WO2022017339A1 - Fused pyridazine derivative, preparation method therefor and pharmaceutical use thereof - Google Patents

Fused pyridazine derivative, preparation method therefor and pharmaceutical use thereof Download PDF

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Publication number
WO2022017339A1
WO2022017339A1 PCT/CN2021/107220 CN2021107220W WO2022017339A1 WO 2022017339 A1 WO2022017339 A1 WO 2022017339A1 CN 2021107220 W CN2021107220 W CN 2021107220W WO 2022017339 A1 WO2022017339 A1 WO 2022017339A1
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Prior art keywords
alkyl
cancer
cycloalkyl
haloalkyl
group
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PCT/CN2021/107220
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French (fr)
Chinese (zh)
Inventor
李心
陈阳
王斌
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2022017339A1 publication Critical patent/WO2022017339A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused pyridazine derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SOS1 inhibitor Use of the agent and use in the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of SOS1.
  • RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies are associated with mutations in the RAS gene.
  • the RAS family includes KRAS, NRAS and HRAS, of which KRAS mutations are the most common, accounting for about 85%.
  • KRAS is activated, it regulates the functions of cell proliferation, survival, migration and metabolism through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc.
  • the protein is continuously activated, which leads to the continuous activation of downstream signaling pathways and promotes tumorigenesis.
  • KRAS Due to the lack of traditional small-molecule binding sites on the surface of KRAS protein, and its ultra-high affinity for guanylate, it is extremely difficult to inhibit, and it has long been regarded as an undruggable drug target. However, based on the importance and prevalence of aberrant KRAS activation in cancer progression, KRAS has been and remains a target of great interest in drug development.
  • the current drug development ideas for inhibiting the KRAS pathway mainly include the following aspects:
  • KRAS G12C The small-molecule covalent inhibitor developed for KRAS G12C can irreversibly lock the G12C mutant in an inactive state.
  • the clinical phase I data of Amgen and mirati have shown good results.
  • the mutation of KRAS G12C is only one of its many mutations, and other important mutants such as G12V, G12D, G12S, G12A, G13V/D still lack effective drugs.
  • KRAS such as farnesyl transferase
  • KRAS G12C inhibitors there is still a lack of broad-spectrum KRAS inhibitors that are effective against multiple mutations.
  • Blocking the binding of KRAS activating molecules to KRAS such as selective inhibition of SOS1, a small molecule inhibitor of guanine nucleotide exchange factor (GEF) can block KRAS activation by interfering with the RAS-SOS1 interaction. It can achieve the purpose of broad-spectrum inhibition of KRAS activity.
  • GEF guanine nucleotide exchange factor
  • KARS protein is a small GTPase (small GTPase), in cells, KRAS protein is between inactive state (binding to guanosine diphosphate (GDP)) and activated state (binding to guanosine triphosphate (GTP)) convert. This transition is regulated by guanine nucleotide exchange factor (GEF) and GTPases activating protein (GAP).
  • GEF guanine nucleotide exchange factor
  • GAP GTPases activating protein
  • SOS1 Since the expression level of SOS1 is higher than that of SOS2, and its activity is stronger than that of SOS2, the current research on SOS mainly focuses on SOS1.
  • the specific activation pathway of SOS1 for KRAS protein is as follows: after upstream signals (such as growth factors) activate membrane surface receptors, SOS1 is activated through SHP2-Grb2, SOS1 binds to KRAS, and catalyzes the dissociation of KRAS from GDP by causing a series of conformational changes , and then combined with GTP to form active KRAS-GTP.
  • Patent applications that have disclosed compounds as SOS1 inhibitors include WO2018115380A1, WO2019122129A1, WO2018172250A1, and WO2016077793A1, among others.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
  • Ring A is aryl or heteroaryl
  • G is CR 5 or N atom
  • R 1 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
  • R 2 is selected from halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with Substituted with one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;
  • R 3 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH 2 ) p NR 6 R 7 ;
  • R and R 5 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heterocycle Aryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro and -(CH 2 ) q NR 11 R 12 is substituted with one or more substituents;
  • R 8 is the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH 2 ) p NR 6 R 7 , nitro alkyl, hydroxy, hydroxyalkyl, -S(O) 2 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, - (CH 2) q Substituted with one or more substituents in NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 and R 10 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH 2 ) q NR 11 R 12 , a cycloalkyl group and a heterocyclic group, wherein said Alkyl, cycloalkyl and heterocyclyl are each independently optionally selected from hydroxy, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino and nitro One or more substituents are substituted;
  • R 6 , R 7 , R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • p and q are the same or different, each independently selected from 0, 1 and 2;
  • n is selected from 0, 1, 2, 3, 4 and 5.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
  • Ring A is aryl or heteroaryl
  • G is CR 5 or N atom
  • R 0 is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , cycloalkyloxy , heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S(O) 2 Substituted with one or more substituents in R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
  • R 2 is selected from halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with Substituted with one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;
  • R 3 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH 2 ) p NR 6 R 7 ;
  • R and R 5 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heterocycle Aryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro and -(CH 2 ) q NR 11 R 12 is substituted with one or more substituents;
  • R 8 is the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH 2 ) p NR 6 R 7 , nitro alkyl, hydroxy, hydroxyalkyl, -S(O) 2 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, - (CH 2) q Substituted with one or more substituents in NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 and R 10 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH 2 ) q NR 11 R 12 , a cycloalkyl group and a heterocyclic group;
  • R 6 , R 7 , R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • p and q are the same or different, each independently selected from 0, 1 and 2;
  • n is selected from 0, 1, 2, 3, 4 and 5.
  • a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein G is CR 5 , and R 5 is as defined in general formula (I); preferably, G is CH.
  • a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt which is the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Rings A, R, R 0 , R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (I).
  • a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 0 is selected from alkoxy, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, hetero Cyclic, aryl and heteroaryl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , a 10 alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) 2 R 9 and -C (O) R or wherein, R 9 and R 10 are the same or different, and each is independently selected from a hydrogen atom, an
  • R 0 is selected from cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from hydroxy and -C(O)R 10 ; R 10 is alkyl;
  • R 0 is selected from C 1-6 alkoxy, five-membered heterocyclyloxy and six-membered heterocyclyl, and the five-membered heterocyclyloxy and six-membered heterocyclyl are each independently any optionally substituted by -C(O)R 10 and/or hydroxy, wherein R 10 is C 1-6 alkyl;
  • R 0 is selected from tetrahydrofuranyloxy and piperidinyl, each of said tetrahydrofuranyloxy and piperidinyl is independently optionally substituted by -C(O)R 10 and/or hydroxy, wherein R 10 is C 1-6 alkyl.
  • R 0 is selected from W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • u 0, 1, 2, 3, 4, or 5;
  • v 0, 1, 2, or 3;
  • R 9 to R 10 are as defined in the general formula (I).
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • v 0, 1, 2, or 3;
  • R 9 to R 10 are as defined in the general formula (I).
  • a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 13a is -C(O)R 10 ; R 10 is C 1-6 alkyl or C 1-6 hydroxyalkyl, The C 1-6 alkyl groups may optionally be substituted with C 1-6 alkoxy groups and cyano groups.
  • a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 13 and R 13b are preferably hydrogen atoms.
  • a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, Diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 13c is -C(O)R 10 ; R 10 is diC 1-6 alkylamino or 3-6 membered heterocycle base; preferably, R 13c is -C(O) -diC 1-6 alkylamino or -C(O)-5- to 6-membered heterocyclyl; more preferably, R 13c is -C(O)N (CH 3 ) 2 or -C(O)morpholinyl.
  • a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, Diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is the compound represented by the general formula (III) or its tautomer, meso, racemate, para Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R, R 0 , R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (I).
  • R 8 are the same or different, each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, -(CH 2 ) p NR 6 R 7 and C 1-6 hydroxyalkyl , wherein the C 1-6 haloalkyl group is optionally substituted by one or more hydroxyl groups; R 6 and R 7 are hydrogen atoms or C 1-6 alkyl groups, and p is 0, 1 or 2.
  • R 1 is selected from hydrogen atom, C 1-6 alkyl and halogen.
  • R 1 is C 1-6 alkyl.
  • R 1 is methyl
  • R 2 is selected from halogen, alkyl, haloalkyl and hydroxyalkyl;
  • R 2 is a hydrogen atom or a C 1-6 alkyl group.
  • R 2 is methyl
  • a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 3 is selected from a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl, wherein said alkyl, haloalkyl , hydroxyalkyl, and cycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, and hydroxyalkyl;
  • R 3 is selected from a hydrogen atom, alkyl, haloalkyl, and hydroxyalkyl.
  • R 3 is a hydrogen atom or a C 1-6 alkyl group.
  • R 2 is C 1-6 alkyl.
  • R 3 is a hydrogen atom.
  • a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 4 is selected from hydrogen, halo, alkyl, haloalkyl and hydroxyalkyl; preferably, R 4 is selected from From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl;
  • R 4 is a hydrogen atom.
  • R is C 1-6 alkoxy
  • R is methoxy
  • a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, - ( CH 2 ) p NR 6 R 7 and cyano; R 6 and R 7 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; p is 0, 1 or 2;
  • R 5 is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 5 is a hydrogen atom.
  • a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 6 and R 7 are the same or different, are each independently selected from hydrogen atom, alkyl, haloalkyl, and hydroxyalkyl base;
  • R 6 and R 7 are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
  • R 11 and R 12 are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
  • R 9 and R 10 are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
  • a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • rings A, G, R, R 0 , R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
  • R 13a is -C(O)R 10 ;
  • R 10 is C 1-6 alkyl or C 1-6 hydroxyalkyl, the C 1-6 alkyl optionally can be replaced by C 1-6 alkane Oxygen and cyano group substitution;
  • R 13 and R 13b are hydrogen atoms;
  • R 13c is -C(O) -diC 1-6 alkylamino or -C(O)-5- to 6-membered heterocyclic group;
  • R 8 The same or different, each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, -(CH 2 ) p NR 6 R 7 and C 1-6 hydroxyalkyl, wherein said C 1-6 haloalkyl is optionally substituted with one or more hydroxyl groups;
  • R 6 and R 7 are hydrogen atoms or C 1-6 alkyl groups, p is 0, 1 or 2;
  • R 1 is selected from hydrogen atoms, C 1 -6 alky
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure pertains to compounds of general formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
  • X is halogen, preferably chlorine
  • R 0 is selected from bromine, iodine, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , heterocyclyl Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl
  • the groups are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S(O) 2 R 9 , - Substituted with one or more substituents in C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1 is selected from bromine, iodine, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
  • R is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy Alkyl, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, and -(CH 2 ) q NR 11 R 12 substituted by one or more substituents;
  • R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , p, q and R 4 are as defined in general formula (I).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
  • X is halogen, preferably chlorine
  • R, R 0 , R 1 , R 4 and R 5 are as defined in general formula (II).
  • Another aspect of the present disclosure pertains to compounds of general formula (IVA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
  • Rings A, G, R, R 0 , R 1 -R 4 , R 8 and n are as defined in general formula (I).
  • Another aspect of the present disclosure pertains to compounds of general formula (IAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • Ring A, G, R, R 1- R 4, the R 8- R 10 and n are as in formula (I) as defined above.
  • Another aspect of the present disclosure pertains to compounds of general formula (IIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • Ring A, R, R 1, R 3- R 5, are R 8- R 10 and n are as formula (II) as defined above.
  • Another aspect of the present disclosure pertains to compounds of general formula (IIIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
  • W is selected from oxygen atoms, sulfur atoms, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • R, R 1 , R 4- R 5 , R 8- R 10 and n are as defined in general formula (III).
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • a compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IB) or its salt to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;
  • X is halogen
  • Rings A, G, R, R 0 , R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • R 0 is
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • Rings A, G, R, R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • a compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIB) or its salt to obtain the compound of general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;
  • X is halogen
  • Rings A, R, R 0 , R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • R 0 is
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • Rings A, R, R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • a compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIIB) or its salt to obtain the compound of general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;
  • X is halogen
  • R, R 0 , R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • R 0 is
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • R, R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • a compound of general formula (IVA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Through reduction reaction, the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its mixture is obtained medicinal salt,
  • Rings A, G, R, R 0 , R 1 -R 4 , R 8 and n are as defined in general formula (IV).
  • compositions comprising a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or Table A of the present disclosure or Its tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceuticals acceptable carrier, diluent or excipient.
  • the present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof Use of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting SOS1.
  • the present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, are prepared for use in the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS ), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Use in medicine for Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer; the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer , gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer,
  • the present disclosure also relates to a method of inhibiting SOS1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (II), (III), (IV) or Table A or shown, or an interconversion thereof Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • a compound of general formula (I), (II), (III), (IV) or Table A or shown or an interconversion thereof Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method of treating and/or preventing an SOS1-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV) or Table A
  • formula (I), (II), (III), (IV) or Table A The compounds shown or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or containing pharmaceutical composition.
  • the present disclosure also relates to a treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM) -AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably for the treatment of cancer
  • a method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or shown in Table A or a tautomer, meso, exoisomer thereof Racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the cancer is preferably selected from melanoma, skin Cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer
  • the present disclosure further relates to a compound represented by the general formula (I), (II), (III), (IV) or Table A or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as SOS1 inhibitors.
  • the present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of SOS1-mediated diseases.
  • the present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome ( NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC) , Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer , nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer,
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation.
  • the compounds of the present disclosure can be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health of the patient condition, behavior of the patient, diet of the patient, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimal mode of treatment such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 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-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from H atoms, D atoms, halogens, alkyl groups , alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heterocycle One or more substituents in an aryl group.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1- ethylene (-CH (CH 3) -) , 1,2- ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl , one or more substituents of heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms Carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferably
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from H atom, D atom, halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heterocyclic atom; more preferably contains 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-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 monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above have one residue derived by removing one hydrogen atom from the parent ring atom, or two residues by removing two from the same or two different ring atoms of the parent.
  • a residue derived from a hydrogen atom namely "divalent cycloalkyl", “divalent heterocyclic group", “arylene”, “heteroarylene”.
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • hydroxyl protecting group is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups.
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silicon, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy substituted alkyl or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted with C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, t-butyl, benzyl
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2.
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl, cycloalkyl are as defined above.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or or both and Two configurations.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • the present disclosure having the structure, except that "deuterium” or “tritium” in place of a hydrogen, fluorine or instead of fluorine-labeled with 18 F- (18 F isotope), or with 11 C- 13 C-, 14 C- or rich, Compounds in which a set of carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) in place of carbon atoms are within the scope of this disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • the present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • solvate refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of the crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • Prodrug means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the preparation method of medicinal salt comprises the following steps:
  • a compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IB) or its salt (preferably hydrochloride) under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (I) or its tautomer, internal a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction being a substitution reaction;
  • X is halogen
  • Rings A, G, R, R 0 , R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
  • the preparation method of medicinal salt comprises the following steps:
  • R 0 is
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • Rings A, G, R, R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
  • the preparation method of medicinal salt comprises the following steps:
  • a compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIB) or its salt (preferably hydrochloride) under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (II) or its tautomer, internal a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction being a substitution reaction;
  • X is halogen
  • Rings A, R, R 0 , R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
  • the preparation method of medicinal salt comprises the following steps:
  • R 0 is
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • Rings A, R, R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
  • the preparation method of medicinal salt comprises the following steps:
  • a compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIIB) or its salt (preferably hydrochloride) under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (III) or its tautomer, internal a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction being a substitution reaction;
  • X is halogen
  • R, R 0 , R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
  • the preparation method of medicinal salt comprises the following steps:
  • R 0 is
  • W is selected from oxygen atom, sulfur atom, NR 13a and CR 13b R 13c ;
  • R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • j 0, 1 or 2;
  • k 1 or 2;
  • v 0, 1, 2, or 3;
  • R, R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
  • the preparation method of medicinal salt comprises the following steps:
  • a compound of general formula (IVA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Under the action of a catalyst, the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof is obtained by reduction reaction form, or a pharmaceutically acceptable salt thereof,
  • Rings A, G, R, R 0 , R 1 -R 4 , R 8 and n are as defined in general formula (IV).
  • Reagents that provide the acidic conditions described in the above reactions include, but are not limited to: ammonium chloride, trifluoroacetic acid, hydrochloric acid, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, Methanesulfonic acid, nitric acid, phosphoric acid and p-toluenesulfonic acid; preferably ammonium chloride.
  • the reagents that provide the alkaline conditions described in the above reaction include organic bases and inorganic bases, and the organic bases include but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyllithium , lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazacyclo[5,4,0]undec-7-ene, said inorganic bases Including but not limited to: sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine .
  • the catalyst system used in the above-mentioned oxidation reaction includes but is not limited to: PhSiH/Mn(dpm) 2 (or Mn(dpm) 3 or Mn(acac) 2 or Co(sdmg) 3 ), tetraphenylporphyrin manganese (III) Complex/NaBH 4 (or Pt-H 2 ), Tetraphenylporphyrin cobalt(II) complex/NaBH 4 (or EtNBH 4 ), (bis(salicyl- ⁇ -iminopropyl)methylamine) cobalt (II) / primary alcohol, Co (acac) 2, Co (salen), Co (acacen), BH 3 and the like.
  • the oxidant used includes but is not limited to oxygen, air, hydrogen peroxide, etc., wherein Mn(dpm) 2 is bis(2,2,6,6-tetramethyl-3,5-heptanedione) manganese, Mn(dpm) ) 3 is three (2,2,6,6-tetramethyl-3,5-heptanedione) manganese (CAS registration number is 14324-99-3, also known as: three (2,2,6,6- Tetramethyl-3,5-heptenoic acid) manganese), Mn(acac) 2 is bis(acetylacetonate) manganese(II) (CAS Registry No.
  • Co(acac) 2 is bis(acetylacetonate) Acetone) cobalt(II) (CAS Reg. No. 193620-63-2)
  • Co(salen) is N,N'-bis(salicyl)ethylenediamine cobalt(II) (CAS Reg. No. 14167-18-1)
  • Co(acacen) is N,N'-bis(acetylacetonate) ethylenediamine cobalt(II)
  • Co(sdmg) 3 is bis(N-salicylidene-2-aminoisobutanone) sodium cobaltate (CAS registered No. 704900-51-6);
  • the preferred catalyst system is PhSiH/Mn(dpm) 3 or PhSiH/Mn(acac) 2
  • the preferred oxidant is oxygen.
  • the catalyst used in the above-mentioned reduction reaction includes but is not limited to: palladium carbon, iron powder, Raney nickel, zinc powder, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzyl) (phosphorus) dipentyl iron palladium dichloro, tris(dibenzylideneacetone) dipalladium, etc., preferably palladium carbon.
  • the reducing agent used includes, but is not limited to, hydrogen, dilute hydrochloric acid, acetic acid or dilute sulfuric acid, preferably hydrogen.
  • the above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water, N,N-dimethylacetamide or N,N-dimethylformamide and mixtures thereof.
  • the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Agilent 1200/1290DAD-6110/6120Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography chromatography and the developing solvent system of the thin layer chromatography adopted for purifying the compound include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethyl ether can also be added Basic or acidic reagents such as amines and acetic acid are used for adjustment.
  • TLC thin layer chromatography
  • Methyl 3-hydroxy-4-methoxybenzoate 1a (5.00 g, 27.45 mmol, Shanghai Bide), (3R)-tetrahydrofuran-3-ol (2.42 g, 27.45 mmol, Shanghai Bide) and triphenyl Phosphine (8.64 g, 32.94 mmol, Titan) was dissolved in tetrahydrofuran (50 mL), replaced by argon three times, and diisopropyl azodicarboxylate (6.66 g, 32.94 mmol, Shanghai Shao) was slowly added dropwise at 0°C under argon atmosphere. Far). The reaction was warmed to room temperature and stirred under an argon atmosphere for 16 hours.
  • reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 1b (4.5 g), yield: 64%.
  • the first step raw material compound (3R)-tetrahydrofuran-3-ol was replaced with the compound 4-hydroxytetrahydro-2H-thiopyran 1,1-diol oxide
  • the seventh step raw material compound (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride is replaced by compound (R)-1-(3-( Difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride to obtain compound 11 (10 mg), yield: 5.8%.
  • the first step raw material compound 3a was replaced with compound tetrahydro-2H-thiopyran-4-ol 17a, and the tenth step raw material compound (R)-2-(3-( 1-Aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride was replaced by compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl
  • the amine hydrochloride gave the title compound 17b (100 mg), yield: 34%.
  • Test Example 1 The compound of the present disclosure inhibits the interaction ability between each subtype G12D or G12V of KRAS protein and SOS1 protein
  • PBS Phosphate Buffered Saline
  • PH7.4 Phosphate Buffered Saline
  • KRAS G12D and KRAS-G12V proteins were biotin-labeled with a biotin labeling kit.
  • the biotin-labeled KRAS G12V or KRAS G12D protein was incubated with SOS1 protein (GST-TEV-SOS1(564-1049) (Via Biotechnology, SOS1-191010)) and GDP at room temperature for use.
  • SOS1 protein GST-TEV-SOS1(564-1049) (Via Biotechnology, SOS1-191010)
  • the present disclosure subtypes compounds inhibit the interaction between the ability G12D or SOS1 protein KRAS G12V and the protein, the measured IC 50 values are shown in Table 1.
  • Table 1 IC 50 values of the compounds of the present disclosure to inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein
  • the disclosed compounds can well inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein.
  • H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum.
  • RPMI1640 Hyclone, SH30809.01
  • complete medium containing 10% fetal bovine serum.
  • H358 cells were seeded at a density of 25,000 cells/well in a 96-well plate using complete medium, with 190 ⁇ L of cell suspension per well, and placed in a 37°C, 5% CO 2 cell incubator overnight.
  • 10 ⁇ L of the compound to be tested in a serial dilution prepared in complete medium was added to each well, and the final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 ⁇ M, and a blank control containing 0.1% DMSO was set.
  • lysis buffer lysis buffer, Cisbio, 64KL1FDF
  • blocking reagent Cisbio, 64KB1AAC
  • Example number IC 50 (nM) 1 15.7 2 78.0 4 83.0 7 55.0 8 91.0 11 118.0 13 105.0
  • H358 cells (ATCC, CRL-5807) were cultured in complete medium, ie RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV).
  • RPMI1640 medium Hyclone, SH30809.01
  • fetal bovine serum (Corning, 35-076-CV)
  • H358 cells were seeded on 96 low-adsorption plates (Corning, CLS7007-24EA) at a density of 1500 cells/well using complete medium, 90 ⁇ L of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature and placed at 37°C , 5% CO 2 cell incubator overnight.
  • Example number IC 50 (nM) 1 9.5 2 68.7 4 107.0 6 62.7 7 130.4 8 133.5 11 126.2 14 101.7 16 77.2
  • LC/MS/MS method Using LC/MS/MS method as a mouse test animal, the drug concentration in the plasma of mice at different times after intravenous injection of the compound of Example 1 was determined. The pharmacokinetic behavior of the disclosed compounds in mice was studied, and their pharmacokinetic characteristics were evaluated.
  • a certain amount of medicine is weighed, and 5% DMSO+5% Tween 80+90% normal saline is added to prepare a liquid.
  • mice were administered intravenously at a dose of 1 mg/kg and an administration volume of 0.1 mL/10 g.
  • mice were intravenously injected with the compound of Example 1, and 0.1 mL of blood was collected before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24.0 hours after administration, and placed in an EDTA-K2 anticoagulation test tube , centrifuge at 10,000 rpm for 1 minute at 4°C, separate the plasma within 1 hour, store it at -20°C for testing, and operate under ice-bath conditions until the centrifugation process.
  • Determination of the content of the test compound in mouse plasma after intravenous administration of the drug take 25 ⁇ L of mouse plasma at each time after administration, add 50 ⁇ L of internal standard solution (100ng/ml camptothecin), 200 ⁇ L of acetonitrile, and vortex for 5 minutes , centrifuged for 15 minutes (3600 rpm), and 0.1 ⁇ L of the supernatant was taken from the plasma samples for LC/MS/MS analysis.
  • Test Example 5 Inhibitory effect of compounds of the present disclosure on human liver microsomal CYP450 enzymes
  • CYP probe substrates phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, testosterone
  • MgCl 2 powder Weigh an appropriate amount of MgCl 2 powder, prepare a 300 mM stock solution with PBS solution, and store it in a 4°C refrigerator for later use. Precisely weigh an appropriate amount of the solution, add 100 mM PBS solution and dilute it into a 15 mM working solution, and that's it (prepared and used now).
  • Precisely pipette an appropriate amount of the stock solution add an appropriate amount of DMSO solution to dilute to a series of solution I with a concentration of 10, 3, 1, 0.3, 0.03 and 0.003 mM.
  • Precisely pipet an appropriate amount of the above series of solution I add an appropriate amount of acetonitrile to dilute to a series of solution II with a concentration of 3, 1, 0.3, 0.1, 0.03, 0.003, 0.0003 mM.
  • Precisely pipette an appropriate amount of the above-mentioned series of solutions II add an appropriate amount of PBS to dilute to a working solution with a concentration of 150, 50, 15, 5, 1.5, 0.15, 0.015 ⁇ M, and set aside.
  • probe substrate stock solution Preparation of probe substrate stock solution: Weigh an appropriate amount of each probe substrate, add DMSO to prepare a stock solution, and its concentration is shown in Table 5 below.
  • probe substrate working solution Precisely pipette an appropriate amount of probe substrate stock solution, add PBS solution and dilute 200 times to obtain probe substrate working solution, the concentration of which is shown in Table 5 below.
  • CYP probe substrate Stock concentration mM
  • Working solution concentration ⁇ M
  • 1A2 phenacetin 12 60 2C9 Diclofenac 4 20 2C19 (S)-Mephentoin 20 100 2D6 Dextromethorphan 4 20 3A4T testosterone 75 375
  • the protein concentration, substrate and inhibitor concentration in the reaction system are shown in Table 6-1 and Table 6-2 below.
  • Table 7 discloses compounds CYP1A2 in human liver microsomes that non-IC 50 values cefoxitin, CYP2C9 diclofenac, CYP2C19 mephenytoin, CYP2D6 inhibition of dextromethorphan metabolism of testosterone CYP3A4T site (in [mu] M)
  • the compounds of this disclosure do not occur in the concentration range of 30 ⁇ M based on CYP1A2 phenacetin O-deethylation, CYP2C9 diclofenac 4'-hydroxylation, CYP2C19 mephentoin 4'-hydroxylation, CYP2D6 dextromethorphan Metabolic drug interactions at the Fen O-demethylation and testosterone 6 ⁇ -hydroxylation metabolic sites of CYP3A4T.
  • Test Example 6 Effect of the disclosed compound on hERG potassium channel
  • the cells used in this experiment were CHO cell lines (provided by Sophion Bioscience, Denmark) transfected with hERG cDNA and stably expressing hERG channel, and the cell passages were P9&P11.
  • Cells were grown in medium (all from Invitrogen) containing the following components: Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 ⁇ g/mL hygromycin B, 100 ⁇ g/mL Geneticin .
  • CHO hERG cells were grown in petri dishes containing the above medium and cultured at 37°C in an incubator containing 5% CO 2 . Twenty-four to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in petri dishes and grown in the same medium and culture conditions as above. The density of CHO hERG cells on each circular slide needs to be such that the vast majority of cells are independent and single.
  • a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) was used for whole-cell current recording.
  • the circular slides with CHO hERG cells grown on the surface were placed in the electrophysiological recording chamber under an inverted microscope.
  • the recording tank was continuously perfused with extracellular fluid (approximately 1 ml per minute).
  • the experimental process used conventional whole-cell patch-clamp current recording technology. Unless otherwise specified, the experiments were carried out at normal room temperature ( ⁇ 25°C). Cells were clamped at -80mV.
  • Cisapride (cisapride, purchased from Sigma) was used in the experiments as a positive control to ensure that the cells used were of normal quality.
  • the experimental data were analyzed by HEKA Patchmaster (V2x73.2), Microsoft Excel and data analysis software provided by Graphpad Prism 5.0.
  • the disclosed compounds have weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

Abstract

A fused pyridazine derivative as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative and use thereof as a therapeutic agent, in particular use thereof as an SOS1 inhibitor and use thereof in the preparation of a medicament for treating conditions or disorders which are ameliorated by the inhibition of SOS1.

Description

稠合哒嗪类衍生物、其制备方法及其在医药上的应用Condensed pyridazine derivative, its preparation method and its application in medicine 技术领域technical field
本公开属于医药领域，涉及一种通式(I)所示的稠合哒嗪类衍生物、其制备方法、含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为SOS1抑制剂的用途和在制备用于治疗通过对SOS1的抑制而改善的病况或病症的药物中的用途。The present disclosure belongs to the field of medicine, and relates to a fused pyridazine derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SOS1 inhibitor Use of the agent and use in the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of SOS1.
背景技术Background technique
RAS是在肿瘤中突变率最高的致癌基因之一，约30％的人类恶性肿瘤与RAS基因的突变有关。RAS家族包括KRAS、NRAS和HRAS，其中KRAS突变最为常见，约占85％。KRAS被激活以后，通过以RAF-MEK-ERK、PI3K-AKT-mTOR及TIAM1-RAc为代表的众多下游信号通路，调控细胞增殖、存活、迁移及代谢等多个方面的功能。KRAS基因突变后，蛋白持续处于活化状态，导致下游信号通路持续激活而促进肿瘤发生。RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies are associated with mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, of which KRAS mutations are the most common, accounting for about 85%. After KRAS is activated, it regulates the functions of cell proliferation, survival, migration and metabolism through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After KRAS gene mutation, the protein is continuously activated, which leads to the continuous activation of downstream signaling pathways and promotes tumorigenesis.
由于KRAS蛋白表面缺乏传统意义上的小分子结合位点，并与鸟苷酸有着超高亲和力而极难被抑制，长久以来被认为是不可成药的药物靶点。但基于KRAS异常激活在癌症进展中的重要性和普遍性，KRAS一直并仍然是药物开发非常关注的靶点。目前针对抑制KRAS通路的药物开发思路主要有以下几个方面：Due to the lack of traditional small-molecule binding sites on the surface of KRAS protein, and its ultra-high affinity for guanylate, it is extremely difficult to inhibit, and it has long been regarded as an undruggable drug target. However, based on the importance and prevalence of aberrant KRAS activation in cancer progression, KRAS has been and remains a target of great interest in drug development. The current drug development ideas for inhibiting the KRAS pathway mainly include the following aspects:
1)针对KRAS G12C开发的小分子共价抑制剂，可以将G12C突变体不可逆地锁定在失活状态，目前安进和mirati公司的临床I期数据都显示了不俗的效果。但KRAS G12C的突变只是其诸多突变的一种，其他重要突变体诸如G12V、G12D、G12S、G12A、G13V/D等依然缺乏有效药物。1) The small-molecule covalent inhibitor developed for KRAS G12C can irreversibly lock the G12C mutant in an inactive state. Currently, the clinical phase I data of Amgen and mirati have shown good results. However, the mutation of KRAS G12C is only one of its many mutations, and other important mutants such as G12V, G12D, G12S, G12A, G13V/D still lack effective drugs.
2)在KRAS上寻找其他可以靶向更多突变体的位点：主要针对结合下游效应分子的位点/与蛋白分子激活相关的位点，目前都处于临床前阶段，对活性抑制的IC 50普遍在微摩尔级别。 2) Look for other sites on KRAS that can target more mutants: mainly targeting sites that bind downstream effector molecules/sites related to protein molecule activation, which are currently in the preclinical stage, and the IC 50 for activity inhibition Generally at the micromolar level.
3)针对KRAS下游信号蛋白的抑制：例如针对RAF、MEK、ERK等抑制剂的开发，目前临床上单用多效果不佳。3) Inhibition of KRAS downstream signaling proteins: For example, the development of inhibitors such as RAF, MEK, ERK, etc., is currently clinically ineffective.
4)针对KRAS上游通路的抑制：如SHP2的抑制剂等。4) Inhibition of the upstream pathway of KRAS: such as inhibitors of SHP2, etc.
5)针对KRAS的修饰及定位：如法尼基转移酶等阻断KRAS的膜定位从而达到抑制其作用的效果。5) Modification and localization of KRAS: such as farnesyl transferase, block the membrane localization of KRAS to achieve the effect of inhibiting its effect.
6)通过RNAi的方法敲低KRAS的表达。6) KRAS expression was knocked down by RNAi.
总体而言，除了KRAS G12C抑制剂以外，目前仍缺乏对多种突变有效的广谱KRAS抑制剂。而阻断KRAS的激活分子与KRAS的结合，比如选择性抑制SOS1-即鸟嘌呤核苷酸交换因子(GEF)的小分子抑制剂，能通过干扰RAS-SOS1相互作用而阻断KRAS的激活，能达到广谱抑制KRAS活性的目的。Overall, with the exception of KRAS G12C inhibitors, there is still a lack of broad-spectrum KRAS inhibitors that are effective against multiple mutations. Blocking the binding of KRAS activating molecules to KRAS, such as selective inhibition of SOS1, a small molecule inhibitor of guanine nucleotide exchange factor (GEF), can block KRAS activation by interfering with the RAS-SOS1 interaction. It can achieve the purpose of broad-spectrum inhibition of KRAS activity.
KARS蛋白是一种小GTP酶(small GTPase)，在细胞内，KRAS蛋白在失活状态(与鸟苷二磷酸(GDP)结合)和激活状态(与鸟苷三磷酸(GTP)结合)之间转换。这种转变受到鸟嘌呤核苷酸交换因子(GEF)和GTP酶激活蛋白(GAP)的调控。KRAS的GEF主要有三类，分别是SOS(sevenless son)1&2、Ras-GRF和Ras-GRP，其中后两类只在神经元及白细胞中表达，只有SOS在多种组织中广泛表达，被认为在RAS的激活中起到主导作用。由于SOS1的表达量较SOS2更高，且较SOS2的活性更强，目前针对SOS的研究主要集中在SOS1。SOS1对于KRAS蛋白的具体激活途径如下：上游信号(如生长因子)激活膜表面受体后，通过SHP2-Grb2激活SOS1，SOS1与KRAS结合，通过引起一系列构象变化，催化KRAS与GDP的解离，进而与GTP结合，形成具有活性的KRAS-GTP。KARS protein is a small GTPase (small GTPase), in cells, KRAS protein is between inactive state (binding to guanosine diphosphate (GDP)) and activated state (binding to guanosine triphosphate (GTP)) convert. This transition is regulated by guanine nucleotide exchange factor (GEF) and GTPases activating protein (GAP). There are three main types of GEFs in KRAS, namely SOS (sevenless son) 1&2, Ras-GRF and Ras-GRP. The latter two types are only expressed in neurons and leukocytes. Only SOS is widely expressed in various tissues and is considered to be in play a leading role in the activation of RAS. Since the expression level of SOS1 is higher than that of SOS2, and its activity is stronger than that of SOS2, the current research on SOS mainly focuses on SOS1. The specific activation pathway of SOS1 for KRAS protein is as follows: after upstream signals (such as growth factors) activate membrane surface receptors, SOS1 is activated through SHP2-Grb2, SOS1 binds to KRAS, and catalyzes the dissociation of KRAS from GDP by causing a series of conformational changes , and then combined with GTP to form active KRAS-GTP.
已经公开的作为SOS1抑制剂的化合物的专利申请包括WO2018115380A1、WO2019122129A1、WO2018172250A1和WO2016077793A1等。Patent applications that have disclosed compounds as SOS1 inhibitors include WO2018115380A1, WO2019122129A1, WO2018172250A1, and WO2016077793A1, among others.
发明内容SUMMARY OF THE INVENTION
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000001
Figure PCTCN2021107220-appb-000001
其中：in:
环A为芳基或杂芳基；Ring A is aryl or heteroaryl;
G为CR 5或N原子； G is CR 5 or N atom;
R 0选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、羟基、氨基、-(CH 2) pNR 6R 7、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 0 is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , cycloalkyloxy , heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S(O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
R 1选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和环烷基； R 1 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
R 2选自卤素、烷基、卤代烷基、羟烷基、羟基、氰基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基和氰基中的一个或多个取代基取代； R 2 is selected from halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with Substituted with one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;
R 3选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 3 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基和-(CH 2) pNR 6R 7； R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH 2 ) p NR 6 R 7 ;
R和R 5相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、芳基氧基、杂芳基氧基、-(CH 2) pNR 6R 7、氰基和硝基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氰基、硝基和-(CH 2) qNR 11R 12中的一个或多个取代基所取代； R and R 5 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heterocycle Aryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro and -(CH 2 ) q NR 11 R 12 is substituted with one or more substituents;
R 8相同或不同，各自独立地选自卤素、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、-(CH 2) pNR 6R 7、硝基、羟基、羟烷基、-S(O) 2烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自羟基、卤素、卤代烷基、烷氧基、卤代烷氧基、氰基、硝基、羟烷基、-(CH 2) qNR 11R 12、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 8 is the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH 2 ) p NR 6 R 7 , nitro alkyl, hydroxy, hydroxyalkyl, -S(O) 2 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, - (CH 2) q Substituted with one or more substituents in NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、-(CH 2) qNR 11R 12、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选地被选自羟基、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、氨基和硝基中的一个或多个取代基取代； R 9 and R 10 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH 2 ) q NR 11 R 12 , a cycloalkyl group and a heterocyclic group, wherein said Alkyl, cycloalkyl and heterocyclyl are each independently optionally selected from hydroxy, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino and nitro One or more substituents are substituted;
R 6、R 7、R 11和R 12相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基； R 6 , R 7 , R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
p和q相同或不同，各自独立地选自0、1和2；p and q are the same or different, each independently selected from 0, 1 and 2;
n选自0、1、2、3、4和5。n is selected from 0, 1, 2, 3, 4 and 5.
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000002
Figure PCTCN2021107220-appb-000002
其中：in:
环A为芳基或杂芳基；Ring A is aryl or heteroaryl;
G为CR 5或N原子； G is CR 5 or N atom;
R 0选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、羟基、氨基、-(CH 2) pNR 6R 7、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 0 is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , cycloalkyloxy , heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S(O) 2 Substituted with one or more substituents in R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 1选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和环烷基； R 1 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
R 2选自卤素、烷基、卤代烷基、羟烷基、羟基、氰基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基和氰基中的一个或多个取代基取代； R 2 is selected from halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with Substituted with one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;
R 3选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 3 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基和-(CH 2) pNR 6R 7； R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH 2 ) p NR 6 R 7 ;
R和R 5相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、芳基氧基、杂芳基氧基、-(CH 2) pNR 6R 7、氰基和硝基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氰基、硝基和-(CH 2) qNR 11R 12中的一个或多个取代基所取代； R and R 5 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heterocycle Aryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro and -(CH 2 ) q NR 11 R 12 is substituted with one or more substituents;
R 8相同或不同，各自独立地选自卤素、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、-(CH 2) pNR 6R 7、硝基、羟基、羟烷基、-S(O) 2烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自羟基、卤素、卤代烷基、烷氧基、卤代烷氧基、氰基、硝基、羟烷基、-(CH 2) qNR 11R 12、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 8 is the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH 2 ) p NR 6 R 7 , nitro alkyl, hydroxy, hydroxyalkyl, -S(O) 2 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, - (CH 2) q Substituted with one or more substituents in NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、-(CH 2) qNR 11R 12、环烷基和杂环基； R 9 and R 10 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH 2 ) q NR 11 R 12 , a cycloalkyl group and a heterocyclic group;
R 6、R 7、R 11和R 12相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基； R 6 , R 7 , R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
p和q相同或不同，各自独立地选自0、1和2；p and q are the same or different, each independently selected from 0, 1 and 2;
n选自0、1、2、3、4和5。n is selected from 0, 1, 2, 3, 4 and 5.
在本公开的一些优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐,其中G为CR 5，R 5如通式(I)中所定义；优选地，G为CH。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is CR 5 , and R 5 is as defined in general formula (I); preferably, G is CH.
在本公开的一些优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt, which is the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000003
Figure PCTCN2021107220-appb-000003
其中，环A、R、R 0、R 1、R 3、R 4、R 5、R 8和n如通式(I)中所定义。 wherein Rings A, R, R 0 , R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (I).
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 0选自烷氧基、羟烷基、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9和-C(O)R 10中的一个或多个取代基取代；其中，R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、氨基和羟烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 is selected from alkoxy, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, hetero Cyclic, aryl and heteroaryl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , a 10 alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) 2 R 9 and -C (O) R or wherein, R 9 and R 10 are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an amino group and a hydroxyalkyl group;
优选地，R 0选自环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自羟基和-C(O)R 10中的一个或多个取代基取代；R 10为烷基； Preferably, R 0 is selected from cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from hydroxy and -C(O)R 10 ; R 10 is alkyl;
进一步优选地，R 0选自C 1-6烷氧基、五元杂环基氧基和六元杂环基，所述的五元杂环基氧基和六元杂环基各自独立地任选地被-C(O)R 10和/或羟基取代，其中R 10为C 1-6烷基； Further preferably, R 0 is selected from C 1-6 alkoxy, five-membered heterocyclyloxy and six-membered heterocyclyl, and the five-membered heterocyclyloxy and six-membered heterocyclyl are each independently any optionally substituted by -C(O)R 10 and/or hydroxy, wherein R 10 is C 1-6 alkyl;
更优选地，R 0选自四氢呋喃基氧基和哌啶基，所述的四氢呋喃基氧基和哌啶基各自独立地任选地被-C(O)R 10和/或羟基取代，其中R 10为C 1-6烷基。 More preferably, R 0 is selected from tetrahydrofuranyloxy and piperidinyl, each of said tetrahydrofuranyloxy and piperidinyl is independently optionally substituted by -C(O)R 10 and/or hydroxy, wherein R 10 is C 1-6 alkyl.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 0为
Figure PCTCN2021107220-appb-000004
环B选自环烷基、杂环基、芳基和杂芳基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 is
Figure PCTCN2021107220-appb-000004
Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
优选地，R 0选自
Figure PCTCN2021107220-appb-000005
W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000006
NR 13a和CR 13bR 13c； Preferably, R 0 is selected from
Figure PCTCN2021107220-appb-000005
W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000006
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
u为0、1、2、3、4或5；u is 0, 1, 2, 3, 4, or 5;
v为0、1、2或3；v is 0, 1, 2, or 3;
R 9～R 10如通式(I)中所定义。 R 9 to R 10 are as defined in the general formula (I).
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 0选自
Figure PCTCN2021107220-appb-000007
Figure PCTCN2021107220-appb-000008
In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non-pair or as a mixture of enantiomers, or a pharmaceutically acceptable salt thereof, in which R 0 is selected from
Figure PCTCN2021107220-appb-000007
Figure PCTCN2021107220-appb-000008
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
v为0、1、2或3；v is 0, 1, 2, or 3;
R 9～R 10如通式(I)中所定义。 R 9 to R 10 are as defined in the general formula (I).
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 13a为-C(O)R 10；R 10为C 1-6烷基或C 1-6羟烷基，所述C 1-6 烷基任选可被C 1-6烷氧基和氰基取代。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 13a is -C(O)R 10 ; R 10 is C 1-6 alkyl or C 1-6 hydroxyalkyl, The C 1-6 alkyl groups may optionally be substituted with C 1-6 alkoxy groups and cyano groups.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 13和R 13b优选为氢原子。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 13 and R 13b are preferably hydrogen atoms.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 13c为-C(O)R 10；R 10为二C 1-6烷基氨基或3-6元杂环基；优选地，R 13c为-C(O)-二C 1-6烷基氨基或-C(O)-5至6元杂环基；更优选地，R 13c为-C(O)N(CH 3) 2或-C(O)吗啉基。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, Diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 13c is -C(O)R 10 ; R 10 is diC 1-6 alkylamino or 3-6 membered heterocycle base; preferably, R 13c is -C(O) -diC 1-6 alkylamino or -C(O)-5- to 6-membered heterocyclyl; more preferably, R 13c is -C(O)N (CH 3 ) 2 or -C(O)morpholinyl.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中u为0或1。In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中j为1。In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein j is 1.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中v为0。In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein v is 0.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, Diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its tautomer, meso, racemate, para Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure PCTCN2021107220-appb-000009
Figure PCTCN2021107220-appb-000009
其中，R、R 0、R 1、R 4、R 5、R 8和n如通式(I)中所定义。 wherein R, R 0 , R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (I).
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 8相同或不同，各自独立地选自卤素、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、-(CH 2) pNR 6R 7、硝基、羟基、羟烷基和-S(O) 2烷基，其中所述的烷基、卤代烷基和羟烷基各自独立地任选地被选自羟基、卤素、卤代烷基、烷氧基、卤代烷氧基、氰基、硝基、羟烷基和-(CH 2) qNR 11R 12中的一个或多个取代基取代；p和q各自独立地选自0、1或2；R 6、R 7、R 11和R 12相同或不同，各自独立地选自氢原子、烷基、卤代烷基和羟烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 8 are the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, Alkoxy, haloalkoxy, cyano, amino, -(CH 2 ) p NR 6 R 7 , nitro, hydroxy, hydroxyalkyl and -S(O) 2 alkyl, wherein said alkyl, haloalkane and hydroxyalkyl are each independently optionally selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl and -(CH 2 ) q NR 11 R 12 substituted with one or more substituents; p and q are each independently selected from 0, 1 or 2; R 6 , R 7 , R 11 and R 12 are the same or different, each independently selected from hydrogen atoms, alkyl groups, haloalkanes groups and hydroxyalkyl groups;
优选地，R 8相同或不同，各自独立地选自卤素、C 1-6烷基、C 1-6卤代烷基、氨 基、-(CH 2) pNR 6R 7和C 1-6羟烷基，其中所述的C 1-6卤代烷基任选地被一个或多个羟基取代；R 6和R 7为氢原子或C 1-6烷基，p为0、1或2。 Preferably, R 8 are the same or different, each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, -(CH 2 ) p NR 6 R 7 and C 1-6 hydroxyalkyl , wherein the C 1-6 haloalkyl group is optionally substituted by one or more hydroxyl groups; R 6 and R 7 are hydrogen atoms or C 1-6 alkyl groups, and p is 0, 1 or 2.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基和羟烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 is selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and hydroxyalkane base;
优选地，R 1选自氢原子、C 1-6烷基和卤素。 Preferably, R 1 is selected from hydrogen atom, C 1-6 alkyl and halogen.
进一步优选地，R 1为C 1-6烷基。 Further preferably, R 1 is C 1-6 alkyl.
更优选地，R 1为甲基。 More preferably, R 1 is methyl.
在本公开的一些优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2选自卤素、烷基、卤代烷基、羟烷基和环烷基，其中所述的烷基和环烷基各自独立地任选地被选自烷氧基、卤代烷氧基和氨基中的一个或多个取代基取代； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl, wherein said alkyl and cycloalkyl are each independently optionally substituted with one or more substituents selected from alkoxy, haloalkoxy and amino;
优选地，R 2选自卤素、烷基、卤代烷基和羟烷基； Preferably, R 2 is selected from halogen, alkyl, haloalkyl and hydroxyalkyl;
进一步优选地，R 2为氢原子或C 1-6烷基。 Further preferably, R 2 is a hydrogen atom or a C 1-6 alkyl group.
更优选地，R 2为甲基。 More preferably, R 2 is methyl.
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3选自氢原子、烷基、卤代烷基、羟烷基和环烷基，其中所述的烷基、卤代烷基、羟烷基和环烷基各自独立地任选地被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氨基和羟烷基中的一个或多个取代基所取代； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl, wherein said alkyl, haloalkyl , hydroxyalkyl, and cycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, and hydroxyalkyl;
优选地，R 3选自氢原子、烷基、卤代烷基和羟烷基。 Preferably, R 3 is selected from a hydrogen atom, alkyl, haloalkyl, and hydroxyalkyl.
进一步优选地，R 3为氢原子或C 1-6烷基。 Further preferably, R 3 is a hydrogen atom or a C 1-6 alkyl group.
再进一步优选地，R 2为C 1-6烷基。 Still further preferably, R 2 is C 1-6 alkyl.
更优选地，R 3为氢原子。 More preferably, R 3 is a hydrogen atom.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 4选自氢原子、卤素、烷基、卤代烷基和羟烷基；优选地，R 4选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halo, alkyl, haloalkyl and hydroxyalkyl; preferably, R 4 is selected from From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl;
更优选地，R 4为氢原子。 More preferably, R 4 is a hydrogen atom.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、-(CH 2) p NR 6R 7、氰基和硝基；R 6和R 7相同或不同，各自独立地选自氢原子、烷基、卤代烷基和羟烷基；p为0、1或2； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro; R 6 and R 7 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; p is 0, 1 or 2;
优选地，R为C 1-6烷氧基； Preferably, R is C 1-6 alkoxy;
更优选地，R为甲氧基。More preferably, R is methoxy.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、-(CH 2) p NR 6R 7和氰基；R 6和R 7相同或不同，各自独立地选自氢原子、烷基、卤代烷基和羟烷基；p为0、1或2； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, - ( CH 2 ) p NR 6 R 7 and cyano; R 6 and R 7 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; p is 0, 1 or 2;
优选地，R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 5为氢原子。 Preferably, R 5 is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 5 is a hydrogen atom.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 6和R 7相同或不同，各自独立地选自氢原子、烷基、卤代烷基和羟烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are the same or different, are each independently selected from hydrogen atom, alkyl, haloalkyl, and hydroxyalkyl base;
优选地，R 6和R 7相同或不同，各自独立地为氢原子或C 1-6烷基。 Preferably, R 6 and R 7 are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 11和R 12相同或不同，各自独立地选自氢原子、烷基、卤代烷基和羟烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 11 and R 12 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;
优选地，R 11和R 12相同或不同，各自独立地为氢原子或C 1-6烷基。 Preferably, R 11 and R 12 are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基和羟烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 9 and R 10 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;
优选地，R 9和R 10相同或不同，各自独立地为氢原子或C 1-6烷基。 Preferably, R 9 and R 10 are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中p为0或1，优选为0。In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein p is 0 or 1, preferably 0.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中q为0或1，优选为0。In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein q is 0 or 1, preferably 0.
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中n为1、2或3，优选为2。In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein n is 1, 2 or 3, preferably 2.
在本公开的一些优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、 对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000010
Figure PCTCN2021107220-appb-000010
其中，环A、G、R、R 0、R 1、R 2、R 3、R 4、R 8和n如通式(I)中所定义。 wherein rings A, G, R, R 0 , R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环A为苯基或5至6元杂芳基。In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (IV) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Ring A is phenyl or 5- to 6-membered heteroaryl.
在本公开的一些优选的实施方案中，一种通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环A为苯基或5至6元杂芳基；R 0选自
Figure PCTCN2021107220-appb-000011
In some preferred embodiments of the present disclosure, a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt, wherein ring A is phenyl or 5- to 6-membered heteroaryl; R 0 is selected from
Figure PCTCN2021107220-appb-000011
Figure PCTCN2021107220-appb-000012
Figure PCTCN2021107220-appb-000012
v为0；R 13a为-C(O)R 10；R 10为C 1-6烷基或C 1-6羟烷基，所述C 1-6烷基任选可被C 1-6烷氧基和氰基取代；R 13和R 13b为氢原子；R 13c为-C(O)-二C 1-6烷基氨基或-C(O)-5至6元杂环基；R 8相同或不同，各自独立地选自卤素、C 1-6烷基、C 1-6卤代烷基、氨基、-(CH 2) pNR 6R 7和C 1-6羟烷基，其中所述的C 1-6卤代烷基任选地被一个或多个羟基取代；R 6和R 7为氢原子或C 1-6烷基，p为0、1或2；R 1选自氢原子、C 1-6烷基和卤素；R 3为氢原子或C 1-6烷基；R 4选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；R为C 1-6烷氧基；R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；n为1、2或3。 v is 0; R 13a is -C(O)R 10 ; R 10 is C 1-6 alkyl or C 1-6 hydroxyalkyl, the C 1-6 alkyl optionally can be replaced by C 1-6 alkane Oxygen and cyano group substitution; R 13 and R 13b are hydrogen atoms; R 13c is -C(O) -diC 1-6 alkylamino or -C(O)-5- to 6-membered heterocyclic group; R 8 The same or different, each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, -(CH 2 ) p NR 6 R 7 and C 1-6 hydroxyalkyl, wherein said C 1-6 haloalkyl is optionally substituted with one or more hydroxyl groups; R 6 and R 7 are hydrogen atoms or C 1-6 alkyl groups, p is 0, 1 or 2; R 1 is selected from hydrogen atoms, C 1 -6 alkyl and halogen; R 3 is hydrogen atom or C 1-6 alkyl; R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl ; R is C 1-6 alkoxy; R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; n is 1, 2 or 3.
表A本公开的典型化合物包括但不限于：Table A Typical compounds of the present disclosure include, but are not limited to:
Figure PCTCN2021107220-appb-000013
Figure PCTCN2021107220-appb-000013
Figure PCTCN2021107220-appb-000014
Figure PCTCN2021107220-appb-000014
Figure PCTCN2021107220-appb-000015
Figure PCTCN2021107220-appb-000015
Figure PCTCN2021107220-appb-000016
Figure PCTCN2021107220-appb-000016
Figure PCTCN2021107220-appb-000017
Figure PCTCN2021107220-appb-000017
本公开的另一方面涉及通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000018
Figure PCTCN2021107220-appb-000018
其中，X为卤素，优选为氯；Wherein, X is halogen, preferably chlorine;
R 0选自溴、碘、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、羟基、氨基、-(CH 2) pNR 6R 7、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 0 is selected from bromine, iodine, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , heterocyclyl Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl The groups are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S(O) 2 R 9 , - Substituted with one or more substituents in C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 1选自溴、碘、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和环烷基； R 1 is selected from bromine, iodine, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
R选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、芳基氧基、杂芳基氧基、-(CH 2) pNR 6R 7、氰基和硝基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氰基、硝基和-(CH 2) qNR 11R 12中的一个或多个取代基所取代； R is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy Alkyl, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, and -(CH 2 ) q NR 11 R 12 substituted by one or more substituents;
G、R 6、R 7、R 9、R 10、R 11、R 12、p、q和R 4如通式(I)中所定义。 G, R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , p, q and R 4 are as defined in general formula (I).
本公开的另一方面涉及通式(IIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000019
Figure PCTCN2021107220-appb-000019
其中，X为卤素，优选为氯；Wherein, X is halogen, preferably chlorine;
R、R 0、R 1、R 4和R 5如通式(II)中所定义。 R, R 0 , R 1 , R 4 and R 5 are as defined in general formula (II).
本公开的另一方面涉及通式(IVA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IVA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000020
Figure PCTCN2021107220-appb-000020
其中，环A、G、R、R 0、R 1-R 4、R 8和n如通式(I)中所定义。 wherein Rings A, G, R, R 0 , R 1 -R 4 , R 8 and n are as defined in general formula (I).
本公开的另一方面涉及通式(IAA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000021
Figure PCTCN2021107220-appb-000021
其中，W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000022
NR 13a和CR 13bR 13c； Wherein, W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000022
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
环A、G、R、R 1-R 4、R 8-R 10和n如通式(I)中所定义。 Ring A, G, R, R 1- R 4, the R 8- R 10 and n are as in formula (I) as defined above.
本公开的另一方面涉及通式(IIAA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000023
Figure PCTCN2021107220-appb-000023
其中，W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000024
NR 13a和CR 13bR 13c； Wherein, W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000024
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
环A、R、R 1、R 3-R 5、R 8-R 10和n如通式(II)中所定义。 Ring A, R, R 1, R 3- R 5, are R 8- R 10 and n are as formula (II) as defined above.
本公开的另一方面涉及通式(IIIAA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IIIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021107220-appb-000025
Figure PCTCN2021107220-appb-000025
其中W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000026
NR 13a和CR 13bR 13c； wherein W is selected from oxygen atoms, sulfur atoms,
Figure PCTCN2021107220-appb-000026
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
R、R 1、R 4-R 5、R 8-R 10和n如通式(III)中所定义。 R, R 1 , R 4- R 5 , R 8- R 10 and n are as defined in general formula (III).
本公开的典型化合物包括但不限于：Typical compounds of the present disclosure include, but are not limited to:
Figure PCTCN2021107220-appb-000027
Figure PCTCN2021107220-appb-000027
Figure PCTCN2021107220-appb-000028
Figure PCTCN2021107220-appb-000028
Figure PCTCN2021107220-appb-000029
Figure PCTCN2021107220-appb-000029
本公开的另一方面涉及一种制备通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021107220-appb-000030
Figure PCTCN2021107220-appb-000030
通式(IA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IB)或其盐反应，得到通式(I)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，所述反应为取代反应；A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IB) or its salt to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;
其中，X为卤素；Wherein, X is halogen;
环A、G、R、R 0、R 1、R 2、R 3、R 4、R 8和n如通式(I)中所定义。 Rings A, G, R, R 0 , R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
本公开的另一方面涉及一种制备通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021107220-appb-000031
Figure PCTCN2021107220-appb-000031
通式(IAA)经氧化反应得到通式(I)；The general formula (IAA) is oxidized to obtain the general formula (I);
其中，R 0为
Figure PCTCN2021107220-appb-000032
Wherein, R 0 is
Figure PCTCN2021107220-appb-000032
W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000033
NR 13a和CR 13bR 13c； W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000033
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
环A、G、R、R 1、R 2、R 3、R 4、R 8和n如通式(I)中所定义。 Rings A, G, R, R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
本公开的另一方面涉及一种制备通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的 盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021107220-appb-000034
Figure PCTCN2021107220-appb-000034
通式(IIA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IIB)或其盐反应，得到通式(II)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，所述反应为取代反应；A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIB) or its salt to obtain the compound of general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;
其中，X为卤素；Wherein, X is halogen;
环A、R、R 0、R 1、R 3、R 4、R 5、R 8和n如通式(II)中所定义。 Rings A, R, R 0 , R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
本公开的另一方面涉及一种制备通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021107220-appb-000035
Figure PCTCN2021107220-appb-000035
通式(IIAA)经氧化反应得到通式(II)；The general formula (IIAA) is oxidized to obtain the general formula (II);
其中，R 0为
Figure PCTCN2021107220-appb-000036
Wherein, R 0 is
Figure PCTCN2021107220-appb-000036
W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000037
NR 13a和CR 13bR 13c； W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000037
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
环A、R、R 1、R 3、R 4、R 5、R 8和n如通式(II)中所定义。 Rings A, R, R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
本公开的另一方面涉及一种制备通式(III)所示的化合物或其互变异构体、内消 旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021107220-appb-000038
Figure PCTCN2021107220-appb-000038
通式(IIA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IIIB)或其盐反应，得到通式(III)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，所述反应为取代反应；A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIIB) or its salt to obtain the compound of general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;
其中，X为卤素；Wherein, X is halogen;
R、R 0、R 1、R 4、R 5、R 8和n如通式(III)中所定义。 R, R 0 , R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
本公开的另一方面涉及一种制备通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021107220-appb-000039
Figure PCTCN2021107220-appb-000039
通式(IIIAA)经氧化反应得到通式(III)；The general formula (IIIAA) is oxidized to obtain the general formula (III);
其中，R 0为
Figure PCTCN2021107220-appb-000040
Wherein, R 0 is
Figure PCTCN2021107220-appb-000040
W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000041
NR 13a和CR 13bR 13c； W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000041
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
R、R 1、R 4、R 5、R 8和n如通式(III)中所定义。 R, R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021107220-appb-000042
Figure PCTCN2021107220-appb-000042
通式(IVA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐经还原反应，得到通式(IV)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IVA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Through reduction reaction, the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its mixture is obtained medicinal salt,
其中，环A、G、R、R 0、R 1-R 4、R 8和n如通式(IV)中所定义。 wherein Rings A, G, R, R 0 , R 1 -R 4 , R 8 and n are as defined in general formula (IV).
本公开的另一方面涉及一种药物组合物，所述药物组合物含有治疗有效量的本公开通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or Table A of the present disclosure or Its tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceuticals acceptable carrier, diluent or excipient.
本公开进一步涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备用于抑制SOS1的药物中的用途。The present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof Use of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting SOS1.
本公开进一步涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备用于治疗和/或预防癌症、炎症、RAS病、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征、遗传性牙龈纤维瘤病、或其它增殖性疾病的药物中的用途，优选为癌症；所述的癌症优选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、***、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、***癌、***瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述的RAS病优选为1型神经纤维瘤病(NF1)；所述的肺癌优选为非小细胞肺癌，进一步优选为转移性非小细胞肺癌；所述的白血病优选为慢性淋巴细胞白血病或急性髓性白血病；所述的淋巴瘤优选为弥漫性大B细胞淋巴瘤；所述的骨髓瘤优选为多发性骨髓瘤；所述的骨瘤优选为骨软骨瘤；所述的肝癌优选为肝细胞癌；所述的结肠直肠癌优选为结肠癌或直肠癌；所述的头颈癌优 选为头颈鳞状细胞癌；所述的肉瘤优选为骨肉瘤。The present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, are prepared for use in the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS ), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Use in medicine for Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer; the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer , gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureter Tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, bone tumor, neuroblastoma, neuroblastoma, brain tumor, myeloma, Astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; The tumor is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably Osteosarcoma.
本公开还涉及一种抑制SOS1的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(IV)或表A或所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method of inhibiting SOS1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (II), (III), (IV) or Table A or shown, or an interconversion thereof Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
本公开还涉及一种治疗和/或预防SOS1介导的疾病的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method of treating and/or preventing an SOS1-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV) or Table A The compounds shown or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or containing pharmaceutical composition.
本公开还涉及一种治疗和/或预防癌症、炎症、RAS病、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征、遗传性牙龈纤维瘤病、或其它增殖性疾病的方法，优选为治疗癌症的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物；其中所述的癌症优选选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、***、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、***癌、***瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述的RAS病优选为1型神经纤维瘤病(NF1)；所述的肺癌优选为非小细胞肺癌，进一步优选为转移性非小细胞肺癌；所述的白血病优选为慢性淋巴细胞白血病或急性髓性白血病；所述的淋巴瘤优选为弥漫性大B细胞淋巴瘤；所述的骨髓瘤优选为多发性骨髓瘤；所述的骨瘤优选为骨软骨瘤；所述的肝癌优选为肝细胞癌；所述的结肠直肠癌优选为结肠癌或直肠癌；所述的头颈癌优选为头颈鳞状细胞癌；所述的肉瘤优选为骨肉瘤。The present disclosure also relates to a treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM) -AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably for the treatment of cancer A method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or shown in Table A or a tautomer, meso, exoisomer thereof Racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the cancer is preferably selected from melanoma, skin Cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophagus cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, Breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma , neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably Non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the bone marrow The tumor is preferably multiple myeloma; the bone tumor is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.
本公开进一步涉及一种通式(I)、(II)、(III)、(IV)或表A示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物，其用作药物。The present disclosure further relates to a compound represented by the general formula (I), (II), (III), (IV) or Table A or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
本公开还涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物，其用作SOS1抑制剂。The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as SOS1 inhibitors.
本公开还涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防SOS1介导的疾病。The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of SOS1-mediated diseases.
本公开还涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防癌症、炎症、RAS病、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征、遗传性牙龈纤维瘤病、或其它增殖性疾病，优选为用于治疗和/或预防癌症；其中所述的癌症优选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、***、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、***癌、***瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述的RAS病优选为1型神经纤维瘤病(NF1)；所述的肺癌优选为非小细胞肺癌，进一步优选为转移性非小细胞肺癌；所述的白血病优选为慢性淋巴细胞白血病或急性髓性白血病；所述的淋巴瘤优选为弥漫性大B细胞淋巴瘤；所述的骨髓瘤优选为多发性骨髓瘤；所述的骨瘤优选为骨软骨瘤；所述的肝癌优选为肝细胞癌；所述的结肠直肠癌优选为结肠癌或直肠癌；所述的头颈癌优选为头颈鳞状细胞癌；所述的肉瘤优选为骨肉瘤。The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome ( NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC) , Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer , nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urinary tract cancer Skin cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, bone tumor, neuroblastoma, neuroblastoma, brain tumor , myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; The osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; The sarcoma is preferably osteosarcoma.
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation. The compounds of the present disclosure can be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
作为一般性指导，本公开的活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、疾病的严重性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health of the patient condition, behavior of the patient, diet of the patient, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimal mode of treatment such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
术语说明Glossary
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、 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、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、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。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 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-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Alkylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from H atoms, D atoms, halogens, alkyl groups , alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heterocycle One or more substituents in an aryl group.
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、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、杂环烷硫基和氧代基中的一个或多个取代基。 The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1- ethylene (-CH (CH 3) -) , 1,2- ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl , one or more substituents of heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .
术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至8个碳原子(例如3、4、5、6、7和8个)，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、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；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms Carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或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环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:
Figure PCTCN2021107220-appb-000043
Figure PCTCN2021107220-appb-000043
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或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3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2021107220-appb-000044
Figure PCTCN2021107220-appb-000044
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或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例包括：The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:
Figure PCTCN2021107220-appb-000045
Figure PCTCN2021107220-appb-000045
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2021107220-appb-000046
等；优选为
Figure PCTCN2021107220-appb-000047
The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include
Figure PCTCN2021107220-appb-000046
etc.; preferably
Figure PCTCN2021107220-appb-000047
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from H atom, D atom, halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heterocyclic atom; more preferably contains 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、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例包括：The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-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 monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl include:
Figure PCTCN2021107220-appb-000048
Figure PCTCN2021107220-appb-000048
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10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3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括：The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
Figure PCTCN2021107220-appb-000049
Figure PCTCN2021107220-appb-000049
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或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例包括：The term "bridged heterocyclyl" refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2021107220-appb-000050
Figure PCTCN2021107220-appb-000050
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
Figure PCTCN2021107220-appb-000051
等。
Figure PCTCN2021107220-appb-000051
Wait.
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
Figure PCTCN2021107220-appb-000052
Figure PCTCN2021107220-appb-000052
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、***基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
Figure PCTCN2021107220-appb-000053
Figure PCTCN2021107220-appb-000053
Figure PCTCN2021107220-appb-000054
Figure PCTCN2021107220-appb-000054
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .
上述环烷基、杂环基、芳基和杂芳基具有1个从母体环原子上除去一个氢原子所衍生的残基，或2个从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。The cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above have one residue derived by removing one hydrogen atom from the parent ring atom, or two residues by removing two from the same or two different ring atoms of the parent. A residue derived from a hydrogen atom, namely "divalent cycloalkyl", "divalent heterocyclic group", "arylene", "heteroarylene".
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。The term "amino protecting group" is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
术语“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基取代的烷基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基、叔丁基、苄基、甲氧基甲基(MOM)、乙氧基乙基、等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基、对硝基苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基。 The term "hydroxyl protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups. As an example, preferably, the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silicon, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy substituted alkyl or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted with C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, t-butyl, benzyl , methoxymethyl (MOM), ethoxyethyl, etc.; can be (C 1-10 alkyl or aryl) acyl, such as: formyl, acetyl, benzoyl, p-nitrobenzyl Acyl and the like; may be (C 1-6 alkyl or C 6-10 aryl)sulfonyl; may also be (C 1-6 alkoxy or C 6-10 aryloxy)carbonyl.
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.
术语“烷硫基”指烷基-S-，其中烷基如上所定义。The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”指-OH。The term "hydroxy" refers to -OH.
术语“巯基”指-SH。The term "thiol" refers to -SH.
术语“氨基”指-NH 2。 The term "amino" means -NH 2.
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO 2.
术语“氧代基”或“氧代”指“＝O”。The term "oxo" or "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基、环烷基如上所定义。The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl, cycloalkyl are as defined above.
本公开所述化合物的化学结构中，键
Figure PCTCN2021107220-appb-000055
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021107220-appb-000056
可以为
Figure PCTCN2021107220-appb-000057
或
Figure PCTCN2021107220-appb-000058
或者同时包含
Figure PCTCN2021107220-appb-000059
和
Figure PCTCN2021107220-appb-000060
两种构型。 In the chemical structure of the compound described in the present disclosure, the bond
Figure PCTCN2021107220-appb-000055
Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond
Figure PCTCN2021107220-appb-000056
can be
Figure PCTCN2021107220-appb-000057
or
Figure PCTCN2021107220-appb-000058
or both
Figure PCTCN2021107220-appb-000059
and
Figure PCTCN2021107220-appb-000060
Two configurations.
本公开的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-、 13C-、或者 14C-富集的碳( 11C-、 13C-、或者 14C-碳标记； 11C-、 13C-、或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。本公开还包括各种氘化形式的化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。 The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, the present disclosure having the structure, except that "deuterium" or "tritium" in place of a hydrogen, fluorine or instead of fluorine-labeled with 18 F- (18 F isotope), or with 11 C- 13 C-, 14 C- or rich, Compounds in which a set of carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) in place of carbon atoms are within the scope of this disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为1～5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。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定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。"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
“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。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
“可药用的盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
本文所用的术语“溶剂化物”是指本公开的化合物与一种或多种，优选地为1-3种，无论是有机的还是无机的溶剂分子的物理结合。该物理结合包括氢键。在某些情况下，例如，当在结晶固体的晶格中掺入一种或多种，优选1-3种溶剂分子时，溶剂化物将被分离。示例性的溶剂化物包括但不限于水合物、乙醇化物、甲醇化物和异丙醇化物。溶剂化方法是本领域公知的。The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of the crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
“前药”是指可以在生理条件下，例如通过在血液中水解，在体内转化以产生活性原药化合物。"Prodrug" means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.
当将术语“约”应用于如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，而不是限制。When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will appreciate, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.
本公开化合物的合成方法Synthetic methods of compounds of the present disclosure
为了完成本公开的目的，本公开采用如下技术方案：In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
方案一Option One
本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，该方法包括以下步骤：The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The preparation method of medicinal salt, the method comprises the following steps:
Figure PCTCN2021107220-appb-000061
Figure PCTCN2021107220-appb-000061
通式(IA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IB)或其盐(优选为盐酸盐)在酸性或碱性条件下(可选在微波条件下)反应，得到通式(I)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，所述反应为取代反应；A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IB) or its salt (preferably hydrochloride) under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (I) or its tautomer, internal a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction being a substitution reaction;
其中，X为卤素；Wherein, X is halogen;
环A、G、R、R 0、R 1、R 2、R 3、R 4、R 8和n如通式(I)中所定义。 Rings A, G, R, R 0 , R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
方案二Option II
本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，该方法包括以下步骤：The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The preparation method of medicinal salt, the method comprises the following steps:
Figure PCTCN2021107220-appb-000062
Figure PCTCN2021107220-appb-000062
通式(IAA)经氧化反应得到通式(I)；The general formula (IAA) is oxidized to obtain the general formula (I);
其中，R 0为
Figure PCTCN2021107220-appb-000063
Wherein, R 0 is
Figure PCTCN2021107220-appb-000063
W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000064
NR 13a和CR 13bR 13c； W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000064
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
环A、G、R、R 1、R 2、R 3、R 4、R 8和n如通式(I)中所定义。 Rings A, G, R, R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in general formula (I).
方案三third solution
本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，该方法包括以下步骤：The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The preparation method of medicinal salt, the method comprises the following steps:
Figure PCTCN2021107220-appb-000065
Figure PCTCN2021107220-appb-000065
通式(IIA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IIB)或其盐(优选为盐酸盐)在酸性或碱性条件下(可选在微波条件下)反应，得到通式(II)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，所述反应为取代反应；A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIB) or its salt (preferably hydrochloride) under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (II) or its tautomer, internal a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction being a substitution reaction;
其中，X为卤素；Wherein, X is halogen;
环A、R、R 0、R 1、R 3、R 4、R 5、R 8和n如通式(II)中所定义。 Rings A, R, R 0 , R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
方案四Option 4
本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，该方法包括以下步骤：The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The preparation method of medicinal salt, the method comprises the following steps:
Figure PCTCN2021107220-appb-000066
Figure PCTCN2021107220-appb-000066
通式(IIAA)经氧化反应得到通式(II)；The general formula (IIAA) is oxidized to obtain the general formula (II);
其中R 0为
Figure PCTCN2021107220-appb-000067
Wherein R 0 is
Figure PCTCN2021107220-appb-000067
W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000068
NR 13a和CR 13bR 13c； W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000068
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
环A、R、R 1、R 3、R 4、R 5、R 8和n如通式(II)中所定义。 Rings A, R, R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in general formula (II).
方案五Option five
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，该方法包括以下步骤：The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The preparation method of medicinal salt, the method comprises the following steps:
Figure PCTCN2021107220-appb-000069
Figure PCTCN2021107220-appb-000069
通式(IIA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IIIB)或其盐(优选为盐酸盐)在酸性或碱性条件下(可选在微波条件下)反应，得到通式(III)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，所述反应为取代反应；A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IIIB) or its salt (preferably hydrochloride) under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (III) or its tautomer, internal a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction being a substitution reaction;
其中，X为卤素；Wherein, X is halogen;
R、R 0、R 1、R 4、R 5、R 8和n如通式(III)中所定义。 R, R 0 , R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
方案六Option 6
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，该方法包括以下步骤：The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The preparation method of medicinal salt, the method comprises the following steps:
Figure PCTCN2021107220-appb-000070
Figure PCTCN2021107220-appb-000070
通式(IIIAA)经氧化反应得到通式(III)；The general formula (IIIAA) is oxidized to obtain the general formula (III);
其中，R 0为
Figure PCTCN2021107220-appb-000071
Wherein, R 0 is
Figure PCTCN2021107220-appb-000071
W选自氧原子、硫原子、
Figure PCTCN2021107220-appb-000072
NR 13a和CR 13bR 13c； W is selected from oxygen atom, sulfur atom,
Figure PCTCN2021107220-appb-000072
NR 13a and CR 13b R 13c ;
R 13相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13 are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 13a、R 13b和R 13c相同或不同，各自独立地选自卤素、烷基、卤代烷基、羟基、 羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基； R 13a , R 13b and R 13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S( O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
j为0、1或2；j is 0, 1 or 2;
k为1或2；k is 1 or 2;
v为0、1、2或3；v is 0, 1, 2, or 3;
R、R 1、R 4、R 5、R 8和n如通式(III)中所定义。 R, R 1 , R 4 , R 5 , R 8 and n are as defined in general formula (III).
方案七Option 7
本公开通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，该方法包括以下步骤：The compound represented by the general formula (IV) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The preparation method of medicinal salt, the method comprises the following steps:
Figure PCTCN2021107220-appb-000073
Figure PCTCN2021107220-appb-000073
通式(IVA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐在催化剂作用下经还原反应，得到通式(IV)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IVA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Under the action of a catalyst, the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof is obtained by reduction reaction form, or a pharmaceutically acceptable salt thereof,
其中，环A、G、R、R 0、R 1-R 4、R 8和n如通式(IV)中所定义。 wherein Rings A, G, R, R 0 , R 1 -R 4 , R 8 and n are as defined in general formula (IV).
提供上述反应中所述的酸性条件的试剂包括但不限于：氯化铵、三氟乙酸、盐酸、氯化氢的1,4-二氧六环溶液、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸和对苯甲磺酸；优选为氯化铵。Reagents that provide the acidic conditions described in the above reactions include, but are not limited to: ammonium chloride, trifluoroacetic acid, hydrochloric acid, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, Methanesulfonic acid, nitric acid, phosphoric acid and p-toluenesulfonic acid; preferably ammonium chloride.
提供上述反应中所述的碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于：三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂环[5,4,0]十一碳-7-烯，所述的无机碱类包括但不限于：氢化钠、磷酸钾、碳酸钠、醋酸钠、醋酸钾、碳酸钾或碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；优选为N,N-二异丙基乙胺。The reagents that provide the alkaline conditions described in the above reaction include organic bases and inorganic bases, and the organic bases include but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyllithium , lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazacyclo[5,4,0]undec-7-ene, said inorganic bases Including but not limited to: sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine .
上述氧化反应中所用的催化剂体系包括但不限于：PhSiH/Mn(dpm) 2(或Mn(dpm) 3或Mn(acac) 2或Co(sdmg) 3)、四苯基卟啉锰(III)配合物/NaBH 4(或Pt-H 2)、四苯基卟啉钴(II)配合物/NaBH 4(或EtNBH 4)、(二(水杨基-γ-亚氨基丙基)甲胺)钴(II)/伯醇、Co(acac) 2、Co(salen)、Co(acacen)、BH 3等。所用的氧化剂包括但不限于氧气、空气、过氧化氢等，其中Mn(dpm) 2为二(2,2,6,6-四甲基-3,5-庚二酮)锰，Mn(dpm) 3为三(2,2,6,6-四甲基-3,5-庚二酮)锰(CAS登记号为14324-99-3，又名：三(2,2,6,6-四甲基-3,5-庚烯酸)锰)，Mn(acac) 2为二(乙酰丙酮)锰(II)(CAS登记号14024-58-9)，Co(acac) 2为二(乙酰丙酮)钴(II)(CAS登记号193620-63-2)、Co(salen) 为N,N'-二(水杨基)乙二胺钴(II)(CAS登记号14167-18-1)、Co(acacen)为N,N'-二(乙酰丙酮)乙二胺钴(II)、Co(sdmg) 3为二(N-水杨亚基-2-氨基异丁酮)钴酸钠(CAS登记号704900-51-6)；优选催化剂体系为PhSiH/Mn(dpm) 3或PhSiH/Mn(acac) 2，优选氧化剂为氧气。 The catalyst system used in the above-mentioned oxidation reaction includes but is not limited to: PhSiH/Mn(dpm) 2 (or Mn(dpm) 3 or Mn(acac) 2 or Co(sdmg) 3 ), tetraphenylporphyrin manganese (III) Complex/NaBH 4 (or Pt-H 2 ), Tetraphenylporphyrin cobalt(II) complex/NaBH 4 (or EtNBH 4 ), (bis(salicyl-γ-iminopropyl)methylamine) cobalt (II) / primary alcohol, Co (acac) 2, Co (salen), Co (acacen), BH 3 and the like. The oxidant used includes but is not limited to oxygen, air, hydrogen peroxide, etc., wherein Mn(dpm) 2 is bis(2,2,6,6-tetramethyl-3,5-heptanedione) manganese, Mn(dpm) ) 3 is three (2,2,6,6-tetramethyl-3,5-heptanedione) manganese (CAS registration number is 14324-99-3, also known as: three (2,2,6,6- Tetramethyl-3,5-heptenoic acid) manganese), Mn(acac) 2 is bis(acetylacetonate) manganese(II) (CAS Registry No. 14024-58-9), Co(acac) 2 is bis(acetylacetonate) Acetone) cobalt(II) (CAS Reg. No. 193620-63-2), Co(salen) is N,N'-bis(salicyl)ethylenediamine cobalt(II) (CAS Reg. No. 14167-18-1) , Co(acacen) is N,N'-bis(acetylacetonate) ethylenediamine cobalt(II), Co(sdmg) 3 is bis(N-salicylidene-2-aminoisobutanone) sodium cobaltate (CAS registered No. 704900-51-6); the preferred catalyst system is PhSiH/Mn(dpm) 3 or PhSiH/Mn(acac) 2 , and the preferred oxidant is oxygen.
上述还原反应中所用的催化剂包括但不限于：钯碳、铁粉、雷尼镍、锌粉、四-三苯基膦钯、二氯化钯、醋酸钯、1,1’-双(二苄基磷)二氯二戊铁钯、三(二亚苄基丙酮)二钯等，优选为钯碳。所用的还原剂包括但不限于氢气、稀盐酸、醋酸或稀硫酸，优选为氢气。The catalyst used in the above-mentioned reduction reaction includes but is not limited to: palladium carbon, iron powder, Raney nickel, zinc powder, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzyl) (phosphorus) dipentyl iron palladium dichloro, tris(dibenzylideneacetone) dipalladium, etc., preferably palladium carbon. The reducing agent used includes, but is not limited to, hydrogen, dilute hydrochloric acid, acetic acid or dilute sulfuric acid, preferably hydrogen.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水、N,N-二甲基乙酰胺或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water, N,N-dimethylacetamide or N,N-dimethylformamide and mixtures thereof.
具体实施方式detailed description
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<"6> (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) , the internal standard is tetramethylsilane (TMS).
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)For MS determination, Agilent 1200/1290DAD-6110/6120Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC1200VWD和Waters HPLC e2695-2489高效液相色谱仪。High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.
高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High performance liquid preparative chromatography used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
手性制备使用Shimadzu LC-20AP制备型色谱仪。Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
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。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 The average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a CEM Discover-S 908860 microwave reactor.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析色谱法的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography chromatography and the developing solvent system of the thin layer chromatography adopted for purifying the compound include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethyl ether can also be added Basic or acidic reagents such as amines and acetic acid are used for adjustment.
实施例1Example 1
N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-甲氧基-4-甲基-7-(((S)-四氢呋喃-3-基)氧基)酞嗪-1-胺1N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-4-methyl-7-(((S)-tetrahydrofuran- 3-yl)oxy)phthalazin-1-amine 1
Figure PCTCN2021107220-appb-000074
Figure PCTCN2021107220-appb-000074
Figure PCTCN2021107220-appb-000075
Figure PCTCN2021107220-appb-000075
第一步first step
(S)-4-甲氧基-3-((四氢呋喃-3-基)氧基)苯甲酸甲酯1b(S)-Methyl 4-methoxy-3-((tetrahydrofuran-3-yl)oxy)benzoate 1b
将3-羟基-4-甲氧基苯甲酸甲酯1a(5.00g，27.45mmol，上海毕得)、(3R)-四氢呋喃-3-醇(2.42g，27.45mmol，上海毕得)和三苯基膦(8.64g，32.94mmol，泰坦)溶于四氢呋喃(50mL)中，氩气置换三次，0℃并且氩气氛下缓慢滴加偶氮二甲酸二异丙酯(6.66g，32.94mmol，上海韶远)。反应液升至室温并且氩气氛下搅拌16小时。将反应液倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取。合并有机相，饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥并过滤。滤液减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1b(4.5g)，产率：64％。Methyl 3-hydroxy-4-methoxybenzoate 1a (5.00 g, 27.45 mmol, Shanghai Bide), (3R)-tetrahydrofuran-3-ol (2.42 g, 27.45 mmol, Shanghai Bide) and triphenyl Phosphine (8.64 g, 32.94 mmol, Titan) was dissolved in tetrahydrofuran (50 mL), replaced by argon three times, and diisopropyl azodicarboxylate (6.66 g, 32.94 mmol, Shanghai Shao) was slowly added dropwise at 0°C under argon atmosphere. Far). The reaction was warmed to room temperature and stirred under an argon atmosphere for 16 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 1b (4.5 g), yield: 64%.
MS m/z(ESI)：253.1[M+1]。MS m/z (ESI): 253.1 [M+1].
第二步second step
(S)-2-溴-4-甲氧基-5-((四氢呋喃-3-基)氧基)苯甲酸甲酯1c(S)-Methyl 2-bromo-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoate 1c
将化合物1b(3.30g，13.08mmol)溶解于二氯甲烷(30mL)中，0℃分三批加入N-溴代琥珀酰亚胺(3.03g，17.01mmol，上海韶远)，加完后加入氢溴酸(1mL，50％水溶液)，反应液缓慢升至室温搅拌16小时。反应液减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1c(1.6g)，产率：29％。Compound 1b (3.30 g, 13.08 mmol) was dissolved in dichloromethane (30 mL), N-bromosuccinimide (3.03 g, 17.01 mmol, Shanghai Shaoyuan) was added in three batches at 0°C, and after the addition Hydrobromic acid (1 mL, 50% aqueous solution), the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 1c (1.6 g), yield: 29%.
MS m/z(ESI)：331.0[M+1]。MS m/z (ESI): 331.0 [M+1].
第三步third step
(S)-2-(1-乙氧基乙烯基)-4-甲氧基-5-((四氢呋喃-3-基)氧基)苯甲酸甲酯1d(S)-Methyl 2-(1-ethoxyvinyl)-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoate 1d
将化合物1c(1.6g，4.83mmol)、双三苯基膦二氯化钯(339mg，0.48mmol，百灵威)溶于1,4-二氧六环(20mL)，氩气置换3次后缓慢滴加三丁基(1-乙氧基乙烯)锡(1.92g，5.31mmol，上海毕得)。反应液升至100℃搅拌16小时。反应液冷却后倒入到饱和氟化钾水溶液(50mL)中淬灭，乙酸乙酯(25mL×3)萃取。合并有机 相，饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥并过滤。滤液减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1d(1.3g)，产率：83％。Compound 1c (1.6 g, 4.83 mmol) and bistriphenylphosphine palladium dichloride (339 mg, 0.48 mmol, Bailingwei) were dissolved in 1,4-dioxane (20 mL), replaced with argon for 3 times and slowly dropped Tributyl(1-ethoxyethylene)tin (1.92 g, 5.31 mmol, Shanghai Bidder) was added. The reaction solution was raised to 100°C and stirred for 16 hours. After cooling, the reaction solution was poured into saturated aqueous potassium fluoride solution (50 mL) to quench, and extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 1d (1.3 g), yield: 83%.
MS m/z(ESI)：323.0[M+1]。MS m/z (ESI): 323.0 [M+1].
第四步the fourth step
(S)-2-乙酰基-4-甲氧基-5-((四氢呋喃-3-基)氧基)苯甲酸甲酯1e(S)-Methyl 2-acetyl-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoate 1e
将化合物1d(1.3g，4.0mmol)溶于四氢呋喃(8mL)，加入浓盐酸(8mL)，搅拌反应2小时。反应液减压浓缩，得到标题产物1e(1.1g)，产品不经纯化直接用于下一步反应。Compound 1d (1.3 g, 4.0 mmol) was dissolved in tetrahydrofuran (8 mL), concentrated hydrochloric acid (8 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title product 1e (1.1 g), which was used in the next reaction without purification.
MS m/z(ESI)：295.1[M+1]。MS m/z (ESI): 295.1 [M+1].
第五步the fifth step
(S)-6-甲氧基-4-甲基-7-((四氢呋喃-3-基)氧基)酞嗪-1-酚1f(S)-6-Methoxy-4-methyl-7-((tetrahydrofuran-3-yl)oxy)phthalazin-1-ol 1f
将化合物1e(1.1g，4.0mmol)、甲醇(6mL)和水合肼(3mL，80％水溶液)混合，升至80℃搅拌16小时。反应液冷却后减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1f(620mg)，产率：55.9％。Compound 1e (1.1 g, 4.0 mmol), methanol (6 mL) and hydrazine hydrate (3 mL, 80% aqueous solution) were mixed, raised to 80°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 1f (620 mg), yield: 55.9%.
MS m/z(ESI)：277.1[M+1]。MS m/z (ESI): 277.1 [M+1].
第六步Step 6
(S)-1-氯-6-甲氧基-4-甲基-7-((四氢呋喃-3-基)氧基)酞嗪1g(S)-1-Chloro-6-methoxy-4-methyl-7-((tetrahydrofuran-3-yl)oxy)phthalazine 1g
将化合物1f(200mg，0.724mmol)溶解于三氯氧磷(2mL)中，加热至80℃搅拌16小时。反应液冷却后减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1g(170mg)，产率：79％。Compound 1f (200 mg, 0.724 mmol) was dissolved in phosphorus oxychloride (2 mL), heated to 80°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain 1 g (170 mg) of the title compound, yield: 79%.
MS m/z(ESI)：295.0[M+1]。MS m/z (ESI): 295.0 [M+1].
第七步Step 7
6-甲氧基-4-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-7-(((S)-四氢呋喃-3-基)6-Methoxy-4-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran -3-base)
氧基)酞嗪-1-胺1hoxy)phthalazine-1-amine 1h
将化合物1g(170mg，0.577mmol)、化合物(R)-1-(3-硝基-5-(三氟甲基)苯基)乙胺盐酸盐(162mg，0.692mmol，采用专利申请“CN110167928A”中说明书第89页的实施例B-6a公开的方法制备而得)、氯化铵(62mg，1.15mmol)和正丁醇(2mL)混合。反应液升温至110℃搅拌16小时。反应液冷却后减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1h(190mg)，产率：66％。Compound 1g (170mg, 0.577mmol), compound (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride (162mg, 0.692mmol) were prepared using patent application "CN110167928A" "prepared by the method disclosed in Example B-6a on page 89 of the manual), ammonium chloride (62 mg, 1.15 mmol) and n-butanol (2 mL). The reaction solution was heated to 110°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 1h (190 mg), yield: 66%.
MS m/z(ESI)：493.1[M+1]。MS m/z (ESI): 493.1 [M+1].
第八步Step 8
N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-甲氧基-4-甲基-7-(((S)-四氢呋喃-3-基)氧基)酞嗪-1-胺1N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-4-methyl-7-(((S)-tetrahydrofuran- 3-yl)oxy)phthalazin-1-amine 1
将化合物1h(130mg，0.26mmol)溶于甲醇(2mL)，加入10％钯碳(32mg，0.03mmol)，氢气置换三次后搅拌16小时。将反应液用硅藻土过滤，滤液减压浓缩后用高效液相制备色谱法纯化得到标题化合物1(20.6mg，白色固体)，产率：13％。Compound 1h (130 mg, 0.26 mmol) was dissolved in methanol (2 mL), 10% palladium on carbon (32 mg, 0.03 mmol) was added, and the mixture was replaced with hydrogen three times and stirred for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 1 (20.6 mg, white solid), yield: 13%.
MS m/z(ESI)：463.1[M+1]。MS m/z (ESI): 463.1 [M+1].
1H NMR(400MHz,DMSO-d 6):δ7.77(s,1H),7.25(s,1H),7.19(d,1H),6.84(d,2H),6.66(s,1H),5.49(s,2H),5.43-5.39(m,1H),5.36-5.32(m,1H),4.04-4.01(m,1H),3.96(s,3H),3.92-3.81(m,3H),2.60(s,3H),2.43-2.32(m,1H),2.09-2.01(m,1H),1.55(d,3H)。 1 H NMR (400MHz, DMSO-d 6 ): δ7.77(s,1H), 7.25(s,1H), 7.19(d,1H), 6.84(d,2H), 6.66(s,1H), 5.49 (s,2H),5.43-5.39(m,1H),5.36-5.32(m,1H),4.04-4.01(m,1H),3.96(s,3H),3.92-3.81(m,3H),2.60 (s, 3H), 2.43-2.32 (m, 1H), 2.09-2.01 (m, 1H), 1.55 (d, 3H).
实施例2Example 2
2,2-二氟-2-(2-氟-3-((R)-1-((6-甲氧基-4-甲基-7-(((S)-四氢呋喃-3-基)氧基)酞嗪-1-基)氨基)乙基)苯基)乙醇22,2-Difluoro-2-(2-fluoro-3-((R)-1-((6-methoxy-4-methyl-7-(((S)-tetrahydrofuran-3-yl) Oxy)phthalazin-1-yl)amino)ethyl)phenyl)ethanol 2
Figure PCTCN2021107220-appb-000076
Figure PCTCN2021107220-appb-000076
将化合物1g(45mg，0.15mmol)、化合物(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2,2-二氟乙醇盐酸盐2a(47mg，0.18mmol，采用专利申请“US2019194192”中说明书第105页的实施例B-5公开的方法制备而得)、N,N-二异丙基乙胺(60mg，0.46mmol)溶于2mL 1,4-二氧六环，微波120℃反应2小时。反应液冷却后减压浓缩，用高效液相制备色谱法纯化所得标题化合物2(36mg)，产率：49.3％。Compound 1 g (45 mg, 0.15 mmol), compound (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride 2a (47 mg, 0.18 mmol, prepared by the method disclosed in Example B-5 on page 105 of the specification in the patent application "US2019194192"), N,N-diisopropylethylamine (60mg, 0.46mmol) was dissolved in 2mL of 1,4- Dioxane, microwave reaction at 120°C for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained title compound 2 (36 mg) was purified by preparative high performance liquid chromatography. Yield: 49.3%.
MS m/z(ESI)：478.1[M+1]。MS m/z (ESI): 478.1 [M+1].
1H NMR(500MHz,CD 3OD):δ7.80(s,1H),7.57-7.54(m,1H),7.44-7.41(m,1H),7.35(s,1H),7.16-7.13(m,1H),5.76-5.72(m,1H),5.40-5.38(m,1H),4.13-3.95(m,9H),2.67(s,3H),2.45-2.37(m,1H),2.29-2.23(m,1H),1.71-1.70(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ 7.80(s, 1H), 7.57-7.54(m, 1H), 7.44-7.41(m, 1H), 7.35(s, 1H), 7.16-7.13(m) ,1H),5.76-5.72(m,1H),5.40-5.38(m,1H),4.13-3.95(m,9H),2.67(s,3H),2.45-2.37(m,1H),2.29-2.23 (m, 1H), 1.71-1.70 (d, 3H).
实施例3Example 3
1-((S)-3-((4-(((R)-1-(3-(1,1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)吡咯烷-1-基)乙酮31-((S)-3-((4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino) -7-Methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3
Figure PCTCN2021107220-appb-000077
Figure PCTCN2021107220-appb-000077
Figure PCTCN2021107220-appb-000078
Figure PCTCN2021107220-appb-000078
第一步first step
(R)-3-(甲苯磺酰氧基)吡咯烷-1-甲酸叔丁酯3b(R)-3-(Tosyloxy)pyrrolidine-1-carboxylate tert-butyl ester 3b
将化合物(R)-1-叔丁氧羰基-3-羟基吡咯烷3a(1.5g，8mmol，上海毕得)、对甲苯磺酰氯(1.83g，9.6mmol，上海毕得)和三乙胺(1.62g，16mmol)溶于二氯甲烷(50mL)中，加入4-二甲氨基吡啶(0.1g，0.8mmol)，反应液搅拌2小时。将反应液倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取。合并有机相，饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥并过滤。滤液减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物3b(1.1g)，产率：40.2％。Compound (R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine 3a (1.5 g, 8 mmol, Shanghai Bide), p-toluenesulfonyl chloride (1.83 g, 9.6 mmol, Shanghai Bide) and triethylamine ( 1.62 g, 16 mmol) was dissolved in dichloromethane (50 mL), 4-dimethylaminopyridine (0.1 g, 0.8 mmol) was added, and the reaction solution was stirred for 2 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 3b (1.1 g), yield: 40.2%.
MS m/z(ESI)：342.4[M+1]。MS m/z (ESI): 342.4 [M+1].
第二步second step
2-溴-5-羟基-4-甲氧基苯甲酸甲酯3dMethyl 2-bromo-5-hydroxy-4-methoxybenzoate 3d
将化合物2-溴-5-羟基-4-甲氧基苯甲酸3c(5g，20.2mmol)溶于30mL甲醇中，冰浴下滴加浓硫酸(1.98g，20.2mmol)，回流搅拌反应14小时，反应液冷却后减压浓缩，残余物倒入冰水中，析出固体，过滤，干燥后得到标题化合物3d(5g)，产率：94.6％。The compound 2-bromo-5-hydroxy-4-methoxybenzoic acid 3c (5 g, 20.2 mmol) was dissolved in 30 mL of methanol, concentrated sulfuric acid (1.98 g, 20.2 mmol) was added dropwise under an ice bath, and the reaction was stirred under reflux for 14 hours , the reaction solution was cooled and concentrated under reduced pressure, the residue was poured into ice water, the solid was precipitated, filtered and dried to obtain the title compound 3d (5 g), yield: 94.6%.
MS m/z(ESI)：261.1[M+1]。MS m/z (ESI): 261.1 [M+1].
第三步third step
5-乙酰氧基-2-溴-4-甲氧基苯甲酸甲酯3eMethyl 5-acetoxy-2-bromo-4-methoxybenzoate 3e
将化合物3d(2g，7.66mmol)溶于20mL二氯甲烷中，加入N,N-二异丙基乙基胺(2.97g，22.98mmol)，冰浴下滴加乙酸酐(0.937g，9.19mmol)，自然升至室温反应14小时，反应液减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物3e(2g)，产率：86％。Compound 3d (2 g, 7.66 mmol) was dissolved in 20 mL of dichloromethane, N,N-diisopropylethylamine (2.97 g, 22.98 mmol) was added, and acetic anhydride (0.937 g, 9.19 mmol) was added dropwise under an ice bath ), the reaction was naturally raised to room temperature for 14 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 3e (2 g), yield: 86%.
MS m/z(ESI)：303.1[M+1]。MS m/z (ESI): 303.1 [M+1].
第四步the fourth step
5-乙酰氧基-2-(1-乙氧基乙烯基)-4-甲氧基苯甲酸甲酯3fMethyl 5-acetoxy-2-(1-ethoxyvinyl)-4-methoxybenzoate 3f
将化合物3e(2.3g，7.59mmol)、双三苯基膦二氯化钯(532mg，0.76mmol，百灵威)溶于1,4-二氧六环(20mL)，氩气置换3次后缓慢滴加三丁基(1-乙氧基乙烯)锡(3g，8.35mmol，上海毕得)。反应液升至100℃搅拌16小时。反应液冷却后减压浓缩，得到标题化合物3f(2.3g)，产品不经纯化直接用于下一步反应。Compound 3e (2.3 g, 7.59 mmol) and bistriphenylphosphine palladium dichloride (532 mg, 0.76 mmol, Bailingwei) were dissolved in 1,4-dioxane (20 mL), replaced with argon for 3 times and slowly dropped Tributyl(1-ethoxyethylene)tin (3 g, 8.35 mmol, Shanghai Bide) was added. The reaction solution was raised to 100°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain the title compound 3f (2.3 g), which was used in the next reaction without purification.
MS m/z(ESI)：295.1[M+1]。MS m/z (ESI): 295.1 [M+1].
第五步the fifth step
5-乙酰氧基-2-乙酰基-4-甲氧基苯甲酸甲酯3gMethyl 5-acetoxy-2-acetyl-4-methoxybenzoate 3g
将化合物3f(2.2g，7.45mmol)溶于四氢呋喃(8mL)中，加入浓盐酸(10mL)，搅拌反应2小时。反应液减压浓缩，所得残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物3g(2g)，产率：98％。Compound 3f (2.2 g, 7.45 mmol) was dissolved in tetrahydrofuran (8 mL), concentrated hydrochloric acid (10 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 3g (2g), yield: 98%.
MS m/z(ESI)：267.1[M+1]。MS m/z (ESI): 267.1 [M+1].
第六步Step 6
6-甲氧基-4-甲基酞嗪-1,7-二酚3h6-Methoxy-4-methylphthalazine-1,7-diol 3h
将化合物3g(2g，7.51mmol)，甲醇(10mL)和水合肼(521mg，10.2mmol)混合，升至80℃搅拌16小时。反应液冷却，减压浓缩后过滤，固体用冰乙醇洗涤后干燥得到标题化合物3h(1.4g)，产率90.7％。Compound 3 g (2 g, 7.51 mmol), methanol (10 mL) and hydrazine hydrate (521 mg, 10.2 mmol) were mixed, and the mixture was heated to 80°C and stirred for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, filtered, and the solid was washed with ice ethanol and dried to obtain the title compound 3h (1.4 g) in a yield of 90.7%.
MS m/z(ESI):207.1[M+1]。MS m/z(ESI): 207.1[M+1].
第七步Step 7
(S)-3-((4-羟基-7-甲氧基-1-甲基酞嗪-6基)氧基)吡咯烷-1-甲酸叔丁酯3i(S)-3-((4-Hydroxy-7-methoxy-1-methylphthalazin-6yl)oxy)pyrrolidine-1-carboxylate tert-butyl ester 3i
将化合物3b(120mg，0.38mmol)、3h(90mg，0.41mmol)、N,N-二甲基甲酰胺(3mL)加入反应瓶中，升至70℃搅拌5小时。反应液冷却后减压浓缩，将反应液倒入水(20mL)中，用乙酸乙酯(15mL×3)萃取。合并有机相，饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥并过滤。滤液减压浓缩得到粗品标题化合物3i(80mg)，产率：51％。Compound 3b (120 mg, 0.38 mmol), 3h (90 mg, 0.41 mmol), and N,N-dimethylformamide (3 mL) were added to the reaction flask, and the mixture was heated to 70° C. and stirred for 5 hours. The reaction solution was cooled, concentrated under reduced pressure, poured into water (20 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 3i (80 mg), yield: 51%.
MS m/z(ESI)：376.4[M+1]。MS m/z (ESI): 376.4 [M+1].
第八步Step 8
(S)-1-氯-6-甲氧基-4-甲基-7-(吡咯烷-3-基氧基)酞嗪盐酸盐3j(S)-1-Chloro-6-methoxy-4-methyl-7-(pyrrolidin-3-yloxy)phthalazine hydrochloride 3j
将化合物3i(40mg，0.106mmol)溶于三氯氧磷(2mL)，升至70℃搅拌3小时。反应液冷却后减压浓缩得到标题化合物3j(50mg)，产品不经纯化直接用于下一步反应。Compound 3i (40 mg, 0.106 mmol) was dissolved in phosphorus oxychloride (2 mL), raised to 70°C and stirred for 3 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain the title compound 3j (50 mg). The product was used in the next reaction without purification.
MS m/z(ESI)：294.1[M+1]。MS m/z (ESI): 294.1 [M+1].
第九步Step 9
(S)-1-(3-((4-氯-7-甲氧基-1-甲基酞嗪-6-基)氧基)吡咯烷-1-基)乙酮3k(S)-1-(3-((4-Chloro-7-methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3k
将化合物3j(50mg，0.17mmol)溶于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(70mg，0.51mmol)、乙酰氯(20mg，0.25mmol)搅拌反应2小时。所得残余物用 柱层析色谱法以洗脱剂体系B纯化得到标题化合物3k(50mg)，产率：87.4％。Compound 3j (50 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), N,N-diisopropylethylamine (70 mg, 0.51 mmol) and acetyl chloride (20 mg, 0.25 mmol) were added and the reaction was stirred for 2 hours. The obtained residue was purified by column chromatography with eluent system B to give the title compound 3k (50 mg), yield: 87.4%.
MS m/z(ESI)：336.3[M+1]。MS m/z (ESI): 336.3 [M+1].
第十步Step 10
1-((S)-3-((4-(((R)-1-(3-(1,1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)吡咯烷-1-基)乙酮31-((S)-3-((4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino) -7-Methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3
将化合物3k(30mg，0.089mmol)、(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2,2-二氟乙醇盐酸盐(2a)(40mg，0.178mmol)、氯化铵(10mg，0.178mmol)和正丁醇(1mL)混合。微波升温至110℃搅拌1小时。将反应液用硅藻土过滤，滤液减压浓缩后用高效液相制备色谱法纯化得到标题化合物3(3mg)，产率：6.5％。Compound 3k (30 mg, 0.089 mmol), (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride (2a) (40 mg, 0.178 mmol), ammonium chloride (10 mg, 0.178 mmol) and n-butanol (1 mL). The microwave was heated to 110°C and stirred for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 3 (3 mg), yield: 6.5%.
MS m/z(ESI)：519.2[M+1]。MS m/z (ESI): 519.2 [M+1].
1H NMR(500MHz,CD 3OD):δ7.73(s,1H),7.61-7.58(m,1H),7.50-7.47(m,2H),7.27-7.25(m,1H),5.75-5.71(m,1H),4.15-4.10(m,3H),3.82-3.79(m,2H),3.62-3.59(m,2H),2.81-2.77(m,1H),2.31-2.28(m,2H),2.25-2.22(m,3H),2.15-2.12(m,2H),1.72-1.69(m,3H),1.56-1.54(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ 7.73 (s, 1H), 7.61-7.58 (m, 1H), 7.50-7.47 (m, 2H), 7.27-7.25 (m, 1H), 5.75-5.71 (m,1H),4.15-4.10(m,3H),3.82-3.79(m,2H),3.62-3.59(m,2H),2.81-2.77(m,1H),2.31-2.28(m,2H) , 2.25-2.22 (m, 3H), 2.15-2.12 (m, 2H), 1.72-1.69 (m, 3H), 1.56-1.54 (d, 3H).
实施例4Example 4
(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基哌啶-1-基)乙酮4(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine -6-yl)-4-hydroxypiperidin-1-yl)ethanone 4
Figure PCTCN2021107220-appb-000079
Figure PCTCN2021107220-appb-000079
第一步first step
1,7-二氯-6-甲氧基-4-甲基酞嗪4a1,7-Dichloro-6-methoxy-4-methylphthalazine 4a
将化合物3h(2g，9.7mmol)与三氯氧磷(15mL)混合，缓慢加入N,N-二异丙基乙胺(3.8g，29.1mmol)，升温至90℃反应14小时。反应液减压浓缩，倒入冰水，用饱和碳酸氢钠水溶液调节pH至7-8左右，二氯甲烷萃取(30mL×2)，无水硫酸钠 干燥，过滤，减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物4a(1.4g)，产率：59.4％。Compound 3h (2 g, 9.7 mmol) was mixed with phosphorus oxychloride (15 mL), N,N-diisopropylethylamine (3.8 g, 29.1 mmol) was slowly added, and the temperature was raised to 90° C. to react for 14 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography with eluent system B afforded the title compound 4a (1.4 g), yield: 59.4%.
MS m/z(ESI)：243.1[M+1]。MS m/z (ESI): 243.1 [M+1].
第二步second step
(R)-7-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-甲氧基-4-甲基酞嗪-1-胺4b(R)-7-Chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-4-methylphthalazin-1-amine 4b
将化合物4a(150mg，0.62mmol)、化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺盐酸盐(139mg，0.62mmol，采用专利申请“EP2018086197”中说明书第141页的实施例B-5公开的方法制备而得)、氯化铵(16.5mg，0.31mmol)和正丁醇(2mL)混合。微波120℃反应1小时。反应液冷却后减压浓缩，所得残余物用高效液相制备色谱法纯化得到标题化合物4b(15mg)，产率：6.15％。Compound 4a (150 mg, 0.62 mmol), compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (139 mg, 0.62 mmol) were prepared using patent application "EP2018086197" prepared by the method disclosed in Example B-5 on page 141 of the specification), ammonium chloride (16.5 mg, 0.31 mmol) and n-butanol (2 mL). Microwave at 120°C for 1 hour. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid preparative chromatography to obtain the title compound 4b (15 mg), yield: 6.15%.
MS m/z(ESI)：396.1[M+1]。MS m/z (ESI): 396.1 [M+1].
第三步third step
(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-5,6-二氢吡啶-1(2H)-基)乙酮4c(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine -6-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone 4c
将化合物4b(15mg，0.038mmol)、化合物1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-基)乙酮(11mg，0.042mmol，上海毕得)、三(二亚苄基丙酮)二钯(10.4mg，0.011mmol，百灵威)、2-双环己基膦-2'-甲基联苯(4.4mg，0.011mmol，上海韶远)、无水碳酸钾(16mg，0.011mmol)溶于1,4-二氧六环(2mL)和水(0.5mL)，微波100℃反应1小时，反应液减压浓缩，采用薄层色谱法以洗脱剂体系A纯化得到标题化合物4c(10mg)，产率：54.5％。Compound 4b (15 mg, 0.038 mmol), compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6- Dihydropyridin-1(2H)-yl)ethanone (11 mg, 0.042 mmol, Shanghai Bide), tris(dibenzylideneacetone)dipalladium (10.4 mg, 0.011 mmol, Bailingwei), 2-dicyclohexylphosphine- 2'-Methylbiphenyl (4.4mg, 0.011mmol, Shanghai Shaoyuan), anhydrous potassium carbonate (16mg, 0.011mmol) were dissolved in 1,4-dioxane (2mL) and water (0.5mL), microwave The reaction was carried out at 100° C. for 1 hour, the reaction solution was concentrated under reduced pressure, and purified by thin layer chromatography with eluent system A to obtain the title compound 4c (10 mg), yield: 54.5%.
MS m/z(ESI)：485.2[M+1]。MS m/z (ESI): 485.2 [M+1].
第四步the fourth step
(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基哌啶-1-基)乙酮4(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine -6-yl)-4-hydroxypiperidin-1-yl)ethanone 4
将化合物4c(10mg，20.6μmol)、三(2,2,6,6-四甲基-3,5-庚烯酸)锰(3mg，5μmol，上海毕得)、苯硅烷(4.5mg，41.2μmol，泰坦)溶于异丙醇(2mL)和二氯甲烷(0.2mL)，氧气置换，搅拌反应14小时。反应液减压浓缩，残余物用高效液相制备色谱法纯化得到标题化合物4(1.2mg)，产率：11.5％。Compound 4c (10 mg, 20.6 μmol), tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (3 mg, 5 μmol, Shanghai Bide), phenylsilane (4.5 mg, 41.2 μmol, Titan) was dissolved in isopropanol (2 mL) and dichloromethane (0.2 mL), oxygen was replaced, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 4 (1.2 mg), yield: 11.5%.
MS m/z(ESI)：503.2[M+1]。MS m/z (ESI): 503.2 [M+1].
1H NMR(500MHz,CD 3OD):δ8.53(s,1H),7.61-7.58(m,1H),7.46-7.44(m,1H),7.43(s,1H),7.30-7.24(m,1H),7.19-6.90(q,1H),5.76-5.55(m,1H),4.66-4.49(m,1H),4.11(s,3H),3.91-3.90(m,1H),3.88-3.87(m,1H),3.21-3.20(m,1H),2.64(s,3H),2.62-2.52(m,2H),2.20(s,3H),1.86-1.76(m,2H),1.70(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ8.53(s,1H), 7.61-7.58(m,1H), 7.46-7.44(m,1H), 7.43(s,1H), 7.30-7.24(m ,1H),7.19-6.90(q,1H),5.76-5.55(m,1H),4.66-4.49(m,1H),4.11(s,3H),3.91-3.90(m,1H),3.88-3.87 (m,1H),3.21-3.20(m,1H),2.64(s,3H),2.62-2.52(m,2H),2.20(s,3H),1.86-1.76(m,2H),1.70(d , 3H).
实施例5Example 5
(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基哌啶-1-基)-2-甲氧基乙-1-酮5(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine -6-yl)-4-hydroxypiperidin-1-yl)-2-methoxyethan-1-one 5
Figure PCTCN2021107220-appb-000080
Figure PCTCN2021107220-appb-000080
第一步first step
4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1,2,3,6-四氢吡啶盐酸盐5b4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride 5b
将化合物4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯5a(1g，3.23mmol，上海毕得)溶于4N盐酸1,4-二氧六环溶液中，搅拌反应3小时。反应液减压浓缩得到粗产物5b(790mg)，产率：99.4％，产物不经纯化，直接用于下一步反应。The compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid Tert-butyl ester 5a (1 g, 3.23 mmol, Shanghai Bide) was dissolved in 4N hydrochloric acid 1,4-dioxane solution, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 5b (790 mg), yield: 99.4%, and the product was directly used in the next reaction without purification.
MS m/z(ESI)：210.1[M+1]。MS m/z (ESI): 210.1 [M+1].
第二步second step
2-甲氧基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮5c2-Methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine- 1(2H)-yl)ethan-1-one 5c
将化合物5b(1.7g，6.92mmol)、甲氧基乙酸(805mg，8.93mmol，上海韶远)溶解于四氢呋喃(5mL)中，依次加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(4.63g，12.17mmol)与N,N-二异丙基乙胺(2.63g，20.35mmol)，搅拌反应14小时。反应液减压浓缩，残余物柱层析色谱法以洗脱剂体系A纯化，得到标题化合物5c(1.2g)，产率：52.5％。Compound 5b (1.7 g, 6.92 mmol), methoxyacetic acid (805 mg, 8.93 mmol, Shanghai Shaoyuan) were dissolved in tetrahydrofuran (5 mL), followed by adding 2-(7-azobenzotriazole)-N , N,N,N-tetramethylurea hexafluorophosphate (4.63 g, 12.17 mmol) and N,N-diisopropylethylamine (2.63 g, 20.35 mmol), and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain the title compound 5c (1.2 g), yield: 52.5%.
MS m/z(ESI)：282.0[M+1]。MS m/z (ESI): 282.0 [M+1].
第三步third step
(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基哌啶-1-基)-2-甲氧基乙-1-酮5(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine -6-yl)-4-hydroxypiperidin-1-yl)-2-methoxyethan-1-one 5
采用实施例4中的合成路线第三至第四步，将第三步原料化合物1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-基)乙酮替换为化合物5c，制得化合物5(15mg)，产率：22％。Using the third to fourth steps of the synthetic route in Example 4, the raw material compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane in the third step) -2-yl)-3,6-dihydropyridin-1(2H)-yl)ethanone was replaced with compound 5c to obtain compound 5 (15 mg), yield: 22%.
MS m/z(ESI)：533.1[M+1]。MS m/z (ESI): 533.1 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.51(s,1H),7.59(t,1H),7.43(t,1H),7.34(s,1H),7.17(t,1H),7.00(t,1H),5.72(d,1H),4.47(s,1H),4.31(d,1H),4.20(s,1H),4.05(s,3H),3.83(dd,1H),3.63(t,1H),3.47(s,3H),3.23(t,1H),2.67(s,3H),2.64-2.50(m,2H),1.80(t,2H),1.69(d,3H)。 1 H NMR (500MHz, methanol-d 4 ): δ 8.51(s,1H), 7.59(t,1H), 7.43(t,1H), 7.34(s,1H), 7.17(t,1H), 7.00 (t, 1H), 5.72(d, 1H), 4.47(s, 1H), 4.31(d, 1H), 4.20(s, 1H), 4.05(s, 3H), 3.83(dd, 1H), 3.63( t, 1H), 3.47(s, 3H), 3.23(t, 1H), 2.67(s, 3H), 2.64-2.50(m, 2H), 1.80(t, 2H), 1.69(d, 3H).
实施例6Example 6
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟 基-N,N-二甲基环己烷-1-甲酰胺6(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6- yl)-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide 6
Figure PCTCN2021107220-appb-000081
Figure PCTCN2021107220-appb-000081
第一步first step
4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)环己-3-烯羧酸6b4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-enecarboxylic acid 6b
将化合物4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)环己-3-烯羧酸甲酯6a(1g，3.76mmol)、一水合氢氧化锂(631mg，15mmol)溶于10mL四氢呋喃、2mL水和5mL甲醇的混合溶剂中，搅拌反应16小时，滴加2N盐酸，调节pH至5-6，减压浓缩至干，得到标题化合物6b(1.8g)，不经纯化直接下一步。The compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-enecarboxylic acid methyl ester 6a (1 g, 3.76 mmol ), lithium hydroxide monohydrate (631mg, 15mmol) were dissolved in a mixed solvent of 10mL of tetrahydrofuran, 2mL of water and 5mL of methanol, stirred for 16 hours, added dropwise 2N hydrochloric acid, adjusted pH to 5-6, concentrated to dryness under reduced pressure, The title compound 6b (1.8 g) was obtained, which was directly next step without purification.
MS m/z(ESI)：251.1[M-1]。MS m/z (ESI): 251.1 [M-1].
第二步second step
N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)环己-3-烯甲酰胺6cN,N-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxolaboran-2-yl)cyclohex-3-enecarboxamide 6c
将化合物6b(150mg，595μmol)和2M的N,N-二甲基胺(595μL，1.2mmol)溶解于N,N-二甲基甲酰胺(2mL)中，依次加入N,N-二异丙基乙胺(154mg，1.2mmol)和2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(280mg，1.2mmol)，氮气氛下反应14小时。反应液浓缩，残余物用柱层析色谱法以洗脱剂体系A纯化，得到标题化合物6c(150mg)，产率：90％。Compound 6b (150 mg, 595 μmol) and 2M N,N-dimethylamine (595 μL, 1.2 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by N,N-diisopropyl Ethylethylamine (154 mg, 1.2 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (280 mg, 1.2 mmol) under nitrogen atmosphere React for 14 hours. The reaction solution was concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 6c (150 mg), yield: 90%.
MS m/z(ESI)：280.1[M+1]。MS m/z (ESI): 280.1 [M+1].
第三步third step
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基-N,N-二甲基环己烷-1-甲酰胺6(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6- yl)-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide 6
采用实施例4中的合成路线，将第三步原料化合物1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-基)乙酮替换为化合物6c，制得化合物6(3mg)，产率：14.4％。Using the synthetic route in Example 4, the third step starting material compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)- 3,6-Dihydropyridin-1(2H)-yl)ethanone was replaced with compound 6c to obtain compound 6 (3 mg), yield: 14.4%.
MS m/z(ESI)：531.1[M+1]。MS m/z (ESI): 531.1 [M+1].
1H NMR(400MHz,CD 3OD):δ8.41(s,1H),7.60(t,1H),7.46-7.43(m,2H),7.20-7.14(m,1H),7.02-6.92(m,1H),5.74(q,1H),4.08(s,3H),3.16(s,3H),3.02-2.91(m,6H),2.69(s,3H),2.13-2.07(m,3H),1.82-1.70(m,6H)。 1 H NMR (400MHz, CD 3 OD): δ 8.41 (s, 1H), 7.60 (t, 1H), 7.46-7.43 (m, 2H), 7.20-7.14 (m, 1H), 7.02-6.92 (m ,1H),5.74(q,1H),4.08(s,3H),3.16(s,3H),3.02-2.91(m,6H),2.69(s,3H),2.13-2.07(m,3H), 1.82-1.70 (m, 6H).
实施例7Example 7
(S)-1-(4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基) 哌啶-1-基)-2-羟基丙-1-酮7(S)-1-(4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1- Methylphthalazin-6-yl)piperidin-1-yl)-2-hydroxypropan-1-one7
Figure PCTCN2021107220-appb-000082
Figure PCTCN2021107220-appb-000082
第一步first step
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯7a(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6- base)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester 7a
将化合物4b(35mg，0.088mmol)、化合物4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(42mg，0.132mmol，上海毕得)、[1,1'-双(二异丙基膦)二茂铁]二氯钯(10mg，0.017mmol)、无水碳酸钾(37mg，0.265mmol)溶于1,4-二氧六环(2mL)和水(0.5mL)，110℃反应4小时，反应液减压浓缩，采用薄层色谱法以洗脱剂体系A纯化得到标题化合物7a(45mg)，产率：93.7％。Compound 4b (35 mg, 0.088 mmol), compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-3,6-dihydro- 2H-Pyridine-1-carboxylate tert-butyl ester (42 mg, 0.132 mmol, Shanghai Bide), [1,1'-bis(diisopropylphosphino)ferrocene]dichloropalladium (10 mg, 0.017 mmol), Anhydrous potassium carbonate (37 mg, 0.265 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), reacted at 110 °C for 4 hours, the reaction solution was concentrated under reduced pressure, and thin layer chromatography was used to elute Reagent system A was purified to give the title compound 7a (45 mg), yield: 93.7%.
MS m/z(ESI)：543.2[M+1]。MS m/z (ESI): 543.2 [M+1].
第二步second step
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)哌啶(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6- base) piperidine
-1-羧酸叔丁酯7b-1-Carboxylic acid tert-butyl ester 7b
将化合物7a(45mg，82μmol)溶于甲醇(3mL)，加入钯碳(10％)(13mg)，氢气置换，搅拌反应14小时。反应液减压浓缩得到标题化合物7b(40mg)，产率：88.6％。MS m/z(ESI):545.3[M+1]。Compound 7a (45 mg, 82 μmol) was dissolved in methanol (3 mL), palladium carbon (10%) (13 mg) was added, hydrogen was replaced, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 7b (40 mg), yield: 88.6%. MS m/z (ESI): 545.3 [M+1].
第三步third step
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-甲氧基-4-甲基-7-(哌啶-4-基)酞嗪-1-胺盐酸盐7c(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-4-methyl-7-(piperidine-4- base) phthalazine-1-amine hydrochloride 7c
将化合物7b(40mg，0.073mmol)溶于4N盐酸1,4-二氧六环溶液中，搅拌反应2小时。反应液减压浓缩得到粗产物7c(35mg)，产率：99.1％，产物不经纯化，直接用于下一步反应。Compound 7b (40 mg, 0.073 mmol) was dissolved in a 4N hydrochloric acid solution in 1,4-dioxane, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 7c (35 mg), yield: 99.1%, and the product was directly used in the next reaction without purification.
MS m/z(ESI)：445.2[M+1]。MS m/z (ESI): 445.2 [M+1].
第四步the fourth step
(S)-1-(4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)哌啶-1-基)-2-羟基丙-1-酮7(S)-1-(4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1- Methylphthalazin-6-yl)piperidin-1-yl)-2-hydroxypropan-1-one 7
将化合物7c(35mg，0.072mmol)、L-乳酸(13mg，0.145mmol，上海韶远试剂有限公司)溶解于N,N-二甲基甲酰胺(2mL)中，依次加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(25mg，0.109mmol)与N,N-二异丙基乙胺(46mg，0.364mmol)，搅拌反应3小时。反应液减压浓缩，残余物高效液相制备色法纯化得到标题化合物7(12mg)，产率：31.9％。Compound 7c (35 mg, 0.072 mmol), L-lactic acid (13 mg, 0.145 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) were dissolved in N,N-dimethylformamide (2 mL), followed by adding 2-(7-dimethicone) Nitrobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (25mg, 0.109mmol) and N,N-diisopropylethylamine (46mg, 0.364mmol), the reaction was stirred 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain the title compound 7 (12 mg), yield: 31.9%.
MS m/z(ESI)：517.2[M+1]。MS m/z (ESI): 517.2 [M+1].
1H NMR(500MHz,CD 3OD):δ8.27(t,1H),7.56(t,1H),7.44(t,1H),7.32(d,1H),7.20-7.10(m,1H),5.74(q,1H),4.77(d,1H),4.07(d,2H),3.52(d,2H),3.29(d,4H),2.91-2.83(m,1H),2.68(s,2H),2.00(d,3H),1.88(s,2H),1.69(d,3H),1.37(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ8.27(t,1H), 7.56(t,1H), 7.44(t,1H), 7.32(d,1H), 7.20-7.10(m,1H), 5.74(q, 1H), 4.77(d, 1H), 4.07(d, 2H), 3.52(d, 2H), 3.29(d, 4H), 2.91-2.83(m, 1H), 2.68(s, 2H) , 2.00(d, 3H), 1.88(s, 2H), 1.69(d, 3H), 1.37(d, 3H).
实施例8Example 8
1-((S)-3-((4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)吡咯烷-1-基)乙酮81-((S)-3-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1 -Methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 8
Figure PCTCN2021107220-appb-000083
Figure PCTCN2021107220-appb-000083
采用实施例3中的合成路线，将第十步原料化合物(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2,2-二氟乙醇盐酸盐替换为化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺盐酸盐，制得标题化合物8(5mg)，产率：4.3％。Using the synthetic route in Example 3, the tenth step raw material compound (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride was replaced As compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride, the title compound 8 (5 mg) was obtained, yield: 4.3%.
MS m/z(ESI)：489.2[M+1]。MS m/z (ESI): 489.2 [M+1].
1H NMR(500MHz,CD 3OD):δ7.93(d,1H),7.58(t,1H),7.48-7.40(m,2H),7.18(t,1H),5.71-5.66(m,1H),4.04-4.04(m,2H),3.89-3.82(m,2H),3.63-3.52(m,2H),2.70(s,1H),2.47-2.29(m,2H),2.24-2.15(m,3H),2.13-2.21(m,2H),1.71(d,3H),1.61(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ 7.93 (d, 1H), 7.58 (t, 1H), 7.48-7.40 (m, 2H), 7.18 (t, 1H), 5.71-5.66 (m, 1H) ), 4.04-4.04(m, 2H), 3.89-3.82(m, 2H), 3.63-3.52(m, 2H), 2.70(s, 1H), 2.47-2.29(m, 2H), 2.24-2.15(m , 3H), 2.13-2.21 (m, 2H), 1.71 (d, 3H), 1.61 (d, 3H).
实施例9Example 9
(R)-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基环己基)(吗啉基)甲酮9(R)-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-4-hydroxycyclohexyl)(morpholinyl)methanone 9
Figure PCTCN2021107220-appb-000084
Figure PCTCN2021107220-appb-000084
采用实施例6中的合成路线，将第二步原料化合物N,N-二甲基胺替换为化合物***啉，制得化合物9(10mg)，产率：48.4％。Using the synthetic route in Example 6, the raw material compound N,N-dimethylamine of the second step was replaced with the compound morpholine to obtain compound 9 (10 mg), yield: 48.4%.
MS m/z(ESI)：573.1[M+1]。MS m/z (ESI): 573.1 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.40(s,1H),7.60(t,1H),7.44(t,1H),7.36(s,1H),7.17(t,1H),7.01(t,1H),5.77(q,1H),4.09(s,3H),3.69-3.61(m,8H),3.02-2.98(m,1H),2.90-2.81(m,2H),2.70(s,3H),2.58-2.53(m,2H),2.23-2.17(m,2H),1.76-1.70(m,2H),1.68(d,3H)。 1 H NMR (500MHz, methanol-d 4 ): δ 8.40(s,1H), 7.60(t,1H), 7.44(t,1H), 7.36(s,1H), 7.17(t,1H), 7.01 (t,1H),5.77(q,1H),4.09(s,3H),3.69-3.61(m,8H),3.02-2.98(m,1H),2.90-2.81(m,2H),2.70(s , 3H), 2.58-2.53 (m, 2H), 2.23-2.17 (m, 2H), 1.76-1.70 (m, 2H), 1.68 (d, 3H).
实施例10Example 10
(R)-3-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基哌啶-1-基)-3-氧代丙烷腈10(R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine -6-yl)-4-hydroxypiperidin-1-yl)-3-oxopropanenitrile 10
Figure PCTCN2021107220-appb-000085
Figure PCTCN2021107220-appb-000085
采用实施例5中的合成路线，将第二步原料化合物甲氧基乙酸替换为化合物氰基乙酸，制得化合物10(7mg)，产率：48.2％。Using the synthetic route in Example 5, the second-step raw material compound methoxyacetic acid was replaced with compound cyanoacetic acid to obtain compound 10 (7 mg), yield: 48.2%.
MS m/z(ESI)：528.2[M+1]。MS m/z (ESI): 528.2 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.55(s,1H),7.62(t,1H),7.47(t,1H),7.39(s,1H),7.20(t,1H),7.02(t,1H),5.76(q,1H),4.65(s,3H),4.47-4.40(m,2H),4.36(s,2H),3.76-3.73(m,2H),2.69(s,3H),2.29-2.24(m,2H),1.84-1.80(m,2H),1.71(d,3H)。 1 H NMR (500MHz, methanol-d 4 ): δ8.55(s,1H), 7.62(t,1H), 7.47(t,1H), 7.39(s,1H), 7.20(t,1H), 7.02 (t, 1H), 5.76(q, 1H), 4.65(s, 3H), 4.47-4.40(m, 2H), 4.36(s, 2H), 3.76-3.73(m, 2H), 2.69(s, 3H) ), 2.29-2.24(m, 2H), 1.84-1.80(m, 2H), 1.71(d, 3H).
实施例11Example 11
(R)-4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)四氢-2H-硫代吡喃1,1-二氧化物11(R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide 11
Figure PCTCN2021107220-appb-000086
Figure PCTCN2021107220-appb-000086
采用实施例1中第一至第七步的合成路线，将第一步原料化合物(3R)-四氢呋 喃-3-醇替换为化合物4-羟基四氢-2H-硫代吡喃1,1-二氧化物，将第七步原料化合物(R)-1-(3-硝基-5-(三氟甲基)苯基)乙胺盐酸盐替换为化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺盐酸盐，制得化合物11(10mg)，产率：5.8％。Using the synthetic route of the first to seventh steps in Example 1, the first step raw material compound (3R)-tetrahydrofuran-3-ol was replaced with the compound 4-hydroxytetrahydro-2H-thiopyran 1,1-diol oxide, the seventh step raw material compound (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride is replaced by compound (R)-1-(3-( Difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride to obtain compound 11 (10 mg), yield: 5.8%.
MS m/z(ESI)：510.2[M+1]。MS m/z (ESI): 510.2 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.01(s,1H),7.57(t,1H),7.44(t,1H),7.39(s,1H),7.17(t,1H),7.01(t,1H),5.72(q,1H),5.06(tt,1H),4.08(s,3H),3.48(ddd,2H),3.14-3.05(m,2H),2.68(s,3H),2.62-2.52(m,2H),2.48-2.38(m,2H),1.70(d,3H)。 1 H NMR (500 MHz, methanol-d 4 ): δ 8.01(s,1H), 7.57(t,1H), 7.44(t,1H), 7.39(s,1H), 7.17(t,1H), 7.01 (t,1H),5.72(q,1H),5.06(tt,1H),4.08(s,3H),3.48(ddd,2H),3.14-3.05(m,2H),2.68(s,3H), 2.62-2.52 (m, 2H), 2.48-2.38 (m, 2H), 1.70 (d, 3H).
实施例12Example 12
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基-1-亚氨基四氢-2H-硫代吡喃1-氧化物12(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6- base)-4-hydroxy-1-iminotetrahydro-2H-thiopyran 1-oxide 12
Figure PCTCN2021107220-appb-000087
Figure PCTCN2021107220-appb-000087
第一步first step
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-(3,6-二氢-2H-硫代吡喃-4-基)-6-甲氧基-4-甲基酞嗪-1-胺12b(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-(3,6-dihydro-2H-thiopyran-4-yl) -6-Methoxy-4-methylphthalazin-1-amine 12b
将化合物4b(82mg，124.3μmol)、化合物2-(3,6-二氢-2H-硫代吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷12a(42.2mg，186.4μmol，上海毕得)、三(二亚苄基丙酮)二钯(29.6mg，49.7μmol)、无水碳酸钾(68.7mg，497.2μmol)溶于1,4-二氧六环(2mL)和水(0.5mL)中，加热至110℃反应8小时，反应液减压浓缩，用柱层析色谱法以洗脱剂体系A纯化得到标题化合物12b(50mg)，产率：87.5％。Compound 4b (82 mg, 124.3 μmol), compound 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2 -Dioxaborolane 12a (42.2mg, 186.4μmol, Shanghai Bide), tris(dibenzylideneacetone)dipalladium (29.6mg, 49.7μmol), anhydrous potassium carbonate (68.7mg, 497.2μmol) dissolved In 1,4-dioxane (2 mL) and water (0.5 mL), heated to 110 °C for 8 hours, the reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain the title compound 12b (50 mg), yield: 87.5%.
MS m/z(ESI)：460.2[M+1]。MS m/z (ESI): 460.2 [M+1].
第二步second step
4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-1-亚氨基-1,2,3,6-四氢-1λ 6-硫代吡喃1-氧化物12c 4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6- base)-1-imino-1,2,3,6-tetrahydro-1λ 6 -thiopyran 1-oxide 12c
将化合物12b(100mg，217.6μmol)溶于5mL乙醇中，加入醋酸碘苯(222mg， 652.8μmol)和乙酸铵(67.1mg，870.4μmol)，搅拌反应3小时，反应液减压浓缩，用柱层析色谱法以洗脱剂体系A纯化得到标题化合物12c(37mg)，产率：34.6％。Compound 12b (100 mg, 217.6 μmol) was dissolved in 5 mL of ethanol, iodobenzene acetate (222 mg, 652.8 μmol) and ammonium acetate (67.1 mg, 870.4 μmol) were added, and the reaction was stirred for 3 hours. Purification by analytical chromatography with eluent system A afforded the title compound 12c (37 mg), yield: 34.6%.
MS m/z(ESI)：491.1[M+1]。MS m/z (ESI): 491.1 [M+1].
第三步third step
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基-1-亚氨基四氢-2H-硫代吡喃1-氧化物12(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6- base)-4-hydroxy-1-iminotetrahydro-2H-thiopyran 1-oxide 12
将化合物12c(37mg，75.4μmol)、三(2,2,6,6-四甲基-3,5-庚烯酸)锰(22.8mg，37.7μmol)、苯硅烷(16.3mg，150.8μmol)溶于异丙醇(2mL)和二氯甲烷(0.2mL)，氧气置换，搅拌反应14小时。反应液减压浓缩，残余物用高效液相制备色谱法纯化得到标题化合物12(6mg)，产率：15.6％。Compound 12c (37 mg, 75.4 μmol), tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (22.8 mg, 37.7 μmol), phenylsilane (16.3 mg, 150.8 μmol) Dissolve in isopropanol (2 mL) and dichloromethane (0.2 mL), replace with oxygen, and stir the reaction for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 12 (6 mg), yield: 15.6%.
MS m/z(ESI)：509.2[M+1]。MS m/z (ESI): 509.2 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.59(d,1H),7.61(t,1H),7.45(t,1H),7.38(d,1H),7.18(t,1H),7.01(t,1H),5.75(q,1H),4.10(d,3H),3.74-3.61(m,2H),3.31-3.25(m,2H),3.19-3.08(m,2H),2.70(d,3H),2.05(dt,2H),1.70(d,3H)。 1 H NMR (500 MHz, methanol-d 4 ): δ 8.59(d,1H), 7.61(t,1H), 7.45(t,1H), 7.38(d,1H), 7.18(t,1H), 7.01 (t, 1H), 5.75(q, 1H), 4.10(d, 3H), 3.74-3.61(m, 2H), 3.31-3.25(m, 2H), 3.19-3.08(m, 2H), 2.70(d , 3H), 2.05 (dt, 2H), 1.70 (d, 3H).
实施例13Example 13
(R)-1-(3-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)氮杂环丁烷-1-基)乙-1-酮13(R)-1-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein Azin-6-yl)oxy)azetidine-1-yl)ethan-1-one 13
Figure PCTCN2021107220-appb-000088
Figure PCTCN2021107220-appb-000088
第一步first step
1-乙酰氮杂环丁烷-3-基4-甲基苯磺酸酯13b1-Acetylazetidine-3-yl 4-methylbenzenesulfonate 13b
将化合物1-(3-羟基氮杂环丁烷-1-基)乙酮13a(10g，86.8mmol，上海毕得)、4-二甲氨基吡啶(534mg，4.3mmol，上海韶远)、三乙胺(17.5g，173mmol)溶于200mL二氯甲烷中，加入4-甲苯磺酰氯(24.8g，130.3mmol)，搅拌反应14小时，反应液减压浓缩后，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物13b(15g)，产率64.1％。Compound 1-(3-hydroxyazetidin-1-yl)ethanone 13a (10 g, 86.8 mmol, Shanghai Bide), 4-dimethylaminopyridine (534 mg, 4.3 mmol, Shanghai Shaoyuan), three Ethylamine (17.5 g, 173 mmol) was dissolved in 200 mL of dichloromethane, 4-toluenesulfonyl chloride (24.8 g, 130.3 mmol) was added, and the reaction was stirred for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to column chromatography. Purification with eluent system C afforded the title compound 13b (15 g) in 64.1% yield.
MS m/z(ESI)：270.1[M+1]。MS m/z (ESI): 270.1 [M+1].
第二步second step
(R)-7-(苄氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-甲氧基-4-甲基酞嗪-1-胺13c(R)-7-(Benzyloxy)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-4-methylphthalazine- 1-amine 13c
采用实施例3中的合成路线第七步和第十步，将第七步原料化合物3b替换为化合物苄溴，将第十步原料化合物(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2,2-二氟乙醇盐酸盐替换为化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺盐酸盐，制得标题化合物13c(120mg)，产率：40.4％。Adopt the seventh step and tenth step of the synthetic route in Example 3, replace the seventh step raw material compound 3b with compound benzyl bromide, and the tenth step raw material compound (R)-2-(3-(1-aminoethyl) )-2-fluorophenyl)-2,2-difluoroethanol hydrochloride was replaced by compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride, The title compound 13c was obtained (120 mg), yield: 40.4%.
MS m/z(ESI)：468.2[M+1]。MS m/z (ESI): 468.2 [M+1].
第三步third step
(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-酚13d(R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazin-6-ol 13d
将化合物13c(120mg，256.7μmol)溶于用甲醇(10mL)，加入10％钯碳催化剂(湿)(30mg)，氢气置换，搅拌反应14小时。反应液用硅藻土过滤，减压得到粗品化合物13d(80mg)，产率：82.5％，不经纯化直接下一步。Compound 13c (120 mg, 256.7 μmol) was dissolved in methanol (10 mL), 10% palladium-carbon catalyst (wet) (30 mg) was added, hydrogen was replaced, and the reaction was stirred for 14 hours. The reaction solution was filtered through celite, and the crude compound 13d (80 mg) was obtained under reduced pressure. The yield was 82.5%, and the next step was directly carried out without purification.
MS m/z(ESI)：378.2[M+1]。MS m/z (ESI): 378.2 [M+1].
第四步the fourth step
(R)-1-(3-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)氮杂环丁烷-1-基)乙-1-酮13(R)-1-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein Azin-6-yl)oxy)azetidine-1-yl)ethan-1-one 13
将化合物13b(14.3mg，53μmol)、化合物13d(20mg，53μmol)、碳酸铯(34.5mg，106μmol)、N,N-二甲基甲酰胺(3mL)加入反应瓶中，升至70℃搅拌5小时。反应液冷却后减压浓缩，残余物用高效液相制备色谱法纯化得到标题化合物13(6mg)，产率：23.8％。Compound 13b (14.3 mg, 53 μmol), compound 13d (20 mg, 53 μmol), cesium carbonate (34.5 mg, 106 μmol), N,N-dimethylformamide (3 mL) were added to the reaction flask, and the mixture was heated to 70 °C and stirred for 5 Hour. The reaction solution was cooled, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 13 (6 mg), yield: 23.8%.
MS m/z(ESI)：475.2[M+1]。MS m/z (ESI): 475.2 [M+1].
1H NMR(500MHz,甲醇-d 4):δ7.58(d,2H),7.44(t,1H),7.38(s,1H),7.18(t,1H),7.01(t,1H),5.73(q,1H),5.37-5.31(m,1H),4.77-4.61(m,1H),4.55(dd,1H),4.38(ddd,1H),4.16-4.08(m,1H),4.07(s,3H),2.68(s,3H),1.97(s,3H),1.71(d,3H)。 1 H NMR (500 MHz, methanol-d 4 ): δ 7.58(d,2H), 7.44(t,1H), 7.38(s,1H), 7.18(t,1H), 7.01(t,1H), 5.73 (q,1H),5.37-5.31(m,1H),4.77-4.61(m,1H),4.55(dd,1H),4.38(ddd,1H),4.16-4.08(m,1H),4.07(s , 3H), 2.68 (s, 3H), 1.97 (s, 3H), 1.71 (d, 3H).
实施例14Example 14
(S)-1-(4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羟基哌啶-1-基)-2-羟基丙-1-酮14(S)-1-(4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1- Methylphthalazin-6-yl)-4-hydroxypiperidin-1-yl)-2-hydroxypropan-1-one 14
Figure PCTCN2021107220-appb-000089
Figure PCTCN2021107220-appb-000089
采用实施例5中的合成路线，将第二步原料化合物甲氧基乙酸替换为化合物L-乳酸，制得化合物14(12mg)，产率：9.6％。Using the synthetic route in Example 5, the second step starting material compound methoxyacetic acid was replaced with compound L-lactic acid to obtain compound 14 (12 mg), yield: 9.6%.
MS m/z(ESI)：533.2[M+1]。MS m/z (ESI): 533.2 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.52(d,1H),7.60(t,1H),7.44(t,1H),7.36(s,1H),7.19(t,1H),7.06(d,1H),5.73(q,1H),4.06(d,3H),3.99(s,1H),3.67(d,1H),3.26(t,2H),2.69(s,3H),2.66-2.43(m,2H),1.82(q,2H),1.70(d,3H),1.41(dd,3H),1.32(d,1H)。 1 H NMR (500MHz, methanol-d 4 ): δ8.52(d,1H), 7.60(t,1H), 7.44(t,1H), 7.36(s,1H), 7.19(t,1H), 7.06 (d, 1H), 5.73(q, 1H), 4.06(d, 3H), 3.99(s, 1H), 3.67(d, 1H), 3.26(t, 2H), 2.69(s, 3H), 2.66- 2.43(m, 2H), 1.82(q, 2H), 1.70(d, 3H), 1.41(dd, 3H), 1.32(d, 1H).
实施例15Example 15
(R)-4-((4-((1-(3-(1,1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)四氢-2H-硫代吡喃1,1-二氧化物15(R)-4-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy- 1-Methylphthalazin-6-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide 15
Figure PCTCN2021107220-appb-000090
Figure PCTCN2021107220-appb-000090
采用实施例3中的合成路线，将第一步原料化合物3a替换为化合物4-羟基四氢-2H-硫代吡喃1,1-二氧化物，制得标题化合物15(15mg)，产率：19.3％。Using the synthetic route in Example 3, the first step starting material compound 3a was replaced with the compound 4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide to obtain the title compound 15 (15 mg), yield : 19.3%.
MS m/z(ESI)：540.2[M+1]。MS m/z (ESI): 540.2 [M+1].
1H NMR(400MHz,CD 3OD):δ8.02(s,1H),7.54(t,1H),7.43-7.40(m,1H),7.14(t,1H)5.73(q,1H),5.07-5.06(m,1H),4.08-4.03(m,5H),3.52-3.47(m,3H),3.12-3.08(m,2H),2.69(s,3H),2.59-2.56(m,2H),2.44-2.42(m,2H),1.70(d,3H)。 1 H NMR (400MHz, CD 3 OD): δ 8.02 (s, 1H), 7.54 (t, 1H), 7.43-7.40 (m, 1H), 7.14 (t, 1H) 5.73 (q, 1H), 5.07 -5.06(m,1H),4.08-4.03(m,5H),3.52-3.47(m,3H),3.12-3.08(m,2H),2.69(s,3H),2.59-2.56(m,2H) , 2.44-2.42 (m, 2H), 1.70 (d, 3H).
实施例16Example 16
(R)-2,2-二氟-2-(2-氟-3-(1-((15-甲基-2,3,5,6,8,9-六氢-[1,4,7,10]四氧杂环十二并[2,3-g]酞嗪-12-基)氨基)乙基)苯基)乙烷-1-醇16(R)-2,2-Difluoro-2-(2-fluoro-3-(1-((15-methyl-2,3,5,6,8,9-hexahydro-[1,4, 7,10] Tetraoxanedodeco[2,3-g]phthalazin-12-yl)amino)ethyl)phenyl)ethane-1-ol 16
Figure PCTCN2021107220-appb-000091
Figure PCTCN2021107220-appb-000091
第一步first step
4-甲基酞嗪-1,6,7-三醇氢溴酸盐16a4-Methylphthalazine-1,6,7-triol hydrobromide 16a
将化合物3h(1g，4.84mmol)用30mL氢溴酸溶液溶解，加热至120℃反应16小时。冷却至室温后过滤，滤液减压浓缩真空干燥得到粗品标题化合物16a(1.1g)，产率：83％。Compound 3h (1 g, 4.84 mmol) was dissolved in 30 mL of hydrobromic acid solution, heated to 120° C. and reacted for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and dried in vacuo to obtain the crude title compound 16a (1.1 g). Yield: 83%.
MS m/z(ESI)：274.0[M+1]。MS m/z (ESI): 274.0 [M+1].
第二步second step
15-甲基-2,3,5,6,8,9-六氢-[1,4,7,10]四氧杂环十二并[2,3-g]酞嗪-12-酚16b15-Methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxanedodecodo[2,3-g]phthalazin-12-ol 16b
将化合物16a(130mg，476μmol)、化合物三乙二醇二(对甲苯磺酸酯)(261.9mg，571.2μmol，上海毕得医药科技有限公司)、无水碳酸钾(329mg，2.38mmol)溶于10mL N,N-二甲基甲酰胺中，90℃搅拌2小时，反应液减压浓缩，用薄层层析色谱法以展开剂体系A纯化所得残余物，得到标题化合物16b(100mg)，产率：68.5％。Compound 16a (130 mg, 476 μmol), compound triethylene glycol bis(p-toluenesulfonate) (261.9 mg, 571.2 μmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.), and anhydrous potassium carbonate (329 mg, 2.38 mmol) were dissolved in In 10 mL of N,N-dimethylformamide, the mixture was stirred at 90°C for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography with developing solvent system A to obtain the title compound 16b (100 mg), which was Rate: 68.5%.
MS m/z(ESI)：307.1[M+1]。MS m/z (ESI): 307.1 [M+1].
第三步third step
12-氯-15-甲基-2,3,5,6,8,9-六氢-[1,4,7,10]四氧杂环十二并[2,3-g]酞嗪16c12-Chloro-15-methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxanedodecano[2,3-g]phthalazine 16c
将化合物16b(100mg，326.4μmol)溶解于10mL三氯氧磷中，120℃搅拌反应3小时。反应液减压浓缩，倒入冰水，饱和碳酸氢钠调节pH至中性，乙酸乙酯萃取(10mL×2)后，合并有机相，无水硫酸钠干燥，减压浓缩即得标题化合物16c(60mg)，收率：56.5％。Compound 16b (100 mg, 326.4 μmol) was dissolved in 10 mL of phosphorus oxychloride, and the reaction was stirred at 120° C. for 3 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, adjusted to neutral pH with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×2), combined with the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 16c (60 mg), yield: 56.5%.
MS m/z(ESI)：325.1[M+1]。MS m/z (ESI): 325.1 [M+1].
第四步the fourth step
(R)-2,2-二氟-2-(2-氟-3-(1-((15-甲基-2,3,5,6,8,9-六氢-[1,4,7,10]四氧杂环十二并[2,3-g]酞嗪-12-基)氨基)乙基)苯基)乙烷-1-醇16(R)-2,2-Difluoro-2-(2-fluoro-3-(1-((15-methyl-2,3,5,6,8,9-hexahydro-[1,4, 7,10] Tetraoxanedodeco[2,3-g]phthalazin-12-yl)amino)ethyl)phenyl)ethane-1-ol 16
将化合物16c(30mg，92.3μmol)、化合物2a(24.3mg，110.8μmol)、氯化铵(2.47mg，46.2μmol)和正丁醇(1mL)混合。微波升温至110℃搅拌1小时。将反应液用硅藻土过滤，滤液减压浓缩后用高效液相制备色谱法纯化得到标题化合物16(5mg)，产率：10.6％。Compound 16c (30 mg, 92.3 μmol), compound 2a (24.3 mg, 110.8 μmol), ammonium chloride (2.47 mg, 46.2 μmol) and n-butanol (1 mL) were mixed. The microwave was heated to 110°C and stirred for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 16 (5 mg), yield: 10.6%.
MS m/z(ESI)：508.2[M+1]。MS m/z (ESI): 508.2 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.02(s,1H),7.56-7.53(m,2H),7.44(t,1H),7.16(t,1H),5.74(q,1H),4.43-4.42(m,2H),4.38-4.37(m,2H),4.17-4.07(m,2H),3.95-3.90(m,4H),3.80(s,4H),2.65(s,3H),1.70(d,3H)。 1 H NMR (500 MHz, methanol-d 4 ): δ 8.02 (s, 1H), 7.56-7.53 (m, 2H), 7.44 (t, 1H), 7.16 (t, 1H), 5.74 (q, 1H) ,4.43-4.42(m,2H),4.38-4.37(m,2H),4.17-4.07(m,2H),3.95-3.90(m,4H),3.80(s,4H),2.65(s,3H) , 1.70(d,3H).
实施例17Example 17
(R)-4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)-1-亚氨基四氢-2H-硫代吡喃1-氧化物17(R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)oxy)-1-iminotetrahydro-2H-thiopyran 1-oxide 17
Figure PCTCN2021107220-appb-000092
Figure PCTCN2021107220-appb-000092
第一步first step
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-甲氧基-4-甲基-7-((四氢-2H-硫代吡喃-4-基)氧基)酞嗪-1-胺17b(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-4-methyl-7-((tetrahydro-2H-sulfur Pyran-4-yl)oxy)phthalazin-1-amine 17b
采用实施例3中的合成路线，将第一步原料化合物3a替换为化合物四氢-2H-硫代吡喃-4-醇17a，将第十步原料化合物(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2,2-二氟乙醇盐酸盐替换为化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺盐酸盐，制得标题化合物17b(100mg)，产率：34％。Using the synthetic route in Example 3, the first step raw material compound 3a was replaced with compound tetrahydro-2H-thiopyran-4-ol 17a, and the tenth step raw material compound (R)-2-(3-( 1-Aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride was replaced by compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl The amine hydrochloride gave the title compound 17b (100 mg), yield: 34%.
MS m/z(ESI)：478.2[M+1]。MS m/z (ESI): 478.2 [M+1].
第二步second step
(R)-4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)-1-亚氨基四氢-2H-硫代吡喃1-氧化物17(R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)oxy)-1-iminotetrahydro-2H-thiopyran 1-oxide 17
将化合物17b(100mg，209.4μmol)溶于5mL乙醇中，加入醋酸碘苯(214mg，629.2μmol)和乙酸铵(65mg，843.2μmol)，室温反应3小时，反应液减压浓缩，用高效液相制备色谱法纯化所得标题化合物17(8mg)，产率：7.5％。Compound 17b (100 mg, 209.4 μmol) was dissolved in 5 mL of ethanol, iodobenzene acetate (214 mg, 629.2 μmol) and ammonium acetate (65 mg, 843.2 μmol) were added, and the reaction was carried out at room temperature for 3 hours. The obtained title compound 17 (8 mg) was purified by preparative chromatography, yield: 7.5%.
MS m/z(ESI)：509.1[M+1]。MS m/z (ESI): 509.1 [M+1].
1H NMR(500MHz,甲醇-d 4):δ8.02-8.01(d,1H),7.59-7.56(q,1H),7.46-7.43(q,1H),7.39(d,1H),7.19-7.16(q,1H),7.12-6.90(q,1H),5.74-5.70(t,1H),5.08-5.06(m,1H),4.08-4.07(d,3H),3.57-3.47(m,2H),3.20-3.17(m,2H),2.68(s,3H),2.55-2.50(m,2H),2.45-2.39(m,2H),1.71-1.70(d,3H)。 1 H NMR (500 MHz, methanol-d 4 ): δ 8.02-8.01(d,1H), 7.59-7.56(q,1H), 7.46-7.43(q,1H), 7.39(d,1H), 7.19- 7.16(q,1H), 7.12-6.90(q,1H), 5.74-5.70(t,1H), 5.08-5.06(m,1H), 4.08-4.07(d,3H), 3.57-3.47(m,2H) ), 3.20-3.17(m, 2H), 2.68(s, 3H), 2.55-2.50(m, 2H), 2.45-2.39(m, 2H), 1.71-1.70(d, 3H).
生物学评价Biological evaluation
测试例1本公开化合物抑制KRAS蛋白各亚型G12D或G12V与SOS1蛋白间的相互作用能力Test Example 1 The compound of the present disclosure inhibits the interaction ability between each subtype G12D or G12V of KRAS protein and SOS1 protein
以下方法用来测定化合物抑制KRAS蛋白各亚型G12D或G12V与SOS1蛋白间的相互作用能力。实验方法简述如下：The following methods were used to determine the ability of compounds to inhibit the interaction between the KRAS protein isoforms G12D or G12V and the SOS1 protein. The experimental method is briefly described as follows:
1、实验材料及仪器1. Experimental materials and instruments
1)生物素标记试剂盒(Dojindo，LK03)1) Biotin labeling kit (Dojindo, LK03)
2)GDP(SIGMA，G7127)2) GDP (SIGMA, G7127)
3)AlphaLISA谷胱甘肽受体珠(Glutathione Acceptor Beads)(PerkinElmer，AL109C)3) AlphaLISA Glutathione Acceptor Beads (PerkinElmer, AL109C)
4)AlphaScreen链霉亲和素供体珠(Streptavidin Donor Beads)(PerkinElmer，6760002S)4) AlphaScreen Streptavidin Donor Beads (PerkinElmer, 6760002S)
5)384-孔微板(PerkinElmer，6007290)5) 384-well microplate (PerkinElmer, 6007290)
6)BSA(上海生工，A600332-0100)6) BSA (Shanghai Shenggong, A600332-0100)
7)吐温-20(Diamond，A100777-0500)7) Tween-20 (Diamond, A100777-0500)
8)GST-TEV-SOS1(564-1049)(维亚生物科技，SOS1-191010)8) GST-TEV-SOS1 (564-1049) (Via Biotechnology, SOS1-191010)
9)KRAS G12D、KRAS G12V(由上海磐超生物科技有限公司生产提供)9) KRAS G12D, KRAS G12V (produced by Shanghai Panchao Biotechnology Co., Ltd.)
10)磷酸盐缓冲液(PBS)PH7.4(上海源培生物科技股份有限公司，B320)10) Phosphate Buffered Saline (PBS) PH7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)
11)多功能酶标仪(PerkinElmer，Envision)11) Multi-function microplate reader (PerkinElmer, Envision)
2、实验步骤2. Experimental steps
实验准备：Experiment preparation:
1)实验开始之前先配制实验缓冲液：1x PBS+0.1％BSA+0.05％吐温-20。1) Before starting the experiment, prepare the experimental buffer: 1x PBS+0.1%BSA+0.05%Tween-20.
2)KRAS G12D、KRAS-G12V蛋白用生物素标记试剂盒进行生物素标记。2) The KRAS G12D and KRAS-G12V proteins were biotin-labeled with a biotin labeling kit.
实验步骤：Experimental steps:
1)先将生物素标记后的KRAS G12V或KRAS G12D蛋白分别与SOS1蛋白(GST-TEV-SOS1(564-1049)(维亚生物科技，SOS1-191010))和GDP混合室温孵育备用。1) First, the biotin-labeled KRAS G12V or KRAS G12D protein was incubated with SOS1 protein (GST-TEV-SOS1(564-1049) (Via Biotechnology, SOS1-191010)) and GDP at room temperature for use.
2)将AlphaLISA谷胱甘肽受体珠和AlphaScreen链霉亲和素供体珠在使用前1:1混合成40μg/mL备用。2) Mix AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads 1:1 to 40 μg/mL before use.
3)将化合物用实验缓冲液配制成起始浓度为40μM，5倍梯度稀释，10个梯度系列浓度点。3) Compounds were prepared with experimental buffer to an initial concentration of 40 μM, 5-fold gradient dilution, and 10 gradient series concentration points.
4)在384-孔微板中，每孔加入10μL KRAS G12V或KRAS G12D蛋白与SOS1和GDP混合物和5μL稀释好的化合物，室温，避光孵育30分钟。4) In a 384-well microplate, add 10 μL of KRAS G12V or KRAS G12D protein, SOS1 and GDP mixture and 5 μL of diluted compounds to each well, and incubate at room temperature for 30 minutes in the dark.
5)然后每孔加入5μL AlphaLISA谷胱甘肽受体珠和AlphaScreen链霉亲和素供体珠混合物，室温，避光孵育60分钟。5) Then add 5 μL of AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads mixture to each well, and incubate at room temperature for 60 minutes in the dark.
6)在多功能酶标仪上读取荧光值。6) Read the fluorescence value on the multi-function microplate reader.
7)用Graphpad Prism计算得到化合物的IC 50值。 7) to give compound IC 50 value calculated using Graphpad Prism.
3、实验数据3. Experimental data
本公开化合物抑制KRAS蛋白各亚型G12D或G12V与SOS1蛋白间的相互作用能力，测得的IC 50值见表1。 The present disclosure subtypes compounds inhibit the interaction between the ability G12D or SOS1 protein KRAS G12V and the protein, the measured IC 50 values are shown in Table 1.
表1本公开化合物抑制KRAS蛋白各亚型G12D或G12V与SOS1蛋白间的相互作用能力的IC 50值 Table 1 IC 50 values of the compounds of the present disclosure to inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein
Figure PCTCN2021107220-appb-000093
Figure PCTCN2021107220-appb-000093
结论：本公开化合物能很好的抑制KRAS蛋白各亚型G12D或G12V与SOS1蛋白间的相互作用。Conclusion: The disclosed compounds can well inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein.
测试例2H358细胞ERK磷酸化抑制生物学评价Test Example 2H358 Cell ERK Phosphorylation Inhibition Biological Evaluation
1、测试目的1. Test purpose
本实验通过检测化合物对细胞ERK磷酸化抑制作用，根据IC 50大小评价本公开化合物对KRAS靶点(含G12C突变)的抑制作用。 In this experiment, the inhibitory effect of the compound on cellular ERK phosphorylation was detected, and the inhibitory effect of the disclosed compound on KRAS target (containing G12C mutation) was evaluated according to the IC 50 size.
2、实验方法2. Experimental method
H358细胞(ATCC，CRL-5807)用含有10％胎牛血清的RPMI1640(Hyclone，SH30809.01)完全培养基进行培养。实验第一天，使用完全培养基将H358细胞以25,000个/孔的密度种于96孔板，每孔190μL细胞悬液，放置37℃，5％CO 2细胞培养箱培养过夜。第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM开始进行5倍梯度稀释的9个浓度点，设置含有0.1％DMSO的空白对照，孔板放置37℃，5％CO 2的细胞培养箱孵育1个小时。1小时后，取出96孔细胞培养板，吸掉培养基，每孔加入200μL PBS(上海源培生物科技股份有限公司，B320)洗一遍。吸掉PBS，每孔加入50μL含封闭液(blocking reagent，Cisbio，64KB1AAC)的裂解缓冲液(lysis buffer，Cisbio，64KL1FDF)，孔板放置振荡器上室温震荡裂解40分钟。裂解后用移液器吹打混匀，每孔各转移16μL裂解液分别至两块HTRF 96孔检测板(Cisbio，66PL96100) 中，之后两块板分别加入4μL预混的phospho-ERK1/2抗体溶液(Cisbio，64AERPEG)或4μL预混的total-ERK1/2抗体溶液(Cisbio，64NRKPEG)。微孔板用封板膜密封，在微孔板离心机中离心1分钟，室温避光孵育过夜。第三天，使用PHERAstar多功能酶标仪(BMG Labtech，S/N 471-0361)读取337nm波长激发，665nm和620nm波长发射的荧光值。 H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, H358 cells were seeded at a density of 25,000 cells/well in a 96-well plate using complete medium, with 190 μL of cell suspension per well, and placed in a 37°C, 5% CO 2 cell incubator overnight. On the second day, 10 μL of the compound to be tested in a serial dilution prepared in complete medium was added to each well, and the final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM, and a blank control containing 0.1% DMSO was set. Place the plate in a 37 °C, 5% CO 2 cell incubator for 1 hr. One hour later, the 96-well cell culture plate was taken out, the medium was aspirated, and 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well for washing. PBS was aspirated, 50 μL of lysis buffer (lysis buffer, Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well, and the plate was placed on a shaker for 40 minutes at room temperature. After lysis, pipette and mix well, transfer 16 μL of lysate to each well of two HTRF 96-well detection plates (Cisbio, 66PL96100), and then add 4 μL of premixed phospho-ERK1/2 antibody solution to the two plates. (Cisbio, 64AERPEG) or 4 μL of premixed total-ERK1/2 antibody solution (Cisbio, 64NRKPEG). The microplate was sealed with sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark. On the third day, use a PHERAstar multifunctional microplate reader (BMG Labtech, S/N 471-0361) to read the fluorescence values for excitation at 337 nm and emission at 665 nm and 620 nm.
3、数据分析3. Data analysis
用Graphpad Prism软件根据化合物浓度和pERK/total ERK的比值计算化合物抑制活性的IC 50值，结果见下表2。 Using Graphpad Prism software to calculate IC 50 values of compounds to inhibit the activity of the results in Table 2 below and the concentration of compound according to the ratio of pERK / total ERK's.
表2 H358细胞ERK磷酸化抑制活性数据Table 2 ERK phosphorylation inhibitory activity data in H358 cells
实施例编号Example number IC 50(nM) IC 50 (nM)
11 15.715.7
22 78.078.0
44 83.083.0
77 55.055.0
88 91.091.0
1111 118.0118.0
1313 105.0105.0
结论：本公开化合物对H358细胞ERK磷酸化具有较好的抑制作用。Conclusion: The disclosed compounds have a good inhibitory effect on ERK phosphorylation in H358 cells.
测试例3H358细胞增殖抑制生物学评价Test Example 3H358 Cell Proliferation Inhibition Biological Evaluation
1、测试目的1. Test purpose
通过测试本公开化合物对H358细胞的增殖抑制作用，评价本公开化合物对KRAS靶点(含G12C突变)的抑制作用。By testing the proliferation inhibitory effect of the disclosed compounds on H358 cells, the inhibitory effect of the disclosed compounds on KRAS targets (containing G12C mutation) was evaluated.
2、实验方法2. Experimental method
H358细胞(ATCC，CRL-5807)用完全培养基即含有10％胎牛血清(Corning，35-076-CV)的RPMI1640培养基(Hyclone，SH30809.01)进行培养。实验第一天，使用完全培养基将H358细胞以1500个细胞/孔的密度种于96低吸附板(Corning，CLS7007-24EA)，每孔90μL细胞悬液，2000rpm室温离心5分钟后放置37℃，5％CO 2细胞培养箱培养过夜。第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM开始进行5倍梯度稀释的9个浓度点，设置含有0.1％DMSO的空白对照，孔板放置37℃，5％CO 2的细胞培养箱培养120小时。第七天，取出96孔细胞培养板，每孔加入50μL
Figure PCTCN2021107220-appb-000094
3D Reagent(Promega，G9682)，室温震荡25分钟后，吹吸混匀并取出50μL转移至白色不透底的96孔板(PE，6005290)中，使用多功能微孔板酶标仪(PerkinElmer，VICTOR 3)读取发光信号值。 H358 cells (ATCC, CRL-5807) were cultured in complete medium, ie RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded on 96 low-adsorption plates (Corning, CLS7007-24EA) at a density of 1500 cells/well using complete medium, 90 μL of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature and placed at 37°C , 5% CO 2 cell incubator overnight. On the second day, 10 μL of the compound to be tested in a serial dilution prepared in complete medium was added to each well, and the final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM, and a blank control containing 0.1% DMSO was set. Place the plate in a 37 °C, 5% CO 2 cell incubator for 120 hr. On the seventh day, remove the 96-well cell culture plate and add 50 μL to each well
Figure PCTCN2021107220-appb-000094
3D Reagent (Promega, G9682), shake at room temperature for 25 minutes, mix by pipetting, remove 50 μL and transfer it to a white impermeable bottom 96-well plate (PE, 6005290), use a multi-function microplate reader (PerkinElmer, VICTOR) 3) Read the luminous signal value.
3、数据分析3. Data analysis
用Graphpad Prism软件计算化合物抑制活性的IC 50值，结果见下表3。 Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values, the results in Table 3 below.
表3 H358细胞增殖抑制活性数据Table 3 H358 cell proliferation inhibitory activity data
实施例编号Example number IC 50(nM) IC 50 (nM)
11 9.59.5
22 68.768.7
44 107.0107.0
66 62.762.7
77 130.4130.4
88 133.5133.5
1111 126.2126.2
1414 101.7101.7
1616 77.277.2
结论：本公开化合物对H358细胞增殖具有较好的抑制作用。Conclusion: The disclosed compounds have a good inhibitory effect on the proliferation of H358 cells.
药代动力学评价Pharmacokinetic evaluation
测试例4本公开化合物的药代动力学测试Test Example 4 Pharmacokinetic test of the disclosed compound
1、摘要1. Abstract
以小鼠受试动物，应用LC/MS/MS法测定了小鼠静脉注射给予实施例1化合物后不同时刻血浆中的药物浓度。研究本公开化合物在小鼠体内的药代动力学行为，评价其药动学特征。Using LC/MS/MS method as a mouse test animal, the drug concentration in the plasma of mice at different times after intravenous injection of the compound of Example 1 was determined. The pharmacokinetic behavior of the disclosed compounds in mice was studied, and their pharmacokinetic characteristics were evaluated.
2、试验方案2. Test plan
2.1试验药品2.1 Test drug
实施例1化合物。Compound of Example 1.
2.2试验动试验动物2.2 Experimental animals
健康成年C57小鼠18只，雌性，购自维通利华实验动物有限公司。Eighteen healthy adult C57 mice, female, were purchased from Weitong Lihua Laboratory Animal Co., Ltd.
2.3药物配制2.3 Drug preparation
称取一定量药物，加入5％DMSO+5％吐温80+90％生理盐水配制成液体。A certain amount of medicine is weighed, and 5% DMSO+5% Tween 80+90% normal saline is added to prepare a liquid.
2.4给药2.4 Administration
小鼠禁食过夜后静脉注射给药，给药剂量均为1mg/kg，给药体积均为0.1mL/10g。After overnight fasting, the mice were administered intravenously at a dose of 1 mg/kg and an administration volume of 0.1 mL/10 g.
3、操作3. Operation
小鼠静脉注射给药实施例1化合物，于给药前及给药后5分、0.25、0.5、1.0、2.0、4.0、8.0、11.0、24.0小时采血0.1mL，置于EDTA-K2抗凝试管中，4℃、10000转/分钟离心1分钟，1小时内分离血浆，于-20℃保存待测，采血至离心过程在冰浴条件下操作。Mice were intravenously injected with the compound of Example 1, and 0.1 mL of blood was collected before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24.0 hours after administration, and placed in an EDTA-K2 anticoagulation test tube , centrifuge at 10,000 rpm for 1 minute at 4°C, separate the plasma within 1 hour, store it at -20°C for testing, and operate under ice-bath conditions until the centrifugation process.
测定药物静脉给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆25μL，加入内标溶液(100ng/ml喜树碱)50μL，乙腈200μL，涡旋混合5分钟，离心15分钟(3600转/分钟)，血浆样品取上清液0.1μL进行LC/MS/MS分 析。Determination of the content of the test compound in mouse plasma after intravenous administration of the drug: take 25 μL of mouse plasma at each time after administration, add 50 μL of internal standard solution (100ng/ml camptothecin), 200 μL of acetonitrile, and vortex for 5 minutes , centrifuged for 15 minutes (3600 rpm), and 0.1 μL of the supernatant was taken from the plasma samples for LC/MS/MS analysis.
4、药代动力学参数结果4. Pharmacokinetic parameter results
表4本公开化合物的药代动力学参数Table 4 Pharmacokinetic parameters of the disclosed compounds
Figure PCTCN2021107220-appb-000095
Figure PCTCN2021107220-appb-000095
结论：本公开化合物的药代良好，具有明显的药代动力学优势。Conclusion: The disclosed compounds have good pharmacokinetics and obvious pharmacokinetic advantages.
测试例5本公开化合物对人肝微粒体CYP450酶的抑制作用Test Example 5 Inhibitory effect of compounds of the present disclosure on human liver microsomal CYP450 enzymes
本公开化合物对人肝微粒体CYP450酶的抑制作用采用如下实验方法测定：The inhibitory effect of the compounds of the present disclosure on human liver microsomal CYP450 enzymes was determined by the following experimental methods:
1、实验材料及仪器1. Experimental materials and instruments
1)磷酸缓冲液(20×PBS，购买自生工)1) Phosphate buffer solution (20×PBS, purchased from the manufacturer)
2)NADPH(ACROS，A2646-71-1)2) NADPH (ACROS, A2646-71-1)
3)人肝微粒体(Corning Gentest，Cat No，452161，Lot No.905002,Donor35)3) Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 905002, Donor35)
4)ABI QTrap 4000液质两用仪(AB Sciex)4) ABI QTrap 4000 LC/MS (AB Sciex)
5)ZORBAX Extend-C18,3×50mm,3.5μm(美国安捷伦公司)5) ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)
6)CYP探针底物(非那西丁，双氯酚酸，(S)-美芬妥英，右美沙芬，睾酮)6) CYP probe substrates (phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, testosterone)
购自Sigma-Aldrich。Purchased from Sigma-Aldrich.
2、实验步骤2. Experimental steps
2.1、溶液配制2.1. Solution preparation
1)100mM磷酸缓冲液(PBS)的配制1) Preparation of 100mM Phosphate Buffered Saline (PBS)
取50mL浓度为2000mM的PBS溶液，加超纯水950mL，稀释至1000mL，混合均匀，即得pH 7.4的PBS溶液，放置4℃冰箱保存(保存期限为6个月)。Take 50 mL of PBS solution with a concentration of 2000 mM, add 950 mL of ultrapure water, dilute to 1000 mL, and mix evenly to obtain a PBS solution with pH 7.4, which is stored in a 4°C refrigerator (the shelf life is 6 months).
2)NADPH溶液的配制2) Preparation of NADPH solution
精密称取NADPH粉末适量，加入PBS缓冲溶液溶解，配成浓度为5mM的溶液，备用(现配现用)。Precisely weigh an appropriate amount of NADPH powder, add PBS buffer solution to dissolve, and prepare a solution with a concentration of 5 mM, for later use (prepared and used now).
3)肝微粒体溶液的配制3) Preparation of liver microsome solution
取人肝微粒体储存液(浓度为20mg/mL)适量，用浓度为15mM的MgCl 2溶液稀释至0.5mg/mL微粒体溶液，备用(现配现用)。 Take an appropriate amount of human liver microsome stock solution (concentration of 20 mg/mL) and dilute it to 0.5 mg/mL microsomal solution with 15 mM MgCl 2 solution for later use (prepared for current use).
4)MgCl 2溶液的配制 4) Preparation of MgCl 2 solution
称取MgCl 2粉末适量，用PBS溶液配制成300mM的储备液，置于4℃冰箱保存，备用。精密称取该溶液适量，加入100mM PBS溶液稀释成15mM的工作液，即可(现配现用)。 Weigh an appropriate amount of MgCl 2 powder, prepare a 300 mM stock solution with PBS solution, and store it in a 4°C refrigerator for later use. Precisely weigh an appropriate amount of the solution, add 100 mM PBS solution and dilute it into a 15 mM working solution, and that's it (prepared and used now).
5)受试化合物溶液的制备5) Preparation of test compound solutions
a.精密称取适量的受试化合物标准品，加入DMSO配成浓度为30mM的储备液，置于4℃冰箱保存。a. Precisely weigh an appropriate amount of the test compound standard, add DMSO to prepare a stock solution with a concentration of 30 mM, and store in a refrigerator at 4°C.
b.精密移取该储备液适量，加入DMSO溶液适量稀释成浓度为10、3、1、0.3、0.03和0.003mM的系列溶液I。精密移取上述系列溶液I适量，加入乙腈适量稀释成浓度为3、1、0.3、0.1、0.03、0.003、0.0003mM的系列溶液II。精密移取上述系列溶液II适量，加入PBS适量稀释成浓度为150、50、15、5、1.5、0.15、0.015μM的工作液，备用。b. Precisely pipette an appropriate amount of the stock solution, add an appropriate amount of DMSO solution to dilute to a series of solution I with a concentration of 10, 3, 1, 0.3, 0.03 and 0.003 mM. Precisely pipet an appropriate amount of the above series of solution I, add an appropriate amount of acetonitrile to dilute to a series of solution II with a concentration of 3, 1, 0.3, 0.1, 0.03, 0.003, 0.0003 mM. Precisely pipette an appropriate amount of the above-mentioned series of solutions II, add an appropriate amount of PBS to dilute to a working solution with a concentration of 150, 50, 15, 5, 1.5, 0.15, 0.015 μM, and set aside.
6)CYP探针底物和选择性抑制剂的选择6) Selection of CYP probe substrates and selective inhibitors
a.探针底物储备液的配制：称取各探针底物适量，加入DMSO配制成储备液，其浓度如下表5所示。a. Preparation of probe substrate stock solution: Weigh an appropriate amount of each probe substrate, add DMSO to prepare a stock solution, and its concentration is shown in Table 5 below.
b.探针底物工作液的配制：精密移取探针底物储备液适量，加入PBS溶液稀释200倍，得探针底物工作液，其浓度如下表5所示。b. Preparation of probe substrate working solution: Precisely pipette an appropriate amount of probe substrate stock solution, add PBS solution and dilute 200 times to obtain probe substrate working solution, the concentration of which is shown in Table 5 below.
表5table 5
CYPCYP 探针底物probe substrate 储备液浓度(mM)Stock concentration (mM) 工作液浓度(μM)Working solution concentration (μM)
1A21A2 非那西丁phenacetin 1212 6060
2C92C9 双氯酚酸Diclofenac 44 2020
2C192C19 (S)-美芬妥英(S)-Mephentoin 2020 100100
2D62D6 右美沙芬Dextromethorphan 44 2020
3A4T3A4T 睾酮testosterone 7575 375375
2.2、肝微粒体孵育及样品制备2.2. Incubation of liver microsomes and sample preparation
反应体系中蛋白浓度、底物和抑制剂的浓度如下表6-1和表6-2所示。The protein concentration, substrate and inhibitor concentration in the reaction system are shown in Table 6-1 and Table 6-2 below.
表6-1Table 6-1
Figure PCTCN2021107220-appb-000096
Figure PCTCN2021107220-appb-000096
表6-2Table 6-2
试剂reagent 体积(μL)Volume (μL)
人肝微粒体(0.25mg/mL)Human liver microsomes (0.25mg/mL) 40μL40μL
探针底物probe substrate 20μL20μL
待测化合物/阳性对照抑制剂Test compound/positive control inhibitor 20μL20μL
2.3、操作过程2.3. Operation process
1)精密移取人肝微粒体溶液(0.25mg/mL)40μL，探针底物溶液20μL和受试化合物溶液20μL于96孔板中，在37℃水浴中预孵育5分钟。1) Precisely pipette 40 μL of human liver microsome solution (0.25 mg/mL), 20 μL of probe substrate solution and 20 μL of test compound solution into a 96-well plate, and pre-incubate in a 37°C water bath for 5 minutes.
2)预孵育5分钟后取出，加入20μL浓度为5mM的NADPH溶液，启动反应，在37℃水浴中孵育30分钟。每个样本平行两份。2) Take out after 5 minutes of pre-incubation, add 20 μL of NADPH solution with a concentration of 5 mM, start the reaction, and incubate in a 37° C. water bath for 30 minutes. Each sample was replicated in duplicate.
3)孵育结束后，加入250μL含内标的乙腈溶液终止反应，800rpm摇10分钟后，3700rpm离心10分钟，精密移取上清液100μL加入80μL蒸馏水稀释，并于800rpm摇10分钟，吸取上清液进行LC-MS/MS分析。3) After the incubation, add 250 μL of acetonitrile solution containing internal standard to stop the reaction, shake at 800 rpm for 10 minutes, centrifuge at 3700 rpm for 10 minutes, precisely pipette 100 μL of the supernatant, add 80 μL of distilled water to dilute, shake at 800 rpm for 10 minutes, and absorb the supernatant. LC-MS/MS analysis was performed.
数值经Graphpad Prism计算分别得到药物对人肝微粒体CYP1A2非那西丁O-去乙基化、CYP2C9双氯酚酸4’-羟基化、CYP2C19美芬妥英4’-羟基化、CYP2D6右美沙芬O-去甲基化和CYP3A4T睾酮6β-羟基化代谢抑制的IC 50值见表7。 The values were calculated by Graphpad Prism to obtain the drug effects on human liver microsomes CYP1A2 phenacetin O-deethylation, CYP2C9 diclofenac 4'-hydroxylation, CYP2C19 mephentoin 4'-hydroxylation, CYP2D6 dextromethorphan Fen O- demethylation and CYP3A4T hydroxylated metabolite of testosterone 6β- inhibition IC 50 values are shown in Table 7.
表7本公开化合物对人肝微粒体CYP1A2非那西丁、CYP2C9双氯酚酸、CYP2C19美芬妥英、CYP2D6右美沙芬和CYP3A4T睾酮代谢位点的抑制的IC 50值(单位μM) Table 7 discloses compounds CYP1A2 in human liver microsomes that non-IC 50 values cefoxitin, CYP2C9 diclofenac, CYP2C19 mephenytoin, CYP2D6 inhibition of dextromethorphan metabolism of testosterone CYP3A4T site (in [mu] M)
实施例编号Example number CYP1A2CYP1A2 CYP2C9CYP2C9 CYP2C19CYP2C19 CYP2D6CYP2D6 CYP3A4TCYP3A4T
22 >30>30 23.823.8 >30>30 >30>30 >30>30
结论：本公开化合物30μM浓度范围内不会发生基于CYP1A2非那西丁O-去乙基化、CYP2C9双氯酚酸4’-羟基化、CYP2C19美芬妥英4’-羟基化、CYP2D6右美沙芬O-去甲基化和CYP3A4T睾酮6β-羟基化代谢位点的代谢性药物相互作用。Conclusion: The compounds of this disclosure do not occur in the concentration range of 30 μM based on CYP1A2 phenacetin O-deethylation, CYP2C9 diclofenac 4'-hydroxylation, CYP2C19 mephentoin 4'-hydroxylation, CYP2D6 dextromethorphan Metabolic drug interactions at the Fen O-demethylation and testosterone 6β-hydroxylation metabolic sites of CYP3A4T.
测试例6本公开化合物对hERG钾离子通道的作用Test Example 6 Effect of the disclosed compound on hERG potassium channel
1、测试目的1. Test purpose
应用手动膜片钳技术在转染hERG钾通道的稳定细胞株上测试本公开化合物对hERG钾电流的阻断作用The blocking effect of the compounds of the present disclosure on hERG potassium current was tested on stable cell lines transfected with hERG potassium channel using manual patch clamp technique
2、测试方法2. Test method
2.1、细胞培养2.1. Cell culture
本试验所用的细胞为转染有hERG cDNA与稳定表达hERG通道的CHO细胞系(由丹麦Sophion Bioscience公司提供),细胞代数为P9&P11。细胞培养在含有下列成分的培养基中(皆来源于Invitrogen)：Ham’s F12培养基，10％(v/v)灭活的胎牛血清，100μg/mL潮霉素B，100μg/mL遗传霉素。The cells used in this experiment were CHO cell lines (provided by Sophion Bioscience, Denmark) transfected with hERG cDNA and stably expressing hERG channel, and the cell passages were P9&P11. Cells were grown in medium (all from Invitrogen) containing the following components: Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/mL hygromycin B, 100 μg/mL Geneticin .
CHO hERG细胞生长于含上述培养液的培养皿中，并在37℃、含5％CO 2的培养箱中进行培养。电生理实验之前24到48小时，CHO hERG细胞被转移到放置于培养皿中的圆形玻璃片上，并在以上相同的培养液及培养条件下生长。每个圆形玻片上CHO hERG细胞的密度需要达到绝大多数细胞是独立、单个的要求。 CHO hERG cells were grown in petri dishes containing the above medium and cultured at 37°C in an incubator containing 5% CO 2 . Twenty-four to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in petri dishes and grown in the same medium and culture conditions as above. The density of CHO hERG cells on each circular slide needs to be such that the vast majority of cells are independent and single.
2.2、实验溶液2.2. Experimental solution
表8细胞内液和外液的组成成分Table 8 Composition of intracellular fluid and extracellular fluid
Figure PCTCN2021107220-appb-000097
Figure PCTCN2021107220-appb-000097
表9试剂详细信息Table 9 Reagent Details
Figure PCTCN2021107220-appb-000098
Figure PCTCN2021107220-appb-000098
2.3、电生理记录***2.3. Electrophysiological recording system
本实验采用手动膜片钳***(HEKA EPC-10信号放大器及数字转换***,购自德国HEKA Electronics)作全细胞电流的记录。表面生长有CHO hERG细胞的圆形玻片被放置于倒置显微镜下的电生理记录槽中。记录槽内以细胞外液作持续灌流(大约每分钟1毫升)。实验过程采用常规全细胞膜片钳电流记录技术。如无特殊说明，实验都是在常规室温下进行(～25℃)。细胞钳制在-80mV的电压下。细胞钳制电压去极化到+20mV以激活hERG钾通道，5秒后再钳制到-50mV以消除失活并产生尾电流。尾电流峰值用作hERG电流大小的数值。上述步骤所记录 的hERG钾电流在记录槽内持续的细胞外液灌流下达到稳定后则可以叠加灌流待测试的药物，直到药物对hERG电流的抑制作用达到稳定状态。一般以最近的连续3个电流记录线重合作为判断是否稳定状态的标准。达到稳定态势以后以细胞外液灌流冲洗直到hERG电流回复到加药物之前的大小。一个细胞上可以测试一个或多个药物，或者同一种药物的多个浓度，但是在不同药物之间需要以细胞外液冲洗。Cisapride(西沙必利，购自Sigma)被用于实验中作为阳性对照以保证所使用的细胞质量正常。In this experiment, a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) was used for whole-cell current recording. The circular slides with CHO hERG cells grown on the surface were placed in the electrophysiological recording chamber under an inverted microscope. The recording tank was continuously perfused with extracellular fluid (approximately 1 ml per minute). The experimental process used conventional whole-cell patch-clamp current recording technology. Unless otherwise specified, the experiments were carried out at normal room temperature (~25°C). Cells were clamped at -80mV. Cells were depolarized to +20 mV to activate the hERG potassium channel, and then clamped to -50 mV for 5 s to abolish inactivation and generate tail currents. The peak tail current was used as a numerical value for the magnitude of hERG current. After the hERG potassium current recorded in the above steps reaches stability under the continuous extracellular fluid perfusion in the recording tank, the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a stable state. Generally, the recent coincidence of three consecutive current recording lines is used as the criterion for judging whether it is in a stable state. After reaching a steady state, the cells were perfused with extracellular fluid until the hERG current returned to the level before the drug was added. One or more drugs, or multiple concentrations of the same drug, can be tested on a cell, but need to be flushed with extracellular fluid between drugs. Cisapride (cisapride, purchased from Sigma) was used in the experiments as a positive control to ensure that the cells used were of normal quality.
2.4、试验步骤2.4. Test steps
为了取得化合物的IC 50，选择下列浓度(30、10、3、1、0.3和0.1μM)来作测试。在试验之前，用DMSO以梯度稀释的方式稀释成10、3、1、0.3和0.1mM的储备液，用细胞外液稀释成最终的μM测试浓度。各浓度化合物溶液中DMSO的最终浓度都为0.1％。阳性对照Cisapride(西沙比利)的测试浓度为0.1μM。所有的化合物溶液都经过常规的5到10分钟超声和振荡以保证化合物完全溶解。 In order to obtain the compound IC 50, select the following concentrations (0.1 uM and 30,10,3,1,0.3) to be tested. Stock solutions of 10, 3, 1, 0.3 and 0.1 mM were serially diluted with DMSO and the final [mu]M test concentrations were diluted with extracellular fluid prior to the assay. The final concentration of DMSO in each concentration compound solution was 0.1%. The positive control Cisapride (cisapride) was tested at a concentration of 0.1 μM. All compound solutions were routinely sonicated and shaken for 5 to 10 minutes to ensure complete compound dissolution.
试验数据由HEKA Patchmaster(V2x73.2)，Microsoft Excel以及Graphpad Prism5.0提供的数据分析软件进行分析。The experimental data were analyzed by HEKA Patchmaster (V2x73.2), Microsoft Excel and data analysis software provided by Graphpad Prism 5.0.
2.5、试验结果2.5. Test results
本公开化合物对hERG钾电流的阻断作用通过以上的试验进行测定，测得的IC 50值见表10。 The blocking effect of the compounds of the present disclosure on hERG potassium current was determined by the above experiments, and the measured IC 50 values are shown in Table 10.
表10本公开化合物对hERG钾离子通道的阻断作用的IC 50 Table 10 Compound IC disclosure on hERG potassium ion channel blocking effect of 50
实施例编号Example number IC 50(μM) IC 50 (μM)
22 13.513.5
结论：本公开化合物对hERG的抑制作用弱，可降低由hERG通路引起的副作用。Conclusion: The disclosed compounds have weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

Claims (21)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：A compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salt:
    Figure PCTCN2021107220-appb-100001
    Figure PCTCN2021107220-appb-100001
    其中：in:
    环A为芳基或杂芳基；Ring A is aryl or heteroaryl;
    G为CR 5或N原子； G is CR 5 or N atom;
    R 0选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、羟基、氨基、-(CH 2) pNR 6R 7、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氧代、＝NH、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 0 is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , cycloalkyloxy , heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, oxo, =NH, amino, nitro, cyano, -S(O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
    R 1选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和环烷基； R 1 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
    R 2选自卤素、烷基、卤代烷基、羟烷基、羟基、氰基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基和氰基中的一个或多个取代基取代； R 2 is selected from halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with Substituted with one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;
    R 3选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 3 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 4选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基和-(CH 2) pNR 6R 7； R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH 2 ) p NR 6 R 7 ;
    R和R 5相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、芳基氧基、杂芳基氧基、-(CH 2) pNR 6R 7、氰基和硝基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氰基、硝基和-(CH 2) qNR 11R 12中的一个或 多个取代基所取代； R and R 5 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heterocycle Aryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro and -(CH 2 ) q NR 11 R 12 is substituted with one or more substituents;
    R 8相同或不同，各自独立地选自卤素、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、-(CH 2) pNR 6R 7、硝基、羟基、羟烷基、-S(O) 2烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自羟基、卤素、卤代烷基、烷氧基、卤代烷氧基、氰基、硝基、羟烷基、-(CH 2) qNR 11R 12、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 8 is the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH 2 ) p NR 6 R 7 , nitro alkyl, hydroxy, hydroxyalkyl, -S(O) 2 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, - (CH 2) q Substituted with one or more substituents in NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、-(CH 2) qNR 11R 12、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选地被选自羟基、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、氨基和硝基中的一个或多个取代基取代； R 9 and R 10 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH 2 ) q NR 11 R 12 , a cycloalkyl group and a heterocyclic group, wherein said Alkyl, cycloalkyl and heterocyclyl are each independently optionally selected from hydroxy, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino and nitro One or more substituents are substituted;
    R 6、R 7、R 11和R 12相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基； R 6 , R 7 , R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
    p和q相同或不同，各自独立地选自0、1和2；p and q are the same or different, each independently selected from 0, 1 and 2;
    n选自0、1、2、3、4和5。n is selected from 0, 1, 2, 3, 4 and 5.
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐,其中R 0选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、羟基、氨基、-(CH 2) pNR 6R 7、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； The compound represented by the general formula (I) according to claim 1 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein R 0 is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyloxy, heterocyclyloxy , cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro substituted with one or more substituents in group, cyano group, -S(O) 2 R 9 , -C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、-(CH 2) qNR 11R 12、环烷基和杂环基； R 9 and R 10 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH 2 ) q NR 11 R 12 , a cycloalkyl group and a heterocyclic group;
    R 6、R 7、R 11、R 12、p和q如权利要求1中所定义。 R 6 , R 7 , R 11 , R 12 , p and q are as defined in claim 1 .
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐,其中G为CR 5，R 5如权利要求1或2中所定义；优选地，G为CH。 The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is CR 5, R 5 as claimed in claim 1 or 2, defined; preferably, G is CH.
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt, which is the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021107220-appb-100002
    Figure PCTCN2021107220-appb-100002
    其中，环A、R、R 0、R 1、R 3、R 4、R 5、R 8和n如权利要求1或2中所定义。 wherein rings A, R, R 0 , R 1 , R 3 , R 4 , R 5 , R 8 and n are as defined in claim 1 or 2 .
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 0选自环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的环烷基氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自羟基和-C(O)R 10中的一个或多个取代基取代；R 10为烷基。 The compound represented by the general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 is selected from cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl group, a heterocyclic group, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one of the 10 selected from hydroxyl and -C (O) R or Multiple substituents are substituted; R 10 is alkyl.
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 0为四氢呋喃基氧基或哌啶基，所述的四氢呋喃基氧基和哌啶基各自独立地任选地被-C(O)R 10和/或羟基取代，其中R 10为C 1-6烷基。 The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 is tetrahydrofuranyloxy or piperidinyl, and said tetrahydrofuranyloxy and piperidinyl are each independently optionally replaced by -C( O) R 10 and/or hydroxy substitution, wherein R 10 is C 1-6 alkyl.
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt, which is the compound represented by general formula (III) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021107220-appb-100003
    Figure PCTCN2021107220-appb-100003
    其中，R、R 0、R 1、R 4、R 5、R 8和n如权利要求1或2中所定义。 wherein R, R 0 , R 1 , R 4 , R 5 , R 8 and n are as defined in claim 1 or 2 .
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 8相同或不同，各自独立地选自卤素、C 1-6烷基、C 1-6卤代烷基、氨基、-(CH 2) pNR 6R 7和C 1-6羟烷基，其中所述的C 1-6卤代烷基任选地被一个或多个羟基取代；R 6和R 7为氢原子或C 1-6烷基，p为0、1或2。 The compound represented by the general formula (I) according to any one of claims 1 to 7 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 is the same or different, each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, -(CH 2 ) p NR 6 R 7 and C 1-6 hydroxyalkyl, wherein said C 1-6 haloalkyl is optionally substituted by one or more hydroxyl groups; R 6 and R 7 are hydrogen atoms or C 1-6 alkanes base, p is 0, 1 or 2.
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1选自氢原子、C 1-6烷基和卤素；优选地，R 1为甲基。 The compound represented by the general formula (I) according to any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen atom, C 1-6 alkyl and halogen; preferably, R 1 is methyl.
  10. 根据权利要求1、2、3、5、6、8和9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2为氢原子或C 1-6烷基；优选地，R 2为甲基。 The compound represented by the general formula (I) according to any one of claims 1, 2, 3, 5, 6, 8 and 9 or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 2 is a hydrogen atom or a C 1-6 alkyl group; preferably, R 2 is a methyl group.
  11. 根据权利要求1至6、8至10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3为氢原子或C 1-6烷基；优选地，R 3为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 6, 8 to 10 or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom or a C 1-6 alkyl group; preferably, R 3 is a hydrogen atom.
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 4为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom.
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R为C 1-6烷氧基。 The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is C 1-6 alkoxy.
  15. 一种化合物，其选自以下任一结构：A compound selected from any of the following structures:
    Figure PCTCN2021107220-appb-100004
    Figure PCTCN2021107220-appb-100004
    Figure PCTCN2021107220-appb-100005
    Figure PCTCN2021107220-appb-100005
  16. 一种通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：A compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salt:
    Figure PCTCN2021107220-appb-100006
    Figure PCTCN2021107220-appb-100006
    其中X为卤素；wherein X is halogen;
    R 0选自溴、碘、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、羟基、氨基、-(CH 2) pNR 6R 7、杂环基氧基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、羟基、羟烷基、烷氧基、卤代烷氧基、氨基、硝基、氰基、-S(O) 2R 9、-C(O)R 10、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代； R 0 is selected from bromine, iodine, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH 2 ) p NR 6 R 7 , heterocyclyl Oxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optional selected from halo, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) 2 R 9 , -C (O) R 10 , substituted with one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 1选自溴、碘、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和环烷基； R 1 is selected from bromine, iodine, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
    R选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、芳基氧基、杂芳基氧基、-(CH 2) pNR 6R 7、氰基和硝基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、烷氧基、卤代烷氧基、卤 素、氰基、硝基和-(CH 2) qNR 11R 12中的一个或多个取代基所取代； R is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy Alkyl, aryloxy, heteroaryloxy, -(CH 2 ) p NR 6 R 7 , cyano and nitro, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, and -(CH 2 ) q NR 11 R 12 substituted by one or more substituents;
    G、R 6、R 7、R 9、R 10、R 11、R 12、p、q和R 4如权利要求1或2中所定义。 G, R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , p, q and R 4 are as defined in claim 1 or 2 .
  17. 一种化合物，其选自以下任一结构：A compound selected from any of the following structures:
    Figure PCTCN2021107220-appb-100007
    Figure PCTCN2021107220-appb-100007
  18. 一种制备通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：A kind of preparation of the compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its A method of a pharmaceutically acceptable salt, the method comprising the steps of:
    Figure PCTCN2021107220-appb-100008
    Figure PCTCN2021107220-appb-100008
    通式(IA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IB)或其盐反应，得到通式(I)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof React with general formula (IB) or its salt to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中，X为卤素；Wherein, X is halogen;
    环A、G、R、R 0、R 1、R 2、R 3、R 4、R 8和n如权利要求1或2中所定义。 Rings A, G, R, R 0 , R 1 , R 2 , R 3 , R 4 , R 8 and n are as defined in claim 1 or 2 .
  19. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1至15中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、 非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 15 or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  20. 根据权利要求1至15中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者根据权利要求19所述的药物组合物在制备用于抑制SOS1的药物中的用途。The compound according to any one of claims 1 to 15, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19 in the preparation of a medicament for inhibiting SOS1.
  21. 根据权利要求1至15中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者根据权利要求19所述的药物组合物在制备用于治疗和/或预防癌症、炎症、RAS病、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征、遗传性牙龈纤维瘤病、或其它增殖性疾病的药物中的用途，优选为癌症；所述的癌症优选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、***、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、***癌、***瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述的RAS病优选为1型神经纤维瘤病(NF1)；所述的肺癌优选为非小细胞肺癌，进一步优选为转移性非小细胞肺癌；所述的白血病优选为慢性淋巴细胞白血病或急性髓性白血病；所述的淋巴瘤优选为弥漫性大B细胞淋巴瘤；所述的骨髓瘤优选为多发性骨髓瘤；所述的骨瘤优选为骨软骨瘤；所述的肝癌优选为肝细胞癌；所述的结肠直肠癌优选为结肠癌或直肠癌；所述的头颈癌优选为头颈鳞状细胞癌；所述的肉瘤优选为骨肉瘤。The compound according to any one of claims 1 to 15, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19 in preparation for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardiofacial-Skin Syndrome (CFC), Leggers Syndrome, Hereditary Gingival Fibrosis Use in the drug of neoplastic disease, or other proliferative diseases, preferably cancer; the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, Gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, Testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, bone tumor, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic Lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma; the The liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.
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