CN116535379B - Compound and medical application thereof - Google Patents
Compound and medical application thereof Download PDFInfo
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- CN116535379B CN116535379B CN202310783142.9A CN202310783142A CN116535379B CN 116535379 B CN116535379 B CN 116535379B CN 202310783142 A CN202310783142 A CN 202310783142A CN 116535379 B CN116535379 B CN 116535379B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
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- 239000001257 hydrogen Substances 0.000 claims description 49
- 239000011737 fluorine Substances 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 5
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- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
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- 208000035475 disorder Diseases 0.000 claims description 3
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides a compound and medical application thereof, wherein the compound is shown in a formula I. Pharmaceutically acceptable salts of the compounds are also provided. Pharmaceutical compositions relating to the compounds of the application and uses of the compounds and pharmaceutical compositions of the application are also provided.I is a kind of
Description
Technical Field
The application belongs to the field of medicines, and particularly relates to a compound and application thereof in the field of medicines.
Background
The Hippo pathway has become a useful target for the treatment of hyperproliferative disorders and diseases, particularly Cancer (s.a. smith et al, j.med. Chem. 2019, 62, 1291-1305;K.C.Lin et al, annu. Rev. Cancer biol. 2018, 2:59-79; c. -l.kim et al, cells (2019), 8, 468;K.F.Harvey et al, nature Reviews Cancer, vol.13, 246-257 (2013)). The Hippo signaling pathway regulates a number of biological processes including cell proliferation, survival, differentiation, organ size, and tissue homeostasis. The pathway consists of a complex cascade of serine/threonine protein kinases including serine threonine kinase 3 (STK 3) and STK4. The complex of these kinases with the adaptor protein salvador homolog 1 (SAV 1) phosphorylates and activates effector proteins, LATS1/2.LATS1/2, upon activation, binds to MOB kinase activator 1A/B (MOB 1A/B) and inhibits the transcription cofactor yes-associated protein (YAP 1) and the transcription coactivator with a PDZ binding motif (TAZ or WWTR 1). When the Hippo pathway is "closed," phosphorylated YAP/TAZ is retained in the cytoplasm and protein degradation may occur. When the Hippo pathway is "on", the non-phosphorylated YAP/TAZ enters the nucleus and binds to the transcription factor TEA DNA binding protein (TEAD 1-4). Deregulation of the Hippo pathway results in increased activity of YAP/TAZ and is thus associated with tumour, hyperproliferative, cellular invasion, metastasis and chemoresistance.
The TEAD transcription factor family is the ultimate effector of the Hippo pathway, which regulates the expression of target genes (Kras, braf, ctgf, cyr6, axl, myc, etc.) through integration of a variety of signal transduction pathways (including Hippo, wnt, tgfβ, and EGFR), thereby mediating tumor growth, metastasis, tissue homeostasis. Numerous clinical studies have found that TEAD is expressed at high levels in a variety of solid tumors, including prostate cancer, gastric cancer, breast cancer, germ cell tumors, head and neck squamous cell carcinoma, renal cell carcinoma, and the like. Since it is highly correlated with clinical pathological parameters of human malignancy, TEAD can be used as a prognostic biomarker for solid tumors. The Hippo pathway serves as an important anti-tumor target discovered in the last decade, and inhibitors targeting TEAD-YAP may be more effective and directly correcting deregulated Hippo signaling pathways than modulators upstream of the Hippo signaling pathway, thereby achieving tumor treatment goals.
Thus, cancers and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction may be prevented and/or treated by targeting YAP, TAZ, or TEAD, thereby inhibiting protein-protein interactions of YAP-TEAD, TAZ-TEAD, or other functional proteins with TEAD.
Disclosure of Invention
A first aspect of the present application relates to a compound, or a pharmaceutically acceptable salt thereof, represented by formula I:
the compound of the formula I,
R 1 、R 2 、R 3 each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, cyano, nitro, substituted or unsubstituted C2-C10 heterocyclyl, substituted or unsubstituted C1-C10 heteroaryl,And->Wherein X is selected from the group consisting of single bond, -O-, C6-C12 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituted or unsubstituted C3-C6 heteroarylene, substituted or unsubstituted C2-C10 heterocyclylene; r is R 18 And R is 19 Each independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl;
R 4 to R 17 Each independently selected from hydrogen or halogen;
wherein the substituents are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, nitro.
In some embodiments, the compound is represented by formula I-1:
the compound of the formula I-1,
wherein R is 1 、R 2 And R is 3 Is as defined for formula I.
In some embodiments, R 1 Selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, cyano, nitro, substituted or unsubstituted C1-C10 heteroaryl;
R 2 and R is 3 One of which is hydrogen and the other is selected from halogen, C1-C6 alkyl with or without substituent, C1-C6 alkoxy with or without substituent, cyano, nitro, C2-C10 heterocyclic group with or without substituent, and,、/>A group of; wherein X is selected from the group consisting of single bond, -O-, C6-C12 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituted or unsubstituted C3-C6 heteroarylene, substituted or unsubstituted C2-C10 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl with or without substituents, C2-C6 alkenyl with or without substituents,
wherein the substituents are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, nitro.
In some embodiments, R 2 Is hydrogen, R 3 Selected from halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, cyano, nitro, substituted or unsubstituted C2-C10 heterocyclyl,、/>A group of; wherein X is selected from the group consisting of single bond, -O-, C6-C12 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituted or unsubstituted C3-C6 heteroarylene, substituted or unsubstituted C2-C10 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl with or without substituents, C2-C6 alkenyl with or without substituents.
In some embodiments, the substituents are selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, fluoro-n-butyl, fluoroisobutyl, fluorotert-butyl, fluoro-n-pentyl, fluoroisopentyl, fluoro-n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy, fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, fluoro-n-butoxy, fluoroisobutoxy, fluorotert-butoxy, fluoro-n-pentoxy, fluoroisopentoxy, fluoro-hexoxy, cyano, nitro.
In some embodiments, R 1 Selected from the group consisting of hydrogen, halogen, C1-C4 alkyl with or without substituents, C1-C6 heteroaryl with or without substituents, wherein the substituents are selected from the group consisting of fluorine, cyano, nitro, C1-C4 alkyl, C1-C6 alkoxy.
In some embodiments, R 1 Selected from hydrogen, bromine, fluorine, substituted or unsubstituted pyrazoles, substituted or unsubstituted tetrazolesWherein the substituents are selected from the group consisting of C1-C4 alkyl.
In some embodiments, R 1 Selected from the group consisting of hydrogen, halogen, C1-C4 alkyl without substituents, C1-C6 heteroaryl with one or two substituents, wherein the substituents are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, R 1 Selected from hydrogen, fluorine, chlorine, bromine, pyrazole without substituents, pyrazole with one or two substituents, tetrazole without substituents, tetrazole with one substituent, pyrazole without substituentsWherein the substituents are selected from the group consisting of methyl, ethyl, n-propyl or isopropyl.
In some embodiments, R 1 Selected from the group consisting of hydrogen, bromine, fluorine or the following groups:
。
in some embodiments, R 2 And R is 3 One of which is hydrogen and the other is selected from substituent-containing or substituent-free C1-C4 alkyl, substituent-containing or substituent-free C2-C5 heterocyclic group,、A group of; wherein X is selected from the group consisting of single bond, -O-, C6-C10 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituent-containing or substituent-free C2-C5 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, wherein the substituents are selected from the group consisting of fluoro, cyano, nitro, C1-C4 alkyl, C1-C6 alkoxyIs a group of (a).
In some embodiments, R 2 Is hydrogen, R 3 Selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C5 heterocyclyl,、A group of; wherein X is selected from the group consisting of single bond, -O-, C6-C10 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituent-containing or substituent-free C2-C5 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkyl with or without substituents, C2-C4 alkenyl with or without substituents, wherein the substituents are selected from the group consisting of fluoro, cyano, nitro, C1-C4 alkyl, C1-C6 alkoxy.
In some embodiments, R 2 And R is 3 One of which is hydrogen and the other is selected from the group consisting of C1-C4 alkyl without substituent, C2-C5 heterocyclic with one or two substituents, wherein the substituent is selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
In some embodiments, R 2 Is hydrogen, R 3 Selected from the group consisting of C1-C4 alkyl groups without substituents, C2-C5 heterocyclic groups without substituents, and C2-C5 heterocyclic groups with one or two substituents, wherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
In some embodiments, R 2 And R is 3 One of which is hydrogen and the other is selected from the group consisting of non-substituted radicalsContaining one substituent->Wherein the substituents are selected fromFrom the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, R 2 Is hydrogen, R 3 Selected from the group consisting of non-substituted radicalsContaining one substituentWherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, R 2 And R is 3 One of which is hydrogen and the other is selected fromOr->Wherein X is selected from the group consisting of single bond, -O-, C6-C8 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituent-containing or substituent-free C2-C5 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl with or without substituents, and C2-C4 alkenyl with or without substituents, wherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
In some embodiments, R 2 Is hydrogen, R 3 Selected from the group consisting ofOr (b)Wherein X is selected from the group consisting of single bond, -O-, C6-C8 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituent-containing or substituent-free C2-C5 heterocyclylene, R 18 And R is 19 Each independently of the otherSelected from the group consisting of hydrogen, halogen, C1-C4 alkyl with or without substituents, and C2-C4 alkenyl with or without substituents, wherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
In some embodiments, R 2 And R is 3 One of which is hydrogen and the other is selected fromOr->Wherein X is selected from the group consisting of single bond, -O-, phenylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, azetidine without substituents, azetidine with one or two substituents, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl free of substituents, C2-C4 alkenyl containing one or two substituents, wherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, R 2 Is hydrogen, R 3 Selected from the group consisting ofOr (b)Wherein X is selected from the group consisting of single bond, -O-, phenylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, azetidine without substituents, azetidine with one or two substituents, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl free of substituents, C2-C4 alkenyl containing one or two substituents, wherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, R 2 And R is 3 One of which is hydrogen and the other of which is selected from the group consisting of:
,
wherein X is selected from-O-or phenylene, R 18 And R is 19 Each independently selected from the group consisting of hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, wherein the substituents are selected from the group consisting of C1-C4 alkyl and fluoro.
In some embodiments, R 2 Is hydrogen, R 3 Selected from the group consisting of:
,
wherein X is selected from-O-or phenylene, R 18 And R is 19 Each independently selected from the group consisting of hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, wherein the substituents are selected from the group consisting of C1-C4 alkyl and fluoro.
In some embodiments, R 18 And R is 19 Each independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, fluoro-n-butyl, fluoroisobutyl, fluoro-t-butyl, fluorovinyl, fluoro-n-propenyl, fluoroisopropenyl, fluoro-n-butenyl, fluoroisobutenyl.
In some embodiments, R 2 And R is 3 One of which is hydrogen and the other of which is selected from the group consisting of:
。
in some embodiments, R 2 Is hydrogen, R 3 Selected from the group consisting of:
。
in some embodiments, the compound is represented by formula I-2:
the compound of the formula I-2,
in the formula I-2, R 1 Selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C6 heteroaryl, preferably R 1 Selected from hydrogen, halogen, C1-C4 alkyl without substituents, C1-C6 heteroaryl with one or two substituents, more preferably R 1 Selected from hydrogen, fluorine, chlorine, bromine, pyrazole without substituents, pyrazole with one or two substituents, tetrazole without substituents, tetrazole with one substituent, pyrazole without substituentsWherein the substituents are selected from the group consisting of fluorine, cyano, nitro, C1-C4 alkyl;
R 3 a heterocyclic group selected from the group consisting of C2-C10 containing a substituent or not containing a substituent,、A group of; wherein X is selected from the group consisting of single bond, -O-, C6-C12 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituted or unsubstituted C3-C6 heteroarylene, substituted or unsubstituted C2-C10 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, wherein the substituents are selected from the group consisting of fluoroCyano, nitro, C1-C4 alkyl, C1-C6 alkoxy.
In some embodiments, in formula I-2, R 3 Selected from the group consisting of C1-C4 alkyl groups with or without substituents, C2-C5 heterocyclic groups with or without substituents, preferably from the group consisting of non-substituted groupsContaining one substituentWherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, in formula I-2, R 3 Selected from the group consisting ofOr (b)Wherein X is selected from the group consisting of single bond, -O-, C6-C8 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituent-containing or substituent-free C2-C5 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl with or without substituents, C2-C4 alkenyl with or without substituents, preferably X is selected from the group consisting of single bonds, -O-, phenylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, azetidine without substituents, azetidine with one or two substituents, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl free of substituents, C2-C4 alkenyl containing one or two substituents, wherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, in formula I-2, R 3 Selected from the group consisting of:
,
wherein X is selected from-O-or phenylene, R 18 And R is 19 Each independently selected from the group consisting of hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, preferably R 18 And R is 19 Each independently selected from the group consisting of hydroxy, C1-C4 alkyl without substituents, C2-C4 alkenyl with one or two substituents, wherein the substituents are selected from C1-C4 alkyl or fluoro.
In some embodiments, in formula I-2, R 1 Selected from the group consisting of hydrogen, bromine, fluorine or the following groups:
;
R 3 selected from the group consisting of:
。
in some embodiments, the compound is represented by formula I-3:
the compound of the formula I-3,
wherein R is 2 Selected from the group consisting of、/>A group of; wherein X is selected from the group consisting of single bond, -O-, C6-C12 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituted or unsubstituted C3-C6 heteroarylene, substituted or unsubstituted C2-C10 heterocyclylene, R 18 And R is 19 Each independently selected from hydrogen, halogen, and hydroxyA group, a C1-C6 alkyl group with or without substituents, a C2-C6 alkenyl group with or without substituents, wherein the substituents are selected from the group consisting of fluorine, cyano, nitro, C1-C4 alkyl, C1-C6 alkoxy.
In some embodiments, in formula I-3, R 2 Selected from the group consisting ofOr (b)Wherein X is selected from the group consisting of single bond, -O-, C6-C8 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituent-containing or substituent-free C2-C5 heterocyclylene, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl with or without substituents, C2-C4 alkenyl with or without substituents, preferably X is selected from the group consisting of single bonds, -O-, phenylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, azetidine without substituents, azetidine with one or two substituents, R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl free of substituents, C2-C4 alkenyl containing one or two substituents, wherein the substituents are selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, in formula I-3, R 2 Selected from the group consisting of:
,
wherein X is selected from-O-or phenylene, R 18 And R is 19 Each independently selected from the group consisting of hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, preferably R 18 And R is 19 Each independently selected from the group consisting of hydroxy, C1-C4 alkyl containing no substituents,C2-C4 alkenyl without substituents, C2-C4 alkenyl with one or two substituents, wherein the substituents are selected from C1-C4 alkyl or fluorine.
In some embodiments, in formula I-3, R 2 Selected from the group consisting of:
。
in a second aspect the present application provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
In a third aspect the application provides the use of a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above as a TEAD inhibitor.
In a fourth aspect, the application provides the use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with the modulation of TEAD.
In particular, the disease or condition associated with the modulation of TEAD is selected from the following: brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, stomach cancer, breast cancer or prostate cancer.
The compound can inhibit YAP, TAZ or TEAD by targeting, so that YAP-TEAD, TAZ-TEAD or other functional proteins can be inhibited from interacting with TEAD proteins to prevent and/or treat cancers and other hyperproliferative diseases and diseases related to Hippo pathway dysfunction, and has good clinical application prospects.
Drawings
FIG. 1 shows the inhibition of YAP/TAZ downstream target genes by Compound 4 of the present application.
Detailed Description
The application is illustrated in detail below with reference to examples: this example, while being carried out on the premise of the technical proposal of the present application, gives detailed embodiments and procedures, but the embodiments provided by the present application are exemplary and intended to explain the present application and should not be construed as limiting the present application. Conditions, methods, etc., not specified in the examples below were carried out conventionally.
The present inventors have conducted extensive and intensive studies and have unexpectedly found a class of compounds having a superior TEAD inhibitory activity. In addition, the compounds have better pharmacodynamic/pharmacokinetic properties. On this basis, the present application has been completed.
The compound is shown as a formula I:
the compound of the formula I,
wherein,,
R 1 、R 2 、R 3 each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, cyano, nitro, substituted or unsubstituted C2-C10 aromatic or non-aromatic heterocyclic group,And->Wherein X is selected from the group consisting of single bond, -O-, C6-C12 arylene, X 1 To X 4 Each independently selected from the group consisting of single bond, -NH-, substituted or unsubstituted C3-C6 heteroarylene, substituted or unsubstituted C2-C10 heterocyclylene; r is R 18 And R is 19 Each independently selected from the group consisting of hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl;
R 4 to R 17 Each independently selected from hydrogen or halogen;
wherein the substituents are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, nitro.
In some embodiments, the compound is represented by formula I-1:
formula I-1
Wherein R is 1 、R 2 And R is 3 Is as defined for formula I.
In particular, the compound may be selected from the group consisting of:
,/>
,
。
In the present application, the term "alkyl" refers to an aliphatic hydrocarbon group, which may be branched or straight chain alkyl. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., alkylene). In the present application, the alkyl group is a "lower alkyl group" having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like. It is to be understood that references herein to "alkyl" include such alkyl groups in all configurations and conformations that may be present, e.g., references herein to "propyl" include n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and references herein to "pentyl" include n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl, and the like.
In the present application, the term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
In the present application, the term "aryl" means that each of the atoms constituting the ring in the aromatic ring is a carbon atom. The aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. "aryl" includes "conjugated" or polycyclic ring systems having at least one aromatic ring and no heteroatoms in the ring structure. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, and indenyl. Depending on the structure, the aryl group may be a monovalent group or a divalent group (i.e., arylene).
In the present application, "heteroaryl" refers to an aryl group as defined above, except that it has 1-4 heteroatoms in the ring structure, which may also be referred to as an "aromatic heterocycle" or "heteroaromatic compound". As used herein, the term "heteroaryl" is meant to include stable 5, 6 or 7 membered monocyclic or 7, 8, 9, 10, 11 or 12 membered bicyclic aromatic heterocycles consisting of carbon atoms and one or more heteroatoms, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or such as 1, 2, 3, 4, 5 or 6 heteroatoms, independently selected from nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is hydrogen or other substituents as defined herein). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., n→o and S (O) p, where p=1 or 2). It should be noted, however, that the total number of sulfur and oxygen atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include, but are not limited to, pyrazole, tetrazole,Etc. According to structure, heteroaryl groups may be monovalent or divalent (i.e., heteroarylene).
The term "heterocyclyl" refers to a saturated or unsaturated, non-aromatic, 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic (fused, bridged or spiro) ring system having one or more heteroatoms, such as oxygen, nitrogen, sulfur or selenium atoms. The heterocyclyl ring may be optionally substituted. Examples of heterocyclyl groups include, but are not limited to, azetidine, Etc. Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group (i.e., a heterocyclylene group).
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
In the present application, a heterocyclyl, aryl or heteroaryl group may be substituted at one or more ring positions (e.g., a ring-forming carbon atom or heteroatom, such as nitrogen atom) with substituents as described above.
By "pharmaceutically acceptable salt" is meant a salt of a compound that is reacted with a pharmaceutically acceptable (relatively non-toxic, safe, suitable for patient use) acid or base. When the compound contains a relatively acidic functional group, the base addition salt may be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, ammonium salts, and the like. When the compound contains a relatively basic functional group, the acid addition salt may be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, acetate, trifluoroacetate, sulfate, mesylate, and the like. See in particular Handbook of PharmaceuticalSalts Properties, selection, and Use (P. Heinrich Stahl, 2002).
Dosage forms of the pharmaceutical composition of the present application include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, external liniment, controlled release or sustained release preparation, or nanometer preparation.
The pharmaceutical compositions of the present application comprise a safe and effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound/agent of the application, more preferably 10-1000mg of the compound/agent of the application. Preferably, the "one dose" is a capsule or tablet.
In the present application, "pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present application without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate and the like), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil and the like), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol and the like), emulsifiers (e.g. tween), wetting agents (e.g. sodium lauryl sulphate), colorants, flavourings, stabilizers, antioxidants, preservatives, pyrogen-free water and the like.
I. Preparation of the Compounds
Example 1 method for the synthesis of compound 1:
。
step 1:1-2 Synthesis
To a solution of compound 1-1 (5000 mg, 22.83 mmol) in concentrated sulfuric acid (30 mL) was slowly added dropwise concentrated nitric acid (3 mL) under ice-water bath, slowly warmed to room temperature and stirred at room temperature for 2 hours. After the reaction is completed, cooling to 0 ℃, slowly dropwise adding the mixture into ice water, precipitating solids, cooling to room temperature, filtering, washing a filter cake with water, and drying to obtain the compound 1-2.
Step 2:1-3 synthesis
Borane tetrahydrofuran complex (11.36 mL, 11.36 mmol) was slowly added dropwise to a solution of compounds 1-2 (2000 mg, 7.58 mmol) in tetrahydrofuran (20 mL) under an ice-water bath under nitrogen, slowly warmed to room temperature and stirred overnight at room temperature. After the reaction was completed, methanol (20 mL) was slowly added dropwise after cooling to 0 ℃, stirred for 1 hour at 50 ℃, cooled to room temperature, quenched with water (20 mL) and extracted with EA (20 mL). The organic phase was washed with water (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 65/35) to give compound 1-3.
Step 3:1-4 synthesis
To a solution of compounds 1-3 (1700 mg, 6.80 mmol) in tetrahydrofuran (20 mL) under an ice-water bath under nitrogen protection was slowly added dropwise boron tribromide (1278.16 μl, 13.60 mmol), slowly warmed to room temperature and stirred at room temperature for 2 hours. After the reaction was completed, after cooling to 0 ℃, saturated sodium bicarbonate solution was slowly added dropwise to adjust the pH to about 7, diluted with water (10 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 80/20) to give compound 1-4.
Step 4:1-5 Synthesis
To a solution of ethyl-4, 4-difluorocyclohexane carboxylate (1186.72 mg, 6.17 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise a solution of LDA in tetrahydrofuran (3858.81 μl, 7.72 mmol) at-78 ℃ under nitrogen, reacted at this temperature for 0.5 hours, a solution of compound 1-4 (1610 mg, 5.15 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred overnight at room temperature. After completion of the reaction, the reaction was quenched by slowly dropping saturated ammonium chloride solution, diluted with water (10 mL), and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 85/15) to give compound 1-5.
Step 5:1-6 synthesis
To a solution of compounds 1 to 5 (1785 mg, 4.21 mmol) in tetrahydrofuran (20 mL) under an ice-water bath under nitrogen gas was slowly added dropwise a solution of diisobutylaluminum hydride in tetrahydrofuran (10.52 mL, 10.52 mmol), and after the addition was stirred at 0℃for 3 hours. After completion of the reaction, a saturated potassium sodium tartrate solution (20 mL) was slowly added dropwise after 0 ℃ and stirred at room temperature for 1 hour, diluted with water (10 mL) and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 80/20) to give compound 1-6.
Step 6:1-7 synthesis
To a solution of compounds 1-6 (1570 mg, 4.11 mmol) in tetrahydrofuran (15 mL) under nitrogen was added potassium tert-butoxide (1382.88 mg, 12.32 mmol) and the mixture was stirred at 60 ℃ for 2 hours. After completion of the reaction, water (10 mL) was added for dilution and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 90/10) to give compounds 1-7.
Step 7:1-8 synthesis
To a mixed solution of compounds 1-7 (780 mg, 2.15 mmol) in methanol (9 mL) and water (3 mL) under nitrogen atmosphere were added iron powder (962 mg, 17.23 mmol) and ammonium chloride (962 mg, 17.23 mmol), and the mixture was stirred at 65 ℃ for 1 hour. After completion of the reaction, the mixture was filtered while it was still hot, and the filtrate was diluted with water (10 mL) and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 40/60) to give compound 1-8.
Step 8: synthesis of Compound 1
To a solution of compounds 1-8 (200 mg, 0.60 mmol) and triethylamine (166.91 μl, 1.20 mmol) in dichloromethane (5 mL) under nitrogen protection was slowly added p-toluenesulfonyl chloride (116.49 μl, 1.51 mmol) and the mixture stirred at 0deg.C for 1 hr. After completion of the reaction, the mixture was diluted with DCM (10 mL), washed with saturated brine (10 mL ×2), and the organic phase was dried and concentrated. The resulting residue was dissolved in tetrahydrofuran (5 mL), sodium hydroxide solution (6N, 0.5 mL) was slowly added at 0 ℃ and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water (10 mL) was added for dilution and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL X2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 70/30) to give compound 1 (154 mg, 0.38 mmol, yield: 73.32%). MS (ESI): m/z=410.0 [ m+h ] ] + 。
1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.51 (s, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 4.00 (s, 2H), 2.94 (s, 3H), 2.73 (s, 2H), 2.05 - 1.88 (m, 4H), 1.48 (q, J = 5.8 Hz, 4H)。
Example 2 method of synthesis of compound 2:
。
step 1:2-1 Synthesis
Cuprous chloride (59.60 mg, 0.60 mmol) was added to a solution of thionyl chloride (436.72 μl, 6.02 mmol) in water (3 mL) under ice-water bath, and the mixture was reacted at 0deg.C for 0.5 hr, designated as reaction solution 1; in a further round bottom flask was added compound 1-8 (200 mg, 0.60 mmol) and dissolved with concentrated hydrochloric acid (1.5 mL), cooled to-5 ℃ and slowly added dropwise a solution of sodium nitrite (80.50 μl, 1.51 mmol) in water (0.8 mL). The mixture was stirred at this temperature for 0.5 hours and designated as reaction solution 2. Reaction 2 was slowly added dropwise to reaction 1, and the mixture was slowly warmed to room temperature and stirred for 1 hour. After completion of the reaction, the mixture was diluted with EA ethyl acetate (10 mL), washed with saturated brine (10 mL ×2), and the organic phase was dried and concentrated. The resulting residue was dissolved in tetrahydrofuran (5 mL) and added slowly to methylamine hydrochloride (405.12 mg, 6.00 mmol) and sodium bicarbonate NaHCO at 0 ℃ 3 (1010.54 mg, 12.03 mmol) in a mixture of tetrahydrofuran (4 mL) and water (6 mL), the mixture was stirred at room temperature overnight. After completion of the reaction, water (10 mL) was added for dilution and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 60/40) to give compound 2-1.
Step 2: synthesis of Compound 2
To a mixed solution of 1, 4-dioxane (1 mL) and water (0.2 mL) of compound 2-1 (10 mg, 0.02 mmol) under nitrogen was added 1-methylpyrazole-4-boronic acid pinacol ester (15.21 mg, 0.07 mmol), pd (dppf) Cl 2 (3.57 mg, 0.005 mmol) and sodium carbonate(5.17 mg, 0.05 mmol). The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, water was added, diluted with water (10 mL) and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 25/75) to give compound 2 (3.85 mg, 0.01 mmol, yield: 46.78%). MS (ESI): m/z=412.2 [ m+h ]] + 。
1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.16 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.23 (br d, J = 5.0 Hz, 1H), 4.14 (s, 2H), 3.88 (s, 3H), 2.82 (s, 2H), 2.43 - 2.38 (m, 3H), 2.03 - 1.93 (m, 4H), 1.57 - 1.47 (m, 4H)。
Example 3 method for synthesis of compound 3:
。
to a mixed solution of 1, 4-dioxane (3 mL) and water (0.6 mL) of compound 1 (66 mg, 0.16 mmol) under nitrogen was added 1-methylpyrazole-4-boronic acid pinacol ester (100.42 mg, 0.48 mmol), pd (dppf) Cl 2 (23.54 mg, 0.03 mmol) and sodium carbonate (34.10 mg, 0.32 mmol). The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, water was added, diluted with water (10 mL) and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 70/30) to give compound 3 (55 mg, 0.13 mmol, yield: 83.09%). MS (ESI): m/z=412.2 [ m+h ] ] + 。
1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.29 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 4.00 (s, 2H), 3.86 (s, 3H), 2.93 (s, 3H), 2.76 - 2.68 (s, 2H), 1.99 (m, 4H), 1.58 - 1.44 (m, 4H)。
Example 4 method for synthesis of compound 4:
。
DIEA (44.89. Mu.L, 0.27 mmol) and acryloyl chloride (8.76. Mu.L, 0.11 mmol) were added to a solution of compounds 1-8 (30 mg, 0.09 mmol) in DCM (5 mL) under an ice-water bath. The reaction mixture was stirred at 25 ℃ for 2 hours, cooled to 0 ℃ and quenched with water and extracted with DCM (20 mL). The organic phase was washed with saturated brine (10 mL ×2), dried, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate ratio 100/0 to 50/50) to give compound 4 (20 mg, 0.05 mmol, yield: 57.34%). MS (ESI): m/z=386.1 [ m+h] + 。
1 H NMR (DMSO-d 6 ) δ: 10.06 (br s, 1H), 7.80 (br s, 1H), 7.46 - 7.19 (m, 1H), 6.44 - 6.17 (m, 2H), 5.88 - 5.61 (m, 1H), 4.01 (br s, 2H), 2.72 (br s, 2H), 2.06 - 1.82 (m, 4H), 1.49 (br s, 4H)。
II, activity test: test example 1 TEAD reporter Gene experiment-MCF 7
And (3) cells: hippo Pathway/TEAD Luciferase Reporter MCF7 cells (BPS Bioscience, 60618).
The steps are as follows:
1. prior to the experiment, growth medium (BPS Bioscience, 79531) was preheated in a 37 ℃ water bath.
2. MCF7 cells (BPS Bioscience, 60618) were removed from the 37 ℃ incubator and washed once with PBS.
3. 2 mL trypsin was added to a T75 cell flask and CO at 37 ℃C 2 Digestion was performed in an incubator for 3 minutes.
4. Digestion was stopped by adding 4.5. 4.5 mL medium, cells were collected in 50 mL centrifuge tubes, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and cells were resuspended in 10 mL fresh medium.
5. mu.L of the cell suspension was mixed with 30. Mu.L of trypan blue and counted with a cell counter.
6. Cell density was adjusted to 2.5X10 5 Per mL, 40. Mu.L of cells per wellInoculated into white transparent bottom 384 microwell plates (Corning, 3765).
7. The cells were incubated at 37℃with CO 2 Incubate overnight in incubator.
8. Ehco650 was used to add 40 nL compound in DMSO to 384 microwell plates. The final concentration of DMSO in the assay medium was 0.1%.
9. At 37 ℃, CO 2 Cells were cultured in the incubator for 24 hours.
10. mu.L of ONE-Step ™ Luciferase Assay System (BPS, 60690) reagent was added to each well and the wells were allowed to stand at room temperature for 5 minutes. Luminescence values were measured using EnVision Xcite Multilabel Reader (PerkinElmer, 2105-0020).
11. And (3) data processing:
%Inhibition={(Signalcompound-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)}×100%
IC50 (nM) calculation: the calculation was performed using the cut fit (Prism 9, non-liner inhibitor, 4 parameter) algorithm in Prism 9 software cut fit.
Signalc combined: a dosing group signal value;
SignalAve_PC: average signal value of yang ginseng group;
SignalAve_VC: mean signal values for DMSO control.
The results are shown in table 1 below:
the experimental results show that the compounds of the application have the effect of inhibiting TEAD reporter gene activity.
Test example 2 CellTiter-Glo chemiluminescent assay to detect the effect of TEAD inhibitor on NCI-H226 cell viability
1. Preparation before experiment: kang Ning 96 well black transparent bottom cell plate, corning company, cat: #3603; cellTiter-Glo detection kit: promega Corp, cat: g7570; spectraMax cube type ID3 enzyme labeling instrument.
2. NCI-H226 cell culture: NCI-H226 from ATCC accession number CRL-5826 is cultured in89% RPMI-1640+10% FBS+1% double antibody, placed in a mixture containing 5% CO 2 Is a 37 ℃ incubator.
3. The first day: after the cell confluency reaches 90%, the culture medium is sucked away, 3mL of PBS is added to clean the residual culture medium, 1mL of Trypsin is added, and the mixture is placed in an incubator for 5 min for incubation. After most of the cells were shed, digestion was stopped by adding 2mL of medium. Dilution of cell concentration to 5X 10 3 Each mL was plated with 500 cells/well, i.e., 100. Mu.L per well, in a Kang Ning-96-well black clear bottom cell plate.
4. Dosing the following day: the 10mM TEAD inhibitor stock solution (DMSO solution) was removed and thawed at room temperature to prepare a working solution with the following concentration: 0.0015 mu.M, 0.0046. Mu.M, 0.0137. Mu.M, 0.0412. Mu.M, 0.1235. Mu.M, 0.3704. Mu.M, 1.1111. Mu.M, 3.3333. Mu.M, 10. Mu.M. 0.6 The total culture medium is added with 1.2 mu L of 10mM stock solution to prepare 20 mu M working solution; the liquid medicine of 0.2. 0.2 mL is added into a complete culture medium of 0.4. 0.4 mL to prepare working solution of 6.6666 mu M, and other concentrations are prepared according to 3-time gradient dilution. 100. Mu.L of working fluid was added to the plated 96-well plate.
5. Fresh liquid medicine is replaced on the 3 rd day after the medicine addition.
6. The detection is carried out on the 6 th day of administration by using CellTiter-Glo cube kit. The detection procedure of CellTiter-Glo was selected on a microplate reader and luminescence values were read.
And (3) data processing: cell viability value = 100× (dosing well luminescence value-blank empty luminescence value)/(solvent well luminescence value-blank empty luminescence value), IC50 calculation: cell viability values and corresponding drug concentration values were calculated using the (log (inhibitor) vs. normalized response-Variable slope algorithm) in Prism 8 software Curve fit.
The selectivity results are shown in table 2 below:
experimental results show that the compound can inhibit proliferation of target sensitive tumor cells H226.
Test example 3 real-time fluorescent quantitative nucleic acid amplification detection System (qPCR) detection of the influence of TEAD inhibitor on the YAP/TEAD transcriptional Activity of NCI-H226 cells
1. Reagent and cell
NCI-H226 cell culture: NCI-H226 from ATCC accession No. CRL-5826 was incubated with 89% RPMI-1640+10% FBS+1% diabody in a medium containing 5% CO 2 Is a constant temperature incubator at 37 ℃.
RNA extraction kit (Tiangen, DP430, standing at ambient temperature).
SYBR dye (well known as century, CW0957M, placed at-20deg.C).
2. RNA extraction procedure
2.1 After adding 1. Mu.M of the drug (DMSO solution) to the medium for culturing the cells for 24 hours, the cells were collected (the cell amount was not more than 1X 10) 7 ) The cell culture supernatant was aspirated, washed once with PBS, the PBS was aspirated, and the second lysis step was immediately performed.
2.2 Lysing cells
Preparing a lysate: beta-mercaptoethanol was added to the RL to a final concentration of 1%, e.g., 10. Mu.L beta-mercaptoethanol was added to 1 mL of RL; cracking: and adding a proper amount of lysate RL, transferring the cell lysate into a centrifuge tube, and vortex shaking and uniformly mixing. Parameters are shown in table 3:
2.3 All the solutions were transferred to a filter column CS (filter column CS was placed in a collection tube), centrifuged at 12000 rpm (13400 Xg) for 2 min, and the filtrate was collected.
2.4 1 time volume of 70% ethanol (usually 350 mu L or 600 mu L) is added to the filtrate, the mixture is mixed, the obtained solution and the precipitate are transferred to an adsorption column CR3, the mixture is centrifuged at 12000 rpm (13400 Xg) for 30-60 sec, waste liquid in a collecting pipe is poured out, and the adsorption column CR3 is placed back into the collecting pipe.
2.5 350. Mu.L of deproteinized liquid RW1 was added to the adsorption column CR3, and the mixture was centrifuged at 12000 rpm (13400 Xg) for 30-60 sec, and the waste liquid in the collection tube was discarded, and the adsorption column CR3 was returned to the collection tube.
2.6 Preparing DNase I working solution: 10. Mu.L of DNase I stock was placed in a fresh RNase-Free centrifuge tube, 70. Mu.L of RDD buffer was added and gently mixed.
2.7 80. Mu.L of DNase I working solution was added to the center of the column CR3 and left at room temperature for 15 min.
2.8 350. Mu.L deproteinized liquid RW1 was added to the adsorption column CR3, and the mixture was centrifuged at 12000 rpm (13400 Xg) for 30-60 sec, and the waste liquid in the collection tube was discarded, and the adsorption column CR3 was returned to the collection tube.
2.9 500. Mu.L of a rinsing liquid RW was added to the adsorption column CR3, the mixture was allowed to stand at room temperature for 2 minutes, centrifuged at 12000 rpm (13400 Xg) for 30-60 sec, the waste liquid in the collection tube was discarded, and the adsorption column CR3 was returned to the collection tube.
2.10 Step 9 is repeated.
2.11 The mixture was centrifuged at 12000 rpm (13400 Xg) for 2 min, and the waste liquid was discarded. The adsorption column CR3 was left at room temperature for 3-5 minutes to thoroughly dry the residual rinse solution in the adsorption material.
2.12 Transferring the CR3 column into a new RNase-Free centrifuge tube, adding 30-100 μl RNase-Free ddH 2 O is placed at room temperature for 2 min, and is centrifuged at 12000 rpm (13400 Xg) for 2 min, so that an RNA solution is obtained.
2.13 The concentration of the extracted RNA was measured using Nanodrop.
3. Reverse transcription procedure
3.1 Reagents for preparing a reverse transcribed RNA sample and a reverse transcription kit (thermo, 4368814, placed at-20 ℃) were completely dissolved on ice.
3.2 The 2×RT master mix was configured according to the kit instructions.
3.3 The prepared 2 XRT master mix (mixed solution) flick tube bottom is evenly mixed, and is flicked by a palm centrifuge and placed on ice for standby.
3.4 Firstly, calculating the volume required by each sample to absorb 500ng RNA according to the concentration of the extracted RNA, and then calculating RNase-free H to be supplemented according to a 10 mu L system 2 The volume of O. Numbering PCR8 joint tubes of RNase, and adding RNase-free H into corresponding numbers 2 O, adding 500ng RNA with corresponding volume, blowing for several times, mixing, adding 10 μl of 2×RT master mix, mixing with a flick tube bottom, flicking with a palm centrifuge, and placing on ice.
3.5 The PCR tube was put into a PCR instrument, and the PCR procedure was set with the following conditions by screwing the cap, and the reaction volume was 20. Mu.L.
3.6 The inverted cDNA was stored at-20℃until use.
4. qPCR procedure
4.1 Forward and reverse primers (specific primer sequences are shown in table 4) of the detected genes 36B4, CTGF and CYR61, and the sample cDNA and SYBR green were completely dissolved on ice and mixed uniformly.
4.2 Dilution of primers
The synthesized forward and reverse primers were subjected to ddH in terms of on-line volume 2 O was dissolved and mixed well (typically at a concentration of 100. Mu.M). mu.L of 100. Mu.M primer stock was added to the solution containing 47.5. Mu.LddH 2 In the EP tube of O, it was diluted to 5. Mu.M. Then 5. Mu.M of forward primer and reverse primer were mixed in equal volumes to 2.5. Mu.M of F/R primer mix.
4.3 Dilution of cDNA
After complete dissolution of the reverse transcribed cDNA on ice, mixing well, adding 4. Mu.L cDNA per well in 384QPCR plates according to each experiment, repeating 3 times, calculating the required sample volume, taking out PCR 8-ligation tube, and subjecting cDNA to ddH 2 Diluting O by 20 times, uniformly mixing the bottom of the flick pipe, throwing the mixture on a palm centrifugal machine, and placing the mixture on ice for standby.
4.4 The mixed solution of SYBR and primer is prepared in a 1.5mL centrifuge tube, the bottom of a flick tube is uniformly mixed, and the mixture is thrown on a palm centrifuge and placed on ice for standby.
4.5 And (3) adding samples, sucking 6 mu L of SYBR of the corresponding genes and 2.5 mu M F/R primer mixture by using a discharge gun after all holes are added, attaching a sealing plate film after the addition, compacting four sides, and centrifuging for 5min by using a centrifuge before loading, so that the liquids are all at the bottom of the plate. The QPCR reaction program is set, the pre-denaturation reaction of SYBR dye must be completed in the century at 95 ℃ for 10min, and the reaction system is 10 mu L and 40 cycles. And storing the data for analysis.
The experimental results are shown in FIG. 1, and it can be seen from FIG. 1 that the compound of the application can inhibit YAP/TEAD transcriptional activity of target sensitive tumor cells H226.
Claims (5)
1. A compound, or a pharmaceutically acceptable salt thereof, represented by formula I-1:
;
In the formula I-1, R 1 Selected from the group consisting of hydrogen, bromine, fluorine or the following groups:
;
R 2 is hydrogen, R 3 Selected from the group consisting of:
。
2. a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
。
3. a pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, for the manufacture of a medicament for the prevention or treatment of a disease or disorder associated with the modulation of TEAD.
5. The use according to claim 4, characterized in that the disease or condition associated with the modulation of TEAD is selected from the following: brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, stomach cancer, breast cancer or prostate cancer.
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CN86104075A (en) * | 1985-05-21 | 1987-03-11 | 美国辉瑞有限公司 | The preparation method of flood sugar reducing medicine-thiazolidinedions |
WO1991004738A1 (en) * | 1989-09-27 | 1991-04-18 | Rorer International (Holdings), Inc. | Dibenzofurancarboxamides |
CN101296925A (en) * | 2005-09-01 | 2008-10-29 | 詹森药业有限公司 | Novel benzopyran derivatives as potassium channel openers |
CN114907389A (en) * | 2021-02-07 | 2022-08-16 | 首药控股(北京)股份有限公司 | Boronic acid derivatives |
CN115103670A (en) * | 2019-12-24 | 2022-09-23 | 达纳-法伯癌症研究所股份有限公司 | Transcription Enhancement Associated Domain (TEAD) transcription factor inhibitors and uses thereof |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN86104075A (en) * | 1985-05-21 | 1987-03-11 | 美国辉瑞有限公司 | The preparation method of flood sugar reducing medicine-thiazolidinedions |
WO1991004738A1 (en) * | 1989-09-27 | 1991-04-18 | Rorer International (Holdings), Inc. | Dibenzofurancarboxamides |
CN101296925A (en) * | 2005-09-01 | 2008-10-29 | 詹森药业有限公司 | Novel benzopyran derivatives as potassium channel openers |
CN115103670A (en) * | 2019-12-24 | 2022-09-23 | 达纳-法伯癌症研究所股份有限公司 | Transcription Enhancement Associated Domain (TEAD) transcription factor inhibitors and uses thereof |
CN114907389A (en) * | 2021-02-07 | 2022-08-16 | 首药控股(北京)股份有限公司 | Boronic acid derivatives |
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