CN116478100A - Quinazoline derivative and preparation method and application thereof - Google Patents

Quinazoline derivative and preparation method and application thereof Download PDF

Info

Publication number
CN116478100A
CN116478100A CN202310056017.8A CN202310056017A CN116478100A CN 116478100 A CN116478100 A CN 116478100A CN 202310056017 A CN202310056017 A CN 202310056017A CN 116478100 A CN116478100 A CN 116478100A
Authority
CN
China
Prior art keywords
group
alkyl
cycloalkyl
ethyl
mol
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
CN202310056017.8A
Other languages
Chinese (zh)
Inventor
郭阳辉
廖伟伟
张恒
陈友喜
叶成
徐代旺
徐肖杰
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.)
Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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 Zhejiang Hisun Pharmaceutical Co Ltd, Shanghai Aryl Pharmtech Co Ltd filed Critical Zhejiang Hisun Pharmaceutical Co Ltd
Publication of CN116478100A publication Critical patent/CN116478100A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to a substituted quinazoline derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. In particular, the invention relates to a substituted quinazoline derivative shown in a general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application of the derivative as a therapeutic agent, particularly an SOS1 inhibitor, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Quinazoline derivative and preparation method and application thereof
Technical Field
The invention relates to a substituted quinazoline derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, particularly as an SOS1 inhibitor.
Background
RAS genes are widely present in various eukaryotes such as mammals, drosophila, fungi, nematodes and yeast, have important physiological functions in various living systems, and the mammalian RAS gene family has three members, H-RAS, K-RAS and N-RAS, respectively, and the various RAS genes have similar structures, all composed of four exons, distributed on DNA of about 30kb in length. The encoded products are monomeric globular proteins of relative molecular mass 21 kDa. The active and inactive states of RAS proteins have a significant impact on the life processes such as cell growth, differentiation, proliferation and apoptosis. The protein is a membrane-bound guanine nucleotide binding protein, has weak GTPase activity, and can regulate the active state of RAS through GTPase Activating Proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities, and is in an active state when RAS proteins and GTP are bound to form RAS-GTP, and the GTPase activating proteins can convert RAS-GTP into RAS-GDP through dephosphorylation and then inactivate; the inactivated RAS-GDP is converted into active RAS-GTP under the action of guanine nucleotide exchange factors, so that a series of downstream channels such as RAF/MER/ERK, PI3K/AKT/mTOR and the like are activated.
The RAS gene is also closely related to various diseases of human beings, especially in the aspect of cancers, RAS is an oncogene with frequent mutation, wherein KRAS subtype gene mutation accounts for 86% of total RAS gene mutation, about 90% of pancreatic cancers, 30% -40% of colon cancers and 15-20% of lung cancers, and KRAS gene mutation occurs to different degrees. In view of the prevalence of KRAS gene mutations, this target has been the focus of drug research and development workers. Beginning with the publication of AMG-510 clinical results directly acting on KRAS-G12C targets, KRAS inhibitor studies have been a hot trend at home and abroad.
The SOS (Son of sevenless homolog) protein was originally discovered in Drosophila studies and was a guanosine-releasing protein encoded by the SOS gene. Humans have 2 SOS homologs, hSOS1 and hSOS2, both members of the guanine nucleotide exchange factor family, with 70% homology, although they are highly similar in structure and sequence, there is a difference in their physiological functions. The hSOS1 protein is 150kDa in size and is a multi-structural protein domain consisting of 1333 amino acids, comprising an N-terminal protein domain (HD), multiple homologous domains, a helical junction (HL), a RAS exchange sequence (REM), and a proline-rich C-terminal domain. The hSOS1 has 2 binding sites with RAS proteins, namely a catalytic site and an allosteric site, wherein the catalytic site binds to RAS proteins on the RAS-GDP complex to promote guanine nucleotide exchange, and the allosteric site binds to RAS proteins on the RAS-GTP complex to further enhance the catalytic action, thereby participating in and activating the signal transduction of RAS family proteins. Studies have shown that inhibition of SOS1 not only results in complete inhibition of the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also results in a 50% reduction in phospho-ERK activity in mutant KRAS cell lines. Therefore, inhibition of SOS1 can also reduce RAS activity, thereby treating various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, colorectal cancer, non-small cell lung cancer, and the like.
There are no drugs on the market that are selectively targeted to SOS1, but a series of related patents have been published, including WO2018115380A1, WO2019122129A1, WO2019201848A1, WO2020180768A1, WO2020180770A1, etc. of Bayer, and the drugs currently in clinical trial phase are BI-1701963. However, these are far from adequate for anti-tumor studies, and there is still a need to study and develop new selective SOS1 kinase inhibitors to address unmet medical needs.
Disclosure of Invention
In view of the above technical problems, the present invention provides a substituted quinazoline compound represented by general formula (I):
wherein:
R 1 identical or different, each independently selected from hydrogen, alkyl, halogen, cyano, alkoxy or-NR 6 R 7 Wherein said alkyl is optionally further substituted with one or more halogens or-CH 2 -NR 6 N 7 Substituted;
R 2 selected from methoxy, -S (O) r R 5 、-C(O)OR 5 、-NR 11 R 12 OR-OR B ；
R 3 Selected from alkyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NR 13 C(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 、-S(O) r R 5 or-C (O) NHS (O) r R 5 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Is substituted by a substituent of (2);
R B selected from C 3 -C 6 Cycloalkyl or 4-11 membered heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, nitro, C 1 -C 6 Alkyl, C 1 -C 6 Halogen-containing alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or = O substituent;
the conditions are as follows: when R is 2 Selected from-OR B When R is 3 Selected from the group consisting of heterocyclyl, heteroaryl, -OR 5 、-C(O)OR 5 or-C (O) NR 6 R 7 ；
R 4 Selected from a hydrogen atom, an alkyl group, a halogen group, a cycloalkyl group or a heterocyclic group, preferably a hydrogen atom;
R 5 selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group is optionally further substituted with one or more groups selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 6 and R is 7 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
alternatively, R 6 And R is 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 8 、R 9 and R is 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
R 11 selected from hydrogen atoms or alkyl groups;
R 12 selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said cycloalkyl groupOptionally further substituted with one OR more groups selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Is substituted by a substituent of (2);
R 13 selected from a hydrogen atom, an alkyl group or a cycloalkyl group;
r are each independently selected from 0, 1 or 2;
m is selected from 1, 2, 3 or 4.
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II):
wherein: r is R 1 、R 3 、R 4 And m is as defined in formula (I).
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III):
wherein: r is R 1 、R 2 、R 4 And m is as defined in formula (I).
In a preferred embodiment of the invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 Identical or different, eachSelected independently from hydrogen atom, alkyl group, halogen, alkoxy group, amino group, haloalkyl group or haloalkoxy group, preferably hydrogen atom, fluorine, trifluoromethyl group, difluoromethyl group or amino group.
In a preferred embodiment of the invention, a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 Selected from:
methoxy, carboxylic acid, methylsulfonyl,
In a preferred embodiment of the invention, a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R 3 selected from alkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NR 13 C(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-S(O) r R 5 or-C (O) NHS (O) r R 5 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, hydroxy, halogen, alkoxy, cycloalkyl, =o, -C (O) R 5 or-NR 6 R 7 Is substituted by a substituent of (2);
R 5 selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, and heterocyclyl;
R 6 and R is 7 Each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with oneOr a plurality of groups selected from halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 R 10 Or = O;
alternatively, R 6 And R is 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, alkyl, alkoxy, =o, -C (O) R 8 or-NR 9 R 10 Is substituted by a substituent of (2);
R 8 、R 9 and R is 10 Each independently selected from a hydrogen atom or an alkyl group;
R 13 selected from hydrogen atoms or alkyl groups;
r are each independently selected from 0, 1 or 2.
In a preferred embodiment of the invention, a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R 3 selected from cyano, methoxy, methylsulfonyl, methylsulfinyl, methylcarboxylate, amide, hydroxy, carboxylic acid, acetyl, cyclopropyl, phenyl, pyridyl,
In a preferred embodiment of the invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms or cyclopropyl groups.
In a preferred embodiment of the invention, a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R 11 Selected from hydrogen atomsA child or alkyl group, wherein the alkyl group is preferably methyl;
R 12 selected from aryl or heteroaryl, wherein the aryl is preferably phenyl and the heteroaryl is preferably pyridinyl or pyrimidinyl.
In a preferred embodiment of the invention, the compounds of formula (I) are selected from:
/>
/>
/>
/>
/>
/>
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.
Still further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.
The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing an SOS1 inhibitor.
The invention also provides the use of a compound of general formula (I), (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a SOS1 mediated disease, preferably a cancer associated with RAS family protein signaling pathway dependence, a cancer caused by SOS1 mutation or a genetic disease caused by SOS1 mutation; wherein the SOS1 mediated disease is preferably lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibromatosis, noonan syndrome, heart-face skin syndrome, hereditary gingival fibromatosis type I, embryonal rhabdomyosarcoma, seltoril cell testicular tumor, or skin granulocytoma.
The invention further provides application of the compound shown in the general formula (I), (II) or (III) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating RAS family protein signal transduction pathway dependent cancers, SOS1 mutation-caused cancers or SOS1 mutation-caused genetic diseases.
The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B cell lymphoma, neurofibromatosis, noonan syndrome, cardio-facial skin syndrome, type I hereditary gingival fibroma, embryonal rhabdomyosarcoma, seltol cell testicular tumor or skin granulocytoma.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl groups. Example package for monocyclic cycloalkylIncluding but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, which may contain 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 18 members, two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.
"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.
"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, and include monocyclic, polycyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered double or triple ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur.
Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-onyl, piperazinyl, hexahydropyrimidinyl,
the monocyclic heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, which ring may contain 1 or more double bonds, but no ring has a completely conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ] ]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl, 5-oxaspiro [2.4 ]]Heptyl group,
The spiroheterocyclyl groups may be substituted or unsubstituted.
"fused heterocyclyl" refers to a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ]]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1,4]Dioxin (dioxin).
"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2-azabicyclo [3.3.2]Decyl group,
The bridged heterocyclic group may be substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridonyl, benzoimidazolyl, benzil-yl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzil-yl, and the like,
Heteroaryl groups may be substituted or unsubstituted.
"fused ring" means a polycyclic group having two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a fully conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more of the ring atoms are selected from nitrogen, oxygen, or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. "condensedExamples of rings "include, but are not limited to:
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
“C 1 -C 6 Hydroxyalkyl "refers to hydroxy-substituted C 1 -C 6 An alkyl group.
“C 1 -C 3 Halogen-containing alkyl "refers to halogen-substituted C 1 -C 3 An alkyl group.
“C 1 -C 6 Halogen-containing alkyl "refers to halogen-substituted C 1 -C 6 An alkyl group.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"DMSO" refers to dimethyl sulfoxide.
"BOP" refers to benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate.
"DBU" refers to 1, 8-diazabicyclo [5.4.0] undec-7-ene.
"DCC" refers to dicyclohexylcarbodiimide.
"EDCI" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
“PdCl 2 (dppf) "means [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride.
“RuPhos-Pd-G 3 "Trionycesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenylPhenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II).
"RuPhos" refers to 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl.
"BIPPYPHOS" refers to 5-di-tert-butylphosphine-1 ',3',5' -triphenyl-1 ' H- [1,4' ] bipyrazole.
“Pd(PPh 3)2 Cl 2 "refers to bis (triphenylphosphine) palladium dichloride.
“Pd 2 (dba) 3 "means tris (dibenzylideneacetone) dipalladium.
“Pd(dba) 2 "means bis (dibenzylideneacetone) palladium.
"XantPhos" means 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene.
"HATU" refers to 2- (7-azabenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate.
"9-BBN" means 9-borobicyclo [3.3.1] nonane.
The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, or-OH.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more substituents: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Is substituted by a substituent of (2);
R 5 selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more groups selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 6 and R is 7 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
alternatively, R 6 And R is 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) R, and said 4-8 membered heterocyclic group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 8 、R 9 and R is 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
r is selected from 0, 1 or 2;
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically 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.
Synthesis method of compound of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
scheme one:
reacting a compound of the general formula (IA) with a compound of the general formula (IB) under the action of a metal catalyst and a base to obtain a compound of the general formula (I); when R is 1 When the nitro group is contained, the amino group may be further reduced. The compounds of the general formula (I) may be further rationally converted.
Or alternatively, the process may be performed,
/>
reacting a compound shown in a general formula (IIA) with a compound shown in a general formula (IIB) under the action of a metal catalyst and alkali to obtain a compound shown in a general formula (I); when R is 1 When the nitro group is contained, the amino group may be further reduced. The compounds of the general formula (I) may be further rationally converted.
X is selected from halogen, preferably bromine;
m is selected from H, -B (OH) 2 、-BF 3 K. -MgX or
Ring A, R 1 、R 2 、R 3 、R 4 And m is as defined in formula (I).
Scheme II:
the compound of the general formula (IA) is subjected to a carbointercalation reaction under the catalysis of metal to obtain R 3 Compounds of formula (I) which are ester groups, i.e. compounds of formula (IC); the compounds of the formula (IC) are optionally further hydrolysed to give R 3 A compound of formula (I) which is a carboxylic acid, i.e. a compound of formula (ID); the compounds of formula (IC) are optionally further subjected to addition reaction with a formative reagent to give R 3 Is of the general formula (I) A compound, i.e. a compound of formula (IF); the compounds of formula (ID) are optionally further reacted with HNR 6 R 7 Condensation reaction is carried out under the condition of condensing agent to obtain R 3 is-C (O) NR 6 R 7 A compound of formula (I), i.e. a compound of formula (IE). When R is 1 When the nitro group is contained, the amino group may be further reduced. The compounds of the general formula (IC), the general formula (ID), the general formula (IE) and the general formula (IF) can be further reasonably converted.
Or alternatively, the process may be performed,
the compound of the general formula (IIA) is subjected to a carbointercalation reaction under the catalysis of metal to obtain R 2 Compounds of formula (I) which are ester groups, i.e. compounds of formula (IIC); the compounds of the formula (IIC) are optionally further hydrolysed to give R 2 A compound of formula (I), i.e. a compound of formula (IID), which is a carboxylic acid; when R is 1 When the nitro group is contained, the amino group may be further reduced. The compounds of the general formula (IIC) and (IID) can be further converted reasonably.
X is selected from halogen, preferably bromine;
ring A, R 1 、R 2 、R 3 、R 4 And m is as defined in formula (I).
Scheme III:
reacting a compound of the general formula (IA) with a bisboronic acid pinacol ester under metal catalysis to obtain a compound of the general formula (IG); the compound of formula (IG) is oxidized to give R 3 Compounds of formula (I) which are hydroxy, i.e. compounds of formula (IH); when R is 1 When the nitro group is contained, the amino group may be further reduced. The compounds of the general formula (IH) may be further rationalized.
X is selected from halogen, preferably bromine;
ring A, R 1 、R 2 、R 4 And m isThe definition is as described in the general formula (I).
Scheme IV:
reacting a compound of formula (IA) with sodium alkylsulfinate under metal catalysis to give R 3 Compounds of formula (I) which are alkylsulfonyl, i.e. compounds of formula (IJ); when R is 1 When the nitro group is contained, the amino group may be further reduced. The compounds of the general formula (IJ) may be further rationally converted.
Or alternatively, the process may be performed,
/>
reacting a compound of formula (IIA) with sodium alkylsulfinate under metal catalysis to give R 2 Compounds of formula (I) which are alkylsulfonyl, i.e. compounds of formula (IIJ); when R is 1 When the nitro group is contained, the amino group may be further reduced. The compounds of the general formula (IIJ) can be further converted reasonably.
R is selected from alkyl, preferably methyl or ethyl;
x is selected from halogen, preferably bromine;
ring A, R 1 、R 2 、R 3 、R 4 And m is as defined in formula (I).
Scheme five:
the compound of formula (IA) is reacted with zinc cyanide under metal catalysis, wherein the metal is preferably tetrakis (triphenylphosphine) palladium, to give R 3 Compounds of formula (I) which are cyano groups, i.e. compounds of formula (IK); the compounds of formula (IK), optionally further reduced, give R 3 Compounds of formula (I) which are amides, i.e. compounds of formula (IL). When R is 1 When containing nitro groups, can enterOne-step reduction to amino. The compounds of the general formula (IK) and the general formula (IL) can be further reasonably transformed.
X is selected from halogen, preferably bromine;
ring A, R 1 、R 2 、R 4 And m is as defined in formula (I).
Scheme six:
reacting a compound shown in a general formula (IIIA) with a compound shown in a general formula (IIIB) under the action of alkali to obtain a compound shown in the general formula (I); when R is 1 When containing nitro, can be further reduced into amino; the compounds of the general formula (I) may be further rationally converted.
Ring A, R 1 、R 2 、R 3 、R 4 And m is as defined in formula (I).
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Examples
The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, shanghai Haohong biological medicine technologies, shanghai Shaoshao reagent, shanghai Pico medicine, saen chemical technologies (Shanghai) and Shanghai Ling Kai medicine technologies, and the like.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
The nitrogen atmosphere is defined as the reaction flask being connected to a nitrogen balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound using an eluent/developing solvent system selected from the group consisting of silica gel column chromatography and thin layer chromatography: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane and ethyl acetate system, D: dichloromethane and ethanol, wherein the volume ratio of the solvent varies according to the polarity of the compound, and small amount of acidic or basic reagent such as acetic acid or triethylamine can be added.
Example 1
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(4-methylpiperazin-
1-yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (4-methylpiperazin-1-yl) quinazolin-4-amine
First step
7-bromo-6-methoxy-2-methylquinazolin-4(3H)-one
7-bromo-6-methoxy-2-methylquinazolin-4 (3H) -one
Methyl 2-amino-4-bromo-5-methoxybenzoate 1a (1.69 g,6.15mmol, prepared according to WO 2010135524) was dissolved in a 4M solution of HCl in 1, 4-dioxane (20 mL) and acetonitrile (10 mL), heated to 80℃and stirred for 12 hours. A large amount of solid was precipitated, filtered and the solid was dried to give 7-bromo-6-methoxy-2-methylquinazolin-4 (3H) -one 1b (1.0 g,3.7 mmol) in 60% yield.
MS m/z(ESI):271.0[M+1] +
Second step (R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorohedyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine
7-bromo-6-methoxy-2-methylquinazolin-4 (3H) -one 1b (540 mg,2.01 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine 1c (56 mg,2.51mmol, prepared according to WO 2019122129), a catter condensing agent (1.78 g,4.01 mmol) and DBU (1.22 g,8.03 mmol) were dissolved in N, N-dimethylformamide (10 mL) in this order, argon was replaced 3 times, and heated to 60℃under argon atmosphere with stirring for 5 hours. After completion of the reaction, ethyl acetate (50 mL) and water (25 mL) were added, the mixture was extracted, the separated liquid was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to give (R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (600 mg,1.36 mmol) in 68% yield.
MS m/z(ESI):440.1[M+1] +
Third step (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (4-methylpiperazine)
1-yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (4-methylpiperazin-1-yl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (20 mg, 45.43. Mu. Mol), 1-methylpiperazine (13.65 mg, 136.28. Mu. Mol), ruPhos-Pd-G 3 (5.71 mg, 6.81. Mu. Mol) and sodium t-butoxide (13.10 mg, 136.28. Mu. Mol) were sequentially dissolved in tetrahydrofuran (1 mL), argon was replaced 3 times, and the reaction was continued with stirring by heating to 100℃under the protection of argon for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (30 mL) and water (15 mL) were added, the mixture was extracted, the separated liquid and the aqueous phase were extracted with ethyl acetate (30 mL), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (4-methylpiperazin-1-yl) quinazolin-4-amine 1 (13.4 mg, 27.70. Mu. Mol), with a yield of 60.98%.
MS m/z(ESI):460.0[M+1] +
1 H NMR(400MHz,CDCl 3 )δ8.42(br,1H),7.77(t,J＝6.8Hz,1H),7.69(s,1H),7.46(t,J＝7.0Hz,1H),7.32-7.30(m,1H),7.17(t,J＝7.4Hz,1H),6.90(t,J＝55Hz,1H),5.91-5.84(m,1H),4.03(s,3H),3.38-3.27(m,4H),2.88-2.79(m,4H),2.58(s,3H),2.53(s,3H),1.83(d,J＝6.8Hz,3H).
Example 2
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-
(methylsulfonyl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-6- (methylsulfonyl) quinazolin-4-amine
First step
2-amino-5-bromo-4-methoxybenzonitrile
2-amino-5-bromo-4-methoxybenzonitrile
2-amino-4-methoxybenzonitrile 2a (1 g,6.75 mmol) and 1-bromopyrrolidine-2, 5-dione (1.32 g,7.42 mmol) were dissolved in N, N-dimethylformamide (0.5 mL) and the reaction was stirred at room temperature overnight. After completion of the reaction, the residue was purified by column chromatography on silica gel (eluent: A system) to give 2-amino-5-bromo-4-methoxybenzonitrile 2b (1.4 g), yield 91.35%.
MS m/z(ESI):227.0[M+1] +
Second step
2-amino-5-bromo-4-methoxybenzamide
2-amino-5-bromo-4-methoxybenzamide
2-amino-5-bromo-4-methoxybenzonitrile 2b (50 mg, 220.21. Mu. Mol) and potassium hydroxide (24.71 mg, 440.42. Mu. Mol) were dissolved in dimethyl sulfoxide (0.5 mL), and a 30% hydrogen peroxide solution (0.5 mL) was slowly added dropwise thereto, followed by reaction under ice bath for 0.5 hours. After completion of the reaction, 5mL of water was added to precipitate a solid, which was filtered, and the cake was dried under vacuum to give 2-amino-5-bromo-4-methoxybenzamide 2c (48 mg) in 88.94% yield.
MS m/z(ESI):244.9[M+1] +
Third step
6-bromo-7-methoxy-2-methylquinazolin-4(3H)-one
6-bromo-7-methoxy-2-methylquinazolin-4 (3H) -one
2-amino-5-bromo-4-methoxybenzamide 2c (20 mg, 81.61. Mu. Mol) and acetic acid (9.80 mg, 163.22. Mu. Mol) were sequentially dissolved in triethyl orthoacetate (0.5 mL), argon was replaced three times, and heated to 110℃under argon atmosphere to react for 16 hours. After completion of the reaction, 5mL of water was added to precipitate a solid, which was filtered, and the cake was dried in vacuo to give 6-bromo-7-methoxy-2-methylquinazolin-4 (3H) -one 2d (15 mg) in 68.30% yield.
MS m/z(ESI):269.0[M+1] +
Fourth step (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorohedyl) ethyl) -7-methoxy-2-methylquinazolin-4-
amine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-quinazolin-4-amine
6-bromo-7-methoxy-2-methylquinazolin-4 (3H) -one 2d (30 mg, 111.49. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1c (42.18 mg, 222.97. Mu. Mol), DBU (50.92 mg, 334.46. Mu. Mol) and a carbo condensing agent (64.10 mg, 144.93. Mu. Mol) were sequentially dissolved in dimethyl sulfoxide (350.25. Mu. L), argon was replaced 3 times, and the reaction was stirred at room temperature under argon atmosphere for 16 hours. After completion of the reaction, 5mL of water was added to precipitate a solid, which was filtered, and the cake was dried in vacuo to give (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinazolin-4-amine 2e (30 mg), yield 61.12%.
MS m/z(ESI):439.9[M+1] +
Fifth step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-
(methylsulfonyl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-6- (methylsulfonyl) quinazolin-4-amine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-quinazolin-4-amine 2e (260 mg, 590.57. Mu. Mol), cuprous iodide (224.95 mg,1.18 mmol) and sodium methylsulfinate (156.76 mg,1.54 mmol) were sequentially dissolved in dimethyl sulfoxide (1 mL), argon was replaced three times, and heated to 80℃under argon protection for 16 hours. After completion of the reaction, the reaction mixture was separated and purified by preparative liquid phase (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-6- (methylsulfonyl) quinazolin-4-amine 2 (5 mg), yield 1.93%.
MS m/z(ESI):439.9[M+1] +
Example 3
(R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-N 6 -(pyridin-2-
yl)quinazoline-4,6-diamine
(R)-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-N 6 - (pyridin-2-yl) quinazoline-4, 6-diamines
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-quinazolin-4-amine 2e (50 mg, 113.57. Mu. Mol), pyridin-2-amine 3a (21.38 mg, 227.14. Mu. Mol), pd 2 (dba) 3 (31.20 mg, 34.07. Mu. Mol), xantphos (26.29 mg, 45.43. Mu. Mol) and cesium carbonate (111.01 mg, 340.71. Mu. Mol) were sequentially dissolved in 1, 4-dioxane (0.5 mL), argon was replaced three times, and the mixture was refluxed at 100℃under the protection of argon for 3 hours. After completion of the reaction, the reaction mixture was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-N 6 - (pyridin-2-yl) quinazoline-4, 6-diamine 3 (5 mg) in 9.71% yield.
MS m/z(ESI):454.2[M+1] +
Example 4
(R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-N 6 -(oxazol-2-
yl)quinazoline-4,6-diamine
(R)-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-N 6 - (oxazol-2-yl) quinazoline-4, 6-diamine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-quinazolin-4-amine 2e (50 mg, 113.57. Mu. Mol), oxazol-2-amine 4a (19.10 mg, 227.14. Mu. Mol, 15.40. Mu. L), pd 2 (dba) 3 (31.20 mg, 34.07. Mu. Mol), xantphos (26.29 mg, 45.43. Mu. Mol) and cesium carbonate (111.01 mg, 340.71. Mu. Mol) were added sequentially to 1, 4-dioxane (0.5 mL), argon was replaced three times, and the mixture was refluxed at 100℃for 3 hours under argon atmosphere. After the reaction, the reaction mixture was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-N 6 - (oxazol-2-yl) quinazoline-4, 6-diamine 4 (3 mg) in 5.96% yield.
MS m/z(ESI):444.1[M+1] +
Example 5
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-
carboxylic acid
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methyl quinazoline-6-carboxylic acid
First step
methyl(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-
methylquinazoline-6-carboxylate
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methyl quinazoline-6-carboxylic acid methyl ester
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-quinazolin-4-amine 2e (150 mg, 340.71. Mu. Mol), N-diethyl ethylamine (172.38 mg,1.70mmol, 236.79. Mu.L) and PdCl 2 (dppf) (28.17 mg, 34.07. Mu. Mol) was added sequentially to methanol (0.5 mL) to displace the oxidationThree times of carbon, heating to 100 ℃ and reacting for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to give crude product 5a.
MS m/z(ESI):420.0[M+1] +
Second step (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinazoline-6-
carboxylic acid
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methyl quinazoline-6-carboxylic acid
The crude product 5a was added to water (1 mL) followed by sodium hydroxide (28.61 mg, 715.31. Mu. Mol), heated to 100deg.C and stirred for 5 hours. The residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methyl quinazoline-6-carboxylic acid 5 (46 mg), 31.73% yield.
MS m/z(ESI):406.0[M+1] +
Example 6
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-
(methylsulfonyl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (methylsulfonyl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 114. Mu. Mol), cuprous iodide (86.5 mg, 454. Mu. Mol) and sodium methylsulfinate (58 mg, 568. Mu. Mol) were added sequentially to dimethyl sulfoxide (1 mL), and the mixture was heated to 100℃with stirring for 5 hours. Concentrated under reduced pressure, ethyl acetate (30 mL) and water (15 mL) were added, the extracts were separated, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (15 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid; mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (methylsulfonyl) quinazolin-4-amine 6 (3.3 mg, 6.6. Mu. Mol), yield 6%.
MS m/z(ESI):439.9[M+1] +
Example 7
methyl(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-
methylquinazoline-7-carboxylate
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid methyl ester
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (45 mg, 102. Mu. Mol), pdCl 2 (dppf) (15 mg, 20. Mu. Mol) and triethylamine (52 mg, 511. Mu. Mol, 71. Mu.L) were added sequentially to methanol (3 mL), carbon monoxide was replaced 3 times, and the reaction was heated to 100℃with stirring for 16 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, ethyl acetate (30 mL) and water (15 mL) were added, the mixture was extracted, the separated liquid and the aqueous phase were extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (15 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by preparative chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylate 7 (5.0 mg, 11. Mu. Mol), yield 11%.
MS m/z(ESI):419.9[M+1] +
1 H NMR(400MHz,CDCl 3 )δ10.25(br,1H),8.01(s,1H),7.77(s,1H),7.60(t,J＝7.2Hz,1H),7.47(t,J＝6.0Hz,1H),7.17(t,J＝7.6Hz,1H),6.89(t,J＝52.2Hz,1H),5.80-5.69(m,1H),4.01(s,3H),3.95(s,3H),2.47(s,3H),1.75(d,J＝6.4Hz,3H).
Example 8
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-
carbonitrile
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carbonitrile
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 114. Mu. Mol), zinc cyanide (20 mg, 170. Mu. Mol) and tetrakis (triphenylphosphine) palladium (19.7 mg, 17. Mu. Mol) were sequentially added to N, N-dimethylformamide (1 mL), argon was replaced 3 times, and the reaction was heated to 100℃with stirring for 16 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (15 mL. Times.2), washing with saturated sodium chloride solution (15 mL. Times.2), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) gave (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carbonitrile 8 (12 mg, 28. Mu. Mol), 24% yield.
MS m/z(ESI):386.9[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ9.98(br,1H),8.24(s,1H),8.15(s,1H),7.67(t,J＝7.4Hz,1H),7.57(t,J＝7.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.25(t,J＝54.4Hz,1H),5.95-5.88(m,1H),4.09(s,3H),2.52(s,3H),1.71(d,J＝6.8Hz,3H).
Example 9
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-phenylquinazolin-4-
amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7-phenylquinazolin-4-amine
Into a sealed tube was added (R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (50 mg, 114. Mu. Mol), phenylboronic acid (28 mg, 227. Mu. Mol), potassium phosphate (72 mg, 341. Mu. Mol), ruPhos (21 mg, 45. Mu. Mol), ruPhos-Pd-G 3 (19 mg, 23. Mu. Mol), 1, 4-dioxane (1 mL) and water (0.1 mL), and after replacing argon, the sealed tube was sealed and the temperature was raised to 100℃for reaction for 12 hours. Ethyl acetate (30 mL) and water (10 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.2), combining the organic phases, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) gave (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7-phenylquinazolin-4-amine 9 (8.0 mg, 17. Mu. Mol) in 15% yield.
MS m/z(ESI):438.0[M+1] +
Example 10
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-
morpholinoquinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7-morpholinylquinazolin-4-amine
/>
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (20 mg, 45. Mu. Mol), morpholine (12 mg, 136. Mu. Mol), ruPhos-Pd-G 3 (5.7 mg, 6.8. Mu. Mol) and sodium t-butoxide (13 mg, 136. Mu. Mol) and tetrahydrofuran (1 mL) were added to a sealed tube, argon was replaced, the sealed tube was sealed, and the reaction was heated to 100℃with stirring for 12 hours. The residue was purified by preparative chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7-morpholinoquinazolin-4-amine 10 (7.0 mg, 15. Mu. Mol) in 34% yield.
MS m/z(ESI):447.2[M+1] +
1 H NMR(400MHz,CDCl 3 )δ9.18(br,1H),7.68(s,1H),7.54(t,J＝7.6Hz,1H),7.45(t,J＝6.8Hz,1H),7.14(t,J＝7.8Hz,1H),6.89(t,J＝54.8Hz,1H),6.79(s,1H),5.71-5.67(m,1H),4.02(s,3H),3.89-3.82(m,4H),3.25-3.18(m,4H),2.47(s,3H),1.78(d,J＝6.8Hz,3H).
Example 11
N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-amine
N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 114. Mu. Mol), tetrahydrofuran-3-ol (30 mg, 341. Mu. Mol), pd 2 (dba) 3 (10 mg, 23. Mu. Mol), BIPPYPHOS (23 mg, 45. Mu. Mol) and toluene (1 mL) were put into a sealed tube, the sealed was replaced with argon 3 times, and the reaction was stirred for 16 hours at 100 ℃. After the reaction, the residue was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (chromatographyColumn: AKZONOBEL Kromasil,250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give the product N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-amine 11 (1.5 mg,3.3 μmol) in 3% yield.
MS m/z(ESI):448.2[M+1] +
Example 12
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(piperidin-1-
yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (piperidin-1-yl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (20 mg, 45. Mu. Mol), piperidine (11.6 mg, 136. Mu. Mol), ruPhos-Pd-G 3 (5.7 mg, 6.8. Mu. Mol) and sodium t-butoxide (13 mg, 136. Mu. Mol) were successively added to tetrahydrofuran (1 mL), argon was replaced 3 times, and the reaction was heated to 100℃with continuous stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.2), washing of the combined organic phases with saturated sodium chloride solution (30 mL. Times.2), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) gave (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (piperidin-1-yl) quinazolin-4-amine 12 (6.0 mg, 13. Mu. Mol), 29% yield.
MS m/z(ESI):445.0[M+1] +
1 H NMR(400MHz,CDCl 3 )δ8.74(br,1H),7.72-7.64(m,2H),7.46-7.41(m,1H),7.25-7.19(m,1H),7.15-7.08(m,1H),6.88(t,J＝55Hz,1H),5.90-5.82(m,1H),4.06(s,3H),3.21-3.11(m,4H),2.58(s,3H),2.53(s,3H),1.84-1.62(m,6H).
Example 13
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(pyrrolidin-1-
yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (pyrrolidin-1-yl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (30 mg, 68. Mu. Mol), pyrrolidine (15 mg, 205. Mu. Mol), ruPhos-Pd-G 3 (11 mg, 13. Mu. Mol) and sodium t-butoxide (19.7 mg, 204. Mu. Mol) were successively added to tetrahydrofuran (1 mL), argon was replaced 3 times, and the reaction was heated to 100℃with continuous stirring for 12 hours. After the completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, the mixture was extracted, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the combined organic phases were washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid; mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (pyrrolidin-1-yl) quinazolin-4-amine 13 (5.0 mg, 11. Mu. Mol), 17% yield.
MS m/z(ESI):431.2[M+1] +
Example 14
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-7-(2-methoxyethoxy)-2-
methylquinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-7- (2-methoxyethoxy) -2-methylquinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (20 mg, 45.43. Mu. Mol), ethylene glycol monomethyl ether (10.37 mg, 136.28. Mu. Mol) and Pd 2 (dba) 3 (8.32 mg, 9.09. Mu. Mol), BIPPYPHOS (9.21 mg, 18.17. Mu. Mol) and cesium carbonate (44.40 mg, 136.28. Mu. Mol) were successively added to toluene (1 mL), argon was replaced 3 times, and the mixture was heated to 100℃and stirred for reaction for 12 hours. After the completion of the reaction, the residue obtained was concentrated under reduced pressure and purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-7- (2-methoxyethoxy) -2-methylquinazolin-4-amine 14 (4.5 mg, 9.82. Mu. Mol) in 21.61% yield.
MS m/z(ESI):436.0[M+1] +
Example 15
(R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-
yl)pyrrolidin-2-one
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) pyrrolidin-2-one
/>
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), pyrrolidin-2-one (29.00 mg, 340.71. Mu. Mol), cuprous iodide (21.63 mg, 113.57. Mu. Mol), potassium carbonate (47.09 mg, 340.71. Mu. Mol) and N, N' -dimethylethylenediamine (20.02 mg, 227.14. Mu. Mol) were sequentially added to N, N-dimethylformamide (1 mL), argon was replaced, and the reaction was heated to 100℃with continuous stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.2), and concentration of the combined organic phases under reduced pressure gave a residue which was purified by column chromatography on silica gel (eluent: B system) to give (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) pyrrolidin-2-one 15 (5.0 mg, 10.12. Mu. Mol) in 8.92% yield.
MS m/z(ESI):445.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ8.32(d,J＝7.6Hz,1H),7.89(s,1H),7.67(t,J＝7.4Hz,1H),7.51-7.47(m,2H),7.28(t,J＝7.6Hz,1H),7.24(t,J＝54.6Hz,1H),5.85-5.78(m,1H),3.96(s,3H),3.80-3.71(m,2H),2.43(t,J＝8.2Hz,2H),2.31(s,3H),2.15-2.08(m,2H),1.63(d,J＝7.2Hz,3H).
Example 16
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-
pyrazol-4-yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (1-methyl-1H-pyrazol-4-yl) quinazolin-4-
Amines
/>
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol) and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole 16a (47.26 mg, 227.14. Mu. Mol), potassium phosphate (72.32 mg, 340.71. Mu. Mol), ruPhos (21.20 mg, 45.43. Mu. Mol) and RuPhos-Pd-G 3 (19.02 mg, 22.71. Mu. Mol) was added sequentially to 1, 4-dioxane (1 mL), argon was replaced, and the mixture was heated to 100℃with continuous stirring for reaction for 12 hoursWhen (1). Ethyl acetate (30 mL) and water (15 mL) were added, the mixture was extracted, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (1-methyl-1H-pyrazol-4-yl) quinazolin-4-amine 16 (9.0 mg, 20.04. Mu. Mol) in 17.65% yield.
MS m/z(ESI):442.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ9.67(br,1H),8.37(s,1H),8.05(s,1H),8.04(s,1H),7.85(s,1H),7.76(t,J＝7.0Hz,1H),7.57(t,J＝6.8Hz,1H),7.36(t,J＝8.0Hz,1H),7.25(t,J＝54.0Hz,1H),5.98-5.91(m,1H),4.09(s,3H),3.93(s,3H),2.53(s,3H),1.71(d,J＝6.8Hz,3H).
Example 17
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-
carboxylic acid
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid
/>
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid methyl ester 7 (57 mg, 135.91. Mu. Mol) and lithium hydroxide monohydrate (14.83 mg, 353.37. Mu. Mol) were sequentially added to a mixed solvent of methanol (5 mL) and water (0.5 mL), and heated to 50℃for continuous stirring reaction for 12 hours. Dilute hydrochloric acid was added dropwise to adjust the pH to 1, and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil,250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid 17 (25 mg,59.21 μmol) in 43.56% yield.
MS m/z(ESI):405.9[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ9.02(br,1H),7.97(s,1H),7.77(s,1H),7.71(t,J＝7.4Hz,1H),7.53(t,J＝7.0Hz,1H),7.32(t,J＝7.0Hz,1H),7.24(t,J＝54.4Hz,1H),5.90-5.83(m,1H),3.98(s,3H),2.41(s,3H),1.67(d,J＝7.2Hz,3H).
Example 18
(R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-
yl)(4-methylpiperazin-1-yl)methanone
(R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) (4-methylpiperazine-1-
Radical) methanones
/>
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid 17 (10 mg, 24.67. Mu. Mol), 1-methylpiperazine (7.41 mg, 74.01. Mu. Mol), HATU (14.07 mg, 37.00. Mu. Mol) and N, N-diisopropylethylamine (9.56 mg, 74.01. Mu. Mol) were added sequentially to N, N-dimethylformamide (2 mL) and the reaction was continued with stirring at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the extracts, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) (4-methylpiperazin-1-yl) methanone 18 (7.0 mg, 13.11. Mu. Mol) in 53.14% yield.
MS m/z(ESI):488.2[M+1] +
Example 19
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(2-(dimethylamino)ethyl)-6-
methoxy-N,2-dimethylquinazoline-7-carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N- (2- (dimethylamino) ethyl) -6-methoxy-N, 2-dimethylquinazoline-7-carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid 17 (10 mg, 24.67. Mu. Mol), N, N, N' -trimethylethylenediamine (7.56 mg, 74.01. Mu. Mol), HATU (14.07 mg, 37.00. Mu. Mol) and N, N-diisopropylethylamine (9.56 mg, 74.01. Mu. Mol) were added sequentially to N, N-dimethylformamide (1 mL), and the reaction was continued with stirring at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the extracts, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N- (2- (dimethylamino) ethyl) -6-methoxy-N, 2-dimethylquinazoline-7-carboxamide 19 (5.2 mg, 10.42. Mu. Mol) in 42.mol yield.
MS m/z(ESI):490.3[M+1] +
Example 20
(R)-7-cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-
methylquinazolin-4-amine
(R) -7-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), cyclopropylboronic acid (29.27 mg, 340.71. Mu. Mol), potassium phosphate (72.32 mg, 340.71. Mu. Mol) and RuPhos (21.20 mg, 45.43. Mu. Mol) and RuPhos-Pd-G 3 (19.02 mg, 22.71. Mu. Mol) was added to a mixed solvent of 1, 4-dioxane (1 mL) and water (0.1 mL) in this order, argon was replaced, and the reaction was heated to 100℃with stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.2), combining the organic phases, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) gave (R) -7-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 20 (5.5 mg, 12.95. Mu. Mol) in 11.40% yield.
MS m/z(ESI):402.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ9.69(br,1H),7.95(s,1H),7.74(t,J＝7.2Hz,1H),7.57(t,J＝6.8Hz,1H),7.36-7.7.34(m,1H),7.24(t,J＝56Hz,1H),7.10(s,1H),5.97-5.90(m,1H),4.03(s,3H),2.98-2.89(m,1H),2.51(s,3H),1.70(d,J＝7.2Hz,3H),1.19-1.13(m,2H),0.80-0.74(m,2H).
Example 21
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(2-
morpholinoethoxy)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (2-morpholinoethoxy) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (20 mg, 45.43. Mu. Mol), 2-morpholine Ethanol (17.88 mg, 136.28. Mu. Mol) and Pd 2 (dba) 3 (4.06 mg, 9.09. Mu. Mol) and BIPPYPHOS (9.21 mg, 18.17. Mu. Mol) and cesium carbonate (44.40 mg, 136.28. Mu. Mol) were sequentially dissolved in toluene (1 mL), and the reaction was continued with stirring by substituting argon and heating to 100℃for 12 hours. The residue obtained was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (2-morpholinoethoxy) quinazolin-4-amine 21 (3.2 mg, 4.70. Mu. Mol) in 10.34% yield. MS m/z (ESI): 491.3[ M+1 ]] +
1 H NMR(400MHz,DMSO-d 6 )δ8.34(br,1H),7.80(s,1H),7.70(t,J＝7.2Hz,1H),7.50(t,J＝7.0Hz,1H),7.37-7.06(m,3H),5.86-5.79(m,1H),4.24-4.20(m,2H),3.94(s,3H),3.61-3.59(m,4H),2.82-2.76(m,2H),2.57-2.53(m,4H),2.33(s,3H),1.62(d,J＝6.8Hz,3H).
Example 22
(R)-N-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)cyclopropanecarboxamide
(R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) cyclopropylcarboxyform
Amines
/>
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (20 mg, 45.43. Mu. Mol), cyclopropanecarboxamide (11.60 mg, 136.28. Mu. Mol), cuprous iodide (8.65 mg, 45.43. Mu. Mol), potassium carbonate (18.84 mg, 136.28. Mu. Mol) and N, N' -dimethylethylenediamine (8.01 mg, 90.86. Mu. Mol) were added to N, N-dimethylformamide (1 mL) in this order, argon was replaced, and the mixture was heated to 100℃with stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the extracts, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid; mobile phase B: acetonitrile) to give (R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) cyclopropylcarboxamide 22 (2.7 mg, 5.77. Mu. Mol) in 12.70% yield.
MS m/z(ESI):445.2[M+1] +
Example 23
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(pyridin-4-
yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (pyridin-4-yl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), 4-pyridineboronic acid (41.88 mg, 340.71. Mu. Mol), potassium phosphate (72.32 mg, 340.71. Mu. Mol), ruPhos (21.20 mg, 45.43. Mu. Mol) and RuPhos-Pd-G 3 (19.02 mg, 22.71. Mu. Mol) was added to a mixed solvent of 1, 4-dioxane (1 mL) and water (0.1 mL) in this order, argon was replaced, and the reaction was heated to 100℃with stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the extracts were separated, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2) and the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (pyridin-4-yl) quinazolin-4-amine 23 (11.0 mg, 19.13. Mu. Mol) in 16.85% yield.
MS m/z(ESI):439.0[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ10.25(d,J＝6.8Hz,1H),8.77(d,J＝4.8Hz,2H),8.23(s,1H),7.79(t,J＝7.4Hz,1H),7.71(s,1H),7.67(d,J＝5.2Hz,2H),7.60(t,J＝6.8Hz,1H),7.39(t,J＝7.6Hz,1H),7.25(t,J＝54.4Hz,1H),6.03-5.96(m,1H),4.00(s,3H),2.59(s,3H),1.75(d,J＝7.2Hz,3H).
Example 24
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(1H-pyrazol-4-
yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (1H-pyrazol-4-yl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), (1H-pyrazol-4-yl) boronic acid 24a (38.12 mg, 340.71. Mu. Mol), potassium phosphate (72.32 mg, 340.71. Mu. Mol), ruPhos (21.20 mg, 45.43. Mu. Mol) and RuPhos-Pd-G 3 (19.02 mg, 22.71. Mu. Mol) was added to a mixed solvent of 1, 4-dioxane (1 mL) and water (0.1 mL) in this order, argon was replaced, and the reaction was heated to 100℃with stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.2), combining the organic phases, concentration under reduced pressure, and purification of the residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) gave (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (1H-pyrazol-4-yl) quinazolin-4-amine 24 (5.5 mg, 11.98. Mu. Mol) in 10.55% yield.
MS m/z(ESI):428.2[M+1] +
Example 25
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-(1H-imidazol-1-yl)-6-methoxy-2-
methylquinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7- (1H-imidazol-1-yl) -6-methoxy-2-methyl-quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (30 mg, 68.14. Mu. Mol), imidazole (13.92 mg, 204.43. Mu. Mol), cuprous iodide (12.98 mg, 68.14. Mu. Mol), cesium carbonate (66.61 mg, 204.43. Mu. Mol) and N, N' -dimethylethylenediamine (6.01 mg, 68.14. Mu. Mol) were sequentially added to N, N-dimethylformamide (1 mL), argon was replaced, and the reaction was heated to 120℃with stirring for 8 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.2), combining the organic phases, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) gave (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7- (1H-imidazol-1-yl) -6-methoxy-2-methyl-quinazolin-4-amine 25 (5.7 mg, 12.86. Mu. Mol) in 18.87% yield.
MS m/z(ESI):428.2[M+1] +
1 H NMR(400MHz,CDMSO-d 6 )δ10.18(br,1H),9.00(br,1H),8.36(s,1H),7.95(br,1H),7.90(s,1H),7.79(t,J＝7.2Hz,1H),7.66-7.57(m,2H),7.38(t,J＝8.0Hz,1H),7.26(t,J＝54.4Hz,1H),5.99-5.95(m,1H),4.06(s,3H),2.58(s,3H),1.74(d,J＝7.2Hz,3H).
Example 26
(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-
yl)morpholin-3-one
(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) morpholin-3-one
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), 3-morpholone (34.45 mg, 340.71. Mu. Mol), cuprous iodide (21.63 mg, 113.57. Mu. Mol), potassium carbonate (47.09 mg, 340.71. Mu. Mol) and N, N' -dimethylethylenediamine (20.02 mg, 227.14. Mu. Mol) were sequentially dissolved in N, N-dimethylformamide (1.5 mL), and argon was replaced, and the reaction was heated to 100℃with continuous stirring for 8 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the extracts, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid; mobile phase B: acetonitrile) to give (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) morpholin-3-one 26 (5.0 mg, 10.64. Mu. Mol) in 9.37% yield.
MS m/z(ESI):461.2[M+1] +
1 H NMR(400MHz,CDMSO-d 6 )δ10.08(br,1H),8.21(s,1H),7.77(t,J＝7.6Hz,1H),7.67(s,1H),7.59(t,J＝6.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.26(t,J＝54.4Hz,1H),6.00-5.94(m,1H),4.24(s,2H),4.03-4.01(m,5H),3.67-3.64(m,2H),2.56(s,3H),1.72(d,J＝6.8Hz,3H).
Example 27
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-
carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carbonitrile 8 (10 mg, 25.88. Mu. Mol) was dissolved in a solution of 1M sodium hydroxide solution (0.5 mL) and dimethyl sulfoxide (0.5 mL), and 30% hydrogen peroxide (0.3 mL) was added dropwise under ice-bath conditions, followed by stirring for 1 hour. Ethyl acetate (30 mL) and water (15 mL) were added, the extracts, the aqueous phase was extracted with ethyl acetate (30 mL x 2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil,250 x 21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxamide 27 (3.5 mg,8.42 μmol) in 32.54% yield.
MS m/z(ESI):405.2[M+1] +
Example 28
(R)-2-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-
yl)propan-2-ol
(R) -2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) propan-2-ol
/>
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid methyl ester 7 (20 mg, 47.69. Mu. Mol) was dissolved in tetrahydrofuran (1 mL), and a methyl magnesium bromide solution (3.0M, 47.69. Mu.L) was added dropwise under ice bath conditions, and after gradually warming to room temperature, the mixture was heated to 50℃and stirred for 4 hours. Cooled to room temperature, ethyl acetate (30 mL) and saturated aqueous ammonium chloride (20 mL) were added, the mixture was extracted, the aqueous phase was extracted with ethyl acetate (30 mL), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) propan-2-ol 28 (3.6 mg, 8.41. Mu. Mol) in 17.64% yield.
MS m/z(ESI):420.2[M+1] +
1 H NMR(400MHz,CDCl 3 )δ9.61(br,1H),7.85(s,1H),7.80(s,1H),7.56(t,J＝7.0Hz,1H),7.45(t,J＝7.0Hz,1H),7.13(t,J＝7.8Hz,1H),6.87(t,J＝54.4Hz,1H),5.71-5.66(m,1H),4.05(s,3H),2.47(s,3H),1.71(d,J＝7.2Hz,3H),1.69(s,3H),1.61(s,3H).
Example 29
(R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-
yl)(morpholino)methanone
(R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) (morpholinyl) methanone
/>
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid 17 (50 mg, 123.34. Mu. Mol), morpholine (32.24 mg, 370.03. Mu. Mol), HATU (70.35 mg, 185.02. Mu. Mol) and N, N-diisopropylethylamine (47.82 mg, 370.03. Mu. Mol) were dissolved in N, N-dimethylformamide (2 mL) in this order and the reaction was stirred at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added to the system, the extracts, the aqueous phase was extracted with ethyl acetate (30 mL), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) (morpholino) methanone 29 (23 mg, 43.63. Mu. Mol), yield 35.37%.
MS m/z(ESI):475.2[M+1] +
Example 30
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-(4-fluoro-1H-pyrazol-1-yl)-6-methoxy-2-
methylquinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7- (4-fluoro-1H-pyrazol-1-yl) -6-methoxy-2-methyl-quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (30 mg, 68.14. Mu. Mol), 4-fluoro-1H-pyrazole (17.59 mg, 204.43. Mu. Mol), cuprous iodide (12.98 mg, 68.14. Mu. Mol) and cesium carbonate (66.61 mg, 204.43. Mu. Mol) were sequentially added to N, N-dimethylformamide (1 mL), the argon was replaced 3 times, and the mixture was heated to 120℃with stirring for reaction for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL), washing of the combined organic phases with saturated sodium chloride solution (20 mL. Times.2), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography (eluent B system) gave (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7- (4-fluoro-1H-pyrazol-1-yl) -6-methoxy-2-methyl-quinazolin-4-amine 30 (5.0 mg, 7.97. Mu. Mol) in 11.70% yield.
MS m/z(ESI):446.1[M+1] +
1 H NMR(400MHz,CDCl 3 )δ8.15(s,1H),8.10-8.09(m,1H),7.62-7.49(m,4H),7.24-7.20(m,1H),6.92(t,J＝54.8Hz,1H),5.81-5.77(m,1H),4.06(s,3H),2.53(s,3H),1.75(d,J＝7.2Hz,3H).
Example 31
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-ol
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-ol
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), pinacol biboronate (57.68 mg, 227.14. Mu. Mol), pdCl 2 (dppf) (16.62 mg, 22.71. Mu. Mol) and potassium acetate (33.44 mg, 340.71. Mu. Mol) were sequentially dissolved in 1, 4-dioxane (1 mL), and the reaction was heated to 110℃with stirring for 2 hours. The reaction solution was directly used for the next reaction.
Second step (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methylquinazolin-7-ol
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-ol
Hydrogen peroxide (18.34 mg, 188.79. Mu. Mol,35% purity), sodium hydroxide solution (1M, 82.08. Mu.L) and tetrahydrofuran (2 mL) were sequentially added to the reaction mixture, and the reaction was continued with stirring at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL), combining the organic phases, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) afforded (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methylquinazolin-7-ol 31 (6.0 mg, 15.74. Mu. Mol) in 19.18% yield.
MS m/z(ESI):377.9[M+1] +
1 H NMR(400MHz,CDCl 3 )δ14.18(br,1H),8.98(br,1H),7.69(t,J＝6.6Hz,1H),7.63(s,1H),7.51(t,J＝7.0Hz,1H),7.24(t,J＝6.8Hz,1H),6.92(t,J＝55Hz,1H),6.89(s,1H),5.88-5.85(m,1H),3.97(s,3H),2.52(s,3H),1.78(d,J＝6.8Hz,3H).
Example 32
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-
pyrazol-3-yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinazolin-4-
Amines
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (25 mg, 56.79. Mu. Mol), 1-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole 32a (23.63 mg, 113.57. Mu. Mol), potassium phosphate (36.16 mg, 170.36. Mu. Mol), ruPhos (10.60 mg, 22.71. Mu. Mol) and RuPhos-Pd-G 3 (9.51 mg, 11.36. Mu. Mol) was added to a mixed solvent of 1, 4-dioxane (1 mL) and water (0.1 mL) in this order, argon was replaced, and the reaction was continued with stirring at 100℃under sealed heating. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL), combining the organic phases, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) afforded (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinazolin-4-amine 32 (10.0 mg, 21.93. Mu. Mol) in 38.62% yield.
MS m/z(ESI):442.0[M+1] +
1 H NMR(400MHz,CDCl 3 )δ9.09(br,1H),8.09(s,1H),7.69(s,1H),7.53(t,J＝7.0Hz,1H),7.46-7.41(m,2H),7.15(t,J＝7.8Hz,1H),6.93(s,1H),6.86(t,J＝55Hz,1H),5.50-5.41(m,1H),4.06(s,3H),4.00(s,3H),2.34(s,3H),1.70(d,J＝6.8Hz,3H).
Example 33
(R)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-
methoxy-2-methylquinazolin-4-amine
(R) -7- (1-cyclopropyl-1H-pyrazol-4-yl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl quinazoline
4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (25.00 mg, 56.79. Mu. Mol), 1-cyclopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole 33a (26.59 mg, 113.57. Mu. Mol), potassium phosphate (36.16 mg, 170.36. Mu. Mol), ruPhos (10.60 mg, 22.71. Mu. Mol) and RuPhos-Pd-G 3 (9.51 mg, 11.36. Mu. Mol) was dissolved in a mixed solvent of 1, 4-dioxane (1 mL) and water (0.1 mL) in this order, argon was replaced, and the reaction was continued with stirring by heating to 100℃for 12 hours under sealed tube heating. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL), combining the organic phases, concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) afforded (R) -7- (1-cyclopropyl-1H-pyrazol-4-yl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 33 (2.7 mg, 5.05. Mu. Mol) in 8.90% yield.
MS m/z(ESI):468.2[M+1] +
1 H NMR(400MHz,CDCl 3 )δ8.23(br,1H),8.05-7.90(m,2H),7.79(s,1H),7.65(m,3H),7.27-7.23(m,1H),6.91(t,J＝54.8Hz,1H),5.82-5.77(m,1H),4.10(s,3H),3.73-3.60(m,1H),2.47(s,3H),1.70(d,J＝6.8Hz,3H),1.32-1.28(m,2H),1.16-1.12(m,2H).
Example 34
(R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-
yl)piperidin-4-one
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) piperidin-4-one
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), 4-piperidone (33.77 mg, 340.71. Mu. Mol, 33.77. Mu.L), ruPhos-Pd-G 3 (14.27 mg, 17.04. Mu. Mol) and sodium t-butoxide (32.74 mg, 340.71. Mu. Mol) were successively dissolved in tetrahydrofuran (0.5 mL), argon was replaced 3 times, and the reaction was stirred for 12 hours at 100℃with heating of the tube to seal. After completion of the reaction, the resulting residue was concentrated under reduced pressure and purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl-quinazolin-7-yl) piperidin-4-one 34 (7 mg) in 13.44% yield.
MS m/z(ESI):458.9[M+1] +
Example 35
(R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 7 -(2-(dimethylamino)ethyl)-6-methoxy-
N 7 ,2-dimethylquinazoline-4,7-diamine
(R)-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N 7 - (2- (dimethylamino) ethyl) -6-methoxy-N 7 2-dimethylquinazoline-4, 7-diamines
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluoro)Phenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (30 mg, 68.14. Mu. Mol), N, N, N' -trimethylethylenediamine (20.89 mg, 204.43. Mu. Mol, 26.57. Mu.L), ruPhos-Pd-G 3 (8.56 mg, 10.22. Mu. Mol) and sodium t-butoxide (19.65 mg, 204.43. Mu. Mol) were sequentially added to tetrahydrofuran (0.5 mL), argon was replaced 3 times, and the reaction was continued with stirring at 100℃for 12 hours by heating the tube to a closed state. After completion of the reaction, the residue obtained was concentrated under reduced pressure and purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N 7 - (2- (dimethylamino) ethyl) -6-methoxy-N 7 2-Dimethylquinazoline-4, 7-diamine 35 (2.45 mg) in 7.79% yield.
MS m/z(ESI):462.2[M+1] +
Example 37
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-phenoxyquinazolin-
4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7-phenoxyquinazolin-4-amine
/>
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (20 mg, 45.43. Mu. Mol), phenol (8.55 mg, 90.86. Mu. Mol), potassium phosphate (19.29 mg, 90.86. Mu. Mol), cuprous iodide (865.18. Mu.g, 4.54. Mu. Mol) and 1, 10-phenanthroline (818.64. Mu.g, 4.54. Mu. Mol) were sequentially added to dimethyl sulfoxide (0.5 mL), argon was replaced 3 times, and the mixture was heated to 120℃under argon atmosphere and stirred for 16 hours. After completion of the reaction, the mixture was separated and purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7-phenoxyquinazolin-4-amine 37 (2 mg, 4.41. Mu. Mol) in 9.71% yield.
MS m/z(ESI):454.2[M+1] +
Example 38
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(piperazin-1-
yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (piperazin-1-yl) quinazolin-4-amine
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), piperazine (29.35 mg, 340.71. Mu. Mol), ruPhos Pd G3 (14.27 mg, 17.04. Mu. Mol) and sodium t-butoxide (32.74 mg, 340.71. Mu. Mol) were sequentially added to tetrahydrofuran (1 mL), replaced with argon for 3 times, and heated to 100℃with continuous stirring for reaction for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, the mixture was separated, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil,250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (piperazin-1-yl) quinazolin-4-amine 38 (10 mg, 16.09. Mu. Mol) in 14.16% yield.
MS m/z(ESI):446.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ9.86(br,1H),9.09(br,1H),8.01(s,1H),7.76(t,J＝7.0Hz,1H),7.56(t,J＝6.8Hz,1H),7.35(t,J＝7.6Hz,1H),7.24(t,J＝54.4Hz,1H),7.188(s,1H),5.99-5.89(m,1H),4.01(s,3H),3.51-3.25(m,8H),2.53(s,3H),1.70(d,J＝6.8Hz,3H).
Example 39
(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-
methylquinazolin-7-yl)piperazin-1-yl)ethan-1-one
(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) piperazin-1-yl)
Ethyl-1-one
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), 1-piperazin-1-one (43.67 mg, 340.71. Mu. Mol), ruPhos Pd G3 (14.27 mg, 17.04. Mu. Mol) and sodium t-butoxide (32.74 mg, 340.71. Mu. Mol) were sequentially added to tetrahydrofuran (1 mL), argon was replaced 3 times, and the reaction was heated to 100℃with continuous stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the solution was separated, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil,250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) piperazin-1-yl) ethan-1-one 39 (12 mg,24.02 μmol) in 21.15% yield.
MS m/z(ESI):488.2[M+1] +
1 H NMR(400MHz,CDCl 3 )δ9.34(br,1H),7.74(s,1H),7.57(t,J＝6.8Hz,1H),7.44(t,J＝6.8Hz,1H),7.13(t,J＝7.6Hz,1H),6.94(s,1H),6.88(t,J＝55Hz,1H),5.77-5.74(m,1H),4.01(s,3H),3.75-3.62(m,4H),3.28-3.15(m,4H),2.49(s,3H),2.14(s,3H),1.74(d,J＝6.8Hz,3H).
Example 40
(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-
yl)-1-methylpiperazin-2-one
(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methylquinazolin-7-yl) -1-methylpiperazine-
2-Ketone
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-quinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), 1-methylpiperazin-2-one (38.89 mg, 340.71. Mu. Mol), ruPhos Pd G3 (14.27 mg, 17.04. Mu. Mol) and sodium t-butoxide (32.74 mg, 340.71. Mu. Mol) were successively added to tetrahydrofuran (1 mL), replaced with argon 3 times, and heated to 100℃with stirring for reaction for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the solution was separated, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil,250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) -1-methylpiperazin-2-one 40 (13 mg,27.34 μmol) in 24.07% yield.
MS m/z(ESI):474.2[M+1] +
1 H NMR(400MHz,CDCl 3 )δ9.50(d,J＝5.6Hz,1H),7.82(s,1H),7.61(t,J＝7.0Hz,1H),7.43(t,J＝7.0Hz,1H),7.11(t,J＝7.8Hz,1H),7.02(s,1H),6.88(t,J＝55.2Hz,1H),5.83-5.80(m,1H),3.98(s,3H),3.92-3.82(m,2H),3.56-3.42(m,4H),3.02(s,3H),2.51(s,3H),1.72(d,J＝6.8Hz,3H).
Example 41
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N-(2-(dimethylamino)ethyl)-6-
methoxy-2-methylquinazoline-7-carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N- (2- (dimethylamino) ethyl) -6-methoxy-2-methylquinazoline-7-carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid 17 (15 mg, 37.00. Mu. Mol), N-dimethylethylenediamine (9.79 mg, 111.0. Mu. Mol), HATU (21.1 mg, 55.50. Mu. Mol) and N, N-diisopropylethylamine (14.35 mg, 111.0. Mu. Mol) were added sequentially to N, N-dimethylformamide (1 mL) and the reaction was continued with stirring at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the extracts, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N- (2- (dimethylamino) ethyl) -6-methoxy-2-methyl quinazoline-7-carboxamide 41 (3.4 mg, 5.02. Mu. Mol) in 13.58% yield. MS m/z (ESI): 476.0[ M+1 ]] +
Example 42
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-N-(2-methoxyethyl)-N,2-
dimethylquinazoline-7-carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-N- (2-methoxyethyl) -N, 2-dimethylquinazoline-7-carboxamide
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazoline-7-carboxylic acid 17 (20 mg, 49.34. Mu. Mol), 2-methoxy-N-methylethyl-1-amine (13.19 mg, 148.01. Mu. Mol), HATU (28.14 mg, 74.01. Mu. Mol) and N, N-diisopropylethylamine (19.13 mg, 148.01. Mu. Mol) were added sequentially to N, N-dimethylformamide (1 mL) and the reaction stirred at room temperature for 5 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, the mixture was extracted, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-N- (2-methoxyethyl) -N, 2-dimethylquinazoline-7-carboxamide 42 (7.0 mg, 11.90. Mu. Mol) in 24.12% yield.
MS m/z(ESI):477.2[M+1] +
Example 43
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-(3,6-dihydro-2H-pyran-4-yl)-6-methoxy-
2-methylquinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7- (3, 6-dihydro-2H-pyran-4-yl) -6-methoxy-2-methylquinazoline-
4-amine
/>
(R) -7-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylquinazolin-4-amine 1d (50 mg, 113.57. Mu. Mol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (47.72 mg, 227.14. Mu. Mol), ruPhos Pd G3 (19.02 mg, 22.71. Mu. Mol) and sodium carbonate (36.11 mg, 340.71. Mu. Mol) were added to 1, 4-dioxane (1 mL), after nitrogen substitution, the temperature was raised to 100℃for reaction for 3 hours. After completion of the reaction, filtration and concentration of the filtrate, the resulting residue was separated and purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7- (3, 6-dihydro-2H-pyran-4-yl) -6-methoxy-2-methylquinazolin-4-amine 43 (10 mg, 22.12. Mu. Mol), yield 19.48%.
MS m/z(ESI):444.2[M+1] +
1 H NMR(400MHz,CDCl 3 )δ9.82(s,1H),7.82(s,1H),7.56-7.46(m,2H),7.32-7.16(m,2H),6.88(t,J＝55.2Hz,1H),6.13-6.03(m,1H),5.71-5.57(m,1H),4.40-4.26(m,2H),4.07-3.82(m,5H),2.65-2.45(m,2H),2.40(s,3H),1.71(s,3H).
Example 44
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(tetrahydro-2H-
pyran-4-yl)quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (tetrahydro-2H-pyran-4-yl) quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7- (3, 6-dihydro-2H-pyran-4-yl) -6-methoxy-2-methyl-quinazolin-4-amine 43 (7.5 mg, 16.91. Mu. Mol) was dissolved in methanol (1 mL), and palladium on carbon catalyst (10%, 1.0 mg) was added. After hydrogen substitution, the reaction was carried out at room temperature. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated, and the obtained residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-7- (tetrahydro-2H-pyran-4-yl) quinazolin-4-amine 44 (1.5 mg), yield 17.72%.
MS m/z(ESI):446.0[M+1] +
Example 45
(R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)piperidin-4-ol
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl quinazolin-7-yl) piperidin-4-ol
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl-quinazolin-7-yl) piperidin-4-one 34 (6 mg, 13.09. Mu. Mol) and sodium borohydride (594.13. Mu.g, 15.70. Mu. Mol) were added sequentially to methanol (0.5 mL) and the reaction was stirred at 0℃for 4 hours. The reaction was quenched by slowly adding saturated sodium bicarbonate solution dropwise to the reaction solution under ice-bath cooling. The residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methyl-quinazolin-7-yl) piperidin-4-ol 45 (1.8 mg, 3.91. Mu. Mol) in 29.87% yield.
MS m/z(ESI):461.0[M+1] +
Example 46
(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-morpholinoquinazolin-4-amine
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methoxy-2-methyl-7-morpholinylquinazolin-4-amine
/>
First step (R) -7-bromo-6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine
(R) -7-bromo-6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine
7-bromo-6-methoxy-2-methylquinazolin-4 (3H) -one 1b (200 mg, 743.23. Mu. Mol), (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine 46a (217.56 mg, 929.04. Mu. Mol), a Kate condensing agent (657.43 mg,1.49 mmol) and DBU (452.60 mg,2.97 mmol) were added sequentially to DMF (4 mL), and the reaction was heated to 60℃with stirring for 6 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation and aqueous phase extraction with ethyl acetate 2 times, the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to give (R) -7-bromo-6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine 46B (200 mg, 412.16. Mu. Mol), yield 55.45%.
MS m/z(ESI):484.8[M+1] +
Second step
(R)-6-methoxy-2-methyl-7-morpholino-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine
(R) -methoxy-2-methyl-7-morpholinyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine
(R) -7-bromo-6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine 46b (40 mg, 82.43. Mu. Mol), morpholine (21.54 mg, 247.29. Mu. Mol), ruPhos Pd G3 (10.35 mg, 12.36. Mu. Mol) and sodium tert-butoxide (23.77 mg, 247.29. Mu. Mol) were added sequentially to tetrahydrofuran (0.5 mL), argon was replaced three times, and the tube was capped and heated to 100℃with continuous stirring for hours. After completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give (R) -methoxy-2-methyl-7-morpholinyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine 46c (20 mg, 40.69. Mu. Mol) in 49.37% yield.
MS m/z(ESI):491.9[M+1] +
Third step
(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-morpholinoquinazolin-4-amine
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methoxy-2-methyl-7-morpholinylquinazolin-4-amine
(R) -methoxy-2-methyl-7-morpholinyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine 46c (20 mg, 40.69. Mu. Mol), iron powder (22.73 mg, 406.95. Mu. Mol) and ammonium chloride (8.71 mg, 162.78. Mu. Mol) were successively added to a mixed solvent of water (0.5 mL), tetrahydrofuran (1 mL) and ethanol (1 mL), and the mixture was heated to 100℃with stirring for 16 hours. After completion of the reaction, the filtrate was filtered and concentrated under reduced pressure, and the obtained residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm,5 μm, mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile; 20 mL/min) to give (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methoxy-2-methyl-7-morpholinoquinazolin-4-amine 46 (1.8 mg, 3.90. Mu. Mol) in 9.58% yield.
MS m/z(ESI):462.0[M+1] +
Example 47
N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine
N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (1-methyl-1H-pyrazol-4-yl) -6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-4-amine
First step
(S)-4-bromo-2-nitro-5-((tetrahydrofuran-3-yl)oxy)benzoic acid
(S) -4-bromo-2-nitro-5- ((tetrahydrofuran-3-yl) oxy) benzoic acid
Methyl 4-bromo-5-fluoro-2-nitrobenzoate 47a (1.0 g,3.60 mmol), (S) -tetrahydrofuran-3-ol (792.22 mg,8.99 mmol), sodium hydride (431.61 mg,10.79mmol,60% purity) were added sequentially to tetrahydrofuran (10 mL), argon was replaced 3 times, and stirring was continued at room temperature for 12 hours. 2M diluted hydrochloric acid was added to adjust pH=5, ethyl acetate (50 mL) and water (25 mL) were added, the solution was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude (S) -4-bromo-2-nitro-5- ((tetrahydrofuran-3-yl) oxy) benzoic acid 47b (1.0 g,3.01 mmol) in 83.72% yield.
MS m/z(ESI):333.8[M+1] +
Second step
(S)-2-amino-4-bromo-5-((tetrahydrofuran-3-yl)oxy)benzoic acid
(S) -2-amino-4-bromo-5- ((tetrahydrofuran-3-yl) oxy) benzoic acid
(S) -4-bromo-2-nitro-5- ((tetrahydrofuran-3-yl) oxy) benzoic acid 47b (1.0 g,3.01 mmol), iron powder (840.85 mg,15.06 mmol) and ammonium chloride (322.13 mg,6.02 mmol) were added sequentially to a mixed solvent of ethanol (20 mL), tetrahydrofuran (20 mL) and water (10 mL), and heated to 100deg.C with stirring for 4 hours. Ethyl acetate (50 mL) was added, the iron powder was filtered using celite, the filter cake was washed with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure to give crude (S) -2-amino-4-bromo-5- ((tetrahydrofuran-3-yl) oxy) benzoic acid 47c (850 mg,2.81 mmol) in 93.44% yield.
MS m/z(ESI):301.8[M+1] +
Third step
(S)-7-bromo-2-methyl-6-((tetrahydrofuran-3-yl)oxy)-4H-benzo[d][1,3]oxazin-4-one
(S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) -4H-benzo [ d ] [1,3] oxazin-4-one
(S) -2-amino-4-bromo-5- ((tetrahydrofuran-3-yl) oxy) benzoic acid 47c (1.0 g,3.31 mmol) was added to acetic anhydride (20 mL) and heated to 120℃with stirring for 4 hours. Cooled to room temperature and concentrated under reduced pressure to give crude (S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) -4H-benzo [ d ] [1,3] oxazin-4-one 47d (1.0 g,3.07 mmol) in 92.63% yield.
MS m/z(ESI):325.8[M+1] +
Fourth step
(S)-7-bromo-2-methyl-6-((tetrahydrofuran-3-yl)oxy)quinazolin-4(3H)-one
(S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) quinazolin-4 (3H) -one
(S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) -4H-benzo [ d ] [1,3] oxazin-4-one 47d (400 mg,1.23 mmol) was added to aqueous ammonia (5 mL), the tube was capped, and heated to 100deg.C for stirring for 8 hours. The system was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography (eluent: A system) to give (S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) quinazolin-4 (3H) -one 47e (200 mg, 615.09. Mu. Mol) in 50.15% yield.
MS m/z(ESI):327.0[M+1] +
Fifth step
7-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-
3-yl)oxy)quinazolin-4-amine
7-bromo-N- ((R) -1- (3- (difluoromethyl) -2-difluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-
4-amine
(S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) quinazolin-4 (3H) -one 47e (600 mg,1.85 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1c (520.45 mg,2.31 mmol), a catter condensing agent (1.63 g,3.69 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.12 g,7.38 mmol) were added sequentially to N, N-dimethylformamide (10 mL), argon was replaced 3 times, and stirring was continued at 60℃for 12 hours. Ethyl acetate (50 mL) and water (25 mL) were added, the solution was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid solution; mobile phase B: acetonitrile) to give 7-bromo-N- ((R) -1- (3- (difluoromethyl) -2-difluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine 47f (460 mg,1.55 mmol), yield 84.08%.
MS m/z(ESI):497.8[M+1] +
Sixth step
N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-
(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine
N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (1-methyl-1H-pyrazol-4-yl) -6- (((S) -tetrahydrofurane)
3-yl) oxy) quinazolin-4-amine
7-bromo-N- ((R) -1- (3- (difluoromethyl) -2-difluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-4-amine 47f (50 mg, 100.74. Mu. Mol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole 16a (41.92 mg, 201.48. Mu. Mol), sodium carbonate (32.03 mg, 302.22. Mu. Mol) and RuPhos Pd G3 (16.87 mg, 20.15. Mu. Mol) were sequentially added to a mixed solvent of 1, 4-dioxane (1 mL) and water (0.1 mL), argon was replaced 3 times, and heated to 100℃with continuous stirring for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (1-methyl-1H-pyrazol-4-yl) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine 47 (5.0 mg, 9.30. Mu. Mol), 9.23% yield.
MS m/z(ESI):498.2[M+1] +
Example 48
N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7-(2-morpholinoethoxy)-6-(((S)-
tetrahydrofuran-3-yl)oxy)quinazolin-4-amine
N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (2-morpholinoethoxy) -6- (((S) -tetrahydrofurane-3-yl)
Oxy) quinazolin-4-amines
7-bromo-N- ((R) -1- (3- (difluoromethyl) -2-difluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofurane)Pyran-3-yloxy) quinazolin-4-amine 47f (50 mg, 100.74. Mu. Mol), 2-morpholinoethanol (39.64 mg, 302.22. Mu. Mol), pd 2 (dba) 3 (9.01 mg, 20.15. Mu. Mol), BIPPYPHOS (20.42 mg, 40.30. Mu. Mol) and cesium carbonate (98.47 mg, 302.22. Mu. Mol) were added sequentially to toluene (1 mL), replaced with argon, and the tube was sealed and heated to 100℃with stirring for 12 hours. The system was concentrated under reduced pressure and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (2-morpholinoethoxy) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine 48 (2.5 mg, 7.98. Mu. Mol) in 4.5% yield.
MS m/z(ESI):547.2[M+1] +
Example 49
N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7-((tetrahydro-2H-pyran-4-
yl) methoxy) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine
7-bromo-N- ((R) -1- (3- (difluoromethyl) -2-difluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-4-amine 47f (50 mg, 100.74. Mu. Mol) methanol (35.11 mg, 302.22. Mu. Mol), pd 2 (dba) 3 (9.01 mg, 20.15. Mu. Mol), BIPPYPHOS (20.42 mg, 40.30. Mu. Mol) and cesium carbonate (98.47 mg, 302.22. Mu. Mol) were added sequentially to toluene (1 mL), replaced with argon, and the tube was sealed and heated to 100℃with stirring for 12 hours. Concentrating under reduced pressure, and purifying the residue by preparative liquid chromatography(column: AKZONOBEL Kromasil, 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) afforded N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine 49 (4.7 mg, 8.84. Mu. Mol), 8.8% yield.
MS m/z(ESI):531.9[M+1] +
Example 50
2-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(((S)-
tetrahydrofuran-3-yl) oxy) quinazolin-7-yl oxy) ethane-1-ol 2- ((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazoline
-7-yl) oxy) ethan-1-ol
7-bromo-N- ((R) -1- (3- (difluoromethyl) -2-difluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-4-amine 47f (50 mg, 100.74. Mu. Mol), ethylene glycol (18.76 mg, 302.22. Mu. Mol), pd 2 (dba) 3 (9.01 mg, 20.15. Mu. Mol), BIPPYPHOS (20.42 mg, 40.30. Mu. Mol) and cesium carbonate (98.47 mg, 302.22. Mu. Mol) were added sequentially to toluene (1 mL), replaced with argon, and the tube was sealed and heated to 100℃with stirring for 12 hours. The system was concentrated under reduced pressure and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give 2- ((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-7-yl) oxy) ethan-1-ol 50 (7.0 mg, 14.87. Mu. Mol) in 14.8% yield.
MS m/z(ESI):478.2[M+1] +
Example 51
1-(2-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(((S)-
tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)oxy)ethyl)pyrrolidin-2-one
1- (2- ((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-7-yl) oxy) ethyl) pyrrolidin-2-one
/>
7-bromo-N- ((R) -1- (3- (difluoromethyl) -2-difluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-4-amine 47f (50 mg, 100.74. Mu. Mol), 1- (2-hydroxyethyl) pyrrolidin-2-one (39.03 mg, 302.22. Mu. Mol), pd 2 (dba) 3 (9.01 mg, 20.15. Mu. Mol), BIPPYPHOS (20.42 mg, 40.30. Mu. Mol) and cesium carbonate (98.47 mg, 302.22. Mu. Mol) were added sequentially to toluene (1 mL), replaced with argon, and the tube was sealed and heated to 100℃with stirring for 12 hours. The system was concentrated under reduced pressure and the resulting residue was purified by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give 1- (2- ((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-7-yl) oxy) ethyl) pyrrolidin-2-one 51 (3.8 mg, 6.98. Mu. Mol) in 6.9% yield.
MS m/z(ESI):545.2[M+1] +
Biological evaluation
Test example 1, test of the Compounds of the invention blocking SOS1 binding to KRAS G12C protein
The following method was used to determine the ability of the compounds of the invention to block SOS1 interaction with KRAS G12C protein under in vitro conditions. The method uses KRAS-G12C/SOS1 BINDING ASSAY KITS kit (product number 63ADK000CB16 PEG) from Cisbio company, and the detailed experimental operation can be referred to the kit instruction.
The experimental procedure is briefly described as follows: the working fluid concentrations of Tag1-SOS1 and Tag2-KRAS-G12C proteins were set to 5X using a current buffer (cat No. 62 DLBDDF) for use. Subject chemicalThe compounds were dissolved in DMSO to prepare 10mM stock solution, which was then diluted using a diluet buffer. Firstly, adding 2 mu L of a tested compound (the final concentration of a reaction system is 10000nM-0.1 nM) into a hole, then adding 4 mu L of a Tag1-SOS1 5X working solution and 4 mu L of a Tag2-KRAS-G12C 5X working solution, centrifuging and mixing uniformly, and standing for 15 minutes; then 10 mu L of pre-mixed anti-Tag1-Tb is added 3+ And anti-Tag2-XL665, incubated for 2 hours at room temperature; finally, the fluorescence intensities of the wells at excitation wavelengths of 304nM, at which the emission wavelengths of 620nM and 665nM are measured in the TF-FRET mode using an enzyme-labeled instrument, and the fluorescence intensity ratio of 665/620 is calculated for each well. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO) and nonlinear regression analysis was performed by GraphPad Prism 5 software with the test compound concentration log-inhibition to obtain compound IC 50 The values are shown in Table 1.
TABLE 1 IC of the compounds of the invention blocking SOS1 interaction with KRAS G12C protein 50 Data
Conclusion: as can be seen from table 1, the compounds of the present invention have a strong blocking effect on the interaction of SOS1 with KRAS G12C protein.
The structure of BI-3406 is as follows, prepared according to CN 110167928.
Test example 2 study of the metabolic stability of the Compounds of the invention in human liver microsomes
1. Purpose of experiment
The purpose of this experimental study was to investigate the metabolic stability of the compounds of the invention in human liver microsomes.
2. Experimental protocol
The compound will be co-incubated with human liver microsomes and the reaction initiated by the addition of coenzyme NADPH. The reaction was stopped by withdrawing 20. Mu.L of the incubation and transferring to 200. Mu.L of acetonitrile containing internal standard at 0, 5, 15, 30 and 60 minutes. After protein precipitation, the supernatant was removed by centrifugation at 3,700rpm for 10 minutes. The supernatant was diluted 1:1 with water and analyzed by LC-MS/MS method. The in vitro intrinsic clearance was calculated from the clearance half-life of the test compound in the incubation system. Midazolam as an internal reference compound was incubated in 2 parts in parallel. The incubation conditions are summarized in the following table:
3. data analysis
Ratio of analyte/internal standard peak area (A analyte /A IS ) Will be derived from the instrument, the percentage remaining (% Control) will be determined from the non-zero time point sample and the zero time point sample A analyte /A IS And calculating the ratio. Ln (% Control) is plotted against incubation time and fitted linearly. Test compound clearance constant (k, min -1 ) And clearance half-life (T) 1/2 Min) and in vitro intrinsic Clearance (CL) int ，mL·min -1 ·mg -1 protein) is calculated from the following equation.
k＝-slope
T 1/2 ＝0.693/k
CL int ＝k/C protein
C protein (mg·mL -1 ) Refers to the concentration of microsomal protein in the incubation system.
4. Experimental results
The relevant parameters of the stability of the human liver microsomes of the compound of the embodiment of the invention are shown in the following table:
conclusion: the compound of the embodiment 1 has longer half-life period, low in-vitro internal clearance rate and higher stability of human liver microsomes.

Claims (14)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
wherein:
R 1 identical or different, each independently selected from hydrogen, alkyl, halogen, cyano, alkoxy or-NR 6 R 7 Wherein said alkyl is optionally further substituted with one or more halogens or-CH 2 -NR 6 N 7 Substituted;
R 2 selected from methoxy, -S (O) r R 5 、-C(O)OR 5 、-NR 11 R 12 OR-OR B ；
R 3 Selected from alkyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NR 13 C(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 、-S(O) r R 5 or-C (O) NHS (O) r R 5 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Is substituted by a substituent of (2);
R B selected from C 3 -C 6 Cycloalkyl or 4-11 membered heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, nitro, C 1 -C 6 Alkyl, C 1 -C 6 Halogen-containing alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or = O substituent;
the conditions are as follows: when R is 2 Selected from-OR B When R is 3 Selected from the group consisting of heterocyclyl, heteroaryl, -OR 5 、-C(O)OR 5 or-C (O) NR 6 R 7 ；
R 4 Selected from a hydrogen atom, an alkyl group, a halogen group, a cycloalkyl group or a heterocyclic group, preferably a hydrogen atom;
R 5 selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group is optionally further substituted with one or more groups selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 6 and R is 7 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
alternatively, R 6 And R is 7 Connected with themThe linked atoms together form a 4-to 8-membered heterocyclic group, wherein the 4-to 8-membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 8 、R 9 and R is 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
R 11 selected from hydrogen atoms or alkyl groups;
R 12 selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Is substituted by a substituent of (2);
R 13 selected from a hydrogen atom, an alkyl group or a cycloalkyl group;
r are each independently selected from 0, 1 or 2;
m is selected from 1, 2, 3 or 4.
2. A compound of formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II):
wherein: r is R 1 、R 3 、R 4 And m is as defined in claim 1.
3. A compound of formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III):
wherein: r is R 1 、R 2 、R 4 And m is as defined in claim 1.
4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 The same or different are each independently selected from a hydrogen atom, an alkyl group, a halogen group, an alkoxy group, an amino group, a haloalkyl group or a haloalkoxy group, preferably a hydrogen atom, fluorine, trifluoromethyl, difluoromethyl or amino group.
5. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from:
methoxy, carboxylic acid, methylsulfonyl,
6. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 3 selected from alkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NR 13 C(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-S(O) r R 5 or-C (O) NHS (O) r R 5 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, hydroxy, halogen, alkoxy, cycloalkyl, =o, -C (O) R 5 or-NR 6 R 7 Is substituted by a substituent of (2);
R 5 selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, and heterocyclyl;
R 6 and R is 7 Each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, and-NR 9 R 10 Or = O;
alternatively, R 6 And R is 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, alkyl, alkoxy, =o, -C (O) R 8 or-NR 9 R 10 Is substituted by a substituent of (2);
R 8 、R 9 and R is 10 Each independently ofA site selected from a hydrogen atom or an alkyl group;
R 13 selected from hydrogen atoms or alkyl groups;
r are each independently selected from 0, 1 or 2.
7. The compound according to claim 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from cyano, methoxy, methylsulfonyl, methylsulfinyl, methylcarboxylate, amide, hydroxy, carboxylic acid, acetyl, cyclopropyl, phenyl, pyridyl,
8. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms or cyclopropyl groups.
9. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 11 selected from a hydrogen atom or an alkyl group, wherein the alkyl group is preferably a methyl group;
R 12 Selected from aryl or heteroaryl, wherein the aryl is preferably phenyl and the heteroaryl is preferably pyridinyl or pyrimidinyl.
10. A compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
11. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
12. Use of a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a SOS1 inhibitor.
13. Use of a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the treatment of a SOS1 mediated disease, preferably a cancer associated with RAS family protein signaling pathway dependence, a cancer caused by SOS1 mutation or a genetic disease caused by SOS1 mutation.
14. The use according to claim 13, wherein the SOS1 mediated disease is selected from lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibromatosis, noonan syndrome, cardiac skin syndrome, hereditary gingival fibroma type i, embryonal rhabdomyosarcoma, celetoly cell testicular tumor, or skin granulocytoma.
CN202310056017.8A 2022-01-21 2023-01-19 Quinazoline derivative and preparation method and application thereof Pending CN116478100A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022100693739 2022-01-21
CN202210069373 2022-01-21

Publications (1)

Publication Number Publication Date
CN116478100A true CN116478100A (en) 2023-07-25

Family

ID=87218351

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310056017.8A Pending CN116478100A (en) 2022-01-21 2023-01-19 Quinazoline derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN116478100A (en)

Similar Documents

Publication Publication Date Title
CN114761394B (en) Pyridine or pyrimidine derivative and preparation method and application thereof
JP6726677B2 (en) Substituted 2-H-pyrazole derivatives as anticancer agents
US10703746B2 (en) Mutant IDH1 inhibitors useful for treating cancer
TWI601718B (en) 2-arylaminopyridines, pyrimidine or triazine derivatives, processes for preparing the same, and uses thereof
EP3677583A1 (en) Nitrogenous heterocyclic compound, preparation method, intermediate, composition, and application
AU2018235139A1 (en) Compounds useful in the treatment or prevention of a PRMT5-mediated disorder
EA035499B1 (en) Novel glutaminase inhibitors
AU2021400942A1 (en) PRMT5 inhibitors
JP2019529444A (en) Alkyl-substituted heterocyclic compounds, preparation methods therefor and medical uses thereof
CA3009669A1 (en) Bruton's tyrosine kinase inhibitors
RU2692479C2 (en) (5,6-dihydro)pyrimido[4,5-e]indolysines
AU2015276699B2 (en) Pyridino[1,2-a]pyrimidone analogue used as PI3K inhibitor
EA017442B1 (en) 2-ARYL-6-PHENYLIMIDAZO[1,2-a]PYRIDINE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
CN116546985A (en) Pyridopyrimidine derivative and preparation method and application thereof
CN116323622A (en) Bicyclic heteroaryl derivatives, preparation method and application thereof
KR20200090828A (en) Pyrazolopyridinone compounds
TW201900644A (en) Fgfr4 inhibitor and preparation and use thereof
CN109384785B (en) Pyrrolopyridinone derivatives, preparation method and medical application thereof
CN109384784B (en) Sulfonamide derivative, preparation method thereof and application thereof in medicine
CN115490671A (en) PARP7 inhibitors and process for preparing the same
CN115611888A (en) Pyridopyrimidinone derivative and preparation method and application thereof
CN116478100A (en) Quinazoline derivative and preparation method and application thereof
CN113727984B (en) Macrocyclic derivatives, preparation method and application thereof
CN112939982A (en) Alkyne heterocyclic BTK inhibitor and preparation method and application thereof
WO2011093365A1 (en) Nitrogenated heterocyclic compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication