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CN118715229A - Tricyclic derivative and preparation method and application thereof - Google Patents

Tricyclic derivative and preparation method and application thereof Download PDF

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Publication number
CN118715229A
CN118715229A CN202380022322.3A CN202380022322A CN118715229A CN 118715229 A CN118715229 A CN 118715229A CN 202380022322 A CN202380022322 A CN 202380022322A CN 118715229 A CN118715229 A CN 118715229A
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group
nitro
alkyl
methyl
dihydro
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Inventor
郭阳辉
张恒
廖伟伟
陈友喜
叶成
徐代旺
徐肖杰
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Publication of CN118715229A publication Critical patent/CN118715229A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a substituted tricyclic derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. In particular, the invention relates to a substituted tricyclic derivative shown in a general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application thereof 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

Tricyclic derivative and preparation method and application thereof Technical Field
The present invention relates to a substituted tricyclic derivative, a process for its preparation, pharmaceutical compositions containing the derivative and its use as a therapeutic agent, in particular 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.
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 by BI, WO2019201848A1 by Bayer, WO2020180768A1 by Revolition, WO2020180770A1, etc., 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 tricyclic compound represented by general formula (I):
wherein:
Ring A is selected from C 6-C10 aryl, 5-10 membered heteroaryl, 5-8 membered heterocyclyl or 9-10 membered bicyclic heterocyclyl;
Ring B is selected from 4-11 membered heterocycle, C 6-C10 aromatic ring or 5-10 membered aromatic heterocycle;
r 1, which are identical or different, are each independently selected from the group consisting of a hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 or-S (O) rR3, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further taken by one or more substituents of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 or-S (O) rR3;
R 2, which are identical or different, are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, a halogen group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 and-S (O) rR3, wherein the alkyl group, alkenyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further taken by one or more substituents of the alkyl group, halogen group, nitro group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 or-S (O) rR3;
X is selected from N or CR a; x is preferably CR a;
R a is selected from a hydrogen atom, alkyl, halogen or cycloalkyl;
R 3 is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, 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)R6、-C(O)OR6、-OC(O)R6、-NR7R8、-C(O)NR7R8、-SO2NR7R8, or-NR 7C(O)R8;
R 4 and R 5 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group 、＝O、-C(O)R6、-C(O)OR6、-OC(O)R6、-NR7R8、-C(O)NR7R8、-SO2NR7R8, or-NR 7C(O)R8;
Or R 4 and R 5 together with the atoms to which they are attached form a 4-8 membered heterocyclyl wherein the 4-8 membered heterocyclyl contains one or more N, O or S (O) r groups and said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R6、-C(O)OR6、-OC(O)R6、-NR7R8、-C(O)NR7R8、-SO2NR7R8 or-NR 7C(O)R8;
R 6、R7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;
r are each independently selected from 0,1 or 2;
m is selected from 1,2,3 or 4;
n 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: the definitions of rings B, R 1、R2, m and n are as described in formula (I).
In a preferred embodiment of the present invention, a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-C4 alkyl, halogen, C 1-C4 haloalkyl, or amino; preferably trifluoromethyl, difluoromethyl, amino or fluorine atom.
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 2 is selected from halogen, C 1-C4 alkyl, C 1-C4 alkenyl, C 1-C4 haloalkyl, C 5-C6 aryl, -C (O) R 3, or = O; wherein the alkyl is preferably methyl, ethyl, propyl or isopropyl; wherein the alkenyl group is preferably allyl; wherein the aryl is preferably phenyl;
R 3 is selected from C 1-C4 alkyl, preferably methyl.
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5-6 membered heterocycle or a 5-6 membered aromatic heterocycle; ring B is preferably of the structure:
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Selected from the following specific structures:
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) or (II), 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) or (II) 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 a use of a compound of general formula (I) or (II) 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, wherein the SOS1 mediated disease is 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) or (II) 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) or (II) 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, heart-face skin syndrome, type I hereditary gingival fibroma, embryonal rhabdomyosarcoma, seltoli 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 used as a group or part of a group is meant to include C 1-C20 straight or branched chain aliphatic hydrocarbon groups. Preferably a C 1-C10 alkyl group, more preferably a C 1-C6 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-C12 cycloalkyl, more preferably C 3-C8 cycloalkyl, most preferably C 3-C6 cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are 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 a5 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.
"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be optionally substituted or unsubstituted.
"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 a5 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 sharing one atom between monocyclic rings, which may contain 1 or more double bonds within the ring, but none of the rings has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or a heteroatom of 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,
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 a heteroatom of S (O) n (where 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 (dioxine).
"Bridged heterocyclyl" means a5 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 a heteroatom of 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,
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-C10 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, isoindolyl, and benzisothiazolyl,
Heteroaryl groups may be substituted or unsubstituted.
"Alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. Alkoxy of C 1-C6 is a preferred choice. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"C 1-C6 hydroxyalkyl" refers to hydroxy-substituted C 1-C6 alkyl.
"C 1-C3 haloalkyl" refers to a halogen substituted C 1-C3 alkyl.
"C 1-C6 haloalkyl" refers to a halogen substituted C 1-C6 alkyl.
"Hydroxy" refers to an-OH group.
"Halogen" refers to fluorine, chlorine, bromine and iodine.
"Amino" refers to-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)" refers to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
"RuPhos-Pd-G 3" means sulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II).
"Pd (PPh 3)2Cl2" refers to bis (triphenylphosphine) palladium dichloride.
"Pd (dba) 3" refers to tris (dibenzylideneacetone) dipalladium.
"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.
"Calt condensing agent" refers to benzotriazole-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate.
The term "leaving group (leaving group)", or leaving group, is used in the terms nucleophilic substitution reaction and elimination reaction as an atom or functional group that breaks away 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.
As used herein, "substituted" or "substituted" refers to a group that may be substituted with one or more substituents, unless otherwise indicated.
"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:
The present invention provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:
The compound of the general formula (IA) and the compound of the general formula (IB) are subjected to condensation reaction under the condition of condensing agents, preferably a Kate condensing agent, a BOP condensing agent, a DCC condensing agent, an EDCI condensing agent and a HATU condensing agent, so as to obtain the compound of the general formula (I); when R 1 contains a nitro group, it can be further reduced to amino;
the definitions of ring A, ring B, X, R 1、R2, m and n are as described in formula (I).
The present invention provides a process for the preparation of a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:
The compound of formula (IIA) and the compound of formula (IIB) are subjected to condensation reaction under the condition of condensing agent, preferably a Kate condensing agent, BOP condensing agent, DCC condensing agent, EDCI condensing agent or HATU condensing agent, so as to obtain the compound of formula (II); when R 1 contains a nitro group, it can be further reduced to amino;
the definitions of rings B, R 1、R2, m and n are as described in formula (II).
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=single peak, d=double peak, t=triplet-peak, t=triplet the peak is the peak value of the peak, dd = double peak of double peaks, dt=triplet is a double peak of (2). 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 0.15mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-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 by adopting a silica gel column chromatography eluent system and a thin layer chromatography; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
Example 1
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4-amine
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine
First step
7-Amino-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carboxylic acid methyl ester
methyl 7-amino-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate
7-Nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxine-6-carboxylic acid methyl ester 1a (1.0 g,4.18 mmol) was dissolved in methanol (6 mL), iron powder (2.33 g,41.8 mmol) was added, and heated to reflux. After the reaction was completed, it was cooled to room temperature. Filtration, concentration, addition of water (10 mL), extraction with ethyl acetate (50 mL. Times.3), washing with saturated brine (30 mL. Times.2), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure gave methyl 7-amino-2, 3-dihydrobenzo [ b ] [1,4] dioxine-6-carboxylate 1b (0.809 g), 92.5% yield.
MS m/z(ESI):210.0[M+H]+
Second step
2-Methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4 (3H) -one
2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4(3H)-one
Methyl 7-amino-2, 3-dihydrobenzo [ b ] [1,4] dioxine-6-carboxylate 1b (200 mg, 956. Mu. Mol) was dissolved in acetonitrile (0.5 mL), methanesulfonic acid (598 mg,6.22 mmol) was added, and the mixture was heated to 100℃and reacted for 72 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (2 mL) was added, ph=9 was adjusted with 1M aqueous sodium hydroxide solution, and a solid was precipitated, filtered, and dried to give 2-methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4 (3H) -one 1c (120 mg), yield 57.6%.
MS m/z(ESI):219.0[M+H]+
Third step
4-Chloro-2-methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazoline
4-chloro-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline
2-Methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4 (3H) -one 1c (50 mg, 229.14. Mu. Mol) was dissolved in 1, 2-dichloroethane (1 mL), triethylamine (92.8 mg, 917. Mu. Mol) and phosphorus oxychloride (105 mg, 687. Mu. Mol) were added in this order, and the mixture was heated to 90℃and reacted for 4 hours. Cooled to room temperature, ethyl acetate (20 mL) and water (20 mL) were added, and the organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-chloro-2-methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazoline 1d (52 mg) in 95.9% yield.
MS m/z(ESI):236.9[M+H]+
Fourth step
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4-amine
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine
4-Chloro-2-methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazoline 1d (50 mg, 211. Mu. Mol) was dissolved in N, N-dimethylformamide (1 mL), and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (47.9 mg, 253. Mu. Mol, obtained in accordance with the preparation of patent WO 2019122129) and potassium carbonate (29.2 mg, 211. Mu. Mol) were added and heated to 100℃and stirred overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to prepare a separate (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- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4-amine 1 (25.9 mg), yield 30.8%. MS m/z (ESI): 389.9[ M+1] +
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.21(s,1H),7.72(t,J＝7.5Hz,1H),7.56(t,J＝7.1Hz,1H),7.35(t,J＝8.0Hz,1H),7.23(t,J＝54.4Hz,1H),7.12(d,J＝3.6Hz,1H),5.87-5.94(m,1H),4.36-4.51(m,4H),2.52(s,3H),1.66(d,J＝7.0Hz,3H).
Example 2
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methyl- [1,3] dioxazole [4,5-g ] quinazolin-8-amine
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methyl-[1,3]dioxolo[4,5-g]quinazolin-8-amine
First step
6-Nitropheno [ d ] [1,3] dioxazole-5-carbonitrile
6-nitrobenzo[d][1,3]dioxole-5-carbonitrile
Benzo [ d ] [1,3] dioxazole-5-carbonitrile 2a (500 mg,3.40 mmol) was dissolved in acetic acid (5 mL), fuming nitric acid (7.20 g,114.3 mmol) was slowly added and reacted overnight at room temperature. After completion of the reaction, ethyl acetate (20 mL) and water (20 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6-nitrobenzo [ d ] [1,3] dioxazole-5-carbonitrile 2b (306 mg) in 46.9% yield.
MS m/z(ESI):192.9[M+H]+
Second step
6-Nitropheno [ d ] [1,3] dioxazole-5-carboxamide
6-nitrobenzo[d][1,3]dioxole-5-carboxamide
6-Nitropheno [ d ] [1,3] dioxazole-5-carbonitrile 2b (287 mg,1.49 mmol) was dissolved in dimethyl sulfoxide (3 mL), potassium hydroxide (168 mg,3.00 mmol) was added, hydrogen peroxide (30% by weight, 2 mL) was slowly dropped, and after the dropping was completed, the temperature was raised to room temperature, and the reaction was stirred for 30 minutes. Water (30 mL) was added to the reaction solution to precipitate a white solid, which was filtered, and the cake was washed with water and dried under vacuum to give 6-nitrobenzo [ d ] [1,3] dioxazole-5-carboxamide 2c (297 mg) in 94.6% yield.
MS m/z(ESI):211.0[M+H]+
Third step
6-Aminobenzo [ d ] [1,3] dioxazole-5-carboxamide
6-aminobenzo[d][1,3]dioxole-5-carboxamide
6-Nitropheno [ d ] [1,3] dioxazole-5-carboxamide 2c (130 mg, 619. Mu. Mol) was dissolved in ethyl acetate (0.5 mL), and palladium on carbon (10%, 75.1 mg) was added to replace hydrogen to react at room temperature for 3 hours. Filtration and concentration under reduced pressure gave 6-aminobenzo [ d ] [1,3] dioxazole-5-carboxamide 2d (101 mg) in 90.6% yield.
MS m/z(ESI):180.9[M+H]+
Fourth step
6-Methyl- [1,3] dioxazol [4,5-g ] quinazolin-8 (7H) -one
6-methyl-[1,3]dioxolo[4,5-g]quinazolin-8(7H)-one
6-Aminobenzo [ d ] [1,3] dioxazole-5-carboxamide 2d (50 mg, 278. Mu. Mol) and triethoxymethane (123 mg, 833. Mu. Mol) were dissolved in ethanol (1 mL), heated to 80℃and reacted overnight. Concentration gave 6-methyl- [1,3] dioxazol [4,5-g ] quinazolin-8 (7H) -one 2e (50 mg) in 88.2% yield.
MS m/z(ESI):205.0[M+H]+
Fifth step
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methyl- [1,3] dioxazole [4,5-g ] quinazolin-8-amine
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methyl-[1,3]dioxolo[4,5-g]quinazolin-8-amine
6-Methyl- [1,3] dioxazol [4,5-g ] quinazolin-8 (7H) -one 2e (60 mg, 294. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (83.4 mg, 441. Mu. Mol), a Kate condensing agent (169 mg, 382. Mu. Mol) and DBU (67.10 mg, 440.78. Mu. Mol) were dissolved in acetonitrile (2 mL) at room temperature, and the reaction was stirred at room temperature overnight. After completion of the reaction, the obtained residue was concentrated under reduced pressure, and the liquid phase was separated and purified (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- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methyl- [1,3] dioxazole [4,5-g ] quinazolin-8-amine 2 (1.3 mg), yield 1.2%.
MS m/z(ESI):375.9[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.99(d,J＝7.4Hz,1H),7.87(s,1H),7.65(t,J＝7.5Hz,1H),7.48(t,J＝7.2Hz,1H),7.27(t,J＝7.8Hz,1H),7.22(s,J＝54.4Hz,1H),6.99(s,1H),6.16(d,J＝6.6Hz,2H),5.72-5.79(m,1H),2.29(s,3H),1.57(d,J＝7.1Hz,3H).
Example 3
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
First step
3-Oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester
methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
Methyl 3-amino-4-hydroxybenzoate (1 g,5.98 mmol) and N-benzyl-N, N-diethyl-ethyl-ammonium chloride (5.45 g,23.9 mmol) were dissolved in chloroform (30 mL), sodium bicarbonate (4.02 g,47.9 mmol) was added, the mixture was cooled in an ice-water bath, 2-chloroacetyl chloride (810.78 mg,7.18 mmol) was added dropwise, and after completion of the dropwise addition, the mixture was heated to 100℃and reacted for 16 hours. Concentrated under reduced pressure, water (30 mL) was added to precipitate a solid, which was filtered and dried to give methyl 3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 3b (1.20 g) in 96.8% yield.
MS m/z(ESI):208.1[M+H]+
Second step
7-Nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester
methyl 7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
3-Oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 3b (400 mg,1.93 mmol) was dissolved in acetic acid (10 mL) in ice bath, fuming nitric acid (12.2 g,193mmol,8.45 mL) was slowly added dropwise, and stirred at room temperature for 16 hours. Ethyl acetate (30 mL) and water (30 mL) were added, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 3c (162 mg) in 33.3% yield.
MS m/z(ESI):252.9[M+H]+
Third step
4-Methyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester
methyl 4-methyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
Methyl 7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 3c (1 g,3.97 mmol) was dissolved in N, N-dimethylformamide (2 mL), potassium carbonate (268 mg,3.97 mmol) was added, methyl iodide (28.1 g,198 mmol) was added, and the reaction was carried out overnight at room temperature. Ethyl acetate (30 mL) and water (30 mL) were added, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 4-methyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 3d (1.04 g) in 98.7% yield.
MS m/z(ESI):266.9[M+H]+
Fourth step
4-Methyl-7-amino-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester
methyl 7-amino-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
Methyl 4-methyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 3d (1.04 g,3.91 mmol), iron powder (2.19 g,39.1 mmol), ammonium chloride (1.05 g,19.57 mmol) and water (2 mL), methanol (6 mL) were mixed and heated to 90℃for 16H. Filtering, concentrating, adding ethyl acetate (20 mL), filtering, drying, concentrating under reduced pressure to obtain 4-methyl-7-amino-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 3e (880 mg), yield 95.2%.
MS m/z(ESI):236.9[M+H]+
Fifth step
2, 6-Dimethyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4, 7 (8H) -dione
2,6-dimethyl-3,6-dihydro-4H-[1,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione
Methyl 4-methyl-7-amino-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 3e (500 mg,2.12 mmol) and methanesulfonic acid (1.32 g,13.8 mmol) were dissolved in acetonitrile (15 mL), and after sealing, heated to 100deg.C and reacted for 72 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 2, 6-dimethyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione 3f (213 mg), yield 41.0%. MS m/z (ESI): 245.9[ M+H ] +
Sixth step
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
2, 6-Dimethyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione 3f (50 mg, 204. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (57.9 mg, 306. Mu. Mol), benzotriazol-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate (117 mg, 265. Mu. Mol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (46.6 mg, 306. Mu. Mol) were mixed with acetonitrile (1 mL) and stirred at room temperature for 48 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give a liquid phase (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) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 3 (1.5 mg), yield 1.78%.
MS m/z(ESI):416.7[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.00(d,J＝7.1Hz,1H),8.18(s,1H),7.75(t,J＝7.6Hz,1H),7.58(t,J＝7.2Hz,1H),7.37(t,J＝7.6Hz,1H),7.24(t,J＝54.0Hz,1H),7.20(s,1H),5.95(m,1H),4.93(s,2H),3.44(s,3H),2.54(s,3H),1.71(d,J＝7.0Hz,3H).
Example 4
(R) -6-allyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
(R)-6-allyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
First step
4-Allyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester
methyl 4-allyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
Methyl 7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 3c (1 g,3.97 mmol) was dissolved in N, N-dimethylformamide (2 mL), potassium carbonate (268 mg,3.97 mmol) was added, 3-chloropro-1-ene (603 mg,7.93 mmole 7) was added, and stirred overnight at room temperature. Ethyl acetate (30 mL) and water (30 mL) were added, the solution was separated, and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-allyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 4a (1.11 g) in 96.0% yield.
MS m/z(ESI):292.9[M+H]+
Second step
4-Allyl-7-amino-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester
methyl 4-allyl-7-amino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate
Methyl 4-allyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 4a (1.11 g,3.80 mmol), iron powder (2.12 g,38.0 mmol), ammonium chloride (1.02 g,19.0 mmol) and water (2 mL), methanol (6 mL) were mixed and heated to 90℃for 16H. Filtering, concentrating, adding ethyl acetate (20 mL), filtering, drying, concentrating under reduced pressure to obtain 4-allyl-7-amino-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 4b (901 mg), yield 90.5%.
MS m/z(ESI):263.1[M+H]+
Third step
6-Allyl-2-methyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4, 7 (8H) -dione
6-allyl-2-methyl-3,6-dihydro-4H-[1,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione
Methyl 4-allyl-7-amino-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate 4b (500 mg,1.91 mmol) and methanesulfonic acid (1.19 g,12.4 mmol) were dissolved in acetonitrile (15 mL), and after sealing, heated to 100deg.C and reacted for 72 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 6-allyl-2-methyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione 4c (234 mg) in 45.3% yield.
MS m/z(ESI):271.9[M+H]+
Fourth step
(R) -6-allyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
(R)-6-allyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
6-Allyl-2-methyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione 4c (50 mg, 184. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (52.3 mg, 276. Mu. Mol), benzotriazol-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate (106 mg, 240. Mu. Mol) and acetonitrile (1 mL) were mixed, 1, 8-diazabicyclo [5.4.0] undec-7-ene (42.1 mg, 276. Mu. Mol) were added and stirred overnight at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure to give a liquid phase (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) -6-allyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 4 (2 mg), yield: 2.46%; at the same time, by-product 4d (1.17 mg) was obtained.
4
MS m/z(ESI):442.9[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.27(d,J＝7.3Hz,1H),7.94(s,1H),7.63(t,J＝7.5Hz,1H),7.49(t,J＝7.1Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),7.11(s,1H),5.92(ddt,J＝15.7,10.1,5.0Hz,1H),5.76-5.83(m,1H),5.21(dd,J＝20.2,13.8Hz,2H),4.82(s,2H),4.76(dd,J＝8.4,5.1Hz,2H),2.30(s,3H),1.62(d,J＝7.2Hz,3H).
4d
MS m/z(ESI):424.0[M+H]+
Example 5
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
(R) -4- ((1- (3- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
(R) -6-allyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one 4 (40 mg, 90.41. Mu. Mol), rhodium trichloride (662.18. Mu.g, 3.16. Mu. Mol) and sodium periodate (38.68 mg, 180.82. Mu. Mol) were dissolved in water (2 mL) under nitrogen, and heated to 100℃for reflux reaction for 6 hours. After completion of the reaction, the reaction mixture 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) to give (R) -4- ((1- (3- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 5 (1.66 mg, 4.13. Mu. Mol) in 4.56% yield.
MS m/z(ESI)：402.9[M+H]+
Example 6
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-propyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-propyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
(R) -6-allyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 4 (10 mg, 22.60. Mu. Mol), palladium tetraphenylphosphine (1.31 mg, 1.13. Mu. Mol), formic acid (2.08 mg, 45.20. Mu. Mol) and triethylamine (5.72 mg, 56.51. Mu. Mol) were dissolved in 1, 4-dioxane (1 mL) and the reaction was stirred at room temperature overnight. 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,5 μm, mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-propyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 6 (1 mg, 2.25. Mu. Mol) in 9.95% yield.
MS m/z(ESI):444.9[M+H]+
Example 7
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-8,9-dihydropyrido[2,3-g]quinazolin-7(6H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethyl-8, 9-dihydropyrido [2,3-g ] quinazolin-7 (6H) -one
First step
7-hydroxy-6-nitro-3,4-dihydroquinolin-2(1H)-one
7-Hydroxy-6-nitro-3, 4-dihydroquinolin-2 (1H) -one
Concentrated nitric acid (712.90 mg,7.35mmol,65% purity) was slowly added dropwise to a solution of 7-hydroxy-3, 4-dihydroquinolin-2 (1H) -one 7a (1.0 g,6.13 mmol) in acetic acid (15 mL) with stirring at room temperature for 30 min. After completion of the reaction, water (50 mL) was slowly added under ice bath, stirred to precipitate a yellow solid, which was filtered and dried to give 7-hydroxy-6-nitro-3, 4-dihydroquinolin-2 (1H) -one 7b (600 mg,2.88 mmol) in 47.03% yield.
MS m/z(ESI):209.1[M+1]+
Second step
6-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate
6-Nitro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl triflate
7-Hydroxy-6-nitro-3, 4-dihydroquinolin-2 (1H) -one 7b (500 mg,2.40 mmol) and pyridine (417.97 mg,5.28mmol, 425.68. Mu.L) were successively added to methylene chloride (10 mL), stirred for 10 minutes, and trifluoromethanesulfonic anhydride (813.20 mg,2.88mmol, 484.91. Mu.L) was slowly added dropwise to the reaction mixture under ice-bath, and the reaction was continued under stirring at room temperature for 12 hours. Dichloromethane (55 mL) and water (20 mL) were added, extraction, separation, extraction of the aqueous phase with dichloromethane 2 times, the organic phases were combined, and concentration under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to give 6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl trifluoromethanesulfonate 7c (560 mg,1.73 mmol), yield 72.20%.
MS m/z(ESI):340.8[M+1]+
Third step
6-nitro-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile
6-Nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile
6-Nitro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl trifluoromethane sulfonate 7c (400 mg,1.18 mmol), zinc cyanide (165.66 mg,1.41 mmol) and tetrakis (triphenylphosphine) palladium (203.78 mg, 176.35. Mu. Mol) were added sequentially to N, N-dimethylformamide (8 mL), argon was replaced 3 times, and the reaction was heated to 110℃with continuous stirring for 24 hours. Ethyl acetate (50 mL) and water (25 mL) were added to the system, extraction, separation, extraction of the aqueous phase with ethyl acetate 2 times, and the combined organic phases were 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 separated and purified by silica gel column chromatography (eluent: B system) to give 6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile 7d (220 mg,1.01 mmol), yield 86.16%.
MS m/z(ESI):218.0[M+1]+
Fourth step
1-methyl-6-nitro-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile
1-Methyl-6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile
6-Nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile 7d (100 mg, 460.45. Mu. Mol), methyl iodide (130.71 mg, 920.89. Mu. Mol) and potassium carbonate (127.28 mg, 920.89. Mu. Mol) were successively added to acetonitrile (1 mL), and the reaction was continued with stirring at room temperature for 24 hours. After completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 1-methyl-6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile 7e (58 mg, 250.86. Mu. Mol) in a yield of 54.48%.
MS m/z(ESI):231.9[M+1]+
Fifth step
1-methyl-6-nitro-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide
1-Methyl-6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carboxamide
1-Methyl-6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile 7e (50 mg, 216.26. Mu. Mol) was dissolved in methanol (1 mL), 5M sodium hydroxide solution (1 mL) was added, and hydrogen peroxide (0.5 mL) was slowly added dropwise and the reaction was stirred at room temperature for 30 minutes. 1M diluted hydrochloric acid was added to neutralize to neutrality, ethyl acetate (30 mL. Times.2) was used for extraction, 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 to give crude 1-methyl-6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carboxamide 7f (45 mg, 180.56. Mu. Mol) which was used directly in the next reaction.
MS m/z(ESI):250.1[M+1]+
Sixth step
6-amino-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide
6-Amino-1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carboxamide
1-Methyl-6-nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carboxamide 7f (45 mg, 180.56. Mu. Mol) and 10% palladium on charcoal catalyst (3.84 mg) were added sequentially to methanol (1 mL), hydrogen was replaced 3 times, and the reaction was continued with stirring at room temperature for 2 hours. Filtration and concentration under reduced pressure gave 7g (35 mg, 159.64. Mu. Mol) of crude 6-amino-1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carboxamide in 88.41% yield.
MS m/z(ESI):220.0[M+1]+
Seventh step
2,6-dimethyl-3,6,8,9-tetrahydropyrido[2,3-g]quinazoline-4,7-dione
2, 6-Dimethyl-3,6,8,9-tetrahydropyrido [2,3-g ] quinazoline-4, 7-dione
6-Amino-1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carboxamide 7g (35 mg, 159.64. Mu. Mol), triethyl orthoacetate (77.70 mg, 478.93. Mu. Mol) and acetic acid (19.17 mg, 319.29. Mu. Mol) were added sequentially to ethanol (2 mL), and the mixture was heated to 110℃with stirring for 6 hours. To the resulting residue were added ethyl acetate (30 mL) and water (15 mL), extracted, separated, the aqueous phase was extracted with ethyl acetate, and 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 2, 6-dimethyl-3,6,8,9-tetrahydropyrido [2,3-g ] quinazoline-4, 7-dione (38 mg, 156.21. Mu. Mol) in 97.85% yield.
MS m/z(ESI):244.1[M+1]+
Eighth step
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-8,9-dihydropyrido[2,3-g]quinazolin-7(6H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethyl-8, 9-dihydropyrido [2,3-g ] quinazolin-7 (6H) -one
2, 6-Dimethyl-3,6,8,9-tetrahydropyrido [2,3-g ] quinazoline-4, 7-dione (38 mg, 156.21. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (70.49 mg, 312.42. Mu. Mol), a catter condensing agent (89.82 mg, 203.07. Mu. Mol) and DBU (35.67 mg, 234.32. Mu. Mol) were added sequentially to N, N-dimethylformamide (1 mL), and the reaction was continued with stirring at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (10 mL) were added, the mixture was extracted, the separated liquid and the aqueous phase were extracted 2 times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution (20 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,5 μm, mobile phase A:0.05% aqueous trifluoroacetic acid solution, mobile phase B: acetonitrile) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethyl-8, 9-dihydropyrido [2,3-g ] quinazolin-7 (6H) -one 7 (5.3 mg, 12.75. Mu. Mol) in 8.16% yield.
MS m/z(ESI):414.8[M+1]+
Example 8
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-ethyl-2-methyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-ethyl-2-methyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
First step
3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
3-Oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
To a solution of 3-amino-4-hydroxybenzonitrile 8a (1 g,7.46 mmol) and sodium bicarbonate (1.25 g,14.91 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise 2-chloroacetyl chloride (1.26 g,11.18mmol, 889.45. Mu.L) at 0℃and the reaction was continued at 70℃for 16 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 3-oxo-3, 4-dihydro-2H-benzo [ B ] [1,4] oxazine-6-carbonitrile 8B (1.2 g,6.89 mmol) in 92.42% yield.
MS m/z(ESI):175.0[M+H]+
Second step
7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
7-Nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
To a solution of 3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 8b (600 mg,3.45 mmol) in acetic acid (8 mL) at room temperature was slowly added dropwise fuming nitric acid (21.70 g,344.52mmol,15.07 mL) and the reaction was stirred at room temperature overnight. After completion of the reaction, ethyl acetate (30 mL) and water (30 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.3) and concentration of the combined organic phases under reduced pressure were performed, followed by drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure to give crude 7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 8c (540 mg,2.46 mmol) in a yield of 71.52%.
MS m/z(ESI):220.0[M+H]+
Third step
4-ethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
4-Ethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
7-Nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 8c (250 mg,1.14 mmol), iodoethane (1.78 g,11.41mmol, 912.37. Mu.L) and potassium carbonate (315.33 mg,2.28 mmol) were added sequentially to N, N-dimethylformamide (1 mL) and the reaction stirred at room temperature overnight. After completion of the reaction, ethyl acetate (30 mL) and water (30 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (30 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-ethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 8d (240 mg, 970.85. Mu. Mol) in a yield of 85.11%.
MS m/z(ESI):248.1[M+H]+
Fourth step
4-ethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
4-Ethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
4-Ethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 8d (230 mg, 930.40. Mu. Mol) and potassium hydroxide (104.40 mg,1.86 mmol) were added sequentially to dimethylsulfoxide (2 mL), hydrogen peroxide (2 mL) was slowly added dropwise, and the reaction was stirred at room temperature overnight. After completion of the reaction, water (6 mL) was added, filtered, and the filter cake was dried under vacuum to give 4-ethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 8e (120 mg) in 24.31% yield.
MS m/z(ESI):266.0[M+H]+
Fifth step
7-amino-4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
7-Amino-4-ethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
To a solution of 4-ethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 8e (120 mg, 452. Mu. Mol) in ethyl acetate (1.0 mL) under nitrogen atmosphere was added 10% palladium on charcoal catalyst (10 mg), the hydrogen was replaced three times, and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, filtration and concentration under reduced pressure gave 7-amino-4-ethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 8f (80 mg) in 75.3% yield.
MS m/z(ESI):235.9[M+H]+
Sixth step
6-ethyl-4-hydroxy-2-methyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
6-Ethyl-4-hydroxy-2-methyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one
7-Amino-4-ethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 8f (80 mg, 340.08. Mu. Mol), acetic acid (40.84 mg, 680.16. Mu. Mol, 38.90. Mu. L) and triethyl orthoacetate (165.51 mg,1.02mmol, 195.25. Mu. L) were added sequentially to ethanol (1.97 mL), and heated to 110℃for reflux reaction for 16 hours. After the reaction was completed, the mixture was suction-filtered and vacuum-dried to give 8g (88 mg) of 6-ethyl-4-hydroxy-2-methyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one in a yield of 99.81%
LCMS:260.0[M+H]+
Seventh step
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-ethyl-2-methyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
6-Ethyl-4-hydroxy-2-methyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 8g (100 mg, 385.71. Mu. Mol), kate condensing agent (221.77 mg, 501.43. Mu. Mol), DBU (176.16 mg,1.16mmol, 173.04. Mu.L) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (72.97 mg, 385.71. Mu. Mol) were added sequentially to N, N-dimethylformamide (0.8 mL), and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated and 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) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-ethyl-2-methyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 8 (6 mg) in 3.61% yield.
LCMS:431.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.56(d,J＝7.2Hz,1H),8.11(s,1H),7.74(t,J＝7.5Hz,1H),7.54(t,J＝7.1Hz,1H),7.32(dd,J＝15.5,7.9Hz,1H),7.14(s,1H),5.86(m,1H),4.80(s,2H),4.29-4.12(m,J＝7.2Hz,2H),2.59(s,3H),1.69(d,J＝7.1Hz,3H),1.29(t,J＝7.1Hz,3H).
Example 9
(R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)ethan-1-one
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazin [3,2-g ] quinazolin-6-yl) ethan-1-one
First step
4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
4-Acetyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
3, 4-Dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 9a (200 mg,1.25 mmol) was added to acetic anhydride (1.5 mL) and the reaction stirred at room temperature for 4 hours. After completion of the reaction, the crude title product 9b was obtained by concentration under reduced pressure and was used directly in the next reaction.
MS m/z(ESI):203.1[M+1]+
Second step
4-acetyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
4-Acetyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
4-Acetyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 9b (250 mg,1.24 mmol) was added to acetic acid (1.5 mL), concentrated nitric acid (299.62 mg,3.09mmol, 214.02. Mu.L) was slowly added dropwise to the reaction at room temperature, and the reaction was vigorously exothermic and stirred for 2 hours. Water was added thereto under stirring to precipitate a solid, the solid was filtered, and the filtrate was concentrated under reduced pressure to give 4-acetyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 9c (220 mg, 889.94. Mu. Mol) as a solid in 71.98% yield.
MS m/z(ESI):248.1[M+1]+
Third step
7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
7-Nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
4-Acetyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 9c (177 mg, 716.00. Mu. Mol) was added to a mixture of 5M sodium hydroxide solution (1 mL) and methanol (2 mL), and hydrogen peroxide (0.5 mL) was added dropwise thereto, and the reaction was continued with stirring at room temperature for 2 hours. After completion of the reaction, ethyl acetate (30 mL) and water (10 mL) were added, the mixture was extracted, the separated liquid was extracted with ethyl acetate, and 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 7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 9d (100 mg, 487.40. Mu. Mol) in a yield of 68.07%.
MS m/z(ESI):206.1[M+1]+
Fourth step
7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
7-Nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
7-Nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 9d (100 mg, 487.40. Mu. Mol) was added to a mixed solvent of 5M sodium hydroxide solution (1 mL) and dimethyl sulfoxide (1.5 mL), and hydrogen peroxide (0.8 mL) was added dropwise, followed by stirring at room temperature for 30 minutes. After completion of the reaction, ethyl acetate (30 mL) and water (10 mL) were added, the solution was separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed successively with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 9e (80 mg, 358.45. Mu. Mol) in 73.54% yield.
MS m/z(ESI):223.9[M+H]+
Fifth step
4-acetyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
4-Acetyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
7-Nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 9e (100 mg, 448.06. Mu. Mol) was added to a mixed solution of acetic anhydride (1 mL) and triethylamine (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 separated, extracted with ethyl acetate, 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 to give crude 4-acetyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 9f (100 mg, 377.04. Mu. Mol), in 84.15% yield.
MS m/z(ESI):266.0[M+1]+
Sixth step
4-acetyl-7-amino-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
4-Acetyl-7-amino-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
4-Acetyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 9f (100 mg, 377.04. Mu. Mol) and 10% palladium on charcoal catalyst (40.12 mg, 377.04. Mu. Mol) were added sequentially to ethyl acetate (2 mL), hydrogen was replaced 3 times, and the reaction was continued with stirring at room temperature for 2 hours. Filtration and concentration of the filtrate under reduced pressure gave 9g (80 mg, 340.08. Mu. Mol) of crude 4-acetyl-7-amino-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide in 90.20% yield.
MS m/z(ESI):236.0[M+1]+
Seventh step
6-acetyl-2-methyl-3,6,7,8-tetrahydro-4H-[1,4]oxazino[3,2-g]quinazolin-4-one
6-Acetyl-2-methyl-3, 6,7, 8-tetrahydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4-one
9G (100 mg, 425.10. Mu. Mol) of 4-acetyl-7-amino-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide, triethyl orthoacetate (206.89 mg,1.28 mmol) and acetic acid (51.05 mg, 850.20. Mu. Mol) were added sequentially to ethanol (5 mL), and the mixture was heated to 110℃with stirring for 6 hours. Concentrating under reduced pressure, adding ethyl acetate (30 mL) and water (15 mL), extracting, separating liquid, extracting aqueous phase with ethyl acetate, combining organic phases, washing with saturated sodium chloride solution (30 mL. Times.2), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the obtained residue by thin layer chromatography (developing agent: A system) to obtain 6-acetyl-2-methyl-3, 6,7, 8-tetrahydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4-one 9H (21 mg, 81.00. Mu. Mol), yield 19.05%.
MS m/z(ESI):260.0[M+1]+
Eighth step
(R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)ethan-1-one
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazin [3,2-g ] quinazolin-6-yl) ethan-1-one
6-Acetyl-2-methyl-3, 6,7, 8-tetrahydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4-one was added to DMF (2 mL) in this order for 9H (20 mg, 77.14. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (34.81 mg, 154.29. Mu. Mol), a Kate condensing agent (44.35 mg, 100.29. Mu. Mol) and DBU (35.23 mg, 231.43. Mu. Mol), and the reaction was continued with stirring at room temperature for 12 hours. Ethyl acetate (30 mL) and water (10 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate 2 times, 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 preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm,5 μm, mobile phase A:0.05% aqueous trifluoroacetic acid solution, mobile phase B: acetonitrile; 20 mL/min) afforded (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazin [3,2-g ] quinazolin-6-yl) ethyl-1-one 9 (1.9 mg, 4.33. Mu. Mol) in 5.61% yield.
MS m/z(ESI):431.0[M+1]+
Example 10
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2,6,8,8-tetramethyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
First step
2-bromo-N-(5-cyano-2-hydroxyphenyl)-2-methylpropanamide
2-Bromo-N- (5-cyano-2-hydroxyphenyl) -2-methylpropanamide
3-Amino-4-hydroxybenzonitrile 8a (1 g,7.46 mmol) and sodium bicarbonate (1.25 g,14.91 mmol) were added sequentially to a mixed solvent of ethyl acetate (5 mL) and water (5 mL) in an ice bath, 2-methyl-2-bromopropionyl bromide (2.57 g,11.18 mmol) was added dropwise, and the reaction was continued with stirring overnight. After completion of the reaction, ethyl acetate (30 mL) and water (30 mL) were added, extracted, separated, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude 2-bromo-N- (5-cyano-2-hydroxyphenyl) -2-methylpropanamide 10b (2 g), yield 94.75%
MS m/z(ESI):283.0[M+H]+
Second step
2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
2, 2-Dimethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
2-Bromo-N- (5-cyano-2-hydroxyphenyl) -2-methylpropanamide 10b (2 g,7.06 mmol) and potassium carbonate (1.46 g,10.60 mmol) were added sequentially to DMF (2 mL), heated to 45℃and stirred for 16 h. After completion of the reaction, ethyl acetate (20 mL) and water (20 mL) were added, the mixture was extracted, the organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2, 2-dimethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 10c (1.2 g) in 84.01% yield.
MS m/z(ESI):203.0[M+H]+
Third step
2,2-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
2, 2-Dimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
2, 2-Dimethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 10c (700 mg,3.46 mmol) and concentrated nitric acid (21.81 g,346.18mmol,15.15 mL) were added sequentially to a solution of acetic acid (5 mL) at room temperature and the reaction stirred overnight. After the completion of the reaction, water was added and stirred to precipitate a solid, which was filtered, and the filtrate was concentrated under reduced pressure to give crude 2, 2-dimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 10d (850 mg) in a yield of 99.33%.
MS m/z(ESI):248.1[M+H]+
Fourth step
2,2,4-trimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
2, 4-Trimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
2, 2-Dimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 10d (400 mg,1.62 mmol), potassium carbonate (894.51 mg,6.47 mmol) and methyl iodide (2.30 g,16.18mmol,1.01 mL) were successively added to acetonitrile (2.0 mL) and the reaction stirred at room temperature for 16 hours. After completion of the reaction, suction filtration and concentration of the filtrate under reduced pressure gave crude 2, 4-trimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 10e (400 mg) in 94.63% yield. MS m/z (ESI): 262.1[ M+H ] +
Fifth step
2,2,4-trimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
2, 4-Trimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
2, 4-Trimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 10e (350 mg,1.34 mmol), potassium hydroxide (150.34 mg,2.68 mmol) and hydrogen peroxide (0.5 mL) were sequentially added to dimethyl sulfoxide (0.5 mL), and the reaction was stirred at room temperature for 0.5 hours. After completion of the reaction, water (10 mL) was added, extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2, 4-trimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 10f (300 mg), yield 80.18%.
MS m/z(ESI):262.9[M-NH2]+
Sixth step
7-amino-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
7-Amino-2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
2, 4-Trimethyl-7-nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 10f (50 mg, 179.05. Mu. Mol) and 10% palladium on charcoal catalyst (217.47. Mu.g, 1.79. Mu. Mol) were added sequentially to ethyl acetate (1 mL), hydrogen was replaced three times, and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, filtration and concentration under reduced pressure gave 10g (40 mg) of crude 7-amino-2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide in a yield of 89.62%.
MS m/z(ESI):250.1[M+H]+
Seventh step
2,6,8,8-tetramethyl-3,6-dihydro-4H-[1,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione
2,6,8,8-Tetramethyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4, 7 (8H) -dione
10G (50 mg, 200.59. Mu. Mol) of 7-amino-2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide, triethyl orthoacetate (97.62 mg, 601.77. Mu. Mol, 115.16. Mu.L) and acetic acid (24.09 mg, 401.18. Mu. Mol, 22.94. Mu. L) were successively added to ethanol (1 mL), and the mixture was heated to 110℃to reflux for 16 hours. After completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: B system) to give 2,6,8,8-tetramethyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione (50 mg) in a yield of 91.21%.
MS m/z(ESI):274.0[M+H]+
Eighth step
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2,6,8,8-tetramethyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
2,6,8,8-Tetramethyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione 10H (50 mg, 182.96. Mu. Mol), DBU (83.56 mg, 548.87. Mu. Mol, 82.08. Mu. L), kate condensing agent (105.19 mg, 237.85. Mu. Mol) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (69.22 mg, 365.92. Mu. Mol) were added sequentially to DMF (917.91. Mu. L) and the reaction was stirred at room temperature overnight. After completion of the reaction, the obtained residue was concentrated and 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) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2,6,8,8-tetramethyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 10 (15 mg), yield 18.45%.
MS m/z(ESI):445.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝7.3Hz,1H),8.06(s,1H),7.75(t,J＝7.5Hz,1H),7.56(t,J＝7.2Hz,1H),7.36(t,J＝7.7Hz,1H),7.30(s,1H),7.13(s,1H),5.88(m,1H),3.52(s,3H),2.56(s,3H),2.37(s,3H),1.68(d,J＝7.1Hz,3H),1.53(s,3H).
Example 11
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,6-dimethyl-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 6-dimethyl-7, 8-dihydro-6H- [1,4] oxazin [3,2-g ] quinazolin-4-amine
First step
4-methyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
4-Methyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
7-Nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 9e (100 mg, 448.06. Mu. Mol), potassium carbonate (123.85 mg, 896.12. Mu. Mol) and methyl iodide (190.79 mg,1.34 mmol) were added sequentially to DMF (1 mL) and the reaction stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate, and combination of the organic phases were washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 4-methyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 11a (100 mg,421.56 μmol), yield 94.09%.
MS m/z(ESI):238.1[M+1]+
Second step
7-amino-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
7-Amino-4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
4-Methyl-7-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 11a (110 mg, 463.72. Mu. Mol) and 10% palladium on charcoal catalyst (49.35 mg, 463.72. Mu. Mol) were added sequentially to ethyl acetate (3 mL), hydrogen was replaced 3 times, and the reaction was continued with stirring at room temperature for 2 hours. Filtration and concentration of the filtrate under reduced pressure gave crude 7-amino-4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 11b (88 mg, 424.65. Mu. Mol) in 91.57% yield.
MS m/z(ESI):208.1[M+1]+
Third step
2,6-dimethyl-3,6,7,8-tetrahydro-4H-[1,4]oxazino[3,2-g]quinazolin-4-one
2, 6-Dimethyl-3, 6,7, 8-tetrahydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4-one
7-Amino-4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 11b (88 mg, 424.65. Mu. Mol), triethyl orthoacetate (206.67 mg,1.27 mmol) and acetic acid (51.00 mg, 849.30. Mu. Mol) were added sequentially to ethanol (3 mL), and heated to 110℃with stirring for reaction for 6 hours. Concentrated under reduced pressure, ethyl acetate (30 mL) and water (15 mL) were added, the extracts, the separated liquid and the aqueous phase were extracted with ethyl acetate, 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 separated and purified by thin layer chromatography (developer: A system) to give 2, 6-dimethyl-3, 6,7, 8-tetrahydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4-one 11c (90 mg, 389.19. Mu. Mol), yield 91.65%. MS m/z (ESI): 232.0[ M+1] +
Fourth step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,6-dimethyl-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 6-dimethyl-7, 8-dihydro-6H- [1,4] oxazin [3,2-g ] quinazolin-4-amine
2, 6-Dimethyl-3, 6,7, 8-tetrahydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4-one 11c (90 mg, 389.19. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (175.63 mg, 778.38. Mu. Mol), a catchment (223.77 mg, 505.95. Mu. Mol) and DBU (177.75 mg,1.17mmol, 164.58. Mu. L) were added sequentially to DMF (3 mL) and the reaction stirred at room temperature for 12 hours. Ethyl acetate (30 mL) and water (10 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate, washing of the combined organic phases with saturated sodium chloride solution (20 mL. Times.2), concentration under reduced pressure, and purification of the resulting residue by preparative liquid chromatography (column: AKZONOBEL Kromasil, 250X 21.2mm,5 μm, mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) gave (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 6-dimethyl-7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-4-amine 11 (8.0 mg, 17.89. Mu. Mol), yield 4.60%.
MS m/z(ESI):403.0[M+1]+
Example 12
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,7,7-trimethyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 7-trimethyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4-amine
First step
3-hydroxy-4-((2-methylallyl)oxy)benzonitrile
3-Hydroxy-4- ((2-methylallyl) oxy) benzonitrile
3, 4-Dihydroxybenzonitrile 12a (2 g,14.80 mmol), 2-methyl-3-bromo-1-propene (2.4 g,17.76 mmol) and lithium carbonate (1.31 g,17.76 mmol) were added sequentially to DMF (5 mL), heated to 55deg.C and stirred for 16h. After completion of the reaction, the residue was purified by silica gel column chromatography (eluent: A system) to give 3-hydroxy-4- ((2-methallyl) oxy) benzonitrile 12b (1.3 g) in 46.42% yield.
MS m/z(ESI):190.0[M+H]+
Second step
3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile
3, 3-Dimethyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonitrile
3-Hydroxy-4- ((2-methallyl) oxy) benzonitrile 12b (760 mg,4.02 mmol) was added to formic acid (10 mL), heated to 100deg.C and stirred overnight. After completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 3, 3-dimethyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonitrile 12c (275.8 mg), yield 36.29%.
MS m/z(ESI):190.1[M+H]+
Third step
3,3-dimethyl-7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile
3, 3-Dimethyl-7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonitrile
3, 3-Dimethyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonitrile 12c (276 mg,1.46 mmol) and fuming nitric acid (9.19 g,145.87mmol,6.38 mL) were added sequentially to acetic acid (2 mL) and the reaction stirred at room temperature overnight. After completion of the reaction, water (5 mL) was added, and the filter cake was filtered and dried under vacuum to give 3, 3-dimethyl-7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonitrile 12d (300 mg) in a yield of 87.81%.
MS m/z(ESI):235.1[M+H]+
Fourth step
3,3-dimethyl-7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide
3, 3-Dimethyl-7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxine-6-carboxamide
3, 3-Dimethyl-7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonitrile 12d (250 mg,1.07 mmol), potassium hydroxide (119.78 mg,2.13 mmol) and hydrogen peroxide (2 mL) were sequentially added to dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature to react for 0.5 hours. After completion of the reaction, ethyl acetate (20 mL) and water (20 mL) were added, the mixture was extracted, the organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 3, 3-dimethyl-7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carboxamide 12e (200 mg) in a yield of 74.29%.
MS m/z(ESI):253.1[M+H]+
Fifth step
7-amino-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide
7-Amino-3, 3-dimethyl-2, 3-dihydrobenzo [ b ] [1,4] dioxine-6-carboxamide
3, 3-Dimethyl-7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carboxamide 12e (100 mg, 396.47. Mu. Mol) and 10% palladium on charcoal catalyst (421.93. Mu.g, 3.96. Mu. Mol) were added sequentially to ethyl acetate (1 mL), hydrogen was replaced three times, and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, filtration and concentration of the filtrate under reduced pressure gave crude 7-amino-3, 3-dimethyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carboxamide 12f (80 mg) in a yield of 90.79%.
MS m/z(ESI):223.0[M+H]+
Sixth step
2,7,7-trimethyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4(3H)-one
2, 7-Trimethyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4 (3H) -one
7-Amino-3, 3-dimethyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carboxamide 12f (80 mg, 359.97. Mu. Mol), triethyl orthoacetate (175.19 mg,1.08mmol, 206.67. Mu.L) and acetic acid (43.23 mg, 719.94. Mu. Mol, 41.18. Mu.L) were added to ethanol (1 mL) in this order, and heated to 110℃for reflux reaction for 16 hours. After completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 12g (44.5 mg) of 2, 7-trimethyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4 (3H) -one in 50.20% yield.
MS m/z(ESI):247.0[M+H]+
Seventh step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,7,7-trimethyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 7-trimethyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4-amine
12G (44.5 mg, 180.70. Mu. Mol) of 2, 7-trimethyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4 (3H) -one, DBU (82.53 mg, 542.11. Mu. Mol, 81.07. Mu.L), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (68.37 mg, 361. Mu. Mol) and a Kate condensing agent (103.90 mg, 234.91. Mu. Mol) were added sequentially to DMF (918.94. Mu.L), and the reaction was heated to 50℃with stirring overnight. 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,5 μm, mobile phase A:0.05% aqueous trifluoroacetic acid and mobile phase B: acetonitrile) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 7-trimethyl-7, 8-dihydro- [1,4] dioxin [2,3-g ] quinazolin-4-amine 12 (15 mg) in 19.89% yield.
MS m/z(ESI):418.2[M+1]+
1H NMR(400MHz,DMSO-d6)δ9.57(d,J＝44.1Hz,1H),8.20(d,J＝19.3Hz,1H),7.72(s,1H),7.57(d,J＝7.4Hz,1H),7.33(d,J＝8.2Hz,1H),7.15(s,1H),5.89(m,1H),5.26-4.90(m,1H),4.18(d,J＝20.5Hz,2H),2.54(s,3H),1.64(t,J＝6.5Hz,3H),1.36(d,J＝10.5Hz,6H).
Example 13
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-phenyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-phenyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
First step
7-nitro-3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile
7-Nitro-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile
7-Nitro-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 8c (300 mg,1.37 mmol), phenylboronic acid (333.82 mg,2.74 mmol), triethylamine (415.55 mg,4.11mmol, 570.82. Mu.L) and copper acetate (372.96 mg,2.05 mmol) were added sequentially to tetrahydrofuran (2 mL), and the mixture was heated to 60℃and stirred for 4 hours. After completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 7-nitro-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 13a (75 mg), in 18.56% yield.
MS m/z(ESI):296.1[M+H]+
Second step
7-nitro-3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
7-Nitro-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
7-Nitro-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carbonitrile 13a (75 mg, 254.02. Mu. Mol), potassium hydroxide (28.50 mg, 508.05. Mu. Mol) and hydrogen peroxide (0.5 mL) were sequentially added to dimethyl sulfoxide (1 mL), and the mixture was stirred at room temperature for half an hour. After completion of the reaction, ethyl acetate (20 mL) and water (20 mL) were added, the mixture was extracted, the organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 7-nitro-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 13b (70 mg) in a yield of 87.97%.
MS m/z(ESI):314.0[M+H]+
Third step
7-amino-3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
7-Amino-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide
7-Nitro-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 13b (70 mg, 223.45. Mu. Mol) and 10% palladium on charcoal catalyst (237.80. Mu.g, 2.23. Mu. Mol) were added sequentially to ethyl acetate (1 mL), hydrogen was replaced 3 times, and the reaction was stirred at room temperature for 4 hours. After completion of the reaction, filtration and concentration under reduced pressure gave crude 7-amino-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 13c (60 mg) in 94.79% yield.
MS m/z(ESI):283.9[M+H]+
Fourth step
2-methyl-6-phenyl-3,6-dihydro-4H-[1,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione
2-Methyl-6-phenyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazolin-4, 7 (8H) -dione
7-Amino-3-oxo-4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide 13c (60 mg, 211.80. Mu. Mol), triethyl orthoacetate (206.16 mg,1.27mmol, 243.20. Mu.L) and acetic acid (50.88 mg, 847.21. Mu. Mol, 48.45. Mu.L) were added sequentially to ethanol (2 mL), and heated to 110℃for reflux reaction for 16 hours. After completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 2-methyl-6-phenyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione 13d (48 mg), yield 73.75%.
MS m/z(ESI):307.9[M+H]+
Fifth step
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-phenyl-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-phenyl-6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one
2-Methyl-6-phenyl-3, 6-dihydro-4H- [1,4] oxazine [3,2-g ] quinazoline-4, 7 (8H) -dione 13d (48 mg, 156.20. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (59.10 mg, 312.40. Mu. Mol), DBU (71.34 mg, 468.59. Mu. Mol, 70.63. Mu. L) and a Kate condensing agent (103.62 mg, 234.30. Mu. Mol) were sequentially added to DMF (0.5 mL), and heated to 70℃for reaction for 16 hours. After completion of the reaction, the obtained residue was concentrated under reduced pressure, and the 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) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-phenyl-6H- [1,4] oxazine [3,2-g ] quinazolin-7 (8H) -one 13 (15 mg), yield 20.07%.
MS m/z(ESI):479.0[M+H]+
Example 14
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,6-dimethyl-1H-imidazo[4,5-g]quinazolin-8-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -1, 6-dimethyl-1H-imidazo [4,5-g ] quinazolin-8-amine
First step
methyl 5-nitro-1H-benzo[d]imidazole-6-carboxylate
5-Nitro-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester
Under ice bath conditions, methyl 1H-benzo [ d ] imidazole-6-carboxylate 14a (1.0 g,5.68 mmol) was added to fuming nitric acid (10 mL), concentrated sulfuric acid (10 mL) was slowly added to the reaction system and stirred for 20min, and heated to 90℃for 3H. The reaction solution was slowly poured into ice water (150 mL) and stirred to precipitate a solid, which was filtered, and the solid was dried using a small amount of water to give methyl 5-nitro-1H-benzo [ d ] imidazole-6-carboxylate 14b (1.1 g,4.97 mmol) in 87.62% yield.
MS m/z(ESI):221.9[M+1]+
Second step
methyl 1-methyl-5-nitro-1H-benzo[d]imidazole-6-carboxylate
1-Methyl-5-nitro-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester
Methyl 5-nitro-1H-benzo [ d ] imidazole-6-carboxylate 14b (1.0 g,4.52 mmol) and sodium hydride (235.20 mg,5.43mmol,60% purity) were added sequentially to tetrahydrofuran (20 mL), stirred for 10 min, methyl iodide (1.28 g,9.04mmol, 562.96. Mu.L) was added, and the reaction was continued with stirring at room temperature for 12 hours. Ethyl acetate (30 mL) and water (10 mL) were added to the reaction mixture to quench the reaction, the mixture was separated, the aqueous phase was extracted 2 times 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 resulting residue was purified by thin layer chromatography (developer: A system) to give methyl 1-methyl-5-nitro-1H-benzo [ d ] imidazole-6-carboxylate 14c (1.0 g,4.25 mmol) in a yield of 94.04%.
MS m/z(ESI):235.9[M+1]+
Third step
methyl 5-amino-1-methyl-1H-benzo[d]imidazole-6-carboxylate
5-Amino-1-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester
Methyl 1-methyl-5-nitro-1H-benzo [ d ] imidazole-6-carboxylate 14c (70 mg, 297.62. Mu. Mol) and 10% palladium on charcoal catalyst (31.67 mg, 297.62. Mu. Mol) were added sequentially to methanol (5 mL), hydrogen was replaced 3 times, and the reaction was continued with stirring at room temperature for 3 hours. Filtering, concentrating the filtrate under reduced pressure to obtain crude 5-amino-1-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester 14d, which is directly used for the next reaction.
MS m/z(ESI):206.1[M+1]+
Fourth step
1,6-dimethyl-1H-imidazo[4,5-g]quinazolin-8-ol
1, 6-Dimethyl-1H-imidazo [4,5-g ] quinazolin-8-ol
Methyl 5-amino-1-methyl-1H-benzo [ d ] imidazole-6-carboxylate 14d (60 mg, 292.38. Mu. Mol) was added to a solution of acetonitrile (2 mL) and 2M hydrogen chloride in 1, 4-dioxane (3 mL), and the reaction was heated to 100deg.C with stirring for 12 hours. Concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1, 6-dimethyl-1H-imidazo [4,5-g ] quinazolin-8-ol 14e (60 mg, 280.08. Mu. Mol) in 95.79% yield.
MS m/z(ESI):215.1[M+1]+
Fifth step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,6-dimethyl-1H-imidazo[4,5-g]quinazolin-8-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -1, 6-dimethyl-1H-imidazo [4,5-g ] quinazolin-8-amine
1, 6-Dimethyl-1H-imidazo [4,5-g ] quinazolin-8-ol 14e (60 mg, 280.08. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (94.80 mg, 420.12. Mu. Mol), a Kate condensing agent (185.81 mg, 420.12. Mu. Mol) and DBU (127.92 mg, 840.25. Mu. Mol, 118.44. Mu. L) are added sequentially to DMF (3 mL), and heated to 60℃with stirring for reaction for 1 hour. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate 2 times, washing of the combined organic phases with saturated sodium chloride solution (10 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,5 μm, mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) gave (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -1, 6-dimethyl-1H-imidazo [4,5-g ] quinazolin-8-amine 14 (5.0 mg, 11.81. Mu. Mol), yield 4.22%. MS m/z (ESI): 386.0[ M+1] +
Example 15
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethylpyrido[2,3-g]quinazolin-7(6H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethylpyrido [2,3-g ] quinazolin-7 (6H) -one
First step
6-nitro-2-oxo-1,2-dihydroquinoline-7-carbonitrile
6-Nitro-2-oxo-1, 2-dihydroquinoline-7-carbonitrile
6-Nitro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile 7d (72 mg, 331.52. Mu. Mol), N-bromosuccinimide (76.71 mg, 430.98. Mu. Mol) and azobisisobutyronitrile (8.17 mg, 49.73. Mu. Mol) were added sequentially to 1, 2-dichloroethane (2 mL), heated to 80℃and reacted with stirring for 10 hours. The residue was purified by silica gel column chromatography (eluent: B system) to give 6-nitro-2-oxo-1, 2-dihydroquinoline-7-carbonitrile 15a (55 mg, 255.62. Mu. Mol) in a yield of 77.10%.
MS m/z(ESI):216.1[M+1]+
Second step
1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-7-carbonitrile
1-Methyl-6-nitro-2-oxo-1, 2-dihydroquinoline-7-carbonitrile
6-Nitro-2-oxo-1, 2-dihydroquinoline-7-carbonitrile 15a (55 mg, 255.62. Mu. Mol), iodomethane (72.56 mg, 511.24. Mu. Mol, 31.83. Mu. L) and potassium carbonate (70.66 mg, 511.24. Mu. Mol) were successively added 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, extraction, separation, extraction of the aqueous phase with ethyl acetate, combination of the organic phases, washing with saturated sodium chloride solution (15 ml×2), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and separation and purification of the obtained residue by thin layer chromatography (developer: system a) gave 1-methyl-6-nitro-2-oxo-1, 2-dihydroquinoline-7-carbonitrile 15b (32 mg,139.62 μmol), yield 54.62%.
MS m/z(ESI):230.0[M+1]+
Third step
1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-7-carboxamide
1-Methyl-6-nitro-2-oxo-1, 2-dihydroquinoline-7-carboxamide
1-Methyl-6-nitro-2-oxo-1, 2-dihydroquinoline-7-carbonitrile 15b (32 mg, 139.62. Mu. Mol) was added to dimethyl sulfoxide (1 mL) and 5M sodium hydroxide solution (1 mL), hydrogen peroxide (0.5 mL) was added dropwise, and the reaction was continued with stirring at room temperature for 1 hour. Ethyl acetate (30 mL) and water (15 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution (10 mL. Times.2), and concentrated under reduced pressure to give crude 1-methyl-6-nitro-2-oxo-1, 2-dihydroquinoline-7-carboxamide 15c (30 mg, 121.36. Mu. Mol) in 86.92% yield.
MS m/z(ESI):247.9[M+1]+
Fourth step
6-amino-1-methyl-2-oxo-1,2-dihydroquinoline-7-carboxamide
6-Amino-1-methyl-2-oxo-1, 2-dihydroquinoline-7-carboxamide
1-Methyl-6-nitro-2-oxo-1, 2-dihydroquinoline-7-carboxamide 15c (30 mg, 121.36. Mu. Mol) and 10% palladium on charcoal catalyst (12.91 mg, 121.36. Mu. Mol) were added to methanol (1 mL) to replace hydrogen 3 times and the reaction was continued with stirring at room temperature for 3 hours. Filtration and concentration under reduced pressure gave crude 6-amino-1-methyl-2-oxo-1, 2-dihydroquinoline-7-carboxamide 15d (25 mg, 115.09. Mu. Mol) in 94.84% yield.
MS m/z(ESI):218.0[M+1]+
Fifth step
2,6-dimethyl-3,6-dihydropyrido[2,3-g]quinazoline-4,7-dione
2, 6-Dimethyl-3, 6-dihydropyrido [2,3-g ] quinazoline-4, 7-dione
6-Amino-1-methyl-2-oxo-1, 2-dihydroquinoline-7-carboxamide 15d (25 mg, 115.09. Mu. Mol), triethyl orthoacetate (56.01 mg, 345.27. Mu. Mol) and acetic acid (13.82 mg, 230.18. Mu. Mol) were added sequentially to absolute ethanol (1 mL), and the mixture was heated to 110℃with stirring for reaction for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 2, 6-dimethyl-3, 6-dihydropyrido [2,3-g ] quinazoline-4, 7-dione 15e (11 mg, 45.60. Mu. Mol) in 39.62% yield.
MS m/z(ESI):242.0[M+1]+
Sixth step
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethylpyrido[2,3-g]quinazolin-7(6H)-one
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethylpyrido [2,3-g ] quinazolin-7 (6H) -one
2, 6-Dimethyl-3, 6-dihydropyrido [2,3-g ] quinazoline-4, 7-dione 15e (11 mg, 45.60. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1e (15.43 mg, 68.40. Mu. Mol), a Kate condensing agent (30.25 mg, 68.40. Mu. Mol) and DBU (20.82 mg, 136.79. Mu. Mol) were sequentially added to DMF (0.5 mL), and the reaction was continued with stirring at room temperature for 12 hours. Ethyl acetate (30 mL) and water (10 mL) were added, the extracts, the aqueous phase was separated, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution (20 mL. Times.2), and concentrated under reduced pressure, the resulting 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) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 6-dimethylpyrido [2,3-g ] quinazolin-7 (6H) -one 15 (2.3 mg, 5.02. Mu. Mol) in 11.01% yield.
MS m/z(ESI):413.0[M+1]+
Example 16
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,2,6-trimethyl-[1,3]dioxolo[4,5-g]quinazolin-8-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 6-trimethyl- [1,3] dioxazole [4,5-g ] quinazolin-8-amine
First step
methyl 2,2-dimethylbenzo[d][1,3]dioxole-5-carboxylate
2, 2-Dibenzo [ d ] [1,3] dioxazole-5-carboxylic acid methyl ester
Methyl 3, 4-dihydroxybenzoate 16a (500 mg,2.97 mmol), phosphorus pentoxide (633.38 mg,4.46 mmol) and acetone (345.41 mg,5.95mmol, 437.22. Mu.L) were added sequentially to toluene (5 mL) under nitrogen, and heated to 80℃for reflux reaction for 2 hours. After completion of the reaction, the reaction was quenched with 25% sodium hydroxide solution, water (10 mL) was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude methyl 2, 2-dimethylbenzo [ d ] [1,3] dioxazole-5-carboxylate 16b (580 mg) in 93.68% yield.
MS m/z(ESI):209.1[M+H]+
Second step
methyl 2,2-dimethyl-6-nitrobenzo[d][1,3]dioxole-5-carboxylate
2, 2-Dimethyl-6-nitrobenzo [ d ] [1,3] dioxazole-5-carboxylic acid methyl ester
Methyl 2, 2-dimethylbenzo [ d ] [1,3] dioxazole-5-carboxylate 16b (20 mg, 96.06. Mu. Mol, 17.01. Mu.L) and concentrated nitric acid (605.28 mg,9.61mmol, 420.33. Mu.L) were successively added to acetic acid (500.00. Mu.L), and the reaction was stirred at room temperature overnight. After completion of the reaction, ethyl acetate (10 mL) and water (10 mL) were added, extraction, separation, extraction of the aqueous phase with ethyl acetate (5 mL. Times.2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude methyl 2, 2-dimethyl-6-nitrobenzo [ d ] [1,3] dioxazole-5-carboxylate 16c (20 mg) in a yield of 82.23%.
MS m/z(ESI):254.1[M+H]+
Third step
methyl 6-amino-2,2-dimethylbenzo[d][1,3]dioxole-5-carboxylate
6-Amino-2, 2-dimethylbenzo [ d ] [1,3] dioxazole-5-carboxylic acid methyl ester
Methyl 2, 2-dimethyl-6-nitrobenzo [ d ] [1,3] dioxazole-5-carboxylate 16c (500 mg,1.97 mmol) and 10% palladium on charcoal catalyst (2.10 mg, 19.75. Mu. Mol) were successively added to ethyl acetate (2 mL), hydrogen was replaced three times, and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was filtered and concentrated to give methyl 6-amino-2, 2-dimethylbenzo [ d ] [1,3] dioxazole-5-carboxylate 16d (420 mg) as a crude product in a yield of 95.28%.
MS m/z(ESI):224.1[M+H]+
Fourth step
2,2,6-trimethyl-[1,3]dioxolo[4,5-g]quinazolin-8(7H)-one
2, 6-Trimethyl- [1,3] dioxazol [4,5-g ] quinazolin-8 (7H) -one
Methyl 6-amino-2, 2-dimethylbenzo [ d ] [1,3] dioxazole-5-carboxylate 16d (440 mg,1.97 mmol) and a1, 4-dioxane solution of 4M hydrogen chloride (25 mL) were successively added to acetonitrile (13 mL), and heated to 100℃for reflux reaction for 16 hours. After completion of the reaction, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 2, 6-trimethyl- [1,3] dioxazol [4,5-g ] quinazolin-8 (7H) -one 16e (443.2 mg), yield 96.82%.
MS m/z(ESI):233.1[M+H]+
Fifth step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,2,6-trimethyl-[1,3]dioxolo[4,5-g]quinazolin-8-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 6-trimethyl- [1,3] dioxazole [4,5-g ] quinazolin-8-amine
2, 6-Trimethyl- [1,3] dioxazol [4,5-g ] quinazolin-8 (7H) -one 16e (200 mg, 861.20. Mu. Mol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine 1e (325.84 mg,1.72 mmol), DBU (393.32 mg,2.58mmol, 385.60. Mu.L) and a Kate condensing agent (495.16 mg,1.12 mmol) were successively added to DMF (5.00 mL) and the reaction stirred at room temperature overnight. After completion of the reaction, 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) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 6-trimethyl- [1,3] dioxazole [4,5-g ] quinazolin-8-amine 16 (10 mg), yield 2.88%.
MS m/z(ESI):404.0[M+H]+
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/SOS1BINDING ASSAY KITS kit (product number 63ADK000CB16 PEG) from Cisbio company, and the detailed experimental operation can be referred to the instruction manual of the kit.
The experimental procedure is briefly described as follows: the working fluid concentrations of 5X for Tag1-SOS1 and Tag2-KRAS-G12C proteins were configured using diluent buffer (cat No. 62 DLBDDF). Test compounds were dissolved in DMSO to prepare 10mM stock solutions, which were subsequently diluted using diluent buffer for use. 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 3+ and anti-Tag2-XL665 are added for incubation for 2 hours at room temperature; finally, the fluorescence intensities of the wells at the excitation wavelength of 304nm were measured on a TF-FRET model using a microplate reader, the emission wavelengths of which were 620nm and 665nm, and the fluorescence intensity ratio of each well 665/620 was calculated. 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 software on the values of the inhibition with the test compound concentration to obtain IC 50 values for the compounds, see table 1.
TABLE 1 IC 50 data for compounds of the invention blocking SOS1 interaction with KRAS G12C protein
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.
Test example 2, mouse pharmacokinetic study of the Compounds of the invention
1. Purpose of experiment
BALB/c mice are taken as test animals, the LC/MS/MS method is adopted to determine the drug concentration of the BALB/c mice injected with the compound of the invention in plasma at different moments, and the pharmacokinetic characteristics of the compound of the invention in the mice are studied.
2. Experimental protocol
2.1 Experimental drugs and animals;
the compound of example 3;
BALB/c mice, male, 20-24g, purchased from Venlhua laboratory animal technologies Co.
2.2 Pharmaceutical formulation
Intravenous injection group: weighing a proper amount of a compound to be tested, adding a proper amount of DMAC (dimethyl ether carbonate) 30% solution HS15 (solution HS15: water=3:7): saline=10%: 10%:80% (v/v/v), and preparing a solution with a final configuration concentration of 0.2 mg/mL;
Oral gavage group: weighing a proper amount of a compound to be tested, adding a proper amount of DMAC (dimethyl ether carbonate) 30% solution HS15 (solution HS15: water=3:7): saline=5%: 5%:95% (v/v/v), and preparing a solution with a final configuration concentration of 1 mg/mL;
2.3 administration of drugs
BALB/c mice 18, i.v. group (9/group) and oral gavage group (9/group) of test compound, were given by i.v. and oral gavage respectively after overnight fast, and fed after 4 hours of administration.
3. Operation of
100 Μl of EDTA-K2 was collected via the orbit before and after administration for 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours. Blood samples were collected and placed on ice and the plasma was centrifuged within 30 minutes (centrifugation conditions: 1500g,10 minutes). The collected plasma was stored at-40 to-20℃prior to analysis.
LC-MS/MS was used to determine the amount of test compound in the plasma of mice following intravenous and intragastric administration.
4. Pharmacokinetic parameter results
The pharmacokinetic parameters of the compounds of the invention in mice are shown in the following table.
Remarks: N/A indicates no correlation result
Conclusion: the compound of the invention, example 3, has good drug absorption, high bioavailability and better pharmacokinetic properties.

Claims (11)

  1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
    wherein:
    Ring A is selected from C 6-C10 aryl, 5-10 membered heteroaryl, 5-8 membered heterocyclyl or 9-10 membered bicyclic heterocyclyl;
    Ring B is selected from 4-11 membered heterocycle, C 6-C10 aromatic ring or 5-10 membered aromatic heterocycle;
    r 1, which are identical or different, are each independently selected from the group consisting of a hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 or-S (O) rR3, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further taken by one or more substituents of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 or-S (O) rR3;
    R 2, which are identical or different, are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, a halogen group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 and-S (O) rR3, wherein the alkyl group, alkenyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further taken by one or more substituents of the alkyl group, halogen group, nitro group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group 、＝O、-OR3、-C(O)R3、-C(O)OR3、-NHC(O)R3、-NHC(O)OR3、-NR4R5、-C(O)NR4R5、-CH2NHC(O)OR3、-CH2NR4R5 or-S (O) rR3;
    X is selected from N or CR a; x is preferably CR a;
    R a is selected from a hydrogen atom, alkyl, halogen or cycloalkyl;
    R 3 is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, 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)R6、-C(O)OR6、-OC(O)R6、-NR7R8、-C(O)NR7R8、-SO2NR7R8, or-NR 7C(O)R8;
    R 4 and R 5 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group 、＝O、-C(O)R6、-C(O)OR6、-OC(O)R6、-NR7R8、-C(O)NR7R8、-SO2NR7R8, or-NR 7C(O)R8;
    Or R 4 and R 5 together with the atoms to which they are attached form a 4-8 membered heterocyclyl wherein the 4-8 membered heterocyclyl contains one or more N, O or S (O) r groups and said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R6、-C(O)OR6、-OC(O)R6、-NR7R8、-C(O)NR7R8、-SO2NR7R8 or-NR 7C(O)R8;
    R 6、R7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;
    r are each independently selected from 0,1 or 2;
    m is selected from 1,2,3 or 4;
    n 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: the definition of rings B, R 1、R2, m and n is as defined in claim 1.
  3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-C4 alkyl, halogen, C 1-C4 haloalkyl, or amino; preferably trifluoromethyl, difluoromethyl, amino or fluorine atom.
  4. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from halogen, C 1-C4 alkyl, C 1-C4 alkenyl, C 1-C4 haloalkyl, C 5-C6 aryl, -C (O) R 3, or = O; wherein the alkyl is preferably methyl, ethyl, propyl or isopropyl; wherein the alkenyl group is preferably allyl; wherein the aryl is preferably phenyl;
    R 3 is selected from C 1-C4 alkyl, preferably methyl.
  5. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5-6 membered heterocycle or a 5-6 membered aromatic heterocycle; ring B is preferably of the structure:
  6. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Selected from the following specific structures:
  7. A compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
  8. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
  9. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the preparation of a SOS1 inhibitor.
  10. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, 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.
  11. The use according to claim 10, 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.
CN202380022322.3A 2022-03-03 2023-02-27 Tricyclic derivative and preparation method and application thereof Pending CN118715229A (en)

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