CN116041369A - Pyrimidine ring derivatives, preparation method and medical application thereof - Google Patents

Pyrimidine ring derivatives, preparation method and medical application thereof Download PDF

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CN116041369A
CN116041369A CN202210874683.8A CN202210874683A CN116041369A CN 116041369 A CN116041369 A CN 116041369A CN 202210874683 A CN202210874683 A CN 202210874683A CN 116041369 A CN116041369 A CN 116041369A
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alkyl
cycloalkyl
group
pharmaceutically acceptable
heterocyclyl
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张盼盼
何智鹏
苟俊
田圆圆
叶成
钱文建
陈磊
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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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    • 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
    • C07D498/12—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 three hetero rings
    • C07D498/14—Ortho-condensed 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
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—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
    • C07D491/12—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 three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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
    • C07D491/12—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 three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • 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
    • C07D498/22—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 four or more hetero rings

Abstract

The invention relates to a pyrimido-ring derivative, a preparation method thereof and a pharmaceutical composition containing the pyrimido-ring derivativeIs used in the application of (a). In particular, the invention relates to substituted pyrimido ring derivatives represented by the general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application thereof as therapeutic agents, particularly SOS1 inhibitors, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Pyrimidine ring derivatives, preparation method and medical application thereof
Technical Field
The invention relates to a pyrimido-ring derivative, a preparation method thereof, a pharmaceutical composition containing the pyrimido-ring derivative and application of the pyrimido-ring derivative as a therapeutic agent, particularly as an SOS1 inhibitor.
Background
RAS genes are widely present in various eukaryotes such as mammals, drosophila, fungi, nematodes and yeast, have important physiological functions in various living systems, and the mammalian RAS gene family has three members, H-RAS, K-RAS and N-RAS, respectively, and the various RAS genes have similar structures, all composed of four exons, distributed on DNA of about 30kb in length. The encoded products are monomeric globular proteins of relative molecular mass 21 kDa. The active and inactive states of RAS proteins have a significant impact on the life processes such as cell growth, differentiation, proliferation and apoptosis. The protein is a membrane-bound guanine nucleotide binding protein, has weak GTPase activity, and can regulate the active state of RAS through GTPase Activating Proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities, and is in an active state when RAS proteins and GTP are bound to form RAS-GTP, and the GTPase activating proteins can convert RAS-GTP into RAS-GDP through dephosphorylation and then inactivate; the inactivated RAS-GDP is converted into active RAS-GTP under the action of guanine nucleotide exchange factors, so that a series of downstream channels such as RAF/MER/ERK, PI3K/AKT/mTOR and the like are activated.
The RAS gene is also closely related to various diseases of human beings, especially in the aspect of cancers, RAS is an oncogene with frequent mutation, wherein KRAS subtype gene mutation accounts for 86% of total RAS gene mutation, about 90% of pancreatic cancers, 30% -40% of colon cancers and 15-20% of lung cancers, and KRAS gene mutation occurs to different degrees. In view of the prevalence of KRAS gene mutations, this target has been the focus of drug research and development workers. Beginning with the publication of AMG-510 clinical results directly acting on KRAS-G12C targets, KRAS inhibitor studies have been a hot trend at home and abroad.
The SOS (Son of sevenless homolog) protein was originally discovered in Drosophila studies and was a guanosine-releasing protein encoded by the SOS gene. Humans have 2 SOS homologs, hSOS1 and hSOS2, both members of the guanine nucleotide exchange factor family, with 70% homology, although they are highly similar in structure and sequence, there is a difference in their physiological functions. The hSOS1 protein is 150kDa in size and is a multi-structural protein domain consisting of 1333 amino acids, comprising an N-terminal protein domain (HD), multiple homologous domains, a helical junction (HL), a RAS exchange sequence (REM), and a proline-rich C-terminal domain. The hSOS1 has 2 binding sites with RAS proteins, namely a catalytic site and an allosteric site, wherein the catalytic site binds to RAS proteins on the RAS-GDP complex to promote guanine nucleotide exchange, and the allosteric site binds to RAS proteins on the RAS-GTP complex to further enhance the catalytic action, thereby participating in and activating the signal transduction of RAS family proteins. Studies have shown that inhibition of SOS1 not only results in complete inhibition of the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also results in a 50% reduction in phospho-ERK activity in mutant KRAS cell lines. Therefore, inhibition of SOS1 can also reduce RAS activity, thereby treating various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, colorectal cancer, non-small cell lung cancer, and the like.
In addition, alterations in SOS1 are also implicated in cancer. Studies have shown that SOS1 mutations are found in embryonal rhabdomyosarcoma, seltoli cell testicular tumor, skin granulosa cell tumor, and lung adenocarcinoma. Meanwhile, there have been studies describing overexpression of SOS1 in bladder cancer and prostate cancer. In addition to cancer, inherited SOS1 mutations are also involved in the pathogenesis of RAS diseases such as, for example, noonan Syndrome (NS), cardio-facial-skin syndrome (CFC), and inherited gum fibromatosis type 1.
SOS1 is also a GEF for activating GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1). As with RAS family proteins, RAC1 is involved in the pathogenesis of a variety of human cancers and other diseases.
There are no drugs on the market that are selectively targeted to SOS1, but a series of related patents have been published, including WO2018115380A1, WO2019122129A1, WO2019201848A1, WO2020180768A1, WO2020180770A1, etc. of Bayer, and the drugs currently in clinical trial phase are BI-1701963. However, these are far from adequate for anti-tumor studies, and there is still a need to study and develop new selective SOS1 kinase inhibitors to address unmet medical needs.
Disclosure of Invention
The invention aims to provide a pyrimido-cyclic derivative shown in a general formula (I), or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof:
Figure BDA0003757267550000021
wherein:
w is selected from N or CH;
v is selected from N, -CR 2 ；
L is selected from bond or-CH 2 -；
X is selected from-O-or-N (R) 3 )-；
Y is selected from-C (O) -or-CH 2 -；
Z is selected from-O-or-N (R) 5 )-；
Ring A is selected from C 6 -C 10 Aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered fused ring;
R 1 the same or different are each independently selected from hydrogen atom, halogen, cyano, amino, nitro, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 Aryl or 5-to 10-membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, alkoxy, =o, -C (O) R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH 2 NR 7 R 8 、-CH 2 NHC(O)OR 6 or-SO 2 R 6 Is substituted by a substituent of (2);
R 2 selected from fluorine atom, hydroxyl, cyano, methoxy or amino;
R 3 selected from hydrogen atoms, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or-C (O) R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl or cycloalkyl is optionally further substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C 1 -C 3 Alkoxy, C 1 -C 3 Hydroxyalkyl, 4-11 membered heterocyclyl; wherein said 4-11 membered heterocyclyl is optionally further C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, alkoxy, =o, -C (O) R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH 2 NR 7 R 8 、-CH 2 NHC(O)OR 6 or-SO 2 R 6 Is substituted by a substituent of (2);
R 4 selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-10 membered heterocyclyl; wherein said alkyl, cycloalkyl orThe heterocyclic radical optionally being further substituted by one or more R A Substitution;
R A each independently selected from halogen, cyano, hydroxy, amino, C 1 -C 3 Alkoxy, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Haloalkyl or 4-11 membered heterocyclyl; wherein said 4-11 membered heterocyclyl is optionally further C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, alkoxy, =o, -C (O) R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH 2 NR 7 R 8 、-CH 2 NHC(O)OR 6 or-SO 2 R 6 Substituted by substituents of (2)
R 5 Selected from hydrogen atoms, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl; wherein said alkyl or cycloalkyl is optionally further substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C 1 -C 3 Alkoxy or C 1 -C 3 Substituted by a substituent of hydroxyalkyl;
R 6 each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl group, heterocyclic group, aryl group, heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
R 7 and R is 8 Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, and cyanoGroup, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
alternatively, R 7 And R is 8 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, where the 4-8 membered heterocyclic group contains one or more N, O, S or SO 2 And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
R 9 、R 10 and R is 11 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
m is 1, 2 or 3.
In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (II):
Figure BDA0003757267550000041
wherein ring A, R 1 The definitions of W, X, Y, Z, L and m are as described in the general formula (I).
In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (III):
Figure BDA0003757267550000042
wherein ring A, R 1 、R 2 The definitions of W, X, Y, Z, L and m are as described in the general formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1), (II-2), (II-3) or (II-4) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure BDA0003757267550000043
wherein: ring A, R 1 、R 5 The definitions of W, X and m are as described in formula (II).
In a preferred embodiment of the present invention, the compound represented by the general formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1), (III-2), (III-3) or (III-4) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure BDA0003757267550000051
Wherein: ring A, R 1 、R 2 、R 5 The definitions of W, X and m are as described in formula (III).
In a preferred embodiment of the invention, the compounds of the general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
wherein the method comprises the steps of
Figure BDA0003757267550000052
Selected from the following structures: />
Figure BDA0003757267550000053
Wherein: r is R 1 And m is as defined in formula (I).
In a preferred embodiment of the invention, the compounds of the general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
wherein the method comprises the steps of
Figure BDA0003757267550000054
Selected from the following structures:
Figure BDA0003757267550000055
in a preferred embodiment of the invention, the compound of formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is-O-.
In a preferred embodiment of the invention, the compound of formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
X is selected from-N (R) 3 )-；
R 3 Selected from-C (O) R 4 ；
R 4 The definition of (C) is as described in the general formula (I).
In a preferred embodiment of the invention, the compound of formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
x is selected from-N (R) 3 )-；
R 3 Selected from-C (O) R 4 ；
R 4 Selected from methyl or cyclopropyl.
In a preferred embodiment of the invention, the compound of formula (II-2), (II-4), (III-2) or (III-4) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R5 is selected from methyl.
Typical compounds of the present invention include, but are not limited to:
Figure BDA0003757267550000061
note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.
Still further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4), 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 general formulas (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing an SOS1 inhibitor.
The invention also provides the use of a compound of general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of SOS1 mediated diseases, preferably RAS family protein signaling pathway dependent cancers, SOS1 mutation-induced cancers or SOS1 mutation-induced genetic diseases; 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 an application of the compound shown in the general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating RAS family protein signal transduction pathway dependent cancers, SOS1 mutation-induced cancers or SOS1 mutation-induced genetic diseases.
The invention provides an application of a compound shown in a general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3) or (III-4) 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 gum fibromatosis, embryonal rhabdomyosarcoma, seltoril cell testicular tumor or skin granulocytoma.
The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, intraperitoneal, subcutaneous, subcuticular or by inhalation. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that is capable of producing a therapeutic effect.
Dosage forms for topical or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.
When the compounds of the invention are administered to humans and animals in the form of a medicament, the compounds may be provided alone or in the form of a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable carrier, for example 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.
Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) Cyclodextrins, e.g., targeting ligands attached to nanoparticles, e.g., accursinTM; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.
Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) Water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated Hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Solid dosage forms (e.g., capsules, dragees, powders, granules and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) Fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) Binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerin; (4) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) an absorption accelerator, such as a quaternary ammonium compound; (7) Humectants, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) a colorant. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Suspensions, in addition to the active compounds, may also contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
In addition to the active compounds, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
In addition to the active compounds, the powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray may contain other conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.
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:
"bond" means that the indicated substituent is absent and that the two end portions of the substituent are directly linked to form a bond.
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"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.
"alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be straight or branched. Preferably is C 2 -C 10 More preferably C 2 -C 6 Alkynyl, most preferably C 2 -C 4 Alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl groups. 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 optionally substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 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. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.
"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds in the ring, but no ring having a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. 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 and 5-oxaspiro [2.4 ]]A heptyl group.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) r (wherein r 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 (dioxane) or
Figure BDA0003757267550000101
"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain oneOr multiple double bonds, but none of the rings has a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. 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 and 2-azabicyclo [3.3.2]And (3) a decyl group.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. 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. Preferred bicyclic heteroaryl groups, 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, benzothiazolyl.
Figure BDA0003757267550000111
Heteroaryl groups may be substituted or unsubstituted.
"fused ring" means two or more ring-like knotsPolycyclic groups having a pair of atoms common to each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a completely conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more of nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:
Figure BDA0003757267550000112
Figure BDA0003757267550000121
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"haloalkyl" refers to a group wherein the alkyl is optionally further substituted with one or more halogens, where alkyl is as defined herein.
"hydroxyalkyl" refers to a group in which the alkyl group is optionally further substituted with one or more hydroxyl groups, where alkyl is as defined herein.
"hydroxymethyl" refers to a group that is optionally further substituted with one or more hydroxyl groups.
"haloalkoxy" refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
AmmoniaThe radical "means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"carboxy" means-C (O) OH.
"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"BOC" refers to t-butoxycarbonyl.
"Ts" refers to p-toluenesulfonyl.
"T3P" refers to propyl phosphoric anhydride.
"DPPA" refers to diphenyl azide phosphate.
"DEA" refers to diethylamine.
"X-PHOS Pd G2" refers to chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II).
"RuPhos Pd G3" refers to sulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II).
"cataCXium A Pd-G3" means [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium sulfonate.
“Pd(dppf)Cl 2 "refers to [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride.
"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", unless otherwise indicated, means that the groups may be substituted by oneOr a plurality of substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -C (O) R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH 2 NHC(O)OR 6 、-CH 2 NR 7 R 8 or-S (O) r R 6 Is substituted by a substituent of (2);
R 6 selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more groups selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
R 7 and R is 8 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
alternatively, R 7 And R is 8 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group containsOne or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
R 9 、R 10 and R is 11 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
r is 0, 1 or 2.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Unless otherwise indicated, the structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
"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 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.
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 HNMR spectra were determined using a Bruker instrument (400 MHz) and chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 HNMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, shanghai Haohong biological medicine technologies, shanghai Shaoshao reagent, shanghai Pico medicine, saen chemical technologies (Shanghai) and Shanghai Ling Kai medicine technologies, and the like.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound using an eluent system of column chromatography and thin layer chromatography, wherein the system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: ethyl acetate and methanol system, D: dichloromethane and ethanol, wherein the volume ratio of the solvent is different according to the polarity of the compound, and small amount of acidic or alkaline reagent can be added for the conditions such as acetic acid or triethylamine.
Room temperature: 20-30 ℃.
Example 1
8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,10-dimethyl-1,2,4,4a-tetrahydro-[1,4]oxazino[4',3':4,5]pyrazino[2,3-g]quinazolin-5(6H)-one
8- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6, 10-dimethyl-1, 2,4 a-tetrahydro- [1,4] oxazino [4',3':4,5] pyrazino [2,3-g ] quinazolin-5 (6H) -one
Figure BDA0003757267550000151
First step
7-fluoro-2-methyl-6-nitroquinazolin-4-ol
7-fluoro-2-methyl-6-nitroquinazolin-4-ol
In a 50mL single-necked flask, 7-fluoro-2-methylquinazolin-4-ol 1a (1.2 g,6.7mmol, prepared according to WO2009046536A 1) was added, concentrated sulfuric acid (6 mL) and concentrated nitric acid (1 mL) were added while ice-bath, and the temperature was raised to 70℃and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into ice water (250 mL), filtered, and the cake was collected and dried to give 7-fluoro-2-methyl-6-nitroquinazolin-4-ol 1b (990 mg), yield: 66%.
MS m/z(ESI):224.1[M+1] +
Second step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-fluoro-2-methyl-6-nitroquinazolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-fluoro-2-methyl-6-nitroquinazolin-4-amine
In a 50mL single flask, 7-fluoro-2-methyl-6-nitroquinazolin-4-ol 1b (99mg, 4.42 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine hydrochloride 1c (1.1 g,4.91mmol, prepared according to published patent WO2020254451A 1), benzotriazole-1-bis (trimethylamino) phosphine-hexafluorophosphate (3.96 g,8.95 mmol), dimethyl sulfoxide (6 mL), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (2 g,13.14 mmol) were sequentially added, and the reaction solution was warmed to 40℃for 2 hours. Ethyl acetate (100 mL) and saturated brine (50 mL) were added to extract, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: a system) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-fluoro-2-methyl-6-nitroquinazolin-4-amine 1d (600 mg), yield: 34%.
MS m/z(ESI):395.1[M+1] +
Third step
4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-nitroquinazolin-7-yl)morpholine-3-carboxylic acid
4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-nitroquinazolin-7-yl) morpholine-3-carboxylic acid
In a 50mL two-necked flask, R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-fluoro-2-methyl-6-nitroquinazolin-4-amine 1d (280 mg,0.71 mmol), morpholine-3-carboxylic acid methyl ester 1e (206 mg,1.42 mmol), potassium tert-butoxide (239 mg,2.13 mmol) and dimethyl sulfoxide (3 mL) were sequentially added, the mixture was replaced with nitrogen three times, and the reaction mixture was heated to 60℃and stirred for 16 hours. The reaction solution was cooled to room temperature, saturated brine (20 mL) was added, extraction was performed with a mixed solvent of dichloromethane and methanol (30 mL, v: v=10:1), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1f (242 mg, yield: 67%) of 4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-nitroquinazolin-7-yl) morpholine-3-carboxylic acid.
MS m/z(ESI):506.2[M+1] + 。
Fourth step
methyl 4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-nitroquinazolin-7-yl)morpholine-3-carboxylate
4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-nitroquinazolin-7-yl) morpholine-3-carboxylic acid methyl ester
In a 50mL single-necked flask, 4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-nitroquinazolin-7-yl) morpholine-3-carboxylic acid 1f (242 mg,0.49 mmol), methanol (10 mL) and thionyl chloride (5 mL) were added sequentially, and the mixture was heated to 85℃and stirred for 6 hours. The reaction solution was concentrated under reduced pressure, most of the solvent was removed by spin-drying, saturated brine (20 mL) was added, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: A system) to give methyl 4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-nitroquinazolin-7-yl) morpholine-3-carboxylate 1g (125 mg), yield: 49%.
MS m/z(ESI):520.2[M+1] +
Fifth step
8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-1,2,4,4a-tetrahydro-[1,4]oxazino[4',3':4,5]pyrazino[2,3-g]quinazolin-5(6H)-one
8- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,4 a-tetrahydro- [1,4] oxazino [4',3':4,5] pyrazino [2,3-g ] quinazolin-5 (6H) -one
In a 25mL single-necked flask, 1g (125 mg,0.23 mmol) of methyl 4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-nitroquinazolin-7-yl) morpholine-3-carboxylate, ethanol (5 mL) and iron powder (41.6 mg, 0) were sequentially added.92 mmol) and concentrated hydrochloric acid (0.2 mL), and stirred at 100deg.C for 2 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (30 mL) and water (20 mL) were added, the pH was adjusted to be alkaline by adding a saturated solution of sodium hydrogencarbonate, the mixture was filtered through celite, the filtrate was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,4 a-tetrahydro- [1, 4)]Oxazino [4',3':4,5]Pyrazino [2,3-g]Quinazolin-5 (6H) -one 1H (63 mg), yield: 60%. MS m/z (ESI) 458.2[ M+1 ]] +
Sixth step
8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,10-dimethyl-1,2,4,4a-tetrahydro-[1,4]oxazino[4',3':4,5]pyrazino[2,3-g]quinazolin-5(6H)-one
8- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6, 10-dimethyl-1, 2,4 a-tetrahydro- [1,4] oxazino [4',3':4,5] pyrazino [2,3-g ] quinazolin-5 (6H) -one
In a 25mL single vial, 8- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,4 a-tetrahydro- [1,4] oxazino [4',3':4,5] pyrazino [2,3-g ] quinazolin-5 (6H) -one was added for 1H (30 mg,0.066 mmol) and 18mg potassium carbonate (18 mg,0.132 mmol), acetonitrile (15 mL) and methyl iodide (0.1 mL) were added and stirred at room temperature for 6H. The reaction solution was concentrated under reduced pressure, methylene chloride (30 mL) and saturated brine (20 mL) were added, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by thin layer chromatography (developing solvent: C system) to give 8- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6, 10-dimethyl-1, 2,4 a-tetrahydro- [1,4] oxazino [4',3':4,5] pyrazino [2,3-g ] quinazolin-5 (6H) -one 1 (3.8 mg), yield: 12%.
MS m/z(ESI):472.2[M+1] + 。
Biological evaluation
Test example 1, test of the Compounds of the invention blocking SOS1 binding to KRAS G12C protein
The following method was used to determine the ability of the compounds of the invention to block SOS1 interaction with KRAS G12C protein under in vitro conditions. The method uses KRAS-G12C/SOS1 BINDING ASSAY KITS kit (product number 63ADK000CB16 PEG) from Cisbio company, and the detailed experimental operation can be referred to the kit instruction.
The experimental procedure is briefly described as follows: the working fluid concentrations of Tag1-SOS1 and Tag2-KRAS-G12C proteins were set to 5X using a current buffer (cat No. 62 DLBDDF) for use. Test compounds were dissolved in DMSO to prepare 10mM stock solutions, which were then diluted using a diluet 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 is added 3+ And anti-Tag2-XL665, incubated for 2 hours at room temperature; finally, the fluorescence intensities of the wells at excitation wavelengths of 304nM, at which the emission wavelengths of 620nM and 665nM are measured in the TF-FRET mode using an enzyme-labeled instrument, and the fluorescence intensity ratio of 665/620 is calculated for each well. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% dmso) and nonlinear regression analysis was performed by GraphPad Prism 5 software with the test compound concentration log-inhibition to obtain compound IC 50 The values are shown in Table 1.
TABLE 1 IC of the inhibition of SOS1 and KRAS G12C protein interactions by the compounds of the present invention 50 Value of
Numbering of compounds IC 50
1 27.8nM
Conclusion: the compound has a strong blocking effect on the interaction of SOS1 and KRAS G12C protein.
Test example 2 measurement of inhibition of OCI-AML5 cell proliferation by Compounds of the invention
The following methods were used to determine the effect of the compounds of the invention on the proliferation of OCI-AML5 cells. OCI-AML5 cells (containing the SOS 1N 233Y mutation) were purchased from Nanjac, bai Biotechnology, inc. and cultured in MEM alpha medium containing 10% fetal bovine serum, 100U penicillin and 100. Mu.g/mL streptomycin. Cell viability by
Figure BDA0003757267550000181
Luminescent Cell Viability Assay kit (Promega, cat# G7573).
The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows: test compounds were first prepared as 10mM stock solutions in DMSO, then diluted with medium to prepare test samples with final concentrations ranging from 10000nM to 0.15nM. Cells in the logarithmic growth phase were seeded at a density of 1000 cells per well in 96-well cell culture plates at 37℃with 5% CO 2 The culture was continued overnight in the incubator, followed by the addition of the test compound and continued for 120 hours. After the incubation was completed, a 50uL volume of CellTiter-Glo assay was added to each well, and after shaking for 5 minutes, the wells were allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), followed by nonlinear regression analysis of the compound concentration log-inhibition in GraphPad Prism 5 software to obtain IC compounds that inhibited cell proliferation 50 Values, results are shown in Table 2 below.
TABLE 2 IC of the compounds of the invention for inhibition of OCI-AML5 cell proliferation 50 Value of
Numbering of compounds IC 50
1 71.2nM
Conclusion: the compound has better inhibition effect on the proliferation inhibition of OCI-AML5 cells.
Test example 3 determination of the inhibitory Activity of the Compounds of the invention on p-ERK1/2 in DLD-1 cells
The following methods were used to determine the p-ERK1/2 inhibitory activity of the compounds of the invention on DLD-1 cells. The method uses an Advanced phospho-ERK1/2 (Thr 202/tyr 204) kit (cat No. 64 AERPEH) from Cisbio, and the detailed experimental procedure is referred to the kit instructions. DLD-1 cells (containing KRAS G13D mutation) were purchased from Shanghai institute of life sciences cell resource center, china academy of sciences.
The experimental procedure is briefly described as follows: DLD-1 cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100U penicillin, 100. Mu.g/mL streptomycin and 1mM Sodium Pyruvate. DLD-1 cells were plated in 96-well plates at 30000 cells per well, and the medium was complete medium and cultured overnight in a 5% CO2 incubator at 37 ℃. Test compounds were dissolved in DMSO to prepare 10mM stock solution, and then diluted with RPMI 1640 basal medium, 90uL of RPMI 1640 basal medium containing the test compound at the corresponding concentration was added to each well, and the test compound was placed in a cell culture incubator for 3 hours and 40 minutes at a final concentration range of 10000nM to 0.15nM in the reaction system. Subsequently, 10uL of hEGF (available from Roche under the trade designation 11376454001) in RPMI 1640 basal medium was added to a final concentration of 5nM and incubated in an incubator for 20 minutes. Cell supernatants were discarded, cells were washed with ice-bath PBS, after which 45. Mu.l of 1 Xcell phospho/total protein lysis buffer (Advanced phospho-ERK1/2 kit component) were added to each well for lysis, and 96-well plates were placed on ice for half an hour, followed by detection of lysates with reference to Advanced phospho-ERK1/2 (Thr 202/tyr 204) kit instructions. Finally, fluorescence with emission wavelength of 620nM and 665nM for each well at excitation wavelength of 304nM is measured on an enzyme-labeled instrument in TF-FRET mode Light intensity, and calculate the fluorescence intensity ratio for each well 665/620. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% dmso) and nonlinear regression analysis was performed by GraphPad Prism 5 software with the test compound concentration log-inhibition to obtain compound IC 50 Values, results are shown in Table 3 below.
TABLE 3 IC for inhibition of ERK phosphorylation of DLD-1 cells by the compounds of the invention 50 Value of
Numbering of compounds IC 50
1 90nM
Conclusion: the compound has a good inhibition effect on the ERK phosphorylation of DLD-1 cells.

Claims (16)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure FDA0003757267540000011
wherein:
w is selected from N or CH;
v is selected from N, -CR 2 ；
L is selected from bond or-CH 2 -；
X is selected from-O-or-N (R) 3 )-；
Y is selected from-C (O) -or-CH 2 -；
Z is selected from-O-or-N (R) 5 )-；
Ring A is selected from C 6 -C 10 Aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered fused ring;
R 1 the same or different are each independently selected from hydrogen atom, halogen, cyano, amino, nitro, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 Aryl or 5-to 10-membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, alkoxy, =o, -C (O) R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH 2 NR 7 R 8 、-CH 2 NHC(O)OR 6 or-SO 2 R 6 Is substituted by a substituent of (2);
R 2 selected from fluorine atom, hydroxyl, cyano, methoxy or amino;
R 3 selected from hydrogen atoms, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or-C (O) R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl or cycloalkyl is optionally further substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C 1 -C 3 Alkoxy, C 1 -C 3 Hydroxyalkyl, 4-11 membered heterocyclyl; wherein said 4-11 membered heterocyclyl is optionally further C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, alkoxy, =o, -C (O) R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH 2 NR 7 R 8 、-CH 2 NHC(O)OR 6 or-SO 2 R 6 Is substituted by a substituent of (2);
R 4 selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-10 membered heterocyclyl; wherein said alkyl, cycloalkyl or heterocyclyl is optionally further substituted with one or more R A Substitution;
R A each independently selected from halogen, cyano, hydroxy, amino, C 1 -C 3 Alkoxy, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Haloalkyl or 4-11 membered heterocyclyl; wherein said 4-11 membered heterocyclyl is optionally further C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, alkoxy, =o, -C (O) R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH 2 NR 7 R 8 、-CH 2 NHC(O)OR 6 or-SO 2 R 6 Is substituted by a substituent of (2);
R 5 selected from hydrogen atoms, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl; wherein said alkyl or cycloalkyl is optionally further substituted with one or more groups selected from halogen, cyano, hydroxy, amino, C 1 -C 3 Alkoxy or C 1 -C 3 Substituted by a substituent of hydroxyalkyl;
R 6 Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl group, heterocyclic group, aryl group, heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
R 7 and R is 8 Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and aryl,Heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
alternatively, R 7 And R is 8 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, where the 4-8 membered heterocyclic group contains one or more N, O, S or SO 2 And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or-NR 10 C(O)R 11 Is substituted by a substituent of (2);
R 9 、R 10 and R is 11 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
m is 1, 2 or 3.
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):
Figure FDA0003757267540000021
wherein ring A, R 1 The definitions of W, X, Y, Z, L and m are as defined in claim 1.
3. A compound of formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula ((III):
Figure FDA0003757267540000031
wherein ring A, R 1 、R 2 The definitions of W, X, Y, Z, L and m are as defined in claim 1.
4. The compound represented by the general formula (II) according to claim 2, which is a compound represented by the general formula (II-1), (II-2), (II-3) or (II-4), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure FDA0003757267540000032
Wherein: ring A, R 1 、R 5 The definitions of W, X and m are as defined in claim 2.
5. A compound of the general formula (III) according to claim 3, which is a compound of the general formula (III-1), (III-2), (III-3) or (III-4), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure FDA0003757267540000033
wherein: ring A, R 1 、R 2 、R 5 The definitions of W, X and m are as defined in claim 3.
6. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Figure FDA0003757267540000034
Selected from the following structures:
Figure FDA0003757267540000041
wherein: r is R 1 And m is as defined in claim 1.
7. The compound according to claim 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Figure FDA0003757267540000042
Selected from the following structures:
Figure FDA0003757267540000043
8. a compound according to any one of claims 1-6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is-O-.
9. A compound according to any one of claims 1-6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
x is selected from-N (R) 3 )-；
R 3 Selected from-C (O) R 4 ；
R 4 Is defined as in claim 1.
10. A compound according to claim 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from methyl or cyclopropyl.
11. A compound according to claim 4 or 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 5 Is methyl.
12. A compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
Figure FDA0003757267540000044
/>
Figure FDA0003757267540000051
13. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
14. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of a SOS1 inhibitor.
15. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, 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.
16. The use according to claim 15, 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.
CN202210874683.8A 2021-07-23 2022-07-21 Pyrimidine ring derivatives, preparation method and medical application thereof Pending CN116041369A (en)

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