WO2023030216A1 - 喹唑啉类衍生物、或其制备方法和用途 - Google Patents

喹唑啉类衍生物、或其制备方法和用途 Download PDF

Info

Publication number
WO2023030216A1
WO2023030216A1 PCT/CN2022/115379 CN2022115379W WO2023030216A1 WO 2023030216 A1 WO2023030216 A1 WO 2023030216A1 CN 2022115379 W CN2022115379 W CN 2022115379W WO 2023030216 A1 WO2023030216 A1 WO 2023030216A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
alkyl
cycloalkyl
cyano
alkoxy
Prior art date
Application number
PCT/CN2022/115379
Other languages
English (en)
French (fr)
Inventor
张盼盼
程超英
何智鹏
林承才
邵林江
叶成
钱文建
陈磊
Original Assignee
浙江海正药业股份有限公司
上海昂睿医药技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江海正药业股份有限公司, 上海昂睿医药技术有限公司 filed Critical 浙江海正药业股份有限公司
Priority to CN202280057101.5A priority Critical patent/CN117940411A/zh
Publication of WO2023030216A1 publication Critical patent/WO2023030216A1/zh

Links

Images

Classifications

    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to a substituted quinazoline derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as an SOS1 inhibitor.
  • RAS genes are widely found in various eukaryotic organisms such as mammals, fruit flies, fungi, nematodes and yeasts, and have important physiological functions in various life systems.
  • the mammalian RAS gene family has three members, namely H- RAS, K-RAS and N-RAS, each RAS gene has a similar structure, and all of them are composed of four exons, which are distributed on the DNA with a total length of about 30 kb.
  • Their encoded products are monomeric globular proteins with a relative molecular mass of 21kDa.
  • the activation and inactivation state of RAS protein has a significant impact on the life processes such as cell growth, differentiation, proliferation and apoptosis.
  • This protein is a membrane-bound guanine nucleotide-binding protein with weak GTPase activity and regulates RAS through GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities
  • GAPs GTPase-activating proteins
  • GEFs guanine nucleotide exchange factors
  • the active state when the RAS protein combines with GTP to form RAS-GTP, it is the active state, and the GTPase activating protein can dephosphorylate RAS-GTP into RAS-GDP, and then inactivate it; the inactivated RAS-GDP is in the guanine Under the action of nucleotide exchange factors, it is transformed into active RAS-GTP, thereby activating a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR.
  • the RAS gene is also closely related to various human diseases, especially in cancer.
  • RAS is a frequently mutated oncogene, and the KRAS subtype gene mutation accounts for 86% of the total number of RAS gene mutations, and about 90% of pancreatic cancers. 30%-40% of colon cancer and 15-20% of lung cancer have different degrees of KRAS gene mutation.
  • this target has always been the focus of drug research and development workers. Since the announcement of the clinical results of AMG-510, which directly acts on the KRAS-G12C target, research on KRAS inhibitors has set off a wave of upsurge at home and abroad.
  • SOS Seon of sevenless homolog
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • the hSOS1 protein is 150kDa in size and is a multi-structural protein domain consisting of 1333 amino acids, including an N-terminal protein domain (HD), multiple homology domains, a helical linker (HL), a RAS exchange sequence (REM) and a rich Proline C-terminal domain.
  • HD N-terminal protein domain
  • HL helical linker
  • REM RAS exchange sequence
  • RAS protein on hSOS1 There are two binding sites for RAS protein on hSOS1, namely the catalytic site and the allosteric site.
  • the catalytic site binds to the RAS protein on the RAS-GDP complex to promote the exchange of guanine nucleotides
  • the allosteric site binds
  • the RAS protein on the RAS-GTP complex further enhances the catalytic effect, and then participates in and activates the signal transduction of RAS family proteins.
  • Studies have shown that inhibition of SOS1 can not only completely inhibit the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also lead to a 50% reduction in phospho-ERK activity in mutant KRAS cell lines.
  • the inhibition of SOS1 can also reduce the activity of RAS, thereby treating various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, non-small cell lung cancer, etc.
  • SOS1 alterations in SOS1 have also been implicated in cancer.
  • inherited SOS1 mutations have also been implicated in the pathogenesis of RAS disorders such as Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and hereditary gingival fibroma type I. .
  • SOS1 is also a GEF for activation of the GTPase RAC1 (Ras-associated C3 botulinum toxin substrate 1). Like RAS family proteins, RAC1 has been implicated in the pathogenesis of a variety of human cancers and other diseases.
  • the present invention provides a kind of substituted quinazoline compound shown in a kind of general formula (I) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
  • R a is cyano, -C(O)R 3 or C 1 -C 6 alkoxy.
  • R 1 are the same or different, each independently halogen, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein said alkyl or alkoxy is optionally further replaced by one or more Substituents selected from halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; R 1 is preferably C 1 -C 6 alkyl; more preferably methyl base;
  • R 2 is C 3 -C 6 cycloalkyl, 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered fused heterocyclic group or 6 -11-membered fused ring; wherein said cycloalkyl, monocyclic heterocyclyl, spiroheterocyclyl, bridging heterocyclyl, fused heterocyclyl or fused ring is optionally further substituted by one or more RA ;
  • RA are each independently halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-8 membered hetero Cyclic group, -C(O)R 3 or -SO 2 R 4 , wherein the alkyl, alkoxy or cycloalkyl is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl , amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 substituents; the heterocyclic group is optionally further One or more selected from halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, -C (O)R 3 and -
  • R 3 are each independently C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, -NR 5 R 6 or 3-6 membered heterocyclyl, wherein said Alkyl or cycloalkyl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 Substituents of haloalkyl and C 1 -C 6 haloalkoxy; the heterocyclic group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, cyano, oxo, C Substituents of 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy;
  • Each R 4 is independently amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 5 and R 6 are each independently a hydrogen atom or a C 1 -C 6 alkyl group, wherein the alkyl group is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano and C 1 -C 6 alkoxy substituents are substituted;
  • R 5 , R 6 and the connected N atom form a 4-10 membered heterocyclic ring, and the formed heterocyclic ring is optionally further selected from halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 Substituents of alkyl, C 1 -C 6 alkoxy, -C(O)R 7 and C 3 -C 6 cycloalkyl;
  • R 7 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano and C 1 -C 6 alkoxy substituents are substituted;
  • n 0, 1, 2, 3 or 4.
  • the compound represented by the general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof which is the general formula (II)
  • R is cyano, acetyl or methoxy
  • Ring B is C 3 -C 6 cycloalkyl, 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered condensed heterocyclic group or 6 -11-membered fused ring;
  • RA are each independently halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-8 membered hetero Cyclic group, -C(O)R 3 or -SO 2 R 4 , wherein the alkyl, alkoxy or cycloalkyl is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl , amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 substituents; the heterocyclic group is optionally further One or more selected from halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, -C (O)R 3 and -
  • R 3 is C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, -NR 5 R 6 or 3-6 membered heterocyclic group; wherein said alkyl or Cycloalkyl is optionally further substituted by one or more substituents selected from halogen, cyano and C 1 -C 6 alkyl; said heterocyclic group is optionally further substituted by one or more selected from halogen, cyano Substituents of radicals, oxo groups and C 1 -C 6 alkyl groups;
  • Each R 4 is independently amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 5 and R 6 are each independently a hydrogen atom or a C 1 -C 6 alkyl group, wherein the alkyl group is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano and C 1 -C 6 alkoxy substituents are substituted;
  • R 5 , R 6 and the connected N atom form a 4-10 membered heterocyclic ring, and the formed heterocyclic ring is optionally further selected from halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 Substituents of alkyl, C 1 -C 6 alkoxy, -C(O)R 7 and C 3 -C 6 cycloalkyl;
  • R 7 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano and C 1 -C 6 alkoxy substituents are substituted;
  • n 0, 1, 2 or 3.
  • ring B is the following group group:
  • the R1 is methyl
  • the Said R a is methoxy
  • the Said R a is acetyl
  • the compound described in general formula (I) is:
  • One or more embodiments of the present application provide compounds represented by general formula (I') or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R 1 are the same or different, each independently halogen, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein said alkyl or alkoxy is optionally further replaced by one or more Substituents selected from halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; R 1 is preferably C 1 -C 6 alkyl; more preferably methyl base;
  • R is 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered fused heterocyclic group or 6-11 membered fused ring; wherein The monocyclic heterocyclic group, spiro heterocyclic group, bridged heterocyclic group, fused heterocyclic group or fused ring are optionally further substituted by one or more RA ;
  • R A is each independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl or -C(O) R 3 , wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl, amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy substituents;
  • R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl is optionally further replaced by one or more selected from hydroxy, halogen, nitro, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy Substituents are substituted;
  • n 0, 1, 2, 3 or 4;
  • One or more embodiments of the present application provide compounds represented by general formula (II') or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring B is a 3-6 membered monocyclic heterocyclic group, a 6-11 membered spiro heterocyclic group, a 6-11 membered bridged heterocyclic group, a 6-11 membered fused heterocyclic group or a 6-11 membered fused ring;
  • R A is each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, 3-6 membered heterocyclyl or -C(O)R 3 ;
  • R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl; wherein said alkyl, cycloalkyl or heterocyclyl is optionally further replaced by one or more Substituents selected from halogen, cyano and C 1 -C 6 alkyl;
  • n 0, 1, 2 or 3.
  • One or more embodiments of the present application provide the compound shown in (I") or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R a is cyano or C 1 -C 6 alkoxy
  • R 1 are the same or different, each independently halogen, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein said alkyl or alkoxy is optionally further replaced by one or more Substituents selected from halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; R 1 is preferably C 1 -C 6 alkyl; more preferably methyl base;
  • R is 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered fused heterocyclic group or 6-11 membered fused ring; wherein The monocyclic heterocyclic group, spiro heterocyclic group, bridged heterocyclic group, fused heterocyclic group or fused ring are optionally further substituted by one or more RA ;
  • R A is each independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl or -C(O) R 3 , wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl, amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy substituents;
  • R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl is optionally further replaced by one or more selected from hydroxy, halogen, nitro, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy Substituents are substituted;
  • n 0, 1, 2, 3 or 4.
  • One or more embodiments of the present application provide compounds represented by general formula (II") or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R a is cyano or methoxy
  • Ring B is a 3-6 membered monocyclic heterocyclic group, a 6-11 membered spiro heterocyclic group, a 6-11 membered bridged heterocyclic group, a 6-11 membered fused heterocyclic group or a 6-11 membered fused ring;
  • R A is each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, 3-6 membered heterocyclyl or -C(O)R 3 ;
  • R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl; wherein said alkyl, cycloalkyl or heterocyclyl is optionally further replaced by one or more Substituents selected from halogen, cyano and C 1 -C 6 alkyl;
  • n 0, 1, 2 or 3.
  • One or more embodiments of the present application provide compounds represented by general formula (I"') or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R a is cyano, -C(O)R 3 or C 1 -C 6 alkoxy
  • R 1 are the same or different, each independently halogen, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein said alkyl or alkoxy is optionally further replaced by one or more Substituents selected from halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; R 1 is preferably C 1 -C 6 alkyl; more preferably methyl base;
  • R 2 is C 3 -C 6 cycloalkyl, 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered fused heterocyclic group or 6 -11-membered fused ring; wherein said cycloalkyl, monocyclic heterocyclyl, spiroheterocyclyl, bridging heterocyclyl, fused heterocyclyl or fused ring is optionally further substituted by one or more RA ;
  • RA are each independently halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-8 membered hetero Cyclic group, -C(O)R 3 or -SO 2 R 4 , wherein the alkyl, alkoxy or cycloalkyl is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl , amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 substituents; the heterocyclic group is optionally further One or more selected from halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 is replaced by a
  • R 3 are each independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -NR 5 R 6 or 3-6 membered heterocyclyl, wherein the alkyl or cycloalkyl is optionally further By one or more selected from hydroxyl, halogen, nitro, amino, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy substituents are substituted; the heterocyclic group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, hydroxyl, cyano, oxo, C 1 -C 6 alkane Substituents of radical, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy;
  • Each R 4 is independently amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 5 and R 6 are each independently a hydrogen atom or a C 1 -C 6 alkyl group
  • R 5 , R 6 and the connected N atom form a 4-6 membered heterocyclic ring, and the formed heterocyclic ring is optionally further selected from halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 Substituents of alkyl, C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl;
  • n 0, 1, 2, 3 or 4.
  • One or more embodiments of the present application provide a compound represented by general formula (II"') or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R is cyano, acetyl or methoxy
  • Ring B is C 3 -C 6 cycloalkyl, 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered condensed heterocyclic group or 6 -11-membered fused ring;
  • RA are each independently halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-8 membered hetero Cyclic group, -C(O)R 3 or -SO 2 R 4 , wherein the alkyl, alkoxy or cycloalkyl is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl , amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 substituents; the heterocyclic group is optionally further One or more selected from halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 is replaced by a
  • R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -NR 5 R 6 or 3-6 membered heterocyclic group; wherein said alkyl or cycloalkyl is optionally further replaced by one or A plurality of substituents selected from halogen, cyano and C 1 -C 6 alkyl are substituted; the heterocyclic group is optionally further substituted by one or more selected from halogen, cyano, oxo and C 1 - Substituents of C 6 alkyl are substituted;
  • Each R 4 is independently amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 5 and R 6 are each independently a hydrogen atom or a C 1 -C 6 alkyl group
  • R 5 , R 6 and the connected N atom form a 4-6 membered heterocyclic ring, and the formed heterocyclic ring is optionally further selected from halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 Substituents of alkyl, C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl;
  • n 0, 1, 2 or 3.
  • One or more embodiments of the present application provide compounds represented by general formula (I"") or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R a is cyano, -C(O)R 3 or C 1 -C 6 alkoxy
  • R 1 are the same or different, each independently halogen, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein said alkyl or alkoxy is optionally further replaced by one or more Substituents selected from halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; R 1 is preferably C 1 -C 6 alkyl; more preferably methyl base;
  • R 2 is C 3 -C 6 cycloalkyl, 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered fused heterocyclic group or 6 -11-membered fused ring; wherein said cycloalkyl, monocyclic heterocyclyl, spiroheterocyclyl, bridging heterocyclyl, fused heterocyclyl or fused ring is optionally further substituted by one or more RA ;
  • RA are each independently halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-8 membered hetero Cyclic group, -C(O)R 3 or -SO 2 R 4 , wherein the alkyl, alkoxy or cycloalkyl is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl , amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 substituents; the heterocyclic group is optionally further One or more selected from halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 is replaced by a
  • R 3 are each independently C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, -NR 5 R 6 or 3-6 membered heterocyclyl, wherein said Alkyl or cycloalkyl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 Substituents of haloalkyl and C 1 -C 6 haloalkoxy; the heterocyclic group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, hydroxyl, cyano, oxo , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy are substituted by substituents;
  • Each R 4 is independently amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 5 and R 6 are each independently a hydrogen atom or a C 1 -C 6 alkyl group, wherein the alkyl group is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano, and C 1 - Substituents of C 6 alkoxy;
  • R 5 , R 6 and the connected N atom form a 4-10 membered heterocyclic ring, and the formed heterocyclic ring is optionally further selected from halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 Substituents of alkyl, C 1 -C 6 alkoxy, -C(O)R 7 and C 3 -C 6 cycloalkyl;
  • R 7 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano, and C 1 -C 6 alkoxy substituents are substituted;
  • n 0, 1, 2, 3 or 4.
  • One or more embodiments of the present application provide compounds represented by general formula (II"") or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R is cyano, acetyl or methoxy
  • Ring B is C 3 -C 6 cycloalkyl, 3-6 membered monocyclic heterocyclic group, 6-11 membered spiro heterocyclic group, 6-11 membered bridged heterocyclic group, 6-11 membered condensed heterocyclic group or 6 -11-membered fused ring;
  • RA are each independently halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-8 membered hetero Cyclic group, -C(O)R 3 or -SO 2 R 4 , wherein the alkyl, alkoxy or cycloalkyl is optionally further replaced by one or more selected from halogen, nitro, cyano, hydroxyl , amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 substituents; the heterocyclic group is optionally further One or more selected from halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and -SO 2 R 4 is replaced by a
  • R 3 is C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, -NR 5 R 6 or 3-6 membered heterocyclic group; wherein said alkyl or Cycloalkyl is optionally further substituted by one or more substituents selected from halogen, cyano and C 1 -C 6 alkyl; said heterocyclic group is optionally further substituted by one or more selected from halogen, cyano Substituents of radicals, oxo groups and C 1 -C 6 alkyl groups;
  • Each R 4 is independently amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 5 and R 6 are each independently a hydrogen atom or a C 1 -C 6 alkyl group, wherein the alkyl group is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano, and C 1 - Substituents of C 6 alkoxy;
  • R 5 , R 6 and the connected N atom form a 4-10 membered heterocyclic ring, and the formed heterocyclic ring is optionally further selected from halogen, cyano, hydroxyl, amino, oxo, C 1 -C 6 Substituents of alkyl, C 1 -C 6 alkoxy, -C(O)R 7 or C 3 -C 6 cycloalkyl;
  • R 7 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from one or more groups selected from hydroxyl, halogen, amino, cyano, and C 1 -C 6 alkoxy substituents are substituted;
  • n 0, 1, 2 or 3.
  • the present invention provides a pharmaceutical composition, which contains an effective dose of the general formula (I), (II), (I'), (II'), (I"), (II” ), (I"'), (II"'), (I"") or (II"”), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and Pharmaceutically acceptable carrier, excipient or their combination.
  • the present invention provides a general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I” ”) or (II””) described compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the purposes of its pharmaceutical composition in the preparation of SOS1 inhibitor.
  • the present invention also provides a general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I "”) or (II””) described compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in preparation for the treatment of diseases mediated by SOS1
  • the disease mediated by SOS1 is preferably RAS family protein signaling pathway-dependent cancer, cancer caused by SOS1 mutation or hereditary disease caused by SOS1 mutation; wherein the disease mediated by SOS1
  • the leading diseases are preferably lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, Noonan syndrome, cardiofacial skin syndrome, type I genetic Gingival fibroma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, or cutaneous granulos
  • the present invention further provides a general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I "") or (II”") described compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition is used in the preparation for the treatment of RAS family protein signaling pathway dependence Use in drugs for sex-related cancers, cancers caused by SOS1 mutations, or hereditary diseases caused by SOS1 mutations.
  • the present invention provides a general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I” ") or (II”") described compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition is used in the preparation for the treatment of lung cancer, pancreatic cancer, colon cancer, Bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, Noonan syndrome, cardiofacial skin syndrome, hereditary gingival fibroma type I, embryonal rhabdomyosarcoma, Selto Use in medicine for leukocyte testicular tumor or cutaneous granulosa cell tumor.
  • the present invention also provides a composition
  • a composition comprising the above general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II "'), (I”") or (II”") the compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, and other drugs, so
  • the other drugs mentioned above are preferably selected from inhibitors of KRAS G12C.
  • the present invention also provides general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I”" ) or (II"") or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is used as a medicament.
  • the present invention also provides general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I”" ) or (II""), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is used as an SOS1 inhibitor.
  • the present invention also provides general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I”" ) or (II"”) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is used for the prevention and/or treatment of SOS1-mediated Disease, wherein the disease mediated by SOS1 is preferably RAS family protein signaling pathway-dependent cancer, cancer caused by SOS1 mutation or hereditary disease caused by SOS1 mutation; wherein the disease mediated by SOS1 Lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, Noonan syndrome, cardiofacial skin syndrome, hereditary gingival fiber type I tumor, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, or cutaneous granul
  • the present invention also provides general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I”" ) or (II"") described compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition, it is used for preventing and/or treating RAS family protein signaling Pathway-dependent cancers, cancers caused by SOS1 mutations, or genetic disorders caused by SOS1 mutations.
  • the present invention also provides general formula (I), (II), (I'), (II'), (I"), (II"), (I"'), (II"'), (I”” ) or (II"”) the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition, which is used for the prevention and/or treatment of lung cancer, pancreatic cancer, Colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, Noonan syndrome, cardiofacial skin syndrome, hereditary gingival fibroma type I, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor or granulosa cell tumor of the skin.
  • lung cancer pancreatic cancer, Colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, Noonan syndrome, cardiofacial skin
  • the present invention also provides a method for preventing and/or treating cancer, which comprises administering the general formula (I), (II), (I'), (II'), (I"), (II") to a subject in need , (I"'), (II"'), (I"") or (II"") described compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition.
  • the present invention also provides a method for inhibiting SOS1 in a subject, comprising administering general formula (I), (II), (I'), (II'), (I"), (II"), ( Compounds described in I"'), (II"'), (I"") or (II"”) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical combinations thereof things.
  • Alkyl when taken as a group or a part of a group means to include C 1 -C 20 straight chain or branched aliphatic hydrocarbon groups (including for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). It is preferably C 1 -C 10 alkyl, more preferably C 1 -C 6 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait.
  • Alkyl groups can be substituted or unsubstituted.
  • Alkenyl means 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 ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl etc. (including for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C 2 -C 10 alkynyl, more preferably C 2 -C 6 alkynyl, most preferably C 2 -C 4 alkynyl (comprising e.g. 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). 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 can be substituted or unsubstituted.
  • Cycloalkyl means saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings (containing, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 carbon atom). It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. Cycloalkyl groups can be substituted or unsubstituted.
  • “Spirocycloalkyl” means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), two or more rings A polycyclic group with a carbon-like structure, and the single rings share a carbon atom (called a spiro atom) with each other.
  • the ring may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron aromatic system .
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.
  • spirocycloalkyl include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two or more An all-carbon polycyclic group in which the ring structures share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl 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 tetrahydrophenanthrenyl.
  • “Bridged cycloalkyl” refers to 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two or more A ring structure, an all-carbon polycyclic group that shares two carbon atoms that are not directly attached to each other, an aromatic system in which one or more rings may contain one or more double bonds, but none of the rings has fully conjugated ⁇ -electrons , preferably 6 to 12 yuan, more preferably 7 to 10 yuan.
  • the number of rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, bicyclo[2.2.1]heptyl or adamantyl.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more (eg 1, 2, 3 or 4)
  • the atoms forming the ring are heteroatoms, such as oxygen, nitrogen, sulfur, phosphorus atoms, etc., including monocyclic rings, polycyclic rings, condensed rings, bridged rings and spiro rings.
  • bicyclic or tricyclic ring which may contain 1, 2 or 3 members selected from nitrogen, oxygen, A heteroatom of P(O) n or S(O) n (wherein n is selected from 0, 1 or 2).
  • Examples of “monocyclic heterocyclyl” include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, Linyl, piperidinyl, pyrrolidinyl, piperazinyl, hexahydropyrimidinyl,
  • Monocyclic heterocyclyl groups may be substituted or unsubstituted.
  • “Spiroheterocyclyl” means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), two or more rings like structure, and the single rings share one atom with each other, the ring may contain 1 or more double bonds, but none of the rings has a fully conjugated ⁇ -electron aromatic system, one or more of which (e.g. 1, 2, 3, 4) ring atoms selected from nitrogen, oxygen, P(O) n or S(O) n (where n is selected from 0, 1 or 2) heteroatoms, the remaining ring atoms being carbon .
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxo Spiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,
  • a spiroheterocyclyl can be substituted or unsubstituted.
  • “Fused heterocyclic group” refers to a polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has complete conjugation
  • the aromatic system of the ⁇ electron wherein one or more (eg 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen, P (O) n or S (O) n (wherein n is selected from 0, 1 or 2), the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 6, 7, 8, 9, 10, 11, 12, 13, 14 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • 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]dioxine,
  • “Bridged heterocyclic group” means 5 to 14 members, 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two A polycyclic group of one or more ring structures sharing two atoms not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has fully conjugated ⁇ electrons
  • the aromatic system of wherein one or more (for example 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen, P (O) n or S (O) n (wherein n is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, cyclo[3.3.2]decyl,
  • Bridged heterocyclyl groups can be substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably naphthyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered (e.g. 8, 9, 10 membered) bicyclic ring, which may contain 1 to 4 (e.g. 1, 2, 3, 4) optional from nitrogen, oxygen and/or sulfur atoms. Bicyclic heteroaryl is preferred.
  • heteroaryl examples 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-thiazolyl Adiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl , Indazolyl, Benzisothiazolyl, Benzoxazolyl, Benzisoxazolyl,
  • Heteroaryl groups can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring does not have complete conjugation
  • the ⁇ -electron aromatic system wherein the ring atoms are selected from 0, one or more (for example, 1, 2, 3, 4) selected from nitrogen, oxygen, P (O) n or S (O) r (where r heteroatoms selected from 0, 1 or 2), the remaining ring atoms being carbon.
  • the fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. It is preferably 7 to 14 yuan (for example, 7, 8, 9, 10, 11, 12, 13, 14 yuan), more preferably 8 to 10 yuan. Examples of "fused rings” include, but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Acyl refers to the monovalent atomic group left after the hydroxyl group is removed from an organic or inorganic oxyacid, preferably C 1 -C 6 alkyl-C(O)-alkyl, C 3 -C 6 cycloalkyl-C(O) )-. Examples include, but are not limited to, formyl, acetyl, n-propanoyl, isopropanoyl, cyclopropanoyl, cyclobutanoyl, and the like.
  • Hydroalkyl refers to a hydroxy-substituted alkyl group.
  • Haloalkyl means an alkyl group substituted with a halogen.
  • Haldroxy means an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl means -CH2 -phenyl.
  • DMSO dimethylsulfoxide
  • HATU refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • Carter condensing agent refers to benzotriazole-1-bis(trimethylamino)phosphine-hexafluorophosphate.
  • leaving group an atom or functional group that is separated from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution reactions and elimination reactions.
  • the reactant attacked by the nucleophile is called the substrate, and the atom or atomic group that breaks off with a pair of electrons from the substrate molecule is called the leaving group.
  • Groups that are easy to accept electrons and have strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules.
  • Common leaving groups include, but are not limited to, halogens, methanesulfonyl, -OTs, or -OH.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • substitution or “substituted” in this specification, unless otherwise specified, means that a group can be substituted by one or more substituents.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • R 8' , R 9' and R 10' 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, Heterocyclyl, aryl or heteroaryl is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituents of heteroaryl, carboxyl or carboxylate;
  • r 0, 1 or 2.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (conformational) isomers and Mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
  • structures depicted herein also include all isomeric (eg, diastereoisomers, 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.
  • isomeric e.g. diastereoisomers, enantiomers, and atropisomers
  • 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.
  • the individual stereoisomers of the compounds of the present invention and the pair Mixtures of enantiomers, diastereoisomers and geometric (conformational) isomers are within the scope of the present invention.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the preparation method of the compound described in general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • General formula (IA) compound and general formula (IB) compound carry out condensation reaction, obtain general formula (IC) compound, general formula (IC) compound and R 2 -H carry out Buckward coupling reaction, optionally carry out further deprotection group and Amino substitution reaction, obtains the compound of general formula (I);
  • X is a leaving group, preferably a hydroxyl group
  • X is a leaving group, preferably halogen, more preferably bromine
  • R 1 , R 2 , R a and m are as described in the general formula (I).
  • Fig. 1 shows the change of tumor volume of mice in each group in the NCI-H2122 model of the compound of the present invention.
  • the mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD deuterated methanol.
  • the nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 L.
  • the solution in the reaction refers to an aqueous solution.
  • the system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C : Dichloromethane and ethyl acetate system, D: Dichloromethane and ethanol system, wherein the volume ratio of the solvent varies according to the polarity of the compound, and can also be carried out by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethyl ether Amines etc.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and methanol system
  • C Dichloromethane and ethyl acetate system
  • D Dichloromethane and ethanol system
  • the volume ratio of the solvent varies according to the polarity of the compound, and can also be carried out by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethyl ether Amines etc.
  • 6-bromo-7-methoxy-2-methylquinazolin-4-ol 1h 500mg, 1.86mmol, prepared according to published patent WO 2018115380
  • (R)-3-( 1-aminoethyl)-2-methylbenzonitrile hydrochloride 1g 562.3mg, 2.42mmol
  • Carter condensing agent (1.07g, 2.42mmol
  • One-carb-7-ene (848.62mg, 5.57mmol) and N,N-dimethylformamide (5mL), stirred overnight at room temperature.
  • Test example 1 The compound of the present invention blocks the test that KRAS G12C protein combines with SOS1
  • the following method is used to determine the ability of the compound of the present invention to block the interaction between SOS1 and KRAS G12C protein under in vitro conditions.
  • This method uses the KRAS-G12C/SOS1BINDING ASSAY KITS kit (Cat. No. 63ADK000CB16PEG) from Cisbio.
  • Kit instructions for detailed experimental operations, please refer to the kit instructions.
  • the experimental procedure is briefly described as follows: use diluent buffer (product number 62DLBDDF) to prepare Tag1-SOS1 and Tag2-KRAS-G12C proteins to a working solution concentration of 5X for later use.
  • the test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with dilution buffer for use.
  • the compound of the present invention has a strong blocking effect on the interaction between KRAS G12C and SOS1 protein.
  • Test example 2 The compounds of the present invention inhibit the proliferation of OCI-AML5 cells
  • OCI-AML5 cells containing the SOS1N233Y mutation
  • MEM ⁇ medium containing 10% fetal bovine serum, 100 U penicillin and 100 ⁇ g/mL streptomycin.
  • Cell viability via CellTiter- Luminescent Cell Viability Assay Kit was used for determination.
  • test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample.
  • concentration of the compound ranges from 10000nM to 0.15nM .
  • Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, cultured overnight at 37°C in a 5% CO2 incubator, and then continued to culture for 120 hours after adding the test compound.
  • the compound of the present invention has a good inhibitory effect on the proliferation of OCI-AML5 cells.
  • Test example 3 Determination of the compounds of the present invention to p-ERK1/2 inhibitory activity in DLD-1 cells
  • the following method is used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in DLD-1 cells.
  • This method uses the Advanced phospho-ERK1/2 (Thr202/tyr204) kit (Cat. No. 64AERPEH) from Cisbio, and the detailed experimental operation can refer to the kit instruction manual.
  • DLD-1 cells (containing the KRAS G13D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • DLD-1 cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100 U penicillin, 100 ⁇ g/mL streptomycin and 1 mM Sodium Pyruvate. DLD-1 cells were plated in 96-well plates at a rate of 30,000 per well, the medium was complete medium, and cultured overnight at 37° C. in a 5% CO2 incubator.
  • test compound was dissolved in DMSO to prepare a 10mM stock solution, then diluted with RPMI 1640 basal medium, and 90uL of RPMI 1640 basal medium containing the corresponding concentration of the test compound was added to each well, and the final concentration of the test compound in the reaction system was The concentration range is 10000nM-0.15nM, and cultured in a cell incubator for 3 hours and 40 minutes. Subsequently, 10 uL of hEGF prepared with RPMI 1640 basal medium (purchased from Roche, product number 11376454001) was added to make the final concentration 5 nM, and cultured in an incubator for 20 minutes.
  • the compound of the present invention has a better inhibitory effect on ERK phosphorylation in DLD-1 cells.
  • Test example 4 The compounds of the present invention inhibit NCI-H358 cell proliferation
  • NCI-H358 cells containing KRAS G12C mutation
  • RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100 ⁇ g/mL streptomycin and 1mM Sodium Pyruvate middle.
  • Cell viability via CellTiter- 3D Cell Viability Assay kit was used for determination.
  • the experimental method is operated according to the steps of the kit instructions, which are briefly described as follows: the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample. The final concentration of the compound ranges from 10000nM to 0.15nM . Cells in the logarithmic growth phase were seeded into an ultra-low adsorption 384-well cell culture plate (PerkinElmer, #3830) at a density of 2000 cells per well, and the test compound was added and cultured for 120 hours.
  • the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample. The final concentration of the compound ranges from 10000nM to 0.15nM .
  • Cells in the logarithmic growth phase were seeded into an ultra-low adsorption 384-well cell culture plate (PerkinElmer, #3830) at a density of 2000 cells per well, and the test compound was added and culture
  • the compound of the present invention has a good inhibitory effect on the proliferation of H358 cells.
  • LC/MS/MS was used to determine the drug concentration in the plasma of ICR mice at different times after intragastric administration of the compound. Study the pharmacokinetic behavior of the compound of the present invention in ICR mice, and evaluate its pharmacokinetic characteristics.
  • ICR mice male, 27.8-38g, were purchased from Zhejiang Weitong Lihua Experimental Animal Co., Ltd.
  • ICR mice each test compound group (nine mice in each group), were intragastrically administered after overnight fasting, the dosage was 10 mg/kg, and the administration volume was 10 mL/kg. , eat 4 hours after administration.
  • 0.1 mL of blood was collected from the orbit, and placed in an EDTA-K2 anticoagulant tube. After blood samples were collected, they were placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at –40 to –20°C before analysis.
  • LC-MS/MS was used to determine the content of the compound to be tested in mouse plasma after intragastric administration.
  • the compound of the present invention has good pharmacokinetic properties in ICR mice.
  • Test example 6 Pharmacokinetic evaluation of compounds of the present invention in Balb/c mice
  • LC/MS/MS was used to determine the drug concentration in the blood plasma of balb/c mice at different times after intragastric administration of the compound. Study the pharmacokinetic behavior of this compound in Balb/c mice, and evaluate its pharmacokinetic characteristics.
  • mice Nine Balb/c normal mice, male, were equally divided into 3 groups, with 3 mice in each group, purchased from Zhejiang Weitong Lihua Experimental Animal Co., Ltd.
  • test compound group (nine rats in each group) was intragastrically administered after fasting overnight, the dosage was 10 mg/kg, and the administration volume was 10 mL/kg, and food was taken 4 hours after administration.
  • 0.1 mL of blood was collected from the jugular vein, and placed in a 0.1% heparin sodium anticoagulant test tube. Blood samples were placed on ice after collection, and plasma was separated by centrifugation (centrifugation conditions: 7000g, 5 minutes). The collected plasma was stored at –80°C until analysis.
  • LC-MS/MS was used to determine the content of the compound to be tested in mouse plasma after intragastric administration.
  • the compound of the present invention has good pharmacokinetic properties in Balb/c mice.
  • Test example 7 Pharmacokinetic evaluation of the compounds of the present invention in rats
  • the LC/MS/MS method was used to determine the compound 11 of the present invention administered intravenously or intragastrically to the rats, and the drug concentration in plasma at different times was measured to study the effect of the compound 11 of the present invention in SD rats. pharmacokinetic characteristics.
  • SD rats were divided into intravenous injection group (3 rats/group) and gavage group (3 rats/group) of the compound to be tested.
  • Intravenous injection group fast overnight and administer intravenously (administration dose 1 mg/kg, administration volume 5 mL/kg), and take food 4 hours after administration.
  • Oral gavage group intragastric administration (administration dose 10 mg/kg, administration volume 10 mL/kg) after fasting overnight, take food 4 hours after administration.
  • Intravenous injection group Collect about 150 ⁇ L of blood into EDTA-K2 anticoagulant tubes via the jugular vein at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. After the samples were collected, they were placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at –40 to –20°C before analysis.
  • Oral gavage group collect about 100 ⁇ L of blood into EDTA-K2 anticoagulant tubes via the jugular vein at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. After the samples were collected, they were placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at –40 to –20°C before analysis.
  • LC-MS/MS was used to determine the content of the compound to be tested in rat plasma after intravenous injection and gavage administration of the compound.
  • the compound of the present invention has good pharmacokinetic properties in rats.
  • Test example 8 Pharmacokinetic evaluation of the compound of the present invention in dogs
  • LC/MS/MS method was used to determine rats administered BI3406 and compound 11 of the present invention intravenously or intragastrically, and the drug concentrations in plasma at different times were measured to study the effect of compound 11 of the present invention on Beagle dogs. Pharmacokinetic profile in dogs.
  • Beagle dogs were divided into intravenous injection group (3 dogs/group) and gavage group (3 dogs/group) of the compound to be tested.
  • Intravenous injection group Fasted overnight and administered by injection (administration dose 0.5 mg/kg, administration volume 1 mL/kg), and took food 4 hours after administration.
  • Oral gavage group intragastric administration (administration dose 10 mg/kg, administration volume 2 mL/kg) after fasting overnight, and take food 4 hours after administration.
  • Intravenous injection group Collect about 0.5 mL of blood into EDTA-K2 anticoagulant tubes via the jugular vein at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. After the samples were collected, they were placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at –40 to –20°C before analysis.
  • Oral gavage group collect about 0.5 mL of blood into EDTA-K2 anticoagulant tubes via the jugular vein at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. After the samples were collected, they were placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at –40 to –20°C before analysis.
  • LC-MS/MS was used to determine the content of the compound to be tested in dog plasma after intravenous injection and intragastric administration of the compound.
  • the compound 11 of the present invention has higher plasma concentration and area under the curve in Beagle dogs at an oral dose of 2 mg/kg, and has good pharmacokinetic properties.
  • BI-3406 is prepared by WO2018115380, the specific structure is as follows:
  • Test Example 9 Pharmacodynamic evaluation of the compound of the present invention in the subcutaneous transplantation model of human lung cancer NCI-H2122 nude mice
  • mice Female, 6-7 weeks (the age of mice at the time of tumor cell inoculation). purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
  • H2122 cells were inoculated subcutaneously on the right side of the back of female Balb/c nude mice. When the average volume of the tumor reached about 150-200 mm 3 , they were randomly divided into groups according to the size of the tumor, with 6 animals in each group.
  • Group 2 intragastric administration of AMG-510, the dosage is 30mg/kg;
  • the 3rd group (G3) administered embodiment 11 by intragastric administration, the dosage is 30mg/kg;
  • AMG-510 and Example 11 were administered in combination, and the doses were: 30 mg/kg (QD) for AMG-510; 30 mg/kg (QD) for Example 11.
  • routine monitoring includes tumor growth and the effect of treatment on the normal behavior of animals.
  • the specific content includes the activity of experimental animals, food intake and drinking, weight gain or loss, eyes, coat and other abnormalities.
  • RTV relative tumor volume
  • T/C relative tumor inhibition rate
  • IR tumor inhibition percentage
  • Tumor volume TV 1/2 ⁇ a ⁇ b 2 , where a and b represent the length and width of the tumor, respectively;
  • Relative tumor volume RTV (relative tumor volume) V t /V 0 , where V 0 is the tumor volume measured during group administration (i.e. d0), and V t is the tumor volume at each measurement;
  • T/C (%) T RTV /C RTV ⁇ 100%, wherein T RTV is the RTV of the treatment group, and C RTV is the RTV of the control group;
  • TGI (%) (1-T/C) ⁇ 100%; wherein, T and C are the relative tumor volumes at a specific time point in the treatment group and the control group, respectively.
  • IR (%) (1-TWt/TWc) ⁇ 100%, where TWt is the tumor weight of the treatment group, and TWc is the tumor weight of the control group.
  • Anti-tumor evaluation criteria are (cytotoxic drugs): T/C (%)>40% is invalid; T/C (%) ⁇ 40%, and after statistical processing P ⁇ 0.05 is effective.
  • Table 11 The drug efficacy analysis table of each group in the NCI-H2122 subcutaneous xenograft model of the compound of the present invention
  • Table 12 The tumor weight and tumor weight inhibition rate of each group of animals at the end of the experiment

Abstract

本发明涉及一种取代的喹唑啉类衍生物、其制备方法及含有该衍生物的药物组合物，以及该喹唑啉类衍生物或其组合物在医药上的应用。具体而言，本发明涉及一种通式(I)所示的取代的喹唑啉类衍生物、其制备方法及其可药用的盐，以及它们作为治疗剂，特别是SOS1抑制剂的用途，其中通式(I)中的各取代基的定义与说明书中的定义相同。

Description

喹唑啉类衍生物、或其制备方法和用途 技术领域
本发明涉及一种取代的喹唑啉类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为SOS1抑制剂的用途。
背景技术
RAS基因广泛存在于各种真核生物如哺乳类、果蝇、真菌、线虫及酵母中，在各种生命体系中具有重要的生理功能，哺乳动物的RAS基因家族有三个成员，分别是H-RAS、K-RAS和N-RAS，各种RAS基因具有相似的结构，均由四个外显子组成，分布于全长约30kb的DNA上。它们的编码产物为相对分子质量21kDa的单体球状蛋白质。RAS蛋白的激活和非激活状态对细胞生长、分化、增殖和凋亡等生命进程有着重大的影响。该蛋白是一种膜结合的鸟嘌呤核苷酸结合蛋白，具有弱的GTP酶活性，在正常生理活动中，通过GTP酶活化蛋白(GAPs)和鸟嘌呤核苷酸交换因子(GEFs)调节RAS的活性状态，当RAS蛋白与GTP结合形成RAS-GTP时为激活状态，GTP酶活化蛋白可以使RAS-GTP去磷酸化转变成RAS-GDP，进而失活；失活的RAS-GDP在鸟嘌呤核苷酸交换因子作用下又转变成有活性的RAS-GTP，从而激活RAF/MER/ERK和PI3K/AKT/mTOR等一系列下游通路。
RAS基因同时也与人类的各种疾病密切相关，尤其在癌症方面，RAS是经常出现突变的致癌基因，其中KRAS亚型基因突变占到RAS基因突变总数的86％，约90％的胰腺癌，30％-40％的结肠癌、15-20％的肺癌中均出现不同程度的KRAS基因突变。鉴于KRAS基因突变的普遍性，该靶点一直是药物研发工作者关注的方向。从直接作用于KRAS-G12C靶点的AMG-510临床结果的公布开始，KRAS抑制剂的研究在国内外掀起一股热潮。
SOS(Son of sevenless homolog)蛋白最初是在果蝇研究中被发现，是由SOS基因编码的鸟苷释放蛋白。人类有2种SOS同源体，hSOS1和hSOS2，二者都是鸟嘌呤核苷酸交换因子家族的成员，具有70％的同源性，尽管它们在结构和序列上高度相似，但各自的生理功能存在一定差异。hSOS1蛋白大小为150kDa，是由1333个氨基酸组成的多结构蛋白域，包含N端蛋白结构域(HD)、多个同源结构域、螺旋接头(HL)、RAS交换序列(REM)和富含脯氨酸的C端结构域。hSOS1上有2个与RAS蛋白的结合位点，分别是催化位点和变构位点，催化位点结合RAS-GDP复合物上的RAS蛋白促进鸟嘌呤核苷酸交换，变构位点结合RAS-GTP复合物上的RAS蛋白进一步增强催化作用，进而参与并激活RAS家族蛋白的信号转导。有研究表明，对SOS1的抑制不仅能够对野生型KRAS细胞中的RAS-RAF-MEK-ERK通路产生完全抑制，在突变的KRAS细胞系中，也能导致磷酸-ERK的活性降低50％。因此，对SOS1的抑制也能够降低RAS的活性，从而治疗由RAS基因突变或RAS蛋白过度激活导致的各种癌症，包括胰腺癌、结直肠癌、胆管癌、胃癌、非小细胞肺癌等。
此外，癌症中亦牵涉SOS1的改变。研究表明，SOS1突变发现于胚胎性横纹肌肉瘤、塞尔托利细胞睾丸瘤、弥漫性大B细胞淋巴瘤、神经纤维瘤、皮肤颗粒细胞瘤和肺腺癌中。 同时，有研究已描述了在膀胱癌和***癌中SOS1的过表达。除了癌症之外，遗传性SOS1突变也牵涉在RAS病的发病机理中，所述RAS病变如像努南综合征(NS)、心面皮肤综合征(CFC)和Ⅰ型遗传性齿龈纤维瘤等。
SOS1也是用于激活GTP酶RAC1(Ras相关的C3肉毒杆菌毒素底物1)的GEF。与RAS家族蛋白一样，RAC1与多种人类癌症和其他疾病的发病机理有关。
市场上还未有选择性地针对于SOS1的药物上市，但已经公布了一系列相关专利，其中包括BI公司的WO2018115380A1，WO2019122129A1，Bayer公司的WO2019201848A1，Revolution公司的WO2020180768A1，WO2020180770A1等，目前处于临床试验阶段的药物为BI-1701963，以及处于临床前阶段的BI-3406。但这些对于抗肿瘤研究是远远不够的，仍有必要研究和开发新的选择性SOS1激酶抑制剂，来解决未满足的医疗需求。
发明内容
针对上述的技术问题，本发明提供一种通式(I)所示的一种取代的喹唑啉类化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000001
其中：
R a为氰基、-C(O)R 3或C 1-C 6烷氧基。
R 1相同或不同，各自独立地为卤素、羟基、氨基、C 1-C 6烷基或C 1-C 6烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基和C 1-C 6烷氧基的取代基所取代；R 1优选为C 1-C 6烷基；更优选为甲基；
R 2为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；其中所述的环烷基、单环杂环基、螺杂环基、桥杂环基、稠杂环基或稠合环任选进一步被一个或多个R A取代；
R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰 基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基、-C(O)R 3和-SO 2R 4的取代基所取代；
R 3各自独立地为C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基，其中所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；所述的杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；
R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
R 5和R 6各自独立地为氢原子或C 1-C 6烷基，其中所述的烷基任选地进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
或者，R 5、R 6与所连的N原子形成4-10元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)R 7和C 3-C 6环烷基的取代基所取代；
R 7为C 1-C 3烷基或C 3-C 6环烷基，所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
m为0、1、2、3或4。
在本申请的一个或多个实施方案中，所述通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000002
其中：
R a为氰基、乙酰基或甲氧基；
环B为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；
R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰 基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基、-C(O)R 3和-SO 2R 4的取代基所取代；
R 3为C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基；其中所述的烷基或环烷基任选进一步被一个或多个选自卤素、氰基和C 1-C 6烷基的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、氰基、氧代基和C 1-C 6烷基的取代基所取代；
R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
R 5和R 6各自独立地为氢原子或C 1-C 6烷基，其中所述的烷基任选地进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
或者，R 5、R 6与所连的N原子形成4-10元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)R 7和C 3-C 6环烷基的取代基所取代；
R 7为C 1-C 3烷基或C 3-C 6环烷基，所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
n为0、1、2或3。
在本申请的一个或多个实施方案中，在所述通式(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐中，环B为以下基团：
Figure PCTCN2022115379-appb-000003
在本申请的一个或多个实施方案中，在所述通式(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐中，所述
Figure PCTCN2022115379-appb-000004
为以下基团：
Figure PCTCN2022115379-appb-000005
在本申请的一个或多个实施方案中，在所述通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐中，所述R 1为甲基。
在本申请的一个或多个实施方案中，在所述通式(I)或(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐中，所述R a为甲氧基。
在本申请的一个或多个实施方案中，在所述通式(I)或(II)所示的化合物或其立体异构体、 互变异构体或其可药用的盐中，所述R a为乙酰基。
在在本申请的一个或多个实施方案中，所述通式(I)所述的化合物为：
Figure PCTCN2022115379-appb-000006
Figure PCTCN2022115379-appb-000007
Figure PCTCN2022115379-appb-000008
Figure PCTCN2022115379-appb-000009
Figure PCTCN2022115379-appb-000010
Figure PCTCN2022115379-appb-000011
Figure PCTCN2022115379-appb-000012
Figure PCTCN2022115379-appb-000013
Figure PCTCN2022115379-appb-000014
Figure PCTCN2022115379-appb-000015
或其立体异构体、互变异构体或其可药用的盐。
注：如果在画出的结构和给出的该结构的名称之间有差异，则画出的结构将给予更大的权重。
本申请的一个或多个实施方式提供通式(I’)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000016
其中：
R 1相同或不同，各自独立地为卤素、羟基、氨基、C 1-C 6烷基或C 1-C 6烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基和C 1-C 6烷氧基的取代基所取代；R 1优选为C 1-C 6烷基；更优选为甲基；
R 2为3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；其中所述的单环杂环基、螺杂环基、桥杂环基、稠杂环基或稠合环任选进一步被一个或多个R A取代；
R A各自独立地为卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-6元杂环基或-C(O)R 3，其中所述的烷基、烷氧基、环烷基或杂环基任选进一步被一个或多个选自卤素、 硝基、氰基、羟基、氨基、C 1-C 6烷基和C 1-C 6烷氧基的取代基所取代；
或者，两个R A与其所连接的同一个碳原子一起形成-C(＝O)-；
R 3为C 1-C 6烷基、C 3-C 6环烷基或3-6元杂环基，其中所述的烷基、环烷基或杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；
m为0、1、2、3或4；
本申请的一个或多个实施方式提供通式(II’)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000017
其中：
环B为3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；
R A各自独立地为C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、3-6元杂环基或-C(O)R 3；
R 3为C 1-C 6烷基、C 3-C 6环烷基或3-6元杂环基；其中所述的烷基、环烷基或杂环基任选进一步被一个或多个选自卤素、氰基和C 1-C 6烷基的取代基所取代；
n为0、1、2或3。
本申请的一个或多个实施方式提供(I”)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000018
其中：
R a为氰基或C 1-C 6烷氧基；
R 1相同或不同，各自独立地为卤素、羟基、氨基、C 1-C 6烷基或C 1-C 6烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基和C 1- C 6烷氧基的取代基所取代；R 1优选为C 1-C 6烷基；更优选为甲基；
R 2为3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；其中所述的单环杂环基、螺杂环基、桥杂环基、稠杂环基或稠合环任选进一步被一个或多个R A取代；
R A各自独立地为卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-6元杂环基或-C(O)R 3，其中所述的烷基、烷氧基、环烷基或杂环基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基和C 1-C 6烷氧基的取代基所取代；
或者，两个R A与其所连接的同一个碳原子一起形成-C(＝O)-；
R 3为C 1-C 6烷基、C 3-C 6环烷基或3-6元杂环基，其中所述的烷基、环烷基或杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；
m为0、1、2、3或4。
本申请的一个或多个实施方式提供通式(II”)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000019
其中：
R a为氰基或甲氧基；
环B为3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；
R A各自独立地为C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、3-6元杂环基或-C(O)R 3；
R 3为C 1-C 6烷基、C 3-C 6环烷基或3-6元杂环基；其中所述的烷基、环烷基或杂环基任选进一步被一个或多个选自卤素、氰基和C 1-C 6烷基的取代基所取代；
n为0、1、2或3。
本申请的一个或多个实施方式提供通式(I”’)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000020
其中：
R a为氰基、-C(O)R 3或C 1-C 6烷氧基；
R 1相同或不同，各自独立地为卤素、羟基、氨基、C 1-C 6烷基或C 1-C 6烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基和C 1-C 6烷氧基的取代基所取代；R 1优选为C 1-C 6烷基；更优选为甲基；
R 2为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；其中所述的环烷基、单环杂环基、螺杂环基、桥杂环基、稠杂环基或稠合环任选进一步被一个或多个R A取代；
R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；
R 3各自独立地为C 1-C 6烷基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基，其中所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；所述的杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、羟基、氰基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；
R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
R 5和R 6各自独立地为氢原子或C 1-C 6烷基；
或者，R 5、R 6与所连的N原子形成4-6元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 6环烷基的取代基所取代；
m为0、1、2、3或4。
本申请的一个或多个实施方式提供通式(II”’)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000021
其中：
R a为氰基、乙酰基或甲氧基；
环B为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；
R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；
R 3为C 1-C 6烷基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基；其中所述的烷基或环烷基任选进一步被一个或多个选自卤素、氰基和C 1-C 6烷基的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、氰基、氧代基和C 1-C 6烷基的取代基所取代；
R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
R 5和R 6各自独立地为氢原子或C 1-C 6烷基；
或者，R 5、R 6与所连的N原子形成4-6元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 6环烷基的取代基所取代；
n为0、1、2或3。
本申请的一个或多个实施方式提供通式(I””)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000022
其中：
R a为氰基、-C(O)R 3或C 1-C 6烷氧基；
R 1相同或不同，各自独立地为卤素、羟基、氨基、C 1-C 6烷基或C 1-C 6烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基和C 1-C 6烷氧基的取代基所取代；R 1优选为C 1-C 6烷基；更优选为甲基；
R 2为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；其中所述的环烷基、单环杂环基、螺杂环基、桥杂环基、稠杂环基或稠合环任选进一步被一个或多个R A取代；
R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；
R 3各自独立地为C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基，其中所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；所述的杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、羟基、氰基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；
R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
R 5和R 6各自独立地为氢原子或C 1-C 6烷基，其中所述的烷基任选地进一步被一个或多个选自羟基、卤素、氨基、氰基、和C 1-C 6烷氧基的取代基所取代；
或者，R 5、R 6与所连的N原子形成4-10元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)R 7和C 3-C 6环烷基的取代基所取代；
R 7为C 1-C 3烷基或C 3-C 6环烷基，所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氨基、氰基、和C 1-C 6烷氧基的取代基所取代；
m为0、1、2、3或4。
本申请的一个或多个实施方式提供通式(II””)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022115379-appb-000023
Figure PCTCN2022115379-appb-000024
其中：
R a为氰基、乙酰基或甲氧基；
环B为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；
R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；
R 3为C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基；其中所述的烷基或环烷基任选进一步被一个或多个选自卤素、氰基和C 1-C 6烷基的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、氰基、氧代基和C 1-C 6烷基的取代基所取代；
R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
R 5和R 6各自独立地为氢原子或C 1-C 6烷基，其中所述的烷基任选地进一步被一个或多个选自羟基、卤素、氨基、氰基、和C 1-C 6烷氧基的取代基所取代；
或者，R 5、R 6与所连的N原子形成4-10元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)R 7或C 3-C 6环烷基的取代基所取代；
R 7为C 1-C 3烷基或C 3-C 6环烷基，所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氨基、氰基、和C 1-C 6烷氧基的取代基所取代；
n为0、1、2或3。
更进一步，本发明提供一种药物组合物，所述的药物组合物含有有效剂量的通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，以及可药用的载体、赋形剂或它们的组合。
本发明提供一种通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备SOS1抑制剂中的用途。
本发明还提供一种通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备用于治疗由SOS1介导的疾病的药物中的用途，其中所述的由SOS1介导的疾病优选为RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性 疾病；其中所述的由SOS1介导的疾病优选为肺癌、胰腺癌、结肠癌、膀胱癌、***癌、胆管癌、胃癌、弥漫性大B细胞淋巴瘤、神经纤维瘤、努南综合征、心面皮肤综合征、Ⅰ型遗传性齿龈纤维瘤、胚胎性横纹肌肉瘤、塞尔托利细胞睾丸瘤或皮肤颗粒细胞瘤。
本发明进一步提供一种通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备用于治疗RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性疾病的药物中的用途。
本发明提供一种通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备用于治疗肺癌、胰腺癌、结肠癌、膀胱癌、***癌、胆管癌、胃癌、弥漫性大B细胞淋巴瘤、神经纤维瘤、努南综合征、心面皮肤综合征、Ⅰ型遗传性齿龈纤维瘤、胚胎性横纹肌肉瘤、塞尔托利细胞睾丸瘤或皮肤颗粒细胞瘤的药物中的用途。
本发明还提供一种组合物，其包含上述通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或上述药物组合物，与其他药物，所述的其他药物优选选自KRAS G12C的抑制剂。
本发明还提供通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用作药物。
本发明还提供通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用作SOS1抑制剂。
本发明还提供通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用于预防和/或治疗由SOS1介导的疾病，其中所述的由SOS1介导的疾病优选为RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性疾病；其中所述的由SOS1介导的疾病优选为肺癌、胰腺癌、结肠癌、膀胱癌、***癌、胆管癌、胃癌、弥漫性大B细胞淋巴瘤、神经纤维瘤、努南综合征、心面皮肤综合征、Ⅰ型遗传性齿龈纤维瘤、胚胎性横纹肌肉瘤、塞尔托利细胞睾丸瘤或皮肤颗粒细胞瘤。
本发明还提供通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用于预防和/或治疗RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性疾病。
本发明还提供通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用于预防和/或治疗肺癌、胰腺癌、结肠癌、膀胱癌、***癌、胆管癌、胃癌、弥漫性大B细胞淋巴瘤、 神经纤维瘤、努南综合征、心面皮肤综合征、Ⅰ型遗传性齿龈纤维瘤、胚胎性横纹肌肉瘤、塞尔托利细胞睾丸瘤或皮肤颗粒细胞瘤。
本发明还提供预防和/或治疗癌症的方法，其包括向有需要的对象给予通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物。
本发明还提供抑制对象中SOS1的方法，其包括向有需要的对象给予通式(I)、(II)、(I’)、(II’)、(I”)、(II”)、(I”’)、(II”’)、(I””)或(II””)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物。
发明的详细说明
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的脂肪烃基团(包含例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子)。优选为C 1-C 10烷基，更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等(包含例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子)。烯基可以是任选取代的或未取代的。
“炔基”是指含有一个碳碳三键的脂肪烃基团，可为直链也可以带有支链。优先选择的是C 2-C 10的炔基，更优选C 2-C 6炔基，最优选C 2-C 4炔基(包含例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子)。炔基基团的实施例包括，但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环(包含例如3、4、5、6、7、8、9、10、11、12个碳原子)。优选为C 3-C 12环烷基，更优选为C 3-C 8环烷基，最优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。环烷基可以是取代或未取代的。
“螺环烷基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、 18元)，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内可以含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基、二环[2.2.1]庚基或金刚烷基。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，都是指非芳香性杂环基，其中一个或多个(例如1个、2个、3个或4个)成环的原子是杂原子，如氧、氮、硫、磷原子等，包括单环、多环、稠环、桥环和螺环。优选具有5至7元单环或7至10元(例如4、5、6、7、8、9、10元)双环或三环，其可以包含1，2或3个选自氮、氧、P(O) n或S(O) n(其中n选自0、1或2)的杂原子。
“单环杂环基”的实例包括但不限于吗啉基、氧杂环丁烷基、硫代吗啉基、四氢呋喃基、四氢吡喃基、1，1-二氧代-硫代吗啉基、哌啶基、吡咯烷基、哌嗪基、六氢嘧啶基、
Figure PCTCN2022115379-appb-000025
单环杂环基可以是取代或未取代的。
“螺杂环基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，环内可以含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个 (例如1、2、3、4个)环原子选自氮、氧、P(O) n或S(O) n(其中n选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于：1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基、5-氧杂螺[2.4]庚基、
Figure PCTCN2022115379-appb-000026
螺杂环基可以是取代或未取代的。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个(例如1、2、3、4个)环原子选自氮、氧、P(O) n或S(O) n(其中n选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如6、7、8、9、10、11、12、13、14元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基，3-氮杂二环[3.1.0]己基，八氢苯并[b][1,4]二噁英(dioxine)，
Figure PCTCN2022115379-appb-000027
“桥杂环基”指5至14元，5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个(例如1、2、3、4个)环原子选自氮、氧、P(O) n或S(O) n(其中n选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：2-氮杂二环[2.2.1]庚基，2-氮杂二环[2.2.2]辛基、2-氮杂二环[3.3.2]癸基、
Figure PCTCN2022115379-appb-000028
桥杂环基可以是取代或未取代的。
“芳基”是指含有一个或者两个环的碳环芳香***，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基，比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为萘基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或8至10元(例如8、9、10元)双环，其可以包含1至4个(例如1、2、3、4个)选自氮、氧和/或硫中的原子。优选为双环杂芳基，“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1,2-二氢吡啶基，哒嗪基，嘧啶基，吡嗪基，噻吩基，异噁唑基，噁唑基，噁二唑基，咪唑基，吡咯基，吡唑基，***基，四氮唑基，噻唑基，异噻唑基，1,2,3-噻二唑基，苯并间二氧杂环戊烯基，苯并噻吩基、苯并咪唑基，吲哚基，异吲哚基，1,3-二氧代-异吲哚基，喹啉基，吲唑基，苯并异噻唑基，苯并噁唑基、苯并异噁唑基、
Figure PCTCN2022115379-appb-000029
杂芳基可以是取代或未取代的。
“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但至少一个环不具有完全共轭的π电子的芳香***，其中环原子选自0个、一个或多个(例如1、2、3、4个)选自氮、氧、P(O) n或S(O) r(其中r选自0、1或2)的杂原子，其余环原子为碳。稠合环优选包括双环或三环的稠合环，其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环。优选为7至14元(例如7、8、9、10、11、12、13、14元)，更优选为8至10元。“稠合环”的实施例包括但不限于：
Figure PCTCN2022115379-appb-000030
Figure PCTCN2022115379-appb-000031
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“酰基”指有机或无机含氧酸去掉羟基后剩下的一价原子团，优选为C 1-C 6烷基-C(O)-烷基，C 3-C 6环烷基-C(O)-。其实例包括，但不限于：甲酰基、乙酰基、正丙酰基、异丙酰基、环丙酰基、环丁酰基等。
“氧代基”指＝O。
“羟基烷基”指羟基取代的烷基。
“卤代烷基”指卤素取代的烷基。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“苄基”指-CH 2-苯基。
“DMSO”指二甲基亚砜。
“HATU”指2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
“卡特缩合剂”指苯并***-1-二(三甲氨基)瞵-六氟磷酸酯。
“离去基团(leaving group)”，或称离去基，在化学反应中从一较大分子中脱离的原子或 官能基，是亲核取代反应与消除反应中应用的术语。在亲核取代反应中，被亲核试剂进攻的反应物称为底物(substrate)，而从底物分子中带着一对电子断裂出去的原子或原子团称为离去基团。易接受电子、承受负电荷能力强的基团是好的离去基团。当离去基团共轭酸的pKa越小，离去基团越容易从其他分子中脱离。原因是因为当其共轭酸的pKa越小，相应离去基团不需和其他原子结合，以阴离子(或电中性离去基团)的形式存在的趋势也就增强。常见的离去基团包括但不限于卤素、甲磺酰基、-OTs或-OH。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个取代基所取代。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-C(O)R 5’、-C(O)OR 5’、-NHC(O)R 5’、-NHC(O)OR 5’、-NR 6’R 7’、-C(O)NR 6’R 7’、-CH 2NHC(O)OR 5’、-CH 2NR 6’R 7’或-S(O) rR 5’的取代基所取代；
其中：
R 5’选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8’、-C(O)OR 8’、-OC(O)R 8’、-NR 9’R 10’、-C(O)NR 9’R 10’、-SO 2NR 9’R 10’或-NR 9’C(O)R 10’的取代基所取代；
R 6’和R 7’各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8’、-C(O)OR 8’、-OC(O)R 8’、-NR 9’R 10’、-C(O)NR 9’R 10’、-SO 2NR 9’R 10’或-NR 9’C(O)R 10’的取代基所取代；
或者，R 6和R 7与它们相连接的原子一起形成一个4～8元杂环基，其中4～8元杂环基内含有一个或多个N、O或S(O) r，并且所述的4～8元杂环基任选进一步被一个或多个选自羟 基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8’、-C(O)OR 8’、-OC(O)R 8’、-NR 9’R 10’、-C(O)NR 9’R 10’、-SO 2NR 9’R 10’或-NR 9’C(O)R 10’的取代基所取代；
R 8’、R 9’和R 10’各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；
r为0、1或2。
本发明化合物可以含有不对称中心或手性中心，因此以不同的立体异构体形式存在。所预期的是，本发明化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物，如外消旋体混合物，均在本发明的范围内。
除非另外指出，本发明描述的结构还包括此结构的所有异构体(如，非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式；例如，各不对称中心的R和S构型，(Z)和(E)双键异构体，以及(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本发明范围内。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022115379-appb-000032
通式(IA)化合物与通式(IB)化合物进行缩合反应，得到通式(IC)化合物，通式(IC)化合物与R 2-H进行Buckward偶联反应，任选进一步进行脱保护基和氨基取代反应，得到通式(I)化合物；
其中：
X 1为离去基团，优选为羟基；
X 2为离去基团，优选为卤素，更优选为溴；
R 1、R 2、R a和m的定义如通式(I)中所述。
附图说明
图1表示本发明化合物在NCI-H2122模型中各组小鼠肿瘤体积的变化。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。 1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于上海皓鸿生物医药科技有限公司，上海韶远试剂有限公司，上海毕得医药科技有限公司，萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。
CD 3OD：氘代甲醇。
CDCl 3：氘代氯仿。
DMSO-d 6：氘代二甲基亚砜。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
对化合物进行纯化，采用硅胶柱层析和薄层色谱法的洗脱剂/展开剂体系，其中该体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷和乙酸乙酯体系，D：二氯甲烷和乙醇体系，其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行，如醋酸或三乙胺等。
实施例1
(R)-3-(1-((7-methoxy-2-methyl-6-morpholinoquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile(R)-3-(1-((7-甲氧基-2-甲基-6-吗啉喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000033
第一步
N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺的合成
在250mL烧瓶中加入1-(3-溴-2-甲基苯基)乙烷-1-酮(12g,56.32mmol)，(R)-2-甲基丙烷-2-磺酰亚胺(8.87g,73.22mmol)，钛酸四乙酯(19.27g,84.48mmol)，四氢呋喃100mL，置换氮气3次，80度下反应7小时。恢复室温后，加水30mL，硅藻土过滤，乙酸乙酯洗涤，水洗三次，无水硫酸钠干燥，过滤浓缩，硅胶拌样，过柱机过柱得到N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺14g，产率79％。
MS m/z(ESI):316.1[M+1] +
第二步
(S)-N-((R)-1-(3-溴-2-甲基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺的合成
在250mL反应瓶中加入N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺(7g,22.13mmol)，四氢呋喃30mL)，于冰浴下缓慢加入0.5M 9-BBN的四氢呋喃溶液80mL，恢复室温反应继续反应5小时。送LC-MS检测原料消失，加入饱和氯化铵溶液淬灭，浓缩除去四氢呋喃，加入乙酸乙酯，水洗三次，无水硫酸钠干燥。过柱机过柱纯化得到(S)-N-((R)-1-(3-溴-2-甲基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺6.0g，产率85％。
MS m/z(ESI):318.2[M+1] +
第三步
(R)-1-(3-溴-2-甲基苯基)乙烷-1-胺盐酸盐的合成
在25mL反应瓶中加入(S)-N-((R)-1-(3-溴-2-甲基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺(4g,12.57mmol)，加入氯化氢/二氧六环溶液10mL，室温下搅拌。LC-MS检测原料反应完全，浓缩溶剂，加入***搅拌，析出(R)-1-(3-溴-2-甲基苯基)乙烷-1-胺盐酸盐1.8g，产率58％。MS m/z(ESI):214.0[M+1] +
第四步
(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸叔丁酯的合成
在100mL烧瓶中加入(R)-1-(3-溴-2-甲基苯基)乙烷-1-胺盐酸盐(1.3g,5.2mmol)二碳酸二叔丁酯(1.19g,10.90mmol)和二氯甲烷8mL)，冰浴下缓慢加入二异丙基乙胺(1.34g,10.4mmol)，室温下反应3小时。加入300mL二氯甲烷，水洗三次，无水硫酸钠干燥，过柱机过柱纯化得到(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸叔丁酯3.0g，产率93％。
MS m/z(ESI):314.1[M+1] +
第五步
(R)-(1-(3-氰基-2-甲基苯基)乙基)氨基甲酸叔丁酯的合成
在50mL烧瓶中加入(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸叔丁酯(2g,6.37mmol)，Zn(CN) 2(1.49g,12.73mmol)，Pd(PPh 3) 4(735.52mg,636.50μmol)，DMF(8mL，置换氮气三次，于140度下反应8小时。恢复室温后加入乙酸乙酯，水洗三次，无水硫酸钠干燥，过柱机过柱得(R)-(1-(3-氰基-2-甲基苯基)乙基)氨基甲酸叔丁酯0.8g，产率49％。
MS m/z(ESI):261.2[M+1] +
第六步
(R)-3-(1-氨基乙基)-2-甲基苯腈盐酸盐的合成
在100mL烧瓶中加入(R)-(1-(3-氰基-2-甲基苯基)乙基)氨基甲酸叔丁酯(4.5g,17.29mmol)和4M氯化氢/二氧六环溶液20mL，室温下反应5小时，析出白色固体析出。加入***，过滤，得(R)-3-(1-胺基乙基)-2-甲基苯腈盐酸盐1g 3.0g，产率89％。
MS m/z(ESI):161.1[M+1] +
第七步
(R)-3-(1-((6-bromo-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
于15mL反应瓶中依次加入6-溴-7-甲氧基-2-甲基喹唑啉-4-醇1h(500mg,1.86mmol，根据公开专利WO 2018115380制备)、(R)-3-(1-氨基乙基)-2-甲基苯腈盐酸盐1g(562.3mg,2.42mmol)、卡特缩合剂(1.07g,2.42mmol)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(848.62mg,5.57mmol)和N,N-二甲基甲酰胺(5mL)，室温搅拌过夜。LC-MS显示反应完全，反应液中加入乙酸乙酯(30mL)，水洗(30mL×3)，有机相以无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得到(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i 502mg，产率66％。
MS m/z(ESI)：411.0[M+H] +
第八步
(R)-3-(1-((7-methoxy-2-methyl-6-morpholinoquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile(R)-3-(1-((7-甲氧基-2-甲基-6-吗啉喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(115.00mg,0.28mmol)、***啉(48.72mg,0.56mmol)、三(二亚苄基丙酮)二钯(25.58mg,0.028mmol)、叔丁醇钠(80.61mg,0.84mmmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(32.36mg,0.056mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至90℃下持续搅拌5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物依次用硅胶柱层析法(洗脱剂：B体系)和薄层色谱法(展开剂：B体系)分离纯化，得到(R)-3-(1-((7-甲氧基-2-甲基-6-吗啉喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1 24mg，产率20％。
MS m/z(ESI)：418.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.51(s,1H),7.83(dd,J＝8.0,1.4Hz,1H),7.71(s,1H),7.63(dd,J＝7.7,1.4Hz,1H),7.37(t,J＝7.8Hz,1H),7.03(s,1H),5.68(m,1H),3.89(s,3H),3.79(t,J＝4.5Hz,4H),3.09(q,J＝3.8Hz,4H),2.72(s,3H),2.35(s,3H),1.57(d,J＝7.0Hz,3H)ppm.
实施例2
(R)-3-(1-((6-(4-acetylpiperazin-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(4-乙酰哌嗪-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000034
Figure PCTCN2022115379-appb-000035
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(30mg,0.073mmol)，1-乙酰基哌嗪2a(9.35mg,0.073mmol,市售)、三(二亚苄基丙酮)二钯(10mg,0.011mmol)，叔丁醇钠(14.02mg,0.146mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(42.20mg,0.073mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至90℃下反应5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-3-(1-((6-(4-乙酰哌嗪-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈2 20mg，产率60％。
MS m/z(ESI)：459.5[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),7.90(s,1H),7.81(d,J＝7.9Hz,1H),7.70(d,J＝7.6Hz,1H),7.43(t,J＝7.8Hz,1H),7.09(s,1H),5.80(t,J＝7.0Hz,1H),3.99(s,3H),3.65(d,J＝9.2Hz,4H),3.16-2.98(m,4H),2.68(s,3H),2.53(s,3H),2.06(s,3H),1.63(d,J＝6.9Hz,3H)ppm.
实施例3
3-((1R)-1-((7-methoxy-2-methyl-6-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
3-((1R)-1-((7-甲氧基-2-甲基-6-(6-氧代六氢吡咯并[1,2-a]吡嗪-2(1H)-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000036
Figure PCTCN2022115379-appb-000037
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(100mg,0.243mmol)、六氢吡咯并[1,2-a]吡嗪-6-酮3a(51.12mg,0.367mmol,市售)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(40.72mg,0.049mmol)和叔丁醇钠(116.83mg,1.22mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至100℃下持续搅拌5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到3-((1R)-1-((7-甲氧基-2-甲基-6-(6-氧代六氢吡咯并[1,2-a]吡嗪-2(1H)-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈3 18mg，产率15％。
MS m/z(ESI)：471.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.19(d,J＝7.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.68(s,1H),7.64(d,J＝7.6Hz,1H),7.37(t,J＝7.8Hz,1H),7.03(s,1H),5.66(t,J＝7.0Hz,1H),3.95(d,J＝12.6Hz,1H),3.91(s,3H),3.79(d,J＝7.1Hz,1H),3.62(d,J＝11.4Hz,1H),3.46(d,J＝11.6Hz,1H),3.01(dd,J＝13.2,10.0Hz,1H),2.73(s,3H),2.60(d,J＝10.0Hz,1H),2.46-2.35(m,2H),2.32(s,4H),2.20(d,J＝10.2Hz,1H),1.74-1.63(m,1H),1.56(d,J＝7.0Hz,3H)ppm.
实施例4
(R)-3-(1-((7-methoxy-2-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(3-氧杂-9-氮杂螺[5.5]十一烷-9-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000038
Figure PCTCN2022115379-appb-000039
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(100mg,0.243mmol)，3-氧杂-9-氮杂螺[5.5]十一烷4a(69.91mg,0.365mmol,市售)、三(二亚苄基丙酮)二钯(44.53mg,0.049mmol)、叔丁醇钠(93.46mg,0.973mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(60.56mg,0.097mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，微波条件下升温至125℃下持续搅拌1小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-3-(1-((7-甲氧基-2-甲基-6-(3-氧杂-9-氮杂螺[5.5]十一烷-9-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈4 60mg,，产率51％。
MS m/z(ESI)：486.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝7.0Hz,1H),7.82(d,J＝7.9Hz,1H),7.71-7.60(m,2H),7.38(t,J＝7.8Hz,1H),6.99(s,1H),5.68(q,J＝7.1Hz,1H),3.89(s,3H),3.62(t,J＝5.3Hz,4H),3.05(q,J＝4.3Hz,4H),2.73(s,3H),2.32(s,3H),1.70(t,J＝5.5Hz,3H),1.54(q,J＝6.2,5.2Hz,8H)ppm.
实施例5
(R)-3-(1-((7-methoxy-2-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000040
Figure PCTCN2022115379-appb-000041
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(300mg,0.73mmol)，2-氧杂-7-氮杂螺[3.5]壬烷半草酸盐5a(200mg,1.16mmol,市售)、三(二亚苄基丙酮)二钯(66.0mg,0.072mmol)、叔丁醇钠(280mg,2.92mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(91.0mg,0.146mmol)依次加入到1,4-二氧六环(15mL)中，氮气保护，微波条件下升温至125℃下持续搅拌1小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-3-(1-((7-甲氧基-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈5 120mg，产率36％。
MS m/z(ESI)：458.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.22-8.15(m,1H),7.81(d,J＝7.9Hz,1H),7.63(d,J＝6.8Hz,2H),7.37(t,J＝7.8Hz,1H),6.99(s,1H),5.66(t,J＝7.0Hz,1H),4.40(s,4H),3.89(s,3H),3.05-2.88(m,4H),2.73(s,3H),2.31(s,3H),1.99(q,J＝5.6,4.7Hz,4H),1.55(d,J＝7.0Hz,3H)ppm.
实施例6
(R)-3-(1-((7-methoxy-2-methyl-6-(4-morpholinopiperidin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-吗啉哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000042
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(120mg,0.292mmol)，4-(哌啶-4-基)吗啉6a(49.67mg,0.292mmol,市售)、三(二亚苄基丙酮)二钯(26.73mg,0.0292mmol)、叔丁醇钠(56.08mg,0.584mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(36.33mg,0.0584mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至100℃下持续搅拌5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-3-(1-((7-甲氧基-2-甲基-6-(4-吗啉哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈6 30mg，产率21％。
MS m/z(ESI)：501.5[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.21(d,J＝7.1Hz,1H),7.82(d,J＝7.9Hz,1H),7.63(d,J＝8.2Hz,2H),7.37(t,J＝7.8Hz,1H),6.99(s,1H),5.71-5.61(m,1H),3.89(s,3H),3.62(t,J＝4.5Hz,4H),3.52(d,J＝10.8Hz,3H),2.73(s,3H),2.66(q,J＝11.2Hz,2H),2.55(d,J＝4.5Hz,3H),2.36(d,J＝11.5Hz,1H),2.32(s,3H),1.91(d,J＝12.0Hz,2H),1.70-1.60(m,2H),1.55(d,J＝7.0Hz,3H)ppm.
实施例7
(R)-3-(1-((7-methoxy-2-methyl-6-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000043
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(200mg,0.486mmol)，2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮7a(81.81mg,0.486mmol,市售)、三(二亚苄基丙酮)二钯(44.52mg,0.0486mmol)、叔丁醇钠(93.46mg,0.973mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(60.56mg,0.097mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至 100℃下持续搅拌5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-3-(1-((7-甲氧基-2-甲基-6-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈7 30mg，产率12％。MS m/z(ESI)：499.5[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),7.91-7.78(m,2H),7.70(d,J＝7.7Hz,1H),7.43(t,J＝7.8Hz,1H),7.02(s,1H),5.88-5.72(m,1H),3.98(s,3H),3.53-3.40(m,3H),2.84(d,J＝11.8Hz,2H),2.78(s,3H),2.71(s,3H),2.50(s,4H),2.01(t,J＝6.9Hz,2H),1.97-1.87(m,2H),1.63(d,J＝7.0Hz,3H),1.54(d,J＝13.1Hz,2H)ppm.
实施例8
(R)-1-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)piperidine-4-carbonitrile
(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-腈
Figure PCTCN2022115379-appb-000044
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(240mg,0.58mmol)，哌啶-4-腈8a(96.4mg,0.88mmol，市售)，Pd 2(dba) 3(80.2mg,0.088mmol)，BINAP(109.0mg,0.175mmol)，叔丁醇钠(168.2mg,1.75mmol)依次加入到微波管中，加入1,4-二氧六环(12mL)，氮气保护下，125度微波下反应1小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-腈8 65mg，产率23％。
MS m/z(ESI)：441.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.26(d,J＝6.9Hz,1H),7.81(d,J＝7.9Hz,1H),7.69(s,1H),7.64(d,J＝7.6Hz,1H),7.38(t,J＝7.8Hz,1H),7.01(s,1H),5.66(t,J＝7.0Hz,1H),3.89(s,3H),3.20-3.02(m,5H),2.74(s,3H),2.32(s,3H),2.08-2.04(m,2H),1.96-1.88(m,2H),1.56(d,J＝7.0Hz,3H)ppm.
实施例9
3-((1R)-1-((7-methoxy-2-methyl-6-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
3-((1R)-1-((7-甲氧基-2-甲基-6-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000045
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(100mg,0.243mmol)、六氢-1H-呋喃并[3,4-c]吡咯9a(27.51mg,0.243mmol,市售)、三(二亚苄基丙酮)二钯(22.26mg,0.024mmol)、叔丁醇钠(46.73mg,0.486mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30.28mg,0.049mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至100℃下持续搅拌5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到3-((1R)-1-((7-甲氧基-2-甲基-6-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈9 20mg，产率18％。
MS m/z(ESI)：444.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.00(s,1H),7.88(d,J＝7.9Hz,1H),7.72-7.52(m,2H),7.40(t,J＝7.8Hz,1H),7.07(s,1H),5.75(t,J＝7.1Hz,1H),3.94(s,3H),3.88(t,J＝7.4Hz,2H),3.66-3.54(m,3H),3.21(s,1H),3.12(dd,J＝14.5,6.9Hz,2H),2.97(s,2H),2.72(s,3H),2.42(s,3H),1.61(d,J＝7.0Hz,3H)ppm.
实施例10
(R)-3-(1-((7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000046
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(100mg,0.243mmol)、1-甲基哌嗪10a(48.71mg,0.486mmol,市售)、三(二亚苄基丙酮)二钯(22.25mg,0.024mmol)、叔丁醇钠(70.10mg,0.729mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30.28mg,0.049mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至90℃下持续搅拌5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-3-(1-((7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈10 30mg，产率27％。
MS m/z(ESI)：431.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),7.90-7.80(m,2H),7.70(d,J＝7.7Hz,1H),7.43(t,J＝7.8Hz,1H),7.02(s,1H),5.84-5.73(m,1H),3.98(s,3H),3.54-3.42(m,3H),2.84(d,J＝11.8Hz,2H),2.78(s,3H),2.71(s,3H),2.01(t,J＝6.9Hz,2H),1.96-1.88(m,2H),1.63(d,J＝7.0Hz,3H),1.54(d,J＝13.1Hz,2H).
实施例11
(R)-3-(1-((6-(4-hydroxy-4-methylpiperidin-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(4-羟基-4-甲基哌啶-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000047
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(100mg,0.243mmol)、4-甲基-4-羟基哌啶11a(56.01mg,0.486mmol,市售)、三(二亚苄基丙酮)二钯(22.25mg,0.024mmol)、叔丁醇钠(70.10mg,0.729mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30.28mg,0.049mmol)依次加入到1,4-二氧六环(5mL)中，氮气保护，升温至90℃下持续搅拌5小时。LC-MS显示反应完全，反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-3-(1-((6-(4-羟基-4-甲基哌啶-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈11 25mg，产率23％。
MS m/z(ESI)：446.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.39(s,1H),7.80(d,J＝7.9Hz,1H),7.70(s,1H),7.63(d,J＝7.6Hz,1H),7.37(t,J＝7.8Hz,1H),6.96(s,1H),5.65(q,J＝7.0Hz,1H),4.29(s,1H),3.87(s,3H),3.11-2.97(m,4H),2.72(s,3H),2.33(s,3H),1.66(d,J＝10.3Hz,4H),1.55(d,J＝7.0Hz,3H),1.21(s,3H)ppm.
实施例12
(R)-1-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)azetidine-3-carbonitrile
(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氮杂环丁烷-3-腈
Figure PCTCN2022115379-appb-000048
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(80mg,0.195mmol)、氮杂环丁烷-3氰12a(41.5mg,0.35mmol,市售)、三(二亚苄基丙酮)二钯(17.8mg,0.019mmol)、叔丁醇钠(74.77mg,0.778mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(18.54mg,0.039mmol)依次加入到1,4-二氧六环(4mL)中，氮气保护，升温至100℃下持续搅拌6小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，水洗三次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氮杂环丁烷-3-腈12 39mg，产率49％。
MS m/z(ESI)：413.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.07(d,J＝7.1Hz,1H),7.78(d,J＝7.8Hz,1H),7.62(d,J＝7.6Hz,1H),7.35(t,J＝7.7Hz,1H),7.18(s,1H),6.94(s,1H),5.64(t,J＝7.0Hz,1H),4.23(q,J＝8.4Hz,2H),4.15–3.98(m,2H),3.84(s,4H),2.71(s,3H),2.29(s,3H),1.53(d,J＝7.0Hz,3H)ppm.
实施例13
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(甲基砜基)哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000049
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(0.44mmol,180mg)，1-甲磺酰基哌嗪(0.66mmol,108mg)，80mg(0.09mmol)三(二亚苄基丙酮)二钯(0.09mmol,80mg)，1,1'-联萘-2,2'-双二苯膦(0.18mmol,108mg)，叔丁醇钠(1.76mmol,168mg)加入到微波管中，加入1,4-二氧六环(6mL)，氮气保护，125度下微波反应1小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(甲基砜基)哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈13 37mg，产率17％。
MS m/z(ESI):495.3[M+1] +。
1H NMR(400MHz,DMSO-d 6)δ8.23(s,1H),7.82(d,J＝7.9Hz,1H),7.73(d,J＝3.5Hz,1H),7.64(d,J＝7.7Hz,1H),7.38(t,J＝7.8Hz,1H),7.04(s,1H),5.67(q,J＝7.0Hz,1H),3.90(s,3H),3.19(s,6H),2.98(s,3H),2.74(s,3H),2.33(s,3H),1.56(d,J＝7.0Hz,3H)ppm.
实施例14
(R)-3-(1-((7-methoxy-2-methyl-6-(4-oxido-1,4-oxaphosphinan-4-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-氧化-1,4-氧杂亚膦酸-4-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000050
在25mL烧瓶中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(150.0mg,0.36mmol)，1,4-氧杂亚膦酸4-氧化物(87.6mg,0.73mmol)，Pd 2(dba) 3(33.4mg,0.036mmol)，XantPhos(42.20mg,0.073mmol)，三乙胺(110.7mg,1.1mmol)和1,4-二氧六环(6mL)，氮气保护，110度下反应6小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-氧化-1,4-氧杂亚膦酸-4-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈14 25mg，产率16％。
MS m/z(ESI):451.2[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.93(s,1H),8.74(d,J＝13.8Hz,1H),7.84(d,J＝7.9Hz,1H),7.62(d,J＝7.6Hz,1H),7.35(t,J＝7.8Hz,1H),7.12(d,J＝4.7Hz,1H),5.65(q,J＝7.1Hz,1H),4.13-3.98(m,4H),3.95(s,3H),2.71(s,3H),2.56-2.51(m,2H),2.35(s,3H),1.97-1.83(m,2H),1.54(d,J＝7.0Hz,3H)ppm.
实施例15
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(4-甲基哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000051
在25mL微波管中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(100mg,0.24mmol)，1-甲基-4-(哌啶-4-基)哌嗪15a(89.1mg,0.48mmol)，Pd 2(dba) 3(44.5mg,0.048mmol)，BINAP(60.6mg,0.096mmol)和1,4-二氧六环(6mL)中，氮气保护，125度下微波反应1小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(4-甲基哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈15 45mg，产率35％。
1H NMR(400MHz,DMSO-d 6)δ8.20(s,1H),7.80(d,J＝7.9,1H),7.62(s,1H),7.61(d,J＝6.2Hz,1H),7.35(t,J＝7.7Hz,1H),6.97(s,1H),5.64(p,J＝7.0Hz,1H),3.87(s,2H),3.61-3.44(m,2H),2.71(s,3H),2.68-2.54(m,5H),2.39-2.36(m,4H),2.30(s,3H),2.19(s,3H),1.92-1.78(m,2H),1.65-1.59(m,2H),1.53(d,J＝7.0Hz,3H)ppm.
MS m/z(ESI):514.4[M+1] +
实施例16
(R)-3-(1-((7-methoxy-2-methyl-6-(2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(2-(甲基砜基)-2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000052
第一步
tert-butyl(R)-7-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
(R)-7-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-2,7-二氮杂[3.5]壬烷-2-甲酸叔丁酯的合成
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(411mg,1mmol)，2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(347mg,1.5mmol)，三(二亚苄基丙酮)二钯(84mg,0.1mmol)，1,1'-联萘-2,2'-双二苯膦(127mg,0.2mmol)和叔丁醇钠(294mg,3mmol)加入到微波管中，加入1,4-二氧六环(15mL)，N 2保护，125度下微波反应1小时，LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-7-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-2,7-二氮杂[3.5]壬烷-2-甲酸叔丁酯16b 391mg，产率69％，
MS m/z(ESI):557.4[M+1] +。
第二步
(R)-3-(1-((7-methoxy-2-methyl-6-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
将(R)-7-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-2,7-二氮杂[3.5]壬烷-2-甲酸叔丁酯16b(390mg,0.7mmol)加入到25mL圆底烧瓶中，1,4-二氧六环(10mL)，加入4M氯化氢/二氧六环溶液(2mL)，室温下搅拌3小时，LC-MS显示反应完全，加乙酸乙酯和水，水相用无水碳酸钠调节pH至碱性，分液，有机相继续水洗两次，使用无水硫酸钠干燥，减压除去溶剂，得(R)-3-(1-((7-甲氧基-2-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈16c粗品248mg，产率78％。
MS m/z(ESI):457.3[M+1] +。
第三步
(R)-3-(1-((7-methoxy-2-methyl-6-(2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(2-(甲基砜基)-2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
将(R)-3-(1-((7-甲氧基-2-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈16c(47mg,0.1mmol)加入到10mL圆底烧瓶中，加入二氯甲烷(3mL)，三乙胺(0.2mL)，甲磺酰氯(25mg,0.2mmol)，室温下搅拌2小时，LC-MS显示反应完全，加入二氯甲烷，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(2-(甲基砜基)-2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈16 37mg。收率64％。
MS m/z(ESI):535.3[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.35(s,1H),7.82(d,J＝7.9Hz,1H),7.65(s,1H),7.64(d,J＝8.1Hz,1H),7.38(t,J＝7.8Hz,1H),7.00(s,1H),5.67(t,J＝7.1Hz,1H),3.90(s,3H),3.70(s,4H),3.05(s,3H),3.00(s,4H),2.73(s,3H),2.33(s,3H),1.92(s,4H),1.56(d,J＝7.0Hz,3H)ppm.
实施例17
(R)-3-(1-((7-methoxy-6-(4-methoxypiperidin-1-yl)-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-6-(4-甲氧基哌啶-1-基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000053
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(120mg,0.29mmol)，4-甲氧基哌啶17a(67.2mg,0.58mmol)，Pd 2(dba) 3(53.4mg,0.058mmol)，BINAP(72.7mg,0.12mmol)加入到微波管中，加入1,4-二氧六环(3mL)，氮气保护，125度下微波搅拌1小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-6-(4-甲氧基哌啶-1-基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈17 32.1mg，收率25％。
MS m/z(ESI):446.3[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.38(s,1H),7.83(d,J＝7.9Hz,1H),7.70(s,1H),7.64(d,J＝7.7Hz,1H),7.38(t,J＝7.8Hz,1H),7.00(s,1H),5.68(t,J＝7.2Hz,1H),3.90(s,3H),3.41-3.31(m,3H),3.32(s,3H),2.89-2.81(m,2H),2.73(s,3H),2.34(s,3H),2.02-1.97(m,2H),1.69-1.65(m,2H),1.56(d,J＝6.9Hz,3H)ppm.
实施例18
(R)-3-(1-((6-(9-acetyl-3,9-diazaspiro[5.5]undecan-3-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(9-乙酰基-3,9-二氮杂螺[5.5]十一烷-3-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000054
第一步
tert-butyl(R)-9-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
(R)-9-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(250mg,0.608mmol)，3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯18a(231.9mg,0.912mmol，市售)，Pd2(dba)3(111.3mg,0.122mmol)，BINAP(151.4mg,0.243mmol)，叔丁醇钠(175.2mg,1.82mmol)加入到微波管中，加入1,4-二氧六环(10mL)，氮气保护，125度下微波搅拌1小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-9-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯18b 203mg，产率58％。
MS m/z(ESI):585.4[M+1] +
第二步
(R)-3-(1-((7-methoxy-2-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(3,9-二氮杂螺[5.5]十一烷-3-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
将(R)-9-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯18b(203mg,0.347mmol)加入圆底烧瓶中，加入1,4-二氧六环(6mL)，加入4M氯化氢-1,4-二氧六环溶液(3mL)，室温下反应2小时。LC-MS显示反应完全，旋除反应液，加二氯甲烷和水，加入饱和碳酸钠溶液调节水相pH至碱性，加二氯甲烷/甲醇混合溶剂(10:1)萃取，收集有机相，无水硫酸钠干燥，过滤，减压除去溶剂后，得(R)-3-(1-((7-甲氧基-2-甲基-6-(3,9-二氮杂螺[5.5]十一烷-3-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈18c 147mg，直接用于下一步反应。
MS m/z(ESI):485.4[M+1] +
第三步
(R)-3-(1-((6-(9-acetyl-3,9-diazaspiro[5.5]undecan-3-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(9-乙酰基-3,9-二氮杂螺[5.5]十一烷-3-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
将(R)-3-(1-((7-甲氧基-2-甲基-6-(3,9-二氮杂螺[5.5]十一烷-3-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈18c(147mg,0.303mmol)加入到圆底烧瓶中，加入二氯甲烷(5mL)，三乙胺(0.2mL)，乙酰氯(35.7mg,0.455mmol)，室温下反应2小时。LC-MS显示反应完全，加入二氯甲烷，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((6-(9-乙酰基-3,9-二氮杂螺[5.5]十一烷-3-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈18 54.4mg，产率33％。
MS m/z(ESI):527.3[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.21(d,J＝7.0Hz,1H),7.82(d,J＝7.9Hz,1H),7.67(s,1H),7.63(d,J＝7.7Hz,1H),7.37(t,J＝7.8Hz,1H),6.98(s,1H),5.67(t,J＝7.0Hz,1H),3.88(s,3H),3.50-3.40(m,4H),3.07-3.02(m,4H),2.73(s,3H),2.32(s,3H),2.01(s,3H),1.69-1.65(m,4H),1.55(d,J＝7.1Hz,3H),1.54-1.51(m,2H),1.48-1.44(m,2H)ppm.
实施例19
(R)-3-(1-((6-(2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(2-乙酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000055
将(R)-3-(1-((7-甲氧基-2-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈16c(135mg,0.296mmol)加入到圆底烧瓶，加入二氯甲烷(10mL)，三乙胺(0.3mL)，乙酸酐(90.6mg,0.887mmol)，4-二甲氨基吡啶(7.2mg,0.059mmol)，室温下反应过夜。LC-MS显示反应完全，加入二氯甲烷，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((6-(2-乙酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈19 34.2mg，产率21％。
MS m/z(ESI):499.4[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.42(s,1H),7.80(d,J＝8.0Hz,1H),7.66(s,1H),7.63(d,J＝7.7Hz,1H),7.37(t,J＝7.8Hz,1H),6.99(s,1H),5.67(t,J＝7.0Hz,1H),3.89(s,3H),3.87(s,2H),3.61(s,2H),2.99(s,4H),2.71(s,3H),2.33(s,3H),1.89-1.86(m,4H),1.78(s,3H),1.55(d,J＝7.0Hz,3H)ppm.
实施例20
(R)-3-(1-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(4-(2-羟基乙基)哌嗪-1-基)-7-甲氧基-2-甲基喹唑啉-4-yl)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000056
在反应瓶中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(100mg,0.243mmol)，2-(哌嗪-1-基)乙烷-1-醇(57.0mg,0.438mmol)，Pd 2(dba) 3(22.3mg,0.024mmol)，BINAP(30.3mg,0.049mmol)，叔丁醇钠(70.1mg,0.729mmol)和1,4-二氧六环(5mL)，置换氮气，100度下反应6小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((6-(4-(2-羟基乙基)哌嗪-1-基)-7-甲氧基-2-甲基喹唑啉-4-yl)氨基)乙基)-2-甲基苯腈20 16mg，产率14％。
MS m/z(ESI):461.3[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.20(d,J＝7.2Hz,1H),7.80(d,J＝7.9Hz,1H),7.63(s,1H),7.62(d,J＝8.5Hz,1H),7.35(t,J＝7.8Hz,1H),6.98(s,1H),5.65(q,J＝7.0Hz,1H),3.87(s,3H),3.57(t,J＝6.3Hz,2H),3.09(s,4H),2.72(s,3H),2.66(s,4H),2.54-2.50(m,2H),2.30(s,3H),1.54(d,J＝7.0Hz,3H)ppm.
实施例21
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(2-氧代吡咯烷-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000057
在10mL微波反应管中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(150.0mg,0.365mmol)，1-(哌啶-4-基)吡咯啉-2-酮盐酸盐(149.3mg,0.73mmol)，叔丁醇钠(140.2mg,1.46mmol)，1,4-二氧六环(6mL)，Pd 2(dba) 3(66.8mg,0.073μmol)，BINAP(45.4mg,0.073mmol)，氮气保护，130度下反应1小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(2-氧代吡咯烷-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈21 45mg，产率24％。
MS m/z(ESI):499.4[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.20(d,J＝7.1Hz,1H),7.80(d,J＝7.9Hz,1H),7.66(s,1H),7.62(d,J＝7.6Hz,1H),7.36(t,J＝7.8Hz,1H),6.98(s,1H),5.64(p,J＝7.0Hz,1H),3.96-3.90(m,1H),3.88(s,3H),3.54(d,J＝11.5Hz,2H),3.38(t,J＝6.9Hz,2H),2.74-2.68(m,2H),2.72(s,3H),2.30(s,3H),2.25(t,J＝8.1Hz,2H),1.96-1.82(m,4H),1.69–1.65(m,2H),1.54(d,J＝7.0Hz,3H)ppm.
实施例22
(R)-1-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)-N,N-dimethylpiperidine-4-carboxamide
(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-N,N-二甲基哌啶-4-酰胺
Figure PCTCN2022115379-appb-000058
Figure PCTCN2022115379-appb-000059
第一步(R)-1-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)piperidine-4-carboxylic acid
(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-甲酸
在反应瓶中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(400mg,0.97mmol)，哌啶-4-甲酸甲酯22a(280.0mg,1.96mmol)，Pd 2(dba) 3(178.0mg,0.195mmol)，BINAP(242mg,0.389mmol)，叔丁醇钠(841.2mg,8.75mmol)和1,4-二氧六环(10mL)，置换氮气，100度下反应5小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，加入水萃取，收集水相，乙酸乙酯洗一次，水相调节pH为弱酸性，用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，浓缩得(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-甲酸22b 375mg，产率84％。
MS m/z(ESI):460.3[M+1] +
第二步
在25mL烧瓶中加入(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-甲酸22b(119mg,0.26mmol)，加入二甲胺盐酸盐(27.7mg,0.34mmol)，HATU(148.9mg,0.39mmol)，DMF(2mL)，三乙胺(79.3mg,0.78mmol)，室温下反应2小时。LC-MS显示反应完全，反应液冷却至室温，加入乙酸乙酯洗涤，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层 析法(洗脱剂：B体系)纯化，得(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-N,N-二甲基哌啶-4-酰胺22 13mg，产率11％。
1H NMR(400MHz,DMSO-d 6)δ8.20(d,J＝7.0Hz,1H),7.79(d,J＝7.9Hz,1H),7.63(s,1H),7.62(d,J＝8.8Hz,1H),7.36(t,J＝7.7Hz,1H),6.97(s,1H),5.65(t,J＝7.1Hz,1H),3.87(s,3H),3.50-3.46(m,2H),3.06(s,3H),2.84(s,3H),2.80-2.75(m,1H),2.72(s,3H),2.30(s,3H),1.78-1.74(m,4H),1.54(d,J＝7.0Hz,3H)ppm.
MS m/z(ESI):487.3[M+1] +
实施例23
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(4-(甲基砜基)哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000060
第一步
tert-butyl(R)-4-(1-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)piperidin-4-yl)piperazine-1-carboxylate
(R)-4-(1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-基)哌嗪-1-甲酸叔丁酯
在微波管中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(200mg,0.486mmol)，4-(哌啶-4-基)哌嗪-1-甲酸叔丁酯23a(235.8mg,0.875mmol)，Pd 2(dba) 3(44.6mg,0.048mmol)，BINAP(60.6mg,0.097mmol)，叔丁醇钠(140.2mg,1.46mmol)和1,4-二氧六环(6mL)，置换氮气，125度下反应1小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-4-(1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-基)哌嗪-1-甲酸叔丁酯23b 160mg，产率55％。
MS m/z(ESI):600.3[M+1] +
第二步
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(piperazin-1-yl)piperidin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
在25mL烧瓶中加入(R)-4-(1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-基)哌嗪-1-甲酸叔丁酯23b(120mg,0.2mmol)，dioxane(2mL)，加入4M氯化氢/1,4-二氧六环溶液(0.2mL)，室温下反应2小时。LC-MS显示反应完全，浓缩溶剂，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈23c粗品90mg，直接用于下一步。
MS m/z(ESI):500.3[M+1] +
第三步
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(4-(甲基砜基)哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
在25mL烧瓶中加入(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈23c粗品(90.00mg,0.18mmol)，二氯甲烷(8mL)，三乙胺(0.8mL)， 甲烷磺酰氯(61.9mg,0.54mmol)，室温下反应过夜。LC-MS显示反应完全，加入乙酸乙酯，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(4-(甲基砜基)哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈23 52mg，产率48％。
1H NMR(400MHz,DMSO-d 6)δ8.17(d,J＝3.4Hz,1H),7.80(d,J＝8.0,1H),7.63(s,1H),7.62(d,J＝7.0Hz,1H),7.36(t,J＝7.8Hz,1H),6.97(s,1H),5.64(p,J＝6.9Hz,1H),3.87(s,3H),3.51(d,J＝11.1Hz,2H),3.14-3.10(m,4H),2.88(s,3H),2.72(s,3H),2.68–2.59(m,6H),2.30(s,3H),1.88-1.85(m,2H),1.73-1.58(m,2H),1.53(d,J＝7.1Hz,3H)ppm.
MS m/z(ESI):578.4[M+1] +
实施例24
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(1-甲基哌啶-4-基)哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000061
在10mL微波反应管中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(150.0mg,0.365mmol)，1-(1-甲基哌啶-4-基)哌嗪24a(133.7mg,0.73mmol)，叔丁醇钠(105.1mg,1.09mmol)，Pd 2(dba) 3(33.4mg,0.0365mmol)，BINAP(45.4mg,0.073mmol)和1,4-二氧六环(6mL)，氮气保护，125度下反应1小时。LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(1-甲基哌啶-4-基)哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈24 40mg，产率21％。
1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝7.1Hz,1H),7.79(d,J＝7.8Hz,1H),7.63(s,1H),7.62(d,J＝8.3Hz,1H),7.35(t,J＝7.8Hz,1H),6.98(s,1H),5.64(p,J＝6.9Hz,1H),3.86(s,3H),3.17-2.99(m,4H),2.85-2.80(m,2H),2.72(s,3H),2.67-2.64(m,4H),2.30(s,3H),2.24- 2.20(m,1H),2.18(s,3H),2.02-1.86(m,2H),1.79-1.75(m,2H),1.53(d,J＝7.1Hz,3H)1.48-1.45(m,2H)ppm.
MS m/z(ESI):514.4[M+1] +
实施例25
(R)-3-(1-((6-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000062
在25mL烧瓶中加入(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈23c(120.0mg,0.24mmol)，二氯甲烷(6mL)，乙醛(31.7mg,0.721mmol)，醋酸(14.4mg,0.24mmol)，室温下反应2小时，加入氰基硼氢化钠(45.3mg,0.72mmol)，室温下继续反应1小时。LC-MS显示反应完全，加入乙酸乙酯，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((6-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈25 60mg，产率45％。
1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝7.1Hz,1H),7.81(d,J＝8.0,1H),7.65(s,1H),7.62(d,J＝7.9Hz,1H),7.35(t,J＝7.8Hz,1H),6.98(s,1H),5.65(p,J＝6.9Hz,1H),3.87(s,3H),3.67-3.43(m,2H),2.72(s,3H),2.69-2.60(m,3H),2.30(s,3H),1.92-1.89(m,2H),1.68-1.60(m,2H),1.54(d,J＝7.0Hz,3H),1.08(t,J＝7.2Hz,3H)ppm.
MS m/z(ESI):528.3[M+1] +
实施例26
(R)-3-(1-((7-acetyl-2-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-乙酰基-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000063
第一步
methyl 4-bromo-2-nitro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)benzoate
4-溴-2-硝基-5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)苯甲酸甲酯
于50mL反应瓶中依次加入4-溴-5-氟-2-硝基-苯甲酸甲酯26a(1.2g,4.32mmol)，2-氧杂-7-氮杂螺[3.5]壬烷(1.56g,6.47mmol)，碳酸钾(1.79g,12.95mmol)，DMF(12mL)，室温下反应2小时。LC-MS显示反应完全，加入饱和氯化铵水溶液(30mL)，加入乙酸乙酯，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得4-溴-2-硝基-5-(2-氧-7-氮杂螺[3.5]壬-7-基)苯甲酸甲酯26b 1.3g，产率78％。
MS m/z(ESI)：385.1,387.0[M+H] +
第二步
methyl 2-amino-4-bromo-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)benzoate
2-氨基-4-溴-5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)苯甲酸甲酯
于50mL反应瓶中加入4-溴-2-硝基-5-(2-氧-7-氮杂螺[3.5]壬-7-基)苯甲酸甲酯26b(1.3g,3.37mmol)，铁粉(1.01g,18.17mmol)，乙酸(3mL)，乙醇(15mL)，升温至70度反应4h。LC-MS显示反应完全，浓缩蒸干溶剂，加入乙酸乙酯，加入饱和NaHCO 3水 溶液调节pH至8-10，硅藻土过滤，乙酸乙酯洗涤，有机相浓缩，所得残余物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得2-氨基-4-溴-5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)苯甲酸甲酯26c 1.1g，产率85％。
MS m/z(ESI)：355.1,357.1[M+H] +
第三步
2-amino-4-bromo-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)benzoic acid
2-氨基-4-溴-5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)苯甲酸
于反应瓶中加入2-氨基-4-溴-5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)苯甲酸甲酯26c(1.1g,3.10mmol，一水合氢氧化锂(259.9mg,6.19mmol)，甲醇(10mL)，水(2mL)，升温至65度反应3小时。LC-MS显示反应完全，加入1M HCl调节pH至2-4，浓缩蒸干溶剂，加入乙酸乙酯，水洗三次，分出有机相，减压浓缩，得2-氨基-4-溴-5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)苯甲酸26d 1.0g，产率94％。
MS m/z(ESI)：341.1[M+1]
第四步
7-bromo-2-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinazolin-4-ol
7-溴-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-醇
于50mL反应瓶中加入2-氨基-4-溴-5-(2-氧-7-氮杂螺[3.5]壬-7-基)苯甲酸26d(1.0g,2.93mmol)，乙酸酐(12mL)，140度下反应2.5小时。LC-MS显示反应完全，浓缩蒸干溶剂，将反应粗品转移至100mL封管中，加入氨水(30mL)，100度下反应3小时。浓缩除去氨水，硅胶拌样，所得残余物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得7-溴-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-醇26e 900mg，产率85％。
MS m/z(ESI)：365.1,367.1[M+H] +
第五步
(R)-3-(1-((7-bromo-2-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-溴-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
于反应瓶中加入7-溴-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-醇26e(450 mg,1.24mmol)，(R)-3-(1-胺基乙基)-2-甲基苯腈盐酸盐1g(346mg,1.48mmol)，BOP(820mg,1.85mmol)，DBU(565mg,3.71mmol)，DMSO(5mL)，室温下反应3小时。LC-MS显示反应完全，反应液中加入乙酸乙酯，水洗三次，饱和食盐水洗一次，有机相以无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得到(R)-3-(1-((7-溴-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈26f 480mg，产率76％。
MS m/z(ESI)：506.2,508.2[M+H] +
第六步
(R)-3-(1-((7-(1-ethoxyvinyl)-2-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-(1-乙氧基烯基)-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
于25mL反应瓶中加入(R)-3-(1-((7-溴-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈26f(300mg,0.592mmol)，三丁基(1-乙氧基烯基)锡烷(278.1mg,0.77mmol)，Pd(PPh 3) 2Cl 2(83.2mg,0.12mmol)，三乙胺(179.8mg,1.78mmol)，1,4-二氧六环(8mL)，氮气置换3次，100度下反应3小时。LC-MS显示反应完全，加入氟化钾搅拌，硅藻土过滤，浓缩，加入乙酸乙酯，水洗三次，饱和食盐水洗一次，有机相以无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得(R)-3-(1-((7-(1-乙氧基烯基)-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈26g 200mg，产率68％。
MS m/z(ESI)：498.3[M+H] +
第七步
(R)-3-(1-((7-acetyl-2-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-乙酰基-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
于25mL反应瓶中加入(R)-3-(1-((7-(1-乙氧基烯基)-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈26g(200mg,0.402mmol)，二氯甲烷(10mL)，三氟乙酸(0.5mL)，室温下反应1小时。LC-MS显示反应完全，加入饱和NaHCO 3水溶 液调节pH至8-10，加入乙酸乙酯萃取，有机相水洗三次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得(R)-3-(1-((7-乙酰基-2-甲基-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈26 40mg，产率24％。
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝7.0Hz,1H),7.87(s,1H),7.79(d,J＝7.9Hz,1H),7.63(d,J＝7.6Hz,1H),7.42(s,1H),7.36(t,J＝7.8Hz,1H),5.65(t,J＝7.1Hz,1H),4.38(s,4H),2.91-2.88(m,4H),2.71(s,3H),2.59(s,3H),2.33(s,3H),1.97-1.95(m,4H),1.56(d,J＝7.0Hz,3H)ppm.
MS m/z(ESI)：470.2[M+H] +
实施例27
(R)-3-(1-((6-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(4-(4-乙酰基哌嗪-1-基)哌啶-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000064
在25mL烧瓶中加入(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(哌嗪-1-基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈23c(200.0mg,0.4mmol)，乙酸酐(6mL)，140度下反应5小时。LC-MS显示反应完全，浓缩除去乙酸酐，加入水(20mL)，加入饱和碳酸氢钠溶液调节pH至弱碱性，乙酸乙酯萃取三次，有机相用饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((6-(4-(4-乙酰基哌嗪-1-基)哌啶-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈2790mg，产率40％。
MS m/z(ESI):542.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.18(d,J＝7.0Hz,1H),7.80(d,J＝7.9Hz,1H),7.62(s,1H),7.62(d,J＝7.7Hz,1H),7.35(t,J＝7.8Hz,1H),6.97(s,1H),5.64(q,J＝7.2Hz,1H),3.87(s,3H),3.58-3.47(m,3H),3.45-3.41(s,4H),2.72(s,3H),2.71-2.59(m,2H),2.55-2.39(m,3H),2.30(s,3H),1.99(s,3H),1.87-1.84(m,2H),1.68-1.59(m,2H),1.53(d,J＝6.9Hz,3H)ppm.
实施例28
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(morpholine-4-carbonyl)piperidin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(***啉-4-羰基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000065
在25mL烧瓶中加入(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-甲酸22b(200mg,0.435mmol)，加入***啉(49.3mg,0.59mmol)，HATU(248.2mg,0.65mmol)，DMF(5mL)，三乙胺(220.2mg,2.18mmol)，室温下反应过夜。LC-MS显示反应完全，加入乙酸乙酯洗涤，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(***啉-4-羰基)哌啶-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈28 200mg，产率83％。
MS m/z(ESI):529.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.34(s,1H),7.80(d,J＝7.9Hz,1H),7.65(s,1H),7.63(d,J＝8.3Hz,1H),7.36(t,J＝7.8Hz,1H),6.98(s,1H),5.65(q,J＝7.3Hz,1H),3.88(s,3H),3.59-3.56(m,6H),3.48(s,4H),2.85-2.75(m,3H),2.71(s,3H),2.32(s,3H),1.84-1.76(m,4H),1.54(d,J＝6.9Hz,3H)ppm.
实施例29
(R)-1-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)-N-(2-hydroxyethyl)-N-methylpiperidine-4-carboxamide
(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-N-(2-羟基乙基)-N-甲基-哌啶-4-酰胺
Figure PCTCN2022115379-appb-000066
在25mL烧瓶中加入(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-4-甲酸22b(150mg,0.326mmol)，加入2-(甲基氨基)乙基-1-醇盐酸盐(31.9mg,0.424mmol)，HATU(186.2mg,0.49mmol)，DMF(2mL)，三乙胺(165.2mg,1.63mmol)，室温下反应过夜。LC-MS显示反应完全，加入乙酸乙酯洗涤，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-1-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-N-(2-羟基乙基)-N-甲基-哌啶-4-酰胺29 20mg，产率11％。
MS m/z(ESI):517.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.67(s,1H),7.81(d,J＝7.9Hz,1H),7.75(s,1H),7.63(d,J＝7.6Hz,1H),7.37(t,J＝7.8Hz,1H),7.02(s,1H),5.69(q,J＝7.0Hz,1H),4.74(s,1H),3.90(s,3H),3.56-3.53(m,4H),3.24-3.21(m,4H),3.08-3.05(m,4H),2.85(s,3H),2.71(s,3H),2.36(s,3H),1.56(d,J＝7.0Hz,3H)ppm.
实施例30
ethyl(R)-4-(4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)piperazine-1-carboxylate
(R)-4-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌嗪-1-甲酸乙酯
Figure PCTCN2022115379-appb-000067
第一步
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(411mg,1mmol)，Boc-哌嗪(372.5mg,2mmol)，三(二亚苄基丙酮)二钯(84mg,0.1mmol)，1,1'-联萘-2,2'-双二苯膦(127mg,0.2mmol)和叔丁醇钠(384.4mg,4mmol)加入到微波管中，加入1,4-二氧六环(20mL)，N 2保护，125度下微波反应1小时，LC-MS显示反应完全，反应液冷却至室温，硅藻土过滤，乙酸乙酯洗涤，收集有机相，水洗三次，饱和食盐水洗一次，有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-4-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌嗪-1-甲酸叔丁酯30a 358mg，产率70％。
MS m/z(ESI):517.3[M+H] +
第二步
将(R)-4-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌嗪-1-甲酸叔丁酯30a(358mg,0.69mmol)加入到50mL反应瓶中，加入1,4-二氧六环(15mL)，加入4M HCl/1,4-二氧六环溶液(6mL)，室温下搅拌4个小时。LC-MS显示反应完全，减压出去溶剂，加入乙酸乙酯，饱和碳酸氢钠调节pH至弱碱性，萃取，有机相水洗三次，饱和食盐水洗一次，减压出去溶剂，得(R)-3-(1-((7-甲氧基-2-甲基-6-(哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈30b粗品276mg，直接用于下一步反应。
MS m/z(ESI):417.2[M+H] +
第三步
将(R)-3-(1-((7-甲氧基-2-甲基-6-(哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈30b(80mg,0.19mmol)加入到25mL单口瓶中，加入二氯甲烷(10mL)，三乙胺(0.2mL)，氯甲酸乙酯(42mg,0.38mmol)，室温下反应1小时。LC-MS显示反应完全，加入二氯甲烷，水洗三次，饱和食盐水洗一次有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-4-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)哌嗪-1-甲酸乙酯40.5mg，产率41％。
MS m/z(ESI):489.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.19(d,J＝7.5Hz,1H),7.78(d,J＝7.9Hz,1H),7.67(s,1H),7.62(d,J＝7.5Hz,1H),7.36(t,J＝7.8Hz,1H),7.00(s,1H),5.64(p,J＝7.1Hz,1H),4.08(q,J ＝7.0Hz,2H),3.88(s,3H),3.56(s,4H),3.03(d,J＝5.1Hz,4H),2.71(s,3H),2.30(s,3H),1.53(d,J＝6.9Hz,3H),1.21(t,J＝7.1Hz,3H)ppm.
实施例31
(R)-3-(1-((7-methoxy-2-methyl-6-(4-(morpholine-4-carbonyl)piperazin-1-yl)quinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(***啉-4-羰基)哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000068
将(R)-3-(1-((7-甲氧基-2-甲基-6-(哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈30b(80mg,0.19mmol)加入到25mL单口瓶中，加入二氯甲烷(5mL)，三乙胺(0.2mL)，***啉-4-酰氯(57.5mg,0.38mmol)，室温下反应3小时。LC-MS显示反应完全，加入二氯甲烷，水洗三次，饱和食盐水洗一次有机相使用无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((7-甲氧基-2-甲基-6-(4-(***啉-4-羰基)哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-2-甲基苯腈16.1mg，产率16％。
MS m/z(ESI):530.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.19(d,J＝7.4Hz,1H),7.79(d,J＝7.9Hz,1H),7.67(s,1H),7.62(d,J＝7.7Hz,1H),7.36(t,J＝7.8Hz,1H),7.00(s,1H),5.93–5.52(m,1H),3.88(s,3H),3.59(s,4H),3.37-3.18(m,8H),3.07-3.01(m,4H),2.72(s,3H),2.30(s,3H),1.53(d,J＝7.0Hz,3H)ppm.
实施例32
(R)-3-(1-((6-(1-acetyl-4-methoxypiperidin-4-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((6-(1-乙酰基-4-甲氧基-哌啶-4-yl)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
Figure PCTCN2022115379-appb-000069
第一步
将(R)-3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈1i(1.64g,4mmol)，加入到250mL三口瓶中，加入四氢呋喃(40mL)，抽换氮气三次，降温至-78度，加入2.7M甲基锂的二乙氧基甲烷溶液(2.3mL，6mmol)，保温反应15分钟。加入2.5M正丁基锂的正己烷溶液(2.4mL,6mmol)，保温反应1小时。将4-氧代-哌啶-1-甲酸叔丁酯(2.39g,12mmol)溶于四氢呋喃(20mL)中，通过注射器缓慢加入到上述反应液中。加入完毕，恢复室温反应2个小时。加入饱和氯化铵溶液进行淬灭，乙酸乙酯萃取，有机相水洗三次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩有机相，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-4-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-4-羟基-哌啶-1-甲酸叔丁酯32a 500mg，产率24％。
MS m/z(ESI):532.3[M+H] +
第二步
将(R)-4-(4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)-4-羟基-哌啶-1-甲酸叔丁酯32a(500mg，0.71mmol)加入到100mL单口瓶中，加入1,4-二氧六环(20mL)，加入4M氯化氢/1,4-二氧六环溶液(5mL)，室温下反应2个小时。LC-MS检测原料反应完全，减压除去溶剂，得(R)-3-(1-((6-(4-羟基-哌啶-4-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈32b的粗品350mg，直接用于下一步。
MS m/z(ESI):432.3[M+H] +
第三步
将(R)-3-(1-((6-(4-羟基-哌啶-4-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈32b的粗品350mg溶于DMF(5mL)中，加入乙酸(83.5mg)，HATU(528mg)，DIPEA(360mg)，室温下搅拌过夜。LC-MS检测原料反应完全，加入乙酸乙酯，水洗三次，有机相水用饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((6-(1-乙酰基-4-羟基-哌啶-4-yl)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈32c 200mg产物，两步合并产率60％。
MS m/z(ESI):474.3[M+H] +
第四步
将(R)-3-(1-((6-(1-乙酰基-4-羟基-哌啶-4-yl)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈32c(200mg,0.36mmol)加入到二氯甲烷(5mL)中，冰浴下冷却至0度，加入DAST(173.6mg,1.08mmol)，恢复至室温下反应3个小时。LC-MS检测原料反应完全，加入饱和碳酸氢钠水溶液调节pH至7-9，分出有机相，水相用二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物用硅胶柱层析法(洗脱剂：B体系)纯化，得(R)-3-(1-((6-(1-乙酰基-4-氟-哌啶-4-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈32d 110mg，产率65％。
MS m/z(ESI):476.3[M+H] +
第五步
在25mL单口瓶中加入(R)-3-(1-((6-(1-乙酰基-4-氟-哌啶-4-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈32d(110mg,0.23mmol)，甲醇/水(5mL/2.5mL)，甲醇钠(125.0mg,2.3mmol)，70度下反应8小时。LC-MS检测原料转化完全，减压除去溶剂，加入乙酸乙酯，水洗三次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，得(R)-3-(1-((6-(1-乙 酰基-4-甲氧基-哌啶-4-yl)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯腈32 21mg，产率18％。
MS m/z(ESI):488.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.48(s,1H),8.10(s,1H),7.80(s,1H),7.62(d,J＝7.7Hz,1H),7.36(t,J＝7.8Hz,1H),7.05(s,1H),5.66(t,J＝6.9Hz,1H),4.38-4.33(m,1H),3.86(s,3H),3.72-3.67(m,1H),3.43-3.39(m,1H),2.95(s,3H),2.90-2.84(m,1H),2.72(s,3H),2.42-2.37(m,2H),2.32(s,3H),2.27-2.25(m,1H),2.03(s,3H),1.98-1.94(m,1H),1.55(d,J＝6.9Hz,3H)ppm.
生物学评价
测试例1.本发明化合物阻断KRAS G12C蛋白与SOS1结合的测试
以下方法用于测定本发明化合物在体外条件下阻断SOS1与KRAS G12C蛋白相互作用的能力。本方法使用Cisbio公司的KRAS-G12C/SOS1BINDING ASSAY KITS试剂盒(货号63ADK000CB16PEG)，详细实验操作可参考试剂盒说明书。
将实验流程简述如下：使用稀释缓冲液(diluent buffer)(货号62DLBDDF)配置Tag1-SOS1和Tag2-KRAS-G12C蛋白为5X的工作液浓度备用。受试化合物溶解于DMSO中制备为10mM贮存液，随后使用稀释缓冲液进行稀释备用。首先向孔中加入2μL受试化合物(反应体系终浓度为10000nM-0.1nM)，随后加入4μL Tag1-SOS1 5X的工作液和4μL Tag2-KRAS-G12C 5X的工作液，离心并混匀，静置15分钟；随后加入10μL预混匀的anti-Tag1-Tb 3+和anti-Tag2-XL665，室温下孵育2小时；最后使用酶标仪以TF-FRET模式上测定在304nM的激发波长下，各孔发射波长为620nM和665nM的荧光强度，并计算各孔665/620的荧光强度比值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算受试化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以受试化合物浓度对数值-抑制率进行非线性回归分析，获得化合物的IC 50值，结果见下表1。
表1本发明化合物阻断KRAS G12C蛋白与SOS1结合活性表
Figure PCTCN2022115379-appb-000070
Figure PCTCN2022115379-appb-000071
结论：本发明化合物对于KRAS G12C与SOS1蛋白相互作用具有较强的阻断作用。
测试例2.本发明化合物对OCI-AML5细胞增殖抑制测定
以下方法用于测定本发明化合物对OCI-AML5细胞增殖的影响。OCI-AML5细胞(含有SOS1N233Y突变)购于南京科佰生物科技有限公司，培养于含10％胎牛血清、100U青霉素和100μg/mL链霉素的MEMα培养基中。细胞活力通过CellTiter-
Figure PCTCN2022115379-appb-000072
Luminescent Cell Viability Assay试剂盒(Promega，货号G7573)进行测定。
实验方法按照试剂盒说明书的步骤操作，简述如下：受试化合物首先溶解于DMSO中制备为10mM贮存液，随后以培养基进行稀释，配制成测试样品，化合物的终浓度范围在10000nM-0.15nM。将处于对数生长期的细胞以1000个细胞每孔的密度接种至96孔细胞培养板中，在37℃，5％CO 2培养箱中培养过夜，随后加入受试化合物后继续培养120小时。培养结束后，向每孔加入50uL体积的CellTiter-Glo检测液，震荡5分钟后静置10分钟，随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.3％DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率，之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析，获得化合物抑制细胞增殖的IC 50值，结果见下表2。
表2本发明化合物对OCI-AML5细胞增殖抑制活性表
Figure PCTCN2022115379-appb-000073
Figure PCTCN2022115379-appb-000074
结论：本发明化合物对OCI-AML5细胞增殖具有较好的抑制作用。
测试例3.本发明化合物对DLD-1细胞中p-ERK1/2抑制活性的测定
以下方法用于测定本发明化合物对DLD-1细胞中p-ERK1/2抑制活性。本方法使用Cisbio公司的Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒(货号64AERPEH)，详细实验操作可参考试剂盒说明书。DLD-1细胞(含有KRAS G13D突变)购于中国科学院上海生命科学研究院细胞资源中心。
将实验流程简述如下：DLD-1细胞培养于含10％胎牛血清、100U青霉素，100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640完全培养基中。DLD-1细胞按每孔30000个铺于96孔板中，培养基为完全培养基，在37℃，5％CO2培养箱内培养过夜。将受试化合物溶解于DMSO中制备为10mM贮存液，随后使用RPMI 1640基础培养基进行稀释，每孔加入90uL含对应浓度受试化合物的RPMI 1640基础培养基，受试化合物在反应体系中的终浓度范围为10000nM-0.15nM，置于细胞培养箱培养3小时40分钟。随后加入10uL用RPMI 1640基础培养基配制的hEGF(购自Roche，货号11376454001)，使其终浓度为5nM，置于培养箱培养 20分钟。弃去细胞上清，使用冰浴的PBS清洗细胞，之后每孔加入45μl的1×细胞磷酸化/总蛋白裂解缓冲液(cell phospho/total protein lysis buffer)(Advanced phospho-ERK1/2试剂盒组分)进行裂解，96孔板置于冰上裂解半小时，随后参照Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒说明书检测裂解液。最后在酶标仪以TF-FRET模式上测定在304nM的激发波长下，各孔发射波长为620nM和665nM的荧光强度，并计算各孔665/620的荧光强度比值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算受试化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以受试化合物浓度对数值-抑制率进行非线性回归分析，获得化合物的IC 50值，结果见下表3。
表3本发明化合物对DLD-1细胞中p-ERK1/2抑制活性表
Figure PCTCN2022115379-appb-000075
结论：本发明化合物对DLD-1细胞ERK磷酸化具有较好的抑制作用。
测试例4.本发明化合物对NCI-H358细胞增殖抑制测定
以下方法用于测定本发明化合物对NCI-H358细胞在三维(3D)非锚定条件下细胞增殖的影响。NCI-H358细胞(含有KRAS G12C突变)购于中国科学院上海生命科学研究院细胞资源中心，培养于含10％胎牛血清、100U青霉素，100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640培养基中。细胞活力通过CellTiter-
Figure PCTCN2022115379-appb-000076
3D Cell Viability Assay试剂盒(Promega，货号G9683)进行测定。
实验方法按照试剂盒说明书的步骤操作，简述如下：受试化合物首先溶解于DMSO中制备为10mM贮存液，随后以培养基进行稀释，配制成测试样品，化合物的终浓度范围在 10000nM-0.15nM。将处于对数生长期的细胞以2000个细胞每孔的密度接种至超低吸附384孔细胞培养板(PerkinElmer,#3830)中，并加入受试化合物后继续培养120小时。培养结束后，向每孔加入30uL体积的CellTiter-Glo 3D检测液，震荡30分钟后静置120分钟，随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.1％DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率，之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析，获得化合物抑制细胞增殖的IC 50值，结果见下表4。
表4本发明化合物对NCI-H358细胞增殖抑制活性表
Figure PCTCN2022115379-appb-000077
结论：本发明化合物对H358细胞增殖具有较好的抑制作用。
测试例5.本公开化合物在ICR小鼠体内的药代动力学评价
1、摘要
以ICR正常小鼠为受试动物，应用LC/MS/MS测定ICR小鼠灌胃给予化合物后不同时刻血浆中的药物浓度。研究本发明化合物在ICR小鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1试验药品
化合物4、26和32。
2.2试验动物
ICR小鼠，雄性，27.8-38g，购买于浙江维通利华试验动物有限责任公司。
2.3药物配制
称取适量化合物，以DMA:30％Solutol HS-15:Saline＝5:5:90(v/v/v)为溶媒，制成全溶溶 液，给药，得到1mg/mL无色溶液。
2.4给药
ICR小鼠，每个待测化合物灌胃组(每组9只)，禁食过夜后灌胃给药，给药剂量为10mg/kg，给药体积为10mL/kg。，给药4小时后进食。
3.操作
于药前及给药后0.25、0.5、1、2、4、8、12、24小时经眼眶采血0.1mL，置EDTA-K2的抗凝管中。血液样本采集后置于冰上，离心分离血浆(离心条件：1500g，10分钟)，收集的血浆分析前存放于–40～–20℃。
用LC-MS/MS测定灌胃给药后小鼠血浆中待测化合物含量。
4.药代动力学参数结果
本发明的化合物的药代动力学参数如下表所示。
表5本发明化合物的小鼠药代动力学参数
Figure PCTCN2022115379-appb-000078
结论：本发明化合物在ICR小鼠内具有良好的药代动力学性质。
测试例6.本发明化合物在Balb/c小鼠体内的药代动力学评价
1.摘要
以Balb/c正常小鼠为受试动物，应用LC/MS/MS测定balb/c小鼠灌胃给予化合物后不同时刻血浆中的药物浓度。研究本化合物在Balb/c小鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1试验药品
化合物27和30。
2.2试验动物
Balb/c正常小鼠9只，雄性，平均分为3组，每组各3只，购自浙江维通利华试验动物有 限责任公司。
2.3药物配制
称取一定量化合物，以DMA:30％Solutol HS-15:Saline＝5:5:90(v/v/v)为溶媒，制成全溶溶液，浓度为1mg/mL。
2.4给药
每个待测化合物灌胃组(每组9只)，禁食过夜后灌胃给药，给药剂量为10mg/kg，给药体积为10mL/kg，给药4小时后进食。
3.操作
于给药前及给药后0.25、0.5、1、2、4、6、8、24小时经颈静脉采血0.1mL，置0.1％肝素钠抗凝试管中。血液样本采集后置于冰上，离心分离血浆(离心条件：7000g，5分钟)。收集的血浆分析前存放于–80℃。
用LC-MS/MS测定灌胃给药后小鼠血浆中待测化合物含量。
4.药代动力学参数结果
本发明的化合物的药代动力学参数如下表所示。
表6本发明化合物的小鼠药代动力学参数
Figure PCTCN2022115379-appb-000079
结论：本发明化合物在Balb/c小鼠体内具有良好的药代动力学性质。
测试例7.本发明化合物在大鼠体内的药代动力学评价
1.实验目的
以SD大鼠为受试动物，采用LC/MS/MS法测定大鼠静脉注射或灌胃给予本发明化合物11，测定其不同时刻血浆中的药物浓度，研究本发明化合物11在SD大鼠体内的药代动力学特征。
2.实验方案
2.1实验药品
本发明化合物11；
2.2实验动物
SD大鼠，雄性，195-235g，6-8周，购自维通利华实验动物技术有限公司。
2.3药物配制
静脉注射组：称取适量待测化合物，分别加入适量DMA:30％Solutol HS-15:Saline＝5:5:90(v/v/v)，涡旋振荡，配制最终配制浓度为0.2mg/mL的溶液。
口服灌胃组：称取适量待测化合物，分别加入适量DMA:30％Solutol HS-15:Saline＝5:5:90(v/v/v)，涡旋振荡，配制最终配制浓度为1mg/mL的溶液。
2.4给药
将SD大鼠按待测化合物静脉注射组(3只/组)和灌胃组(3只/组)。
静脉注射组：禁食过夜经静脉注射给药(给药剂量1mg/kg，给药体积5mL/kg)，给药4小时后进食。
灌胃组：禁食过夜后经灌胃给药(给药剂量10mg/kg，给药体积10mL/kg)，给药4小时后进食。
3.操作
静脉注射组：于给药后0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时和24小时经颈静脉向EDTA-K2抗凝管中收集约150μL血液。样本采集后置于冰上，离心分离血浆(离心条件：1500g，10分钟)，收集的血浆分析前存放于–40～–20℃。
灌胃组：于给药后0.25小时、0.5小时、1小时、2小时、4小时、8小时和24小时经颈静脉向EDTA-K2抗凝管中收集约100μL血液。样本采集后置于冰上，离心分离血浆(离心条件：1500g，10分钟)，收集的血浆分析前存放于–40～–20℃。
用LC-MS/MS测定化合物经静脉注射和灌胃给药后大鼠血浆中待测化合物含量。
4.药代动力学参数结果
本发明的化合物的药代动力学参数如下表所示。
表7本发明化合物的大鼠药代动力学参数
Figure PCTCN2022115379-appb-000080
结论：本发明化合物在大鼠体内具有良好的药代动力学性质。
测试例8.本发明化合物在犬体内的药代动力学评价
1.实验目的
以比格犬为受试动物，采用LC/MS/MS法测定大鼠静脉注射或灌胃给予BI3406和本发明化合物11，测定其不同时刻血浆中的药物浓度，研究本发明化合物11在比格犬体内 的药代动力学特征。
2.实验方案
2.1实验药品
BI-3406和本发明化合物11；
2.2实验动物
比格犬，雄性，13～14月，购买于北京玛斯生物技术有限公司。
2.3药物配制
静脉注射组：称取适量待测化合物，加入适量DMA:30％Solutol HS-15:Saline＝5:5:90(v/v/v)，涡旋振荡，配制最终配制浓度为0.5mg/mL的溶液。
口服灌胃组：称取适量待测化合物，加入适量DMA:30％Solutol HS-15:Saline＝5:5:90(v/v/v)，涡旋振荡，配制最终配制浓度为1mg/mL的溶液。
2.4给药
将比格犬按待测化合物静脉注射组(3只/组)和灌胃组(3只/组)。
静脉注射组：禁食过夜经注射给药(给药剂量0.5mg/kg，给药体积1mL/kg)，给药4小时后进食。
灌胃组：禁食过夜后经灌胃给药(给药剂量10mg/kg，给药体积2mL/kg)，给药4小时后进食。
3.操作
静脉注射组：于给药后0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时和24小时经颈静脉向EDTA-K2抗凝管中收集约0.5mL血液。样本采集后置于冰上，离心分离血浆(离心条件：1500g，10分钟)，收集的血浆分析前存放于–40～–20℃。
灌胃组：于给药后0.25小时、0.5小时、1小时、2小时、4小时、8小时和24小时经颈静脉向EDTA-K2抗凝管中收集约0.5mL血液。样本采集后置于冰上，离心分离血浆(离心条件：1500g，10分钟)，收集的血浆分析前存放于–40～–20℃。
用LC-MS/MS测定化合物经静脉注射和灌胃给药后犬血浆中待测化合物含量。
4.药代动力学参数结果
本发明的化合物的药代动力学参数如下表所示。
表8本发明化合物的犬药代动力学参数
Figure PCTCN2022115379-appb-000081
Figure PCTCN2022115379-appb-000082
结论：与阳性化合物BI-3406相比，口服2mg/kg剂量下，本发明化合物11在比格犬体内血药浓度和曲线下面积均较高，具有良好的药代动力学性质。
备注：BI-3406通过WO2018115380制备而得，具体结构如下：
Figure PCTCN2022115379-appb-000083
测试例9.本发明化合物在人肺癌NCI-H2122裸小鼠皮下移植模型中的药效学评价
1.实验目的
评价本发明化合物11在NCI-H2122皮下移植Balb/c裸小鼠动物模型中的抗肿瘤作用和安全性评价。
2.实验动物
BALB/c；裸小鼠，雌性，6-7周(肿瘤细胞接种时的小鼠周龄)。购自江苏集萃药康生物科技有限公司。
3.受试物配制
溶媒对照组给予DMSO:蓖麻油:5％葡萄糖注射液＝20:10:70(v/v/v)。
AMG-510：称取适量的AMG-510，加入适量的DMSO:蓖麻油:5％葡萄糖注射液＝20:10:70(v/v/v)充分溶解后，加入适量1M盐酸，涡旋混匀，配置浓度为3mg/mL。
化合物11：称取适量的化合物11，加入适量的DMSO:蓖麻油:5％葡萄糖注射液＝20:10:70(v/v/v)充分溶解后，加入适量1M盐酸，涡旋混匀，配置浓度为3mg/mL。
4.细胞培养
H2122细胞培养在含10％胎牛血清和1％青-链霉素-两性酶素B溶液的1640培养液中。收集指数生长期的H2122细胞，细胞重悬于基质胶溶液(基质胶：PBS＝1:1(V/V))中至适合浓度用于裸鼠皮下肿瘤接种。
6.动物造模和随机分组
雌性Balb/c裸小鼠背部右侧皮下接种约3.0×10 6H2122细胞。待肿瘤平均体积达到约 150-200mm 3时，根据肿瘤大小随机分组，每组6只。
7.动物给药和观察
第1组(G1)，溶剂对照组；
第2组(G2)，灌胃给药AMG-510，给药剂量为30mg/kg；
第3组(G3)，灌胃给药实施例11，给药剂量为30mg/kg；
第4组(G4)，AMG-510和实施例11联合给药，给药剂量分别为：AMG-510为30mg/kg(QD)；实施例11为30mg/kg(QD)。
肿瘤接种后，常规监测包括了肿瘤生长及治疗对动物正常行为的影响，具体内容有实验动物的活动性，摄食和饮水情况，体重增加或降低情况，眼睛、被毛及其它异常情况。
相对肿瘤体积(RTV)、相对肿瘤抑制率(T/C)和肿瘤抑制百分率(IR)计算公式如下：
(1)肿瘤体积TV(tumor volume)＝1/2×a×b 2，其中a、b分别表示肿瘤的长和宽；
(2)相对肿瘤体积RTV(relative tumor volume)＝V t/V 0，其中V 0为分组给药时(即d0)所测得的肿瘤体积，V t为每一次测量时的肿瘤体积；
(3)相对肿瘤增殖率T/C(％)＝T RTV/C RTV×100％，其中T RTV为治疗组的RTV，C RTV为对照组的RTV；
(4)肿瘤生长抑制率TGI(％)＝(1-T/C)×100％；其中，T和C分别为治疗组和对照组某一特定时间点的相对肿瘤体积。
(5)IR(％)＝(1-TWt/TWc)×100％，其中TWt为治疗组瘤重，TWc为对照组瘤重。抗肿瘤评价标准为(细胞毒类药物)：T/C(％)>40％为无效；T/C(％)≤40％，并经过统计学处理P<0.05为有效。
8.结果
表10本发明化合物在NCI-H2122皮下移植瘤模型中各组裸鼠肿瘤体积随治疗时间的变化
Figure PCTCN2022115379-appb-000084
表11本发明化合物在NCI-H2122皮下移植瘤模型中各组药效分析表
Figure PCTCN2022115379-appb-000085
表12实验结束时各组动物瘤重及瘤重抑瘤率
Figure PCTCN2022115379-appb-000086
备注：数据以“平均值±标准误差”表示。
本发明化合物在NCI-H2122模型中各组小鼠肿瘤体积的变化图见图1。结论：采用KRAS-G12C抑制剂不敏感的细胞系NCI-H2122，与AMG-510联用的情况下，化合物11具有良好抗肿瘤活性。相较于溶媒对照组，各治疗组动物体重均无明显变化，给药组和溶媒对照组在实验过程中均无动物死亡，说明在本实验条件下，动物给药耐受性良好。

Claims (13)

  1. 一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2022115379-appb-100001
    其中：
    R a为氰基、-C(O)R 3或C 1-C 6烷氧基；
    R 1相同或不同，各自独立地为卤素、羟基、氨基、C 1-C 6烷基或C 1-C 6烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、氨基、C 1-C 6烷基和C 1-C 6烷氧基的取代基所取代；R 1优选为C 1-C 6烷基；更优选为甲基；
    R 2为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；其中所述的环烷基、单环杂环基、螺杂环基、桥杂环基、稠杂环基或稠合环任选进一步被一个或多个R A取代；
    R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基、-C(O)R 3和-SO 2R 4的取代基所取代；
    R 3各自独立地为C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基，其中所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；所述的杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基的取代基所取代；
    R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
    R 5和R 6各自独立地为氢原子或C 1-C 6烷基，其中所述的烷基任选地进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
    或者，R 5、R 6与所连的N原子形成4-10元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)R 7和C 3-C 6环烷基的取代基所取代；
    R 7为C 1-C 3烷基或C 3-C 6环烷基，所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
    m为0、1、2、3或4。
  2. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2022115379-appb-100002
    其中：
    R a为氰基、乙酰基或甲氧基；
    环B为C 3-C 6环烷基、3-6元单环杂环基、6-11元螺杂环基、6-11元桥杂环基、6-11元稠杂环基或6-11元稠合环；
    R A各自独立地为卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3-8元杂环基、-C(O)R 3或-SO 2R 4，其中所述的烷基、烷氧基或环烷基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基和-SO 2R 4的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、硝基、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基、-C(O)R 3和-SO 2R 4的取代基所取代；
    R 3为C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 6环烷基、-NR 5R 6或3-6元杂环基；其中所述的烷基或环烷基任选进一步被一个或多个选自卤素、氰基和C 1-C 6烷基的取代基所取代；所述的杂环基任选进一步被一个或多个选自卤素、氰基、氧代基和C 1-C 6烷基的取代基所取代；
    R 4各自独立地为氨基、C 1-C 6烷基或C 3-C 6环烷基；
    R 5和R 6各自独立地为氢原子或C 1-C 6烷基，其中所述的烷基任选地进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
    或者，R 5、R 6与所连的N原子形成4-10元杂环，所形成的杂环任选进一步被选自卤素、氰基、羟基、氨基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)R 7和C 3-C 6环烷基的取代基所取代；
    R 7为C 1-C 3烷基或C 3-C 6环烷基，所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氨基、氰基和C 1-C 6烷氧基的取代基所取代；
    n为0、1、2或3。
  3. 根据权利要求2所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中环B为以下基团：
    Figure PCTCN2022115379-appb-100003
  4. 根据权利要求2所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中
    Figure PCTCN2022115379-appb-100004
    为以下基团：
    Figure PCTCN2022115379-appb-100005
    Figure PCTCN2022115379-appb-100006
  5. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 1为甲基。
  6. 根据权利要求1～2中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，R a为甲氧基。
  7. 根据权利要求1～2中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，R a为乙酰基。
  8. 根据权利要求1～2中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中所述的化合物为：
    Figure PCTCN2022115379-appb-100007
    Figure PCTCN2022115379-appb-100008
    Figure PCTCN2022115379-appb-100009
  9. 一种药物组合物，所述的药物组合物含有有效剂量的根据权利要求1～8中任何一项 所述的化合物或其立体异构体、互变异构体或其可药用的盐，以及可药用的载体、赋形剂或它们的组合物。
  10. 权利要求1～8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或权利要求9所述的药物组合物在制备SOS1抑制剂中的用途。
  11. 权利要求1～8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或权利要求9所述的药物组合物在制备用于治疗由SOS1介导的疾病的药物中的用途，其中所述的由SOS1介导的疾病优选为RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性疾病。
  12. 根据权利要求11所述的用途，其中所述的由SOS1介导的疾病为肺癌、胰腺癌、结肠癌、膀胱癌、***癌、胆管癌、胃癌、弥漫性大B细胞淋巴瘤、神经纤维瘤、努南综合征、心面皮肤综合征、Ⅰ型遗传性齿龈纤维瘤、胚胎性横纹肌肉瘤、塞尔托利细胞睾丸瘤或皮肤颗粒细胞瘤。
  13. 组合物，其包含根据权利要求1～8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求9所述的药物组合物，与其他药物，所述的其他药物优选为KRAS G12C的抑制剂。
PCT/CN2022/115379 2021-08-30 2022-08-29 喹唑啉类衍生物、或其制备方法和用途 WO2023030216A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280057101.5A CN117940411A (zh) 2021-08-30 2022-08-29 喹唑啉类衍生物、或其制备方法和用途

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN202111003188.1 2021-08-30
CN202111003188 2021-08-30
CN202111325366 2021-11-10
CN202111325366.2 2021-11-10
CN202210090957 2022-01-26
CN202210090957.4 2022-01-26
CN202210428769.8 2022-04-22
CN202210428769 2022-04-22

Publications (1)

Publication Number Publication Date
WO2023030216A1 true WO2023030216A1 (zh) 2023-03-09

Family

ID=85410850

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/115379 WO2023030216A1 (zh) 2021-08-30 2022-08-29 喹唑啉类衍生物、或其制备方法和用途

Country Status (2)

Country Link
CN (1) CN117940411A (zh)
WO (1) WO2023030216A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101619043A (zh) * 2008-06-30 2010-01-06 和记黄埔医药（上海）有限公司 喹唑啉衍生物及其医药用途
WO2010002845A2 (en) * 2008-06-30 2010-01-07 Hutchison Medipharma Enterprises Limited Quinazoline derivatives
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2021105960A1 (en) * 2019-11-29 2021-06-03 Lupin Limited Substituted tricyclic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101619043A (zh) * 2008-06-30 2010-01-06 和记黄埔医药（上海）有限公司 喹唑啉衍生物及其医药用途
WO2010002845A2 (en) * 2008-06-30 2010-01-07 Hutchison Medipharma Enterprises Limited Quinazoline derivatives
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2021105960A1 (en) * 2019-11-29 2021-06-03 Lupin Limited Substituted tricyclic compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HOU JU; WAN SHANHE; WANG GUANGFA; ZHANG TINGTING; LI ZHONGHUANG; TIAN YUANXIN; YU YONGHUAN; WU XIAOYUN; ZHANG JIAJIE: "Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 118, 20 April 2016 (2016-04-20), AMSTERDAM, NL , pages 276 - 289, XP029562551, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2016.04.026 *
XU YAN-ZHAO; WEN HUI; CUI HUA-QING: "Research progress of KRAS inhibitors", ACTA PHARMACEUTICA SINICA, vol. 56, no. 6, 29 January 2021 (2021-01-29), CN , pages 1562 - 1570, XP009544183, ISSN: 0513-4870, DOI: 10.16438/j.0513-4870.2020-1834 *

Also Published As

Publication number Publication date
CN117940411A (zh) 2024-04-26

Similar Documents

Publication Publication Date Title
JP7381492B2 (ja) Ｍｔｏｒ阻害剤としてのｃ２６－連結ラパマイシン類似体
TWI647214B (zh) 雙環稠合之雜芳基或芳基化合物類
CN114901366A (zh) Ras抑制剂
CN113498342A (zh) 参与协同结合的化合物和其用途
WO2020253862A1 (zh) 含氮芳基磷氧化物类衍生物、其制备方法和应用
DK2947086T3 (en) UNKNOWN CONDENSED PYRIMIDINE COMPOUND OR SALT THEREOF
CN114867735A (zh) Ras抑制剂
CN112119075A (zh) 稠环化合物
JP2020505376A (ja) アロステリックｓｈｐ２阻害剤としてのピリジン化合物
CN112771054A (zh) 作为mTOR抑制剂的C40-、C28-及C-32连接的雷帕霉素类似物
CN115835908A (zh) 作为fgfr抑制剂的双环杂环
WO2019174533A1 (zh) Pd-1/pd-l1类小分子抑制剂及其在药物中的应用
WO2021143823A1 (zh) 吡啶或嘧啶类衍生物及其制备方法和用途
JP2019515931A (ja) イソキノリン−３イル−カルボキサミドならびにその調製および使用の方法
CN114025844A (zh) 蛋白酪氨酸磷酸酶抑制剂及其使用方法
CN110546150B (zh) 含吡唑基的三并环类衍生物、其制备方法和应用
CN114423753A (zh) 作为cd38抑制剂的杂双环酰胺
JP2024513881A (ja) オキサゼピン化合物及びがんの治療におけるその使用
WO2021190417A1 (zh) 新型氨基嘧啶类egfr抑制剂
CN115916194A (zh) 用于延迟、预防和治疗针对ras抑制剂的获得性抗性的方法
WO2023025116A1 (zh) 杂环类衍生物、其制备方法及其医药上的用途
WO2020168927A1 (zh) 含氮并环化合物、其制备方法及用途
CN113387962A (zh) 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用
WO2022111526A1 (zh) 一种苯环衍生物及其组合物和药学上的应用
WO2020238776A1 (zh) 取代的稠合双环类衍生物、其制备方法及其在医药上的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22863352

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE