WO2024019562A1 - Composé hétérobicyclique et composition pharmaceutique le comprenant - Google Patents

Composé hétérobicyclique et composition pharmaceutique le comprenant 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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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/fr

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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

La présente invention concerne un composé hétérobicyclique ayant une activité inhibitrice contre l'activation transcriptionnelle de TEAD par inhibition de la liaison de YAP ou de TAZ à TEAD, et une composition pharmaceutique le comprenant en tant que principe actif. Le composé hétérobicyclique selon la présente invention peut être utilisé de manière avantageuse dans le traitement ou la prévention du cancer.
PCT/KR2023/010500 2022-07-21 2023-07-20 Composé hétérobicyclique et composition pharmaceutique le comprenant WO2024019562A1 (fr)

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WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2021186324A1 (fr) * 2020-03-16 2021-09-23 Novartis Ag Dérivés biaryle en tant qu'inhibiteurs d'interaction protéine-protéine yap/taz-tead
WO2022072741A1 (fr) * 2020-09-30 2022-04-07 Katholieke Universiteit Leuven Dérivés de 1,2,3,4-tétrahydroquinoline servant d'inhibiteurs de l'activation de yap/taz-tead pour le traitement du cancer

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WO2017190109A1 (fr) * 2016-04-29 2017-11-02 Board Of Regents, The University Of Texas System Liants du récepteur sigma
WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2021186324A1 (fr) * 2020-03-16 2021-09-23 Novartis Ag Dérivés biaryle en tant qu'inhibiteurs d'interaction protéine-protéine yap/taz-tead
WO2022072741A1 (fr) * 2020-09-30 2022-04-07 Katholieke Universiteit Leuven Dérivés de 1,2,3,4-tétrahydroquinoline servant d'inhibiteurs de l'activation de yap/taz-tead pour le traitement du cancer

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