-(Naphthalen-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 38);
1-(7-(5-(트리플루오로메틸)피리딘-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 39);1-(7-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 39 );
1-(7-(p-톨릴)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 40);1-(7-(p-tolyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 40);
1-(7-시클로헥실-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 41);1-(7-Cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 41);
2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,4-디히드로이소퀴놀린-3(2H)-온 (화합물 42);2-Acryloyl-7-(4-(trifluoromethyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one (Compound 42);
2-아크릴로일-5-(4-(트리플루오로메틸)페닐)이소인돌린-1-온 (화합물 43);2-Acryloyl-5-(4-(trifluoromethyl)phenyl)isoindolin-1-one (Compound 43);
1-(6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 44);1-(6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 44);
1-(6-(벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 45);1-(6-(benzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 45);
1-(6-((피리딘-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 46);1-(6-((pyridin-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 46);
1-(6-((피리딘-3-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 47);1-(6-((pyridin-3-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 47);
1-(6-((피리딘-4-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 48);1-(6-((pyridin-4-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 48);
1-(6-((4-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 49);1-(6-((4-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 49);
1-(6-((티아졸-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 50);1-(6-((thiazol-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop -2-en-1-one (Compound 50);
1-(6-(((1-메틸피페리딘-4-일)메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 51);1-(6-(((1-methylpiperidin-4-yl)methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H )-yl)prop-2-en-1-one (Compound 51);
1-(6-(벤질(메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 52);1-(6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 52);
1-(6-(디벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 53);1-(6-(dibenzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- On (Compound 53);
1-(6-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 54);1-(6-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 54);
1-(6-메톡시-3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 55);1-(6-methoxy-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 -one (compound 55);
1-(6-(페닐아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 56);1-(6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 56);
1-(5-(벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 57);1-(5-(benzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 57);
1-(5-((피리딘-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 58);1-(5-((pyridin-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 58);
1-(5-((피리딘-4-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 59);1-(5-((pyridin-4-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 59);
1-(5-((피리미딘-5-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 60);1-(5-((pyrimidin-5-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop -2-en-1-one (Compound 60);
1-(5-((4-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 61);1-(5-((4-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 61);
1-(5-((3-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 62);1-(5-((3-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 62);
1-(5-((3-히드록시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 63);1-(5-((3-hydroxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 63);
1-(5-((4-히드록시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 64);1-(5-((4-hydroxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 64);
1-(5-((4-(디메틸아미노)벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 65);1-(5-((4-(dimethylamino)benzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop -2-en-1-one (Compound 65);
1-(5-((시클로헥실메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 66);1-(5-((cyclohexylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene -1-one (Compound 66);
N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)벤자미드 (화합물 67);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide (Compound 67);
N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)아세트아미드 (화합물 68);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide (Compound 68);
N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)프로피온아미드 (화합물 69);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)propionamide (Compound 69);
1-(6-((페닐아미노)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 70);1-(6-((phenylamino)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 70);
1-(6-((4-메틸피페라진-1-일)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 71);1-(6-((4-methylpiperazin-1-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Prop-2-en-1-one (Compound 71);
1-(5-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 72);1-(5-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 72);
N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-6-일)벤자미드 (화합물 73);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)benzamide (Compound 73);
1-(6-(벤질옥시)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 74);1-(6-(benzyloxy)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 74);
(S)-1-(3-(히드록시메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 75);(S)-1-(3-(hydroxymethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- En-1-one (Compound 75);
(R)-1-(3-(히드록시메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 76);(R)-1-(3-(hydroxymethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- En-1-one (Compound 76);
1-(5-(4-메틸피페라진-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 77);1-(5-(4-methylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 77);
1-(5-(피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 78); 및1-(5-(pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- En-1-one (Compound 78); and
1-(5-(3-(디메틸아미노)피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 79).1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Prop-2-en-1-one (Compound 79).
상기 화학식 I로 표시되는 헤테로비시클릭 화합물은 당해 분야에 알려진 방법으로 제조할 수 있다.The heterobicyclic compound represented by Formula I can be prepared by methods known in the art.
예를 들어, 상기 화학식 1로 표시되는 헤테로비시클릭 화합물은 후술하는 합성예에 기재된 방법으로 제조할 수 있다.For example, the heterobicyclic compound represented by Formula 1 can be prepared by the method described in the Synthesis Example described later.
본 발명에 따른 상기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염은 YAP 또는 TAZ와 TEAD의 결합 저해를 통해 TEAD 전사 활성화 저해 활성을 나타낸다(시험예 1 참조).The heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention exhibits TEAD transcriptional activation inhibitory activity through inhibition of the binding of YAP or TAZ to TEAD (see Test Example 1).
또한, 본 발명에 따른 상기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염은 우수한 대사 안정성과 약동학적 특성을 나타낸다(시험예 2 및 3 참조).In addition, the heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent metabolic stability and pharmacokinetic properties (see Test Examples 2 and 3).
아울러, 본 발명에 따른 상기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염은 종양 마우스 모델에서 우수한 종양 억제 활성을 나타낸다(시험예 4 참조).In addition, the heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent tumor suppressive activity in a tumor mouse model (see Test Example 4).
따라서, 본 발명은 상기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염을 약제학적으로 허용되는 담체와 함께 포함하는 YAP 또는 TAZ와 TEAD의 결합 저해용 약제학적 조성물, 구체적으로는 암의 치료 또는 예방용인 약제학적 조성물에 관한 것이다.Therefore, the present invention provides a pharmaceutical composition for inhibiting the binding of YAP or TAZ to TEAD, comprising a heterobicyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, specifically, It relates to a pharmaceutical composition for the treatment or prevention of cancer.
본 발명의 일 실시형태에서, 상기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염은 YAP 또는 TAZ와 TEAD의 결합을 저해함으로써 TEAD 전사 활성화 저해를 통한 항암 효과를 유도하여 암의 치료에 유용하게 사용될 수 있다.In one embodiment of the present invention, the heterobicyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof induces an anticancer effect through inhibition of TEAD transcriptional activation by inhibiting the binding of YAP or TAZ to TEAD, thus preventing cancer. It can be useful in treatment.
본 발명의 일 실시형태에서, 상기 암은 폐 암, 갑상샘 암, 난소 암, 결장직장 암, 전립선 암, 췌장 암, 식도 암, 간 암, 유방 암, 피부 암, 또는 중피종이다.In one embodiment of the invention, the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer, skin cancer, or mesothelioma.
본 발명의 일 실시형태에서, 상기 암은 중피종, 예를 들면, 악성 중피종이다.In one embodiment of the invention, the cancer is mesothelioma, eg malignant mesothelioma.
본 발명의 일 실시형태에서, 상기 암은, 제한없이, 백혈병 (예를 들면, 급성 백혈병, 급성 림프구 백혈병, 급성 골수구 백혈병, 급성 골수모구 백혈병, 급성 전골수구 백혈병, 급성 골수단핵구 백혈병, 급성 단핵구 백혈병, 급성 적백혈병, 만성 백혈병, 만성 골수구 백혈병, 만성 림프구 백혈병), 진성적혈구증가증, 림프종 (예를 들면, 호지킨병 또는 비-호지킨병), 발덴스트롬 마크로글로불린혈증, 다발골수종, 중쇄 질환, 및 고체 종양, 예를 들면, 육종 및 암종 (예를 들면, 섬유육종, 점액육종, 지방육종, 연골육종, 골형성 육종, 척삭종, 혈관육종, 내피육종, 림프관육종, 림프관내피육종 (lymphangioendotheliosarcoma), 윤활막종, 중피종, 유잉 종양, 평활근육종, 횡문근육종, 결장 암종, 췌장 암, 유방 암, 난소 암, 전립선 암, 편평세포 암종, 기저세포 암종, 샘암종, 땀샘 암종, 피지선 암종, 유두모양 암종, 유두모양 샘암종, 낭샘암종, 속질 암종, 기관지원성 암종, 신장세포 암종, 간암, 담관 암종, 융모막암종, 고환종, 배아 암종, 윌름스 종양, 자궁경부 암, 자궁 암, 고환 암, 폐 암종, 소세포 폐 암종, 방광 암종, 상피 암종, 신경아교종, 별아교세포종, 아교모세포종 다형 (GBM), 속질모세포종, 두개인두종, 뇌실막세포종, 송과체종, 혈관모세포종, 청신경집종, 희소돌기아교세포종, 슈반세포종, 신경섬유육종, 수막종, 흑색종, 신경모세포종, 및 망막모세포종)을 포함한다.In one embodiment of the invention, the cancer includes, but is not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, medium chain Diseases, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangiosarcoma ( lymphangioendotheliosarcoma), synoviomas, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma. Carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, testicular tumor, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma. , small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic schwannoma, oligodendroglioma, Schwann cell tumor, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).
본 발명의 일 실시형태에서, 상기 암은 신경아교종, 별아교세포종, 다형성아교모세포종 (GBM), 속질모세포종, 두개인두종, 뇌실막세포종, 송과체종, 혈관모세포종, 청신경집종, 희소돌기아교세포종, 슈반세포종, 신경섬유육종, 수막종, 흑색종, 신경모세포종, 또는 망막모세포종이다.In one embodiment of the present invention, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic schwannoma, oligodendroglioma, Schwann cell tumor, Neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
본 발명의 일 실시형태에서, 상기 암은 청신경집종, 별아교세포종 (예를 들면, 등급 I - 털모양세포 별아교세포종, 등급 II - 하위-등급 별아교세포종, 등급 III - 역형성 별아교세포종, 또는 등급 IV - 아교모세포종 (GBM)), 척삭종, CNS 림프종, 두개인두종, 뇌 줄기 신경아교종, 뇌실막세포종, 혼합 신경아교종, 시신경 신경아교종, 뇌실막하세포종, 속질모세포종, 수막종, 전이성 뇌 종양, 희소돌기아교세포종, 뇌하수체 종양, 원시신경외배엽 (PNET) 종양, 또는 슈반세포종이다.In one embodiment of the invention, the cancer is an acoustic schwannoma, an astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - sub-grade astrocytoma, grade III - anaplastic astrocytoma, or grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma , pituitary tumor, primitive neuroectodermal (PNET) tumor, or Schwann cell tumor.
본 발명의 일 실시형태에서, 상기 암은 성인보다 아동에서 보다 흔히 발견되는 타입, 예를 들면, 뇌 줄기 신경아교종, 두개인두종, 뇌실막세포종, 소아 털모양세포 별아교세포종 (JPA), 속질모세포종, 시신경 신경아교종, 송과체 종양, 원시신경외배엽 종양 (PNET), 또는 간상 종양이다.In one embodiment of the invention, the cancer is of a type more commonly found in children than in adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve. Glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rod tumor.
본 발명의 일 실시형태에서, 상기 암은, 제한없이, 중피종, 간담도 (간관 및 담관) 암, 골 암, 췌장 암, 피부 암, 두경부 암, 피부 또는 안내 흑색종, 난소 암, 결장 암, 직장 암, 항문 영역의 암, 위 암, 위장관 (위, 결장직장, 및 샘창자) 암, 자궁 암, 자궁관의 암종, 자궁내막의 암종, 자궁경부의 암종, 질의 암종, 외음부의 암종, 호지킨병, 식도 암, 소장 암, 내분비계의 암, 갑상샘의 암, 부갑상샘의 암, 부신 암, 연조직의 육종, 요도 암, 음경 암, 전립선 암, 고환 암, 만성 또는 급성 백혈병, 만성 골수성 백혈병, 림프구 림프종, 방광의 암, 콩팥 또는 요관의 암, 신장세포 암종, 신우의 암종, 비-호지킨 림프종, 척수 축 종양, 뇌 줄기 신경아교종, 뇌하수체 샘종, 부신피질 암, 담낭 암, 다발골수종, 담관암종, 섬유육종, 신경모세포종, 망막모세포종, 또는 상기 암 중 하나 이상의 조합을 포함한다.In one embodiment of the invention, the cancer includes, but is not limited to, mesothelioma, hepatobiliary (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, Rectal cancer, cancer of the anal area, stomach cancer, gastrointestinal (stomach, colorectal, and adenocarcinoma) cancer, uterine cancer, carcinoma of the uterine tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, adrenal cancer, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leukemia, Lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, and cholangiocarcinoma. tumor, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.
본 발명의 일 실시형태에서, 상기 암은 간세포 암종 (HCC), 간모세포종, 결장 암, 직장 암, 난소 암, 난소 상피 암, 자궁관암, 유두모양 장액 낭샘암종, 자궁 유두모양 장액 암종 (UPSC), 간담관암종, 연조직 및 뼈 윤활막 육종, 횡문근육종, 골육종, 역형성 갑상샘 암, 부신피질 샘종, 췌장 암, 췌장 관 암종, 췌장 샘암종, 신경아교종, 신경섬유종증-1 연관된 악성 말초신경집 종양 (MPNST), 발덴스트롬 마크로글로불린혈증, 또는 속질모세포종으로부터 선택된다.In one embodiment of the invention, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, uterine tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC) , hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST) ), Waldenstrom's macroglobulinemia, or medulloblastoma.
본 발명의 일 실시형태에서, 상기 암은 고체 종양, 예를 들면, 육종, 암종, 또는 림프종이다. 고체 종양은 일반적으로, 낭포(cysts) 또는 액체 영역을 전형적으로 포함하지 않는 비정상적 대규모 조직을 포함한다.In one embodiment of the invention, the cancer is a solid tumor, such as sarcoma, carcinoma, or lymphoma. Solid tumors generally contain large amounts of abnormal tissue that typically do not contain cysts or areas of fluid.
본 발명의 일 실시형태에서, 상기 암은 신장세포 암종, 또는 콩팥 암; 간세포 암종 (HCC) 또는 간모세포종, 또는 간 암; 흑색종; 유방 암; 결장직장 암종, 또는 결장직장 암; 결장 암; 직장 암; 항문 암; 폐 암, 예를 들면, 비-소세포 폐 암 (NSCLC) 또는 소세포폐암 (SCLC); 난소 암, 난소 상피 암, 난소 암종, 또는 자궁관 암; 유두모양 장액 낭샘암종 또는 자궁 유두모양 장액 암종 (UPSC); 전립선 암; 고환 암; 담낭 암; 간담관암종; 연조직 및 뼈 윤활막 육종; 횡문근육종; 골육종; 연골육종; 유잉 육종; 역형성 갑상샘 암; 부신피질 암종; 췌장 암; 췌장 관 암종 또는 췌장 샘암종; 위장관/위 (GIST) 암; 림프종; 두경부 (SCCHN)의 편평세포 암종; 침샘 암; 신경아교종, 또는 뇌 암; 신경섬유종증-1 연관된 악성 말초신경집 종양 (MPNST); 발덴스트롬 마크로글로불린혈증; 또는 속질모세포종으로부터 선택된다.In one embodiment of the invention, the cancer is renal cell carcinoma, or kidney cancer; Hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; Colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; Lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); Ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or uterine tube cancer; Papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; Anaplastic thyroid cancer; Adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; Gastrointestinal/stomach (GIST) cancer; lymphoma; Squamous Cell Carcinoma of the Head and Neck (SCCHN); Salivary gland cancer; glioma, or brain cancer; Neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.
본 발명의 일 실시형태에서, 상기 암은 신장세포 암종, 간세포 암종 (HCC), 간모세포종, 결장직장 암종, 결장직장 암, 결장암, 직장 암, 항문 암, 난소 암, 난소 상피 암, 난소 암종, 자궁관 암, 유두모양 장액 낭샘암종, 자궁 유두모양 장액 암종 (UPSC), 간담관암종, 연조직 및 뼈 윤활막 육종, 횡문근육종, 골육종, 연골육종, 역형성 갑상샘 암, 부신피질 암종, 췌장 암, 췌장 관 암종, 췌장 샘암종, 신경아교종, 뇌 암, 신경섬유종증-1 연관된 악성 말초신경집 종양 (MPNST), 발덴스트롬 마크로글로불린혈증, 또는 속질모세포종으로부터 선택된다.In one embodiment of the invention, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, Uterine tubal cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatobiliary carcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreas. ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.
본 발명의 일 실시형태에서, 상기 암은 간세포 암종 (HCC), 간모세포종, 결장 암, 직장 암, 난소 암, 난소 상피 암, 난소 암종, 자궁관 암, 유두모양 장액 낭샘암종, 자궁 유두모양 장액 암종 (UPSC), 간담관암종, 연조직 및 뼈 윤활막육종, 횡문근육종, 골육종, 역형성 갑상샘 암, 부신피질 암종, 췌장 암, 췌장 관 암종, 췌장 샘암종, 신경아교종, 신경섬유종증-1 연관된 악성 말초신경집 종양 (MPNST), 발덴스트롬 마크로글로불린혈증, 또는 속질모세포종으로부터 선택된다.In one embodiment of the invention, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, uterine tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous Carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve home tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.
본 발명의 일 실시형태에서, 상기 암은 사람 면역결핍 바이러스 (HIV) 관련 고체 종양, 사람 유두종 바이러스 (HPV)-16 양성불치 고체 종양, 및 사람 T-세포 백혈병 바이러스 I형 (HTLV-I)에 의해 야기되고 백혈병 세포에서 HTLV-I의 클론 통합을 특징으로 하는 매우 공격적인 형태의 CD4+ T-세포 백혈병인 성인 T-세포 백혈병 뿐만 아니라 위 암, 코인두 암종, 자궁경부 암, 질 암, 외음부 암, 두경부의 편평세포 암종, 및 메르켈 세포 암종에서 바이러스-연관된 종양을 포함하는 바이러스-연관된 암이다.In one embodiment of the invention, the cancer is caused by human immunodeficiency virus (HIV)-related solid tumors, human papillomavirus (HPV)-16 benign incurable solid tumors, and human T-cell leukemia virus type I (HTLV-I). Adult T-cell leukemia, a highly aggressive form of CD4+ T-cell leukemia caused by and characterized by clonal integration of HTLV-I in leukemic cells, as well as gastric, nasopharyngeal carcinoma, cervical, vaginal, and vulvar cancers. Virus-associated cancers include virus-associated tumors in squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
본 발명에 따른 약제학적 조성물은 경구적으로(예를 들면, 복용 또는 흡입) 또는 비경구적으로(예를 들면, 주사, 침착, 이식, 좌약) 투여될 수 있으며, 주사는 예를 들면, 정맥주사, 피하주사, 근육내주사 또는 복강내주사일 수 있다. 본 발명에 따른 약제학적 조성물은 투여 경로에 따라, 정제, 캡슐제, 과립제, 파인 서브틸래(fine subtilae), 분제, 설하 정제, 좌약, 연고, 주사제, 유탁액제, 현탁액제, 시럽제, 분무제 등으로 제형화될 수 있다. 상기 여러 가지 형태의 본 발명에 따른 약제학적 조성물은 각 제형에 통상적으로 사용되는 약제학적으로 허용되는 담체(carrier)를 사용하여 공지기술에 의해 제조될 수 있다. 약제학적으로 허용되는 담체의 예는 부형제, 결합제, 붕해제(disintegrating agent), 윤활제, 방부제, 항산화제, 등장제(isotonic agent), 완충제, 피막제, 감미제, 용해제, 기제(base), 분산제, 습윤제, 현탁화제, 안정제, 착색제 등을 포함한다.The pharmaceutical composition according to the present invention can be administered orally (e.g., by ingestion or inhalation) or parenterally (e.g., by injection, deposition, implantation, suppository), and injection is, for example, intravenous. , it may be a subcutaneous injection, an intramuscular injection, or an intraperitoneal injection. The pharmaceutical composition according to the present invention is available as tablets, capsules, granules, fine subtilae, powder, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc., depending on the route of administration. It can be formulated. The various forms of pharmaceutical compositions according to the present invention can be prepared by known techniques using pharmaceutically acceptable carriers commonly used in each dosage form. Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweeteners, solubilizers, bases, dispersants, and wetting agents. , suspending agents, stabilizers, colorants, etc.
본 발명에 따른 약제학적 조성물은 약제의 형태에 따라 다르지만, 본 발명의 화합물 또는 그의 약제학적으로 허용되는 염을 약 0.01 내지 95 중량%로 포함한다. The pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof.
본 발명의 약제학적 조성물의 구체적인 투여량은 치료되는 사람을 포함한 포유동물의 종류, 체중, 성별, 질환의 정도, 의사의 판단 등에 따라 다를 수 있다. 바람직하게는, 경구 투여의 경우에는 하루에 체중 1kg당 활성성분 0.01 내지 50 mg이 투여되고, 비경구투여의 경우에는 하루에 체중 1kg당 활성성분 0.01 내지 10 mg이 투여된다. 상기 총 일일 투여량은 질환의 정도, 의사의 판단 등에 따라 한번에 또는 수회로 나누어 투여될 수 있다.The specific dosage of the pharmaceutical composition of the present invention may vary depending on the type, weight, gender, degree of disease, doctor's judgment, etc. of the mammal, including humans, to be treated. Preferably, for oral administration, 0.01 to 50 mg of the active ingredient per 1 kg of body weight is administered per day, and for parenteral administration, 0.01 to 10 mg of the active ingredient per 1 kg of body weight is administered per day. The total daily dosage may be administered all at once or in several divided doses depending on the degree of the disease, the doctor's judgment, etc.
본 발명의 화합물은 YAP 또는 TAZ와 TEAD의 결합 저해를 통해 TEAD 전사 활성화 저해 활성을 나타낸다. 따라서, 본 발명의 화합물은 암의 치료 또는 예방용 약제학적 조성물에 효과적으로 사용될 수 있다.The compounds of the present invention exhibit TEAD transcriptional activation inhibitory activity through inhibition of the binding of YAP or TAZ to TEAD. Therefore, the compounds of the present invention can be effectively used in pharmaceutical compositions for the treatment or prevention of cancer.
도 1은 실시예 1의 화합물에 대한 종양 마우스 모델에서의 활성 평가 결과이다.Figure 1 shows the results of evaluating the activity of the compound of Example 1 in a tumor mouse model.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다. Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not limited to these examples.
실시예 1: 1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 1)Example 1: Synthesis of 1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one ( Compound 1)
Figure PCTKR2023010500-appb-img-000021
Figure PCTKR2023010500-appb-img-000021
실시예 1-1: tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 1-1: Synthesis of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (9.3g, 30mmol)을 다이옥산/물(3:1) 300ml에 녹인 후 Pd(PPh3)4(3.46g, 3mmol)을 첨가하였다. 그 후 Cs2CO3(11.736g, 36mmol)와 4-(트리플루오로메틸)페닐 보론산 (6.836g, 36mmol)을 순서대로 첨가하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (8.8g, 78%)After dissolving tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (9.3g, 30mmol) in 300ml of dioxane/water (3:1), Pd(PPh 3 ) 4 ( 3.46g, 3mmol) was added. Afterwards, Cs 2 CO 3 (11.736 g, 36 mmol) and 4-(trifluoromethyl)phenyl boronic acid (6.836 g, 36 mmol) were added in that order. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (8.8g, 78%)
MS (ESI) m/z: [M+H]+ 378.16MS (ESI) m/z: [M+H] + 378.16
실시예 1-2: 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린의 합성Example 1-2: Synthesis of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline
상기 실시예 1-1에서 제조한 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (4.4g, 11.15mmol)을 DCM 50ml에 녹인 후 10ml의 TFA를 첨가하여 상온에서 2시간 교반하였다. 2시간 경과 후 반응이 완료됨을 LC-MS로 확인하고 혼합물에 물을 200ml 첨가하였다. 상기 혼합물을 필터하여 하얀색 고체를 얻고 이를 에틸아세테이트, NaHCO3(aq)을 이용하여 중성화하였다. 유기층을 감압 농축하여 하얀색 고체 형태의 표제 화합물을 얻었다. (2.52g, 78%)tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (4.4g, 11.15mmol) prepared in Example 1-1 After dissolving in 50ml of DCM, 10ml of TFA was added and stirred at room temperature for 2 hours. After 2 hours, completion of the reaction was confirmed by LC-MS, and 200 ml of water was added to the mixture. The mixture was filtered to obtain a white solid, which was neutralized using ethyl acetate and NaHCO 3 (aq). The organic layer was concentrated under reduced pressure to obtain the title compound in the form of a white solid. (2.52g, 78%)
MS (ESI) m/z: [M+H]+ 278.11MS (ESI) m/z: [M+H] + 278.11
실시예 1-3: 1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 1-3: 1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one synthesis
상기 실시예 1-2에서 제조한 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린(277mg, 1mmol)을 5ml의 DMF에 녹였다. HATU(456.3mg, 1.2mmol), TEA(121.5mg, 1.2mmol)와 아크릴산(86.5mg, 1.2mmol)를 상기 혼합물에 첨가한 후 상온에서 3시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (112.5mg, 34%)7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (277 mg, 1 mmol) prepared in Example 1-2 was dissolved in 5 ml of DMF. HATU (456.3 mg, 1.2 mmol), TEA (121.5 mg, 1.2 mmol), and acrylic acid (86.5 mg, 1.2 mmol) were added to the mixture and stirred at room temperature for 3 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (112.5 mg, 34%)
1H NMR(CDCl3) δ 7.64-7.68(m, 4H), 7.32-7.44(m, 2H), 7.22-7.28(m, 1H), 6.63-6.67(m, 1H), 6.33-6.39(m, 1H), 5.72-5.75(d, 1H), 4.80-4.86(d, 2H), 3.80-3.93(m, 2H), 2.89-2.98(m, 2H) 1 H NMR(CDCl 3 ) δ 7.64-7.68(m, 4H), 7.32-7.44(m, 2H), 7.22-7.28(m, 1H), 6.63-6.67(m, 1H), 6.33-6.39(m, 1H), 5.72-5.75(d, 1H), 4.80-4.86(d, 2H), 3.80-3.93(m, 2H), 2.89-2.98(m, 2H)
[M+H]+ 332.12[M+H] + 332.12
실시예 2: 1-(3,3-디메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 2)Example 2: 1-(3,3-dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- Synthesis of 1-one (Compound 2)
Figure PCTKR2023010500-appb-img-000022
Figure PCTKR2023010500-appb-img-000022
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-3,3-디메틸-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-3,3-dimethyl-3,4- The title compound was obtained in the same manner as Example 1, except for using dihydroisoquinoline-2(1H)-carboxylate.
1H NMR(CDCl3) δ 7.68-7.69(m, 4H), 7.51-7.52(d, 1H), 7.41(s, 1H), 7.30-7.32(d, 1H), 6.64-6.69(m, 1H), 6.19-6.22(d, 1H), 5.65-5.67(d, 1H), 4.60(s, 2H), 2.86(s, 2H), 1.53(s, 6H) 1H NMR(CDCl 3 ) δ 7.68-7.69(m, 4H), 7.51-7.52(d, 1H), 7.41(s, 1H), 7.30-7.32(d, 1H), 6.64-6.69(m, 1H) , 6.19-6.22(d, 1H), 5.65-5.67(d, 1H), 4.60(s, 2H), 2.86(s, 2H), 1.53(s, 6H)
[M+H]+ 360.15[M+H] + 360.15
실시예 3: 1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로-1,6-나프티리딘-6(5H)-일)프로프-2-엔-1-온의 합성 (화합물 3)Example 3: 1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en-1 Synthesis of -one (Compound 3)
Figure PCTKR2023010500-appb-img-000023
Figure PCTKR2023010500-appb-img-000023
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 3-브로모-7,8-디히드로-1,6-나프티리딘-6(5H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 3-bromo-7,8-dihydro-1,6 The title compound was obtained in the same manner as Example 1, except that -naphthyridine-6(5H)-carboxylate was used.
1H NMR(CDCl3) δ 8.67(s, 1H), 7.73-7.75(d, 2H), 7.62-7.66(m, 3H), 6.67-6.72(m, 1H), 6.36-6.39(d, 1H), 5.78-5.80(d, 1H), 4.91(m, 2H), 3.94(m, 2H), 3.14(m, 2H) 1H NMR(CDCl 3 ) δ 8.67(s, 1H), 7.73-7.75(d, 2H), 7.62-7.66(m, 3H), 6.67-6.72(m, 1H), 6.36-6.39(d, 1H) , 5.78-5.80(d, 1H), 4.91(m, 2H), 3.94(m, 2H), 3.14(m, 2H)
[M+H]+ 332.12[M+H] + 332.12
실시예 4: 1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로피리도[4,3-c]피리다진-6(5H)-일)프로프-2-엔-1-온의 합성 (화합물 4)Example 4: 1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrido[4,3-c]pyridazin-6(5H)-yl)prop-2 Synthesis of -en-1-one (Compound 4)
Figure PCTKR2023010500-appb-img-000024
Figure PCTKR2023010500-appb-img-000024
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 3-브로모-7,8-디히드로피리도[4,3-c]피리다진-6(5H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1, tert-butyl 3-bromo-7,8-dihydropyrido [4 The title compound was obtained in the same manner as Example 1, except that ,3-c]pyridazine-6(5H)-carboxylate was used.
1H NMR(CDCl3) δ 8.18-8.19(d, 2H), 7.66-7.80(d, 2H), 7.67(s, 1H), 6.68-6.72(m, 1H), 6.39-6.42(d, 1H), 5.82-5.84(d, 1H), 4.95(m, 2H), 3.99(m, 2H), 3.39(s, 2H) 1H NMR(CDCl 3 ) δ 8.18-8.19(d, 2H), 7.66-7.80(d, 2H), 7.67(s, 1H), 6.68-6.72(m, 1H), 6.39-6.42(d, 1H) , 5.82-5.84(d, 1H), 4.95(m, 2H), 3.99(m, 2H), 3.39(s, 2H)
[M+H]+ 334.11[M+H] + 334.11
실시예 5: 1-(3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 5)Example 5: 1-(3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- Synthesis of ion (Compound 5)
Figure PCTKR2023010500-appb-img-000025
Figure PCTKR2023010500-appb-img-000025
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-3-메틸-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-3-methyl-3,4-dihydro The title compound was obtained in the same manner as Example 1, except that isoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.66-7.70(m, 4H), 7.34-7.45(m, 2H), 7.24-7.26(s, 1H), 6.66-6.70(m, 1H), 6.35-6.37(d, 1H), 5.73-5.75(d, 1H), 5.17-5.20(m, 1H), 4.44-4.89(m, 2H), 3.18-3.20(m, 1H), 2.69-2.85(m, 1H), 1.19(s, 3H) 1H NMR(CDCl 3 ) δ 7.66-7.70(m, 4H), 7.34-7.45(m, 2H), 7.24-7.26(s, 1H), 6.66-6.70(m, 1H), 6.35-6.37(d, 1H), 5.73-5.75(d, 1H), 5.17-5.20(m, 1H), 4.44-4.89(m, 2H), 3.18-3.20(m, 1H), 2.69-2.85(m, 1H), 1.19( s, 3H)
[M+H]+ 346.13[M+H] + 346.13
실시예 6: 1-(6-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 6)Example 6: 1-(6-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- Synthesis of ion (Compound 6)
Figure PCTKR2023010500-appb-img-000026
Figure PCTKR2023010500-appb-img-000026
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-6-메틸-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-methyl-3,4-dihydro The title compound was obtained in the same manner as Example 1, except that isoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.66-7.68(d, 2H), 7.40-7.42(d, 2H), 6.95-7.11(m, 2H), 6.63-6.68(m, 1H), 6.32-6.36(d, 1H), 5.73-5.75(d, 1H), 4.73-4.80(m, 2H), 3.80-3.93(m, 2H), 2.91-2.94(s, 2H) 2.22(s, 3H) 1H NMR(CDCl 3 ) δ 7.66-7.68(d, 2H), 7.40-7.42(d, 2H), 6.95-7.11(m, 2H), 6.63-6.68(m, 1H), 6.32-6.36(d, 1H), 5.73-5.75(d, 1H), 4.73-4.80(m, 2H), 3.80-3.93(m, 2H), 2.91-2.94(s, 2H) 2.22(s, 3H)
[M+H]+ 346.13[M+H] + 346.13
실시예 7: 1-(6-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 7)Example 7: 1-(6-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 Synthesis of -one (Compound 7)
Figure PCTKR2023010500-appb-img-000027
Figure PCTKR2023010500-appb-img-000027
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-6-메톡시-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-methoxy-3,4-di The title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.67-7.70(m, 2H), 7.60-7.63(m, 2H), 7.11-7.14(m, 1H), 6.90(s, 1H), 6.80-6.86(m, 1H), 6.06-6.10(d, 1H), 5.63-5.66(d, 1H), 4.58-4.68(m, 2H), 3.73-3.76(m, 2H), 3.69(s, 3H), 2.78-2.83(m, 2H) 1 H NMR(CDCl 3 ) δ 7.67-7.70 (m, 2H), 7.60-7.63 (m, 2H), 7.11-7.14 (m, 1H), 6.90 (s, 1H), 6.80-6.86 (m, 1H) , 6.06-6.10(d, 1H), 5.63-5.66(d, 1H), 4.58-4.68(m, 2H), 3.73-3.76(m, 2H), 3.69(s, 3H), 2.78-2.83(m, 2H)
[M+H]+ 362.13[M+H] + 362.13
실시예 8: 1-(5-플루오로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 8)Example 8: 1-(5-Fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 Synthesis of -one (Compound 8)
Figure PCTKR2023010500-appb-img-000028
Figure PCTKR2023010500-appb-img-000028
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-5-플루오로-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-5-fluoro-3,4-di The title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.22 - 7.10 (m, 2H), 6.85 - 6.58 (m, 1H), 6.36 (d, J = 16.6 Hz, 1H), 5.76 (d, J = 10.5 Hz, 1H), 4.84 (d, J = 49.9 Hz, 2H), 3.86 (dd, J = 37.5, 31.9 Hz, 2H), 2.93 (d, J = 5.5 Hz, 2H) 1 H NMR(CDCl 3 ) δ 7.69 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.22 - 7.10 (m, 2H), 6.85 - 6.58 (m, 1H), 6.36 (d, J = 16.6 Hz, 1H), 5.76 (d, J = 10.5 Hz, 1H), 4.84 (d, J = 49.9 Hz, 2H), 3.86 (dd, J = 37.5, 31.9 Hz, 2H), 2.93 (d, J = 5.5 Hz, 2H)
[M+H]+ 350.11[M+H] + 350.11
실시예 9: 메틸 (R)-2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트의 합성 (화합물 9)Example 9: Synthesis of methyl (R)-2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (compound 9)
Figure PCTKR2023010500-appb-img-000029
Figure PCTKR2023010500-appb-img-000029
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 2-(tert-부틸) 3-메틸 (R)-7-브로모-3,4-디히드로이소퀴놀린-2,3(1H)-디카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1, 2-(tert-butyl) 3-methyl (R)-7-bromo The title compound was obtained in the same manner as Example 1, except that -3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate was used.
1H NMR(CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.47 - 7.33 (m, 2H), 7.31 - 7.26 (m, 1H), 6.78 - 6.49 (m, 1H), 6.46 - 6.32 (m, 1H), 5.86 - 5.74 (m, 1H), 5.62 - 5.55 (m, 1H), 5.11 - 4.79 (m, 2H), 3.65 (d, J = 4.2 Hz, 3H), 3.43 - 3.32 (m, 1H), 3.28 - 3.17 (m, 1H) 1 H NMR(CDCl 3 ) δ 7.69 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.47 - 7.33 (m, 2H), 7.31 - 7.26 (m, 1H), 6.78 - 6.49 (m, 1H), 6.46 - 6.32 (m, 1H), 5.86 - 5.74 (m, 1H), 5.62 - 5.55 (m, 1H), 5.11 - 4.79 (m, 2H), 3.65 (d, J = 4.2 Hz, 3H), 3.43 - 3.32 (m, 1H), 3.28 - 3.17 (m, 1H)
[M+H]+ 390.12[M+H] + 390.12
실시예 10: 메틸 (S)-2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트의 합성 (화합물 10)Example 10: Synthesis of methyl (S)-2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Compound 10)
Figure PCTKR2023010500-appb-img-000030
Figure PCTKR2023010500-appb-img-000030
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 2-(tert-부틸) 3-메틸 (S)-7-브로모-3,4-디히드로이소퀴놀린-2,3(1H)-디카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1, 2-(tert-butyl) 3-methyl (S)-7-bromo The title compound was obtained in the same manner as Example 1, except that -3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate was used.
1H NMR(CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.46 - 7.34 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 6.79 - 6.48 (m, 1H), 6.46 - 6.32 (m, 1H), 5.86 - 5.74 (m, 1H), 5.63 - 5.55 (m, 1H), 5.12 - 4.79 (m, 2H), 3.67 - 3.63 (m, 3H), 3.44 - 3.32 (m, 1H), 3.29 - 3.18 (m, 1H) 1 H NMR(CDCl 3 ) δ 7.69 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.46 - 7.34 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 6.79 - 6.48 (m, 1H), 6.46 - 6.32 (m, 1H), 5.86 - 5.74 (m, 1H), 5.63 - 5.55 (m, 1H), 5.12 - 4.79 (m, 2H), 3.67 - 3.63 (m, 3H), 3.44 - 3.32 (m, 1H), 3.29 - 3.18 (m, 1H)
[M+H]+ 390.12[M+H] + 390.12
실시예 11: 1-(6-니트로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 11)Example 11: 1-(6-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- Synthesis of ion (Compound 11)
Figure PCTKR2023010500-appb-img-000031
Figure PCTKR2023010500-appb-img-000031
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-6-니트로-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-nitro-3,4-dihydro The title compound was obtained in the same manner as Example 1, except that isoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.79 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.23 - 7.14 (m, 1H), 6.66 (dd, J = 16.9, 10.6 Hz, 1H), 6.38 (d, J = 16.7 Hz, 1H), 5.79 (d, J = 10.5 Hz, 1H), 4.94 - 4.78 (m, 2H), 3.90 - 3.77 (m, 2H), 3.08 - 2.99 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.79 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.23 - 7.14 (m, 1H), 6.66 ( dd, J = 16.9, 10.6 Hz, 1H), 6.38 (d, J = 16.7 Hz, 1H), 5.79 (d, J = 10.5 Hz, 1H), 4.94 - 4.78 (m, 2H), 3.90 - 3.77 (m , 2H), 3.08 - 2.99 (m, 2H)
[M+H]+ 377.10[M+H] + 377.10
실시예 12: 1-(5-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 12)Example 12: 1-(5-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 Synthesis of -one (Compound 12)
Figure PCTKR2023010500-appb-img-000032
Figure PCTKR2023010500-appb-img-000032
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-5-메톡시-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-5-methoxy-3,4-di The title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.93 (d, J = 7.6 Hz, 2H), 7.81 (d, J = 7.6 Hz, 2H), 7.21-7.15 (m, 2H), 6.95-6.86 (m, 1H), 6.16 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 5.73 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 4.84-4.74 (m, 2H), 3.90 (s, 3H), 3.84-3.78 (m, 2H), 2.74-2.69 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.93 (d, J = 7.6 Hz, 2H), 7.81 (d, J = 7.6 Hz, 2H), 7.21-7.15 (m, 2H), 6.95-6.86 (m, 1H), 6.16 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 5.73 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 4.84-4.74 (m, 2H), 3.90 (s, 3H), 3.84-3.78 ( m, 2H), 2.74-2.69 (m, 2H)
[M+H]+ 362.13[M+H] + 362.13
실시예 13: 1-(6-플루오로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 13)Example 13: 1-(6-Fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 Synthesis of -one (Compound 13)
Figure PCTKR2023010500-appb-img-000033
Figure PCTKR2023010500-appb-img-000033
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 7-브로모-6-플루오로-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 7-bromo-6-fluoro-3,4-di The title compound was obtained in the same manner as Example 1, except that hydroisoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.69 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 34.7, 7.4 Hz, 1H), 6.98 (d, J = 10.6 Hz, 1H), 6.65 (dd, J = 16.7, 10.6 Hz, 1H), 6.36 (d, J = 16.5 Hz, 1H), 5.75 (d, J = 10.5 Hz, 1H), 4.82 (s, 1H), 4.75 (s, 1H), 3.91 (s, 1H), 3.81 (s, 1H), 2.95 (s, 2H) 1H NMR(CDCl 3 ) δ 7.69 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 34.7, 7.4 Hz, 1H), 6.98 (d, J = 10.6 Hz, 1H), 6.65 (dd, J = 16.7, 10.6 Hz, 1H), 6.36 (d, J = 16.5 Hz, 1H), 5.75 (d, J = 10.5 Hz, 1H), 4.82 (s, 1H), 4.75 (s, 1H), 3.91 (s, 1H), 3.81 (s, 1H), 2.95 (s, 2H)
[M+H]+ 350.11[M+H] + 350.11
실시예 14: 1-(5-(4-(트리플루오로메틸)페닐)이소인돌린-2-일)프로프-2-엔-1-온의 합성 (화합물 14)Example 14: Synthesis of 1-(5-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)prop-2-en-1-one (Compound 14)
Figure PCTKR2023010500-appb-img-000034
Figure PCTKR2023010500-appb-img-000034
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-브로모이소인돌린-2-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Using tert-butyl 5-bromoisoindoline-2-carboxylate instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1. The title compound was obtained in the same manner as Example 1, except that.
1H NMR(CDCl3) δ 7.89 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.76-7.67 (m, 2H), 7.52-7.46 (m, 1H), 6.75-6.68 (m, 1H), 6.25 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.02 (d, J = 5.2 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H) 1 H NMR(CDCl 3 ) δ 7.89 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.76-7.67 (m, 2H), 7.52-7.46 (m, 1H), 6.75-6.68 (m, 1H), 6.25 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 5.02 (d, J = 5.2 Hz, 2H) , 4.78 (d, J = 6.8 Hz, 2H)
[M+H]+ 318.10[M+H] + 318.10
실시예 15: 1-(2-(4-(트리플루오로메틸)페닐)-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-일)프로프-2-엔-1-온의 합성 (화합물 15)Example 15: 1-(2-(4-(trifluoromethyl)phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)prop-2 Synthesis of -en-1-one (Compound 15)
Figure PCTKR2023010500-appb-img-000035
Figure PCTKR2023010500-appb-img-000035
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 2-브로모-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1, tert-butyl 2-bromo-5,8-dihydropyrido [3 The title compound was obtained in the same manner as Example 1, except that ,4-d]pyrimidine-7(6H)-carboxylate was used.
1H NMR(CDCl3) δ 8.53-8.63(m, 3H), 7.72-7.73(d, 2H), 6.65-6.70(m, 1H), 6.35-6.40(d, 1H), 5.79-5.81(d, 1H), 4.75-4.94(m, 2H), 3.80-4.11(m, 2H), 2.84-2.93(s, 2H) 1H NMR(CDCl 3 ) δ 8.53-8.63(m, 3H), 7.72-7.73(d, 2H), 6.65-6.70(m, 1H), 6.35-6.40(d, 1H), 5.79-5.81(d, 1H), 4.75-4.94(m, 2H), 3.80-4.11(m, 2H), 2.84-2.93(s, 2H)
[M+H]+ 334.11[M+H] + 334.11
실시예 16: 1-(4-(트리플루오로메틸)-2-(4-(트리플루오로메틸)페닐)-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-일)프로프-2-엔-1-온의 합성 (화합물 16)Example 16: 1-(4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7( Synthesis of 6H)-yl)prop-2-en-1-one (Compound 16)
Figure PCTKR2023010500-appb-img-000036
Figure PCTKR2023010500-appb-img-000036
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 2-브로모-4-(트리플루오로메틸)-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-1, tert-butyl 2-bromo-4-(trifluoromethyl)-5 The title compound was obtained in the same manner as Example 1, except that ,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate was used.
1H NMR(CDCl3) δ 8.59 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 6.66 (dd, J = 16.8, 10.6 Hz, 1H), 6.40 (dd, J = 16.8, 1.6 Hz, 1H), 5.82 (dd, J = 10.6, 1.6 Hz, 1H), 4.99 (dd, J = 64.0, 10.9 Hz, 2H), 3.95 (d, J = 55.7 Hz, 2H), 3.12 (s, 2H) 1 H NMR(CDCl 3 ) δ 8.59 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 6.66 (dd, J = 16.8, 10.6 Hz, 1H), 6.40 (dd, J = 16.8, 1.6 Hz, 1H), 5.82 (dd, J = 10.6, 1.6 Hz, 1H), 4.99 (dd, J = 64.0, 10.9 Hz, 2H), 3.95 (d, J = 55.7 Hz, 2H), 3.12 (s, 2H)
[M+H]+ 402.10[M+H] + 402.10
실시예 17: 2-플루오로-1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 17)Example 17: 2-Fluoro-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 Synthesis of -one (Compound 17)
Figure PCTKR2023010500-appb-img-000037
Figure PCTKR2023010500-appb-img-000037
상기 실시예 1-2에서 제조한 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 (277mg, 1mmol)을 5ml의 DMF에 녹였다. HATU(456.3mg, 1.2mmol), TEA(121.5mg, 1.2mmol)와 2-플루오로아크릴산(108mg, 1.2mmol)을 혼합물에 첨가한 후 상온에서 5시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (105mg, 30%)7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (277 mg, 1 mmol) prepared in Example 1-2 was dissolved in 5 ml of DMF. HATU (456.3 mg, 1.2 mmol), TEA (121.5 mg, 1.2 mmol), and 2-fluoroacrylic acid (108 mg, 1.2 mmol) were added to the mixture and stirred at room temperature for 5 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (105mg, 30%)
1H NMR(CDCl3) δ 7.64-7.69(m, 4H), 7.42-7.44(d, 1H), 7.25-7.36(m, 2H), 5.28-5.36(m, 1H), 5.15-5.20(m, 1H), 4.81(s, 2H), 3.83(b, 2H), 2.98(b, 2H) 1H NMR(CDCl 3 ) δ 7.64-7.69(m, 4H), 7.42-7.44(d, 1H), 7.25-7.36(m, 2H), 5.28-5.36(m, 1H), 5.15-5.20(m, 1H), 4.81(s, 2H), 3.83(b, 2H), 2.98(b, 2H)
[M+H]+ 350.11[M+H] + 350.11
실시예 18: 1-(3,3-디메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)-2-플루오로프로프-2-엔-1-온의 합성 (화합물 18)Example 18: 1-(3,3-dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-fluoroprop- Synthesis of 2-en-1-one (Compound 18)
Figure PCTKR2023010500-appb-img-000038
Figure PCTKR2023010500-appb-img-000038
상기 실시예 17의 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 대신 3,3-디메틸-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린을 사용하는 것을 제외하고, 상기 실시예 17과 동일하게 실시하여 표제 화합물을 얻었다.Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 3,3-dimethyl-7-(4-(trifluoromethyl)phenyl )-1,2,3,4-Tetrahydroisoquinoline was used in the same manner as in Example 17 to obtain the title compound.
1H NMR(CDCl3) δ 7.67-7.70(t, 4H), 7.52-7.53(d, 1H), 7.41(s, 1H), 7.31-7.32(d, 1H), 5.15-5.24(d, 1H), 5.09-5.12(d, 1H), 4.54(s, 2H), 2.87(s, 2H), 1.51(s, 6H) 1H NMR(CDCl 3 ) δ 7.67-7.70(t, 4H), 7.52-7.53(d, 1H), 7.41(s, 1H), 7.31-7.32(d, 1H), 5.15-5.24(d, 1H) , 5.09-5.12(d, 1H), 4.54(s, 2H), 2.87(s, 2H), 1.51(s, 6H)
[M+H]+ 378.14[M+H] + 378.14
실시예 19: 2-플루오로-1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로-1,6-나프티리딘-6(5H)-일)프로프-2-엔-1-온의 합성 (화합물 19)Example 19: 2-Fluoro-1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop- Synthesis of 2-en-1-one (Compound 19)
Figure PCTKR2023010500-appb-img-000039
Figure PCTKR2023010500-appb-img-000039
상기 실시예 17의 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 대신 3-(4-(트리플루오로메틸)페닐)-5,6,7,8-테트라히드로-1,6-나프티리딘을 사용하는 것을 제외하고, 상기 실시예 17과 동일하게 실시하여 표제 화합물을 얻었다.Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 3-(4-(trifluoromethyl)phenyl)-5,6, The title compound was obtained in the same manner as Example 17, except for using 7,8-tetrahydro-1,6-naphthyridine.
1H NMR(CDCl3) δ 8.69(s, 1H), 7.66-7.74(m, 5H), 5.33-5.42(d, 1H), 5.20-5.23(d, 1H), 4.84(s, 2H), 3.95(b, 2H), 3.16-3.18(b, 2H) 1H NMR(CDCl 3 ) δ 8.69(s, 1H), 7.66-7.74(m, 5H), 5.33-5.42(d, 1H), 5.20-5.23(d, 1H), 4.84(s, 2H), 3.95 (b, 2H), 3.16-3.18(b, 2H)
[M+H]+ 351.10[M+H] + 351.10
실시예 20: 2-플루오로-1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로피리도[4,3-c]피리다진-6(5H)-일)프로프-2-엔-1-온의 합성 (화합물 20)Example 20: 2-Fluoro-1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrido[4,3-c]pyridazin-6(5H)-yl ) Synthesis of prop-2-en-1-one (Compound 20)
Figure PCTKR2023010500-appb-img-000040
Figure PCTKR2023010500-appb-img-000040
상기 실시예 17의 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 대신 3-(4-(트리플루오로메틸)페닐)-5,6,7,8-테트라히드로피리도[4,3-c]피리다진을 사용하는 것을 제외하고, 상기 실시예 17과 동일하게 실시하여 표제 화합물을 얻었다.Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 3-(4-(trifluoromethyl)phenyl)-5,6, The title compound was obtained in the same manner as Example 17, except for using 7,8-tetrahydropyrido[4,3-c]pyridazine.
1H NMR(CDCl3) δ 8.17-8.19(d, 2H), 7.78-7.79(d, 2H), 7.65(s, 1H), 5.38-5.47(d, 1H), 5.24-5.27(m, 1H), 4.70(s, 2H), 4.00(s, 2H), 3.41(s, 2H) 1H NMR(CDCl 3 ) δ 8.17-8.19(d, 2H), 7.78-7.79(d, 2H), 7.65(s, 1H), 5.38-5.47(d, 1H), 5.24-5.27(m, 1H) , 4.70(s, 2H), 4.00(s, 2H), 3.41(s, 2H)
[M+H]+ 352.10[M+H] + 352.10
실시예 21: 2-플루오로-1-(3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 21)Example 21: 2-Fluoro-1-(3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one (Compound 21)
Figure PCTKR2023010500-appb-img-000041
Figure PCTKR2023010500-appb-img-000041
상기 실시예 17의 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 대신 3-메틸-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린을 사용하는 것을 제외하고, 상기 실시예 17과 동일하게 실시하여 표제 화합물을 얻었다.Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 3-methyl-7-(4-(trifluoromethyl)phenyl)- The title compound was obtained in the same manner as Example 17, except for using 1,2,3,4-tetrahydroisoquinoline.
1H NMR(CDCl3) δ 7.66-7.70(m, 4H), 7.44-7.46(d, 1H), 7.37(s, 1H), 7.24-7.26(d, 1H), 5.23-5.31(m, 2H), 5.14-5.17(m, 1H), 4.60(b, 1H), 4.38(b, 2H), 3.20-3.23(d, 1H), 2.70-2.73(d, 1H), 1.24-1.25(s, 3H) 1H NMR(CDCl 3 ) δ 7.66-7.70(m, 4H), 7.44-7.46(d, 1H), 7.37(s, 1H), 7.24-7.26(d, 1H), 5.23-5.31(m, 2H) , 5.14-5.17(m, 1H), 4.60(b, 1H), 4.38(b, 2H), 3.20-3.23(d, 1H), 2.70-2.73(d, 1H), 1.24-1.25(s, 3H)
[M+H]+ 364.12[M+H] + 364.12
실시예 22: 2-플루오로-1-(6-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 22)Example 22: 2-Fluoro-1-(6-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one (Compound 22)
Figure PCTKR2023010500-appb-img-000042
Figure PCTKR2023010500-appb-img-000042
상기 실시예 17의 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 대신 6-메틸-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린을 사용하는 것을 제외하고, 상기 실시예 17과 동일하게 실시하여 표제 화합물을 얻었다.Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 6-methyl-7-(4-(trifluoromethyl)phenyl)- The title compound was obtained in the same manner as Example 17, except for using 1,2,3,4-tetrahydroisoquinoline.
1H NMR(CDCl3) δ 7.66-7.68(d, 2H), 7.40-7.42(d, 2H), 6.96-7.01(m, 2H), 7.31-7.32(d, 1H), 5.15-5.24(d, 1H), 5.09-5.12(d, 1H), 4.74(m, 2H), 3.76-3.82(m, 2H), 2.95(s, 2H), 2.22(s, 3H) 1H NMR(CDCl 3 ) δ 7.66-7.68(d, 2H), 7.40-7.42(d, 2H), 6.96-7.01(m, 2H), 7.31-7.32(d, 1H), 5.15-5.24(d, 1H), 5.09-5.12(d, 1H), 4.74(m, 2H), 3.76-3.82(m, 2H), 2.95(s, 2H), 2.22(s, 3H)
[M+H]+ 364.12[M+H] + 364.12
실시예 23: 2-플루오로-1-(6-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 23)Example 23: 2-Fluoro-1-(6-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- Synthesis of 2-en-1-one (Compound 23)
Figure PCTKR2023010500-appb-img-000043
Figure PCTKR2023010500-appb-img-000043
상기 실시예 17의 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 대신 6-메톡시-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린을 사용하는 것을 제외하고, 상기 실시예 17과 동일하게 실시하여 표제 화합물을 얻었다.Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 6-methoxy-7-(4-(trifluoromethyl)phenyl) The title compound was obtained in the same manner as Example 17, except that -1,2,3,4-tetrahydroisoquinoline was used.
1H NMR(CDCl3) δ 7.76-7.67 (m, 4H), 7.23 (s, 1H), 6.99 (s, 1H), 5.36-5.18 (m, 2H), 4.73-4.60 (m, 2H), 3.79-3.73 (m, 5H), 2.96-2.88 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.76-7.67 (m, 4H), 7.23 (s, 1H), 6.99 (s, 1H), 5.36-5.18 (m, 2H), 4.73-4.60 (m, 2H), 3.79 -3.73 (m, 5H), 2.96-2.88 (m, 2H)
[M+H]+ 380.12[M+H] + 380.12
실시예 24: 2-플루오로-1-(5-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 24)Example 24: 2-Fluoro-1-(5-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- Synthesis of 2-en-1-one (Compound 24)
Figure PCTKR2023010500-appb-img-000044
Figure PCTKR2023010500-appb-img-000044
상기 실시예 17의 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 대신 5-메톡시-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린을 사용하는 것을 제외하고, 상기 실시예 17과 동일하게 실시하여 표제 화합물을 얻었다.Instead of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline in Example 17, 5-methoxy-7-(4-(trifluoromethyl)phenyl) The title compound was obtained in the same manner as Example 17, except that -1,2,3,4-tetrahydroisoquinoline was used.
1H NMR(CDCl3) δ 7.94-7.92 (m, 2H), 7.82-7.79 (m, 2H), 7.23 (s, 1H), 7.17 (s, 1H), 5.36-5.19 (m, 2H), 4.81-4.70 (m, 2H), 3.90 (s, 3H), 3.78 (t, J = 5.8 Hz, 2H), 2.79-2.72 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.94-7.92 (m, 2H), 7.82-7.79 (m, 2H), 7.23 (s, 1H), 7.17 (s, 1H), 5.36-5.19 (m, 2H), 4.81 -4.70 (m, 2H), 3.90 (s, 3H), 3.78 (t, J = 5.8 Hz, 2H), 2.79-2.72 (m, 2H)
[M+H]+ 380.12[M+H] + 380.12
실시예 25: (E)-4-(디메틸아미노)-1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)부트-2-엔-1-온의 합성 (화합물 25)Example 25: (E)-4-(dimethylamino)-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)but- Synthesis of 2-en-1-one (Compound 25)
Figure PCTKR2023010500-appb-img-000045
Figure PCTKR2023010500-appb-img-000045
상기 실시예 1-2에서 제조한 7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린 (277mg, 1mmol)을 5ml의 DMF에 녹였다. HATU(456.3mg, 1.2mmol), TEA(121.5mg, 1.2mmol)와 (2E)-4-(디메틸아미노)-2-부텐산(155mg, 1.2mmol)을 혼합물에 첨가한 후 상온에서 5시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (124mg, 32%)7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (277 mg, 1 mmol) prepared in Example 1-2 was dissolved in 5 ml of DMF. HATU (456.3 mg, 1.2 mmol), TEA (121.5 mg, 1.2 mmol) and (2E)-4-(dimethylamino)-2-butenoic acid (155 mg, 1.2 mmol) were added to the mixture and stirred at room temperature for 5 hours. did. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (124 mg, 32%)
1H NMR(CDCl3) δ 7.90(s, 1H), 7.65-7.67(d, 2H), 7.41-7.43(d, 1H), 7.34-7.36(d, 1H), 7.30-7.32(d, 2H), 6.68-6.72(d, 1H), 6.50-6.54(d, 1H), 4.22(s, 2H), 3.57-3.63(m, 2H), 3.09-3.15(m, 2H), 3.00-3.04(d, 2H), 2.75(s, 6H) 1H NMR(CDCl 3 ) δ 7.90(s, 1H), 7.65-7.67(d, 2H), 7.41-7.43(d, 1H), 7.34-7.36(d, 1H), 7.30-7.32(d, 2H) , 6.68-6.72(d, 1H), 6.50-6.54(d, 1H), 4.22(s, 2H), 3.57-3.63(m, 2H), 3.09-3.15(m, 2H), 3.00-3.04(d, 2H), 2.75(s, 6H)
[M+H]+ 389.18[M+H] + 389.18
실시예 26: 1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)부트-2-인-1-온의 합성 (화합물 26)Example 26: Synthesis of 1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-yn-1-one (Compound 26)
Figure PCTKR2023010500-appb-img-000046
Figure PCTKR2023010500-appb-img-000046
상기 실시예 25의 (2E)-4-(디메틸아미노)-2-부텐산 대신 2-부티노산을 사용하는 것을 제외하고, 상기 실시예 25와 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 25, except that 2-butynoic acid was used instead of (2E)-4-(dimethylamino)-2-butenoic acid.
1H NMR(CDCl3) δ 7.81-7.91(m, 2H), 7.79-7.81(m, 2H), 7.55-7.65(m, 2H), 7.30-7.32(d, 1H), 4.72-4.95(m, 2H), 3.72-3.97(m, 2H), 2.84-2.94(m, 2H), 1.99(s, 3H) 1 H NMR(CDCl 3 ) δ 7.81-7.91(m, 2H), 7.79-7.81(m, 2H), 7.55-7.65(m, 2H), 7.30-7.32(d, 1H), 4.72-4.95(m, 2H), 3.72-3.97(m, 2H), 2.84-2.94(m, 2H), 1.99(s, 3H)
[M+H]+ 344.12[M+H] + 344.12
실시예 27: 2-(7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-2-카보닐)아크릴로니트릴의 합성 (화합물 27)Example 27: Synthesis of 2-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)acrylonitrile (Compound 27)
Figure PCTKR2023010500-appb-img-000047
Figure PCTKR2023010500-appb-img-000047
상기 실시예 25의 (2E)-4-(디메틸아미노)-2-부텐산 대신 2-시아노아크릴산을 사용하는 것을 제외하고, 상기 실시예 25와 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 25, except that 2-cyanoacrylic acid was used instead of (2E)-4-(dimethylamino)-2-butenoic acid.
1H NMR(CDCl3) δ 7.91-7.89 (m, 2H), 7.83-7.80 (m, 2H), 7.66 (br, 1H), 7.61-7.58 (m, 1H), 7.36-7.33 (m, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.85-4.77 (m, 2H), 3.81-3.79 (m, 2H), 2.97-2.88 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.91-7.89 (m, 2H), 7.83-7.80 (m, 2H), 7.66 (br, 1H), 7.61-7.58 (m, 1H), 7.36-7.33 (m, 1H) , 6.75 (s, 1H), 6.59 (s, 1H), 4.85-4.77 (m, 2H), 3.81-3.79 (m, 2H), 2.97-2.88 (m, 2H)
[M+H]+ 357.11[M+H] + 357.11
실시예 28: 1-(7-(시클로헥스-1-엔-1-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 28)Example 28: Synthesis of 1-(7-(cyclohex-1-en-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 28)
Figure PCTKR2023010500-appb-img-000048
Figure PCTKR2023010500-appb-img-000048
실시예 28-1: tert-부틸 7-(시클로헥스-1-엔-1-일)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 28-1: Synthesis of tert-butyl 7-(cyclohex-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (9.3g, 30mmol)을 다이옥산/물(3:1) 300ml에 녹인 후 Pd(PPh3)4(3.46g, 3mmol)을 첨가하였다. 그 후 Cs2CO3(11.736g, 36mmol)와 시클로헥스-1-엔-1-일보론산 (4.53g, 36mmol)을 순서대로 첨가하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (8.8g, 78%)After dissolving tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (9.3g, 30mmol) in 300ml of dioxane/water (3:1), Pd(PPh 3 ) 4 ( 3.46g, 3mmol) was added. Afterwards, Cs 2 CO 3 (11.736 g, 36 mmol) and cyclohex-1-en-1-ylboronic acid (4.53 g, 36 mmol) were added in that order. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (8.8g, 78%)
MS (ESI) m/z: [M+H]+ 314.20MS (ESI) m/z: [M+H] + 314.20
실시예 28-2: 7-(시클로헥스-1-엔-1-일)-1,2,3,4-테트라히드로이소퀴놀린의 합성Example 28-2: Synthesis of 7-(cyclohex-1-en-1-yl)-1,2,3,4-tetrahydroisoquinoline
상기 실시예 28-1에서 제조한 tert-부틸 7-(시클로헥스-1-엔-1-일)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (3.45g, 11mmol)을 DCM 50ml에 녹인 후 10ml의 TFA를 첨가하여 상온에서 2시간 교반하였다. 2시간 경과 후 반응이 완료됨을 LC-MS로 확인하고 혼합물에 물을 200ml 첨가하였다. 상기 혼합물을 필터하여 하얀색 고체를 얻고 이를 에틸아세테이트, NaHCO3(aq)을 이용하여 중성화하였다. 유기층을 감압 농축하여 하얀색 고체 형태의 표제 화합물을 얻었다. (1.715g, 73%)tert-butyl 7-(cyclohex-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.45g, 11mmol) prepared in Example 28-1 After dissolving in 50ml of DCM, 10ml of TFA was added and stirred at room temperature for 2 hours. After 2 hours, completion of the reaction was confirmed by LC-MS, and 200 ml of water was added to the mixture. The mixture was filtered to obtain a white solid, which was neutralized using ethyl acetate and NaHCO 3 (aq). The organic layer was concentrated under reduced pressure to obtain the title compound in the form of a white solid. (1.715g, 73%)
MS (ESI) m/z: [M+H]+ 214.15MS (ESI) m/z: [M+H] + 214.15
실시예 28-3: 1-(7-(시클로헥스-1-엔-1-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 28-3: 1-(7-(cyclohex-1-en-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one synthesis of
상기 실시예 28-2에서 제조한 7-(시클로헥스-1-엔-1-일)-1,2,3,4-테트라히드로이소퀴놀린 (267.4mg, 1mmol)을 5ml의 DMF에 녹였다. HATU(456.3mg, 1.2mmol), TEA(121.5mg, 1.2mmol)와 아크릴산(86.5mg, 1.2mmol)를 혼합물에 첨가한 후 상온에서 3시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (136.4mg, 51%)7-(cyclohex-1-en-1-yl)-1,2,3,4-tetrahydroisoquinoline (267.4 mg, 1 mmol) prepared in Example 28-2 was dissolved in 5 ml of DMF. HATU (456.3 mg, 1.2 mmol), TEA (121.5 mg, 1.2 mmol), and acrylic acid (86.5 mg, 1.2 mmol) were added to the mixture and stirred at room temperature for 3 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (136.4mg, 51%)
1H NMR(CDCl3) δ 7.21 - 7.08 (m, 2H), 7.06 - 6.99 (m, 1H), 6.58 (dt, J = 16.0, 10.0 Hz, 1H), 6.26 (d, J = 16.9 Hz, 1H), 6.02 (s, 1H), 5.65 (d, J = 10.5 Hz, 1H), 4.68 (d, J = 43.5 Hz, 2H), 3.75 (d, J = 69.0 Hz, 2H), 2.85 - 2.76 (m, 2H), 2.31 (s, 2H), 2.13 (s, 2H), 1.74 - 1.67 (m, 2H), 1.62 - 1.57 (m, 2H) 1H NMR(CDCl 3 ) δ 7.21 - 7.08 (m, 2H), 7.06 - 6.99 (m, 1H), 6.58 (dt, J = 16.0, 10.0 Hz, 1H), 6.26 (d, J = 16.9 Hz, 1H) ), 6.02 (s, 1H), 5.65 (d, J = 10.5 Hz, 1H), 4.68 (d, J = 43.5 Hz, 2H), 3.75 (d, J = 69.0 Hz, 2H), 2.85 - 2.76 (m , 2H), 2.31 (s, 2H), 2.13 (s, 2H), 1.74 - 1.67 (m, 2H), 1.62 - 1.57 (m, 2H)
[M+H]+ 268.16[M+H] + 268.16
실시예 29: 1-(7-페닐-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 29)Example 29: Synthesis of 1-(7-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 29)
Figure PCTKR2023010500-appb-img-000049
Figure PCTKR2023010500-appb-img-000049
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 페닐보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 28, except that phenylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
1H NMR(CDCl3) δ 7.54-7.55(d, 2H), 7.34-7.43(m, 4H), 7.31-7.33(m, 1H), 7.20-7.24(m, 1H), 6.63-6.67(m, 1H), 6.32-6.35(d, 1H), 5.72-5.74(d, 1H), 4.78-4.85(m, 2H), 3.80-3.92(m, 2H), 2.91-2.95(s, 2H) 1H NMR(CDCl 3 ) δ 7.54-7.55(d, 2H), 7.34-7.43(m, 4H), 7.31-7.33(m, 1H), 7.20-7.24(m, 1H), 6.63-6.67(m, 1H), 6.32-6.35(d, 1H), 5.72-5.74(d, 1H), 4.78-4.85(m, 2H), 3.80-3.92(m, 2H), 2.91-2.95(s, 2H)
[M+H]+ 264.13[M+H] + 264.13
실시예 30: 1-(7-(4-플루오로페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 30)Example 30: Synthesis of 1-(7-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 30)
Figure PCTKR2023010500-appb-img-000050
Figure PCTKR2023010500-appb-img-000050
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (4-플루오로페닐)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 28, except that (4-fluorophenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
1H NMR(CDCl3) δ 7.48-7.52(m, 2H), 7.33-7.37(m, 2H), 7.19-7.24(m, 1H), 7.09-7.13(m, 2H), 6.62-6.67(m, 1H), 6.32-6.35(d, 1H), 5.72-5.74(d, 1H), 4.77-4.85(m, 2H), 3.79-3.92(m, 2H), 2.92-2.95(s, 2H) 1 H NMR(CDCl 3 ) δ 7.48-7.52(m, 2H), 7.33-7.37(m, 2H), 7.19-7.24(m, 1H), 7.09-7.13(m, 2H), 6.62-6.67(m, 1H), 6.32-6.35(d, 1H), 5.72-5.74(d, 1H), 4.77-4.85(m, 2H), 3.79-3.92(m, 2H), 2.92-2.95(s, 2H)
[M+H]+ 282.12[M+H] + 282.12
실시예 31: 1-(7-(3,4-디플루오로페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 31)Example 31: Synthesis of 1-(7-(3,4-difluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 31)
Figure PCTKR2023010500-appb-img-000051
Figure PCTKR2023010500-appb-img-000051
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (3,4-디플루오로페닐)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was prepared in the same manner as in Example 28, except that (3,4-difluorophenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. got it
1H NMR(CDCl3) δ 7.30-7.35(m, 3H), 7.18-7.25(m, 3H), 6.63-6.67(m, 1H), 6.32-6.35(d, 1H), 5.72-5.74(d, 1H), 4.77-4.83(m, 2H), 3.79-3.92(m, 2H), 2.91-3.01(m, 2H) 1H NMR(CDCl 3 ) δ 7.30-7.35(m, 3H), 7.18-7.25(m, 3H), 6.63-6.67(m, 1H), 6.32-6.35(d, 1H), 5.72-5.74(d, 1H), 4.77-4.83(m, 2H), 3.79-3.92(m, 2H), 2.91-3.01(m, 2H)
[M+H]+ 300.11[M+H] + 300.11
실시예 32: 1-(7-(티오펜-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 32)Example 32: Synthesis of 1-(7-(thiophen-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 32)
Figure PCTKR2023010500-appb-img-000052
Figure PCTKR2023010500-appb-img-000052
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 티오펜-2-일보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 28, except that thiophen-2-ylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
1H NMR(CDCl3) δ 7.46-7.53(m, 4H), 7.21-7.23(d, 1H), 7.13-7.14(d, 1H), 6.86-6.94(m, 1H), 6.14-6.18(d, 1H), 5.71-5.74(d, 1H), 4.73-4.83(m, 2H), 3.74-3.82(m, 2H), 2.82-2.87(m, 2H) 1H NMR(CDCl 3 ) δ 7.46-7.53(m, 4H), 7.21-7.23(d, 1H), 7.13-7.14(d, 1H), 6.86-6.94(m, 1H), 6.14-6.18(d, 1H), 5.71-5.74(d, 1H), 4.73-4.83(m, 2H), 3.74-3.82(m, 2H), 2.82-2.87(m, 2H)
[M+H]+ 270.09[M+H] + 270.09
실시예 33: 1-(7-(3-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 33)Example 33: Synthesis of 1-(7-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one ( Compound 33)
Figure PCTKR2023010500-appb-img-000053
Figure PCTKR2023010500-appb-img-000053
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (3-(트리플루오로메틸)페닐)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 28, except that (3-(trifluoromethyl)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. got it
1H NMR(CDCl3) δ 7.98(s, 2H), 7.57-7.71(m, 4H), 7.30-7.32(d, 1H), 6.87-6.94(m, 1H), 6.15-6.19(d, 1H), 5.72-5.74(d, 1H), 4.78-4.87(m, 2H), 3.78-3.85(m, 2H), 2.86-2.90(m, 2H) 1H NMR(CDCl 3 ) δ 7.98(s, 2H), 7.57-7.71(m, 4H), 7.30-7.32(d, 1H), 6.87-6.94(m, 1H), 6.15-6.19(d, 1H) , 5.72-5.74(d, 1H), 4.78-4.87(m, 2H), 3.78-3.85(m, 2H), 2.86-2.90(m, 2H)
[M+H]+ 332.12[M+H] + 332.12
실시예 34: 1-(7-(6-(트리플루오로메틸)피리딘-3-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 34)Example 34: 1-(7-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- Synthesis of ion (Compound 34)
Figure PCTKR2023010500-appb-img-000054
Figure PCTKR2023010500-appb-img-000054
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (6-(트리플루오로메틸)피리딘-3-일)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.Same as Example 28, except that (6-(trifluoromethyl)pyridin-3-yl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
1H NMR(CDCl3) δ 9.09(s, 1H), 8.35-8.37(m, 1H), 7.97-7.99(d, 1H), 7.64-7.73(m, 2H), 7.35-7.37(d, 1H), 6.87-6.94(m, 1H), 6.14-6.19(d, 1H), 5.72-5.75(d, 1H), 4.78-4.87(m, 2H), 3.78-3.85(m, 2H), 2.87-2.94(m, 2H) 1H NMR(CDCl 3 ) δ 9.09(s, 1H), 8.35-8.37(m, 1H), 7.97-7.99(d, 1H), 7.64-7.73(m, 2H), 7.35-7.37(d, 1H) , 6.87-6.94(m, 1H), 6.14-6.19(d, 1H), 5.72-5.75(d, 1H), 4.78-4.87(m, 2H), 3.78-3.85(m, 2H), 2.87-2.94( m, 2H)
[M+H]+ 333.11[M+H] + 333.11
실시예 35: 1-(7-(4-(트리플루오로메톡시)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 35)Example 35: Synthesis of 1-(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one ( Compound 35)
Figure PCTKR2023010500-appb-img-000055
Figure PCTKR2023010500-appb-img-000055
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (4-(트리플루오로메톡시)페닐)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 28, except that (4-(trifluoromethoxy)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. got it
1H NMR(CDCl3) δ 7.77-7.79(m, 2H), 7.43-7.55(m, 4H), 7.27-7.29(d, 1H), 6.86-6.93(m, 1H), 6.13-6.18(d, 1H), 5.71-5.74(d, 1H), 4.75-4.84(m, 2H), 3.75-3.84(m, 2H), 2.84-2.90(m, 2H) 1H NMR(CDCl 3 ) δ 7.77-7.79(m, 2H), 7.43-7.55(m, 4H), 7.27-7.29(d, 1H), 6.86-6.93(m, 1H), 6.13-6.18(d, 1H), 5.71-5.74(d, 1H), 4.75-4.84(m, 2H), 3.75-3.84(m, 2H), 2.84-2.90(m, 2H)
[M+H]+ 348.11[M+H] + 348.11
실시예 36: 1-(7-(2-클로로-4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 36)Example 36: 1-(7-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- Synthesis of ion (Compound 36)
Figure PCTKR2023010500-appb-img-000056
Figure PCTKR2023010500-appb-img-000056
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (2-클로로-4-(트리플루오로메틸)페닐)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The same as Example 28, except that (2-chloro-4-(trifluoromethyl)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.73(s, 1H), 7.55-7.57(d, 1H), 7.42-7.43(d,1H), 7.22-7.25(m, 3H), 6.63-6.68(m, 1H), 6.33-6.35(d, 1H), 5.73-5.75(d, 1H), 4.77-4.85(m, 2H), 3.82-3.93(m, 2H), 2.95-2.98(m, 2H) 1 H NMR(CDCl 3 ) δ 7.73(s, 1H), 7.55-7.57(d, 1H), 7.42-7.43(d, 1H), 7.22-7.25(m, 3H), 6.63-6.68(m, 1H) , 6.33-6.35(d, 1H), 5.73-5.75(d, 1H), 4.77-4.85(m, 2H), 3.82-3.93(m, 2H), 2.95-2.98(m, 2H)
[M+H]+ 366.08[M+H] + 366.08
실시예 37: 1-(7-(3-플루오로-4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 37)Example 37: 1-(7-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 Synthesis of -one (Compound 37)
Figure PCTKR2023010500-appb-img-000057
Figure PCTKR2023010500-appb-img-000057
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (3-플루오로-4-(트리플루오로메틸)페닐)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.Same as Example 28, except that (3-fluoro-4-(trifluoromethyl)phenyl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.53-7.55(t, 1H), 7.35-7.42(m, 4), 7.24-7.31(m, 1H), 6.63-6.68(m, 1H), 6.34-6.37(d, 1H), 5.73-5.75(m, 1H), 4.79-4.85(m, 2H), 3.80-3.93(m, 2H), 2.92-2.97(m, 2H) 1H NMR(CDCl 3 ) δ 7.53-7.55(t, 1H), 7.35-7.42(m, 4), 7.24-7.31(m, 1H), 6.63-6.68(m, 1H), 6.34-6.37(d, 1H), 5.73-5.75(m, 1H), 4.79-4.85(m, 2H), 3.80-3.93(m, 2H), 2.92-2.97(m, 2H)
[M+H]+ 350.11[M+H] + 350.11
실시예 38: 1-(7-(나프탈렌-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 38)Example 38: Synthesis of 1-(7-(naphthalen-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 38)
Figure PCTKR2023010500-appb-img-000058
Figure PCTKR2023010500-appb-img-000058
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 나프탈렌-2-일보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 28, except that naphthalene-2-ylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
1H NMR(CDCl3) δ 8.00(s, 1H), 7.85-7.91(m, 3H), 7.70-7.71(d, 1H), 7.45-7.55(m, 4H), 7.25-7.28(m, 1H), 6.64-6.69(m, 1H), 6.34-6.37(m, 1H), 5.73-5.75(d, 1H), 4.82-4.90(m, 2H), 3.81-3.95(m, 2H), 2.95-2.98(s, 2H) 1H NMR(CDCl 3 ) δ 8.00(s, 1H), 7.85-7.91(m, 3H), 7.70-7.71(d, 1H), 7.45-7.55(m, 4H), 7.25-7.28(m, 1H) , 6.64-6.69(m, 1H), 6.34-6.37(m, 1H), 5.73-5.75(d, 1H), 4.82-4.90(m, 2H), 3.81-3.95(m, 2H), 2.95-2.98( s, 2H)
[M+H]+ 314.15[M+H] + 314.15
실시예 39: 1-(7-(5-(트리플루오로메틸)피리딘-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 39)Example 39: 1-(7-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- Synthesis of ion (Compound 39)
Figure PCTKR2023010500-appb-img-000059
Figure PCTKR2023010500-appb-img-000059
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 (5-(트리플루오로메틸)피리딘-2-일)보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The same as Example 28, except that (5-(trifluoromethyl)pyridin-2-yl)boronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1. This was performed to obtain the title compound.
1H NMR(CDCl3) δ 9.03(s, 1H), 8.16-8.29(m, 2H), 7.98-8.04(m, 2H), 7.34-7.36(d, 1H), 6.88-6.96(m, 1H), 6.14-6.19(d, 1H), 5.72-5.75(d, 1H), 4.79-4.90(m, 2H), 3.77-3.86(m, 2H), 2.88-2.95(m, 2H) 1H NMR(CDCl 3 ) δ 9.03(s, 1H), 8.16-8.29(m, 2H), 7.98-8.04(m, 2H), 7.34-7.36(d, 1H), 6.88-6.96(m, 1H) , 6.14-6.19(d, 1H), 5.72-5.75(d, 1H), 4.79-4.90(m, 2H), 3.77-3.86(m, 2H), 2.88-2.95(m, 2H)
[M+H]+ 333.11[M+H] + 333.11
실시예 40: 1-(7-(p-톨릴)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 40)Example 40: Synthesis of 1-(7-(p-tolyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 40)
Figure PCTKR2023010500-appb-img-000060
Figure PCTKR2023010500-appb-img-000060
상기 실시예 28-1의 시클로헥스-1-엔-1-일보론산 대신 p-톨릴보론산을 사용하는 것을 제외하고, 상기 실시예 28과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as Example 28, except that p-tolylboronic acid was used instead of cyclohex-1-en-1-ylboronic acid in Example 28-1.
1H NMR(CDCl3) δ 7.44-7.56(m, 4H), 7.18-7.27(m, 3H), 6.87-6.94(m, 1H), 6.14-6.19(d, 1H), 5.71-5.74(d, 1H), 4.74-4.84(m, 1H), 3.75-3.83(m, 2H), 2.81-2.89(m, 2H), 2.08(s, 3H) 1H NMR(CDCl 3 ) δ 7.44-7.56(m, 4H), 7.18-7.27(m, 3H), 6.87-6.94(m, 1H), 6.14-6.19(d, 1H), 5.71-5.74(d, 1H), 4.74-4.84(m, 1H), 3.75-3.83(m, 2H), 2.81-2.89(m, 2H), 2.08(s, 3H)
[M+H]+ 278.15[M+H] + 278.15
실시예 41: 1-(7-시클로헥실-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 41)Example 41: Synthesis of 1-(7-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 41)
Figure PCTKR2023010500-appb-img-000061
Figure PCTKR2023010500-appb-img-000061
실시예 41-1: 7-시클로헥실-1,2,3,4-테트라히드로이소퀴놀린의 합성Example 41-1: Synthesis of 7-cyclohexyl-1,2,3,4-tetrahydroisoquinoline
상기 실시예 28-2에서 제조한 7-(시클로헥스-1-엔-1-일)-1,2,3,4-테트라히드로이소퀴놀린 (350mg, 1.63mmol)를 THF 10ml에 녹였다. 10% Pd/C (17.5 mg, 0.16mmol)을 투입한 후 수소 풍선을 이용해 수소 대기 환경을 만들어 주고 상온에서 24시간 교반하였다. 반응 종결을 LC-MS로 확인하고 필터 후 얻은 여과액을 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제한 후 농축하여 표제 화합물을 얻었다. (273.8mg, 78%)7-(cyclohex-1-en-1-yl)-1,2,3,4-tetrahydroisoquinoline (350 mg, 1.63 mmol) prepared in Example 28-2 was dissolved in 10 ml of THF. After adding 10% Pd/C (17.5 mg, 0.16 mmol), a hydrogen atmosphere was created using a hydrogen balloon and stirred at room temperature for 24 hours. The completion of the reaction was confirmed by LC-MS, and the filtrate obtained after filtering was concentrated in vacuum. The residue was purified using column chromatography and concentrated to obtain the title compound. (273.8mg, 78%)
MS (ESI) m/z : [M+H]+ 216.17MS (ESI) m/z: [M+H] + 216.17
실시예 41-2: 1-(7-시클로헥실-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 41-2: Synthesis of 1-(7-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
상기 실시예 41-1에서 얻은 7-시클로헥실-1,2,3,4-테트라히드로이소퀴놀린(215.34mg, 1mmol)을 5ml DMF에 녹였다. HATU(456.3mg, 1.2mmol), TEA(121.5mg, 1.2mmol)와 아크릴산(86.5mg, 1.2mmol)을 상기 혼합물에 첨가한 후 상온에서 5시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (129.3mg, 48%)7-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (215.34 mg, 1 mmol) obtained in Example 41-1 was dissolved in 5 ml DMF. HATU (456.3 mg, 1.2 mmol), TEA (121.5 mg, 1.2 mmol), and acrylic acid (86.5 mg, 1.2 mmol) were added to the mixture and stirred at room temperature for 5 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (129.3mg, 48%)
1H NMR(CDCl3) δ 7.12 - 7.02 (m, 2H), 6.97 (d, J = 42.6 Hz, 1H), 6.62 (dd, J = 17.1, 10.8 Hz, 1H), 6.31 (d, J = 16.9 Hz, 1H), 5.79 (dd, J = 10.8, 3.4 Hz, 1H), 4.75 (d, J = 49.1 Hz, 2H), 3.83 (dt, J = 68.4, 5.9 Hz, 2H), 2.93 - 2.78 (m, 2H), 2.46 (ddd, J = 11.6, 7.2, 2.8 Hz, 1H), 1.84 (s, 2H), 1.74 (d, J = 12.7 Hz, 2H), 1.46 - 1.27 (m, 6H) 1 H NMR(CDCl 3 ) δ 7.12 - 7.02 (m, 2H), 6.97 (d, J = 42.6 Hz, 1H), 6.62 (dd, J = 17.1, 10.8 Hz, 1H), 6.31 (d, J = 16.9 Hz, 1H), 5.79 (dd, J = 10.8, 3.4 Hz, 1H), 4.75 (d, J = 49.1 Hz, 2H), 3.83 (dt, J = 68.4, 5.9 Hz, 2H), 2.93 - 2.78 (m , 2H), 2.46 (ddd, J = 11.6, 7.2, 2.8 Hz, 1H), 1.84 (s, 2H), 1.74 (d, J = 12.7 Hz, 2H), 1.46 - 1.27 (m, 6H)
[M+H]+ 270.18[M+H] + 270.18
실시예 42: 2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,4-디히드로이소퀴놀린-3(2H)-온의 합성 (화합물 42)Example 42: Synthesis of 2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one (Compound 42)
Figure PCTKR2023010500-appb-img-000062
Figure PCTKR2023010500-appb-img-000062
실시예 42-1: 7-(4-(트리플루오로메틸)페닐)-1,4-디히드로이소퀴놀린-3(2H)-온의 합성Example 42-1: Synthesis of 7-(4-(trifluoromethyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one
7-브로모-1,4-디히드로이소퀴놀린-3(2H)-온(6.78g, 30mmol)을 다이옥산/물(3:1) 300ml에 녹인 후 Pd(PPh3)4(3.46g, 3mmol)을 첨가하였다. 그 후 Cs2CO3(11.736g, 36mmol)와 4-(트리플루오로메틸)페닐 보론산 (6.836g, 36mmol)을 순서대로 첨가하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (5.94g, 68%)7-Bromo-1,4-dihydroisoquinolin-3(2H)-one (6.78g, 30mmol) was dissolved in 300ml of dioxane/water (3:1) and then Pd(PPh 3 ) 4 (3.46g, 3mmol) ) was added. Afterwards, Cs 2 CO 3 (11.736 g, 36 mmol) and 4-(trifluoromethyl)phenyl boronic acid (6.836 g, 36 mmol) were added in that order. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (5.94g, 68%)
MS (ESI) m/z : [M+H]+ 292.09MS (ESI) m/z: [M+H] + 292.09
실시예 42-2: 2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,4-디히드로이소퀴놀린-3(2H)-온의 합성Example 42-2: Synthesis of 2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one
상기 실시예 42-1에서 제조한 7-(4-(트리플루오로메틸)페닐)-1,4-디히드로이소퀴놀린-3(2H)-온 (291.3mg, 1mmol)을 다이옥산 10ml에 녹인 후 DMAP(24.4mg, 0.2mmol), 아크릴 무수물(252.2mg, 2mmol)을 첨가하였다. 상기 혼합 용액을 100℃에서 15시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (234.82mg, 0.68mmol, 68%)7-(4-(trifluoromethyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one (291.3 mg, 1 mmol) prepared in Example 42-1 was dissolved in 10 ml of dioxane. DMAP (24.4 mg, 0.2 mmol) and acrylic anhydride (252.2 mg, 2 mmol) were added. The mixed solution was stirred at 100°C for 15 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (234.82mg, 0.68mmol, 68%)
1H NMR(CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.56 - 7.50 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.18 (dd, J = 16.9, 10.4 Hz, 1H), 6.43 (dd, J = 16.9, 1.7 Hz, 1H), 5.80 (dd, J = 10.4, 1.7 Hz, 1H), 5.02 (s, 2H), 3.82 (s, 2H) 1 H NMR(CDCl 3 ) δ 7.70 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.56 - 7.50 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.18 (dd, J = 16.9, 10.4 Hz, 1H), 6.43 (dd, J = 16.9, 1.7 Hz, 1H), 5.80 (dd, J = 10.4, 1.7 Hz, 1H), 5.02 (s, 2H) ), 3.82 (s, 2H)
[M+H]+ 346.10[M+H] + 346.10
실시예 43: 2-아크릴로일-5-(4-(트리플루오로메틸)페닐)이소인돌린-1-온의 합성 (화합물 43)Example 43: Synthesis of 2-acryloyl-5-(4-(trifluoromethyl)phenyl)isoindolin-1-one (Compound 43)
Figure PCTKR2023010500-appb-img-000063
Figure PCTKR2023010500-appb-img-000063
상기 실시예 42-1의 7-브로모-1,4-디히드로이소퀴놀린-3(2H)-온 대신 5-브로모이소인돌린-1-온을 사용하는 것을 제외하고, 상기 실시예 42와 동일하게 실시하여 표제 화합물을 얻었다.Example 42 and above, except that 5-bromoisoindolin-1-one was used instead of 7-bromo-1,4-dihydroisoquinolin-3(2H)-one in Example 42-1. The same procedure was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.85 (d, J = 5.6 Hz, 2H), 7.80 (d, J = 7.4 Hz, 2H), 7.75-7.65 (m, 2H), 7.50-7.43 (m, 1H), 6.72-6.65 (m, 1H), 6.21 (dd, J = 13.8 Hz, 2.2 Hz, 1H), 5.76 (dd, J = 9.4 Hz, 1.4 Hz, 1H), 5.00 (d, J = 4.2 Hz, 2H) 1H NMR(CDCl 3 ) δ 7.85 (d, J = 5.6 Hz, 2H), 7.80 (d, J = 7.4 Hz, 2H), 7.75-7.65 (m, 2H), 7.50-7.43 (m, 1H), 6.72-6.65 (m, 1H), 6.21 (dd, J = 13.8 Hz, 2.2 Hz, 1H), 5.76 (dd, J = 9.4 Hz, 1.4 Hz, 1H), 5.00 (d, J = 4.2 Hz, 2H)
[M+H]+ 332.08[M+H] + 332.08
실시예 44: 1-(6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 44)Example 44: 1-(6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one (Compound 44)
Figure PCTKR2023010500-appb-img-000064
Figure PCTKR2023010500-appb-img-000064
실시예 44-1: tert-부틸 6-니트로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 44-1: Synthesis of tert-butyl 6-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
tert-부틸 7-브로모-6-니트로-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트(10.72g, 30mmol)를 다이옥산/물(3:1) 300ml에 녹인 후 Pd(PPh3)4(3.46g, 3mmol)을 첨가하였다. 그 후 Cs2CO3(11.736g, 36mmol)와 4-(트리플루오로메틸)페닐 보론산 (6.836g, 36mmol)을 순서대로 첨가하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (8.4g, 66%)tert-Butyl 7-bromo-6-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (10.72g, 30mmol) was dissolved in 300ml of dioxane/water (3:1) and then dissolved in Pd(PPh). 3 ) 4 (3.46g, 3mmol) was added. Afterwards, Cs 2 CO 3 (11.736 g, 36 mmol) and 4-(trifluoromethyl)phenyl boronic acid (6.836 g, 36 mmol) were added in that order. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (8.4g, 66%)
MS (ESI) m/z: [M+H]+ 423.15MS (ESI) m/z: [M+H] + 423.15
실시예 44-2: tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 44-2: Synthesis of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 실시예 44-1에서 제조한 tert-부틸 6-니트로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (8.36g, 19.8mmol)을 메탄올 200ml에 녹였다. 10% Pd/C (638.5mg, 6mmol)을 주의하여 투입한 후 수소 풍선을 이용해 수소 대기 환경을 만들어 주고 상온에서 2일간 교반하였다. 반응 종결을 LC-MS로 확인하고 필터 후 얻은 여과액을 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제한 후 농축하여 표제 화합물을 얻었다. (4.9g, 63%)tert-Butyl 6-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate prepared in Example 44-1 (8.36g, 19.8 mmol) was dissolved in 200 ml of methanol. After carefully adding 10% Pd/C (638.5 mg, 6 mmol), a hydrogen atmosphere was created using a hydrogen balloon and stirred at room temperature for 2 days. The completion of the reaction was confirmed by LC-MS, and the filtrate obtained after filtering was concentrated in vacuum. The residue was purified using column chromatography and concentrated to obtain the title compound. (4.9g, 63%)
MS (ESI) m/z: [M+H]+ 393.17MS (ESI) m/z: [M+H] + 393.17
실시예 44-3: tert-부틸 6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 44-3: Synthesis of tert-butyl 6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 실시예 44-2에서 제조한 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (3.92g, 10mmol)을 에탄올 100ml에 녹인 후 포름알데히드(360mg, 12mmol), NaBH(OAc)3(4,24g, 20mmol)와 AcOH(60mg, 1mmol)을 순차적으로 투입하였다. 상기 혼합 용액을 70℃에서 4시간 교반하였다. 얻어진 화합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (3.45g, 85%)tert-Butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.92g, 10 mmol) was dissolved in 100 ml of ethanol, and then formaldehyde (360 mg, 12 mmol), NaBH (OAc) 3 (4,24 g, 20 mmol), and AcOH (60 mg, 1 mmol) were sequentially added. The mixed solution was stirred at 70°C for 4 hours. After cooling the obtained compound, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (3.45g, 85%)
MS (ESI) m/z: [M+H]+ 407.19MS (ESI) m/z: [M+H] + 407.19
실시예 44-4: 1-(6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 44-4: 1-(6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 44-3에서 제조한 tert-부틸 6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of the tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, the product prepared in Example 44-3 The above examples except that tert-butyl 6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The same procedure as 1-2 and 1-3 was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 6.90 - 6.78 (m, 1H), 6.65 (dd, J = 16.7, 10.6 Hz, 1H), 6.47 (d, J = 10.4 Hz, 1H), 6.33 (ddd, J = 16.8, 6.2, 2.0 Hz, 1H), 5.72 (ddd, J = 10.5, 5.8, 2.0 Hz, 1H), 4.72 (s, 1H), 4.65 (s, 1H), 3.91 (t, J = 5.9 Hz, 1H), 3.80 (d, J = 5.9 Hz, 1H), 2.91 (dt, J = 14.6, 6.0 Hz, 2H), 2.79 (s, 3H) 1 H NMR(CDCl 3 ) δ 7.69 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 6.90 - 6.78 (m, 1H), 6.65 (dd, J = 16.7, 10.6 Hz, 1H), 6.47 (d, J = 10.4 Hz, 1H), 6.33 (ddd, J = 16.8, 6.2, 2.0 Hz, 1H), 5.72 (ddd, J = 10.5, 5.8, 2.0 Hz, 1H), 4.72 (s, 1H), 4.65 (s, 1H), 3.91 (t, J = 5.9 Hz, 1H), 3.80 (d, J = 5.9 Hz, 1H), 2.91 (dt, J = 14.6, 6.0 Hz, 2H) , 2.79 (s, 3H)
[M+H]+ 361.14[M+H] + 361.14
실시예 45: 1-(6-(벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 45)Example 45: 1-(6-(benzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one (Compound 45)
Figure PCTKR2023010500-appb-img-000065
Figure PCTKR2023010500-appb-img-000065
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-(벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-2, tert-butyl 6-(benzylamino) Same as Examples 1-2 and 1-3 above, except for using -7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate This was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.60 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.22 (dt, J = 15.8, 7.5 Hz, 4H), 7.17 (t, J = 6.5 Hz, 1H), 6.82 - 6.73 (m, 1H), 6.55 (ddd, J = 16.5, 10.5, 5.4 Hz, 1H), 6.38 (d, J = 14.1 Hz, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.62 (dd, J = 10.6, 1.9 Hz, 1H), 4.62 (s, 1H), 4.55 (s, 1H), 4.23 (s, 2H), 4.13 (s, 1H), 3.77 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 5.9 Hz, 1H), 2.78 - 2.71 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.60 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.22 (dt, J = 15.8, 7.5 Hz, 4H), 7.17 (t, J = 6.5 Hz, 1H), 6.82 - 6.73 (m, 1H), 6.55 (ddd, J = 16.5, 10.5, 5.4 Hz, 1H), 6.38 (d, J = 14.1 Hz, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.62 (dd, J = 10.6, 1.9 Hz, 1H), 4.62 (s, 1H), 4.55 (s, 1H), 4.23 (s, 2H), 4.13 (s, 1H), 3.77 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 5.9 Hz, 1H), 2.78 - 2.71 (m, 2H)
[M+H]+ 437.18[M+H] + 437.18
실시예 46: 1-(6-((피리딘-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 46)Example 46: 1-(6-((pyridin-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of prop-2-en-1-one (Compound 46)
Figure PCTKR2023010500-appb-img-000066
Figure PCTKR2023010500-appb-img-000066
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-((피리딘-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-((pyridine- Example 1- above, except that 2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The title compound was obtained in the same manner as 2 and 1-3.
1H NMR(CDCl3) δ 8.52 (s, 1H), 7.75 - 7.71 (m, 2H), 7.62 (t, J = 10.6 Hz, 3H), 7.27 (dd, J = 11.7, 5.3 Hz, 1H), 7.17 (s, 1H), 6.94 - 6.82 (m, 1H), 6.64 (t, J = 13.8 Hz, 1H), 6.44 (d, J = 18.1 Hz, 1H), 6.32 (d, J = 16.9 Hz, 1H), 5.71 (dd, J = 10.5, 3.0 Hz, 1H), 5.01 - 4.86 (m, 1H), 4.73 - 4.65 (m, 2H), 4.44 (s, 2H), 3.88 (d, J = 6.4 Hz, 1H), 3.76 (d, J = 6.6 Hz, 1H), 2.84 (s, 2H) 1 H NMR(CDCl 3 ) δ 8.52 (s, 1H), 7.75 - 7.71 (m, 2H), 7.62 (t, J = 10.6 Hz, 3H), 7.27 (dd, J = 11.7, 5.3 Hz, 1H), 7.17 (s, 1H), 6.94 - 6.82 (m, 1H), 6.64 (t, J = 13.8 Hz, 1H), 6.44 (d, J = 18.1 Hz, 1H), 6.32 (d, J = 16.9 Hz, 1H) ), 5.71 (dd, J = 10.5, 3.0 Hz, 1H), 5.01 - 4.86 (m, 1H), 4.73 - 4.65 (m, 2H), 4.44 (s, 2H), 3.88 (d, J = 6.4 Hz, 1H), 3.76 (d, J = 6.6 Hz, 1H), 2.84 (s, 2H)
[M+H]+ 438.17[M+H] + 438.17
실시예 47: 1-(6-((피리딘-3-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 47)Example 47: 1-(6-((pyridin-3-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of prop-2-en-1-one (Compound 47)
Figure PCTKR2023010500-appb-img-000067
Figure PCTKR2023010500-appb-img-000067
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-((피리딘-3-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-((pyridine- Example 1- above, except that 3-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The title compound was obtained in the same manner as 2 and 1-3.
1H NMR(CDCl3) δ 8.59 (s, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.29 - 7.26 (m, 1H), 6.92 - 6.83 (m, 1H), 6.64 (dd, J = 17.0, 10.9 Hz, 1H), 6.44 - 6.38 (m, 1H), 6.33 (dd, J = 16.9, 2.5 Hz, 1H), 5.72 (dd, J = 10.6, 1.8 Hz, 1H), 4.72 (s, 1H), 4.65 (s, 1H), 4.35 (s, 2H), 3.87 (t, J = 5.9 Hz, 1H), 3.76 (t, J = 5.9 Hz, 1H), 2.85 - 2.77 (m, 2H) 1 H NMR(CDCl 3 ) δ 8.59 (s, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.29 - 7.26 (m, 1H), 6.92 - 6.83 (m, 1H), 6.64 (dd, J = 17.0, 10.9 Hz, 1H), 6.44 - 6.38 (m, 1H), 6.33 (dd, J = 16.9, 2.5 Hz, 1H), 5.72 (dd, J = 10.6, 1.8 Hz, 1H), 4.72 (s, 1H), 4.65 (s, 1H), 4.35 ( s, 2H), 3.87 (t, J = 5.9 Hz, 1H), 3.76 (t, J = 5.9 Hz, 1H), 2.85 - 2.77 (m, 2H)
[M+H]+ 438.17[M+H] + 438.17
실시예 48: 1-(6-((피리딘-4-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 48)Example 48: 1-(6-((pyridin-4-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of prop-2-en-1-one (Compound 48)
Figure PCTKR2023010500-appb-img-000068
Figure PCTKR2023010500-appb-img-000068
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-((피리딘-4-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-((pyridine- Example 1- above, except that 4-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The title compound was obtained in the same manner as 2 and 1-3.
1H NMR(CDCl3) δ 8.43 (d, J = 6.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 6.1 Hz, 2H), 6.90 (d, J = 4.6 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.29 (d, J = 6.2 Hz, 1H), 6.22 (dd, J = 16.8, 1.9 Hz, 1H), 5.75 (d, J = 10.7 Hz, 1H), 4.66 (d, J = 30.5 Hz, 2H), 4.40 (s, 2H), 3.77 (td, J = 6.0, 3.9 Hz, 2H), 2.73 (dt, J = 25.9, 6.0 Hz, 2H) 1 H NMR(CDCl 3 ) δ 8.43 (d, J = 6.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 6.1 Hz, 2H), 6.90 (d, J = 4.6 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.29 (d, J = 6.2 Hz, 1H), 6.22 (dd, J = 16.8, 1.9 Hz, 1H), 5.75 (d, J = 10.7 Hz, 1H), 4.66 (d, J = 30.5 Hz, 2H), 4.40 (s, 2H), 3.77 (td, J = 6.0, 3.9 Hz, 2H), 2.73 ( dt, J = 25.9, 6.0 Hz, 2H)
[M+H]+ 438.17[M+H] + 438.17
실시예 49: 1-(6-((4-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 49)Example 49: 1-(6-((4-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of prop-2-en-1-one (Compound 49)
Figure PCTKR2023010500-appb-img-000069
Figure PCTKR2023010500-appb-img-000069
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-((4-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-((4- Example 1-2 above, except that methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. and 1-3 to obtain the title compound.
1H NMR(CDCl3) δ 7.81 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.87-6.80 (m, 4H), 6.38 (s, 1H), 6.12 (d, J = 16.4 Hz, 1H), 5.68 (d, J = 10.0 Hz, 1H), 5.32 (br, 1H), 4.62 (s, 1H), 4.53 (s, 1H), 4.20 (s, 2H), 3.71-3.67 (m, 5H), 2.69-2.64 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.81 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.87-6.80 (m, 4H), 6.38 (s, 1H), 6.12 (d, J = 16.4 Hz, 1H), 5.68 (d, J = 10.0 Hz, 1H), 5.32 (br, 1H), 4.62 (s, 1H), 4.53 ( s, 1H), 4.20 (s, 2H), 3.71-3.67 (m, 5H), 2.69-2.64 (m, 2H)
[M+H]+ 467.19[M+H] + 467.19
실시예 50: 1-(6-((티아졸-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 50)Example 50: 1-(6-((thiazol-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)- 1) Synthesis of prop-2-en-1-one (Compound 50)
Figure PCTKR2023010500-appb-img-000070
Figure PCTKR2023010500-appb-img-000070
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-((티아졸-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-((thiazole Example 1 above, except that -2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The title compound was obtained in the same manner as -2 and 1-3.
1H NMR(CDCl3) δ 7.84 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 2.7 Hz, 1H), 6.91 (s, 1H), 6.84 (dd, J = 16.6, 10.5 Hz, 1H), 6.45 (s, 1H), 6.13 (d, J = 16.6 Hz, 1H), 5.83-5.82 (m, 1H), 5.69 (d, J = 10.5 Hz, 1H), 4.65-4.55 (m, 4H), 3.72-3.68 (m, 2H), 2.71-2.51 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.84 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 2.7 Hz, 1H), 6.91 (s, 1H), 6.84 (dd, J = 16.6, 10.5 Hz, 1H), 6.45 (s, 1H), 6.13 (d, J = 16.6 Hz, 1H), 5.83-5.82 ( m, 1H), 5.69 (d, J = 10.5 Hz, 1H), 4.65-4.55 (m, 4H), 3.72-3.68 (m, 2H), 2.71-2.51 (m, 2H)
[M+H]+ 444.13[M+H] + 444.13
실시예 51: 1-(6-(((1-메틸피페리딘-4-일)메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 51)Example 51: 1-(6-(((1-methylpiperidin-4-yl)methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline Synthesis of -2(1H)-yl)prop-2-en-1-one (Compound 51)
Figure PCTKR2023010500-appb-img-000071
Figure PCTKR2023010500-appb-img-000071
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-(((1-메틸피페리딘-4-일)메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-(((1 -methylpiperidin-4-yl)methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is excluded. And the title compound was obtained in the same manner as Examples 1-2 and 1-3.
1H NMR(CDCl3) δ 9.12, (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 6.85-6.84 (m, 2H), 6.53-6.52 (m, 1H), 6.13 (dd, J = 16.4 Hz, 2.0 Hz, 1H), 5.69 (d, J = 16.4 Hz, 1H), 4.87 (br, 1H),　 4.64-4.55 (m, 2H), 3.78-3.72 (m, 2H), 3.41-3.88 (m, 2H), 2.94 (d, J = 6.0 Hz, 2H), 2.93-2.75 (m, 4H), 2.74 (d, J = 4.8 Hz, 3H), 2.00-1.84 (m, 3H), 1.31-1.23 (m, 2H) 1H NMR(CDCl 3 ) δ 9.12, (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 6.85-6.84 (m, 2H), 6.53 -6.52 (m, 1H), 6.13 (dd, J = 16.4 Hz, 2.0 Hz, 1H), 5.69 (d, J = 16.4 Hz, 1H), 4.87 (br, 1H), 4.64-4.55 (m, 2H) , 3.78-3.72 (m, 2H), 3.41-3.88 (m, 2H), 2.94 (d, J = 6.0 Hz, 2H), 2.93-2.75 (m, 4H), 2.74 (d, J = 4.8 Hz, 3H) ), 2.00-1.84 (m, 3H), 1.31-1.23 (m, 2H)
[M+H]+ 458.23[M+H] + 458.23
실시예 52: 1-(6-(벤질(메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 52)Example 52: 1-(6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- Synthesis of 2-en-1-one (Compound 52)
Figure PCTKR2023010500-appb-img-000072
Figure PCTKR2023010500-appb-img-000072
실시예 52-1: tert-부틸 6-(벤질(메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 52-1: Of tert-butyl 6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate synthesis
상기 실시예 44-3에서 제조한 tert-부틸 6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트(406.5mg, 1mmol)를 에탄올 10ml에 녹인 후 벤즈알데히드(424.5mg, 4mmol), NaBH(OAc)3(424mg, 2mmol)와 AcOH(6mg, 0.1mmol)을 순차적으로 투입하였다. 상기 혼합 용액을 80℃에서 1일 교반하였다. 얻어진 화합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (283mg, 57%)tert-Butyl 6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate ( 406.5 mg, 1 mmol) was dissolved in 10 ml of ethanol, and then benzaldehyde (424.5 mg, 4 mmol), NaBH(OAc) 3 (424 mg, 2 mmol), and AcOH (6 mg, 0.1 mmol) were sequentially added. The mixed solution was stirred at 80°C for 1 day. After cooling the obtained compound, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (283mg, 57%)
MS (ESI) m/z: [M+H]+ 497.23MS (ESI) m/z: [M+H] + 497.23
실시예 52-2: 1-(6-(벤질(메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 52-2: 1-(6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop Synthesis of p-2-en-1-one
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 52-1에서 제조한 tert-부틸 6-(벤질(메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of the tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, the product prepared in Example 52-1 Except using tert-butyl 6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, The title compound was obtained in the same manner as Examples 1-2 and 1-3.
1H NMR(CDCl3) δ 7.88-7.79 (m, 4H), 7.40-7.24 (m, 7H), 6.95-6.87 (m, 1H), 6.17 (dd, J = 16.4 Hz, 2.4 Hz, 1H), 5.75-5.71 (m, 1H), 4.80 (m, 2H), 4.12 (s, 2H), 3.81-3.72(m, 2H), 3.01-2.94 (m, 2H), 2.61 (s, 3H) 1 H NMR(CDCl 3 ) δ 7.88-7.79 (m, 4H), 7.40-7.24 (m, 7H), 6.95-6.87 (m, 1H), 6.17 (dd, J = 16.4 Hz, 2.4 Hz, 1H), 5.75-5.71 (m, 1H), 4.80 (m, 2H), 4.12 (s, 2H), 3.81-3.72(m, 2H), 3.01-2.94 (m, 2H), 2.61 (s, 3H)
[M+H]+ 451.19[M+H] + 451.19
실시예 53: 1-(6-(디벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 53)Example 53: 1-(6-(dibenzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- Synthesis of en-1-one (Compound 53)
Figure PCTKR2023010500-appb-img-000073
Figure PCTKR2023010500-appb-img-000073
상기 실시예 52-1의 tert-부틸 6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 44-2에서 제조한 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 52와 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 52-1, Except using tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate prepared in Example 44-2. , the title compound was obtained in the same manner as Example 52.
1H NMR(CDCl3) δ 7.75 - 7.57 (m, 4H), 7.26 - 7.19 (m, 4H), 7.04 - 6.94 (m, 4H), 6.89 - 6.80 (m, 1H), 6.65 (dd, J = 16.8, 10.5 Hz, 1H), 6.35 (dd, J = 16.7, 2.4 Hz, 1H), 5.74 (dd, J = 10.5, 1.9 Hz, 1H), 4.81 - 4.65 (m, 2H), 3.89 (t, J = 5.9 Hz, 4H), 3.86 (d, J = 3.4 Hz, 4H), 3.78 (t, J = 6.0 Hz, 1H), 2.85 (q, J = 6.1 Hz, 2H) 1 H NMR(CDCl 3 ) δ 7.75 - 7.57 (m, 4H), 7.26 - 7.19 (m, 4H), 7.04 - 6.94 (m, 4H), 6.89 - 6.80 (m, 1H), 6.65 (dd, J = 16.8, 10.5 Hz, 1H), 6.35 (dd, J = 16.7, 2.4 Hz, 1H), 5.74 (dd, J = 10.5, 1.9 Hz, 1H), 4.81 - 4.65 (m, 2H), 3.89 (t, J = 5.9 Hz, 4H), 3.86 (d, J = 3.4 Hz, 4H), 3.78 (t, J = 6.0 Hz, 1H), 2.85 (q, J = 6.1 Hz, 2H)
[M+H]+ 527.22[M+H] + 527.22
실시예 54: 1-(6-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 54)Example 54: 1-(6-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one (Compound 54)
Figure PCTKR2023010500-appb-img-000074
Figure PCTKR2023010500-appb-img-000074
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in Example 1-2, tert-butyl 6-(dimethylamino) Same as Examples 1-2 and 1-3 above, except for using -7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate This was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.67 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 41.2 Hz, 1H), 6.83 (d, J = 10.6 Hz, 1H), 6.65 (ddd, J = 17.2, 10.5, 6.8 Hz, 1H), 6.33 (dd, J = 16.8, 8.3 Hz, 1H), 5.76 - 5.69 (m, 1H), 4.79 - 4.64 (m, 2H), 3.94 - 3.78 (m, 2H), 2.96 - 2.87 (m, 2H), 2.52 (d, J = 3.2 Hz, 6H) 1 H NMR(CDCl 3 ) δ 7.67 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 41.2 Hz, 1H), 6.83 (d, J = 10.6 Hz, 1H), 6.65 (ddd, J = 17.2, 10.5, 6.8 Hz, 1H), 6.33 (dd, J = 16.8, 8.3 Hz, 1H), 5.76 - 5.69 (m, 1H), 4.79 - 4.64 (m , 2H), 3.94 - 3.78 (m, 2H), 2.96 - 2.87 (m, 2H), 2.52 (d, J = 3.2 Hz, 6H)
[M+H]+ 375.16[M+H] + 375.16
실시예 55: 1-(6-메톡시-3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 55: 1-(6-methoxy-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one (화합물 55)(Compound 55)
Figure PCTKR2023010500-appb-img-000075
Figure PCTKR2023010500-appb-img-000075
실시예 55-1: (E)-1-브로모-2-메톡시-4-(2-니트로프로프-1-엔-1-일)벤젠의 합성Example 55-1: Synthesis of (E)-1-bromo-2-methoxy-4-(2-nitroprop-1-en-1-yl)benzene
4-브로모-3-메톡시벤즈알데히드를 CH3CH2NO2 10 ml에 녹인 후 CH3COONH4 (150 mg, 2 mmol)을 투입하였다. 상기 혼합 용액을 110℃에서 2시간 교반하였다. 반응 종결을 LC-MS로 확인 후 혼합물을 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 노란색 고체의 표제 화합물을 얻었다. (517mg, 83%)4-Bromo-3-methoxybenzaldehyde was dissolved in 10 ml of CH 3 CH 2 NO 2 and then CH 3 COONH 4 (150 mg, 2 mmol) was added. The mixed solution was stirred at 110°C for 2 hours. After completion of the reaction was confirmed by LC-MS, the mixture was concentrated in vacuum. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a yellow solid. (517mg, 83%)
MS (ESI) m/z: [M+H]+ 272.1MS (ESI) m/z: [M+H] + 272.1
실시예 55-2: 1-(4-브로모-3-메톡시페닐)프로판-2-아민의 합성Example 55-2: Synthesis of 1-(4-bromo-3-methoxyphenyl)propan-2-amine
상기 실시예 55-1에서 제조한 (E)-1-브로모-2-메톡시-4-(2-니트로프로프-1-엔-1-일)벤젠(200mg, 0.74mmol)을 THF 10ml에 녹인 후 0℃에서 DIBAL-H(7.4ml, 1.0M in hexane, 7.4mmol)을 투입하였다. 상기 혼합 용액을 60℃에서 2시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 얻어진 잔류물(171mg)을 추가 정제 없이 다음 단계에 사용하였다.(E)-1-bromo-2-methoxy-4-(2-nitroprop-1-en-1-yl)benzene (200 mg, 0.74 mmol) prepared in Example 55-1 was added to 10 ml of THF. After dissolving in , DIBAL-H (7.4ml, 1.0M in hexane, 7.4mmol) was added at 0°C. The mixed solution was stirred at 60°C for 2 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The obtained residue (171 mg) was used in the next step without further purification.
MS (ESI) m/z: [M+H]+ 244.0MS (ESI) m/z: [M+H] + 244.0
실시예 55-3: N-(1-(4-브로모-3-메톡시페닐)프로판-2-일)-2,2,2-트리플루오로아세트아미드의 합성Example 55-3: Synthesis of N-(1-(4-bromo-3-methoxyphenyl)propan-2-yl)-2,2,2-trifluoroacetamide
상기 실시예 55-2에서 제조한 1-(4-브로모-3-메톡시페닐)프로판-2-아민 (171mg)을 DCM 5ml에 녹인 후 TEA(212mg, 2.1mmol)과 TFAA(220mg, 1.0mmol)을 투입하여 상온에서 1일간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (160mg, 67.4%)1-(4-Bromo-3-methoxyphenyl)propan-2-amine (171 mg) prepared in Example 55-2 was dissolved in 5 ml of DCM, and then TEA (212 mg, 2.1 mmol) and TFAA (220 mg, 1.0 mg) were dissolved in 5 ml of DCM. mmol) was added and stirred at room temperature for 1 day. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (160mg, 67.4%)
MS (ESI) m/z: [M+H]+ 340.0MS (ESI) m/z: [M+H] + 340.0
실시예 55-4: 1-(7-브로모-6-메톡시-3-메틸-3,4-디히드로이소퀴놀린-2(1H)-일)-2,2,2-트리플루오로에탄-1-온의 합성Example 55-4: 1-(7-Bromo-6-methoxy-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane Synthesis of -1-one
상기 실시예 55-3에서 제조한 N-(1-(4-브로모-3-메톡시페닐)프로판-2-일)-2,2,2-트리플루오로아세트아미드(160mg, 0.47mmol)를 AcOH 6ml와 H2SO4 2ml의 혼합용액에 녹였다. (CH2O)n (40 mg, 0.47 mmol)을 혼합물에 투입한 후 30℃에서 2일간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 액상의 표제 화합물을 얻었다. (34mg, 21%)N-(1-(4-bromo-3-methoxyphenyl)propan-2-yl)-2,2,2-trifluoroacetamide (160 mg, 0.47 mmol) prepared in Example 55-3. was dissolved in a mixed solution of 6ml AcOH and 2ml H 2 SO 4 . (CH 2 O) n (40 mg, 0.47 mmol) was added to the mixture and stirred at 30°C for 2 days. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white liquid. (34mg, 21%)
MS (ESI) m/z: [M+H]+ 352.0MS (ESI) m/z: [M+H] + 352.0
실시예 55-5: 7-브로모-6-메톡시-3-메틸-1,2,3,4-테트라히드로이소퀴놀린의 합성Example 55-5: Synthesis of 7-bromo-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline
상기 실시예 55-4에서 제조한 1-(7-브로모-6-메톡시-3-메틸-3,4-디히드로이소퀴놀린-2(1H)-일)-2,2,2-트리플루오로에탄-1-온(34mg, 0.1mmol)을 에탄올 1ml과 물 1ml의 혼합액에 녹인 후 K2CO3 (53 mg, 0.4 mmol)을 투입하였다. 혼합된 용액을 85℃에서 2시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (20mg, 78%)1-(7-bromo-6-methoxy-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tri prepared in Example 55-4 Fluoroethan-1-one (34 mg, 0.1 mmol) was dissolved in a mixture of 1 ml of ethanol and 1 ml of water, and then K 2 CO 3 (53 mg, 0.4 mmol) was added. The mixed solution was stirred at 85°C for 2 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (20mg, 78%)
MS (ESI) m/z: [M+H]+ 256MS (ESI) m/z: [M+H] + 256
실시예 55-6: 6-메톡시-3-메틸-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린의 합성Example 55-6: Synthesis of 6-methoxy-3-methyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline
상기 실시예 55-5에서 제조한 7-브로모-6-메톡시-3-메틸-1,2,3,4-테트라히드로이소퀴놀린(20mg, 0.078mmol)을 다이옥산/물(3:1) 4ml에 녹인 후 Pd(PPh3)4(11.56mg, 0.01mmol)을 첨가하였다. 그 후 Cs2CO3(32.582mg, 0.1mmol)와 4-(트리플루오로메틸)페닐 보론산 (18.993mg, 0.1mmol)을 순서대로 첨가하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하여 표제 화합물을 얻었다. (17mg, 68%)7-Bromo-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline (20 mg, 0.078 mmol) prepared in Example 55-5 was mixed with dioxane/water (3:1). After dissolving in 4ml, Pd(PPh 3 ) 4 (11.56mg, 0.01mmol) was added. Afterwards, Cs 2 CO 3 (32.582 mg, 0.1 mmol) and 4-(trifluoromethyl)phenyl boronic acid (18.993 mg, 0.1 mmol) were added in that order. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography to obtain the title compound. (17mg, 68%)
MS (ESI) m/z: [M+H]+ 322.13MS (ESI) m/z: [M+H] + 322.13
실시예 55-7: 1-(6-메톡시-3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 55-7: 1-(6-methoxy-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop Synthesis of -2-en-1-one
상기 실시예 55-6에서 제조한 6-메톡시-3-메틸-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린(17mg, 0.05mmol)을 1ml의 DMF에 녹였다. HATU(38mg, 0.1mmol), TEA(10mg, 0.1mmol)와 아크릴산(5.77mg, 0.08mmol)를 상기 혼합물에 첨가한 후 상온에서 3시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (8mg, 40%)6-methoxy-3-methyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (17 mg, 0.05 mmol) prepared in Example 55-6. was dissolved in 1ml of DMF. HATU (38 mg, 0.1 mmol), TEA (10 mg, 0.1 mmol), and acrylic acid (5.77 mg, 0.08 mmol) were added to the mixture and stirred at room temperature for 3 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (8mg, 40%)
1H NMR(CDCl3) δ 7.77-7.70 (m, 4H), 7.23 (s, 1H), 6.99 (s, 1H), 6.87 (d, J = 9.6 Hz, 1H), 6.15 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.71 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 4.97-4.93 (m, 1.5H), 4.64-4.48 (m, 1H), 4.24 (d, J = 16.8 Hz, 0.5H), 3.78 (s, 3H), 3.13-3.01 (m, 1H), 2.75 (d, J = 13.2 Hz, 1H), 1.09 (s, 3H) 1H NMR(CDCl 3 ) δ 7.77-7.70 (m, 4H), 7.23 (s, 1H), 6.99 (s, 1H), 6.87 (d, J = 9.6 Hz, 1H), 6.15 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.71 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 4.97-4.93 (m, 1.5H), 4.64-4.48 (m, 1H), 4.24 (d, J = 16.8 Hz) , 0.5H), 3.78 (s, 3H), 3.13-3.01 (m, 1H), 2.75 (d, J = 13.2 Hz, 1H), 1.09 (s, 3H)
[M+H]+ 376.14[M+H] + 376.14
실시예 56: 1-(6-(페닐아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 56)Example 56: 1-(6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one (Compound 56)
Figure PCTKR2023010500-appb-img-000076
Figure PCTKR2023010500-appb-img-000076
실시예 56-1: tert-부틸 6-(페닐아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 56-1: Synthesis of tert-butyl 6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 실시예 44-2에서 제조한 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트(784.8mg, 2mmol)를 톨루엔 20ml에 녹인 후 Pd(OAc)2(46mg, 0.2mmol), NaOt-Bu(480.5mg, 5mmol)와 브로모벤젠(392.5mg, 2.5mmol)을 투입하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하여 표제 화합물을 얻었다. (487.3mg, 52%)tert-Butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (784.8 mg, 2 mmol) was dissolved in 20 ml of toluene, and then Pd(OAc) 2 (46 mg, 0.2 mmol), NaOt-Bu (480.5 mg, 5 mmol), and bromobenzene (392.5 mg, 2.5 mmol) were added. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography to obtain the title compound. (487.3mg, 52%)
MS (ESI) m/z: [M+H]+ 469.20MS (ESI) m/z: [M+H] + 469.20
실시예 56-2: 1-(6-(페닐아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 56-2: 1-(6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 56-1에서 제조한 tert-부틸 6-(페닐아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, prepared in Example 56-1 The above examples except that tert-butyl 6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The same procedure as 1-2 and 1-3 was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.71 - 7.66 (m, 2H), 7.58 - 7.53 (m, 2H), 7.30 - 7.24 (m, 2H), 7.18 (d, J = 3.8 Hz, 1H), 7.07 - 6.92 (m, 4H), 6.69 - 6.62 (m, 1H), 6.35 (d, J = 16.9 Hz, 1H), 5.74 (dd, J = 10.6, 2.7 Hz, 1H), 5.40 (s, 1H), 4.83 - 4.69 (m, 2H), 3.93 - 3.76 (m, 2H), 2.88 (dd, J = 12.1, 6.4 Hz, 2H) 1 H NMR(CDCl 3 ) δ 7.71 - 7.66 (m, 2H), 7.58 - 7.53 (m, 2H), 7.30 - 7.24 (m, 2H), 7.18 (d, J = 3.8 Hz, 1H), 7.07 - 6.92 (m, 4H), 6.69 - 6.62 (m, 1H), 6.35 (d, J = 16.9 Hz, 1H), 5.74 (dd, J = 10.6, 2.7 Hz, 1H), 5.40 (s, 1H), 4.83 - 4.69 (m, 2H), 3.93 - 3.76 (m, 2H), 2.88 (dd, J = 12.1, 6.4 Hz, 2H)
[M+H]+ 423.16[M+H] + 423.16
실시예 57: 1-(5-(벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 57)Example 57: 1-(5-(benzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one (Compound 57)
Figure PCTKR2023010500-appb-img-000077
Figure PCTKR2023010500-appb-img-000077
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 벤질브로마이드를 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- The above except that amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used and benzyl bromide is used instead of bromobenzene. The title compound was obtained in the same manner as in Example 56.
1H NMR(CDCl3) δ 7.63 (d, J = 8.2 Hz, 2H), 7.57 (t, J = 8.0 Hz, 2H), 7.40 - 7.33 (m, 4H), 7.31 (d, J = 6.3 Hz, 1H), 6.76 (d, J = 56.2 Hz, 1H), 6.69 (s, 1H), 6.66 (dd, J = 16.8, 10.6 Hz, 1H), 6.33 (dd, J = 16.8, 7.4 Hz, 1H), 5.73 (d, J = 10.7 Hz, 1H), 4.80 (d, J = 54.8 Hz, 2H), 4.42 (d, J = 6.7 Hz, 2H), 4.00 (s, 1H), 4.00 - 3.86 (m, 2H), 2.70 - 2.51 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.63 (d, J = 8.2 Hz, 2H), 7.57 (t, J = 8.0 Hz, 2H), 7.40 - 7.33 (m, 4H), 7.31 (d, J = 6.3 Hz, 1H), 6.76 (d, J = 56.2 Hz, 1H), 6.69 (s, 1H), 6.66 (dd, J = 16.8, 10.6 Hz, 1H), 6.33 (dd, J = 16.8, 7.4 Hz, 1H), 5.73 (d, J = 10.7 Hz, 1H), 4.80 (d, J = 54.8 Hz, 2H), 4.42 (d, J = 6.7 Hz, 2H), 4.00 (s, 1H), 4.00 - 3.86 (m, 2H) ), 2.70 - 2.51 (m, 2H)
[M+H]+ 437.18[M+H] + 437.18
실시예 58: 1-(5-((피리딘-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 58)Example 58: 1-(5-((pyridin-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of prop-2-en-1-one (Compound 58)
Figure PCTKR2023010500-appb-img-000078
Figure PCTKR2023010500-appb-img-000078
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 2-(브로모메틸)피리딘을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and 2-(bromomethyl)pyridine is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56, except that.
1H NMR(CDCl3) δ 8.60 (d, J = 4.4 Hz, 1H), 7.72 - 7.56 (m, 5H), 7.32 (d, J = 7.7 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.84 - 6.58 (m, 3H), 6.33 (dd, J = 16.2, 7.6 Hz, 1H), 5.79 - 5.60 (m, 1H), 4.83 (t, J = 34.3 Hz, 2H), 4.53 (d, J = 15.4 Hz, 2H), 3.96 (d, J = 69.2 Hz, 2H), 2.77 (d, J = 20.7 Hz, 2H) 1 H NMR(CDCl 3 ) δ 8.60 (d, J = 4.4 Hz, 1H), 7.72 - 7.56 (m, 5H), 7.32 (d, J = 7.7 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.84 - 6.58 (m, 3H), 6.33 (dd, J = 16.2, 7.6 Hz, 1H), 5.79 - 5.60 (m, 1H), 4.83 (t, J = 34.3 Hz, 2H), 4.53 (d, J = 15.4 Hz, 2H), 3.96 (d, J = 69.2 Hz, 2H), 2.77 (d, J = 20.7 Hz, 2H)
[M+H]+ 438.17[M+H] + 438.17
실시예 59: 1-(5-((피리딘-4-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 59)Example 59: 1-(5-((pyridin-4-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of prop-2-en-1-one (Compound 59)
Figure PCTKR2023010500-appb-img-000079
Figure PCTKR2023010500-appb-img-000079
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 4-(브로모메틸)피리딘을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and 4-(bromomethyl)pyridine is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56, except that.
1H NMR(CDCl3) δ 8.57 (d, J = 5.3 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.48 (s, 2H), 7.29 (d, J = 4.3 Hz, 2H), 6.77 (d, J = 52.1 Hz, 2H), 6.50 (d, J = 3.6 Hz, 1H), 6.34 (s, 1H), 5.73 (d, J = 9.6 Hz, 1H), 4.81 (d, J = 52.8 Hz, 2H), 4.49 (s, 2H), 4.11 (d, J = 7.1 Hz, 1H), 2.69 (d, J = 5.8 Hz, 2H) 1 H NMR(CDCl 3 ) δ 8.57 (d, J = 5.3 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.48 (s, 2H), 7.29 (d, J = 4.3 Hz, 2H) , 6.77 (d, J = 52.1 Hz, 2H), 6.50 (d, J = 3.6 Hz, 1H), 6.34 (s, 1H), 5.73 (d, J = 9.6 Hz, 1H), 4.81 (d, J = 52.8 Hz, 2H), 4.49 (s, 2H), 4.11 (d, J = 7.1 Hz, 1H), 2.69 (d, J = 5.8 Hz, 2H)
[M+H]+ 438.17[M+H] + 438.17
실시예 60: 1-(5-((피리미딘-5-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 60)Example 60: 1-(5-((pyrimidin-5-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)- 1) Synthesis of prop-2-en-1-one (Compound 60)
Figure PCTKR2023010500-appb-img-000080
Figure PCTKR2023010500-appb-img-000080
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 5-(브로모메틸)피리미딘을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and 5-(bromomethyl)pyrimidine is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56 except for use.
1H NMR(CDCl3) δ 9.18 (s, 1H), 8.78 (s, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.54 (s, 2H), 6.81 (d, J = 57.5 Hz, 1H), 6.64 (dd, J = 32.5, 13.5 Hz, 2H), 6.34 (dd, J = 16.5, 7.7 Hz, 1H), 5.74 (d, J = 10.6 Hz, 1H), 4.81 (d, J = 54.0 Hz, 2H), 4.50 (d, J = 10.4 Hz, 2H), 4.03 - 3.88 (m, 2H), 3.89 - 3.67 (m, 1H), 2.66 (s, 2H) 1 H NMR(CDCl 3 ) δ 9.18 (s, 1H), 8.78 (s, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.54 (s, 2H), 6.81 (d, J = 57.5 Hz, 1H), 6.64 (dd, J = 32.5, 13.5 Hz, 2H), 6.34 (dd, J = 16.5, 7.7 Hz, 1H), 5.74 (d, J = 10.6 Hz, 1H), 4.81 (d, J = 54.0 Hz, 2H), 4.50 (d, J = 10.4 Hz, 2H), 4.03 - 3.88 (m, 2H), 3.89 - 3.67 (m, 1H), 2.66 (s, 2H)
[M+H]+ 439.17[M+H] + 439.17
실시예 61: 1-(5-((4-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 61)Example 61: 1-(5-((4-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of prop-2-en-1-one (Compound 61)
Figure PCTKR2023010500-appb-img-000081
Figure PCTKR2023010500-appb-img-000081
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 1-(브로모메틸)-4-메톡시벤젠을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and 1-(bromomethyl)-4- is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56, except for using methoxybenzene.
1H NMR(CDCl3) δ 7.66 - 7.62 (m, 2H), 7.60 (d, J = 7.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.93 - 6.88 (m, 2H), 6.80 (s, 1H), 6.72 (s, 1H), 6.65 (dd, J = 16.8, 10.6 Hz, 1H), 6.44 - 6.25 (m, 1H), 5.72 (dd, J = 10.6, 1.6 Hz, 1H), 4.80 (d, J = 54.9 Hz, 2H), 4.35 (d, J = 2.5 Hz, 2H), 3.98 (s, 2H), 3.87 (d, J = 15.8 Hz, 1H), 3.82 - 3.79 (m, 3H), 2.90 - 2.37 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.66 - 7.62 (m, 2H), 7.60 (d, J = 7.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.93 - 6.88 (m, 2H), 6.80 (s, 1H), 6.72 (s, 1H), 6.65 (dd, J = 16.8, 10.6 Hz, 1H), 6.44 - 6.25 (m, 1H), 5.72 (dd, J = 10.6, 1.6 Hz, 1H) , 4.80 (d, J = 54.9 Hz, 2H), 4.35 (d, J = 2.5 Hz, 2H), 3.98 (s, 2H), 3.87 (d, J = 15.8 Hz, 1H), 3.82 - 3.79 (m, 3H), 2.90 - 2.37 (m, 2H)
[M+H]+ 467.19[M+H] + 467.19
실시예 62: 1-(5-((3-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 62)Example 62: 1-(5-((3-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of prop-2-en-1-one (Compound 62)
Figure PCTKR2023010500-appb-img-000082
Figure PCTKR2023010500-appb-img-000082
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 1-(브로모메틸)-3-메톡시벤젠을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and 1-(bromomethyl)-3- is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56, except for using methoxybenzene.
1H NMR(CDCl3) δ 7.72 - 7.51 (m, 4H), 7.26 (ddd, J = 8.5, 4.0, 2.2 Hz, 2H), 7.01 - 6.90 (m, 2H), 6.87 - 6.80 (m, 1H), 6.70 (s, 1H), 6.68 - 6.63 (m, 1H), 6.33 (d, J = 15.5 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 4.80 (d, J = 54.5 Hz, 2H), 4.40 (s, 2H), 3.99 (s, 2H), 3.87 (s, 1H), 3.80 (s, 3H), 2.64 (s, 2H) 1 H NMR(CDCl 3 ) δ 7.72 - 7.51 (m, 4H), 7.26 (ddd, J = 8.5, 4.0, 2.2 Hz, 2H), 7.01 - 6.90 (m, 2H), 6.87 - 6.80 (m, 1H) , 6.70 (s, 1H), 6.68 - 6.63 (m, 1H), 6.33 (d, J = 15.5 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 4.80 (d, J = 54.5 Hz, 2H), 4.40 (s, 2H), 3.99 (s, 2H), 3.87 (s, 1H), 3.80 (s, 3H), 2.64 (s, 2H)
[M+H]+ 467.19[M+H] + 467.19
실시예 63: 1-(5-((3-히드록시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 63)Example 63: 1-(5-((3-hydroxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of prop-2-en-1-one (Compound 63)
Figure PCTKR2023010500-appb-img-000083
Figure PCTKR2023010500-appb-img-000083
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 3-(브로모메틸)페놀을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and 3-(bromomethyl)phenol is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56, except that.
1H NMR(CDCl3) δ 7.63 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.87 (s, 1H), 6.77 (dd, J = 8.2, 2.1 Hz, 1H), 6.70 (s, 1H), 6.68 - 6.65 (m, 1H), 6.64 (d, J = 10.6 Hz, 1H), 6.34 (s, 1H), 5.73 (dd, J = 10.6, 1.5 Hz, 1H), 5.50 - 5.28 (m, 1H), 4.80 (d, J = 54.3 Hz, 2H), 4.37 (s, 2H), 4.03 (dd, J = 32.3, 13.8 Hz, 1H), 3.98 (s, 2H), 3.87 (s, 1H), 2.69 - 2.52 (m, 2H) 1H NMR(CDCl 3 ) δ 7.63 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.92 (s, 1H) , 6.87 (s, 1H), 6.77 (dd, J = 8.2, 2.1 Hz, 1H), 6.70 (s, 1H), 6.68 - 6.65 (m, 1H), 6.64 (d, J = 10.6 Hz, 1H), 6.34 (s, 1H), 5.73 (dd, J = 10.6, 1.5 Hz, 1H), 5.50 - 5.28 (m, 1H), 4.80 (d, J = 54.3 Hz, 2H), 4.37 (s, 2H), 4.03 (dd, J = 32.3, 13.8 Hz, 1H), 3.98 (s, 2H), 3.87 (s, 1H), 2.69 - 2.52 (m, 2H)
[M+H]+ 453.17[M+H] + 453.17
실시예 64: 1-(5-((4-히드록시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 64)Example 64: 1-(5-((4-hydroxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of prop-2-en-1-one (Compound 64)
Figure PCTKR2023010500-appb-img-000084
Figure PCTKR2023010500-appb-img-000084
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 4-(브로모메틸)페놀을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and 4-(bromomethyl)phenol is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56, except that.
1H NMR(CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.58 - 7.51 (m, 1H), 7.23 (s, 1H), 6.87 - 6.82 (m, 3H), 6.78 (t, J = 15.5 Hz, 1H), 6.71 (s, 2H), 6.65 (dd, J = 16.8, 10.6 Hz, 2H), 6.33 (d, J = 16.7 Hz, 1H), 5.73 (dd, J = 10.6, 1.7 Hz, 1H), 4.80 (d, J = 54.4 Hz, 3H), 4.32 (s, 2H), 3.98 (s, 1H), 3.86 (s, 2H), 3.81 - 3.71 (m, 1H), 2.61 (d, J = 16.8 Hz, 3H) 1 H NMR(CDCl 3 ) δ 7.64 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.58 - 7.51 (m, 1H), 7.23 (s, 1H), 6.87 - 6.82 (m, 3H), 6.78 (t, J = 15.5 Hz, 1H), 6.71 (s, 2H), 6.65 (dd, J = 16.8, 10.6 Hz, 2H), 6.33 (d, J = 16.7 Hz, 1H) ), 5.73 (dd, J = 10.6, 1.7 Hz, 1H), 4.80 (d, J = 54.4 Hz, 3H), 4.32 (s, 2H), 3.98 (s, 1H), 3.86 (s, 2H), 3.81 - 3.71 (m, 1H), 2.61 (d, J = 16.8 Hz, 3H)
[M+H]+ 453.17[M+H] + 453.17
실시예 65: 1-(5-((4-(디메틸아미노)벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 65)Example 65: 1-(5-((4-(dimethylamino)benzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)- 1) Synthesis of prop-2-en-1-one (Compound 65)
Figure PCTKR2023010500-appb-img-000085
Figure PCTKR2023010500-appb-img-000085
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 4-(브로모메틸)-N,N-디메틸아닐린을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and instead of bromobenzene, 4-(bromomethyl)-N, The title compound was obtained in the same manner as Example 56, except for using N-dimethylaniline.
1H NMR(CDCl3) δ 7.56 (d, J = 7.9 Hz, 2H), 7.39 (dd, J = 14.2, 7.7 Hz, 2H), 6.88 - 6.82 (m, 2H), 6.75 - 6.70 (m, 1H), 6.68 - 6.61 (m, 2H), 6.60 (s, 1H), 6.17 - 6.08 (m, 1H), 6.00 - 5.93 (m, 1H), 5.45 - 5.36 (m, 1H), 4.67 - 4.55 (m, 1H), 4.48 (s, 2H), 3.87 (ddd, J = 25.6, 12.9, 6.4 Hz, 2H), 3.73 (d, J = 5.6 Hz, 2H), 2.89 (d, J = 1.8 Hz, 6H) 1 H NMR(CDCl 3 ) δ 7.56 (d, J = 7.9 Hz, 2H), 7.39 (dd, J = 14.2, 7.7 Hz, 2H), 6.88 - 6.82 (m, 2H), 6.75 - 6.70 (m, 1H) ), 6.68 - 6.61 (m, 2H), 6.60 (s, 1H), 6.17 - 6.08 (m, 1H), 6.00 - 5.93 (m, 1H), 5.45 - 5.36 (m, 1H), 4.67 - 4.55 (m , 1H), 4.48 (s, 2H), 3.87 (ddd, J = 25.6, 12.9, 6.4 Hz, 2H), 3.73 (d, J = 5.6 Hz, 2H), 2.89 (d, J = 1.8 Hz, 6H)
[M+H]+ 480.22[M+H] + 480.22
실시예 66: 1-(5-((시클로헥실메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 66)Example 66: 1-(5-((cyclohexylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop Synthesis of -2-en-1-one (Compound 66)
Figure PCTKR2023010500-appb-img-000086
Figure PCTKR2023010500-appb-img-000086
상기 실시예 56-1의 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하고, 브로모벤젠 대신 (브로모메틸)사이클로헥산을 사용하는 것을 제외하고, 상기 실시예 56과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 56-1, tert-butyl 5- Amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is used, and (bromomethyl)cyclohexane is used instead of bromobenzene. The title compound was obtained in the same manner as Example 56, except that.
1H NMR(CDCl3) δ 7.74 - 7.56 (m, 4H), 6.75 (s, 1H), 6.71 - 6.56 (m, 3H), 6.32 (dd, J = 16.4, 9.7 Hz, 1H), 5.72 (d, J = 9.5 Hz, 1H), 4.78 (d, J = 54.8 Hz, 2H), 3.93 (d, J = 70.7 Hz, 2H), 3.72 - 3.55 (m, 1H), 3.05 (d, J = 6.6 Hz, 2H), 2.66 - 2.47 (m, 2H), 1.92 - 1.72 (m, 4H), 1.72 - 1.65 (m, 1H), 1.24 (ddddd, J = 18.4, 15.5, 12.4, 9.4, 6.2 Hz, 4H), 1.02 (q, J = 11.4 Hz, 2H) 1H NMR(CDCl 3 ) δ 7.74 - 7.56 (m, 4H), 6.75 (s, 1H), 6.71 - 6.56 (m, 3H), 6.32 (dd, J = 16.4, 9.7 Hz, 1H), 5.72 (d) , J = 9.5 Hz, 1H), 4.78 (d, J = 54.8 Hz, 2H), 3.93 (d, J = 70.7 Hz, 2H), 3.72 - 3.55 (m, 1H), 3.05 (d, J = 6.6 Hz) , 2H), 2.66 - 2.47 (m, 2H), 1.92 - 1.72 (m, 4H), 1.72 - 1.65 (m, 1H), 1.24 (ddddd, J = 18.4, 15.5, 12.4, 9.4, 6.2 Hz, 4H) , 1.02 (q, J = 11.4 Hz, 2H)
[M+H]+ 443.22[M+H] + 443.22
제조예 1: tert-부틸 5-아미노-7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Preparation Example 1: Synthesis of tert-butyl 5-amino-7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate
Figure PCTKR2023010500-appb-img-000087
Figure PCTKR2023010500-appb-img-000087
제조예 1-1: 5-니트로-1,2,3,4-테트라히드로이소퀴놀린의 합성Preparation Example 1-1: Synthesis of 5-nitro-1,2,3,4-tetrahydroisoquinoline
5-니트로이소퀴놀린(1.74g, 10mmol)을 AcOH 50ml에 녹인 후 NaBH4(1.89g, 50mmol)을 투입하였다. 혼합된 용액을 상온에서 2시간 교반하였다. 반응 종결을 LC-MS로 확인하고 혼합물을 진공 농축한 뒤 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (1.39g, 78%)5-nitroisoquinoline (1.74 g, 10 mmol) was dissolved in 50 ml of AcOH, and then NaBH 4 (1.89 g, 50 mmol) was added. The mixed solution was stirred at room temperature for 2 hours. The completion of the reaction was confirmed by LC-MS, the mixture was concentrated under vacuum, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (1.39g, 78%)
MS (ESI) m/z: [M+H]+ 179.07MS (ESI) m/z: [M+H] + 179.07
제조예 1-2: 7-브로모-5-니트로-1,2,3,4-테트라히드로이소퀴놀린의 합성Preparation Example 1-2: Synthesis of 7-bromo-5-nitro-1,2,3,4-tetrahydroisoquinoline
상기 제조예 1-1에서 제조한 5-니트로-1,2,3,4-테트라히드로이소퀴놀린 (1.39g, 7.8mmol)을 TfOH 100ml에 녹인 후 NBS(1.39g, 7.8mmol)을 투입하였다. 상기 혼합 용액을 상온에서 2시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (1.06g, 53%)5-Nitro-1,2,3,4-tetrahydroisoquinoline (1.39g, 7.8mmol) prepared in Preparation Example 1-1 was dissolved in 100ml of TfOH, and then NBS (1.39g, 7.8mmol) was added. The mixed solution was stirred at room temperature for 2 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (1.06g, 53%)
MS (ESI) m/z: [M+H]+ 256.98MS (ESI) m/z: [M+H] + 256.98
제조예 1-3: tert-부틸 7-브로모-5-니트로-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Preparation Example 1-3: Synthesis of tert-butyl 7-bromo-5-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 제조예 1-2에서 제조한 7-브로모-5-니트로-1,2,3,4-테트라히드로이소퀴놀린 (1.06g, 4.12mmol)을 DCM 50ml에 녹였다. 상기 혼합 용액에 Boc2O(1.31g, 6mmol)와 TEA(607.2mg, 6mmol)을 첨가한 후 상온에서 12시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (1.13g, 77%)7-Bromo-5-nitro-1,2,3,4-tetrahydroisoquinoline (1.06 g, 4.12 mmol) prepared in Preparation Example 1-2 was dissolved in 50 ml of DCM. Boc 2 O (1.31 g, 6 mmol) and TEA (607.2 mg, 6 mmol) were added to the mixed solution and stirred at room temperature for 12 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (1.13g, 77%)
MS (ESI) m/z: [M+H]+ 357.04MS (ESI) m/z: [M+H] + 357.04
제조예 1-4: tert-부틸 5-아미노-7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Preparation Example 1-4: Synthesis of tert-butyl 5-amino-7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 제조예 1-3에서 제조한 tert-부틸 7-브로모-5-니트로-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (1g, 2.8mmol)를 메탄올 200ml에 녹였다. 10% Pd/C (106mg, 1mmol)을 주의하여 투입한 후 수소 풍선을 이용해 수소 대기 환경을 만들어 주고 상온에서 1일간 교반하였다. 반응 종결을 LC-MS로 확인하고 필터 후 얻은 여과액을 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제한 후 농축하여 표제 화합물을 얻었다. (654.4mg, 71.4%)tert-Butyl 7-bromo-5-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1 g, 2.8 mmol) prepared in Preparation Example 1-3 was dissolved in 200 ml of methanol. After carefully adding 10% Pd/C (106 mg, 1 mmol), a hydrogen atmosphere was created using a hydrogen balloon and stirred at room temperature for 1 day. The completion of the reaction was confirmed by LC-MS, and the filtrate obtained after filtering was concentrated in vacuum. The residue was purified using column chromatography and concentrated to obtain the title compound. (654.4 mg, 71.4%)
MS (ESI) m/z: [M+H]+ 327.06MS (ESI) m/z: [M+H] + 327.06
실시예 67: N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)벤자미드의 합성 (화합물 67)Example 67: Synthesis of N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide (Compound 67)
Figure PCTKR2023010500-appb-img-000088
Figure PCTKR2023010500-appb-img-000088
실시예 67-1: tert-부틸 5-벤즈아미도-7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 67-1: Synthesis of tert-butyl 5-benzamido-7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 제조예 1에서 제조한 tert-부틸 5-아미노-7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (3.27g, 10mmol)를 DMF 50ml에 녹였다. HATU(4.56g, 12mmol), TEA(1.21g, 12mmol)와 벤조산 (1.46g, 12mmol)을 혼합물에 첨가한 후 상온에서 5시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (3.54g, 82%)tert-Butyl 5-amino-7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.27 g, 10 mmol) prepared in Preparation Example 1 was dissolved in 50 ml of DMF. HATU (4.56g, 12mmol), TEA (1.21g, 12mmol), and benzoic acid (1.46g, 12mmol) were added to the mixture and stirred at room temperature for 5 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (3.54g, 82%)
MS (ESI) m/z: [M+H]+ 431.09MS (ESI) m/z: [M+H] + 431.09
실시예 67-2: N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)벤자미드의 합성Example 67-2: Synthesis of N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 67-1에서 제조한 tert-부틸 5-벤즈아미도-7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1, tert-butyl 5-benzamido- prepared in Example 67-1 was used. The title compound was obtained in the same manner as Example 1, except that 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.90 (d, J = 7.5 Hz, 2H), 7.88 (s, 1H), 7.75 - 7.67 (m, 5H), 7.62 - 7.57 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.31 (s, 1H), 6.71 - 6.59 (m, 1H), 6.35 (d, J = 16.7 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 4.87 (d, J = 46.3 Hz, 2H), 3.85 (s, 2H), 3.17 - 2.79 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.90 (d, J = 7.5 Hz, 2H), 7.88 (s, 1H), 7.75 - 7.67 (m, 5H), 7.62 - 7.57 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.31 (s, 1H), 6.71 - 6.59 (m, 1H), 6.35 (d, J = 16.7 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 4.87 (d) , J = 46.3 Hz, 2H), 3.85 (s, 2H), 3.17 - 2.79 (m, 2H)
[M+H]+ 451.16[M+H] + 451.16
실시예 68: N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)아세트아미드의 합성 (화합물 68)Example 68: Synthesis of N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide (Compound 68)
Figure PCTKR2023010500-appb-img-000089
Figure PCTKR2023010500-appb-img-000089
상기 실시예 67-1의 벤조산 대신 아세트산을 사용하는 것을 제외하고, 상기 실시예 67과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as in Example 67, except that acetic acid was used instead of benzoic acid in Example 67-1.
1H NMR(CDCl3) δ 7.83 (d, J = 137.0 Hz, 1H), 7.69 - 7.56 (m, 4H), 7.44 - 7.26 (m, 1H), 7.17 (s, 1H), 6.99 (s, 1H), 6.64 (dd, J = 16.8, 10.6 Hz, 1H), 6.35 (d, J = 17.2 Hz, 1H), 5.75 (dd, J = 10.6, 1.5 Hz, 1H), 4.83 (d, J = 46.1 Hz, 2H), 3.82 (s, 2H), 2.80 (d, J = 28.8 Hz, 2H), 2.24 (s, 3H) 1 H NMR(CDCl 3 ) δ 7.83 (d, J = 137.0 Hz, 1H), 7.69 - 7.56 (m, 4H), 7.44 - 7.26 (m, 1H), 7.17 (s, 1H), 6.99 (s, 1H) ), 6.64 (dd, J = 16.8, 10.6 Hz, 1H), 6.35 (d, J = 17.2 Hz, 1H), 5.75 (dd, J = 10.6, 1.5 Hz, 1H), 4.83 (d, J = 46.1 Hz) , 2H), 3.82 (s, 2H), 2.80 (d, J = 28.8 Hz, 2H), 2.24 (s, 3H)
[M+H]+ 389.14[M+H] + 389.14
실시예 69: N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)프로피온아미드의 합성 (화합물 69)Example 69: Synthesis of N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)propionamide (compound 69)
Figure PCTKR2023010500-appb-img-000090
Figure PCTKR2023010500-appb-img-000090
상기 실시예 67-1의 벤조산 대신 프로피온산을 사용하는 것을 제외하고, 상기 실시예 67과 동일하게 실시하여 표제 화합물을 얻었다.The title compound was obtained in the same manner as in Example 67, except that propionic acid was used instead of benzoic acid in Example 67-1.
1H NMR(CDCl3) δ 8.12 - 7.75 (m, 1H), 7.68 (s, 4H), 7.27 (s, 2H), 7.20 - 6.97 (m, 1H), 6.66 (dd, J = 16.8, 10.6 Hz, 1H), 6.36 (dd, J = 16.1, 9.6 Hz, 1H), 5.78 - 5.69 (m, 1H), 4.85 (d, J = 45.8 Hz, 2H), 3.99 - 3.77 (m, 2H), 2.81 (s, 2H), 2.48 (d, J = 6.0 Hz, 2H), 1.57 (s, 1H), 1.37 - 1.15 (m, 4H) 1 H NMR(CDCl 3 ) δ 8.12 - 7.75 (m, 1H), 7.68 (s, 4H), 7.27 (s, 2H), 7.20 - 6.97 (m, 1H), 6.66 (dd, J = 16.8, 10.6 Hz , 1H), 6.36 (dd, J = 16.1, 9.6 Hz, 1H), 5.78 - 5.69 (m, 1H), 4.85 (d, J = 45.8 Hz, 2H), 3.99 - 3.77 (m, 2H), 2.81 ( s, 2H), 2.48 (d, J = 6.0 Hz, 2H), 1.57 (s, 1H), 1.37 - 1.15 (m, 4H)
[M+H]+ 403.16[M+H] + 403.16
실시예 70: 1-(6-((페닐아미노)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 70)Example 70: 1-(6-((phenylamino)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- Synthesis of 2-en-1-one (Compound 70)
Figure PCTKR2023010500-appb-img-000091
Figure PCTKR2023010500-appb-img-000091
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-((페닐아미노)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-((phenylamino ) Examples 1-2 and 1- above, except that methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The same procedure as in 3 was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.80 (d, J = 8.0 Hz, 2 H), 7.65 (d, J = 7.6 Hz, 2 H), 7.33 (s, 1H), 7.16-7.13 (m, 1 H), 6.99 (t, J = 8.0 Hz, 2 H), 6.92-6.85 (m, 1 H), 6.49 (t, J = 7.2 Hz, 1 H), 6.42 (d, J = 7.6 Hz, 2 H), 6.14 (dd, J = 16.8 Hz, 2.0 Hz, 1 H), 6.04 (t, J = 4.8 Hz, 1 H), 5.71 (dd, J = 10.4 Hz, 2.0 Hz, 1 H), 4.81-4.71 (m, 2 H), 4.05 (d, J = 5.2 Hz, 2 H), 3.82-3.76 (m, 2 H), 2.86-2.81 (m, 2 H) 1H NMR(CDCl 3 ) δ 7.80 (d, J = 8.0 Hz, 2 H), 7.65 (d, J = 7.6 Hz, 2 H), 7.33 (s, 1H), 7.16-7.13 (m, 1 H) , 6.99 (t, J = 8.0 Hz, 2 H), 6.92-6.85 (m, 1 H), 6.49 (t, J = 7.2 Hz, 1 H), 6.42 (d, J = 7.6 Hz, 2 H), 6.14 (dd, J = 16.8 Hz, 2.0 Hz, 1 H), 6.04 (t, J = 4.8 Hz, 1 H), 5.71 (dd, J = 10.4 Hz, 2.0 Hz, 1 H), 4.81-4.71 (m , 2 H), 4.05 (d, J = 5.2 Hz, 2 H), 3.82-3.76 (m, 2 H), 2.86-2.81 (m, 2 H)
[M+H]+ 437.18[M+H] + 437.18
실시예 71: 1-(6-((4-메틸피페라진-1-일)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 71)Example 71: 1-(6-((4-methylpiperazin-1-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H )-yl) Synthesis of prop-2-en-1-one (Compound 71)
Figure PCTKR2023010500-appb-img-000092
Figure PCTKR2023010500-appb-img-000092
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 6-((4-메틸피페라진-1-일)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 6-((4- The same procedure as above except using methylpiperazin-1-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. The title compound was obtained in the same manner as Examples 1-2 and 1-3.
1H NMR(CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.13-7.11 (m, 1H), 6.93-6.84 (m, 1H), 6.15 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.72 (dd, J = 10.4 Hz, 2.0 Hz, 1 H), 4.80-4.70 (m, 2H), 3.84-3.78 (m, 2H), 3.28 (s, 2H), 2.91-2.81 (m, 2H), 2.33-2.14 (m, 8H), 2.10 (s, 3H) 1 H NMR(CDCl 3 ) δ 7.76 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.13-7.11 (m, 1H), 6.93- 6.84 (m, 1H), 6.15 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.72 (dd, J = 10.4 Hz, 2.0 Hz, 1 H), 4.80-4.70 (m, 2H), 3.84-3.78 (m, 2H), 3.28 (s, 2H), 2.91-2.81 (m, 2H), 2.33-2.14 (m, 8H), 2.10 (s, 3H)
[M+H]+ 444.22[M+H] + 444.22
실시예 72: 1-(5-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 72)Example 72: 1-(5-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one (Compound 72)
Figure PCTKR2023010500-appb-img-000093
Figure PCTKR2023010500-appb-img-000093
실시예 72-1: tert-부틸 7-브로모-5-(디메틸아미노)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 72-1: Synthesis of tert-butyl 7-bromo-5-(dimethylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 제조예 1에서 제조한 tert-부틸 5-아미노-7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (1.63g, 5mmol)를 30ml 에탄올에 녹였다. 상기 혼합 용액에 포름알데히드(300mg, 15mmol), NaBH(OAc)3(2.12g, 10mmol)와 AcOH(60mg, 1mmol)를 순차적으로 투입하였다. 상기 혼합 용액을 80℃에서 1일 교반하였다. 얻어진 화합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (1.49g, 84%)tert-Butyl 5-amino-7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.63 g, 5 mmol) prepared in Preparation Example 1 was dissolved in 30 ml of ethanol. Formaldehyde (300 mg, 15 mmol), NaBH(OAc) 3 (2.12 g, 10 mmol), and AcOH (60 mg, 1 mmol) were sequentially added to the mixed solution. The mixed solution was stirred at 80°C for 1 day. After cooling the obtained compound, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (1.49g, 84%)
MS (ESI) m/z: [M+H]+ 355.09MS (ESI) m/z: [M+H] + 355.09
실시예 72-2: 1-(5-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 72-2: 1-(5-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
상기 실시예 1-1의 tert-부틸 7-브로모-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 72-1에서 제조한 tert-부틸 7-브로모-5-(디메틸아미노)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-1, tert-butyl 7-bromo-5 prepared in Example 72-1 was used. The title compound was obtained in the same manner as in Example 1, except that -(dimethylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used.
1H NMR(CDCl3) δ 7.66 (q, J = 8.4 Hz, 4H), 7.10 (t, J = 6.1 Hz, 2H), 7.00 (s, 1H), 6.67 (ddd, J = 16.7, 10.5, 6.0 Hz, 1H), 6.41 - 6.33 (m, 1H), 5.74 (dd, J = 10.5, 3.7 Hz, 1H), 4.81 (d, J = 27.1 Hz, 2H), 3.79 (dt, J = 62.9, 5.7 Hz, 2H), 2.94 (dt, J = 24.7, 5.6 Hz, 2H), 2.74 (d, J = 10.4 Hz, 6H) 1 H NMR(CDCl 3 ) δ 7.66 (q, J = 8.4 Hz, 4H), 7.10 (t, J = 6.1 Hz, 2H), 7.00 (s, 1H), 6.67 (ddd, J = 16.7, 10.5, 6.0 Hz, 1H), 6.41 - 6.33 (m, 1H), 5.74 (dd, J = 10.5, 3.7 Hz, 1H), 4.81 (d, J = 27.1 Hz, 2H), 3.79 (dt, J = 62.9, 5.7 Hz) , 2H), 2.94 (dt, J = 24.7, 5.6 Hz, 2H), 2.74 (d, J = 10.4 Hz, 6H)
[M+H]+ 375.16[M+H] + 375.16
실시예 73: N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-6-일)벤자미드의 합성 (화합물 73)Example 73: Synthesis of N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)benzamide (Compound 73)
Figure PCTKR2023010500-appb-img-000094
Figure PCTKR2023010500-appb-img-000094
실시예 73-1: tert-부틸 6-벤즈아미도-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 73-1: Synthesis of tert-butyl 6-benzamido-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 실시예 44-2에서 제조한 tert-부틸 6-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 (392.4mg, 1mmol)를 10ml DMF에 녹였다. HATU(456.3mg, 1.2mmol), TEA(121.5mg, 1.2mmol)와 벤조산(146mg, 1.2mmol)을 상기 혼합물에 첨가한 후 상온에서 3시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 표제 화합물을 얻었다. (322.7mg, 0.65mmol, 65%)tert-Butyl 6-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (392.4 mg, 1 mmol) was dissolved in 10 ml DMF. HATU (456.3 mg, 1.2 mmol), TEA (121.5 mg, 1.2 mmol), and benzoic acid (146 mg, 1.2 mmol) were added to the mixture and stirred at room temperature for 3 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained. (322.7mg, 0.65mmol, 65%)
MS (ESI) m/z: [M+H]+ 497.20MS (ESI) m/z: [M+H] + 497.20
실시예 73-2: N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-6-일)벤자미드의 합성Example 73-2: Synthesis of N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)benzamide
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 73-1에서 제조한 tert-부틸 6-벤즈아미도-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of the tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, the product prepared in Example 73-1 Example 1 above, except that tert-butyl 6-benzamido-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used. The title compound was obtained in the same manner as -2 and 1-3.
1H NMR(CDCl3) δ 9.95 (s, 1H), 7.75 (t, J = 8.4 Hz, 4H), 7.64 (d, J = 8.0 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.31-7.29 (m, 2H), 6.95-6.88 (m, 1H), 6.17 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.73 (d, J = 12.0 Hz, 1H), 4.86-4.76 (m, 2H), 3.85-3.80 (m, 2H), 2.93-2.87 (m, 2H) 1H NMR(CDCl 3 ) δ 9.95 (s, 1H), 7.75 (t, J = 8.4 Hz, 4H), 7.64 (d, J = 8.0 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H) , 7.45 (t, J = 7.6 Hz, 2H), 7.31-7.29 (m, 2H), 6.95-6.88 (m, 1H), 6.17 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.73 (d, J = 12.0 Hz, 1H), 4.86-4.76 (m, 2H), 3.85-3.80 (m, 2H), 2.93-2.87 (m, 2H)
[M+H]+ 451.16[M+H] + 451.16
실시예 74: 1-(6-(벤질옥시)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 74)Example 74: 1-(6-(benzyloxy)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one (Compound 74)
Figure PCTKR2023010500-appb-img-000095
Figure PCTKR2023010500-appb-img-000095
실시예 74-1: 1-(6-히드록시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 74-1: 1-(6-hydroxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene Synthesis of -1-one
상기 실시예 7에서 제조한 1-(6-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (361.4mg, 1mmol)을 DCM 10ml에 녹인 후 BBr3 (501mg, 2mmol)를 투입하였다. 상기 혼합 용액을 상온에서 6시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 DCM을 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (201.5mg, 58%)1-(6-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- prepared in Example 7 En-1-one (361.4 mg, 1 mmol) was dissolved in 10 ml of DCM, and then BBr 3 (501 mg, 2 mmol) was added. The mixed solution was stirred at room temperature for 6 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and DCM. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (201.5 mg, 58%)
MS (ESI) m/z: [M+H]+ 348.11MS (ESI) m/z: [M+H] + 348.11
실시예 74-2: 1-(6-(벤질옥시)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 74-2: 1-(6-(benzyloxy)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 Synthesis of -en-1-one
상기 실시예 74-1에서 제조한 1-(6-히드록시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온(201.5mg, 0.58mmol)을 DMF 5ml에 녹였다. 상기 혼합 용액에 K2CO3(96.7mg, 0.7mmol)와 벤질브로마이드(119.7mg, 0.7mmol)를 투입한 후 혼합된 용액을 80℃에서 5시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 DCM을 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제한 후 농축하여 표제 화합물을 얻었다. (159.8mg, 63%)1-(6-hydroxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- prepared in Example 74-1 above 2-en-1-one (201.5 mg, 0.58 mmol) was dissolved in 5 ml of DMF. K 2 CO 3 (96.7 mg, 0.7 mmol) and benzyl bromide (119.7 mg, 0.7 mmol) were added to the mixed solution, and the mixed solution was stirred at 80°C for 5 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and DCM. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography and concentrated to obtain the title compound. (159.8mg, 63%)
1H NMR(CDCl3) δ 7.75 (s, 4H), 7.36-7.34 (m, 4H), 7.32-7.21 (m, 2H), 7.08 (s, 1H), 6.97-6.83 (m, 1H), 6.18-6.13 (m, 1H), 5.72 (d, J = 10.4 Hz, 2.4 Hz, 1H), 5.13 (s, 2H), 4.76-4.66 (m, 2H), 3.81-3.76 (m, 2H), 2.88-2.83 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.75 (s, 4H), 7.36-7.34 (m, 4H), 7.32-7.21 (m, 2H), 7.08 (s, 1H), 6.97-6.83 (m, 1H), 6.18 -6.13 (m, 1H), 5.72 (d, J = 10.4 Hz, 2.4 Hz, 1H), 5.13 (s, 2H), 4.76-4.66 (m, 2H), 3.81-3.76 (m, 2H), 2.88- 2.83 (m, 2H)
[M+H]+ 438.16[M+H] + 438.16
실시예 75: (S)-1-(3-(히드록시메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 75)Example 75: (S)-1-(3-(Hydroxymethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop Synthesis of p-2-en-1-one (Compound 75)
Figure PCTKR2023010500-appb-img-000096
Figure PCTKR2023010500-appb-img-000096
실시예 75-1: 메틸 (S)-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트의 합성Example 75-1: Synthesis of methyl (S)-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
메틸(S)-7-브로모-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트(2.7g, 10mmol)을 다이옥산/물(3:1) 100ml에 녹인 후 Pd(PPh3)4(1.15g, 1mmol)을 첨가하였다. 그 후 Cs2CO3(3.91g, 12mmol)와 4-(트리플루오로메틸)페닐 보론산 (2.28g, 12mmol)을 순서대로 첨가하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (2.78g, 83%)Methyl (S)-7-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2.7 g, 10 mmol) was dissolved in 100 ml of dioxane/water (3:1) and then dissolved in Pd(PPh 3) . ) 4 (1.15g, 1mmol) was added. Afterwards, Cs 2 CO 3 (3.91 g, 12 mmol) and 4-(trifluoromethyl)phenyl boronic acid (2.28 g, 12 mmol) were added in that order. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (2.78g, 83%)
MS (ESI) m/z: [M+H]+ 336.11MS (ESI) m/z: [M+H] + 336.11
실시예 75-2: (S)-(7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-일)메탄올의 합성Example 75-2: Synthesis of (S)-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methanol
상기 실시예 75-1에서 제조한 메틸 (S)-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트(2.78g, 8.3mmol)를 THF 80ml에 녹였다. 상온에서 혼합된 용액에 천천히 1M LiAlH4 THF 용액 24ml를 1시간에 거쳐 투입한 후 상온에서 3시간 교반하였다. 반응 종결을 LC-MS로 확인한 후 과량의 LiAlH4를 HCl 수용액으로 제거하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 정제 후 농축하여 표제 화합물을 합성하였다. (1.37g, 54%)Methyl (S)-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate prepared in Example 75-1 (2.78 g, 8.3 mmol) was dissolved in 80ml of THF. 24ml of 1M LiAlH 4 THF solution was slowly added to the mixed solution at room temperature over 1 hour, and then stirred at room temperature for 3 hours. After the completion of the reaction was confirmed by LC-MS, excess LiAlH 4 was removed with an aqueous HCl solution, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. After purification and concentration, the title compound was synthesized. (1.37g, 54%)
MS (ESI) m/z: [M+H]+ 308.12MS (ESI) m/z: [M+H] + 308.12
실시예 75-3: (S)-1-(3-(히드록시메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 75-3: (S)-1-(3-(hydroxymethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of prop-2-en-1-one
상기 실시예 75-2에서 제조한 (S)-(7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-일)메탄올(31mg, 0.1mmol)을 DMF 2ml에 녹였다. HATU(45.6mg, 0.12mmol), TEA(12.2mg, 0.12mmol)와 아크릴산(8.7mg, 0.12mmol)를 혼합물에 첨가한 후 상온에서 3시간 교반하였다. 반응 종결을 LC-MS로 확인하고 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (11mg, 0.03mmol, 30%)(S)-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (31 mg, 0.1 mg) prepared in Example 75-2. mmol) was dissolved in 2ml of DMF. HATU (45.6 mg, 0.12 mmol), TEA (12.2 mg, 0.12 mmol), and acrylic acid (8.7 mg, 0.12 mmol) were added to the mixture and stirred at room temperature for 3 hours. The completion of the reaction was confirmed by LC-MS, and the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (11mg, 0.03mmol, 30%)
1H NMR(CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 6.9 Hz, 2H), 7.32 (dd, J = 16.5, 7.8 Hz, 1H), 6.92 (dd, J = 16.8, 10.7 Hz, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.79 (ddd, J = 23.5, 10.7, 1.9 Hz, 1H), 5.08 (dd, J = 105.3, 17.0 Hz, 1H), 4.71 - 4.41 (m, 2H), 3.59 - 3.42 (m, 2H), 3.18 - 2.95 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.81 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 6.9 Hz, 2H), 7.32 (dd, J = 16.5, 7.8 Hz, 1H), 6.92 (dd, J = 16.8, 10.7 Hz, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.79 (ddd, J = 23.5, 10.7, 1.9 Hz, 1H) ), 5.08 (dd, J = 105.3, 17.0 Hz, 1H), 4.71 - 4.41 (m, 2H), 3.59 - 3.42 (m, 2H), 3.18 - 2.95 (m, 2H)
[M+H]+ 362.13[M+H] + 362.13
실시예 76: (R)-1-(3-(히드록시메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 76)Example 76: (R)-1-(3-(Hydroxymethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop Synthesis of p-2-en-1-one (Compound 76)
Figure PCTKR2023010500-appb-img-000097
Figure PCTKR2023010500-appb-img-000097
상기 실시예 75-1의 메틸(S)-7-브로모-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트 대신 메틸(R)-7-브로모-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 75와 동일하게 실시하여 표제 화합물을 얻었다.Instead of methyl (S)-7-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate of Example 75-1, methyl (R)-7-bromo-1,2,3 , The title compound was obtained in the same manner as Example 75, except for using 4-tetrahydroisoquinoline-3-carboxylate.
1H NMR(CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 6.5 Hz, 2H), 7.31 (dd, J = 11.5, 7.8 Hz, 1H), 6.90 (dd, J = 11.4, 10.7 Hz, 1H), 6.26 (dd, J = 11.4, 1.9 Hz, 1H), 5.77 (ddd, J = 23.0, 10.7, 1.9 Hz, 1H), 5.06 (dd, J = 100.3, 17.0 Hz, 1H), 4.68 - 4.40 (m, 2H), 3.55 - 3.40 (m, 2H), 3.16 - 2.92 (m, 2H) 1 H NMR(CDCl 3 ) δ 7.80 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 6.5 Hz, 2H), 7.31 (dd, J = 11.5, 7.8 Hz, 1H), 6.90 (dd, J = 11.4, 10.7 Hz, 1H), 6.26 (dd, J = 11.4, 1.9 Hz, 1H), 5.77 (ddd, J = 23.0, 10.7, 1.9 Hz, 1H) ), 5.06 (dd, J = 100.3, 17.0 Hz, 1H), 4.68 - 4.40 (m, 2H), 3.55 - 3.40 (m, 2H), 3.16 - 2.92 (m, 2H)
[M+H]+ 362.13[M+H] + 362.13
실시예 77: 1-(5-(4-메틸피페라진-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 77)Example 77: 1-(5-(4-methylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of prop-2-en-1-one (Compound 77)
Figure PCTKR2023010500-appb-img-000098
Figure PCTKR2023010500-appb-img-000098
실시예 77-1: tert-부틸 5-니트로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 77-1: Synthesis of tert-butyl 5-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 제조예 1-3에서 제조한 tert-부틸 7-브로모-5-니트로-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트(3.57g, 10mmol)를 다이옥산/물(3:1) 100ml에 녹인 후 Pd(PPh3)4(1.15g, 1mmol)을 첨가하였다. 그 후 Cs2CO3(3.91g, 12mmol)와 4-(트리플루오로메틸)페닐 보론산 (2.88g, 12mmol)을 순서대로 첨가하였다. 상기 혼합 용액을 100℃에서 3시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (3.55g, 84%)tert-butyl 7-bromo-5-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.57 g, 10 mmol) prepared in Preparation Example 1-3 was mixed with dioxane/water (3: 1) After dissolving in 100ml, Pd(PPh 3 ) 4 (1.15g, 1mmol) was added. Afterwards, Cs 2 CO 3 (3.91 g, 12 mmol) and 4-(trifluoromethyl)phenyl boronic acid (2.88 g, 12 mmol) were added in that order. The mixed solution was stirred at 100°C for 3 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (3.55g, 84%)
MS (ESI) m/z: [M+H]+ 423.15MS (ESI) m/z: [M+H] + 423.15
실시예 77-2: tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 77-2: Synthesis of tert-butyl 5-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 실시예 77-1에서 제조한 tert-부틸 5-니트로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트(3.55g, 8.4mmol)을 메탄올 100ml에 녹였다. 10% Pd/C (212.8mg, 2mmol)을 주의하여 투입한 후 수소 풍선을 이용해 수소 대기 환경을 만들어 주고 상온에서 1일간 교반하였다. 반응 종결을 LC-MS로 확인하고 필터 후 얻은 여과액을 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제한 후 농축하여 표제 화합물을 얻었다. (2.27g, 69%)tert-Butyl 5-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.55 g, 8.4 mmol) was dissolved in 100 ml of methanol. After carefully adding 10% Pd/C (212.8 mg, 2 mmol), a hydrogen atmosphere was created using a hydrogen balloon and stirred at room temperature for 1 day. The completion of the reaction was confirmed by LC-MS, and the filtrate obtained after filtering was concentrated in vacuum. The residue was purified using column chromatography and concentrated to obtain the title compound. (2.27g, 69%)
MS (ESI) m/z: [M+H]+ 393.17MS (ESI) m/z: [M+H] + 393.17
실시예 77-3: tert-부틸 5-브로모-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 77-3: Synthesis of tert-butyl 5-bromo-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
상기 실시예 77-2에서 제조한 tert-부틸 5-아미노-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트(2.27g, 5.78mmol)를 ACN 80ml에 녹였다. NaNO2(690mg, 10mmol)와 CuBr(1.22g, 8.5mmol)을 투입한 후 혼합된 용액을 80℃에서 16시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (1.5g, 57%)tert-Butyl 5-amino-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.27g, 5.78 mmol) was dissolved in 80 ml of ACN. After adding NaNO 2 (690 mg, 10 mmol) and CuBr (1.22 g, 8.5 mmol), the mixed solution was stirred at 80°C for 16 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (1.5g, 57%)
MS (ESI) m/z: [M+H]+ 456.07MS (ESI) m/z: [M+H] + 456.07
실시예 77-4: tert-부틸 5-(4-메틸피페라진-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트의 합성Example 77-4: tert-Butyl 5-(4-methylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H) -Synthesis of carboxylates
상기 실시예 77-3에서 제조한 tert-부틸 5-브로모-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트(1.5g, 3.29mmol)를 다이옥산 50ml에 녹인 후 Pd2(dba)3(457.9mg, 0.5mmol), Xantphos(289.31mg, 0.5mmol)와 1-메틸피페라진(1g, 10mmol)을 투입하였다. 상기 혼합 용액을 100℃에서 16시간 교반하였다. 얻어진 혼합물을 식힌 후 물과 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층을 염수로 세척하고 무수 MgSO4로 건조시킨 후 진공 농축하였다. 잔류물을 컬럼 크로마토그래피를 이용해 정제하였다. 정제 후 농축하여 하얀색 고체의 표제 화합물을 얻었다. (673mg, 43%)tert-Butyl 5-bromo-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.5 g) prepared in Example 77-3. , 3.29 mmol) was dissolved in 50 ml of dioxane, and then Pd 2 (dba) 3 (457.9 mg, 0.5 mmol), Xantphos (289.31 mg, 0.5 mmol) and 1-methylpiperazine (1 g, 10 mmol) were added. The mixed solution was stirred at 100°C for 16 hours. After cooling the obtained mixture, the organic layer was extracted using water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was purified using column chromatography. After purification and concentration, the title compound was obtained as a white solid. (673mg, 43%)
MS (ESI) m/z: [M+H]+ 476.24MS (ESI) m/z: [M+H] + 476.24
실시예 77-5: 1-(5-(4-메틸피페라진-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성Example 77-5: 1-(5-(4-methylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H) -1) Synthesis of prop-2-en-1-one
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 상기 실시예 77-4에서 제조한 tert-부틸 5-(4-메틸피페라진-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, prepared in Example 77-4 Using tert-butyl 5-(4-methylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate Except for this, the title compound was obtained in the same manner as Examples 1-2 and 1-3.
1H NMR(CDCl3) 7.69 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 9.3 Hz, 2H), 7.13 (q, J = 20.7 Hz, 2H), 6.71 - 6.60 (m, 1H), 6.40 - 6.30 (m, 1H), 5.76 (dd, J = 10.8, 4.0 Hz, 1H), 4.82 (d, J = 28.0 Hz, 2H), 3.88 - 3.73 (m, 2H), 3.14 (ddd, J = 27.6, 25.7, 19.4 Hz, 4H), 2.89 (d, J = 25.6 Hz, 2H), 2.82 - 2.44 (m, 4H), 2.02 (dd, J = 9.0, 6.3 Hz, 3H) 1 H NMR(CDCl 3 ) 7.69 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 9.3 Hz, 2H), 7.13 (q, J = 20.7 Hz, 2H), 6.71 - 6.60 (m, 1H) ), 6.40 - 6.30 (m, 1H), 5.76 (dd, J = 10.8, 4.0 Hz, 1H), 4.82 (d, J = 28.0 Hz, 2H), 3.88 - 3.73 (m, 2H), 3.14 (ddd, J = 27.6, 25.7, 19.4 Hz, 4H), 2.89 (d, J = 25.6 Hz, 2H), 2.82 - 2.44 (m, 4H), 2.02 (dd, J = 9.0, 6.3 Hz, 3H)
[M+H]+ 430.20[M+H] + 430.20
실시예 78: 1-(5-(피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 78)Example 78: 1-(5-(pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop Synthesis of p-2-en-1-one (Compound 78)
Figure PCTKR2023010500-appb-img-000099
Figure PCTKR2023010500-appb-img-000099
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-(피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 5-(pyrrolidine Examples 1-2 and The same procedure as 1-3 was performed to obtain the title compound.
1H NMR(CDCl3) δ 7.74 (t, J = 7.3 Hz, 2H), 7.69 (q, J = 5.1 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.47 (dd, J = 13.0, 5.9 Hz, 1H), 6.67 - 6.63 (m, 1H), 6.35 (dd, J = 17.0, 5.0 Hz, 1H), 5.89 - 5.84 (m, 1H), 4.94 (t, J = 21.6 Hz, 2H), 3.93 (dd, J = 25.4, 11.1 Hz, 4H), 3.87 (dd, J = 17.6, 6.7 Hz, 2H), 3.35 - 3.11 (m, 2H), 3.00 (dt, J = 21.1, 17.5 Hz, 2H), 2.44 - 2.19 (m, 4H) 1H NMR(CDCl 3 ) δ 7.74 (t, J = 7.3 Hz, 2H), 7.69 (q, J = 5.1 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.47 (dd, J = 13.0, 5.9 Hz, 1H), 6.67 - 6.63 (m, 1H), 6.35 (dd, J = 17.0, 5.0 Hz, 1H), 5.89 - 5.84 (m, 1H), 4.94 (t, J = 21.6 Hz, 2H) ), 3.93 (dd, J = 25.4, 11.1 Hz, 4H), 3.87 (dd, J = 17.6, 6.7 Hz, 2H), 3.35 - 3.11 (m, 2H), 3.00 (dt, J = 21.1, 17.5 Hz, 2H), 2.44 - 2.19 (m, 4H)
[M+H]+ 401.18[M+H] + 401.18
실시예 79: 1-(5-(3-(디메틸아미노)피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온의 합성 (화합물 79)Example 79: 1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2( Synthesis of 1H)-yl)prop-2-en-1-one (Compound 79)
Figure PCTKR2023010500-appb-img-000100
Figure PCTKR2023010500-appb-img-000100
상기 실시예 1-2의 tert-부틸 7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트 대신 tert-부틸 5-(3,3-디메틸피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-카복실레이트를 사용하는 것을 제외하고, 상기 실시예 1-2 및 1-3과 동일하게 실시하여 표제 화합물을 얻었다.Instead of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of Example 1-2, tert-butyl 5-(3,3 -Dimethylpyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was used as above. The title compound was obtained in the same manner as Examples 1-2 and 1-3.
1H NMR(CDCl3) δ 7.82 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 7.4 Hz, 2H), 7.22 (d, J = 18.5 Hz, 2H), 7.06 - 6.78 (m, 1H), 6.29 (d, J = 16.7 Hz, 1H), 5.90 - 5.73 (m, 1H), 4.75 (dd, J = 31.5, 16.9 Hz, 2H), 3.99 - 3.79 (m, 2H), 3.79 - 3.60 (m, 2H), 3.53 - 3.42 (m, 2H), 3.36 (d, J = 31.1 Hz, 2H), 2.94 (d, J = 24.8 Hz, 2H), 2.84 (d, J = 20.7 Hz, 6H) 1H NMR(CDCl 3 ) δ 7.82 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 7.4 Hz, 2H), 7.22 (d, J = 18.5 Hz, 2H), 7.06 - 6.78 (m, 1H), 6.29 (d, J = 16.7 Hz, 1H), 5.90 - 5.73 (m, 1H), 4.75 (dd, J = 31.5, 16.9 Hz, 2H), 3.99 - 3.79 (m, 2H), 3.79 - 3.60 (m, 2H), 3.53 - 3.42 (m, 2H), 3.36 (d, J = 31.1 Hz, 2H), 2.94 (d, J = 24.8 Hz, 2H), 2.84 (d, J = 20.7 Hz, 6H)
[M+H]+ 444.22[M+H] + 444.22
시험예 1: TEAD 전사활성화 저해 평가Test Example 1: Evaluation of TEAD transcriptional activation inhibition
TEAD 전사활성화 저해 평가를 측정하기 위해 TEAD 리포터 유전자가 삽입된 MCF7 세포의 TEAD 활성 상태를 평가하였다. 제조된 화합물을 100 pM 부터 1 μM의 사이의 농도로 24시간 처리하여 TEAD의 전사활성에 미치는 영향을 확인하였다. 용해물질인 디메틸 설폭사이드 (DMSO)를 단독 처리한 TEAD 루시퍼라제 리포터의 활성 측정값을 100%로 하여 각각의 화합물의 활성을 측정하였고, Prism 소프트웨어 (v.9.4; GraphPad)를 사용하여 반수 최대 억제 농도인 IC50를 계산하였다.To measure the inhibition of TEAD transactivation, the TEAD activity status of MCF7 cells into which the TEAD reporter gene was inserted was evaluated. The prepared compound was treated at a concentration ranging from 100 pM to 1 μM for 24 hours to confirm its effect on the transcriptional activity of TEAD. The activity of each compound was measured by setting the activity measurement value of the TEAD luciferase reporter treated with dimethyl sulfoxide (DMSO) alone as a dissolving agent as 100%, and half-maximal inhibition was performed using Prism software (v.9.4; GraphPad). The concentration, IC 50 , was calculated.
그 결과를 하기 표 1에 나타내었다.The results are shown in Table 1 below.
실시예Example TEAD 리포터 저해 IC50(nM)TEAD reporter inhibition IC 50 (nM)
1One 0.170.17
22 0.370.37
33 0.590.59
44 8.788.78
55 0.340.34
66 0.620.62
77 0.280.28
88 0.450.45
99 1818
1010 5.745.74
1111 0.190.19
1212 0.080.08
1313 0.150.15
1414 6.496.49
1515 3.13.1
1616 2.52.5
1717 0.170.17
1818 6666
1919 7.57.5
2020 8686
2121 5.985.98
2222 2.802.80
2323 0.690.69
2424 0.160.16
2525 0.170.17
2626 33.533.5
2727 >100>100
2828 3.123.12
2929 3.413.41
3030 0.920.92
3131 2.812.81
3232 5.365.36
3333 0.310.31
3434 4.914.91
3535 0.430.43
3636 0.940.94
3737 0.550.55
3838 1.541.54
3939 3.73.7
4040 3.33.3
4141 0.830.83
4242 >100>100
4343 >100>100
4444 23.3523.35
4545 3.653.65
4646 2.52.5
4747 3.73.7
4848 14.1514.15
4949 6.66.6
5050 6.996.99
5151 >100>100
5252 0.340.34
5353 >100>100
5454 0.170.17
5555 0.160.16
5656 1313
5757 6.166.16
5858 3535
5959 2525
6060 3.153.15
6161 7.97.9
6262 4.364.36
6363 1414
6464 2.82.8
6565 2929
6666 15.315.3
6767 33
6868 14.6714.67
6969 10.0210.02
7070 15.8115.81
7171 61.561.5
7272 0.620.62
7373 9.59.5
7474 3.73.7
7575 8.768.76
7676 5.875.87
7777 >100>100
7878 0.980.98
7979 >100>100
상기 표 1에서 볼 수 있듯이, 본 발명에 따른 헤테로비시클릭 화합물은 우수한 TEAD 전사 활성화 저해 효능을 보였다.As can be seen in Table 1, the heterobicyclic compound according to the present invention showed excellent TEAD transcriptional activation inhibition efficacy.
시험예 2: 마이크로좀 대사 안정성 측정 실험Test Example 2: Microsome metabolic stability measurement experiment
냉동고에 보관된 쥐의 간 마이크로좀(MLM)을 해동하여 NADPH(1mM)와 대사시험용 용액에 분산시킨 마이크로좀을 5분간 반응시키고 시험 약물을 처리하였다. 30분 후 반응을 종료시킨 다음 15분간 원심분리기를 이용해 상등액을 분리하여 LC-MS/MS 시스템으로 분석하였다.Rat liver microsomes (MLM) stored in the freezer were thawed, and the microsomes dispersed in NADPH (1mM) and metabolism test solution were reacted for 5 minutes and treated with the test drug. After 30 minutes, the reaction was terminated, and the supernatant was separated using a centrifuge for 15 minutes and analyzed with an LC-MS/MS system.
그 결과를 하기 표 2에 나타내었다.The results are shown in Table 2 below.
시험예 3: 약동학(PK) 측정 실험Test Example 3: Pharmacokinetic (PK) measurement experiment
마우스에서의 in vivo 경구 약동학 시험을 다음과 같이 수행하고 약동학 파라미터를 산출하였다. An in vivo oral pharmacokinetic study in mice was performed as follows and pharmacokinetic parameters were calculated.
7~8주령의 마우스(약 30~40g)를 약 18시간 전에 절식시켰다. 투여 시험 약물을 비히클(vehicle)에 2mg/mL의 농도로 녹인 후, 10mg/kg 용량으로 5mL/kg 부피로 투여하였다. 투여 후 헤파린이 처리된 채혈용 캐필러리로 안와 채혈하였다. 혈액을 14000rpm의 속도로 10분간 원심분리하여 혈장을 분리하고 LC-MS/MS 시스템으로 분석하였다.7-8 week old mice (approximately 30-40 g) were fasted for approximately 18 hours. Administration The test drug was dissolved in a vehicle at a concentration of 2 mg/mL and then administered at a dose of 10 mg/kg in a volume of 5 mL/kg. After administration, orbital blood was collected using a heparin-treated blood collection capillary. Blood was centrifuged at 14000 rpm for 10 minutes to separate plasma and analyzed with an LC-MS/MS system.
마이크로좀 30분 잔류 용량(%)Microsome 30-minute residual capacity (%) AUC(㎍/mL*min)AUC (㎍/mL*min)
실시예 1Example 1 62.762.7 288.8288.8
실시예 2Example 2 55.355.3 787.3787.3
실시예 5Example 5 N.A.N.A. 636.3636.3
실시예 7Example 7 72.272.2 478.6478.6
실시예 12Example 12 72.372.3 312.4312.4
실시예 13Example 13 70.270.2 373.7373.7
실시예 17Example 17 85.185.1 324.8324.8
실시예 55Example 55 74.174.1 513.4513.4
실시예 72Example 72 78.278.2 737.3737.3
상기 표 2를 통해, 본 발명의 헤테로비시클릭 화합물이 우수한 대사 안정성과 약동학적 특성을 나타내는 것을 알 수 있다.From Table 2 above, it can be seen that the heterobicyclic compound of the present invention exhibits excellent metabolic stability and pharmacokinetic properties.
시험예 4: 종양 마우스 모델에서의 활성 평가Test Example 4: Activity evaluation in tumor mouse model
NOD SCID 마우스에 폐암 세포를 이종이식 (xenograft) 한 후, 화합물을 투여하여 종양 형성 유무와 시험 약물에 대한 영향을 확인하였다.After lung cancer cells were xenografted into NOD SCID mice, compounds were administered to determine the presence or absence of tumor formation and the effect on the test drug.
6 내지 7주된 10마리의 NOD SCID 마우스의 피하에 마트리겔 (Matrigel)과 1:1로 혼합한 NCI-H226 세포주를 1 × 107로 주사하여 종양을 형성시킨 후, 시험 약물로서 실시예 1의 화합물을 10 mg/kg, 30 mg/kg의 농도로 경구 투여하고 28일간 크기 변화를 측정하였다.Tumors were formed by injecting 1 × 10 7 NCI-H226 cell line mixed 1:1 with Matrigel subcutaneously into 10 NOD SCID mice aged 6 to 7 weeks, and then administered the test drug of Example 1 as a test drug. The compounds were administered orally at concentrations of 10 mg/kg and 30 mg/kg, and size changes were measured for 28 days.
그 결과를 도 1에 나타내었다.The results are shown in Figure 1.
도 1을 통해, 본 발명에 따른 화합물이 종양 억제 활성을 나타내는 것을 알 수 있다.Through Figure 1, it can be seen that the compound according to the present invention exhibits tumor suppressive activity.

Claims (19)

  1. 하기 화학식 I로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염:A heterobicyclic compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
    [화학식 I][Formula I]
    Figure PCTKR2023010500-appb-img-000101
    Figure PCTKR2023010500-appb-img-000101
    상기 식에서, In the above equation,
    R1은
    Figure PCTKR2023010500-appb-img-000102
    ,
    Figure PCTKR2023010500-appb-img-000103
    ,
    Figure PCTKR2023010500-appb-img-000104
    ,
    Figure PCTKR2023010500-appb-img-000105
    또는
    Figure PCTKR2023010500-appb-img-000106
    이고,     R 1 is
    Figure PCTKR2023010500-appb-img-000102
    ,
    Figure PCTKR2023010500-appb-img-000103
    ,
    Figure PCTKR2023010500-appb-img-000104
    ,
    Figure PCTKR2023010500-appb-img-000105
    or
    Figure PCTKR2023010500-appb-img-000106
    ego,
    R2 및 R3는 각각 독립적으로 수소 원자, C1-C6의 알킬기, C2-C7의 알콕시카보닐기, 옥소기 또는 C1-C6의 히드록시알킬기이며, R 2 and R 3 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 7 alkoxycarbonyl group, an oxo group, or a C 1 -C 6 hydroxyalkyl group,
    R4는 C1-C6의 할로알킬기, 할로겐 원자, C1-C6의 할로알콕시기 및 C1-C6의 알킬기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 아릴기, C3-C10의 사이클로알케닐기 또는 C3-C10의 사이클로알킬기이고, R 4 is an aryl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, a C 1 -C 6 haloalkoxy group, and a C 1 -C 6 alkyl group, C It is a 3 -C 10 cycloalkenyl group or a C 3 -C 10 cycloalkyl group,
    X, Y 및 Z는 각각 독립적으로 질소 원자 또는 CR5이며, X, Y and Z are each independently a nitrogen atom or CR 5 ,
    R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기, C1-C6의 할로알킬기,
    Figure PCTKR2023010500-appb-img-000107
    또는 아릴옥시기이고,     R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, a C 1 -C 6 haloalkyl group,
    Figure PCTKR2023010500-appb-img-000107
    or an aryloxy group,
    L1은 존재하지 않거나, C1-C6의 알킬렌기이며, L 1 does not exist or is an alkylene group of C 1 -C 6 ,
    R6 및 R7은 각각 독립적으로 수소 원자, C1-C6의 알킬기 또는
    Figure PCTKR2023010500-appb-img-000108
    이거나,     R 6 and R 7 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, or
    Figure PCTKR2023010500-appb-img-000108
    This is,
    R6과 R7은 서로 결합하여, C1-C6의 알킬기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 4 내지 7원의 헤테로 고리를 형성하고, R 6 and R 7 are combined with each other to form a 4- to 7-membered hetero ring that may or may not be substituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group,
    L2는 존재하지 않거나, C1-C6의 알킬렌기 또는 카보닐기이며, L 2 is absent or is an alkylene group or carbonyl group of C 1 -C 6 ,
    R8은 C1-C6의 알콕시기, C1-C6의 알킬기, 히드록시기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 아릴기, C3-C10의 헤테로사이클로알킬기 또는 C3-C10의 사이클로알킬기이거나, C1-C6의 알킬기이고, R 8 is an aryl group substituted or unsubstituted with a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group, a C 3 -C 10 heterocycloalkyl group, or C It is a 3 -C 10 cycloalkyl group or a C 1 -C 6 alkyl group,
    n은 0 내지 2의 정수이다.n is an integer from 0 to 2.
  2. 제1항에 있어서, According to paragraph 1,
    R1은
    Figure PCTKR2023010500-appb-img-000109
    ,
    Figure PCTKR2023010500-appb-img-000110
    또는
    Figure PCTKR2023010500-appb-img-000111
    인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.    R 1 is
    Figure PCTKR2023010500-appb-img-000109
    ,
    Figure PCTKR2023010500-appb-img-000110
    or
    Figure PCTKR2023010500-appb-img-000111
    A heterobicyclic compound or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서, According to paragraph 1,
    R2 및 R3는 각각 독립적으로 수소 원자 또는 C1-C6의 알킬기인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group of a heterobicyclic compound or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서, According to paragraph 1,
    R4는 C1-C6의 할로알킬기, 할로겐 원자 및 C1-C6의 할로알콕시기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 아릴기 또는 C3-C10의 사이클로알킬기인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.R 4 is a hetero aryl group or a C 3 -C 10 cycloalkyl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group , a halogen atom, and a C 1 -C 6 haloalkoxy group. A bicyclic compound or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서, According to paragraph 1,
    R4는 C1-C6의 할로알킬기, 할로겐 원자 및 C1-C6의 할로알콕시기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 페닐기, 나프틸기 또는 C3-C10의 사이클로알킬기인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.R 4 is a phenyl group, a naphthyl group, or a C 3 -C 10 cycloalkyl group that is substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group , a halogen atom, and a C 1 -C 6 haloalkoxy group. A heterobicyclic compound or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서, According to paragraph 1,
    X는 질소 원자 또는 CR5이고, Y 및 Z는 각각 독립적으로 CR5인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.X is a nitrogen atom or CR 5 , and Y and Z are each independently CR 5 A heterobicyclic compound or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서, According to paragraph 1,
    R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기 또는
    Figure PCTKR2023010500-appb-img-000112
    인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.     R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or
    Figure PCTKR2023010500-appb-img-000112
    A heterobicyclic compound or a pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서, According to paragraph 1,
    R6은 C1-C6의 알킬기이고, R7은 C1-C6의 알킬기 또는
    Figure PCTKR2023010500-appb-img-000113
    이거나,     R 6 is an alkyl group of C 1 -C 6 , and R 7 is an alkyl group of C 1 -C 6 or
    Figure PCTKR2023010500-appb-img-000113
    This is,
    R6과 R7은 서로 결합하여, C1-C6의 알킬기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 4 내지 7원의 헤테로 고리를 형성하는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.R 6 and R 7 are combined with each other to form a 4- to 7-membered heterocycle substituted or unsubstituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group, or a pharmaceutical compound thereof. salts permitted.
  9. 제1항에 있어서, According to paragraph 1,
    R6은 C1-C6의 알킬기이고, R7은 C1-C6의 알킬기 또는
    Figure PCTKR2023010500-appb-img-000114
    이거나,     R 6 is an alkyl group of C 1 -C 6 , and R 7 is an alkyl group of C 1 -C 6 or
    Figure PCTKR2023010500-appb-img-000114
    This is,
    R6과 R7은 서로 결합하여, C1-C6의 알킬기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 피롤리딘을 형성하는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.R 6 and R 7 are combined with each other to form a heterobicyclic compound that is substituted or unsubstituted with a C 1 -C 6 alkyl group or a C 1 -C 6 alkylamino group, or a pharmaceutically acceptable salt thereof. .
  10. 제1항에 있어서, According to paragraph 1,
    L2는 존재하지 않거나, C1-C6의 알킬렌기이며, L 2 is absent or is an alkylene group of C 1 -C 6 ,
    R8은 C1-C6의 알콕시기, C1-C6의 알킬기, 히드록시기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 아릴기인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.R 8 is a heterobicyclic compound or a pharmaceutically acceptable salt thereof, wherein R 8 is an aryl group substituted or unsubstituted by a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group. .
  11. 제1항에 있어서, According to paragraph 1,
    L2는 존재하지 않거나, C1-C6의 알킬렌기이며, L 2 is absent or is an alkylene group of C 1 -C 6 ,
    R8은 C1-C6의 알콕시기, C1-C6의 알킬기, 히드록시기 또는 C1-C6의 알킬아미노기로 치환되거나 치환되지 않은 페닐기인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.R 8 is a heterobicyclic compound wherein R 8 is a phenyl group substituted or unsubstituted by a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a hydroxy group, or a C 1 -C 6 alkylamino group, or a pharmaceutically acceptable salt thereof. .
  12. 제1항에 있어서, According to paragraph 1,
    n은 1인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.A heterobicyclic compound where n is 1 or a pharmaceutically acceptable salt thereof.
  13. 제1항에 있어서, According to paragraph 1,
    R1은
    Figure PCTKR2023010500-appb-img-000115
    또는
    Figure PCTKR2023010500-appb-img-000116
    이고,     R 1 is
    Figure PCTKR2023010500-appb-img-000115
    or
    Figure PCTKR2023010500-appb-img-000116
    ego,
    R2 및 R3는 각각 독립적으로 수소 원자 또는 C1-C6의 알킬기이며, R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group,
    R4는 C1-C6의 할로알킬기, 할로겐 원자 및 C1-C6의 할로알콕시기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 페닐기이고,R 4 is a phenyl group substituted or unsubstituted with one or more substituents selected from the group consisting of a C 1 -C 6 haloalkyl group, a halogen atom, and a C 1 -C 6 haloalkoxy group,
    X는 질소 원자 또는 CR5이며, Y 및 Z는 각각 독립적으로 CR5이고, X is a nitrogen atom or CR 5 , Y and Z are each independently CR 5 ,
    R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기 또는
    Figure PCTKR2023010500-appb-img-000117
    이며,     R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or
    Figure PCTKR2023010500-appb-img-000117
    and
    L1은 존재하지 않고, L 1 does not exist,
    R6 및 R7은 각각 독립적으로 C1-C6의 알킬기이며, R 6 and R 7 are each independently an alkyl group of C 1 -C 6 ,
    n은 1인 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염.A heterobicyclic compound where n is 1 or a pharmaceutically acceptable salt thereof.
  14. 제1항에 있어서, 하기 화학식 I-1로 표시되는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염:The heterobicyclic compound according to claim 1, represented by the following formula (I-1) or a pharmaceutically acceptable salt thereof:
    [화학식 I-1][Formula I-1]
    Figure PCTKR2023010500-appb-img-000118
    Figure PCTKR2023010500-appb-img-000118
    상기 식에서, In the above equation,
    R1은
    Figure PCTKR2023010500-appb-img-000119
    이고,     R 1 is
    Figure PCTKR2023010500-appb-img-000119
    ego,
    R2 및 R3는 각각 독립적으로 수소 원자 또는 C1-C6의 알킬기이며, R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 6 alkyl group,
    X는 질소 원자 또는 CR5이고, X is a nitrogen atom or CR 5 ,
    Y 및 Z는 각각 독립적으로 CR5이며, Y and Z are each independently CR 5 ,
    R5는 수소 원자, C1-C6의 알킬기, C1-C6의 알콕시기, 할로겐 원자, 니트로기 또는
    Figure PCTKR2023010500-appb-img-000120
    이고,     R 5 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a nitro group, or
    Figure PCTKR2023010500-appb-img-000120
    ego,
    L1은 존재하지 않으며, L 1 does not exist,
    R6 및 R7은 각각 독립적으로 C1-C6의 알킬기이고, R 6 and R 7 are each independently an alkyl group of C 1 -C 6 ,
    R9은 C1-C6의 할로알킬기, 할로겐 원자 또는 C1-C6의 할로알콕시기이며,R 9 is a C 1 -C 6 haloalkyl group, a halogen atom, or a C 1 -C 6 haloalkoxy group,
    R10은 수소 원자 또는 할로겐 원자이다.R 10 is a hydrogen atom or a halogen atom.
  15. 제1항에 있어서, 하기 화합물로부터 선택되는 것을 특징으로 하는 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염:The heterobicyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following compounds:
    1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 1); 1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 1);
    1-(3,3-디메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 2);1-(3,3-dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one ( Compound 2);
    1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로-1,6-나프티리딘-6(5H)-일)프로프-2-엔-1-온 (화합물 3);1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en-1-one (compound 3);
    1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로피리도[4,3-c]피리다진-6(5H)-일)프로프-2-엔-1-온 (화합물 4);1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrido[4,3-c]pyridazin-6(5H)-yl)prop-2-en-1 -one (compound 4);
    1-(3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 5);1-(3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 5 );
    1-(6-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 6);1-(6-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 6 );
    1-(6-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 7);1-(6-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 7);
    1-(5-플루오로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 8);1-(5-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 8);
    메틸 (R)-2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트 (화합물 9);Methyl (R)-2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Compound 9);
    메틸 (S)-2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-3-카복실레이트 (화합물 10);Methyl (S)-2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Compound 10);
    1-(6-니트로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 11);1-(6-nitro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 11 );
    1-(5-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 12);1-(5-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 12);
    1-(6-플루오로-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 13);1-(6-Fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 13);
    1-(5-(4-(트리플루오로메틸)페닐)이소인돌린-2-일)프로프-2-엔-1-온 (화합물 14);1-(5-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)prop-2-en-1-one (Compound 14);
    1-(2-(4-(트리플루오로메틸)페닐)-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-일)프로프-2-엔-1-온 (화합물 15);1-(2-(4-(trifluoromethyl)phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)prop-2-en-1 -one (compound 15);
    1-(4-(트리플루오로메틸)-2-(4-(트리플루오로메틸)페닐)-5,8-디히드로피리도[3,4-d]피리미딘-7(6H)-일)프로프-2-엔-1-온 (화합물 16);1-(4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl ) Prop-2-en-1-one (Compound 16);
    2-플루오로-1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 17);2-Fluoro-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 17);
    1-(3,3-디메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)-2-플루오로프로프-2-엔-1-온 (화합물 18);1-(3,3-dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-fluoroprop-2-en- 1-one (Compound 18);
    2-플루오로-1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로-1,6-나프티리딘-6(5H)-일)프로프-2-엔-1-온 (화합물 19);2-fluoro-1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en- 1-one (Compound 19);
    2-플루오로-1-(3-(4-(트리플루오로메틸)페닐)-7,8-디히드로피리도[4,3-c]피리다진-6(5H)-일)프로프-2-엔-1-온 (화합물 20);2-fluoro-1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrido[4,3-c]pyridazin-6(5H)-yl)prop- 2-en-1-one (Compound 20);
    2-플루오로-1-(3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 21);2-fluoro-1-(3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 -one (compound 21);
    2-플루오로-1-(6-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 22);2-fluoro-1-(6-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 -one (compound 22);
    2-플루오로-1-(6-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 23);2-fluoro-1-(6-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 23);
    2-플루오로-1-(5-메톡시-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 24);2-fluoro-1-(5-methoxy-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 24);
    (E)-4-(디메틸아미노)-1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)부트-2-엔-1-온 (화합물 25);(E)-4-(dimethylamino)-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-en- 1-one (Compound 25);
    1-(7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)부트-2-인-1-온 (화합물 26);1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-yn-1-one (Compound 26);
    2-(7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-2-카보닐)아크릴로니트릴 (화합물 27);2-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)acrylonitrile (Compound 27);
    1-(7-(시클로헥스-1-엔-1-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 28);1-(7-(Cyclohex-1-en-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 28);
    1-(7-페닐-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 29);1-(7-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 29);
    1-(7-(4-플루오로페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 30);1-(7-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 30);
    1-(7-(3,4-디플루오로페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 31);1-(7-(3,4-difluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 31);
    1-(7-(티오펜-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 32);1-(7-(thiophen-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 32);
    1-(7-(3-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 33);1-(7-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 33);
    1-(7-(6-(트리플루오로메틸)피리딘-3-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 34);1-(7-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 34 );
    1-(7-(4-(트리플루오로메톡시)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 35);1-(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 35);
    1-(7-(2-클로로-4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 36);1-(7-(2-Chloro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 36 );
    1-(7-(3-플루오로-4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 37);1-(7-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (compound 37);
    1-(7-(나프탈렌-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 38);1-(7-(Naphthalen-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 38);
    1-(7-(5-(트리플루오로메틸)피리딘-2-일)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 39);1-(7-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 39 );
    1-(7-(p-톨릴)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 40);1-(7-(p-tolyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 40);
    1-(7-시클로헥실-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 41);1-(7-Cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 41);
    2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,4-디히드로이소퀴놀린-3(2H)-온 (화합물 42);2-Acryloyl-7-(4-(trifluoromethyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one (Compound 42);
    2-아크릴로일-5-(4-(트리플루오로메틸)페닐)이소인돌린-1-온 (화합물 43);2-Acryloyl-5-(4-(trifluoromethyl)phenyl)isoindolin-1-one (Compound 43);
    1-(6-(메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 44);1-(6-(methylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 44);
    1-(6-(벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 45);1-(6-(benzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 45);
    1-(6-((피리딘-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 46);1-(6-((pyridin-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 46);
    1-(6-((피리딘-3-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 47);1-(6-((pyridin-3-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 47);
    1-(6-((피리딘-4-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 48);1-(6-((pyridin-4-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 48);
    1-(6-((4-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 49);1-(6-((4-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 49);
    1-(6-((티아졸-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 50);1-(6-((thiazol-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop -2-en-1-one (Compound 50);
    1-(6-(((1-메틸피페리딘-4-일)메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 51);1-(6-(((1-methylpiperidin-4-yl)methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H )-yl)prop-2-en-1-one (Compound 51);
    1-(6-(벤질(메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 52);1-(6-(benzyl(methyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 52);
    1-(6-(디벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 53);1-(6-(dibenzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1- On (Compound 53);
    1-(6-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 54);1-(6-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 54);
    1-(6-메톡시-3-메틸-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 55);1-(6-methoxy-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1 -one (compound 55);
    1-(6-(페닐아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 56);1-(6-(phenylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 56);
    1-(5-(벤질아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 57);1-(5-(benzylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 57);
    1-(5-((피리딘-2-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 58);1-(5-((pyridin-2-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 58);
    1-(5-((피리딘-4-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 59);1-(5-((pyridin-4-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 59);
    1-(5-((피리미딘-5-일메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 60);1-(5-((pyrimidin-5-ylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop -2-en-1-one (Compound 60);
    1-(5-((4-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 61);1-(5-((4-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 61);
    1-(5-((3-메톡시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 62);1-(5-((3-methoxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 62);
    1-(5-((3-히드록시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 63);1-(5-((3-hydroxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 63);
    1-(5-((4-히드록시벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 64);1-(5-((4-hydroxybenzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2 -en-1-one (Compound 64);
    1-(5-((4-(디메틸아미노)벤질)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 65);1-(5-((4-(dimethylamino)benzyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop -2-en-1-one (Compound 65);
    1-(5-((시클로헥실메틸)아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 66);1-(5-((cyclohexylmethyl)amino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-ene -1-one (Compound 66);
    N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)벤자미드 (화합물 67);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide (Compound 67);
    N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)아세트아미드 (화합물 68);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide (Compound 68);
    N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-5-일)프로피온아미드 (화합물 69);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)propionamide (Compound 69);
    1-(6-((페닐아미노)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 70);1-(6-((phenylamino)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en- 1-one (Compound 70);
    1-(6-((4-메틸피페라진-1-일)메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 71);1-(6-((4-methylpiperazin-1-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Prop-2-en-1-one (Compound 71);
    1-(5-(디메틸아미노)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 72);1-(5-(dimethylamino)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 72);
    N-(2-아크릴로일-7-(4-(트리플루오로메틸)페닐)-1,2,3,4-테트라히드로이소퀴놀린-6-일)벤자미드 (화합물 73);N-(2-acryloyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)benzamide (Compound 73);
    1-(6-(벤질옥시)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 74);1-(6-(benzyloxy)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (Compound 74);
    (S)-1-(3-(히드록시메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 75);(S)-1-(3-(hydroxymethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- En-1-one (Compound 75);
    (R)-1-(3-(히드록시메틸)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 76);(R)-1-(3-(hydroxymethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- En-1-one (Compound 76);
    1-(5-(4-메틸피페라진-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 77);1-(5-(4-methylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop- 2-en-1-one (Compound 77);
    1-(5-(피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 78); 및1-(5-(pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2- En-1-one (Compound 78); and
    1-(5-(3-(디메틸아미노)피롤리딘-1-일)-7-(4-(트리플루오로메틸)페닐)-3,4-디히드로이소퀴놀린-2(1H)-일)프로프-2-엔-1-온 (화합물 79).1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Prop-2-en-1-one (Compound 79).
  16. 제1항 내지 제15항 중 어느 한 항에 따른 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염, 및 약제학적으로 허용되는 담체를 포함하는 YAP 또는 TAZ와 TEAD의 결합 저해용 약제학적 조성물.A pharmaceutical composition for inhibiting the binding of YAP or TAZ to TEAD, comprising the heterobicyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, and a pharmaceutically acceptable carrier.
  17. 제16항에 있어서, 암의 치료 또는 예방용인 약제학적 조성물.The pharmaceutical composition according to claim 16, which is used for the treatment or prevention of cancer.
  18. 유효량의 제1항 내지 제15항 중 어느 한 항에 따른 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염을 이를 필요로 하는 개체에 투여하는 것을 포함하는 암의 치료 또는 예방 방법.A method for treating or preventing cancer, comprising administering an effective amount of the heterobicyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 to an individual in need thereof.
  19. 암을 치료 또는 예방하기 위한, 제1항 내지 제15항 중 어느 한 항에 따른 헤테로비시클릭 화합물 또는 그의 약제학적으로 허용되는 염의 용도.Use of a heterobicyclic compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer.
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WO2022072741A1 (en) * 2020-09-30 2022-04-07 Katholieke Universiteit Leuven 1,2,3,4-tetrahydroquinoline derivatives as inhibitors of the yap/taz-tead activation for treating cancer

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