CN117466870A - Benzo seven-membered ring type difunctional compound and application thereof - Google Patents

Benzo seven-membered ring type difunctional compound and application thereof Download PDF

Info

Publication number
CN117466870A
CN117466870A CN202310957422.7A CN202310957422A CN117466870A CN 117466870 A CN117466870 A CN 117466870A CN 202310957422 A CN202310957422 A CN 202310957422A CN 117466870 A CN117466870 A CN 117466870A
Authority
CN
China
Prior art keywords
compound
added
reaction
pharmaceutically acceptable
independently selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310957422.7A
Other languages
Chinese (zh)
Inventor
李正伟
钱文远
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Original Assignee
Medshine Discovery Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medshine Discovery Inc filed Critical Medshine Discovery Inc
Publication of CN117466870A publication Critical patent/CN117466870A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/14—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 three or more hetero 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
    • 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
    • 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

Abstract

The invention relates to a benzo seven-membered ring difunctional compound and application thereof, in particular to a compound shown in a formula (IV) and pharmaceutically acceptable salts thereof.

Description

Benzo seven-membered ring type difunctional compound and application thereof
Citation of related application
The present application claims priority and equity to the chinese invention patent application No. 202210909049.3 filed on the 29 th 2022 month 07 to the chinese national intellectual property agency, the entire disclosure of which is incorporated herein by reference.
Technical Field
The application relates to a benzo seven-membered ring difunctional compound and application thereof, in particular to a compound shown in a formula (IV) and pharmaceutically acceptable salts thereof.
Background
The Estrogen Receptor (ER) is a member of the nuclear hormone receptor family and acts as a transcription factor for ligand activation, involving up-and down-regulation of gene expression. The ER natural ligand estrogen plays an important role in female sexual development, maintaining bone density and regulating blood lipid level. Reduced estrogen production in postmenopausal women is associated with a number of diseases such as osteoporosis, atherosclerosis, depression, and cognitive disorders. In contrast, certain types of proliferative diseases such as breast and uterine cancers and endometriosis are stimulated by estrogens, and thus antiestrogens (i.e., estrogen antagonists) have utility in the prevention and treatment of these types of conditions.
Endocrine therapy for estrogen-estrogen receptor signaling pathway in breast cancer cells has been the first therapy for treating estrogen receptor positive breast cancer because of minimal hazard and remarkable curative effect. Endocrine therapy mainly comprises the following three treatment methods: ovarian inhibition therapy, aromatase inhibitors, selective estrogen receptor antagonists. Among them, estrogen receptor antagonists are classified into two types, and Selective Estrogen Receptor Modulators (SERMs) directly act on estrogen receptors to block the signal pathway, with remarkable therapeutic effects and long history of use. Among them, tamoxifen is the most representative selective estrogen receptor modulator. As a first-line drug to be preferentially recommended, tamoxifen shows remarkable clinical effects for preventing and treating estrogen receptor positive breast cancer, but after a long time of use, the problem of drug resistance is more serious. While only fulvestrant is currently marketed in Selective Estrogen Receptor Downregulator (SERD), fulvestrant only antagonizes estrogen receptors without agonism, and can degrade ER protein, the medicine can treat ER positive breast cancer patients (including patients with drug resistance to tamoxifen or aromatase inhibitors), but the PK property is poor, and the curative effect is seriously affected. The development of drugs with better pharmacokinetic properties and aimed at solving ER-resistant breast cancers remains an unmet medical need.
PROTAC is a heterobifunctional molecule containing two small molecule binding moieties linked together by a linker. A small molecule ligand is designed to bind with high affinity to a target protein in a cell, while another ligand is capable of binding with high affinity to E3 ubiquitin ligase. In cells, PROTAC seeks and selectively binds to a target protein of interest. The PROTAC recruits specific E3 ligase to the target protein in vivo to form a ternary complex, bringing the target protein and E3 ligase into close proximity. The E3 ubiquitin ligase then recruits the E2-binding enzyme into the ternary complex. E2 is capable of ubiquitinating the protein of interest, labeling an available lysine residue on the protein, and then dissociating from the ternary complex. E3 can recruit additional E2 molecules, resulting in polyubiquitination of target proteins, labeling target proteins as likely to be degraded by the proteasome machinery of the cell. Finally the PROTAC is able to dissociate from the target protein and initiate another catalytic cycle.
According to this principle, ER PROTACs are designed to contain an ER ligand moiety at one end of the linker and an E3 ubiquitin ligase (e.g., cereblon, CRBN) ligand at the other end. ER PROTAC selectively recruits CRBN E3 ubiquitin ligase to the ER in the cell and causes systemic degradation of ER, thereby achieving regulation of ER and treatment of estrogen-related diseases.
Disclosure of Invention
The application provides a compound shown as a formula (IV) or pharmaceutically acceptable salt thereof,
wherein,
R 1 selected from OH, alkoxy or COOH;
each R 2 Independently selected fromHalogen, OH, CN, NH 2 Alkyl, alkoxy, alkylamino, dialkylamino, cycloalkyl, heterocycloalkyl, -O-cycloalkyl or-O-heterocycloalkyl, said alkyl, alkoxy, alkylamino, dialkylamino, cycloalkyl, heterocycloalkyl, -O-cycloalkyl and-O-heterocycloalkyl optionally being independently substituted with 1, 2 or 3R a Substitution;
alternatively, two adjacent ring atoms on ring A are simultaneously bound by R 2 When substituted, two R 2 And the ring atoms to which they are attached may together form a heterocyclic group;
each R a Independently selected from halogen, OH, CN, NH 2 Alkyl, alkoxy, alkylamino or dialkylamino;
each R 3 Independently selected from halogen;
m and n are each independently selected from 0, 1, 2 and 3;
E 1 selected from O and CH 2 ；
L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, cycloalkyl or heterocycloalkyl;
selected from single bonds and double bonds;
ring a is selected from phenyl or heteroaryl.
In some aspects of the present application, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein,
R 1 Selected from OH, alkoxy or COOH;
each R 2 Independently selected from halogen, OH, CN, NH 2 Alkyl, alkoxy, cycloalkyl or-O-cycloalkyl, said alkyl, alkoxy, cycloalkyl and-O-cycloalkyl optionally being independently substituted with 1, 2 or 3R a Substitution;
each R a Independently selected from halogen, CN or OH;
each R 3 Independently selected from halogen;
m and n are each independently selected from 0, 1, 2 and 3;
E 1 selected from O and CH 2 ；
L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, cycloalkyl or heterocycloalkyl;
selected from single bonds and double bonds;
ring a is selected from phenyl or heteroaryl.
In some aspects of the present application, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein,
R 1 selected from OH, C 1-3 Alkoxy or COOH;
each R 2 Independently selected from halogen, OH, CN, NH 2 、C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or-O-C 3-6 Cycloalkyl group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and-O-C 3-6 Cycloalkyl is optionally independently substituted with 1, 2 or 3R a Substitution;
each R a Independently selected from halogen, CN or OH;
each R 3 Independently selected from halogen;
m and n are each independently selected from 0, 1, 2 and 3;
E 1 selected from O and CH 2 ；
L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl substitution;
selected from single bonds and double bonds;
ring a is selected from phenyl or 5-6 membered heteroaryl.
In some aspects of the present application, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein,
R 1 selected from OH, C 1-3 Alkoxy or COOH;
each R 2 Independently selected from halogen, OH, CN, NH 2 、C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl group, the C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens;
each R 3 Independently selected from halogen;
m and n are each independently selected from 0, 1, 2 and 3;
E 1 selected from O and CH 2 ；
L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl substitution;
selected from single bonds and double bonds;
ring a is selected from phenyl or 5-6 membered heteroaryl.
In some aspects of the present application, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein,
R 1 selected from OH, C 1-3 Alkoxy or COOH;
each R 2 Independently selected from halogen, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or-O-C 3-6 Cycloalkyl group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and-O-C 3-6 Cycloalkyl is optionally independently substituted with 1, 2 or 3R a Substitution;
each R a Independently selected from halogen, CN or OH;
Each R 3 Independently selected from halogen;
m and n are each independently selected from 0, 1, 2 and 3;
E 1 selected from O and CH 2 ；
L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, C 3-6 Cycloalkyl or 4-6 membered heteroCycloalkyl substitution;
selected from single bonds and double bonds;
ring a is selected from phenyl or 5-6 membered heteroaryl.
In some aspects of the present application, R is as described above 1 Selected from OH, CH 3 O-or COOH, and the other variables are as defined herein.
In some aspects of the present application, R is as described above 1 Selected from OH, and the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from halogen, OH, CN, NH 2 、C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkyl-NH- (C) 1-3 Alkyl group 2 -N-、C 3-6 Cycloalkyl, C 3-6 Heterocyclylalkyl, -O-C 3-6 Cycloalkyl or-O-C 3-6 Heterocycloalkyl, said C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkyl-NH- (C) 1-3 Alkyl group 2 -N-、C 3-6 Cycloalkyl, C 3-6 Heterocyclylalkyl, -O-C 3-6 Cycloalkyl and-O-C 3-6 Heterocycloalkyl is optionally independently substituted with 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl a Instead, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 Ethyl, isopropyl, methoxyA radical, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl or-O-cyclobutyl, the CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl and-O-cyclobutyl a Instead, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl or-O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl and-O-cyclopropyl a Instead, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from halogen, OH, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Heterocycloalkyl, said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy, aziridinyl or azetidinyl, said C 1-3 Alkyl, C 1-3 Alkoxy, aziridinyl and azetidinyl are each independently optionally substituted with 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, OH, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, 1-azetidinyl or 3-azetidinyl, said CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, 1-azetidinyl and 3-azetidinyl are optionally substituted independently by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the present applicationIn the scheme, R is 2 Independently selected from F, cl, br, I, OH, CH 3 Methoxy, 1-azetidinyl or 3-azetidinyl, said CH 3 Methoxy, 1-azetidinyl and 3-azetidinyl are optionally substituted independently by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some embodiments of the present application, two adjacent ring atoms on ring A are simultaneously bound by R 2 When substituted, two R 2 The ring atoms to which they are attached may together form C 3-6 Heterocyclyl, other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from OH, NH 2 Methyl, ethyl, methoxy or ethoxy; alternatively, two adjacent ring atoms on ring A are simultaneously bound by R 2 When substituted, two R 2 The ring atoms to which they are attached may together form C 3-6 Heterocyclyl, other variables are as defined herein.
In some aspects of the present application, R is as described above a Independently selected from F, cl, br, I, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy, and other variables are as defined herein.
In some aspects of the present application, R is as described above a Independently selected from F, cl, br, I, CN, OH, C 1-3 Alkyl or C 1-3 Alkoxy, and other variables are as defined herein.
In some aspects of the present application, R is as described above a Independently selected from F, cl, br, I, CN, OH, CH 3 Ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the other variables are as defined herein.
In some aspects of the present application, R is as described above a Independently selected from F, cl, br, I, CN, OH, CH 3 Or methoxy, and the other variables are as defined herein.
In some aspects of the present application, R is as described above a Independently selected from F, cl, br, I or CN, the other variables being as defined herein.
In some aspects of the present application, R is as described above a Independently selected from F, cl, br, I or OH, with the other variables being as defined herein.
In some aspects of the present application, R is as described above a Independently selected from F or OH, and the other variables are as defined herein.
In some aspects of the present application, R is as defined above 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl a Substituted, each R a Independently selected from F, cl, br, I or OH, with the other variables being as defined herein.
In some embodiments, R is as described above 2 Independently selected from F, cl, OH, CH 3 Isopropyl, methoxy, cyclopropyl or-O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups a Substituted, each R a Independently selected from F or OH, and the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Heterocycloalkyl, said C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3R a Substituted, each R a Independently selected from halogen, C 1-3 Alkyl or (C) 1-3 Alkyl group 2 -N-, other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, OH, CH 3 Methoxy, 1-azetidinyl or 3-azetidinyl, said CH 3 Methoxy, 1-azetidinyl and 3-azetidinyl are optionally substituted independently by 1, 2 or 3R a Substitution, each ofR a Independently selected from F, cl, br, I, methyl or (CH) 3 ) 2 -N-, other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, CH 3 Or methoxy group, said CH 3 And methoxy is optionally independently substituted with 1, 2 or 3R a Substituted, each R a Selected from F, and the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 、CF 3 Cyclopropyl group,-OCHF 2 、-OCF 3 or-O-cyclopropyl, the other variables being as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, OH, CH 3 、CF 3 Cyclopropyl group,-OCHF 2 、-OCF 3 or-O-cyclopropyl, the other variables being as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 、CF 3 Or cyclopropyl, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, OH, CH 3 、CF 3 Or cyclopropyl, the other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, OH, CH 3 Methoxy, CF 3 Cyclopropyl group,-OCHF 2 、-OCF 3 or-O-cyclopropyl, other variables as defined hereinMeaning.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, OH, CH 3 Methoxy, CHF 2 O-、(CH 3 ) 2 N-CH 2 -、
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, CH 3 Methoxy or CHF 2 O-。
In some aspects of the present application, R is as described above 2 Independently selected from F, CH 3 Methoxy or CHF 2 O-。
In some aspects of the present application, R is as described above 3 Independently selected from F or Cl, and the other variables are as defined herein.
In some embodiments of the present application, L is selected from C 1-6 Alkylene, -O-C 1-5 Alkylene, -C 3-6 Cycloalkyl-, -C 3-6 cycloalkyl-C 1-3 Alkylene, -4-6 membered heterocycloalkyl-or-4-6 membered heterocycloalkyl-C 1-3 Alkylene, other variables are as defined herein.
In some embodiments of the present application, L is selected from C 4-6 Alkylene, -O-C 3-5 Alkylene, -cyclohexyl-C 1-3 Alkylene, -6-membered heterocycloalkyl-or-6-membered heterocycloalkyl-C 1-3 Alkylene, other variables are as defined herein.
In some embodiments of the present application, the L is selected from the group consisting of-O-C 3-5 Alkylene, -piperidinyl-C 1-3 Alkylene or-piperazinyl-C 1-3 Alkylene, other variables are as defined herein.
In some embodiments of the present application, the L is selected from the group consisting of-O-C 3-5 Alkylene, -piperidinyl-C 1-3 Alkylene, other variables are as defined herein.
In some embodiments of the present application, the L is selected from the group consisting of piperazinyl-C 1-3 Alkylene, other variables being as hereinDefined as follows.
In some embodiments of the present application, the L is selected from the group consisting of-O-C 3-5 Alkylene group,The other variables are as defined herein.
In some embodiments of the present application, the L is selected from the group consisting of-O-C 3-5 Alkylene group, The other variables are as defined herein.
In some aspects of the present application, L is selected fromThe other variables are as defined herein.
In some embodiments of the present application, L is selected from C 1-6 Alkylene, of which 1 to 3 methylene groups are optionally replaced by O, NH, cyclohexyl or 6 membered heterocycloalkyl, the other variables being as defined herein.
In some embodiments of the present application, L is selected from C 1-6 Alkylene, of which 1 to 3 methylene groups are optionally replaced by O, NH, cyclohexyl, piperidinyl or piperazinyl, the other variables being as defined herein.
In some embodiments of the present application, L is selected from C 1-6 Alkylene, of which 1 to 3 methylene groups are optionally replaced by O, NH, cyclohexyl or piperidinyl, the other variables being as defined herein.
In some embodiments of the present application, L is selected from C 1-6 Alkylene groups in which 1 to 3 methylene groups are optionally replaced by piperazinyl groups, the other variables being as defined herein.
In some aspects of the present application, L is selected from The other variables are as defined herein.
In some aspects of the present application, L is selected fromThe other variables are as defined herein.
In some aspects of the present application, L is selected fromThe other variables are as defined herein.
In some aspects of the present application, L is selected fromThe other variables are as defined herein.
In some aspects of the present application, L is selected fromThe other variables are as defined herein.
In some aspects of the present application, the aboveSelected from double bonds, and the other variables are as defined herein.
In some embodiments of the present application, ring a is selected from phenyl, pyridyl or pyrazolyl, and the other variables are as defined herein.
In some embodiments of the present application, the ring A is selected from phenyl,The other variables are as defined herein.
In some embodiments of the present application, ring a is selected from phenyl and the other variables are as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of
Said each R 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl a Substituted, each R a Independently selected from F, cl, br, I or OH, with the other variables being as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of Said each R 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups a Substituted, each R a Independently selected from F, cl, br, I or OH, with the other variables being as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of Said each R 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl a Substituted, each R a Independently selected from F, cl, br, I or OH, with the other variables being as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of
Said each R 2 Independently selected from F, cl, OH, CH 3 Isopropyl, methoxy, cyclopropyl, -O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups a Substituted, each R a Independently selected from F or OH, and the other variables are as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of Said each R 2 Independently selected from F, cl, OH, CH 3 Isopropyl, methoxy, cyclopropyl, -O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups a Substituted, each R a Independently selected from F or OH, and the other variables are as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of Said each R 2 Independently selected from F, cl, OH, CH 3 Isopropyl, methoxy, cyclopropyl, -O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups a Substituted, each R a Independently selected from F or OH, and the other variables are as defined herein.
In some aspects of the present application, the structural units described above Selected from the group consisting of Said each R 2 Independently selected from F, cl, OH, CH 3 Isopropyl, methoxy, cyclopropyl, -O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups a Substituted, each R a Independently selected from F or OH, and the other variables are as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of Said each R 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl a Substituted, each R a Independently selected from F, cl, br, I or OH, with the other variables being as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of
Other variables such as the bookAs defined in the application.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of
The other variables are as defined herein.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of/>
In some aspects of the present application, the structural units described aboveSelected from the group consisting of
The other variables are as defined herein.
In some aspects of the present application, m is selected from 0 or 1, and the other variables are as defined herein.
In some aspects of the present application, n is selected from 0, 1 or 2, and the other variables are as defined herein.
In some aspects of the present application, E is as described above 1 Selected from CH 2 The other variables are as defined herein.
The application also provides a compound shown in the formula (I) or pharmaceutically acceptable salt thereof,
wherein,
R 1 selected from OH, C 1-3 Alkoxy or COOH;
each R 2 Independently selected from halogen, OH, CN, C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;
each R 3 Independently selected from halogen;
m and n are each independently selected from 0, 1, 2 and 3;
E 1 selected from O and CH 2 ；
L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl substitution;
selected from single bonds and double bonds;
the "hetero" of the "4-6 membered heterocycloalkyl" includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, S, NH and N.
In some aspects of the present application, R is as described above 1 Selected from OH, CH 3 O-or COOH, and the other variables are as defined herein.
In some aspects of the present application, R is as described above 1 Selected from OH, and the other variables are as defined herein.
In the present applicationIn some aspects of (a), R is as described above 2 Independently selected from F, cl, br, I, OH, CN or CH 3 The other variables are as defined herein.
In some aspects of the present application, R is as described above 2 Independently selected from F, cl, OH or CH 3 The other variables are as defined herein.
In some aspects of the present application, the R 2 Independently selected from F or Cl, and the other variables are as defined herein.
In some aspects of the invention, R is as defined above 3 Selected from F and Cl, and the other variables are as defined herein.
In some aspects of the present application, m is selected from 0 or 1, and the other variables are as defined herein.
In some aspects of the present application, n is selected from 0, 1 or 2, and the other variables are as defined herein.
In some embodiments of the invention, L is selected from C 1-6 Alkyl, wherein 1 to 3 methylene groups are optionally replaced by O, NH, cyclohexyl or 6 membered heterocycloalkyl, and the other variables are as defined herein.
In some embodiments of the invention, L is selected from C 1-6 Alkyl, wherein 1 to 3 methylene groups are optionally replaced by O, NH, cyclohexyl or piperidinyl, and the other variables are as defined herein.
In some aspects of the present application, L is selected fromThe other variables are as defined herein.
In some aspects of the present application, the L is selected fromThe other variables are as defined herein.
In some aspects of the present application, the E 1 Selected from CH 2 The other variables are as defined herein.
In some aspects of the present application, theSelected from double bonds, and the other variables are as defined herein.
In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (I-1) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 、R 3 L, m and n are as defined for the compounds of formula (I).
In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (I-2) or a pharmaceutically acceptable salt thereof,
wherein,
t is selected from 1, 2, 3, 4 or 5;
R 1 、R 2 and n is as defined for the compounds of formula (I).
In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (I-3) or a pharmaceutically acceptable salt thereof,
wherein,
q is selected from 1 or 2;
R 1 、R 2 、E 1 and n is as defined for the compounds of formula (I).
In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (I-3'), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof,
Wherein,
q is selected from 1 or 2;
R 1 、R 2 、E 1 and n is as defined for the compounds of formula (I).
In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (I-3'), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof
q is selected from 1 or 2;
R 1 、R 2 、E 1 and n is as defined for the compounds of formula (I).
In some embodiments of the present application, the compound of formula (IV) above, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds of formula (IV-1),
wherein R is 1 、R 2 、R 3 、L、E 1 Ring A,m and n are as defined for the compounds of formula (IV).
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV-2) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 、R 3 L, ring A, m and n are as defined for the compound of formula (IV).
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV-3) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 、R 3 L, m and n are as defined for the compounds of formula (IV).
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV-4) or a pharmaceutically acceptable salt thereof,
Wherein,
t is selected from 1, 2, 3, 4 or 5;
R 1 、R 2 the rings A and n are defined as compounds of formula (IV).
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV-5) or a pharmaceutically acceptable salt thereof,
wherein,
q is selected from 1 or 2;
R 1 、R 2 、E 1 the rings A and n are defined as compounds of formula (IV).
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV-6) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 And n is as defined for the compound of formula (IV).
In some embodiments of the present application, the compound of formula (IV) above or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IV-5'), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof,
wherein,
q is selected from 1 or 2;
R 1 、R 2 、E 1 the rings A and n are defined as compounds of formula (IV).
In some embodiments of the present application, the compound of formula (IV) above or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IV-5'), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof,
wherein,
q is selected from 1 or 2;
R 1 、R 2 、E 1 the rings A and n are defined as compounds of formula (IV).
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IV-6'), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof
Wherein,R 1 、R 2 and n is as defined for the compound of formula (IV).
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IV-6'), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof
Wherein R is 1 、R 2 And n is as defined for the compound of formula (IV).
The application also provides a compound shown as a formula (V) or pharmaceutically acceptable salt thereof,
wherein,
q is selected from 1, 2 and 3;
R 1 、R 2 、R 3 、E 1 ring A,m and n are as defined for the compounds of formula (IV).
In some aspects of the present application, q is selected from 1 and 2.
In some aspects of the present application, the compound of formula (V) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (V-1) or a pharmaceutically acceptable salt thereof,
wherein q is defined as the compound of formula (V);
R 2 、E 1 and n is as defined for the compound of formula (IV).
In some aspects of the present application, the compound of formula (V-1) or a pharmaceutically acceptable salt thereof, wherein,
Each R is 2 Independently selected from halogen, C 1-3 Alkyl or C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy groups are each independently optionally substituted with 1, 2 or 3 halogens;
q is selected from 1, 2 or 3;
n is selected from 0, 1, 2 or 3;
E 1 selected from CH 2 Or O.
In some aspects of the present application, the structural units described aboveSelected from the group consisting of
The other variables are as defined herein.
In some aspects of the present application, the compound of formula (V-1) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (V-2), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof,
wherein q, R 2 、E 1 And n is as defined for the compound of formula (V-1).
Still other aspects of the present application are derived from any combination of the variables described above.
In some embodiments of the present application, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (V) or a pharmaceutically acceptable salt thereof is not selected from the group consisting of the compounds of formula:
/>
/>
the present application also provides a compound of the formula or a pharmaceutically acceptable salt thereof, selected from,
/>
/>
/>
the present application also provides a compound of the formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from,
/>
/>
/>
/>
/>
/>
/>
The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The application also provides application of the compound, stereoisomer or pharmaceutically acceptable salt thereof in preparing medicines for treating diseases. In some embodiments, the disease is selected from diseases associated with estrogen receptor protein degradation targeting chimeras.
The application also provides application of the compound, stereoisomer or pharmaceutically acceptable salt thereof in preparing medicines for treating diseases related to estrogen receptor protein degradation targeting chimera.
The present application also provides a method of treating a disease associated with estrogen receptor protein degradation targeted chimeras comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present application, stereoisomers or pharmaceutically acceptable salts thereof.
The present application also provides the use of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the treatment of a disease associated with estrogen receptor protein degradation targeting chimeras.
The present application also provides a stereoisomer of a compound represented by formula (IV) of the present application or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with estrogen receptor protein degradation targeting chimeras.
The present application also provides a stereoisomer of a compound represented by formula (I) herein or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with estrogen receptor protein degradation targeting chimeras.
The present application also provides a stereoisomer of a compound represented by formula (V) of the present application or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with estrogen receptor protein degradation targeting chimeras.
In some aspects of the present application, the estrogen receptor protein degradation targeting chimeric related disorder is selected from a tumor or a cancer.
In some aspects of the present application, the estrogen receptor protein degradation targeted chimeric related disorder is selected from the group consisting of breast cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, endometriosis, lung cancer, and esophageal cancer.
In some aspects of the present application, the estrogen receptor protein degradation targeting chimeric related disorder is selected from breast cancer.
Technical effects
The compound in the application is taken as a difunctional ER PROTAC molecule with a brand new structure, and has good inhibition effect on estrogen-induced signal transduction and good degradation effect on ER alpha.
Correlation definition
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present application prepared from the compounds found herein to have a particular substituent with a relatively non-toxic acid or base. When relatively acidic functionalities are included in the compounds of the present application, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When relatively basic functional groups are included in the compounds of the present application, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Certain specific compounds of the present application contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present application.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine isomerisation. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include tautomers by recombination of some bond-forming electrons.
The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
The term "substituted" means that a particular atom or group can be replaced with another atom or group as specified. For example-CH 2 CH 2 CH 2 1 or 2 or 3-CH in 2 Can be replaced by O, S, NH to give-O-CH 2 -CH 2 -、-O-CH 2 -、-CH 2 -O-CH 2 -、-CH 2 -O-、-CH 2 -CH 2 -O-, etc. Also e.g. -CH 2 CH 2 CH 2 1 or 2 or 3-CH in 2 Can be substituted by cyclohexyl or piperidinyl to give
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.
When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example,the linking group L is-M-W-, in which case-M-W-may be a group in which the linking rings A and B are linked in the same direction as the reading order from left to right >Or can read from left to rightThe reverse direction of the sequence connects ring A and ring B to form +.>Combinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, when a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site can be correspondingly reduced to be changed into the corresponding valence group along with the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bondStraight dotted line key->Or wave line->And (3) representing. For example-OCH 3 The straight solid line bond in (a) represents the connection to other groups through the oxygen atom in the group; />The straight dashed bonds in (a) represent the attachment to other groups through both ends of the nitrogen atom in the group; />The wavy line means that the carbon atoms at positions 1 and 2 in the phenyl group are attached to other groups;it means that any of the ligatable sites on the piperidinyl group may be linked to other groups by 1 chemical bond, including at least +. >These 4 connection forms, even though the H atom is depicted on-N-, are +.>Still include->The group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl group.
Unless otherwise specified, the term "alkyl" by itself or as part of another substituent means a straight or branched saturated hydrocarbon group. The alkyl group may be C 1-6 Alkyl or C 1-3 An alkyl group. The alkyl group is optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
Unless otherwise specified, the term "C 1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is 1-6 Alkyl includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 And C 5 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.
Unless otherwise specified, the term "C 1-3 Alkyl "is used to denote a linear or branched saturated radical consisting of 1 to 3 carbon atomsA hydrocarbon group. The C is 1-3 Alkyl includes C 1-2 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
Unless otherwise specified, the term "alkoxy" refers to those alkyl groups that are attached to the remainder of the molecule through one oxygen atom. The alkoxy group may be C 1-6 Alkoxy or C 1-3 An alkoxy group. The alkoxy groups are optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
Unless otherwise specified, the term "C 1-6 Alkoxy "means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-6 Alkoxy includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 And C 5 Alkoxy groups, and the like. C (C) 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, and the like.
Unless otherwise specified, the term "C 1-3 Alkoxy "means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-3 Alkoxy includes C 1-2 、C 2-3 、C 3 And C 2 Alkoxy groups, and the like. C (C) 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
Unless otherwise specified, the term "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
Unless otherwise specified, C n-n+m Or C n -C n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C 1-12 Comprises C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Also included is any one of the ranges n to n+m, e.g. C 1-12 Comprises C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 And C 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and any one of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring, 6-10-membered ring, and the like.
The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 12 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [ 2.2.1)]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, and the like. The cycloalkyl group may be C 3-6 Cycloalkyl groups. The cycloalkyl is optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2 -C (O) NH-alkyl, -C (O) N (alkyl) 2 -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2 NH 2 、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2 NaphtheneA group, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
Unless otherwise specified, "C 3-6 Cycloalkyl "means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, said C 3-6 Cycloalkyl includes C 3-5 、C 4-5 And C 5-6 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like. The heterocyclyl is optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2 -C (O) NH-alkyl, -C (O) N (alkyl) 2 -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2 NH 2 、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2 Cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generallyIs a 4 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaxalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxapanyl, thietanyl. The heterocycloalkyl group may be a 4-6 membered heterocycloalkyl group, or a monocyclic heterocycloalkyl group having 5 or 6 ring atoms. The heterocycloalkyl group is optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2 -C (O) NH-alkyl, -C (O) N (alkyl) 2 -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2 NH 2 、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2 Cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
Unless otherwise specified, the term "4-6 membered heterocycloalkyl" alone or in combination with other terms, refers to a saturated cyclic group consisting of 4 to 6 ring atoms, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O) p P is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, in the case of the "4-6 membered heterocycloalkyl" group, the heteroatom may be taken upDepending on the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 4-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and 1,2,3, 4-tetrahydronaphthalene, and the like. The aryl group is optionally substituted with one or more of the following groups: hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2 -C (O) NH-alkyl, -C (O) N (alkyl) 2 -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2 NH 2 、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2 Cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms . Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like. The heteroaryl group may be a 5-6 membered heteroaryl group. The heteroaryl is optionally substituted with one or more of the following groups: hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2 -C (O) NH-alkyl, -C (O) N (alkyl) 2 -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2 NH 2 、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2 Cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
Unless otherwise specified, the term "5-6 membered heteroaryl" denotes a cyclic group consisting of 5 to 6 ring atoms having a conjugated pi electron system, 1, 2 or 3 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized and the carbon, nitrogen and sulfur heteroatoms are optionally oxidized (i.e., c= O, NO and S (O) p P is 1 or 2)). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl and the like)) Furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), etc.
"pharmaceutical composition" means a composition containing one or more of the compounds described herein, isomers thereof, or pharmaceutically acceptable salts thereof, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, IAP, E3 ubiquitin ligase protein, alone or in combination with E2 ubiquitin conjugating enzyme, causes attachment of ubiquitin to lysine on the target protein and subsequently targets specific protein substrates for degradation by proteasome. Thus, the E3 ubiquitin ligase alone or in complex with the E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to the target protein. Generally, ubiquitin ligases are involved in polyubiquitination such that a second ubiquitin is attached to a first ubiquitin; and a third ubiquitin is attached to the second ubiquitin and so on. Polyubiquitination labels proteins for degradation by proteasome. However, there are some ubiquitination events, which are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by ubiquitin ligases. Monoubiquitinated proteins are not targeted to proteasome for degradation, but rather may be altered in their cellular location or function, for example, via binding to other proteins having domains capable of binding ubiquitin. More complex, different lysines of ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is lysine used to prepare polyubiquitin recognized by the proteasome.
The term "targeting chimera" means a bifunctional molecule comprising two small molecule ligands, one with high affinity for the target protein of interest, and a second for recruiting E3 ligase that ubiquitinates the protein and targets the protein for proteolysis by the 26S proteasome.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The compounds of the present application may be structured by conventional methods well known to those skilled in the art, and if the present application relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning:after scanning and collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97).
In some embodiments, compounds of the present application can be prepared by one of skill in the art of organic synthesis through scheme 1, wherein E 1 、R 2 The parts n and a are as defined above.
In some embodiments, compounds of the present application may be prepared by one of skill in the art of organic synthesis via scheme 2, wherein E 1 、R 2 The parts n and a are as defined above.
Each of the products obtained by the reactions in the above schemes may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials may be synthesized by themselves or purchased from commercial institutions (e.g., without limitation, adrich or Sigma). These materials can be characterized using conventional means such as physical constants and spectral data. The compounds described herein may be synthesized using synthetic methods to give single isomers or mixtures of isomers.
The solvents used in the present application are commercially available.
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
Detailed Description
The present application is described in detail by way of examples below, but is not meant to be limiting in any way. The present application has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the application.
Reference example 1
The synthetic route is as follows:
step 1: synthesis of intermediate 1-C-b
Intermediate 1-C-a (50 g) and trimethyl orthoformate (107.28 g) were dissolved in methanol (450 mL) and p-toluenesulfonic acid monohydrate (3.85 g) was added with stirring. Stirring was carried out under nitrogen at 25℃for 3 hours. After the reaction, adding saturated sodium carbonate solution to the reaction solution until the pH value is=7-8, adding 500mL of dichloromethane and 500mL of water, stirring for 10min, standing for layering separation, extracting the water phase with dichloromethane (300 mL of 2), combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain an intermediate 1-C-b.
1 H NMR(400MHz,CDCl 3 )δ＝7.37-7.27(m,5H),5.11(s,2H),4.20(br s,2H),4.01(d,J＝6.8Hz,1H),3.34(s,6H),2.73(br s,2H),1.82-1.67(m,3H),1.22(br d,J＝10.5Hz,2H).
Step 2: synthesis of intermediate 1-C-C
Intermediate 1-C-b (63 g) was dissolved in methanol (1000 mL), to which was added wet Pd/C (7 g). Stirring was carried out under a hydrogen atmosphere at 25℃for 12 hours. After the reaction was completed, the reaction mixture was filtered through celite, the filter cake was washed with methanol (100 ml×5), and the organic phase was concentrated under reduced pressure to give intermediate 1-C.
1 H NMR(400MHz,DMSO-d 6 )δ＝4.05(br s,1H),4.00(d,J＝6.8Hz,1H),3.24(s,6H),2.97(br d,J＝12.3Hz,2H),2.51-2.50(m,1H),2.47-2.43(m,1H),1.70-1.60(m,1H),1.58(br d,J＝13.3Hz,2H),1.14(dq,J＝3.9,12.3Hz,2H).
Step 3: synthesis of intermediate 1-C-d
Intermediate 1-C-C (34.40 g) and p-chloroiodobenzene (46 g) were dissolved in dimethyl sulfoxide (500 mL), L-proline (8.88 g), cuprous iodide (7.35 g) and potassium carbonate (53.32 g) were added with stirring, and the mixture was stirred under nitrogen at 110℃for 4 hours. After the reaction, the temperature of the reaction solution was lowered to 50℃or lower, the reaction solution was added to 2.5L of water with stirring, stirred for 10 minutes, filtered, and the cake was washed with 1L of water to collect a cake. 480mL of methyl tert-butyl ether were added, followed by ammonia (28%): water=1:2 (200 ml×2), the organic phases were washed with saturated brine (100 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phases concentrated under reduced pressure to give the crude product. Taking 20g crude product, adding 15mL methyl tertiary butyl ether, heating to fully dissolve, naturally cooling to room temperature, stirring for 30min, filtering, washing filter cake with methyl tertiary butyl ether (2 mL 3), collecting filter cake and drying to obtain intermediate 1-C-d.
1 H NMR(400MHz,CDCl 3 )δ＝7.22-7.14(m,2H),6.85(d,J＝8.9Hz,2H),4.08(d,J＝7.3Hz,1H),3.64(br d,J＝12.3Hz,2H),3.37(s,6H),2.65(dt,J＝2.3,12.3Hz,2H),1.84(br d,J＝13.1Hz,2H),1.75(tdt,J＝3.7,7.6,11.4Hz,1H),1.51-1.38(m,2H).
Step 4: synthesis of intermediate 1-C
Intermediate 1-C-d (1 g) and bis-pinacolato borate (1.48 g) were dissolved in methoxycyclopentane (20 mL), tris (dibenzylideneacetone) dipalladium (339.45 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (353.43 mg) and potassium acetate (1.09 g) were added, and the mixture was stirred under nitrogen at 110℃for 16 hours. After the reaction, the temperature of the reaction solution is reduced to room temperature, the reaction solution is filtered by diatomite, a filter cake is washed by methoxy cyclopentane (10 mL. 5), an organic phase is decompressed and concentrated to obtain a crude product, and the crude product is purified by column chromatography (ethyl acetate%: 0-5% and ethyl acetate/petroleum ether) to obtain an intermediate 1-C.
1 H NMR(400MHz,CDCl 3 )δ＝7.69(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),4.06(d,J＝6.8Hz,1H),3.82(br d,J＝12.5Hz,2H),3.36(s,6H),2.79-2.67(m,2H),1.87-1.80(m,2H),1.80-1.72(m,1H),1.49-1.39(m,2H),1.32(s,12H).
Step 5: synthesis of intermediate 1-B
Intermediate 1-A (10 g) was dissolved in methylene chloride (100 mL), pyridine (6.24 g) was added at 0℃and trifluoromethanesulfonic anhydride (37.08 g) was slowly added dropwise thereto, and the mixture was stirred under nitrogen at 15℃for 12 hours. After the reaction, the reaction mixture was added to water (200 mL), extracted with dichloromethane (100 mL x 2), the organic phase was washed with saturated sodium bicarbonate solution (50 mL x 2) and separated, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude intermediate 1-B.
Step 6: synthesis of intermediate 1-D
Intermediate 1-B (300 mg) and intermediate 1-C (369.33 mg) were dissolved in 1, 4-dioxane (12 mL), tetrakis (triphenylphosphine) palladium (95.95 mg) and 1M sodium bicarbonate solution (2.39 mL) were added with stirring, and the temperature was quickly raised to 80℃under nitrogen and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, the filter cake was washed with methyl tert-butyl ether (30 ml×5), 80mL of water was added to the organic phase, stirred for 10min, the mixture was allowed to stand for separation into separate layers, the aqueous phase was extracted with methyl tert-butyl ether (20 ml×3), the organic phases were combined and washed with saturated brine (50 ml×1), the organic phase was dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure to give a crude product, and the crude product was purified by column chromatography (ethyl acetate%: 0 to 5%, ethyl acetate/petroleum ether) to give intermediate 1-D.
1 H NMR(400MHz,CDCl 3 )δ＝7.17(d,J＝8.5Hz,2H),6.97(d,J＝8.5Hz,1H),6.87(br d,J＝6.3Hz,2H),6.82(d,J＝2.8Hz,1H),6.73(dd,J＝2.8,8.5Hz,1H),6.29(t,J＝7.3Hz,1H),4.09(d,J＝7.3Hz,1H),3.83(s,3H),3.71(br d,J＝12.3Hz,2H),3.37(s,6H),2.74-2.58(m,4H),2.14(quin,J＝7.0Hz,2H),1.94(q,J＝7.2Hz,2H),1.85(br d,J＝12.3Hz,2H),1.80-1.70(m,1H),1.53-1.39(m,2H).
Step 7: synthesis of intermediate 1
Intermediate 1-D (943.6 mg) was dissolved in methylene chloride (21 mL), pyridinium tribromide (777.51 mg) was added at-5 to 0℃and the temperature was maintained under stirring for 0.5 hours. After the reaction, adding 2M sodium bisulfate solution into the reaction solution until the color of the mixture is no longer light, stirring for 15min, adding dichloromethane (20 mL), standing for layering and separating, extracting the aqueous phase with dichloromethane (20 mL. Times.3), drying the organic phase with anhydrous sodium sulfate, filtering and concentrating to obtain a crude product, adding 5mL of n-heptane into the crude product, stirring at room temperature for 16 h, and concentrating under reduced pressure to obtain an intermediate 1.
1 H NMR(400MHz,CDCl 3 )δ＝7.17(br d,J＝8.5Hz,2H),7.05-6.86(m,2H),6.80-6.76(m,2H),6.69-6.64(m,1H),4.12(d,J＝7.3Hz,1H),3.82(s,3H),3.77(br d,J＝12.3Hz,2H),3.40(s,6H),2.76(br t,J＝7.0Hz,4H),2.59(t,J＝6.9Hz,2H),2.30(quin,J＝7.0Hz,2H),1.90(br d,J＝11.0Hz,2H),1.79(br s,1H),1.65(br s,2H)
Reference example 2
The synthetic route is as follows:
step 1: synthesis of intermediate 2-B
Intermediate 2-A (37 g) and N-Boc piperazine (32.34 g) were dissolved in dioxane (450 mL) and tris (dibenzylideneacetone) dipalladium (15.90 g), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (10.05 g) and potassium phosphate (73.74 g) were added with stirring. Stirring for 17 hours under nitrogen atmosphere at 90-100 ℃. After the reaction is finished, the reaction solution is cooled to room temperature, filtered and concentrated to obtain a crude product. Ethyl acetate (200 mL) and n-heptane (200 mL) were added, and the mixture was stirred and slurried at 15-20℃for 1 hour, filtered, and the filter cake was dried under vacuum to give intermediate 2-B.
1 H NMR(400MHz,CDCl 3 )δ＝7.77-7.75(m,1H),6.99(br dd,J＝2.0,8.6Hz,1H),6.80(s,1H),5.21(s,2H),3.62-3.59(m,4H),3.40-3.35(m,4H),1.49(s,9H).
Step 2: synthesis of intermediate 2-C
Intermediate 2-B (43 g) was dissolved in tetrahydrofuran (150 mL), methanol (150 mL) and water (150 mL), and sodium hydroxide (21.61 g) was added with stirring. Stirring for 16 hours at 15-25 ℃. After the reaction, a 1M hydrochloric acid solution was added to adjust the pH to 4 to 5, extraction was performed with ethyl acetate (200 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Ethyl acetate (125 mL) and n-heptane (250 mL) were added, stirred and slurried at 15-20℃for 2 hours, filtered, and the filter cake dried under vacuum to give intermediate 2-C.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.79-7.77(m,1H),7.35(br d,J＝5.8Hz,1H),7.21(br s,1H),6.82(br dd,J＝2.4,8.9Hz,1H),4.79(s,2H),3.45(br s,4H),3.30-3.28(m,4H),1.46-1.39(m,9H).
Step 3: synthesis of intermediate 2-D
Intermediate 2-C (15 g) was dissolved in methanol (90 mL) and ethyl acetate (90 mL), and a trimethylsilyl diazomethane 2M n-hexane solution (45 mL) was added at-10 to 0℃and stirred for 1 hour. Trimethylsilyl diazomethane 2M n-hexane solution (10 mL) was added at-10-0deg.C, and stirred at 0-5deg.C for 3 hours. The reaction was quenched by dropwise addition of a small amount of acetic acid, water (450 mL) was added, the solution was separated, and the aqueous layer was extracted with ethyl acetate (120 mL). The organic layers were combined, washed with saturated sodium carbonate solution (140 mL) and saturated brine (140 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 2-D.
Step 4: synthesis of intermediate 2-E
Intermediate 2-D (15 g) was dissolved in tetrahydrofuran (85 mL), triphenylphosphine (16.84 g) and carbon tetrabromide (21.29 g) were added, and the mixture was stirred at 15 to 25℃for 12 hours. 65mL (petroleum ether/ethyl acetate=3/1) was added, stirred, filtered, and the resulting filtrate was concentrated. 320mL (petroleum ether/ethyl acetate=3/1) was added, stirred, filtered, and the resulting filtrate was concentrated. 320mL (petroleum ether/ethyl acetate=3/1) was added, stirred, filtered and concentrated to give intermediate 2-E.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.81(d,J＝8.8Hz,1H),7.10(d,J＝2.8Hz,1H),6.92(dd,J＝2.6,8.9Hz,1H),5.00(s,2H),3.78(s,3H),3.46-3.43(m,4H),3.35-3.29(m,4H),1.41(s,9H).
Step 5: synthesis of intermediate 2-G
Intermediate 2-E (19.2 g) was dissolved in acetonitrile (385 mL), intermediate 2-F (16.63 g) and N, N-diisopropylethylamine (30.02 g) were added, and the mixture was stirred at 75-80℃for 24 hours. Water (260 mL) was added, extracted with ethyl acetate (2X 195 mL), washed with saturated brine (195 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to give crude intermediate 2-G. MS m/z 525.3[ M+Na ]] + 。
Step 6: synthesis of trifluoroacetate salt of intermediate 2
Intermediate 2-G (25G) was dissolved in acetonitrile (375 mL), benzenesulfonic acid (15.74G) was added, and the mixture was stirred at 75-80℃for 16 hours. Filtering, preparing a high-efficiency liquid phase (column type: phenomenex luna C, 250, 80mm, 10 mu m; mobile phase: water (trifluoroacetic acid) -acetonitrile; acetonitrile%: 0-15.5%, duration 18.5 min), and purifying the filter cake to obtain the trifluoroacetate of the intermediate 2.
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),8.92-8.75(m,2H),7.63-7.53(m,1H),7.18-7.08(m,2H),5.05(dd,J＝5.0,13.3Hz,1H),4.38-4.23(m,2H),3.55-3.44(m,4H),3.25(br s,4H),2.96-2.84(m,1H),2.64-2.54(m,1H),2.41-2.31(m,1H),2.02-1.91(m,1H).
Example 1
The synthetic route is as follows:
step 1: synthesis of Compound 1-A
2-methoxy-6, 7,8, 9-tetrahydro-5H-benzo [7 ]]After dissolution of the rota-n-5-one (2 g) in 1, 4-dioxane (30 mL), dichloro bis [ di-t-butyl- (4-dimethylaminophenyl) phosphine was added thereto]Palladium (II) (744.41 mg), potassium t-butoxide (1.77 g), and after the reaction solution was replaced with nitrogen three times, iodobenzene (4.72 g) was added thereto, and the reaction solution was stirred under nitrogen at an external temperature of 100℃for 16 hours. The reaction solution was filtered through celite, and the obtained filtrate was distilled off under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by column chromatography (petroleum ether/ethyl acetate=1:0-20:1) to obtain compound 1-a. MS m/z 266.9[ M+H ]] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.72(d,J＝8.5Hz,1H),7.38-7.33(m,2H),7.29-7.26(m,3H),6.83(dd,J＝2.5,8.5Hz,1H),6.77(d,J＝2.3Hz,1H),4.05(dd,J＝4.8,10.8Hz,1H),3.87(s,3H),3.19-3.08(m,1H),3.00-2.91(m,1H),2.23-2.14(m,2H),1.91-1.80(m,1H),1.57(s,1H)。
Step 2: synthesis of Compound 1-B
Compound 1-A (220 mg) was dissolved in methylene chloride (10 mL), pyridine (130.68 mg) was added thereto, the reaction solution was replaced with nitrogen gas three times, and trifluoromethanesulfonic anhydride (582.64 mg) was added dropwise thereto, and after the completion of the addition, the reaction solution was stirred at an external temperature of 30℃under nitrogen gas protection for 1 hour. To the reaction solution were added water (20 mL) and methylene chloride (20 mL), the mixture was separated, the aqueous phase was extracted with methylene chloride (10 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product is separated by column chromatography (petroleum ether/ethyl acetate=1:0-20:1) to obtain the compound 1-B.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.48-7.41(m,5H),7.39-7.34(m,1H),7.00-6.95(m,2H),3.82(s,3H),2.78(t,J＝7.0Hz,2H),2.43-2.30(m,2H),2.23-2.12(m,2H)。
Step 3: synthesis of Compound 1-C
Compound 1-B (1.67 g) was dissolved in 1, 4-dioxane (20 mL) and water (2 mL), to which was added p-hydroxyphenylboronic acid (693.81 mg), [1, 1-bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (342.32 mg), potassium carbonate (1.16 g), the reaction solution was replaced with nitrogen three times, and the reaction solution was stirred under nitrogen protection at an external temperature of 90℃for 16 hours. The reaction solution was filtered through celite, and the obtained filtrate was distilled off under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by column chromatography (petroleum ether/ethyl acetate=1:0-20:1) to obtain compound 1-C.
1 H NMR(400MHz,DMSO-d 6 )δ＝9.23(s,1H),7.19-7.07(m,5H),6.87(br s,1H),6.73-6.68(m,2H),6.62(br d,J＝8.3Hz,2H),6.47(br d,J＝8.3Hz,2H),3.76(s,3H),2.73(br t,J＝6.1Hz,2H),2.25(br t,J＝6.3Hz,2H),2.10-2.03(m,2H)。
Step 4: synthesis of Compound 1-D
Compound 1-C (35 mg) was dissolved in acetone (5 mL), to which was added 1, 5-dibromopentane (70.51 mg), potassium carbonate (42.38 mg), and the reaction solution was stirred at an external temperature of 70℃under nitrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by thin layer chromatography (petroleum ether/ethyl acetate=15:1) to give compound 1-D.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.26-7.07(m,5H),6.88(br d,J＝2.0Hz,1H),6.80-6.57(m,6H),3.89-3.82(m,2H),3.76(br s,3H),3.56-3.49(m,2H),2.74(br s,2H),2.27(br d,J＝5.5Hz,2H),2.07(br d,J＝6.3Hz,2H),1.87-1.79(m,2H),1.68(br d,J＝6.0Hz,2H),1.49(br d,J＝7.3Hz,2H)。
Step 5: synthesis of Compound 1-F
Compound 1-E (5 g) was dissolved in N, N-dimethylformamide (50 mL), 3-amino-2, 6-piperidinedione hydrochloride (2.94 g), potassium carbonate (6.73 g) was added thereto, and the reaction mixture was stirred at an external temperature of 75-80℃under nitrogen protection for 15 hours. The reaction mixture was added to water (250 mL), stirred for 2 hours, and then suction-filtered under reduced pressure to obtain a cake, which was rinsed with water (20 mL. Times.3). Petroleum ether (25 mL) and ethyl acetate (5 mL) were added to the obtained filter cake, and after stirring for 0.5 hours, the mixture was suction filtered under reduced pressure to obtain compound 1-F. MS m/z 323.8[ [ M+H] + 。
Step 6: synthesis of Compound 1-G
Compound 1-F (3.6 g) was dissolved in anhydrous N, N-dimethylformamide (50 mL), and 1-Boc-piperazine (4.15 g), potassium phosphate (9.46 g), (dibenzylideneacetone) dipalladium (1.02 g) and 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (531.09 mg) were added. The nitrogen was replaced three times and stirred at 100℃for 1.5 hours. After the reaction solution was cooled, it was added to 50mL of water, extracted with 200mL of ethyl acetate (50 ml×4), and the organic phase was washed with saturated brine (90 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a rapid column chromatography (petroleum ether/tetrahydrofuran=3/7 to 55/45) to give compound 1-G. MS m/z 429.1[ M+H ]] + 。
Step 7: synthesis of Compound 1-H hydrochloride
Compound 1-G (0.68G) was dissolved in methylene chloride (7 mL), and hydrogen chloride/dioxane (4M, 396.75. Mu.L) was added thereto and stirred at 20℃for 0.5 hours. Concentrating to obtain 1-H hydrochloride. MS m/z 328.8[ M+H ]] + 。
Step 8: synthesis of Compound 1-I
Compound 1-D (30 mg) was dissolved in 1-methyl-2-pyrrolidone (2 mL), and hydrochloride (26.72 mg) of Compound 1-H was added thereto, and N, N-diisopropylethylamine (39.45 mg) was reacted at 140℃for 2 hours under microwave. Ethyl acetate (15 mL) and water (20 mL) were added to the reaction mixture, the mixture was separated, and the organic phase was washed with water (20 mL. Times.3) and then with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product is separated by column chromatography (dichloromethane: methanol=1:0-50:1) to obtain compound 1-I.
1 H NMR(400MHz,DMSO-d 6 )δ＝10.94(s,1H),7.51(br d,J＝8.5Hz,1H),7.20-7.02(m,7H),6.88(br s,1H),6.77-6.59(m,6H),5.08-5.00(m,1H),4.36-4.14(m,2H),3.86(br s,2H),3.76(s,3H),3.26(br s,8H),2.95-2.82(m,2H),2.74(br s,2H),2.38-2.21(m,6H),2.06(br s,2H),1.68(br s,2H),1.50(br s,2H),1.39(br s,2H)。
Step 9: synthesis of Compound 1
Compound 1-I (50 mg) was dissolved in methylene chloride (2 mL) and tribromide was added under nitrogen at-70-60 ℃Boron (67.81 mg) was stirred at-70 to-60℃for 6hr. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution at 0-5 ℃. The mixture was extracted with dichloromethane (20 mL. Times.3), and the organic phases were combined and washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. The crude product was purified by thin layer chromatography (dichloromethane/methanol=10:1), followed by TLC (dichloromethane/methanol=10:1, rf=0.4) and then by preparation of the liquid phase (neutral, column: welch Xtimate C18.150mmx.5 μm; mobile phase: [ water (10 mM NH 4 HCO 3 ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile percent of 55-85 percent, 9 min) and purifying to obtain the compound 1.MS m/z 725.3[ M+H ]] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.73(d,J＝8.5Hz,1H),7.17-7.13(m,4H),7.12-7.06(m,1H),6.98(m,1H),6.87(s,1H),6.82-6.73(m,4H),6.62-6.56(m,3H),5.35(s,1H),5.20(dd,J＝5.1,13.2Hz,1H),4.44-4.38(m,1H),4.28-4.22(m,1H),3.87(t,J＝6.4Hz,2H),3.34(m,4H),2.95-2.80(m,2H),2.75(t,J＝7.0Hz,2H),2.68-2.58(m,4H),2.44(m,2H),2.40-2.35(m,2H),2.21(m,2H),2.17-2.12(m,2H),1.77(m,2H),1.64-1.59(m,2H),1.49(m,2H)。
Example 2
The synthetic route is as follows:
step 1: synthesis of Compound 2-A
To a solution of compound 1-C (0.98 g) in anhydrous dichloromethane (10 mL) was added pyridine (339.56 mg), and trifluoromethanesulfonic anhydride (1.21 g) was slowly added dropwise at 0 ℃. Stirred at 20℃for 12 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with methylene chloride (20 mL. Times.3), and the organic phase was washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Purifying the crude product by a column machine (0-5 percent) and ethyl acetate/petroleum ether to obtain the compound 2-A. MS m/z 474.8[ M ] H] + 。
Step 2: synthesis of Compound 2-B
Boron tribromide (2.03 g) was slowly added dropwise to a solution of compound 2-A (0.64 g) in anhydrous dichloromethane (3 mL) at-65℃under nitrogen protection, and the reaction was stirred at-65 to 20℃for 1 hour. After the completion of the reaction, the reaction mixture was slowly added to 30mL of water, the pH was adjusted to 7 to 8 with saturated sodium hydrogencarbonate solution (20 mL), extraction was performed with ethyl acetate (20 mL. Times.3), the organic phase was washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated to give Compound 2-B.
Step 3: synthesis of Compound 2-D
Compound 2-C (10 g) and trimethyl orthoformate (21.46 g) were dissolved in absolute methanol (100 mL) and p-toluenesulfonic acid monohydrate (769.21 mg) was added. Stirring is carried out for 12 hours under nitrogen at 15 ℃. Saturated sodium carbonate solution is added to adjust the pH to 7-8, dichloromethane (100 mL) is added to separate the solution, the organic phase is washed once with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to obtain the compound 2-D.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.40-7.28(m,5H),5.06(s,2H),4.05-3.98(m,3H),3.25(s,6H),2.75(s,2H),1.83-1.67(m,1H),1.67-1.56(m,2H),1.09(dq,J＝4.4,12.5Hz,2H)。
Step 4: synthesis of Compound 2-E
Compound 2-D (26 g) was dissolved in methanol (500 mL), wet palladium on carbon (3 g,10% purity) was added, and the mixture was stirred under a hydrogen atmosphere at 50psi at 25℃for 12 hours. The reaction solution was filtered through celite, and the filtrate was spin-dried to give 2-E.
1 H NMR(400MHz,DMSO-d 6 )δ＝5.20(s,1H),4.01(d,J＝6.8Hz,1H),3.24(s,6H),3.01(d,J＝11.8Hz,2H),2.56-2.51(m,2H),1.74-1.64(m,1H),1.60(d,J＝13.1Hz,2H),1.23-1.12(m,2H)。
Step 5: synthesis of Compound 2-F
To a solution of compound 2-B (0.56 g) and compound 2-E (0.29 g) in toluene (5 mL) were added potassium tert-butoxide (0.35 g), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (115.95 mg) and palladium acetate (27.3 mg), and the reaction was stirred under nitrogen at 90℃for 12 hours. The reaction solution was dried under reduced pressure.Purifying the crude product by a column machine (tetrahydrofuran is 0-10%, tetrahydrofuran/petroleum ether system) to obtain the compound 2-F. MS m/z 470.1[ M+H ]] + 。
Step 6: synthesis of Compound 2-G
To a solution of compound 2-F (80 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (616 mg), and the reaction was stirred at 20℃for 1 hour. The reaction solution is decompressed and distilled to obtain crude compound 2-G. MS m/z 423.9[ M+H ]] + 。
Step 7: synthesis of Compound 2
To a solution of compound 2-G (70 mg) and the hydrochloride salt of compound 1-H (72.35 mg) in methanol (5 mL) was added sodium acetate (27.11 mg), and the reaction was stirred at 20℃for 12 minutes. Sodium cyanoborohydride (20.77 mg) was added to the reaction solution, and the reaction was stirred at 20℃for 5 hours. The reaction mixture was quenched with saturated ammonium chloride (30 mL), extracted with dichloromethane (10 mL. Times.3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography (methanol 0-5%, methanol/dichloromethane system) to give compound 2.MS m/z 735.9[ M+H ] ] + 。
1 H NMR(400MHz,DMSO-d 6 )δ＝10.95(s,1H),9.36(s,1H),7.52(d,J＝8.8Hz,1H),7.19-7.02(m,7H),6.70-6.54(m,7H),5.05(dd,J＝5.0,13.3Hz,1H),4.39-4.13(m,2H),3.59(br d,J＝11.5Hz,2H),,3.27(br s,4H),2.99-2.81(m,1H),2.66(br s,2H),2.56(br s,2H),2.5(s,4H),2.41-2.30(m,2H)2.28-2.16(m,4H),2.08-1.92(m,4H),1.77(br d,J＝12.3Hz,2H),1.19-1.07(m,2H)。
Example 3
The synthetic route is as follows:
step 1: synthesis of Compound 3-A
In a three-necked flask, anhydrous toluene (30 mL) was added, followed by gradually adding aluminum trichloride (1.68 g) and then adding 2-methoxybenzocycloheptan-5-one (1 g,1 eq) with stirring, and stirring was performed at 90℃for 1 hour. The reaction was cooled to room temperature, slowly poured into crushed ice (60 g), stirred for 20 min, filtered, the filter cake rinsed with water (15 mL) and isopropyl ether (15 mL), and the filter cake spun dry to give compound 3-A. MS m/z 177.1[ M+H ]] + 。
Step 2: synthesis of Compound 3-B
Compound 3-A (953 mgl) was dissolved in anhydrous dichloromethane (20 mL), 2, 6-lutidine (1.16 g) was added, trifluoromethanesulfonic anhydride (3.05 g) was added under nitrogen at 0℃and stirred under nitrogen at 0℃for 1 hour. Stirred at 20℃for 48 hours. The reaction solution is dried by spin to obtain a crude product. The crude product was column chromatographed (petroleum ether/ethyl acetate=3:1) followed by TLC (petroleum ether/ethyl acetate=3:1) to give compound 3-B. MS m/z 308.8[ M+H ]] + 。
Step 3: synthesis of Compound 3-C
Compound 3-B (460 mg) was dissolved in anhydrous N, N-dimethylformamide (20 mL), methanol (20 mL), N, N-diisopropylethylamine (742.00 mg) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (54.59 mg) were added, and the mixture was stirred under carbon monoxide atmosphere at 45PSI at 75℃for 48 hours. The reaction solution is filtered by diatomite, and the filtrate is dried by spin to obtain a crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate=3:1) to give compound 3-C. MS m/z 218.8[ M+H ] ] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.93(dd,J＝1.4,7.9Hz,1H),7.88(s,1H),7.73(d,J＝8.0Hz,1H),3.93(s,3H),3.01-2.93(m,2H),2.78-2.71(m,2H),1.93-1.86(m,2H),1.85-1.78(m,2H)。
Step 4: synthesis of Compound 3-D
Compound 3-C (500 mg) and 2, 4-dichloroiodobenzene (1.56 g) were dissolved in anhydrous toluene (9 mL) and water (1 mL), cesium carbonate (1.12 g), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (265.12 mg) and palladium acetate (51.43 mg) were added, and the mixture was stirred under nitrogen at 110℃for 22 hours. Water (20 mL) was added, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give crude productThe product is obtained. The crude product was separated by column chromatography (petroleum ether/ethyl acetate=3:1) to give compound 3-D. MS m/z 363.0[ M+H ]] + 。
Step 5: synthesis of Compound 3-E
Sodium hydride (145.35 mg,60% purity) was dissolved in 2-methyltetrahydrofuran (10 mL) and 1.8-diazabicyclo [5.4.0 was added]Undec-7-ene (75.44 mg) was slowly added dropwise a solution of 3-D (600 mg) and N-phenylbis (trifluoromethanesulfonyl) imide (1.18 g) in 2-methyltetrahydrofuran (5 mL) under nitrogen at 20℃and stirred for 12 hours under nitrogen at 20 ℃. The reaction solution was cooled to 0℃and 1M diluted hydrochloric acid (5 mL) was slowly added dropwise thereto, the solution was separated, and the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give a crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate=5:1) to give compound 3-E. MS m/z 494.9[ M+H ] ] + 。
Step 6: synthesis of Compound 3-F
Compound 3-E (1.1 g) and p-hydroxyphenylboronic acid (459.49 mg) were dissolved in 1, 4-dioxane (20 mL), sodium carbonate (470.78 mg) and water (2 mL) were added, and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride dichloromethane complex (181.37 mg) was added under nitrogen atmosphere, and stirred at 90℃for 12 hours. The reaction solution was filtered through celite, water (20 mL) was added to the filtrate, extraction was performed with ethyl acetate (20 ml×3), and the organic phases were combined and washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate=3:1) to give compound 3-F. MS m/z 439.0[ M+H ]] + 。
Step 7: synthesis of Compound 3-G
Compound 3-F (360 mg) was dissolved in anhydrous dichloromethane (10 mL), pyridine (129.63 mg) was added, trifluoromethanesulfonic anhydride (462.39 mg) was added under nitrogen atmosphere, and the mixture was stirred under nitrogen atmosphere at 15℃for 12 hours. The reaction mixture was added with water (20 mL), extracted with methylene chloride (20 mL. Times.3), and the organic phases were combined and washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered to give a crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate=10:1) to give compound 3-G. MS m/z 571.4[ M+H ] ] + 。
Step 8: synthesis of Compound 3-H
Compounds 3-G (240 mg) and 2-E (100.32 mg) were dissolved in anhydrous toluene (10 mL), 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (40.05 mg) and sodium t-butoxide (121.10 mg) were added, palladium acetate (9.43 mg) was added under nitrogen, and the mixture was stirred under nitrogen at 90℃for 4 hours. The reaction solution was filtered through celite, the filter cake was rinsed with ethyl acetate (20 mL), water (20 mL) was added to the filtrate, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, and washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate=3:1) to give compound 3-H. MS m/z 580.1[ M+H ]] + 。
Step 9: synthesis of Compound 3-I
Compound 3-H (180 mg) was dissolved in methanol (10 mL), and a solution of sodium hydroxide (24.80 mg) in water (5 mL) was added thereto, followed by stirring at 65℃for 1 hour. The pH was adjusted to 6-7 with 2M dilute hydrochloric acid, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined and washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spun-dried to give 3-I. MS m/z 566.0[ M+H ]] + 。
Step 10: synthesis of Compound 3-J
Compound 3-I (180 mg) was dissolved in anhydrous dichloromethane (10 mL), and trifluoroacetic acid (7.70 g) was added thereto, followed by stirring at 20℃for 12 hours. The reaction solution is directly dried by spin to obtain crude 3-J which is directly put into the next step. MS m/z 520.0[ M+H ] ] + 。
Step 11: synthesis of hydrochloride salt of Compound 3
Compound 1-H (157.72 mg, hydrochloride) was dissolved in methanol (10 mL), sodium acetate (70.93 mg) was added, and the mixture was stirred under nitrogen at 15℃for 10 minutes, 3-J (150 mg) was added, and the mixture was stirred under nitrogen at 15℃for 10 minutes, sodium borohydride acetate (183.25 mg) was added, and the mixture was stirred under nitrogen at 15℃for 12 hours. The pH was adjusted to 4-5 by addition of 2M dilute hydrochloric acid, extracted with dichloromethane (30 mL. Times.3), the organic phases combined and washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, and spun-dried to give the crude product. The crude product is separated by preparing liquid phase (hydrochloric acid system). Column Xtime C18 x 40mm x 5 μm; mobile phase [ water (0.05% hydrochloric acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile30% -50% and 10min. The hydrochloride salt of 3 was obtained. MS m/z 832.3[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(m,2H),7.93(s,1H),7.77(d,J＝7.9Hz,1H),7.63-7.56(m,2H),7.43(s,1H),7.32-7.23(m,4H),7.18-7.13(m,2H),6.91-6.86(m,2H),5.06(dd,J＝4.8,13.2Hz,1H),4.42-4.19(m,2H),3.98(d,J＝12.6Hz,2H),3.67-3.59(m,8H),3.13(m,3H),2.98-2.89(m,3H),2.75-2.66(m,1H),2.59(d,J＝16.4Hz,2H),2.46-2.31(m,2H),2.17(m,4H),2.12-1.93(m,4H)。
Example 4
The synthetic route is as follows:
step 1: synthesis of Compound 4-A
To a solution of compound 2-B (0.94 g) and compound 4-piperidineethanol (0.38 g) in toluene (5 mL) were added sodium tert-butoxide (0.57 g), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (188.88 mg) and palladium acetate (44.48 mg), and the reaction was stirred under nitrogen at 90℃for 12 hours. The reaction solution was dried under reduced pressure. Purifying the crude product by column chromatography (ethyl acetate percent is 0-20 percent, ethyl acetate/petroleum ether) to obtain the compound 4-A.
1 H NMR(400MHz,CDCl 3 )δ＝7.20-7.07(m,5H),6.87-6.76(m,4H),6.74-6.60(m,3H),3.84(s,3H),3.77-3.70(m,2H),3.60(br d,J＝12.3Hz,2H),2.78(t,J＝7.0Hz,2H),2.63(br t,J＝11.3Hz,2H),2.42-2.32(m,2H),2.22-2.10(m,2H),1.79(br d,J＝12.8Hz,2H),1.61-1.55(m,3H),1.35(br d,J＝8.8Hz,2H)。
Step 2: synthesis of Compound 4-B
To a solution of compound 4-A (80 mg) in methylene chloride (5 mL) was added dessmartin reagent (112.2 mg), and the reaction was stirred at 20℃for 1 hour. The reaction solution was filtered, and the filtrate was dried under reduced pressure. Purifying the crude product by column chromatography (0-5% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 4-B.
1 H NMR(400MHz,CDCl 3 )δ＝9.81(s,1H),7.21-7.06(m,5H),6.88-6.60(m,7H),3.84(s,3H),3.60(br d,J＝12.5Hz,2H),2.79(br t,J＝6.9Hz,2H),2.68(br t,J＝11.5Hz,2H),2.47-2.32(m,4H),2.16(quin,J＝6.9Hz,2H),2.05-1.96(m,1H),1.80(br d,J＝12.5Hz,2H),1.41(br d,J＝10.3Hz,2H)。
Step 3: synthesis of Compound 4-C
Boron tribromide (222.76 mg) was slowly added dropwise to a solution of compound 4-B (40 mg) in anhydrous dichloromethane (50 mL) at-60℃under nitrogen protection, and the reaction was stirred at-60 to 20℃for 3.5 hours. After completion of the reaction, the reaction mixture was slowly added to 100mL of water, extracted with methylene chloride (30 mL. Times.3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 4-C. MS m/z 438.0[ M+H ]] +
Step 4: synthesis of Compound 4
To a solution of compound 4-C (330 mgl) in dichloromethane (10 mL) and methanol (2 mL) was added, in order, 7-H trifluoroacetate (333.63 mg), sodium acetate (123.73 mg), magnesium sulfate (453.89 mg). After stirring the reaction at 20℃for 30 minutes, sodium borohydride acetate (479.51 mg) was added and the reaction was stirred at 20℃for 3.5 hours. After the completion of the reaction, dilute hydrochloric acid (1M, 1 mL) was added dropwise to the reaction mixture, after stirring for 10 minutes, the pH was adjusted to 7 to 8 with saturated sodium bicarbonate (10 mL), the mixture was extracted with methylene chloride (20 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a crude product, which was purified by column chromatography (methanol: 0 to 2%, methanol/methylene chloride) to give Compound 4.MS m/z 750.4[ M+H ] ] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.94(s,1H),9.35(s,1H),7.51(br d,J＝8.5Hz,1H),7.18-7.11(m,4H),7.06(br s,3H),6.69-6.55(m,7H),5.04(br d,J＝8.8Hz,1H),4.38-4.15(m,2H),3.57(br d,J＝11.3Hz,2H),3.27(br s,6H),2.88(br d,J＝12.3Hz,1H),2.70-2.52(m,8H),2.38(br s,4H),2.24(br s,2H),2.02(br s,3H),1.72(br d,J＝10.3Hz,2H),1.41(br s,3H)。
Example 5
The synthetic route is as follows:
step 1: synthesis of Compound 5-A
To the compound 2-methoxy-6, 7,8, 9-tetrahydro-5H-benzo [7 ]]To a toluene (10 mL) solution of chromene-5-one (1.00 g), p-bromochlorobenzene (1.31 g), sodium t-butoxide (656.70 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (501.18 mg) and palladium acetate (118.02 mg) were added, and the mixture was purged with nitrogen for 1 minute to conduct a microwave reaction at 120℃for 1 hour. After the reaction, the reaction mixture was filtered through celite, the cake was washed with ethyl acetate (10 ml×3), and the organic phase was concentrated under reduced pressure to give a crude product. Purifying the crude product by column chromatography (0-4% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 5-A. MS m/z 300.9[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ＝7.70(d,J＝8.5Hz,1H),7.30(d,J＝8.5Hz,2H),7.24-7.17(m,2H),6.82(dd,J＝2.5,8.5Hz,1H),6.76(d,J＝2.0Hz,1H),4.03(dd,J＝5.0,11.0Hz,1H),3.85(s,3H),3.19-3.05(m,1H),3.01-2.88(m,1H),2.23-2.06(m,3H),1.93-1.75(m,1H)。
Step 2: synthesis of Compound 5-B
To a solution of compound 5-A (5.80 g) in anhydrous dichloromethane (120 mL) was added pyridine (2.29 g), and trifluoromethanesulfonic anhydride (13.60 g) was slowly added dropwise at 0deg.C. Stirred at 20℃for 12 hours. After the completion of the reaction, the reaction mixture was poured into 100mL of water, extracted with methylene chloride (30 mL. Times.3), the organic phase was washed with saturated sodium hydrogencarbonate (50 mL. Times.1), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude 5-B.
Step 3: synthesis of Compound 5-C
To a solution of compound 5-B (8.95 g) in 1, 4-dioxane (100 mL)) and water (10 mL) was added para-hydroxyphenylboronic acid (3.42 g), potassium carbonate (5.72 g) and [1, 1-bis (diphenylphosphine) ) Ferrocene]Palladium dichloride dichloromethane (1.69 g), nitrogen was displaced 3 times and reacted at 90℃for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the reaction mixture was filtered through celite, the cake was washed with ethyl acetate (10 ml×3), and the organic phase was concentrated under reduced pressure to give a crude product. Purifying the crude product by column chromatography (0-10% of ethyl acetate/petroleum ether) to obtain the compound 5-C. MS m/z 377.0[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝9.32(s,1H),7.24-7.20(m,2H),7.16-7.12(m,2H),6.88(d,J＝2.5Hz,1H),6.76-6.71(m,1H),6.70-6.67(m,1H),6.63(d,J＝8.5Hz,2H),6.51(d,J＝8.8Hz,2H),3.77(s,3H),2.73(br t,J＝6.8Hz,2H),2.28-2.20(m,2H),2.12-2.03(m,2H)。
Step 4: synthesis of Compound 5-D
To a solution of compound 5-C (3.53 g) in anhydrous dichloromethane (80 mL) was added pyridine (1.11 g), and trifluoromethanesulfonic anhydride (6.61 g) was slowly added dropwise at 0deg.C. Stirred at 20℃for 12 hours. After the completion of the reaction, the reaction mixture was poured into 100mL of water, extracted with methylene chloride (30 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude 5-D.
Step 5: synthesis of Compound 5-E
To a solution of compound 5-D (0.50 g) in toluene (10 mL) was added 2-E (234.64 mg), sodium t-butoxide (188.83 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (93.67 mg) and palladium acetate (22.06 mg), and the mixture was reacted at 90℃for 4 hours with nitrogen substitution 3 times. After the reaction was completed, the reaction mixture was cooled to room temperature, the reaction mixture was filtered through celite, the cake was washed with ethyl acetate (10 ml×3), and the organic phase was concentrated under reduced pressure to give a crude product. Purifying the crude product by column chromatography (0-10% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 5-E. MS m/z 518.3[ M+H ] ] +
1 H NMR(400MHz,CDCl 3 )δ＝7.13-7.07(m,4H),6.83(d,J＝8.3Hz,1H),6.80(d,J＝2.5Hz,1H),6.77-6.72(m,2H),6.68(dd,J＝2.8,8.5Hz,1H),6.66-6.62(m,2H),4.07(d,J＝7.3Hz,1H),3.83(s,3H),3.64(br d,J＝12.3Hz,2H),3.36(s,6H),2.75(br t,J＝7.0Hz,2H),2.60(dt,J＝2.1,12.2Hz,2H),2.38-2.27(m,2H),2.17-2.09(m,2H),1.82(br d,J＝12.3Hz,2H),1.50-1.34(m,3H)。
Step 6: synthesis of Compound 5-F
To a solution of compound 5-E (140 mg) in methylene chloride (28 mL) at 0deg.C was added boron tribromide (676.98 mg), and the reaction was stirred at 20deg.C for 2 hours. After the completion of the reaction, 50mL of water was added to the reaction mixture, the mixture was extracted with methylene chloride (20 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 5-F. MS m/z 476.2[ M+H+H ] 2 O] +
Step 7: synthesis of Compound 5
To a solution of compound 5-F (132 mg) and trifluoroacetate salt of intermediate 2 (191.25 mg) in dichloromethane (5 mL) and methanol (1 mL), sodium acetate (47.29 mg) and magnesium sulfate (173.46 mg) were added and the reaction was stirred at 20℃for 30 minutes, sodium borohydride acetate (183.25 mg) was added to the reaction solution, and the reaction was continued to be stirred at 20℃for 12 hours. The reaction mixture was quenched with water (20 mL), extracted with dichloromethane (20 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography (methanol 0-10%, methanol/dichloromethane) to give compound 5.
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),9.41(s,1H),7.52(br d,J＝8.8Hz,1H),7.26-7.19(m,2H),7.19-7.12(m,2H),7.10-7.03(m,2H),6.72-6.62(m,5H),6.60-6.52(m,2H),5.05(br dd,J＝4.9,13.3Hz,1H),4.39-4.28(m,1H),4.25-4.16(m,1H),3.63(br d,J＝12.0Hz,2H),3.34-3.23(m,6H),2.97-2.84(m,1H),2.69-2.54(m,8H),2.40-2.32(m,2H),2.25-2.16(m,4H),2.12-1.93(m,3H),1.78(br d,J＝11.6Hz,2H),1.67(br s,1H)。
Example 6
The synthetic route is as follows:
step 1: synthesis of Compound 6-B
To compound 6-A (5.25 g) was added anhydrous dichloromethane (100 mL), and trifluoromethanesulfonic anhydride (13.02 g) was added at 0deg.C, followed by slow dropwise addition of pyridine (2.19 g). Stirred at 25℃for 12 hours. After the reaction, the reaction mixture was poured into 30mL of water, extracted with dichloromethane (20 ml×2), the organic layer was washed with saturated sodium bicarbonate solution (20×2 mL), the organic phase was left, 2.5g of anhydrous sodium sulfate was added to the organic layer to dry, and after standing for 10min, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 6-B.
Step 2: synthesis of Compound 6-C
40mL of 1, 4-dioxane and 5mL of water were added to compound 6-B (8.56 g), 4-hydroxyphenylboronic acid (3.40 g) was added thereto, and after stirring and dissolution, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane (1.68 g) and potassium carbonate (5.68 g) were added, nitrogen was replaced 3 times, and the temperature was raised to 90℃and stirred for 4 hours. After the reaction, 20mL of ethanol was added to the reaction mixture, the mixture was concentrated under reduced pressure, the crude product was washed with water (20 mL. Times.2), extracted with ethyl acetate (30 mL. Times.2), and the organic phase was concentrated to give 6-C.
1 H NMR(400MHz,CDCl 3 )δ＝7.18-7.07(m,2H),6.91-6.81(m,4H),6.81-6.75(m,2H),6.75-6.69(m,1H),6.61-6.55(m,2H),3.85(s,3H),2.79(t,J＝7.0Hz,2H),2.41-2.34(m,2H),2.20-2.11(m,2H)；MS m/z:361.1[M+H] + 。
Step 3: synthesis of Compound 6-D
To compound 6-C (7.12 g) was added 100mL of trifluoromethanesulfonic anhydride (13.93 g) at 0℃and pyridine (2.34 g) and reacted at 25℃for 12 hours. After completion of the reaction, water (40 mL) was added to the system, dichloromethane (20 mL. Times.2) was used for extraction, the organic layer was washed with saturated sodium hydrogencarbonate solution (15 mL. Times.2), 2g of anhydrous sodium sulfate was added to the organic layer for drying, and after standing for 10min, filtration was carried out, and the filtrate was concentrated under reduced pressure to give 6-D.
Step 4: synthesis of Compound 6-E
To compound 6-D (641.03 mg) was added 10mL of toluene, 2-E (242.48 mg), sodium t-butoxide (292.70 mg), palladium acetate (22.79 mg), 2-di-t-butylphosphine-2 ',4',6' -triisopropylbiphenyl (96.80 mg) under nitrogen, and the mixture was reacted at 90℃for 6 hours. The reaction system was filtered through celite using a sand core funnel. The filtrate was washed with water (20 mL. Times.2), followed by ethyl acetate (20 mL. Times.) 2) Extracting, and concentrating the organic phase under reduced pressure to obtain 6-E. MS m/z 502.4[ M+H ]] + 。
Step 5: synthesis of Compound 6-F
6-E (0.1541 g) was added to DCM (10 mL), -boron tribromide (772.67 mg) was added at 60℃and dry ice was removed by stirring for 30min and reacted at 20℃for 5h. After completion of the reaction, water (20 mL) was added to the reaction system, the mixture was extracted with methylene chloride (10 mL. Times.2), the organic phase was dried over 1g of anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure after filtration to give 6-F. MS m/z 442.2[ M+H ]] + 。
Step 6: synthesis of Compound 6
To compound 6-F (0.0917 g) was added anhydrous dichloromethane (10 mL), methanol (2 mL), 7-H trifluoroacetate (137.82 mg), anhydrous magnesium sulfate (124.99 mg) and sodium acetate (34.07 mg), followed by stirring at 20℃for 0.5 hours and then sodium triacetoxyborohydride (132.05 mg), and the mixture was reacted at 20℃for 11.5 hours. The crude product after the reaction is purified by column chromatography (0 to 8 percent, methylene dichloride/methanol) to obtain the compound 6.
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),9.39(s,1H),7.52(d,J＝8.3Hz,1H),7.15(br d,J＝5.8Hz,2H),7.11-6.91(m,4H),6.65(s,5H),6.57(s,2H),5.15-4.96(m,1H),4.40-4.26(m,1H),4.23(s,1H),3.73-3.53(m,4H),3.29(br dd,J＝2.4,4.9Hz,4H),3.31-3.24(m,1H),3.17(d,J＝5.3Hz,2H),2.69-2.61(m,6H),2.37-2.31(m,2H),2.27-2.16(m,4H),2.04(br d,J＝6.5Hz,2H),1.76(br s,2H),1.16(br d,J＝9.0Hz,2H)；MS m/z:754.3[M+H] + 。
Example 7
The synthetic route is as follows:
step 1: synthesis of Compound 2-D
Compound 2-C (10 g,40.44 mmol) and trimethyl orthoformate (21.46 g,202.19mmol,22.17 mL) were dissolved in anhydrous methanol (100 mL) and p-toluenesulfonic acid monohydrate (769.21 mg,4.04 mmol) was added. Stirring was carried out under nitrogen at 15℃for 5 hours. Saturated sodium carbonate solution is added to adjust the pH to 7-8, water (100 mL) and dichloromethane (100 mL) are added, the solution is separated, the organic phase is washed once with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to obtain crude compound 2-D.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.37-7.31(m,5H),5.05(s,2H),4.05-3.99(m,3H),3.24(s,6H),2.75(br,2H),1.74(tdt,J＝3.6,7.6,11.3Hz,1H),1.62(br d,J＝12.4Hz,2H),1.09(dq,J＝4.4,12.5Hz,2H)
Step 2: synthesis of Compound 2-E
Compound 2-D (50 g) was dissolved in methanol (1000 mL), wet palladium on carbon (7 g,10% purity) was added, and the mixture was stirred under a hydrogen atmosphere at 50PSI at 25℃for 12 hours. The reaction mixture was filtered through celite, the filter cake was washed with methanol (200 mL. Times.5), and the organic phase was concentrated under reduced pressure to give crude compound 2-E.
1 H NMR(400MHz,DMSO-d 6 )δ＝4.00(d,J＝6.8Hz,1H),3.27-3.21(m,6H),2.94(br d,J＝11.5Hz,2H),2.44(dt,J＝2.0,12.2Hz,2H),1.69-1.60(m,1H),1.56(br d,J＝13.3Hz,2H),1.10(dq,J＝3.9,12.2Hz,2H)
Step 3: synthesis of Compound 7-J
To a solution of compound 7-I (2.5 g) in anhydrous dichloromethane (50 mL) was added pyridine (866.24 mg), and trifluoromethanesulfonic anhydride (5.15 g) was slowly added dropwise at 0deg.C. Stirred at 25℃for 12 hours. After completion of the reaction, the reaction mixture was poured into 50mL of water, extracted with methylene chloride (30 mL. Times.3), and the organic phase was washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 7-J.
Step 4: synthesis of Compound 7-K
7-J (3 g) was dissolved in toluene (60 mL), to which was added 2-E (1.62 g), sodium t-butoxide (1.22 g), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (602.82 mg) and palladium acetate (141.95 mg), N2 was substituted 3 times, and the temperature was raised to 90℃and stirred for 12 hours. Filtering, concentrating to obtain crude product, and purifying the crude product by column chromatography (ethyl acetate 0-20%, petroleum ether/ethyl acetate) to obtain compound 7-K.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.17-7.13(m,5H),6.87(d,J＝2.5Hz,1H),6.72-6.61(m,5H),6.46(d,J＝8.8Hz,1H),4.07–4.00(m,1H),3.77(s,3H),3.61(br d,J＝12.0Hz,1H),3.42(br s,5H),3.25(s,2H),2.74(br t,J＝6.7Hz,2H),2.27-2.24(m,2H),2.06(m,2H),1.76-1.56(m,3H),1.25-1.23(m,2H),1.19-1.16(m,2H)。
Step 5: synthesis of Compound 7-L
7-K (0.9 g) was dissolved in tetrahydrofuran (25 mL), diluted sulfuric acid (1M, 25 mL) was added, and the mixture was stirred at 60℃for 4 hours. Saturated sodium bicarbonate solution was added to adjust pH to 7, extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and spun-dried to give crude compound 7-L. MS m/z 438.2[ M+Na ]] + 。
Step 6: synthesis of Compound 7
Compound 7-L (0.3 g) and trifluoroacetate salt of intermediate 2 (454.95 mg) were dissolved in a solution of methanol (10 mL) and methylene chloride (2 mL), and sodium acetate (112.48 mg) and magnesium sulfate (412.63 mg) were added thereto and stirred at 20℃for 30 minutes. Sodium borohydride acetate (435.92 mg) was added to the reaction solution, and the reaction was stirred at 20℃for an additional 11.5 hours. The reaction was quenched by adding 1M dilute hydrochloric acid (30 mL) with stirring for 30 min, adjusted to pH 7 with saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and spun-dried to give crude compound 7.
1 H NMR(400MHz,DMSO-d 6 )δ＝10.94(s,1H),7.51(d,J＝8.3Hz,1H),7.21-7.02(m,7H),6.88(d,J＝2.3Hz,1H),6.76-6.60(m,6H),5.04(dd,J＝5.0,13.3Hz,1H),4.37-4.13(m,2H),3.77(s,3H),3.60(br d,J＝11.8Hz,2H),3.32-3.23(m,6H),2.96-2.83(m,1H),2.78-2.69(m,2H),2.56(br t,J＝11.7Hz,6H),2.47-2.29(m,2H),2.28-2.17(m,4H),2.12-1.89(m,3H),1.83-1.59(m,3H)。
Example 8
The synthetic route is as follows:
step 1: synthesis of Compound 8-A
Compound 6-E (0.227 g) was dissolved in 10mL of tetrahydrofuran and H was added 2 SO 4 (1M,6.09mL)，N 2 Protection, reaction at 60℃for 4 hours. After the reaction was completed, 40ml×2 water was added to the system, the mixture was washed with a saturated sodium hydrogencarbonate solution until the aqueous phase ph=7, extracted with 20mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure to obtain crude product 8-A. MS m/z 456.2[ M+H ] ] + 。
Step 2: synthesis of Compound 8
Compound 8-A (0.244 g), 7-H trifluoroacetate (355.42 mg) was dissolved in 15mL of methylene chloride, 3mL of methanol, anhydrous magnesium sulfate (322.35 mg), anhydrous sodium acetate (87.87 mg) and sodium borohydride acetate (340.55 mg) were added, followed by stirring for 30min, N 2 The reaction is carried out for 6 hours at 25 ℃, diatomite is used for filtering the reaction system, 20mL of water is added into the filtrate, dichloromethane (20 mL) is used for extraction, the organic phase is decompressed and concentrated to obtain crude product, and the crude product is purified by column chromatography (0-8% of methanol and dichloromethane/methanol) to obtain the compound 8.
1 H NMR(400MHz,DMSO-d 6 )δ＝11.99(br,1H),10.96(s,1H),7.52(d,J＝8.8Hz,1H),7.18(dd,J＝5.6,8.7Hz,2H),7.10-6.97(m,4H),6.88(d,J＝2.5Hz,1H),6.73(br d,J＝2.5Hz,1H),6.70-6.65(m,4H),5.05(dd,J＝4.9,13.2Hz,1H),4.37-4.29(m,1H),4.25-4.16(m,1H),4.03(d,J＝7.0Hz,1H),3.77(s,3H),3.66-3.58(m,2H),3.28(br s,4H),3.17(d,J＝5.3Hz,1H),2.73(br s,2H),2.57(br s,2H),2.41-2.35(m,1H),2.28-2.17(m,4H),2.09(s,2H),1.99(s,2H),1.91(s,4H),1.82-1.72(m,2H),1.18(s,2H)，MS m/z:768.4[M+H] + 。
Example 9
The synthetic route is as follows:
step 1: synthesis of Compound 9-A
To the compound 2-methoxy-6, 7,8, 9-tetrahydro-5H-benzo [7 ]]To a toluene (10 mL) solution of chromene-5-one (1.00 g), p-methoxybromobenzene (1.28 g), sodium t-butoxide (656.70 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (501.18 mg) and palladium acetate (118.02 mg) were added, and the mixture was purged with nitrogen for 1 minute to conduct a microwave reaction at 120℃for 1 hour. After the reaction, the reaction mixture was filtered through celite, the cake was washed with ethyl acetate (10 ml×3), and the organic phase was concentrated under reduced pressure to give a crude product. Purifying the crude product by column chromatography (0-8% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 9-A. MS m/z 296.9[ M+H ] ] +
Step 2: synthesis of Compound 9-B
To a solution of compound 9-A (2.80 g) in anhydrous dichloromethane (60 mL) was added pyridine (1.12 g), and trifluoromethanesulfonic anhydride (6.66 g) was slowly added dropwise at 0deg.C. Stirred at 20℃for 12 hours. After the completion of the reaction, the reaction mixture was poured into 100mL of water, extracted with methylene chloride (30 mL. Times.3), the organic phase was washed with saturated sodium hydrogencarbonate (50 mL. Times.1), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude 9-B.
Step 3: synthesis of Compound 9-C
To a solution of compound 9-B (4.40 g) in 1, 4-dioxane (50 mL)) and water (5 mL) was added p-hydroxyphenylboronic acid (1.70 g), potassium carbonate (2.84 g) and [1, 1-bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane (838.71 mg), nitrogen displaced 3 times, was reacted at 90℃for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the reaction mixture was filtered through celite, the cake was washed with ethyl acetate (10 mL. Times.6), and the organic phase was concentrated under reduced pressure to give a crude product. Purifying the crude product by column chromatography (5-12% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 9-C. MS m/z 373.0[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝9.24(s,1H),7.05(d,J＝8.5Hz,2H),6.87(d,J＝2.5Hz,1H),6.75-6.71(m,3H),6.69-6.66(m,1H),6.64(d,J＝8.5Hz,2H),6.49(d,J＝8.5Hz,2H),3.76(s,3H),3.70(s,3H),2.72(br t,J＝6.8Hz,2H),2.28-2.19(m,2H),2.11-2.02(m,2H)
Step 4: synthesis of Compound 9-D
To a solution of compound 9-C (2.20 g) in anhydrous dichloromethane (50 mL) was added pyridine (692.62 mg), and trifluoromethanesulfonic anhydride (4.12 g) was slowly added dropwise at 0 ℃. Stirred at 20℃for 16 hours. After the completion of the reaction, the reaction mixture was poured into 100mL of water, extracted with methylene chloride (30 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude 9-D.
Step 5: synthesis of Compound 9-E
To a solution of compound 9-D (0.50 g) in toluene (10 mL) was added 2-E (236.70 mg), sodium t-butoxide (190.48 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (94.49 mg) and palladium acetate (22.25 mg), and the mixture was reacted at 90℃for 2 hours with nitrogen substitution 3 times. After the reaction was completed, the reaction mixture was cooled to room temperature, the reaction mixture was filtered through celite, the cake was washed with ethyl acetate (15 ml×6), and the organic phase was concentrated under reduced pressure to give a crude product. The crude product is purified by column chromatography (5-8% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 9-E. MS m/z 514.3[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝7.07(d,J＝8.8Hz,2H),6.87(d,J＝2.5Hz,1H),6.74(d,J＝8.8Hz,3H),6.68(s,1H),6.65(s,4H),4.07(d,J＝6.5Hz,1H),3.76(s,3H),3.70(s,3H),3.62(br d,J＝11.8Hz,2H),3.26(s,6H),2.72(br t,J＝6.7Hz,2H),2.56-2.53(m,2H),2.28-2.18(m,2H),2.10-2.01(m,2H),1.68(br d,J＝10.3Hz,3H),1.26(br d,J＝12.8Hz,2H)。
Step 6: synthesis of Compound 9-F
To a solution of compound 9-E (70 mg) in methylene chloride (14 mL) at 0deg.C was added boron tribromide (341.40 mg), and the reaction was stirred at 20deg.C for 1 hour. After the completion of the reaction, the reaction mixture was added to 50mL of water, extracted with methylene chloride (10 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 9-F. MS m/z 440.2[ M+H ]] +
Step 7: synthesis of Compound 9
To a solution of compound 9-F (40 mg) and trifluoroacetate salt of intermediate 2 (60.39 mg) in dichloromethane (5 mL) and methanol (1 mL), sodium acetate (14.93 mg) and magnesium sulfate (54.77 mg) were added to react at 20 ℃ for 30 minutes, sodium borohydride acetate (57.86 mg) was added to the reaction solution, and the reaction was continued to stir at 20 ℃ for 12 hours. The reaction solution is concentrated under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography (methanol 0-5%, methanol/dichloromethane) to obtain the compound 9.MS m/z 752.4[ M+H ] ] + 。
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),9.33(s,1H),9.24(s,1H),7.53(d,J＝8.4Hz,1H),7.13-7.03(m,2H),6.93(d,J＝8.5Hz,2H),6.65(s,5H),6.59-6.48(m,4H),5.05(dd,J＝5.1,13.3Hz,1H),4.38-4.16(m,2H),3.61(br d,J＝10.5Hz,2H),3.32-3.23(m,6H),2.93-2.85(m,1H),2.70-2.54(m,8H),2.41-2.32(m,3H),2.20(br s,3H),2.06-1.95(m,3H),1.85-1.59(m,3H)。
Example 10
The synthetic route is as follows:
step 1: synthesis of Compound 10-A
To a solution of m-methoxyphenol (10 g) in N, N-dimethylformamide (100 mL) was added ethyl 4-bromobutyrate (15.87 g) and potassium carbonate (33.40 g). The mixture was stirred at 20℃for 12 hours. After completion of the reaction, the reaction mixture was poured into 300mL of water, extracted with ethyl acetate (50 mL. Times.2), and the organic phase was washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 10-A. PE/ea=10/1, rf=0.27.
Step 2: synthesis of Compound 10-B
To a solution of compound 10-A (20 g) in anhydrous methanol (150 mL) and water (50 mL) was added potassium hydroxide (9.42 g). The mixture was stirred at 40℃for 1 hour. The reaction solution was adjusted to pH 3 to 4 with 1M aqueous diluted hydrochloric acid, stirred at room temperature for 30 minutes, and a solid was precipitated, filtered and dried to give crude compound 10-B.
Step 3: synthesis of Compound 10-C
To a solution of compound 10-B (5 g) in chlorobenzene (100 mL) was added polyphosphoric acid (25 g). The mixture was stirred at 80℃for 12 hours. The hot reaction solution was slowly poured into ice water (200 mL), extracted with methylene chloride (100 mL. Times.3), washed with saturated sodium bicarbonate (30 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and rotary distilled under reduced pressure to give crude product. Purifying the crude product by column chromatography (0-15% ethyl acetate/petroleum ether) to obtain the compound 10-C.
1 H NMR(400MHz,CDCl 3 )δ＝7.77(d,J＝8.8Hz,1H),6.66(dd,J＝2.3,8.8Hz,1H),6.56(d,J＝2.3Hz,1H),4.25(t,J＝6.7Hz,2H),3.84(s,3H),2.87(t,J＝7.0Hz,2H),2.20(quin,J＝6.8Hz,2H)
Step 4: synthesis of Compound 10-D
Compound 10-C (1 g), bromobenzene (1.06 g), sodium t-butoxide (999.94 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (496.04 mg) and palladium acetate (116.80 mg) were mixed and stirred in a toluene (10 mL) solution, and the mixture was placed in a microwave tube, and after nitrogen substitution, the reaction was performed under microwave at 120℃for 1 hour. The reaction solution was filtered and distilled under reduced pressure to obtain crude product. Purifying the crude product by column chromatography (0-5% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 10-D. MS m/z 268.9[ M+H ]] +
Step 5: synthesis of Compound 10-E
To a solution of compound 10-D (6.74 g) in methylene chloride (120 mL) was added trifluoromethanesulfonic anhydride (17.72 g) and pyridine (2.98 g) at 0-5 ℃. The mixture was warmed to 33 ℃ and stirred for 12 hours. After completion of the reaction, the reaction mixture was added to water (300 mL), extracted with methylene chloride (50 mL. Times.2), washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give Compound 10-E.
Step 6: synthesis of Compound 10-F
To a solution of compound 10-E (3.24 g) in dioxane (50 mL) and water (5 mL) was added p-hydroxyphenylboronic acid (1.34 g), potassium carbonate (2.24 g) and [1, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane (660.87 mg). The mixture was warmed to 90 ℃ under nitrogen and stirred for 2 hours. After the reaction is finished, the reaction solution is filtered, decompressed and distilled to obtain a crude product, and the crude product is purified by column chromatography (0 to 10 percent of ethyl acetate and 0 to 10 percent of ethyl acetate/petroleum ether) to obtain the compound 10-F.
1 H NMR(400MHz,CDCl 3 )δ＝7.21-7.09(m,5H),6.88-6.77(m,3H),6.70(d,J＝2.8Hz,1H),6.63-6.54(m,3H),4.62(t,J＝6.1Hz,2H),3.83(s,3H),2.74(t,J＝6.0Hz,2H)。
Step 7: synthesis of Compound 10-G
To a solution of compound 10-F (2.75 g) in methylene chloride (50 mL) at 0-5℃was added trifluoromethanesulfonic anhydride (5.63 g) and pyridine (947.40 mg). The mixture was warmed to 25 ℃ and stirred for 12 hours. After the reaction, the reaction mixture was added to water (300 mL), extracted with methylene chloride (50 mL. Times.2), washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a crude product, which was purified by column chromatography (ethyl acetate 0 to 8%, ethyl acetate/petroleum ether) to give compound 10-G.
Step 8: synthesis of Compound 10-H
To a toluene (20 mL) solution of compound 10-G (2G) were added compound 2-E (1.25G), sodium t-butoxide (1.21G), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (400.21 mg) and palladium acetate (94.24 mg). The mixture was warmed to 90 ℃ under nitrogen and stirred for 3 hours. After the reaction is finished, the reaction solution is filtered, decompressed and distilled to obtain a crude product, and the crude product is purified by column chromatography (0 to 25 percent of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 10-H. MS m/z 486.3[ M+H ]] + 。
Step 9: synthesis of Compound 10-I
To a solution of compound 10-H (0.77 g) in tetrahydrofuran (20 mL) was added dilute hydrochloric acid (1M, 20 mL). The mixture was warmed to 60 ℃ and stirred for 12 hours. After the completion of the reaction, the reaction mixture was cooled, added to water (20 mL), pH was adjusted to 7 to 8 with saturated sodium hydrogencarbonate (50 mL), extracted with ethyl acetate (50 mL. Times.2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered And (3) performing rotary evaporation under reduced pressure to obtain a compound 10-I. MS m/z 440.1[ M+H ]] + 。
Step 10: synthesis of Compound 10
To a solution of compound 10-I (0.83 g) in dichloromethane (10 mL) and methanol (1 mL) was added, in order, 7-H trifluoroacetate (375.92 mg), sodium acetate (92.94 mg), magnesium sulfate (340.95 mg). After stirring the reaction at 20℃for 30 minutes, sodium borohydride acetate (360.19 mg) was added, and the reaction was stirred at 20℃for an additional 11.5 hours. After the completion of the reaction, dilute hydrochloric acid (1M, 1 mL) was added dropwise to the reaction mixture, after stirring for 10 minutes, the pH was adjusted to 7 to 8 with saturated sodium bicarbonate (20 mL), the mixture was extracted with methylene chloride (50 mL. Times.3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a crude product, which was purified by column chromatography (methanol 0 to 2%, methanol/methylene chloride) to give compound 10.MS m/z 752.4[ M+H ]] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.99(s,1H),7.73(d,J＝8.5Hz,1H),7.17(d,J＝4.3Hz,4H),7.10(qd,J＝4.3,8.5Hz,1H),6.99(dd,J＝1.9,8.7Hz,1H),6.88(s,1H),6.82(dd,J＝4.1,8.7Hz,3H),6.70-6.63(m,3H),6.58(dd,J＝2.6,8.7Hz,1H),5.20(dd,J＝5.1,13.2Hz,1H),4.60(t,J＝6.0Hz,2H),4.46-4.20(m,2H),3.82(s,3H),3.63(br d,J＝12.3Hz,2H),3.32(br s,4H),2.95-2.76(m,2H),2.71(t,J＝5.9Hz,2H),2.68-2.55(m,6H),2.32(dd,J＝5.3,13.1Hz,1H),2.27(br d,J＝5.8Hz,2H),2.29-2.24(m,1H),2.23-2.19(m,1H),1.86(br d,J＝12.5Hz,2H),1.32(br d,J＝10.8Hz,2H)。
Example 11
The synthetic route is as follows:
step 1: synthesis of Compound 11-B
11-A (1 g), 4-bromotoluene (1.08 g) was dissolved in 10mL of toluene, followed by addition of palladium acetate (118.02 mg), 2-di-tert-Butylphosphine-2 ',4',6' -triisopropylbiphenyl (501.18 mg), sodium tert-butoxide (656.70 mg), N 2 Protecting, carrying out microwave reaction for 1 hour at 120 ℃, and filtering the reacted system by using a sand core funnel through diatomite. The filtrate was washed with water (20 mL. Times.2), extracted with ethyl acetate (20 mL. Times.2), and the organic phase was concentrated under reduced pressure to give 11-B. MS m/z 281.0[ M+H ] ] + 。
Step 2: synthesis of Compound 11-C
Compound 11-B (2.88 g) was dissolved in 30mL of anhydrous methylene chloride, trifluoromethanesulfonic anhydride (7.25 g) was added at 0deg.C, and pyridine (1.22 g) was slowly added dropwise, N 2 The reaction mixture was stirred at 25℃for 12 hours under protection, after the completion of the reaction, the reaction mixture was poured into water (30 mL), extracted with methylene chloride (20 mL. Times.2), the organic layer was washed with a saturated sodium hydrogencarbonate solution (20 mL. Times.2), the organic phase remained, 2.5g of anhydrous sodium sulfate was added to the organic phase to dry, the mixture was allowed to stand for 10 minutes, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 11-C.
Step 3: synthesis of Compound 11-D
Compound 11-C (4.1 g) was dissolved in 40mL of 1, 4-dioxane and 5mL of water, 4-hydroxyphenylboronic acid (1.65 g), anhydrous potassium carbonate (2.75 g) was added thereto, and after stirring and dissolution, [1, 1-bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane (811.84 mg) was added thereto, nitrogen was substituted 3 times, and the reaction was carried out at 90℃for 4 hours. After the reaction, 20mL of ethanol is added into the system for decompression concentration, water (20 mL multiplied by 2) is added into the crude product for washing, ethyl acetate (20 mL multiplied by 2) is used for extraction, the organic phase is concentrated to obtain the crude product, and the crude product is purified by column chromatography (0 to 10 percent of ethyl acetate and 0 to 10 percent of petroleum ether/ethyl acetate) to obtain the compound 11-D.
1 H NMR(400MHz,DMSO-d 6 )δ＝9.25(s,1H),7.05-6.93(m,4H),6.87(d,J＝2.5Hz,1H),6.76-6.66(m,2H),6.66-6.59(m,2H),6.55-6.41(m,2H),3.76(s,3H),3.45(dq,J＝5.1,7.0Hz,2H),2.72(br t,J＝6.8Hz,2H),2.22(s,3H),2.12-1.96(m,2H),MS m/z:357.1[M+H] + 。
Step 4: synthesis of Compound 11-E
Compound 11-D (2.6 g) was dissolved in 20mL of anhydrous methylene chloride, trifluoromethanesulfonic anhydride (5.14 g) was added at 0℃and pyridine (865.44 mg) was slowly added dropwise, N 2 Protecting, stirring at 25deg.C for 6 hr, pouring the reaction solution into 30mL of water after the reaction is completed, and using dichloroMethane (20 mL x 2) extraction, washing the organic layer with saturated sodium bicarbonate solution (20 mL x 2), leaving an organic phase, drying the organic phase over 2.5g anhydrous sodium sulfate, standing for 10min, filtering, concentrating the filtrate under reduced pressure to obtain 11-E. MS m/z 489.1[ M+H ]] + 。
Step 5: synthesis of Compound 11-F
Compound 11-E (0.6 g), 2-E (293.77 mg) was dissolved in 10mL of toluene, sodium t-butoxide (354.61 mg), 2-di-t-butylphosphine-2 ',4',6' -triisopropylbiphenyl (117.27 mg), palladium acetate (27.61 mg), nitrogen protection, and the reaction system was filtered through celite using a sand-core funnel after 6 hours reaction at 90 ℃. The filtrate was washed with water (20 mL. Times.2), extracted with ethyl acetate (20 mL. Times.2), and the organic phase was concentrated under reduced pressure to give 11-F, MS m/z:498.3[ M+H ]] + 。
Step 6: synthesis of Compound 11-G
Compound 11-F (300 mg) was dissolved in DCM (10 mL) at-60℃N 2 Boron tribromide (1.51 g) was slowly added dropwise under protection and reacted at 25℃for 4 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, the mixture was extracted with methylene chloride (20 mL. Times.2), the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 11-G.
Step 7: synthesis of Compound 11
11-G (0.299G), 7-H trifluoroacetate (336.57 mg) was dissolved in 15ml of methylene chloride, and then anhydrous sodium acetate (112.10 mg), anhydrous magnesium sulfate (411.25 mg), nitrogen protection, and sodium borohydride acetate (434.47 mg) were added after stirring for 30 minutes to react at 25℃for 6 hours. The crude product after the reaction is purified by column chromatography (methanol 0-8%, dichloromethane/methanol) to obtain the compound 11.
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),9.35(s,1H),7.52(d,J＝8.5Hz,1H),7.11-7.01(m,4H),7.00-6.94(m,2H),6.72-6.48(m,7H),5.05(dd,J＝5.1,13.2Hz,1H),4.40-4.28(m,1H),4.26-4.15(m,1H),3.61(br d,J＝12.0Hz,2H),3.28(br s,4H),2.97-2.84(m,1H),2.65(br s,2H),2.57(br s,3H),2.43-2.30(m,2H),2.22(s,8H),2.06-1.87(m,4H),1.78(br d,J＝11.3Hz,2H),1.72-1.59(m,1H),1.26-1.08(m,3H).MS m/z:749.94[M+H] +
Example 12
The synthetic route is as follows:
step 1: synthesis of Compound 12-A
To a solution of compound 2-E (562.83 mg) in DMSO (10 mL) was added 4-bromoiodobenzene (1 g), L-proline (162.78 mg), cuprous iodide (134.64 mg), potassium carbonate (977.05 mg). N at 90 DEG C 2 Stirring was carried out in an atmosphere for 12 hours. After completion of the reaction, the reaction mixture was poured into 100mL of water, extracted with ethyl acetate (100 mL. Times.3), and the organic phase was washed with water (100 mL. Times.2), saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Purifying the crude product by column chromatography (0-10% of ethyl acetate/petroleum ether) to obtain the compound 12-A. MS m/z 313.9[ M+H ]] +
Step 2: synthesis of Compound 12-B
Compound 12-A (425 mg) and bis-pinacolato borate (446.51 mg), 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (322.40 mg) and potassium acetate (398.23 mg) were dissolved in dioxane (10 mL), stirred for 5min, and tris (dibenzylideneacetone) dipalladium (371.57 mg), N was added 2 Protecting and stirring at 125 ℃ for 12 hours. 15mL of ethyl acetate is added for dilution, diatomite is filtered, and the crude product is obtained by reduced pressure distillation. Purifying the crude product by column chromatography (0-15% ethyl acetate/petroleum ether) to obtain the compound 12-B. MS m/z 362.1[ M+H ]] +
Step 3: synthesis of Compound 12-C
Compound 12-B (135 mg) and compound 13-E (114.38 mg) were dissolved in 4mL of dioxane and 1mL of water, and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (23.17 mg), K was added 2 CO 3 (131.27 mg) N at 90 DEG C 2 Stirring was carried out in an atmosphere for 1 hour. After completion of the reaction, the reaction mixture was added to 20mL of water, extracted with ethyl acetate (10 mL. Times.3), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfateDrying, filtering and concentrating to obtain the compound 12-C. MS m/z 512.1[ M+H ]] +
Step 4: synthesis of Compound 12-D
Compound 12-C (120 mg) was dissolved in methanol (2 mL) and water (1 mL), and sodium hydroxide (37.52 mg) was added thereto, followed by stirring at 65℃for 1 hour. After the reaction, 20mL of petroleum ether is added for pulping, and then a water layer is separated and taken. The aqueous layer was adjusted to ph=6 with 1M diluted hydrochloric acid, extracted with ethyl acetate (10 ml×3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 12-D. MS m/z 498.2[ M+H ]] +
Step 5: synthesis of Compound 12-E
Compound 12-D (100 mg) was dissolved in 5mL of tetrahydrofuran, and 2.53mL of dilute sulfuric acid (1M, 2.53 mL) was added thereto, followed by stirring at 60℃for 0.5 hours. The reaction mixture was added to 5mL of H 2 O, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and ethyl acetate (10 mL. Times.3) was used. The organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate and concentrated to give Compound 12-E. MS m/z 470.2[ M+H+H ] 2 O] +
Step 6: synthesis of Compound 12
Compound 12-E (102 mg) and trifluoroacetate salt of intermediate 2 (99.93 mg) and sodium acetate (42.25 mg) were dissolved in 2mL of dichloromethane and 1mL of methanol, and after clarification, magnesium sulfate (135.95 mg) was added, followed by stirring at 20℃for 30min, sodium triacetoxyborohydride (143.62 mg) and stirring at 20℃for 2 hours. After the completion of the reaction, the reaction mixture was added to 10mL of water, 1M diluted hydrochloric acid (2 drops) was added, the mixture was extracted with methylene chloride (20 mL. Times.3), and the organic phase was combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and dried by spinning to obtain a crude product. The crude product is purified by column chromatography (methanol: 0-4%, methanol/dichloromethane) to obtain compound 12.
1 H NMR(400MHz,CHLOROFORM-d)δ＝7.89(s,1H),7.78-7.64(m,2H),7.14-7.02(m,5H),6.92(br d,J＝8.0Hz,2H),6.81(br s,1H),6.69-6.51(m,4H),5.14(br dd,J＝4.5,13.3Hz,1H),4.38-4.14(m,2H),3.61-3.50(m,2H),3.32(br s,4H),2.80(br d,J＝13.8Hz,4H),2.67-2.53(m,7H),2.28(br s,4H),2.17-2.07(m,4H),1.80(br d,J＝11.5Hz,2H),1.27(br d,J＝11.5Hz,2H),MS m/z:764.3[M+H] +
Example 13
The synthetic route is as follows:
step 1: synthesis of Compound 13-A
In a three-necked flask, anhydrous toluene (140 mL) was added, followed by gradually adding aluminum trichloride (8.41 g) and then adding 2-methoxybenzocycloheptan-5-one (5 g) with stirring, and stirring was performed at 90℃for 1 hour. The reaction was cooled to room temperature, slowly poured into crushed ice (300 g), stirred for 20 minutes, filtered, the filter cake rinsed with water (75 mL) and isopropyl ether (75 mL), and the filter cake was spin-dried to give compound 13-A. MS m/z 176.8[ M+H ] ] + 。
Step 2: synthesis of Compound 13-B
Compound 13-A (4.2 g) was dissolved in anhydrous dichloromethane (80 mL), 2, 6-lutidine (5.11 g) was added, trifluoromethanesulfonic anhydride (13.45 g) was added under nitrogen atmosphere at 0℃and stirred at 0℃for 1 hour. Stirred at 25℃for 47 hours. The reaction solution is dried by spin to obtain a crude product. The crude product was column chromatographed (petroleum ether/ethyl acetate=3:1) followed by TLC (petroleum ether/ethyl acetate=3:1) to give compound 13-B. MS m/z 308.9[ M+H ]] + 。
Step 3: synthesis of Compound 13-C
Compound 13-B (1 g) was dissolved in anhydrous N, N-dimethylformamide (10 mL), methanol (10 mL), N, N-diisopropylethylamine (1.61 g) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (118.68 mg) were added, and the mixture was stirred under carbon monoxide atmosphere at 45PSI at 75℃for 48 hours. The reaction solution is filtered by diatomite, and the filtrate is dried by spin to obtain a crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate=3:1) to give compound 13-C. MS m/z 218.9[ M+H ]] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.95(dd,J＝1.6,7.9Hz,1H),7.89(s,1H),7.74(d,J＝8.0Hz,1H),3.94(s,3H),3.01-2.95(m,2H),2.78-2.72(m,2H),1.95-1.87(m,2H),1.86-1.79(m,2H)。
Step 4: synthesis of Compound 13-D
Compound 13-C (0.54 g), bromobenzene (505.02 mg), sodium t-butoxide (475.55 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (235.90 mg) and palladium acetate (55.55 mg) were mixed and stirred in a toluene (5 mL) solution, and the mixture was placed in a microwave tube, and after nitrogen substitution, the reaction was performed under microwave at 120℃for 1 hour. The reaction solution was filtered and distilled under reduced pressure to obtain crude product. Purifying the crude product by column chromatography (0-5% ethyl acetate/petroleum ether) to obtain the compound 13-D. MS m/z 294.9[ M+H ] ] +
1 H NMR(400MHz,CDCl 3 )δ＝7.98-7.93(m,2H),7.64(d,J＝8.3Hz,1H),7.39-7.33(m,2H),7.32-7.27(m,2H),7.26(d,J＝1.8Hz,1H),4.09-4.02(m,1H),3.96(s,3H),3.19-3.03(m,2H),2.26-2.10(m,3H),1.96-1.82(m,1H)。
Step 5: synthesis of Compound 13-E
Sodium hydride (298.94 mg,60% purity) was dissolved in 2-methyltetrahydrofuran (15 mL), 1.8-diazabicyclo [5.4.0] undec-7-ene (15.16 mg) was added, and a solution of 13-D (1 g) and N-phenylbis (trifluoromethanesulfonyl) imide (2.43 g) in 2-methyltetrahydrofuran (5 mL) was slowly added dropwise under nitrogen at 20℃under nitrogen, followed by stirring for 12 hours under nitrogen at 20 ℃. The reaction solution was cooled to 0℃and 1M diluted hydrochloric acid (8 mL) was slowly added dropwise thereto, the solution was separated, and the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give a crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate=5:1) to give compound 13-E.
Step 6: synthesis of Compound 13-F
4-piperidineethanol (17 g), 1-chloro-4-iodobenzene (31.38 g) and L-prolyl ammonia (6.06 g) were dissolved in dimethyl sulfoxide (300 mL), and potassium carbonate (36.37 g) and cuprous iodide (5.01 g) were added thereto, followed by stirring at 90℃for 12 hours under nitrogen atmosphere. After completion of the reaction, water (300 mL) was added thereto, stirred for 0.5 hour, extracted with ethyl acetate (300 mL. Times.4), and the organic phase was washed with saturated brine (300 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Purifying the crude product by column chromatography (0-15% ethyl acetate/petroleum ether) to obtain the compound 13-F.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.23-7.14(m,2H),6.91(br d,J＝7.0Hz,2H),3.68-3.59(m,2H),3.51-3.42(m,2H),3.34(s,1H),2.61(br t,J＝12.2Hz,2H),1.71(br d,J＝12.5Hz,2H),1.59-1.46(m,1H),1.38(q,J＝6.5Hz,2H),1.26-1.14(m,2H)。
Step 7: synthesis of Compound 13-G
Dimethyl sulfoxide (26.07 g) was dissolved in methylene chloride (400 mL), the temperature was lowered to-78 ℃, oxalyl chloride (31.77 g) was slowly added dropwise thereto, stirring was performed at-78℃for 0.5 hours, a solution of Compound 13-F (20 g) in methylene chloride (400 mL) was further added dropwise thereto, stirring was performed at-78℃for 0.5 hours, and finally triethylamine (50.65 g) was added, stirring was performed at 25℃for 11 hours. After completion of the reaction, methylene chloride (800 mL) was added to dilute the reaction solution, and the organic phase was washed with a saturated ammonium chloride solution (800 mL), water (800 mL) and a saturated brine (800 mL) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 13-G.
1 H NMR(400MHz,DMSO-d 6 )δ＝9.70(t,J＝1.8Hz,1H),7.40-7.25(m,2H),7.23-6.87(m,2H),3.62(br d,J＝12.5Hz,2H),3.07-2.72(m,2H),2.46-2.41(m,2H),2.12-1.95(m,1H),1.83-1.70(m,2H),1.53-1.29(m,2H)。
Step 8: synthesis of Compound 13-H
Compound 13-G (26G) and trimethyl orthoformate (58.03G) were dissolved in methanol (260 mL), and p-toluenesulfonic acid monohydrate (10.40G) was added. Stirring under nitrogen at 25deg.C for 12hr. Saturated sodium carbonate solution was added to adjust the pH to 7-8, water (260 mL) was added, the mixture was extracted with dichloromethane (260 mL. Times.3), the organic phase was washed with saturated brine (260 mL. Times.2), dried over anhydrous sodium sulfate, and filtered and spun-dried to give Compound 13-H.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.24-7.16(m,2H),6.92(d,J＝9.0Hz,2H),4.47(t,J＝5.5Hz,1H),3.64(br d,J＝12.5Hz,2H),3.23(s,6H),2.67-2.57(m,2H),1.74(br d,J＝12.5Hz,2H),1.49(br d,J＝4.8Hz,3H),1.31-1.18(m,2H)。
Step 9: synthesis of Compound 13-I
Compound 13-H%3.4 g) and 2-Di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (2.28 g) were dissolved in dioxane (100 mL), and bipropylpinacol borate (3.96 g) and potassium acetate (3.53 g) were added thereto, followed by stirring for 5min, and tris (dibenzylideneacetone) dipalladium (2.19 g), N 2 Protecting, and stirring at 125deg.C for 12hr. Adding ethyl acetate (100) for dilution, filtering by diatomite, and distilling under reduced pressure to obtain a crude product. Purifying the crude product by column chromatography (0-5% ethyl acetate/petroleum ether) to obtain the compound 13-I.
1 H NMR(400MHz,DMSO-d 6 )δ＝7.52-7.45(m,2H),6.86(d,J＝8.8Hz,2H),4.46(t,J＝5.6Hz,1H),3.76(br d,J＝12.8Hz,2H),3.21(s,6H),2.68(br t,J＝12.4Hz,2H),1.72(br d,J＝11.5Hz,2H),1.54(br s,1H),1.49-1.42(m,2H),1.25(s,12H),1.24-1.20(m,2H)。
Step 10: synthesis of Compound 13-J
Compounds 13-E (200 mg) and 13-I (176.03 mg) were dissolved in dioxane (6 mL) and water (2 mL), and potassium carbonate (194.47 mg) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (34.32 mg) were added, N at 90 ℃C 2 Stirring was carried out in an atmosphere for 2 hours. After completion of the reaction, the reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 13-J. MS m/z 526.2[ M+H ]] +
Step 11: synthesis of Compound 13-K
To a methanol (5 mL) solution of compound 13-J (250 mg) was added a water (5 mL) solution of sodium hydroxide (57.07 mg), the reaction was warmed to 65℃and stirred for 2.5 hours. After the reaction, the pH was adjusted to 7 to 8 with dilute hydrochloric acid (1M), extracted with dichloromethane (20 mL. Times.3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, which was slurried with petroleum ether (5 mL), filtered and the cake was dried to give compound 13-K. MS m/z 512.1[ M+H ] ] +
Step 12: synthesis of Compound 13-L
To a tetrahydrofuran solution (6 mL) of compound 13-K (240 mg) was added dilute sulfuric acid (1M, 5.91 mL), and the reaction was warmed to 60℃and stirred for 1 hour. Cooling to room temperature after the reaction is finished, and slowly adding water into the reaction solution(30 mL) was stirred at 20℃for 10 minutes, filtered and the cake was dried to give compound 13-L. MS m/z 466.1[ M+H ]] +
Step 13: synthesis of Compound 13
To a solution of compound 13-L (155 mg) in dichloromethane (5 mL) and methanol (1 mL) was added, in order, 7-H trifluoroacetate (176.73 mg), sodium acetate (54.62 mg), and magnesium sulfate (200.36 mg). After stirring the reaction at 20℃for 30 minutes, sodium borohydride acetate (211.68 mg) was added, and the reaction was stirred at 20℃for an additional 11.5 hours. After the completion of the reaction, dilute hydrochloric acid (1M, 1 mL) was added dropwise to the reaction mixture, after stirring for 10 minutes, the pH was adjusted to 7 to 8 with saturated sodium bicarbonate (20 mL), the mixture was extracted with methylene chloride (20 mL. Times.3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a crude product, which was purified by column chromatography (0 to 2% methanol/methylene chloride) to give Compound 13.MS m/z 778.3[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ＝7.96(d,J＝1.3Hz,1H),7.85-7.71(m,2H),7.21-7.15(m,4H),7.15-7.09(m,1H),7.03-6.95(m,2H),6.90(s,1H),6.78-6.58(m,4H),5.21(dd,J＝5.1,13.2Hz,1H),4.46-4.36(m,1H),4.30-4.22(m,1H),3.65-3.49(m,2H),3.44(br s,4H),2.95-2.83(m,7H),2.61(br s,4H),2.38-2.27(m,4H),2.25-2.09(m,4H),1.78(br d,J＝11.0Hz,2H),1.60(br d,J＝8.0Hz,2H),1.50-1.20(m,2H)。
Example 14
The synthetic route is as follows:
step 1: synthesis of Compound 14
To a solution of compound 2-G (1.16G) in dichloromethane (25 mL) and methanol (5 mL) was added, in order, 7-H trifluoroacetate (1.33G), sodium acetate (449.33 mg), and magnesium sulfate (1.65G). After stirring at 20℃for 30 minutes, sodium borohydride acetate (1.74 g) was added and the reaction was continued at 20 Stirring was continued for 3.5 hours at C. After the completion of the reaction, dilute hydrochloric acid (1M, 10 mL) was added dropwise to the reaction mixture, after stirring for 10 minutes, the pH was adjusted to 7 to 8 with saturated sodium bicarbonate (30 mL), the mixture was extracted with methylene chloride (50 mL. Times.3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a crude product, which was purified by column chromatography (methanol: 0 to 5% methanol/methylene chloride) to give compound 14.MS m/z 736.3[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ＝8.16(br s,1H),7.74(br d,J＝8.3Hz,1H),7.21-7.06(m,5H),6.99(br d,J＝8.5Hz,1H),6.88(br s,1H),6.78(br d,J＝7.5Hz,4H),6.65(br d,J＝8.3Hz,2H),6.56(br d,J＝8.3Hz,1H),5.34-5.05(m,1H),4.50-4.15(m,2H),3.62(br d,J＝11.5Hz,2H),3.33(br s,4H),2.99-2.79(m,2H),2.74(br s,2H),2.68-2.54(m,6H),2.39-2.11(m,8H),1.86(br d,J＝11.3Hz,2H),1.70(br s,2H),1.37-1.26(m,2H).
Example 15
The synthetic route is as follows:
step 1: synthesis of Compound 15-A
Intermediate 1 (100 mg) and 2- (trifluoromethyl) pyridine-5-boronic acid (51.02 mg) were dissolved in dioxane (5 mL) and water (1 mL), potassium carbonate (65.37 mg) and tetrakis (triphenylphosphine) palladium (23.76 mg) were added, N at 100deg.C 2 Stirring was carried out in an atmosphere for 12 hours. After completion of the reaction, the reaction mixture was added to water (50 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 15-A. MS m/z 553.1[ M+H ]] + .
Step 2: synthesis of Compound 15-B
To a dichloromethane solution (20 mL) of compound 15-A (100 mg) at 0deg.C under nitrogen blanket was added boron tribromide (4)53.33 mg) and the reaction was warmed to 20℃and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was slowly added to water (30 mL), extracted with methylene chloride (20 mL. Times.3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give compound 15-B. MS m/z 493.0[ M+H ] ] + .
Step 3: synthesis of Compound 15
To a solution of compound 15-B (80 mg) in dichloromethane (25 mL) and methanol (5 mL) was added, in order, 7-H trifluoroacetate (79.04 mg), sodium acetate (26.65 mg), and magnesium sulfate (97.76 mg). After stirring the reaction at 20℃for 30 minutes, sodium borohydride acetate (103.27 mg) was added, and the reaction was stirred at 20℃for an additional 11.5 hours. After the reaction was completed, dilute hydrochloric acid (1 m,10 mL) was added dropwise to the reaction solution, after stirring for 10 minutes, the pH was adjusted to 7 to 8 with saturated sodium bicarbonate (30 mL), extracted with dichloromethane (50 ml×3), washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (0 to 5% methanol, methanol/dichloromethane) to give compound 15.MS m/z 805.2[ M+H ]] + .
1 H NMR(400MHz,DMSO-d 6 )δ＝10.94(br s,1H),9.49(br s,1H),8.42(s,1H),7.86(br d,J＝8.4Hz,1H),7.73(d,J＝8.1Hz,1H),7.51(d,J＝8.5Hz,1H),7.06-7.04(m,2H),6.76-6.63(m,5H),6.62-6.55(m,2H),5.04(dd,J＝4.9,13.3Hz,1H),4.35-4.18(m,2H),3.64(br d,J＝11.9Hz,2H),3.30(br s,4H),2.96-2.84(m,1H),2.76-2.55(m,6H),2.42-2.26(m 6H),2.20(br d,J＝6.9Hz,2H),2.10-1.90(m,4H),1.78(br d,J＝11.3Hz,2H),1.16(br d,J＝12.9Hz,2H).
Example 16
The synthetic route is as follows:
step 1: synthesis of Compound 16-A
Intermediate 1 (0.3 g), 6-dimethylpyridine boronic acid (101.35 mg) and tetrakis (triphenylphosphine) palladium (71.27 mg) were dissolved in dioxane (4 mL), sodium carbonate (196.10 mg) and water (1 mL) were added and the reaction stirred at 100℃for 1 hour. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography (0 to 50 percent of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 16-A. MS m/z 499.1[ M+H ] ] +
Step 2: synthesis of Compound 16-B
Compound 16-A (0.214 g) was dissolved in methylene chloride (10 mL), and boron tribromide (1.08 g) was slowly added dropwise at 0℃and reacted for 1 hour. Adding saturated sodium bicarbonate solution to regulate pH to 6-7, and decompressing and concentrating to obtain 16-B. MS m/z 439.2[ M+H ]] +
Step 3: synthesis of Compound 16
Compound 16-B (0.188 g) and 7-H trifluoroacetate (189.64 mg) and sodium acetate (80.17 mg) were dissolved in dichloromethane (10 mL), 2mL of methanol was added to aid dissolution, after clarification magnesium sulfate (258.00 mg) was added, and stirring was performed at 20℃for 30 minutes. Sodium borohydride acetate (272.56 mg) was added to the reaction mixture, and stirring was continued at 20℃for 2 hours. 2 drops of 1M diluted hydrochloric acid were added, extracted with methylene chloride (20 mL. Times.3), and the combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and spun-dried to give crude product. The crude product is purified by column chromatography (methanol 0-10%, methanol/dichloromethane) to obtain compound 16.MS m/z 751.3[ M+H ]] + .
1 H NMR(400MHz,DMSO-d 6 )δ＝11.97(br s,1H),10.95(s,1H),9.42(s,1H),8.13(s,1H),7.53(br s,1H),7.47(br d,J＝7.8Hz,1H),7.09(br d,J＝8.0Hz,2H),6.72-6.66(m,5H),6.57(s,2H),5.05(br dd,J＝4.9,13.2Hz,1H),4.40-4.16(m,2H),3.64(br d,J＝9.8Hz,2H),3.28(s,4H),2.96–2.86(m,1H),2.68–2.56(m,6H),2.37–2.33(m,4H),2.26–2.22(m,4H),2.07–1.98(m,4H),1.91(s,3H),1.84–1.76(m,2H),1.24–1.15(m,2H)
Example 17
The synthetic route is as follows:
step 1: synthesis of Compound 17-A
Intermediate 1 (0.23 g), 17-C (92.47 mg) was dissolved in dioxane (30 mL), water (10 mL), and tetrakis (triphenylphosphine) palladium (54.64 mg), sodium carbonate (150.34 mg), nitrogen blanket, were added and reacted at 90℃for 12 hours. After the reaction was completed, water (20 mL. Times.2) was added to the filtrate, extraction was performed with ethyl acetate (20 mL. Times.2), drying was performed with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 17-A. MS m/z 525.1[ M+H ] ] + .
Step 2: synthesis of Compound 17-B
Compound 17-A (0.2 g) was dissolved in methylene chloride (40 mL) and BBr was added at-60 ℃ 3 (763.95 mg), nitrogen protection, reaction at-60-25℃for 2 hours. After the reaction, the reaction system was quenched with water, extracted with dichloromethane (20 mL. Times.2), the product was taken up in the aqueous phase, the pH of the aqueous phase was adjusted to neutral, and concentrated under reduced pressure to give 17-B. MS m/z 465.2[ M+H ]] + .
Step 3: synthesis of Compound 17
Compound 17-B (170 mg), 7-H trifluoroacetate (242.81 mg) was dissolved in dichloromethane (15 mL), methanol (5 mL). Sodium acetate (60.03 mg), anhydrous magnesium sulfate (220.22 mg), and sodium triacetoxyborohydride (232.65 mg), nitrogen protection, were added to the mixture after stirring for 30 minutes, and the mixture was reacted at 25℃for 12 hours. After the reaction, the system is filtered, 20mL of water and 10mL of dichloromethane are added to the filtrate for extraction, a water phase is remained, the pH=7 is adjusted, and the water phase is decompressed and concentrated to obtain a crude product. The crude product is purified by column chromatography (methanol%: 0-15%, methanol/dichloromethane) to obtain compound 17.MS m/z 777.5[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ＝10.95(s,1H),9.42(s,1H),8.10(s,1H),7.70-7.53(m,2H),7.41(dd,J＝2.3,8.0Hz,1H),7.34-7.31(m,1H),7.10(br d,J＝8.0Hz,2H),6.69(br s,4H),6.56(s,2H),5.05(br dd,J＝5.1,13.2Hz,1H),4.43-4.29(m,1H),4.28-4.18(m,1H),4.12(br s,3H),3.67-3.60(m,4H),3.17(s,5H),2.90(br s,2H),2.64(br d,J＝12.5Hz,4H),2.22(br d,J＝6.3Hz,2H),2.06-1.96(m,4H),1.91(s,3H),1.88-1.77(m,2H),1.24(br s,1H),0.91-0.80(m,4H)。
Example 18
The synthetic route is as follows:
step 1: synthesis of Compound 18-A
Intermediate 1 (0.23 g), 18-C (126.01 mg) was dissolved in dioxane (20 mL), water (10 mL), and tetrakis (triphenylphosphine) palladium (54.64 mg), sodium carbonate (150.34 mg), nitrogen blanket, were added and reacted at 100℃for 12 hours. After the reaction, the reaction mixture was filtered, the filtrate was extracted with 20 mL. Times.2 of water and 20 mL. Times.2 of ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give 18-A. MS m/z 502.1[ M+H ] ] +
Step 2: synthesis of Compound 18-B
Compound 18-A (0.2 g) was dissolved in methylene chloride (15 mL), boron tribromide (799.02 mg) was added at-60℃and the mixture was allowed to react at-60℃for 2 hours under nitrogen. 3mL of water is added into the system to quench, the pH is adjusted to be neutral, the system is dried by anhydrous sodium sulfate, and 18-B is obtained by decompression concentration. MS m/z 441.8[ M+H ]] +
Step 3: synthesis of Compound 18
Compound 18-B (170 mg), 7-H trifluoroacetate (255.48 mg) was dissolved in dichloromethane (15 mL), methanol (5 mL). Sodium acetate (63.16 mg), anhydrous magnesium sulfate (231.71 mg), and sodium triacetoxyborohydride (244.79 mg), nitrogen protection, were added after stirring for 30min, and the reaction was carried out at 25℃for 12 hours. The system is filtered, 5mL of water is added to the filtrate, the pH value is regulated to be 7, the filtrate is dried by anhydrous sodium sulfate, and the crude product is obtained by decompression and concentration. The crude product is subjected to column chromatography (methanol accounts for 0-10 percent) to obtain the crude product, and the crude product is subjected to column chromatography (methanol accounts for 0-15 percent) to obtain the crude productTo crude product, purification by thin layer chromatography (methanol%: 10%, methanol/dichloromethane) afforded compound 18.MS m/z 754.2[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.95(s,1H),9.31(s,1H),7.57-7.48(m,2H),7.15-7.02(m,2H),6.78-6.47(m,7H),5.05(dd,J＝5.1,13.2Hz,1H),4.39-4.15(m,2H),3.69(s,3H)3.64(br d,J＝13.1Hz,2H),3.28–3.21(m,4H),3.00-2.81(m,1H),2.64-2.53(m,6H),2.50-2.34(m,4H),2.22(br d,J＝6.5Hz,2H),2.13-2.08(m,2H),2.03-1.94(m,2H),1.80(br d,J＝11.8Hz,2H),1.51(s,3H),1.19(br d,J＝11.0Hz,2H)
Example 19
The synthetic route is as follows:
step 1: synthesis of Compound 19-A
Intermediate 1 (250 mg), 2-fluoropyridine-5-boronic acid (94.14 mg) and tetrakis (triphenylphosphine) palladium (59.39 mg) were dissolved in dioxane (10 mL), sodium carbonate (163.42 mg) and water (2 mL) were added, and the reaction was stirred at 100 ℃ for 12 hours. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography (0 to 30 percent of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 19-A. MS m/z 503.2[ M+H ] ] +
1 H NMR(400MHz,DMSO-d 6 )δ＝7.96-7.88(m,1H),7.83-7.73(m,1H),7.07-6.95(m,1H),6.92-6.87(m,1H),6.77-6.62(m,6H),4.10-4.03(m,1H),3.77(s,3H),3.69-3.59(m,2H),3.26(s,6H),2.75(br t,J＝6.5Hz,2H),2.57(br s,2H),2.29-2.23(m,1H),2.29-2.23(m,2H),2.08(br t,J＝7.0Hz,2H),1.67(br d,J＝10.3Hz,2H),1.32-1.17(m,2H)
Step 2: synthesis of Compound 19-B
Compound 19-A (230 mg) was dissolved in methylene chloride (25 mL), and boron tribromide (1.15 g) was added thereto, followed by stirring at-60-20deg.C under nitrogen atmosphere for 4 hours. The reaction solution was slowly added to 50mL of water, the solution was separated, the aqueous phase was taken up in methylene chloride (20 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 19-B. MS m/z 442.8[ M+H ]] +
Step 3: synthesis of Compound 19
Compound 19-B (290.78 mg) and trifluoroacetate (319.76 mg) of intermediate 2 were dissolved in a solution of methanol (10 mL) and methylene chloride (2 mL), and sodium acetate (112.48 mg) and magnesium sulfate (412.63 mg) were added thereto and stirred at 20℃for 30 minutes. Sodium borohydride acetate (435.92 mg) was added to the reaction solution, and the reaction was stirred at 20℃for an additional 11.5 hours. The reaction was quenched by adding 1M dilute hydrochloric acid (5 mL) with stirring for 30 min, adjusted to pH 7 with saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography (methanol 0-10%, methanol/dichloromethane) to give compound 19.MS m/z 755.4[ M+H ] ] + .
1 H NMR(400MHz,DMSO-d 6 )δ＝11.01-10.89(m,1H),7.95-7.86(m,1H),7.80-7.71(m,1H),7.52(d,J＝8.8Hz,1H),7.10-7.00(m,3H),6.76-6.52(m,8H),5.05(dd,J＝5.1,13.3Hz,1H),4.39-4.14(m,2H),3.63(br d,J＝12.0Hz,2H),3.33(br s,6H),2.96-2.84(m,1H),2.73-2.56(m,6H),2.44-2.28(m,2H),2.27-2.15(m,4H),2.12-2.02(m,2H),2.01-1.86(m,3H),1.83-1.73(m,2H),1.72-1.62(m,1H).
Example 20
The synthetic route is as follows:
step 1: synthesis of Compound 20-A
To a solution of intermediate 1 (0.20 g) in 1, 4-dioxane (10 mL) and water (2 mL) was added 4-pyridineboronic acid (50.54 mg), tetrakis (triphenylphosphine) palladium (95.02 mg) and sodium carbonate (130.73 mg), the mixture was purged with nitrogen 3 times, and the reaction was carried out at 100℃for 2 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 10mL of water was added to the reaction mixture, extraction was performed with ethyl acetate (20 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 20-A. MS m/z 485.1[ M+H ]] + .
Step 2: synthesis of Compound 20-B
To a solution of compound 20-A (199 mg) in methylene chloride (15 mL) at 0deg.C was added boron tribromide (1.03 g), and the reaction was stirred at 20deg.C for 1 hour. After the reaction, the reaction mixture was added to 50mL of water, the pH was adjusted to 7 with sodium carbonate solid, dichloromethane (20 mL. Times.3) was used for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 20-B. MS m/z 425.1[ M+H ]] + .
Step 3: synthesis of Compound 20
To a solution of compound 20-B (174 mg) and trifluoroacetate salt of intermediate 2 (235.71 mg) in dichloromethane (10 mL) and methanol (2 mL), sodium acetate (67.24 mg) and magnesium sulfate (246.68 mg) were added to react at 20 ℃ for 30 minutes, sodium borohydride acetate (260.60 mg) was added to the reaction solution, and the reaction was continued to stir at 20 ℃ for 12 hours. 1mL of water is added into the reaction solution, the mixture is stirred for 10 minutes, the mixed solution is concentrated under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography (methanol percent: 0-5 percent, methanol/dichloromethane) to obtain the compound 20.MS m/z 737.2[ M+H ] ] + .
1 H NMR(400MHz,DMSO-d 6 )δ＝10.95(br s,1H),9.47(s,1H),8.33(d,J＝5.8Hz,2H),7.53(d,J＝8.5Hz,1H),7.13-7.03(m,4H),6.73-6.66(m,5H),6.59(s,2H),5.05(dd,J＝4.9,13.2Hz,1H),4.37-4.30(m,1H),4.24-4.17(m,1H),3.64(br d,J＝12.5Hz,2H),3.30(br d,J＝5.5Hz,6H),3.00-2.80(m,1H),2.70-2.53(m,8H),2.40
-2.32(m,2H),2.28-2.19(m,4H),2.06-1.94(m,3H),1.81-1.65(m,3H).
Example 21
The synthetic route is as follows:
step 1: synthesis of Compound 21-C
Intermediate 1 (300 mg), 3-pyridineboronic acid (98.55 mg) and tetrakis (triphenylphosphine) palladium (71.27 mg) were dissolved in dioxane (8 mL), sodium carbonate (196.10 mg) and water (2 mL) were added, and the reaction was stirred at 100℃for 12 hours. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography (0 to 7 percent of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 21-C. MS m/z 485.0[ M+H ]] + .
1 H NMR(400MHz,DMSO-d 6 )δ＝7.68-7.50(m,3H),7.27-7.19(m,1H),6.94-6.86(m,1H),6.78-6.60(m,6H),4.08-4.03(m,1H),3.77(s,3H),3.62(br d,J＝11.8Hz,2H),3.25(s,6H),2.80-2.70(m,2H),2.55(br s,2H),2.26(br t,J＝6.8Hz,2H),2.14-2.01(m,2H),1.73-1.59(m,3H),1.33-1.18(m,2H).
Step 2: synthesis of Compound 21-D
Compound 21-C (250 mg) was dissolved in methylene chloride (25 mL), and boron tribromide (1.29 g) was added thereto, followed by stirring at-60-20deg.C under nitrogen for 12 hours. The reaction liquid was slowly added to 50mL of water, saturated sodium bicarbonate solution was added to adjust the pH to 6 to 7, the solution was separated, the aqueous phase was extracted with dichloromethane/methanol=4/1 (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 21-D. MS m/z 425.1[ M+H ]] + .
Step 3: synthesis of Compound 21
Compound 21-D (280 mg) and trifluoroacetate salt of intermediate 2 (291.78 mg) were dissolved in a solution of methanol (10 mL) and methylene chloride (2 mL), and sodium acetate (108.21 mg) and magnesium sulfate (396.95 mg) were added thereto, followed by stirring at 20℃for 30 minutes. Into the reaction solution Sodium borohydride acetate (419.35 mg) was added and the reaction stirred at 20℃for an additional 11.5 hours. 1M dilute hydrochloric acid (1 mL) is added, stirred for 30 minutes, quenched, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (methanol 0-10%, methanol/dichloromethane) to obtain compound 21.MS m/z 737.2[ M+H ]] + .
1 H NMR(400MHz,DMSO-d 6 )δ＝10.95(s,1H),9.43(s,1H),8.36-8.17(m,2H),7.67-7.45(m,2H),7.28-7.19(m,1H),7.10-7.01(m,2H),6.73-6.52(m,7H),5.05(dd,J＝5.0,13.3Hz,1H),4.39-4.13(m,2H),3.61(br d,J＝11.8Hz,2H),3.28(brs,4H),2.97-2.83(m,1H),2.76-2.54(m,6H),2.50-2.45(m,4H),2.42-2.30(m,2H),2.29-2.14(m,4H),2.12–2.01(m,2H),1.77(br d,J＝12.0Hz,2H),1.27-1.06(m,2H).
Example 22
The synthetic route is as follows:
step 1: synthesis of Compound 22-A
Intermediate 1 (300 mg), 2, 6-lutidine-3-boronic acid (111.73 mg) and tetrakis (triphenylphosphine) palladium (71.27 mg) were dissolved in dioxane (4 mL), sodium carbonate (196.10 mg) and water (1 mL) were added, and the reaction was stirred at 100℃for 1 hour. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 22-A. MS m/z 513.1[ M+H ]] + .
Step 2: synthesis of Compound 22-B
Compound 22-A (550 mg) was dissolved in methylene chloride (10 mL), and boron tribromide (2.69 g) was added thereto, followed by stirring at 0℃for 1 hour under nitrogen. The reaction liquid was adjusted to pH 7 with saturated sodium bicarbonate solution and dried by spin to give crude compound 22-B. MS m/z 453.1[ M+H ]] + .
Step 3: synthesis of Compound 22
22-B (0.4 g) and 7-H trifluoroacetate (390.99 mg) and sodium acetate (165.30 mg) were dissolved in methylene chloride (4 mL), 2mL of methanol was added for auxiliary dissolution, after clarification, magnesium sulfate (851.07 mg) was added, and stirring was performed at 20℃for 30min, and sodium borohydride acetate (561.94 mg) was added and stirring was performed at 20℃for 2 hours. The reaction was quenched by the addition of 2 drops of 1M diluted hydrochloric acid, extracted with dichloromethane (20 mL. Times.3), and the combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and spun dry to give the crude product. The crude product is purified by column chromatography (methanol 0-10%, methanol/dichloromethane) to obtain compound 22.MS m/z 765.3[ M+H ] ] + .
1 H NMR(400MHz,CD 3 OD)δ＝7.67-7.64(d,J＝8.0Hz,1H),7.44-7.40(m,1H),7.13-7.08(m,2H),7.02-6.98(d,J＝8.0Hz,1H),6.75–6.73(m,1H),6.72–6.67(m,5H),6.62–6.58(m,1H),5.15-5.08(m,1H),4.45-4.38(m,2H),3.66-3.56(m,2H),3.39(s,4H),2.98–2.87(m,1H),2.84-2.80(m,2H),2.69-2.58(m,6H),2.51-2.41(m,5H),2.38-2.25(m,7H),2.23–2.18(m,4H),1.93-1.85(m,2H),,1.38-1.33(m,2H).
Example 23
The synthetic route is as follows:
step 1: synthesis of Compound 23-C
Intermediate 1 (0.5 g), (6- (2-hydroxy-prop-2-yl) pyridin-3-yl) boronic acid (744.17 mg) and tetrakis (triphenylphosphine) palladium (237.55 mg) were dissolved in dioxane (10 mL), sodium carbonate (326.83 mg) and water (2 mL) were added and the reaction stirred at 100 ℃ for 12hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a crude product. Purifying the crude product by column chromatography (0-30% of ethyl acetate and ethyl acetate/petroleum ether) to obtain the compound 23-C. MS m/z 543.1[ M+H ]] +
1 H NMR(400MHz,)δ＝8.29(d,J＝1.5Hz,1H),7.47(dd,J＝2.1,8.2Hz,1H),7.14(d,J＝8.3Hz,1H),6.83(d,J＝8.5Hz,1H),6.81(d,J＝2.5Hz,1H),6.75(d,J＝8.8Hz,2H),6.69(dd,J＝2.8,8.5Hz,1H),6.65(br d,J＝8.8Hz,2H),4.99(br s,1H),4.06(d,J＝7.3Hz,1H),3.83(s,3H),3.64(br d,J＝12.3Hz,2H),3.36(s,6H),2.77(t,J＝6.9Hz,2H),2.67-2.56(m,2H),2.41-2.32(m,2H),2.15(quin,J＝6.9Hz,2H),1.82(br d,J＝12.5Hz,2H),1.77-1.57(m,3H),1.50(s,6H).
Step 2: synthesis of Compound 23-D
Compound 23-C (420 mg) was dissolved in methylene chloride (40 mL), and boron tribromide (1.94 g) was added thereto, followed by stirring at-60-20℃for 3 hours under nitrogen. The reaction liquid was slowly added to 50mL of water, saturated sodium bicarbonate solution was added to adjust the pH to 6 to 7, the solution was separated, the aqueous phase was extracted with dichloromethane/methanol=4/1 (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 23-D. MS m/z 483.2[ M+H ]] +
Step 3: synthesis of Compound 23
Compound 23-D (490 mg) and trifluoroacetate salt of intermediate 2 (449.16 mg) were dissolved in a solution of methanol (10 mL) and methylene chloride (2 mL), and sodium acetate (166.57 mg) and magnesium sulfate (611.06 mg) were added thereto, followed by stirring at 20℃for 30 minutes. Sodium borohydride acetate (645.55 mg) was added to the reaction solution, and the reaction was stirred at 20℃for an additional 11.5 hours. 1M dilute hydrochloric acid (1 mL) is added, stirred for 30 minutes, quenched, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (methanol 0-10%, methanol/dichloromethane) to obtain compound 23.MS m/z 795.3[ M+H ] ] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.94(s,1H),9.42(br s,1H),8.17(d,J＝1.5Hz,1H),7.56-7.50(m,2H),7.46(d,J＝8.3Hz,1H),7.08-7.02(m,2H),6.72-6.65(m,5H),6.60-6.53(m,2H),5.04(dd,J＝5.0,13.1Hz,1H),4.36-4.17(m,2H),3.61(br d,J＝12.0Hz,2H),3.28(br s,4H),3.17(d,J＝4.0Hz,2H),2.95-2.84(m,1H),2.73-2.53(m,6H),2.45-2.30(m,2H),2.26(br t,J＝6.3Hz,2H),2.20(br d,J＝6.5Hz,2H),2.11-1.91(m,4H),1.77(br d,J＝11.5Hz,2H),1.67(br d,J＝3.8Hz,1H),1.37(s,6H),1.22-1.11(m,2H).
Example 24
The synthetic route is as follows:
step 1: synthesis of Compound 24-A
To a solution of intermediate 1 (300 mg) in dichloromethane (20 mL) at 0deg.C was added boron tribromide (772.51 mg), and the reaction was stirred at 25deg.C for 12 hours. After the reaction, the reaction mixture was added to 50mL of water, the pH was adjusted to 7 with sodium carbonate solid, dichloromethane (20 mL. Times.3) was used for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 24-A. MS m/z 445.7[ M+H+H ] 2 O] +
Step 2: synthesis of Compound 24-B
To a solution of compound 24-A (0.20 g) in 1, 4-dioxane (10 mL) and water (2 mL) were added 4- (difluoromethoxy) phenylboronic acid (88.16 mg), tetrakis (triphenylphosphine) palladium (108.42 mg) and sodium carbonate (149.16 mg), and the mixture was reacted at 100℃for 2 hours with nitrogen substitution 3 times. After the reaction is finished, the reaction solution is cooled to room temperature, the crude product is obtained by concentration, and the crude product is purified by column chromatography (ethyl acetate percent is 0 to 25 percent, and ethyl acetate/petroleum ether) to obtain the compound 24-B. MS m/z 490.0[ M+H ]] +
Step 3: synthesis of Compound 24
To a solution of compound 24-B (200 mg) and trifluoroacetate salt of intermediate 2 (180.73 mg) in dichloromethane (10 mL) and methanol (2 mL), sodium acetate (67.03 mg) and magnesium sulfate (245.88 mg) were added to react at 20 ℃ for 30 minutes, sodium borohydride acetate (259.76 mg) was added to the reaction solution, and the reaction was continued to stir at 20 ℃ for 12 hours. 1mL of water is added into the reaction solution, the mixture is stirred for 10 minutes, the mixed solution is concentrated under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography (methanol percent: 0-6 percent, methanol/dichloromethane) to obtain a compound 24.MS m/z 802.3[ M+H ] ] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),9.39(s,1H),7.52(d,J＝8.6Hz,1H),7.39-6.95(m,7H),6.72-6.63(m,5H),6.60-6.52(m,2H),5.05(dd,J＝5.1,13.3Hz,1H),4.39-4.15(m,2H),3.62(br d,J＝12.0Hz,2H),3.30(br d,J＝12.9Hz,6H),2.98-2.84(m,1H),2.70-2.52(m,8H),2.45-2.16(m,6H),2.10-1.92(m,3H),1.84-1.61(m,3H).
Example 25
The synthetic route is as follows:
step 1: synthesis of Compound 25-A
To a solution of intermediate 1 (200 mg) in methylene chloride (5 mL) at 0deg.C was added boron tribromide (1.03 g), and the reaction was stirred at 0deg.C for 1 hour. After the reaction was completed, the reaction mixture was added to 10mL of water, the pH was adjusted to 7 with sodium carbonate solid, and methylene chloride: methanol=4: 1 (10 mL. Times.3) and the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 25-A. MS m/z 473.1[ M+H ]] +
Step 2: synthesis of Compound 25-B
To a solution of compound 25-A (190 mg) in 1, 4-dioxane (4 mL) and water (1 mL) were added 4-trifluoromethoxyphenylboronic acid (82.82 mg), tetrakis (triphenylphosphine) palladium (46.48 mg) and sodium carbonate (127.88 mg), and the mixture was reacted at 100℃for 1 hour with nitrogen substitution 3 times. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 10mL of ethyl acetate, filtered through celite, and the filtrate was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate and concentrated to give crude compound 25-B. MS m/z 554.1[ M+H ]] +
Step 3: synthesis of Compound 25-C
25-B (200 mg) was dissolved in THF (5 mL) and H was added 2 SO 4 (1M, 4.34 mL), stirred at 60℃for 0.5 h. After the reaction, the pH was adjusted to 7-8 with saturated sodium bicarbonate and dichloromethane: acetonitrile=4: 1 (20 mL. Times.3) to give an organic phase, washing the organic phase with 10mL of saturated saline, and spin-drying the organic phase to give compound 25-C. MS m/z 508.1[ M+H ]] +
Step 4: synthesis of Compound 25
To a solution of compound 25-C (200 mg) and trifluoroacetate salt of intermediate 2 (174.33 mg) in dichloromethane (4 mL) and methanol (2 mL), sodium acetate (73.70 mg) and magnesium sulfate (379.46 mg) were added and the reaction was stirred at 20℃for 30 minutes, sodium borohydride acetate (250.55 mg) was added to the reaction solution, and the reaction was stirred at 20℃for 2 hours. 2 drops of 1M diluted hydrochloric acid were added, extracted with methylene chloride (20 mL. Times.3), and the combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and spun-dried to give crude product. The crude product is purified by column chromatography (methanol%: 0-4%, methanol/dichloromethane) to obtain compound 25.MS m/z 820.3[ M+H ]] +
1 H NMR(400MHz,DMSO-d6)δ＝10.96(s,1H),9.41(s,1H),7.51(d,J＝8.8Hz,1H),7.5(d,J＝8.0Hz,2H),7.16(d,J＝8.0Hz,2H),7.10-7.04(m,2H),6.73-6.62(m,5H),6.59-6.54(m,2H),5.05(dd,J＝5.0,13.1Hz,1H),4.38-4.16(m,2H),3.66-3.57(m,2H),3.30-3.25(m,4H),2.95-2.86(m,1H),2.73–2.55(m,6H),2.51-2.44(m,4H),2.41-2.32(m,2H),2.29-2.15(m,4H),2.11-2.01(m,2H),1.78(br d,2H),1.25–1.12(m,2H).
Example 26
The synthetic route is as follows:
step 1: synthesis of Compound 24-A
To a solution of intermediate 1 (300 mg) in methylene chloride (20 mL) at 0deg.C was added boron tribromide (1.55 g), and the reaction was stirred at 0deg.C for 1 hour. After the reaction, the reaction mixture was added to 10mL of water, the pH was adjusted to 7 with sodium carbonate solid, dichloromethane (20 mL. Times.3) was used for extraction, and the organic phase was dried over anhydrous sodium sulfateDrying, filtering, and concentrating the organic phase under reduced pressure to obtain a crude compound 24-A. MS m/z 445.9[ M+H+H ] 2 O] +
Step 2: synthesis of Compound 26-A
To a solution of compound 24-A (0.26 g) in 1, 4-dioxane (4 mL) and water (1 mL) were added 4-cyclopropoxyphenylboronic acid (108.55 mg), tetrakis (triphenylphosphine) palladium (70.47 mg) and sodium carbonate (193.91 mg), and the mixture was reacted at 100℃for 1 hour with nitrogen substitution 3 times. After the reaction is finished, the reaction solution is cooled to room temperature, 10mL of ethyl acetate is added for dilution, diatomite is used for filtration, the filtrate is washed by 10mL of saturated saline water and then is dried by anhydrous sodium sulfate, the crude product is obtained after concentration, and the crude product is purified by column chromatography (ethyl acetate percent: 0-25 percent and ethyl acetate/petroleum ether) to obtain the compound 26-A. MS m/z 498.0[ M+H+H ] 2 O] +
Step 3: synthesis of Compound 26
To a solution of compound 26-a (200 mg) and trifluoroacetate salt of intermediate 2 (184.48 mg) in dichloromethane (10 mL) and methanol (2 mL), sodium acetate (68.41 mg) and magnesium sulfate (250.98 mg) were added to react at 20 ℃ for 30 minutes, sodium borohydride acetate (265.14 mg) was added to the reaction solution, and the reaction was continued to stir at 20 ℃ for 12 hours. 1mL of water is added into the reaction solution, the mixture is stirred for 10 minutes, the mixture is concentrated under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography (methanol percent: 0-3 percent, methanol/dichloromethane) to obtain a compound 26.MS m/z 792.3[ M+H ] ] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),9.34(s,1H),7.53(d,J＝8.5Hz,1H),7.09-6.53(m,14H),5.06(dd,J＝5.0,13.1Hz,1H),4.37-4.17(m,2H),3.77(td,J＝3.0,5.8Hz,1H),3.61(br d,J＝11.8Hz,2H),3.34-3.22(m,6H),2.99-2.83(m,1H),2.73-2.52(m,8H),2.46-2.17(m,6H),2.06-1.94(m,3H),1.78(br d,J＝11.8Hz,2H),0.79-0.70(m,2H),0.62(br s,2H).
Example 27
The synthetic route is as follows:
step 1: synthesis of Compound 27-B
To a solution of intermediate 1 (0.30 g) in 1, 4-dioxane (10 mL) and water (2 mL) were added 3-methylphenylboronic acid (83.85 mg), tetrakis (triphenylphosphine) palladium (142.53 mg) and sodium carbonate (196.10 mg), and the mixture was reacted at 100℃for 2 hours with nitrogen substitution 3 times. After the reaction is finished, the reaction solution is cooled to room temperature, the crude product is obtained by concentration, and the crude product is purified by column chromatography (ethyl acetate percent is 0 to 10 percent, and ethyl acetate/petroleum ether) to obtain the compound 27-B. MS m/z 498.1[ M+H ]] +
Step 2: synthesis of Compound 27-C
To a solution of compound 27-B (230 mg) in methylene chloride (10 mL) at 0deg.C was added boron tribromide (578.90 mg), and the reaction was stirred at 25deg.C for 1 hour. After the reaction, the reaction mixture was added to 30mL of water, the pH was adjusted to 7 with sodium carbonate solid, dichloromethane (20 ml×3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 27-C.
Step 3: synthesis of Compound 27
To a solution of compound 27-C (207 mg) and trifluoroacetate (209.28 mg) of intermediate 2 in dichloromethane (10 mL) and methanol (2 mL), sodium acetate (77.61 mg) and magnesium sulfate (284.71 mg) were added and the reaction was stirred at 25℃for 30 minutes, sodium borohydride acetate (300.78 mg) was added to the reaction solution, and the reaction was stirred at 25℃for 1 hour. 1mL of water is added into the reaction solution, the mixture is stirred for 10 minutes, the mixture is concentrated under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography (methanol percent: 0-5 percent, methanol/dichloromethane) to obtain the compound 27.MS m/z 750.2[ M+H ] ] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.96(s,1H),9.45-9.26(m,1H),7.53(br d,J＝8.5Hz,1H),7.10-6.96(m,4H),6.93-6.85(m,2H),6.72-6.52(m,7H),5.06(dd,J＝5.0,13.3Hz,1H),4.38-4.16(m,2H),3.60(br d,J＝11.0Hz,2H),3.28(br s,4H),2.97-2.84(m,1H),2.73-2.52(m,7H),2.44-2.30(m,2H),2.30-2.10(m,7H),2.07-1.93(m,3H),1.77(br d,J＝11.8Hz,2H),1.66(br s,1H),1.36-1.01(m,3H).
Example 28
The synthetic route is as follows:
step 1: synthesis of Compound 28-A
To a solution of intermediate 1 (0.30 g) in 1, 4-dioxane (10 mL) and water (2 mL) were added 2-fluorobenzeneboronic acid (86.29 mg), tetrakis (triphenylphosphine) palladium (142.53 mg) and sodium carbonate (196.10 mg), and the mixture was reacted at 100℃for 2 hours with nitrogen substitution 3 times. After the reaction is finished, the reaction solution is cooled to room temperature, the crude product is obtained by concentration, and the crude product is purified by column chromatography (ethyl acetate percent is 0 to 10 percent, and ethyl acetate/petroleum ether) to obtain the compound 28-A. MS m/z 502.0[ M+H ]] +
Step 2: synthesis of Compound 28-B
To a solution of compound 28-A (220 mg) in methylene chloride (10 mL) at 0deg.C was added boron tribromide (549.35 mg), and the reaction was stirred at 25deg.C for 1 hour. After the reaction, the reaction mixture was added to 30mL of water, the pH was adjusted to 7 with sodium carbonate solid, dichloromethane (20 ml×3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 28-B.
Step 3: synthesis of Compound 28
To a solution of compound 28-B (206 mg) and trifluoroacetate (206.40 mg) of intermediate 2 in dichloromethane (10 mL) and methanol (2 mL) were added sodium acetate (76.54 mg) and magnesium sulfate (280.80 mg), the reaction was stirred at 25 ℃ for 30 minutes, sodium borohydride acetate (296.64 mg) was added to the reaction solution, and the reaction was stirred at 25 ℃ for 1 hour. 1mL of water is added into the reaction solution, the mixture is stirred for 10 minutes, the mixture is concentrated under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography (methanol percent: 0-3 percent, methanol/dichloromethane) to obtain the compound 28.MS m/z 754.0[ M+H ] ] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.95(s,1H),9.41(s,1H),7.52(d,J＝8.5Hz,1H),7.24-6.96(m,6H),6.73-6.54(m,7H),5.05(dd,J＝5.0,13.1Hz,1H),4.38-4.16(m,2H),3.60(br d,J＝11.8Hz,2H),3.28(br s,4H),2.98-2.83(m,1H),2.78-2.53(m,7H),2.46-2.29(m,2H),2.25-2.13(m,4H),2.11-1.94(m,3H),1.83-1.56(m,3H),1.55-0.70(m,3H).
Example 29
The synthetic route is as follows:
step 1: synthesis of Compound 29-A
To a solution of intermediate 1 (0.30 g) in 1, 4-dioxane (10 mL) and water (2 mL) was added 2-methylphenylboronic acid (83.85 mg), tetrakis (triphenylphosphine) palladium (142.53 mg) and sodium carbonate (196.10 mg), and the mixture was reacted at 100℃for 2 hours with nitrogen substitution 3 times. After the reaction is finished, the reaction solution is cooled to room temperature, the crude product is obtained by concentration, and the crude product is purified by column chromatography (ethyl acetate percent is 0 to 10 percent, and ethyl acetate/petroleum ether) to obtain the compound 29-A. MS m/z 498.1[ M+H ]] +
Step 2: synthesis of Compound 29-B
To a solution of compound 29-A (195 mg) in methylene chloride (10 mL) at 0deg.C was added boron tribromide (490.80 mg), and the reaction was stirred at 25deg.C for 1 hour. After the reaction, the reaction mixture was added to 30mL of water, the pH was adjusted to 7 with sodium carbonate solid, dichloromethane (20 ml×3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give crude compound 29-B.
Step 3: synthesis of Compound 29
To a solution of compound 29-B (170 mg) and trifluoroacetate salt of intermediate 2 (171.87 mg) in methylene chloride (10 mL) and methanol (2 mL), sodium acetate (63.74 mg) and magnesium sulfate (233.82 mg) were added, and the reaction was stirred at 25℃for 30 minutes, and borohydride acetate was added to the reaction solution Sodium (247.02 mg) and the reaction was stirred at 25 ℃ for 1 hour. 1mL of water is added into the reaction solution, the mixture is stirred for 10 minutes, the mixture is concentrated under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography (methanol percent: 0-3 percent, methanol/dichloromethane) to obtain a compound 29.MS m/z 750.0[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝10.95(s,1H),9.35(s,1H),7.52(d,J＝8.8Hz,1H),7.12-7.00(m,6H),6.70(d,J＝2.3Hz,1H),6.64-6.52(m,6H),5.05(dd,J＝5.0,13.3Hz,1H),4.46-4.12(m,2H),3.57(br d,J＝11.8Hz,2H),3.28(br s,4H),2.97-2.84(m,1H),2.80-2.52(m,7H),2.45-2.31(m,2H),2.22-2.10(m,7H),2.08-1.94(m,3H),1.76(br d,J＝12.0Hz,2H),1.65(br s,1H),1.14(q,J＝10.9Hz,3H).
Example 30
The synthetic route is as follows:
step 1: synthesis of Compound 30-A
Intermediate 1 (300 mg), 3-fluorophenylboronic acid (86.29 mg) and tetrakis (triphenylphosphine) palladium (142.53 mg) were dissolved in dioxane (4 mL), and sodium carbonate (196.10 mg) and water (1 mL) were added thereto to react with stirring at 100℃for 1 hour. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 30-A. MS m/z 502.0[ M+H ]] + .
Step 2: synthesis of Compound 30-B
Compound 30-A (234 mg) was dissolved in methylene chloride (2 mL), and boron tribromide (1.17 g) was added thereto, followed by stirring at 0℃for 1 hour under nitrogen. The reaction was added to 10ml of water, the pH was adjusted to 7 with sodium carbonate solid, extracted with dichloromethane (20 ml x 3) and dried by spin to give the crude compound 30-B. MS m/z 442.0[ M+H ]] + .
Step 3: synthesis of Compound 30
Compound 30-B (0.21 g) and trifluoroacetate salt of intermediate 2 (210.41 mg) and sodium acetate (88.95 mg) were dissolved in dichloromethane (4 mL), 2mL of methanol was added to aid dissolution, magnesium sulfate (458 mg) was added after clarification, stirring was performed at 20℃for 30min, and sodium borohydride acetate (302.40 mg) was added and stirring was performed at 20℃for 2 hours. The reaction was quenched by adding 2 drops of 1M diluted hydrochloric acid, followed by adding 10mL of water to the reaction system, extracting with methylene chloride (20 mL. Times.3), washing the combined organic phases once with saturated brine (10 mL), drying over anhydrous sodium sulfate, and spin-drying to obtain the crude product. The crude product is purified by column chromatography (methanol 0-4%, methanol/dichloromethane) to give compound 30.MS m/z 754.3[ M+H ] ] + .
1 H NMR(400MHz,DMSO-d 6 )δ＝11.03-10.87(s,1H),9.46-9.33(s,1H),7.52(d,1H),7.20(dd,1H),7.09-7.03(m,2H),7.00-6.88(m,3H),6.71-6.62(m,5H),6.60-6.53(m,2H),5.04(dd,1H),4.38-4.16(m,2H),3.61(d,2H),3.29(s,4H),2.96-2.84(m,1H),2.71-2.53(m,6H),2.48-2.44(m,2H),2.41-2.30(m,2H),2.29-2.16(m,4H),2.10-1.91(m,4H),1.83-1.73(m,2H),1.23-1.11(m,2H).
Example 31
The synthetic route is as follows:
step 1: synthesis of Compound 31-B
Compound 31-A was dissolved in toluene (10 mL) and AlCl was added 3 (8.41g)，N 2 Protection, reaction for 3 hours at 90 ℃. After the reaction, the system was poured into 100g of ice, stirred for 30min, filtered, washed with 20mL of water and 20mL of isopropyl ether, and the cake was dried to obtain compound 31-B. MS m/z 176.8[ M+H ]] +
Step 2: synthesis of Compound 31-C
Compound 31-B (3.2 g), K 2 CO 3 (3.26g) Acetone (30 mL) was added, followed by benzyl bromide (4.04 g), nitrogen blanket, and reacted at 20℃for 12h. The system is filtered, the organic phase is concentrated under reduced pressure to obtain a crude product, 30mL of water is added into the crude product, the crude product is extracted by ethyl acetate (40 mL multiplied by 3), the organic phase is dried by anhydrous sodium sulfate, and the crude product is obtained by concentrating under reduced pressure. The crude product is subjected to column chromatography (ethyl acetate percent is 0-10 percent) to obtain a compound 31-C. MS m/z 266.9[ M+H ]] +
Step 3: synthesis of Compound 31-D
Compound 31-C (1 g), para-bromoanisole (1.40 g), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (357.98 mg), palladium acetate (84.30 mg), sodium t-butoxide (505.17 mg) were added to toluene (10 mL), and the mixture was reacted at 120℃for 2 hours. The system is filtered, and the organic phase is decompressed and concentrated to obtain crude product. The crude product was extracted with ethyl acetate (40 mL. Times.3) and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product is subjected to column chromatography (ethyl acetate percent is 0-10 percent, ethyl acetate/petroleum ether) to obtain the compound 31-D. MS m/z 372.9[ M+H ] ] + 。
Step 4: synthesis of Compound 31-E
Compound 31-D (0.7 g) was dissolved in methylene chloride (40 mL), and trifluoromethanesulfonic anhydride (1.33 g), pyridine (222.99 mg) was added at 0deg.C, and the mixture was reacted at 20deg.C under nitrogen atmosphere for 3 hours. The system is filtered, the organic phase is concentrated under reduced pressure to obtain a crude product, 30mL of water is added into the crude product, the crude product is extracted by ethyl acetate (40 mL multiplied by 3), the organic phase is dried by anhydrous sodium sulfate, and the crude product is obtained by concentrating under reduced pressure. The crude product is subjected to column chromatography (ethyl acetate percentage is 0-10 percent) and ethyl acetate/petroleum ether/ammonia water (0.1 percent) to obtain the compound 31-E.
Step 5: synthesis of Compound 31-F
Compound 31-E (0.3 g), 31-I (429.66 mg) was dissolved in dioxane (35 mL) and water (5 mL), and potassium carbonate (246.54 mg) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (87.02 mg) were added and reacted at 120℃for 3 hours under nitrogen. The system is filtered, the organic phase is concentrated under reduced pressure to obtain a crude product, 30mL of water is added into the crude product, the crude product is extracted by ethyl acetate (40 mL multiplied by 3), the organic phase is dried by anhydrous sodium sulfate, and the crude product is obtained by concentrating under reduced pressure. The crude product is subjected to column chromatography (ethyl acetate percent is 0-10 percent) to obtain the compound 31-F. MS m/z 590.1[ M+H ]] +
Step 6: synthesis of Compound 31-G
Compound 31-F (0.12 g) was dissolved in tetrahydrofuran (15 mL), diluted sulfuric acid (203.47. Mu.L, 2M) was added thereto, and the mixture was reacted at 65℃for 3 hours under nitrogen atmosphere. The system was extracted with 10mL of water and ethyl acetate (40 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 31-G. MS m/z 544.0[ M+H ] ] +
Step 7: synthesis of Compound 31-H
Compound 31-G (160.63 mg), trifluoroacetate salt of intermediate 2 (145.52 mg), dissolved in methylene chloride (20 mL), methanol (5 mL), sodium acetate (48.47 mg), magnesium sulfate (177.81 mg), sodium triacetoxyborohydride (187.85 mg) after 30 minutes, nitrogen blanket, were added and reacted at 20℃for 12 hours, after which time the reaction was completed, compound 31-H was obtained by filtration. MS m/z 856.3[ M+H ]] + 。
Step 8: synthesis of Compound 31
Compound 31-H (0.1 g) was dissolved in tetrahydrofuran (10 mL) and palladium on carbon (621.57. Mu.g), nitrogen blanket, and reacted at 20℃for 36 hours. The crude product was purified by plate chromatography (methanol/dichloromethane, methanol%: 10%) to give compound 31.MS m/z 766.3[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝11.42-10.54(m,1H),10.51-9.42(m,1H),7.52(d,J＝8.5Hz,1H),7.06(d,J＝8.5Hz,4H),6.73(d,J＝8.8Hz,2H),6.69-6.62(m,5H),6.54(s,2H),5.03(dd,J＝5.0,13.3Hz,1H),4.39-4.27(m,1H),4.26-4.15(m,1H),3.70(s,3H),3.66-3.55(m,3H),3.30-3.26(m,4H),2.91-2.83(m,1H),2.71-2.61(m,3H),2.60-2.56(m,3H),2.39-2.32(m,1H),2.21(br d,J＝6.5Hz,4H),2.06-1.91(m,3H),1.78(br d,J＝13.3Hz,2H),1.24(s,2H),1.20-1.10(m,2H),0.92-0.80(m,1H).
Example 32
The synthetic route is as follows:
step 1: synthesis of Compound 32-A
Intermediate 1 (150 mg), 2, 3-difluorophenylboronic acid (48.69 mg) and tetrakis (triphenylphosphine) palladium (35.63 mg) were dissolved in dioxane (4 mL), and sodium carbonate (98.05 mg) and water (1 mL) were added and reacted with stirring at 100℃for 1 hour. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 32-A. MS m/z 520.0[ M+H ]] + .
Step 2: synthesis of Compound 32-B
Compound 32-A (160 mg) was dissolved in methylene chloride (2 mL), and boron tribromide (771.39 mg) was added thereto, followed by stirring at 0℃for 1 hour under nitrogen. The reaction was slowly added to ice water and stirred, extracted with DCM: acetonitrile=1:1 (10 ml x 3) and the organic phase was dried by spinning. Crude compound 32-B was obtained. MS m/z 460.0[ M+H ]] + .
Step 3: synthesis of Compound 32
Compound 32-B (140 mg) and trifluoroacetate (134.78 mg) of intermediate 2 and sodium acetate (56.98 mg) were dissolved in dichloromethane (4 mL), 2mL of methanol was added to aid dissolution, after clarification, magnesium sulfate (293.38 mg) was added, stirring was performed at 20℃for 30min, and sodium borohydride acetate (193.71 mg) was added, stirring was performed at 20℃for 2 hours. The reaction was quenched by adding 2 drops of 1M diluted hydrochloric acid, 10mL of water was added to the reaction system, extracted with dichloromethane (20 mL. Times.3), and the combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and spun-dried to give the crude product. The crude product is purified by column chromatography (methanol 0-4%, methanol/dichloromethane) to give compound 32.MS m/z 772.1[ M+H ]] + .
1 H NMR(400MHz,DMSO-d6)δ＝11.01-10.86(m,1H),9.53-9.35(m,1H),7.54-7.49(m,1H),7.25-7.15(m,1H),7.09-6.97(m,4H),6.73-6.70(m,1H),6.68-6.63(m,4H),6.60-6.56(m,2H),5.11-4.95(m,1H),4.38-4.16(m,2H),3.69-3.53(m,2H),3.32-3.23(m,4H),2.97-2.82(m,1H),2.75-2.53(m,8H),2.41-2.30(m,2H),2.27-2.13(m,4H),2.13-1.90(m,4H),1.86-1.73(m,2H),1.28-1.06(m,2H).
Example 33
The synthetic route is as follows:
step 1: synthesis of Compound 33-A
Intermediate 1 (0.2 g), 33-C (77.91 mg), dissolved in dioxane (15 mL), water (5 mL), was added with tetrakis triphenylphosphine palladium (30.32 mg), sodium carbonate (130.73 mg), 100℃and reacted for 6 hours. The system was filtered, the filtrate was extracted with 10mL of water, ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give compound 33-a. MS m/z:521.0[ M+H ] ] +
Step 2: synthesis of Compound 33-B
Compound 33-A (0.20 g) was dissolved in dichloromethane (30 mL), boron tribromide (964.25 mg) was added at-60℃and the reaction was continued for 6 hours at-60℃under nitrogen protection, the system was filtered, the filtrate was extracted with 20mL of water, dichloromethane (20 mL. Times.2) was added, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give compound 33-B. MS m/z:477.9[ M+H ] 2 O+H] +
Step 3: synthesis of Compound 33
Compound 33-B (0.08 g), the trifluoroacetate salt of intermediate 2 (85.75 mg) was dissolved in methylene chloride (20 mL), magnesium sulfate (104.78 mg), sodium sulfate (28.56 mg, 348.18. Mu. Mol) was added to methanol (3 mL), and after stirring for 30 minutes, sodium triacetoxyborohydride (110.69 mg), nitrogen blanket, was added to react at 20℃for 3 hours. The system is filtered, the organic phase is concentrated under reduced pressure to obtain a crude product, 30mL of water is added into the crude product, the crude product is extracted by ethyl acetate (40 mL multiplied by 3), the organic phase is dried by anhydrous sodium sulfate, and the crude product is obtained by concentrating under reduced pressure. The crude product was purified by plate chromatography (methanol%: 10%, methanol/dichloromethane) to give compound 33.MS m/z:772.4[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝11.08-10.82(m,1H),9.58-9.29(m,1H),7.52(d,J＝8.8Hz,1H),7.26-7.13(m,2H),7.10-7.01(m,2H),7.00-6.90(m,1H),6.73-6.63(m,5H),6.61-6.48(m,2H),5.05(dd,J＝5.0,13.3Hz,1H),4.39-4.28(m,1H),4.26-4.11(m,1H),3.71-3.56(m,2H),3.55-3.44(m,1H),3.22-3.15(m,1H),2.98-2.80(m,1H),2.72-2.55(m,6H),2.43-2.29(m,2H),2.27-2.16(m,4H),2.13-2.00(m,3H),2.00-1.92(m,1H),1.86(s,1H),1.78(br d,J＝12.0Hz,2H),1.72-1.60(m,1H),1.33-1.03(m,4H).
Example 34
The synthetic route is as follows:
step 1: synthesis of Compound 34-A
Intermediate 1 (0.20 g), 8-C (97.39 mg) were dissolved in dioxane (10 mL) and water (3 mL), and tetrakis triphenylphosphine palladium (30.32 mg), sodium carbonate (130.73 mg), nitrogen blanket 100℃were added and reacted for 6 hours. The system was filtered, the filtrate was added with water (40 mL), extracted with ethyl acetate (20 mL. Times.2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give compound 34-A. MS m/z:520.3[ M+H ] ] +
Step 2: synthesis of Compound 34-B
Compound 34-A (90 mg) was dissolved in methylene chloride (30 mL), and boron tribromide (433.91 mg) was added at-60℃and reacted for 6 hours under nitrogen atmosphere at-60℃and-20 ℃. The system was filtered, the filtrate was extracted with 20mL x 2 of water, dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give compound 34-B. MS m/z:478.0[ M+H ] 2 O+H] +
Step 3: synthesis of Compound 34
Compound 34-B (0.08 g), trifluoroacetate salt of intermediate 2 (85.75 mg) was dissolved in methylene chloride (20 mL), magnesium sulfate (104.78 mg), sodium acetate (28.56 mg) were added to methanol (3 mL), and after stirring for 30 minutes, sodium triacetoxyborohydride (110.69 mg) was added and the mixture was reacted at 20℃under nitrogen for 3 hours. System filtration, organicThe phases were concentrated under reduced pressure to give crude product, which was extracted with 30mL of water, ethyl acetate (40 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, and the crude product was purified by plate chromatography (methanol%: 10%, methanol/dichloromethane) to give compound 34.MS m/z:772.4[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ＝11.10-10.77(m,1H),8.48(s,1H),7.53-7.50(m,1H),7.23-7.14(m,1H),7.07(s,2H),6.92(br t,J＝7.8Hz,1H),6.72(s,1H),6.64(s,5H),6.59-6.56(m,2H),5.04(dd,J＝5.3,13.1Hz,1H),4.04(br s,1H),4.02(br s,1H),2.68(br s,5H),2.60(br s,2H),2.58-2.56(m,3H),2.34(br s,4H),2.25(br s,1H),2.20(br d,J＝7.8Hz,4H),2.16-2.14(m,1H),1.80(br dd,J＝3.8,8.0Hz,4H),1.76(br s,1H),1.49(s,1H),1.15(br d,J＝3.0Hz,2H),1.08-1.04(m,1H).
Example 35
The synthetic route is as follows:
step 1: synthesis of Compound 35-A
Intermediate 1 (0.15 g), 9-C (71.21 mg) was dissolved in dioxane (10 mL), water (2 mL), and tetrakis triphenylphosphine palladium (22.74 mg), sodium carbonate (98.05 mg), nitrogen blanket 100℃were added and reacted for 6 hours. The system was filtered, the filtrate was extracted with 20mL of water, ethyl acetate (20 mL. Times.2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give compound 35-A. MS m/z:516.0[ M+H ] ] + 。
Step 2: synthesis of Compound 35-B
Compound 35-A (0.15 g) was dissolved in methylene chloride (15 mL), and boron tribromide (728.75 mg) was added thereto, followed by reaction at 20℃under nitrogen for 1 hour. The system was filtered, the filtrate was extracted with 40mL of water, ethyl acetate (20 mL. Times.2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give compound 35-B.
Step 3: synthesis of Compound 35
Compound 35-B (130.00 mg), trifluoroacetate salt of intermediate 2 (140.55 mg) was dissolved in dichloromethane (20 mL), methanol (3 mL), sodium acetate (46.82 mg), magnesium sulfate (171.75 mg) were added, stirring was carried out at 20℃for 30min, then sodium triacetoxyborohydride (181.44 mg) was added, nitrogen protection was used, reaction was carried out at 20℃for 3 hours, and the crude product was purified by column chromatography (methanol%: 0-15%, methanol/dichloromethane) to give compound 35, MS m/z:768.1[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ＝11.15-10.83(m,1H),8.47(s,1H),7.55-7.45(m,1H),7.07(br d,J＝4.0Hz,3H),6.89(br d,J＝9.3Hz,2H),6.70(s,1H),6.65(s,4H),6.60-6.52(m,2H),5.04(dd,J＝5.1,13.2Hz,1H),4.05(br d,J＝7.3Hz,1H),4.01(br d,J＝7.0Hz,1H),3.64(br s,3H),2.62(br d,J＝14.1Hz,2H),2.57(br s,1H),2.24-2.18(m,6H),2.11(s,3H),2.09(s,3H),2.05-1.99(m,4H),1.83-1.74(m,5H),1.20-1.14(m,3H),1.08-1.03(m,1H),0.85(br t,J＝6.9Hz,1H).
Example 36
The synthetic route is as follows:
step 1: synthesis of Compound 36-A
Intermediate 1 (150 mg), 2-fluoro-3-methylphenylboronic acid (47.47 mg) and tetrakis (triphenylphosphine) palladium (35.63 mg) were dissolved in dioxane (4 mL), and sodium carbonate (98.05 mg) and water (1 mL) were added thereto to react with stirring at 100℃for 1 hour. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 36-A. MS m/z 516.4[ M+H ] ] + .
Step 2: synthesis of Compound 36-B
Compound 36-A (140 mg) was dissolved in methylene chloride (3 mL), and tribromo was addedBoron carbide (771.39 mg) was stirred at 0℃for 1 hour under nitrogen. Adding the reaction solution into ice water, stirring, adjusting pH to 7-8 with sodium bicarbonate solid, and adding CH 2 Cl 2 : acetonitrile=3: 1 (20 ml x 3) extraction, organic phase spin-drying crude compound 36-B. MS m/z 456.2[ M+H ]] + .
Step 3: synthesis of Compound 36
Compound 36-B (150 mg) and trifluoroacetate (145.66 mg) of intermediate 2 and sodium acetate (61.58 mg) were dissolved in methylene chloride (4 mL), 2mL of methanol was added for auxiliary dissolution, after clarification, magnesium sulfate (209.35 mg) was added, stirring was performed at 20℃for 30min, and sodium borohydride acetate (317.07 mg) was added, stirring was performed at 20℃for 2 hours. The reaction was quenched by adding 2 drops of 1M diluted hydrochloric acid, 10mL of water was added to the reaction system, extracted with dichloromethane (20 mL. Times.3), and the combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and spun-dried to give the crude product. The crude product is purified by column chromatography (methanol 0-4%, methanol/dichloromethane) to give compound 36.MS m/z 768.4[ M+H ]] + .
1 H NMR(400MHz,DMSO-d6)δ＝10.95(s,1H),9.46-9.24(m,1H),7.57-7.48(m,1H),7.10-7.01(m,3H),6.94-6.83(m,2H),6.73-6.54(m,7H),5.10-4.99(m,1H),4.39-4.16(m,2H),3.66-3.55(m,2H),3.28(br s,4H),2.99-2.83(m,1H),2.74-2.68(m,2H),2.53(br s,6H),2.42-2.33(m,2H),2.23-2.12(m,7H),2.09-1.88(m,4H),1.81-1.71(m,2H),1.25-1.09(m,2H).
Example 37
The synthetic route is as follows:
step 1: synthesis of Compound 37-A
Intermediate 1 (150 mg), 3-fluoro-5-methyl-difluorophenylboronic acid (47.47 mg) and tetrakis (triphenylphosphine) palladium (35.63 mg) were dissolved in dioxane (4 mL), and sodium carbonate (98.05 mg) and water were added Water (1 mL), and the reaction was stirred at 100deg.C for 1 hour. 10mL of ethyl acetate was added for dilution, the mixture was filtered through celite, the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 37-A. MS m/z 516.0[ M+H ]] + .
Step 2: synthesis of Compound 37-B
Compound 37-A (160 mg) was dissolved in methylene chloride (3 mL), and boron tribromide (777.32 mg) was added thereto, followed by stirring at 0℃for 1 hour under nitrogen. The reaction solution was added to 10mL of water, and dichloromethane was used: acetonitrile=3: 1 (10 ml. Times.3) to give the crude compound 37-B by spin-drying. MS m/z 474.0[ M+H ] 2 O+H] + .
Step 3: synthesis of Compound 37
Compound 37-B (140 mg), intermediate 2 trifluoroacetate (135.95 mg) and sodium acetate (57.48 mg) were dissolved in DCM (4 mL), meOH (2 mL) was added to assist in dissolution, after clarification, magnesium sulfate (295.93 mg) was added, stirred for 30min at 20℃and then sodium borohydride acetate (195.40 mg) was added, stirred for 2h at 20 ℃. The reaction was quenched by adding 2 drops of 1M diluted hydrochloric acid, followed by adding 10mL of water to the reaction system, extracting with methylene chloride (20 mL. Times.3), washing the combined organic phases once with saturated brine (10 mL), drying over anhydrous sodium sulfate, and spin-drying to obtain the crude product. The crude product was purified by column chromatography (methanol 0-4%, methanol/dichloromethane) to give compound 37.MS m/z 768.2[ M+H ] ] + .
1 H NMR(400MHz,DMSO-d6)δ＝11.04-10.85(m,1H),9.45-9.34(m,1H),7.55-7.50(m,1H),7.10-7.00(m,2H),6.86-6.81(m,1H),6.78-6.65(m,7H),6.60-6.54(m,2H),5.12-4.98(m,1H),4.41-4.15(m,2H),3.67-3.55(m,2H),3.29(br s,4H),2.97-2.82(m,1H),2.69-2.53(m,7H),2.44-2.35(m,1H),2.27-2.16(m,7H),2.10-1.89(m,5H),1.83-1.74(m,2H),1.73-1.62(m,1H),1.29-1.09(m,2H).
Example 38
The synthetic route is as follows:
step 1: synthesis of Compound 38-A
Intermediate 1 (100 mg) and 2-chloro-4-fluorobenzeneboronic acid (39.43 mg) were dissolved in dioxane (5 mL) and water (1 mL), sodium carbonate (65.37 mg) and tetrakis (triphenylphosphine) palladium (47.51 mg) were added, N at 100 ℃ 2 Stirring was carried out in an atmosphere for 1.8 hours. After the reaction, the reaction mixture was added to water (30 mL), extracted with ethyl acetate (20 ml×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 38-a. MS m/z 536.1[ M+H ]] +
Step 2: synthesis of Compound 38-B
To a dichloromethane solution (15 mL) of compound 38-A (100 mg) was added boron tribromide (467.32 mg) at-65℃under nitrogen protection, and the reaction was warmed to 20℃and stirred for 12 hours. After the reaction, the reaction mixture was slowly added to water (30 mL), extracted with dichloromethane (20 ml×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound 38-B. MS m/z 476.0[ M+H ]] +
Step 3: synthesis of hydrochloride salt of Compound 38
To a solution of compound 38-B (88 mg) in dichloromethane (25 mL) and methanol (5 mL) was added sequentially trifluoroacetate salt of intermediate 2 (81.79 mg), sodium acetate (30.33 mg), magnesium sulfate (111.27 mg). After stirring the reaction at 20℃for 30 minutes, sodium borohydride acetate (117.55 mg) was added, and the reaction was stirred at 20℃for an additional 11.5 hours. After the reaction is finished, the reaction solution is filtered, the filtrate is dripped into dilute hydrochloric acid (4M, 0.1 mL) for quenching, the redundant solvent is removed under reduced pressure to obtain a crude product, and the crude product is prepared into a high-efficiency liquid phase (column type, xtime C18 is 150 mm by 40mm by 5 mu m; mobile phase is [ water (HCl) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 16% -46%,10 min) to obtain the hydrochloride of the compound 38. MS m/z 788.1[ M+H ]] +
Example 39
The synthetic route is as follows:
step 1: synthesis of Compound 39-A
Intermediate 1 (100 mg) and 2-fluoro-4-chlorobenzeneboronic acid (39.43 mg) were dissolved in dioxane (5 mL) and water (1 mL), sodium carbonate (65.37 mg) and tetrakis (triphenylphosphine) palladium (47.51 mg) were added, and stirred at 100 ℃ in an N2 atmosphere for 2 hours. After the reaction, the reaction mixture was added to water (30 mL), extracted with ethyl acetate (20 ml×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 39-a. MS m/z 536.1[ M+H ]] +
Step 2: synthesis of Compound 39-B
To a dichloromethane solution (15 mL) of compound 39-A (80 mg) was added boron tribromide (373.86 mg) at-65℃under nitrogen protection, and the reaction was warmed to 20℃and stirred for 12 hours. After the reaction, the reaction mixture was slowly added to water (30 mL), extracted with dichloromethane (20 ml×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound 39-B. MS m/z 476.0[ M+H ]] +
Step 3: synthesis of hydrochloride salt of Compound 39
To a solution of compound 39-B (70 mg) in dichloromethane (25 mL) and methanol (5 mL) was added sequentially trifluoroacetate salt of intermediate 2 (66.36 mg), sodium acetate (24.13 mg), magnesium sulfate (88.51 mg). After stirring the reaction at 20℃for 30 minutes, sodium borohydride acetate (93.51 mg) was added, and the reaction was stirred at 20℃for an additional 11.5 hours. After the reaction is finished, the reaction solution is filtered, the filtrate is dripped into dilute hydrochloric acid (4M, 0.1 mL) for quenching, the redundant solvent is removed under reduced pressure to obtain a crude product, and the crude product is prepared into a high-efficiency liquid phase (column type: welch Xtime C18 100 x 40mm x 3 mu m; mobile phase: water (HCl) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 20% -50%,8 min) to obtain the hydrochloride of the compound 39. MS m/z 788.3[ M+H ]] +
1 H NMR(400MHz,CD 3 OD)δ＝7.71(d,J＝8.5Hz,1H),7.47(br d,J＝8.5Hz,2H),7.23-7.10(m,5H),7.09-7.00(m,2H),6.77(d,J＝1.8Hz,1H),6.62-6.52(m,2H),5.12(br dd,J＝5.1,13.3Hz,1H),4.54-4.36(m,2H),4.05(br s,2H),3.85-3.59(m,6H),3.50-3.36(m,2H),3.28-3.23(m,2H),2.99-2.72(m,4H),2.47(dq,J＝4.8,13.2Hz,2H),2.37-2.13(m,7H),1.99-1.83(m,2H),1.41-1.22(m,2H).
Example 40
The synthetic route is as follows:
step 1: synthesis of Compound 40-A
Intermediate 1 (100 mg) and 3-chloro-2-fluorophenylboronic acid (39.43 mg) were dissolved in dioxane (5 mL) and water (1 mL), sodium carbonate (65.37 mg) and tetrakis (triphenylphosphine) palladium (47.51 mg) were added, N at 100 ℃ 2 Stirring was carried out in an atmosphere for 2 hours. After the reaction, the reaction mixture was added to water (30 mL), extracted with ethyl acetate (20 ml×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 40-a. MS m/z 536.1[ M+H ]] +
Step 2: synthesis of Compound 40-B
To a dichloromethane solution (15 mL) of compound 40-A (90 mg) was added boron tribromide (420.59 mg) at-65℃under nitrogen protection, and the reaction was warmed to 20℃and stirred for 12 hours. After the reaction, the reaction mixture was slowly added to water (30 mL), extracted with dichloromethane (20 ml×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound 40-B. MS m/z 476.0[ M+H ]] +
Step 3: synthesis of Compound 40
To a solution of compound 40-B (75 mg) in dichloromethane (25 mL) and methanol (5 mL) was added sequentially trifluoroacetate salt of intermediate 2 (71.10 mg), sodium acetate (25.85 mg), magnesium sulfate (94.83 mg). Reaction in After stirring at 20℃for 30 minutes, sodium borohydride acetate (100.19 mg) was added and the reaction was stirred at 20℃for an additional 11.5 hours. After the reaction is finished, the reaction solution is filtered, the filtrate is dripped into dilute hydrochloric acid (4M, 0.1 mL) for quenching, the redundant solvent is removed under reduced pressure to obtain a crude product, and the crude product is prepared into a high-efficiency liquid phase (column type: welch Xtime C18 100 x 40mm x 3 mu m; mobile phase: water (HCl) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 20% -50%,8 min) to obtain the hydrochloride of the compound 40. MS m/z 788.2[ M+H ]] +
1 H NMR(400MHz,CD 3 OD)δ＝7.70(br d,J＝8.0Hz,1H),7.32-7.08(m,6H),6.99(br s,3H),6.76(br s,1H),6.60(br s,2H),5.11(br dd,J＝4.0,13.3Hz,1H),4.54-4.26(m,2H),4.04(br s,2H),3.91-3.44(m,6H),3.23(br d,J＝4.1Hz,4H),2.96-2.73(m,4H),2.54-2.27(m,3H),2.24-2.12(m,6H),1.74-1.71(m,2H),1.38-1.25(m,2H).
Example 41
The synthetic route is as follows:
step 1: synthesis of Compound 41-A
Intermediate 1 (100 mg) and 2, 4-dichlorobenzoboric acid (43.15 mg) were dissolved in dioxane (5 mL) and water (1 mL), sodium carbonate (65.37 mg) and tetrakis (triphenylphosphine) palladium (47.51 mg) were added, N at 100 ℃ 2 Stirring was carried out in an atmosphere for 2 hours. After the reaction, the reaction mixture was added to water (30 mL), extracted with ethyl acetate (20 ml×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 41-a. MS m/z 552.0[ M+H ]] +
Step 2: synthesis of Compound 41-B
To a dichloromethane solution (15 mL) of compound 41-A (80 mg) was added boron tribromide (362.72 mg) at-65℃under nitrogen protection, and the reaction was warmed to 20℃and stirred for 12 hours. After the completion of the reaction, the reaction mixture, The reaction was slowly added to water (30 mL), extracted with dichloromethane (20 mL x 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give compound 41-B. MS m/z 492.1[ M+H ]] +
Step 3: synthesis of hydrochloride salt of Compound 41
To a solution of compound 41-B (70 mg) in dichloromethane (25 mL) and methanol (5 mL) was added sequentially trifluoroacetate salt of intermediate 2 (64.14 mg), sodium acetate (23.32 mg), magnesium sulfate (85.55 mg). After stirring the reaction at 20℃for 30 minutes, sodium borohydride acetate (90.38 mg) was added, and the reaction was stirred at 20℃for an additional 11.5 hours. After the reaction is finished, the reaction solution is filtered, the filtrate is dripped into dilute hydrochloric acid (4M, 0.1 mL) for quenching, the redundant solvent is removed under reduced pressure to obtain a crude product, and the crude product is prepared into a high-efficiency liquid phase (column type: welch Xtime C18 100 x 40mm x 3 mu m; mobile phase: water (HCl) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 20% -50%,8 min) to obtain the hydrochloride of the compound 41. MS m/z 804.4[ M+H ]] +
1 H NMR(400MHz,CD 3 OD)δ＝7.70(d,J＝8.3Hz,1H),7.49(br d,J＝8.4Hz,2H),7.40(s,1H),7.25-7.08(m,6H),6.77(d,J＝1.9Hz,1H),6.64-6.51(m,2H),5.11(br dd,J＝4.9,13.2Hz,1H),4.52-4.37(m,2H),4.05(br s,2H),3.85-3.61(m,6H),3.51-3.37(m,2H),3.29-3.19(m,2H),2.97-2.74(m,4H),2.57-2.39(m,2H),2.35-2.14(m,7H),1.95-1.91(m,2H),1.35-1.26(m,2H).
Example 42
The synthetic route is as follows:
step 1: synthesis of Compound 42-A
To a solution of 1- (4-bromophenyl) piperazine (5.7 g) and 2-bromo-1, 1-diethoxyethane (4.66 g) in N, N-dimethylformamide (50 mL) was added potassium carbonate (9.80 g), and the mixture was reacted at 90℃with stirring for 16 hours . After the reaction was completed, the reaction mixture was poured into water (150 mL), extracted with ethyl acetate (50 ml×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give crude 42-a. MS m/z 358.9[ M+H+2 ]] +
1 H NMR(400MHz,CDCl 3 )δ＝7.33(d,J＝9.0Hz,2H),6.79(d,J＝9.0Hz,2H),4.69(t,J＝5.3Hz,1H),3.75-3.66(m,2H),3.62-3.52(m,2H),3.21-3.13(m,4H),2.75-2.68(m,4H),2.61(d,J＝5.3Hz,2H),1.23(t,J＝7.1Hz,6H).
Step 2: synthesis of Compound 42-B
To a solvent of compound 42-A (2.4 g), ethylene glycol dimethyl ether (25 mL) of duplex pinacol borate (2.05 g), potassium acetate (1.98 g), 2-dicyclohexylphosphine-2, 4, 7-triisopropylbiphenyl (640.45 mg) and tris (dibenzylideneacetone) dipalladium (615.12 mg) were added, and the reaction was warmed to 90℃under nitrogen atmosphere and stirred for 12 hours. After the reaction, the reaction solution was filtered, and the excess solvent was removed by rotary evaporation under reduced pressure to obtain crude 42-B. MS m/z 405.1[ M+H ]] +
Step 3: synthesis of Compound 42-C
To a solution of intermediate 1-B (4.02 g) and compound 42-B (3.36 g) in dioxane (50 mL) and water (5 mL) were added potassium carbonate (3.45 g) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (608.02 mg), and the mixture was heated to 90℃under nitrogen and reacted with stirring for 12 hours. After the reaction, the reaction liquid was cooled and filtered, and the filtrate was distilled off under reduced pressure to remove the solvent. The crude product is quickly passed through a column machine24g />Silica Flash Column, mobile phase: ethyl acetate/petroleum ether 0-15%, flow rate: 35 mL/min) to give compound 42-C. MS m/z 451.4[ M+H ] ] +1 H NMR(400MHz,CDCl 3 )δ＝7.18(d,J＝8.8Hz,2H),7.01-6.95(m,1H),6.88-6.81(m,3H),6.74(dd,J＝2.6,8.5Hz,1H),6.30(t,J＝7.3Hz,1H),4.72(br s,1H),3.84(s,3H),3.71(qd,J＝7.1,9.4Hz,2H),3.58(qd,J＝7.1,9.3Hz,2H),3.22(br s,4H),2.74(br s,4H),2.67-2.56(m,4H),2.15(quin,J＝7.0Hz,2H),1.95(q,J＝7.2Hz,2H),1.24(t,J＝7.1Hz,6H).
Step 4: synthesis of Compound 42-D
To a solution of compound 42-C (1 g) in methylene chloride (20 mL) at-5 to 0℃under nitrogen protection was added pyridinium tribromide (745.23 mg), and the reaction was maintained at the temperature and stirred for 0.5 hours. After the reaction, the reaction mixture was poured into saturated sodium bisulphite (100 mL), stirred at 5-10℃for 10 minutes, allowed to stand for separation, and the organic phase was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product is added with n-heptane (5 mL) for beating at room temperature, filtered, and the filter cake is collected to obtain the compound 42-D. MS m/z 531.1[ M+H+2 ]] +
1H NMR(400MHz,CDCl 3 )δ＝7.19(d,J＝8.6Hz,2H),6.88(br d,J＝8.1Hz,2H),6.77(d,J＝2.6Hz,1H),6.75-6.71(m,1H),6.68-6.64(m,1H),5.40(t,J＝5.0Hz,1H),3.83-3.61(m,13H),3.11(br s,4H),2.75(br t,J＝7.1Hz,2H),2.58(t,J＝6.9Hz,2H),2.29(quin,J＝7.0Hz,2H),1.29-1.24(m,6H).
Step 5: synthesis of Compound 42-E
To a solution of compound 42-D (0.2 g) and phenylboronic acid (50.66 mg) in dioxane (5 mL) and water (1 mL) under nitrogen atmosphere were added sodium carbonate (120.10 mg) and tetrakis (triphenylphosphine) palladium (87.29 mg), and the mixture was stirred at 110℃for 12 hours. After the reaction, cooling to room temperature, filtering, and removing the solvent by rotary evaporation under reduced pressure. The crude product is quickly passed through a column machine4g/>Silica Flash Column, mobile phase: ethyl acetate/petroleum ether 0-20%, flow rate: 20 mL/min) to give compound 42-E. MS m/z 527.4[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ＝7.24-7.17(m,2H),7.17-7.14(m,2H),7.13-7.07(m,1H),6.85(d,J＝8.5Hz,1H),6.81(d,J＝2.5Hz,1H),6.78(d,J＝8.5Hz,2H),6.72-6.67(m,1H),6.61(d,J＝8.8Hz,2H),4.70(br s,1H),3.84(s,3H),3.74-3.65(m,2H),3.61-3.52(m,2H),3.14(br d,J＝4.3Hz,4H),2.78(br t,J＝6.9Hz,2H),2.69(br s,4H),2.61(br d,J＝5.3Hz,2H),2.43-2.33(m,2H),2.15(quin,J＝6.8Hz,2H),1.22(t,J＝7.0Hz,6H).
Step 6: synthesis of Compound 42-F
To a solution of compound 42-E (140 mg) in methylene chloride (30 mL) at-60℃under nitrogen, boron tribromide (665.90 mg) was added, the reaction was warmed to 20℃and stirred for 12 hours. After the reaction, the reaction mixture was poured into water (50 ml×3), extracted with dichloromethane (20 ml×3), washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent to obtain crude 42-F. MS m/z 439.1[ M+H ] ] +
Step 7: synthesis of hydrochloride salt of Compound 42
To a solution of compound 42-F (120 mg) and trifluoroacetate salt of intermediate 2 (123.47 mg) in methanol (1 mL) and methylene chloride (5 mL) were added sodium acetate (44.89 mg) and anhydrous magnesium sulfate (164.68 mg) and stirred at 20℃for 0.5 hours, then sodium borohydride acetate (173.98 mg) was added, and the reaction was stirred at 20℃for 11.5 hours. After the reaction is finished, the reaction solution is filtered, the filtrate is dripped into dilute hydrochloric acid (4M, 0.1 mL) for quenching, the redundant solvent is removed under reduced pressure to obtain a crude product, and the crude product is prepared into a high-efficiency liquid phase (column type: welch Xtime C18 100 x 40mm x 3 mu m; mobile phase: water (HCl) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 10% -40%,9 min) to obtain the hydrochloride of the compound 42. MS m/z 751.3[ M+H ]] +
1 H NMR(400MHz,DMSO-d6)δ＝10.96(s,1H),9.41(br s,1H),7.60(d,J＝8.5Hz,1H),7.22-7.06(m,7H),6.80-6.67(m,5H),6.55(s,2H),5.06(dd,J＝5.1,13.2Hz,1H),4.45-4.19(m,2H),4.09(br s,2H),3.93-3.61(m,6H),3.40-3.29(m,6H),3.11-3.01(m,2H),2.99-2.81(m,1H),2.73-2.54(m,4H),2.47-2.30(m,2H),2.26(br t,J＝6.7Hz,2H),2.10-1.94(m,3H),1.54-1.38(m,2H).
Biological testing:
experimental example 1: MCF-7ER alpha degradation experiment
The purpose of the experiment is as follows:
compounds were tested for their ability to degrade ER alpha receptors under experimental conditions.
Experimental materials:
phenol red free MEM medium was purchased from Wisent, fetal bovine serum from Biosera, and Human Total erα/NR3A1 ELISA kit from R & D. The MCF-7 cell line was purchased from the China academy of sciences typical culture Collection Committee cell bank. Nivo5 Multilabel Analyzer (Perkinelmer).
Experimental protocol:
the first day:
MCF-7 cells were resuspended in medium (phenol Red MEM+5% Charcoal Dextran Stripped FBS +1% PS) and seeded at 96
Placing the cell culture plate in a carbon dioxide incubator for overnight incubation;
ELISA strip plates were diluted with 1XPBS and incubated overnight at 25 ℃.
The following day:
1. cell dosing: the compound to be tested is diluted to the 8 th concentration, the compound concentration is 20 mu M,4 mu M is diluted downwards to the 8 th concentration of 0.256nM in sequence, and double-compound wells are arranged. Turning the middle plate and then turning the cell plate to make the final concentration of DMSO in each hole be 0.5%, and incubating for 4 hours at 37 ℃;
2. standard curve solution preparation: a standard curve stock solution of 110ng/mL was 6-fold diluted with buffer #8 to give a solution of 18.3ng/mL, and then 8-point gradient diluted with buffer #3 to a final concentration of 200pg/mL-1.56pg/mL.
ELISA plates were washed 3 times with wash solution (1 XPBS contains 0.05% Tween);
4. mu.L of blocking solution (1 XPBS contains 1% BSA) per well was added and incubated for 2 hours at 25 ℃;
5. precooling 1XPBS, removing supernatant after incubation of the compound, washing plate with precooled 1XPBS, adding cell lysate, and lysing on ice
15 minutes;
Removing the sealing liquid from the ELISA plate, washing, and repeating the step 3;
7. after cell lysis, 150 mu L of buffer solution #8 per well is added into a cell plate, 6 times dilution is carried out on the cell lysis solution, the mixture is blown and evenly mixed, and 100 mu L of solution per well is taken into an ELISA plate;
8. mu.L of Standard per well was simultaneously taken in ELISA plates and incubated overnight at 25 ℃.
Third day:
1. removing the supernatant, and washing 3 times by using a washing liquid;
2. the Human Total ER alpha Detection Antibody stock (14.4. Mu.g/mL) was 36-fold diluted with buffer #1 (1 XPBS containing 1% BSA), detection Antibody at a final concentration of 400ng/mL, 100. Mu.L/well solution was applied to ELISA plates and incubated at 25℃for 2 hours;
3. washing the plate with buffer # 1;
4. Strepitavidin-HRP A was 200-fold diluted with buffer #1 (1 XPBS contains 1% BSA) and 100. Mu.L/well solution was placed in ELISA plates and incubated for 20 min at 25 ℃;
5. washing the plate with buffer # 1;
6. mu.L of Substrate Solution (1:1 mix reagent A (H) 2 O 2 ) And reagent B (tetramethylbenzidine)) solution into ELISA plate, incubation at 25 ℃ for 20 min;
7. add 50. Mu.L/Kong Zhongzhi solution and perform OD450 absorbance reading on plate reader.
Data analysis:
calculating ER alpha concentration values of corresponding points according to the OD450 reading values of the original data of the samples and a standard curve, converting the concentration values into inhibition ratios by using the equation (Sample-Min)/(Max-Min) which is 100%, and calculating the ER alpha concentration values according to a four-parameter equation y= (A-D)/[ 1+ (x/C)/(B) ]Curve fitting of +D to obtain DC 50 Is a value of (2).
Max hole: positive control wells read 100nM FUL treated wells.
Min well: negative control wells read 0.5% dmso-treated cell wells.
The experimental results are shown in Table 1.
DC degradation of ERalpha by the compounds of Table 1 50
/>
Conclusion: the compound has good degradation capability for ERalpha.
Experimental example 2: mouse pharmacokinetic test
The purpose of the experiment is as follows:
test compounds for pharmacokinetic conditions in mice under experimental conditions
Experimental materials:
BALB/c mice (female, 7-10 weeks old, beijing vitamin Toril Hua laboratory animal technologies Co., ltd.)
Experimental protocol:
rodent drug substitution profile following oral administration of compounds was tested in standard protocols. After the BALB/c mice arrive at the facility, at least 3 days of acclimation/quarantine will be performed, and after the end of acclimation/quarantine, the veterinarian or prescribing personnel will examine the health status of the BALB/c mice to assess whether the animals are suitable for experimental study. All BALB/c mice were not fasted prior to dosing and mice were given a single oral dose in the experiment. The oral vehicle was 10% DMSO/10% Solutol/80% H 2 A uniform suspension of O. Animals were weighed prior to dosing and dosing volumes were calculated from body weight. The project used 4 female BALB/c mice, all dosed orally at 1 mg/mL. Whole blood samples were collected by saphenous vein puncture at various time points within 24 hours in pairs and all blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, supernatant plasma was aspirated by centrifugation at 3200g for 10 minutes at 4℃and rapidly placed in dry ice and then stored at-60℃or lower for LC-MS/MS analysis. Using a non-compartmental model, blood concentration-time data was analyzed using the WinNonlin software package (Version 6.3 and above) and drug generation parameters were calculated, PK parameters including (if data allow) but not limited to peak concentration (Cmax), peak time (Tmax), elimination half-life (T) 1/2 ) Area under the blood concentration-time curve (AUC), etc.
The experimental results are shown in Table 2.
TABLE 2 pharmacokinetic parameters of a portion of the compounds of the present application in mice
Conclusion: the compounds of the present application have good pharmacokinetic properties.

Claims (13)

1. A compound represented by the formula (IV) or a pharmaceutically acceptable salt thereof,
wherein,
R 1 selected from OH, alkoxy or COOH;
each R 2 Independently selected from halogen, OH, CN, NH 2 Alkyl, alkoxy, alkylamino, dialkylamino, heterocycloalkyl, -O-cycloalkyl or-O-heterocycloalkyl, said alkyl, alkoxy, alkylamino, dialkylamino, heterocycloalkyl, -O-cycloalkyl and-O-heterocycloalkyl optionally being independently substituted with 1, 2 or 3R a Substitution;
alternatively, two adjacent ring atoms on ring A are simultaneously bound by R 2 When substituted, two R 2 And the ring atoms to which they are attached may together form a heterocyclic group;
each R a Independently selected from halogen, OH, CN, NH 2 Alkyl, alkoxy, alkylamino or dialkylamino;
each R 3 Independently selected from halogen;
m and n are each independently selected from 0, 1, 2 and 3;
E 1 selected from O and CH 2 ；
L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, cycloalkyl or heterocycloalkyl;
selected from single bonds and double bonds;
Ring a is selected from phenyl or heteroaryl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from OH, C 1-3 Alkoxy or COOH.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 2 Independently selected from halogen, OH, CN, NH 2 、C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkyl-NH- (C) 1-3 Alkyl group 2 -N-、C 3-6 Heterocyclylalkyl, -O-C 3-6 Cycloalkyl or-O-C 3-6 Heterocycloalkyl, said C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkyl-NH- (C) 1-3 Alkyl group 2 -N-、C 3-6 Heterocyclylalkyl, -O-C 3-6 Cycloalkyl and-O-C 3-6 Heterocycloalkyl is optionally independently substituted with 1, 2 or 3R a Substitution;
alternatively, each R 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl optionally being substituted independently by 1, 2 or 3R a Substitution;
alternatively, R 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl or-O-cyclobutyl, the CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl and-O-cyclobutyl a Substitution;
alternatively, R 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 Second stepA radical, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl or-O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups, ethyl, isopropyl, methoxy, ethoxy, isopropoxy and-O-cyclopropyl a Substitution;
alternatively, R 2 Independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Heterocycloalkyl, said C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3R a Substituted, each R a Independently selected from halogen, C 1-3 Alkyl or (C) 1-3 Alkyl group 2 -N-; alternatively, R 2 Independently selected from F, cl, br, I, OH, CH 3 Methoxy, 1-azetidinyl or 3-azetidinyl, said CH 3 Methoxy, 1-azetidinyl and 3-azetidinyl are optionally substituted independently by 1, 2 or 3R a Substituted, each R a Independently selected from F, cl, br, I, methyl or (CH) 3 ) 2 -N-；
Alternatively, R 2 Independently selected from F, cl, OH, CH 3 Methoxy, CHF 2 O-、(CH 3 ) 2 N-CH 2 -、
Alternatively, two adjacent ring atoms on ring A are simultaneously bound by R 2 When substituted, two R 2 The ring atoms to which they are attached may together form C 3-6 A heterocyclic group.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R a Independently selected from F, cl, br, I, CN, OH, C 1-6 Alkyl or C 1-6 An alkoxy group;
alternatively, R a Independently selected from F, cl, br, I, CN, OH, C 1-3 Alkyl or C 1-3 An alkoxy group;
alternatively, R a Independently selected from F, cl, br, I, CN,OH、CH 3 Ethyl, isopropyl, methoxy, ethoxy or isopropoxy;
alternatively, R a Independently selected from F, cl, br, I, CN, OH, CH 3 Or methoxy;
alternatively, R a Independently selected from F or OH.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is selected from C 1-6 Alkylene, wherein 1 to 3 methylene groups are optionally replaced by O, NH, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl substitution;
alternatively, L is selected from C 1-6 Alkylene, -O-C 1-5 Alkylene, -C 3-6 Cycloalkyl-, -C 3-6 cycloalkyl-C 1-3 Alkylene, -4-6 membered heterocycloalkyl-or-4-6 membered heterocycloalkyl-C 1-3 An alkylene group;
alternatively, L is selected from C 4-6 Alkylene, -O-C 3-5 Alkylene, -cyclohexyl-C 1-3 Alkylene, -6-membered heterocycloalkyl-or-6-membered heterocycloalkyl-C 1-3 An alkylene group;
alternatively, L is selected from the group consisting of-O-C 3-5 Alkylene, -piperidinyl-C 1-3 Alkylene or-piperazinyl-C 1-3 An alkylene group;
alternatively, L is selected from the group consisting of-O-C 3-5 Alkylene group,
Alternatively, L is selected from
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from phenyl or 5-6 membered heteroaryl;
alternatively, ring a is selected from phenyl, pyridinyl or pyrazolyl;
alternatively, ring A is selected from phenyl,
Alternatively, ring a is selected from phenyl.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from-> Said each R 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl optionally being substituted independently by 1, 2 or 3R a Substituted, each R a Independently selected from F, cl, br, I or OH;
alternatively, a structural unitSelected from-> Said each R 2 Independently selected from F, cl, br, I, OH, CN, NH 2 、CH 3 Ethyl, isopropyl, methoxyRadical, ethoxy, isopropyloxy, -O-cyclopropyl, said CH 3 Optionally independently substituted with 1, 2 or 3R groups a Substituted, each R a Independently selected from F, cl, br, I or OH;
alternatively, a structural unitSelected from->Said each R 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl optionally being substituted independently by 1, 2 or 3R a Substituted, each R a Independently selected from F, cl, br, I or OH; alternatively, the structural unit->Selected from the group consisting of Said each R 2 Independently selected from F, cl, br, I, OH, CN, CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl or azetidinyl, said CH 3 Ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, aziridinyl and azetidinyl optionally being substituted independently by 1, 2 or 3R a Substituted, each R a Independently selected from F, cl, br, I or OH;
Alternatively, a structural unitSelected from->
8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of a compound represented by the formula (IV-1) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 、R 3 、L、E 1 Ring A,m and n are as defined in claim 1;
or selected from the compounds represented by the formula (IV-2) or pharmaceutically acceptable salts thereof,
wherein R is 1 、R 2 、R 3 L, ring A, m and n are as defined in claim 1;
or selected from the compounds represented by the formula (IV-3) or pharmaceutically acceptable salts thereof,
wherein R is 1 、R 2 、R 3 L, m and n are as defined in claim 1;
or selected from the compounds represented by the formula (IV-4) or pharmaceutically acceptable salts thereof,
wherein,
t is selected from 1, 2, 3, 4 or 5;
R 1 、R 2 ring a and n are as defined in claim 1;
or selected from the compounds represented by the formula (IV-5) or pharmaceutically acceptable salts thereof,
wherein,
q is selected from 1 or 2;
R 1 、R 2 、E 1 ring a and n are as defined in claim 1;
or selected from the compounds represented by the formula (IV-6) or pharmaceutically acceptable salts thereof,
wherein R is 1 、R 2 And n is as defined in claim 1;
or selected from the compounds shown in the formula (V) or pharmaceutically acceptable salts thereof,
wherein,
q is selected from 1, 2 and 3;
R 1 、R 2 、R 3 、E 1 ring A,m and n are as defined in claim 1; or selected from the compounds represented by the formula (V-1) or pharmaceutically acceptable salts thereof,
Wherein,
q is selected from 1, 2 and 3;
R 2 、E 1 m and n are as defined in claim 1.
9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of a compound represented by the formula (IV-5'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
q is selected from 1 or 2;
R 1 、R 2 、E 1 ring a and n are as defined in claim 1;
or selected from the compounds of formula (IV-6'), stereoisomers thereof, or pharmaceutically acceptable salts thereof,
wherein R is 1 、R 2 And n is as defined in claim 1;
or selected from the compounds represented by the formula (V-2), stereoisomers thereof or pharmaceutically acceptable salts thereof,
wherein,
q is selected from 1, 2 or 3;
R 2 、E 1 and n is as defined in claim 1.
10. The following compounds or pharmaceutically acceptable salts thereof,
11. the compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 10, selected from,
/>
/>
/>
/>
12. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. The use of a compound according to any one of claims 1 to 11, a stereoisomer or a pharmaceutically acceptable salt thereof, in the treatment of a disease.
CN202310957422.7A 2022-07-29 2023-07-31 Benzo seven-membered ring type difunctional compound and application thereof Pending CN117466870A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022109090493 2022-07-29
CN202210909049 2022-07-29

Publications (1)

Publication Number Publication Date
CN117466870A true CN117466870A (en) 2024-01-30

Family

ID=89631930

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310957422.7A Pending CN117466870A (en) 2022-07-29 2023-07-31 Benzo seven-membered ring type difunctional compound and application thereof

Country Status (1)

Country Link
CN (1) CN117466870A (en)

Similar Documents

Publication Publication Date Title
Evans et al. Polyether antibiotics synthesis. Total synthesis and absolute configuration of the ionophore A-23187
AU2003292625A1 (en) Selective estrogen receptor modulators
JPH04103570A (en) 3-aminopiperidine derivative and related nitrogen- containing hetrocyclic compound
Davies et al. Ring-closing iodoamination of homoallylic amines for the synthesis of polysubstituted pyrrolidines: application to the asymmetric synthesis of (−)-codonopsinine
CA3155885A1 (en) Substituted macrocyclic compounds and related methods of treatment
CN116867778A (en) Benzo seven-membered ring type difunctional compound and application thereof
CN116867769A (en) Substituted pyridazine phenol derivatives
JP2001505576A (en) Tropane derivatives and methods for their synthesis
JP2021529214A (en) Kinolinopyrrolidine-2-one-based inducing compounds and their use
JP6790222B2 (en) Substituted indole compound as an estrogen receptor down regulator
Kuehne et al. Studies in biomimetic alkaloid syntheses—9: Two total syntheses of minovincine
JPH02504394A (en) Stereospecific method for producing furo[3,4-c]pyridine enantiomers, compounds thus obtained and pharmaceutical compositions thereof
AIMI et al. Studies on Plants containing Indole Alkaloids. VI. Minor Bases of Uncaria rhynchophylla MIQ.
Kametani et al. Total synthesis of steroid hormones. Efficient stereocontrolled synthesis of 17-methoxy-6-oxo-D-homo-18-nor-5. beta.-androsta-2, 13, 15, 17-tetraene
Heindl et al. Enantiospecific synthesis and receptor binding of novel dopamine receptor ligands employing natural 4-hydroxyproline as a practical and flexible building block
Chrzanowska et al. Asymmetric synthesis of (R)-(+)-and (S)-(−)-2, 3-methylenedioxy-8-oxoberbine (gusanlung D)
CN117466870A (en) Benzo seven-membered ring type difunctional compound and application thereof
Faigl et al. Novel stereoselective synthesis of 1, 2, 3-trisubstituted azetidines
Izquierdo et al. Total synthesis of the 5-epimers of naturally occurring (−)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4
Kuehne et al. Enantioselective syntheses of coronaridine and 18-methoxycoronaridine
Burn et al. Synthesis and dopaminergic properties of some exo-and endo-2-aminobenzonorbornenes designed as rigid analogs of dopamine
Hunter et al. Stereoselective tetrapyrido [2, 1-a] isoindolone synthesis via carbanionic and radical intermediates: a model study for the Tacaman alkaloid D/E ring fusion
Bonjouklian et al. Acid-catalyzed reactions of hapalindoles
CN116457357A (en) Fused tricyclic derivatives and their pharmaceutical use
Friestad et al. Effects of α-alkoxy substitution and conformational constraints on 6-exo radical cyclizations of hydrazones via reversible thiyl and stannyl additions

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication