WO2021249475A1 - Dérivé de quinazoline condensé, son procédé de préparation et son application en médecine - Google Patents

Dérivé de quinazoline condensé, son procédé de préparation et son application en médecine Download PDF

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Publication number
WO2021249475A1
WO2021249475A1 PCT/CN2021/099351 CN2021099351W WO2021249475A1 WO 2021249475 A1 WO2021249475 A1 WO 2021249475A1 CN 2021099351 W CN2021099351 W CN 2021099351W WO 2021249475 A1 WO2021249475 A1 WO 2021249475A1
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general formula
alkyl
compound
cancer
racemate
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PCT/CN2021/099351
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English (en)
Chinese (zh)
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李心
董怀德
曾长根
钟家鑫
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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Priority to CN202180041050.2A priority Critical patent/CN115697994A/zh
Publication of WO2021249475A1 publication Critical patent/WO2021249475A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a condensed quinazoline derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as SOS1
  • a condensed quinazoline derivative represented by the general formula (I) a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as SOS1
  • RAS is one of the oncogenes with the highest mutation rate in tumors. About 30% of human malignancies are related to the mutation of RAS gene.
  • the RAS family includes KRAS, NRAS and HRAS, among which KRAS mutations are the most common, accounting for about 85%.
  • KRAS is activated, it regulates cell proliferation, survival, migration and metabolism through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc.
  • the protein continues to be in an activated state, leading to the continuous activation of downstream signaling pathways and promoting tumorigenesis.
  • KRAS Due to the lack of small molecule binding sites on the surface of KRAS protein in the traditional sense, and its super-high affinity with guanylic acid, it is extremely difficult to be inhibited. It has long been considered a drug target that is not druggable. However, based on the importance and ubiquity of abnormal activation of KRAS in cancer progression, KRAS has been and is still a target of great concern for drug development.
  • the current drug development ideas aimed at 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 current 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, etc. still lack effective drugs.
  • KRAS Modification and localization of KRAS: For example, farnesyl transferase, etc. block the membrane localization of KRAS so as to achieve the effect of inhibiting its effect.
  • KRAS G12C inhibitors In general, in addition to KRAS G12C inhibitors, there is still a lack of broad-spectrum KRAS inhibitors that are effective against multiple mutations. Blocking the binding of KRAS activation molecules to KRAS, such as selective inhibition of SOS1, a small molecule inhibitor of guanine nucleotide exchange factor (GEF), can block the activation of KRAS 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).
  • KRAS protein is between the inactive state (binding with guanosine diphosphate (GDP)) and the activated state (binding with guanosine triphosphate (GTP)). Conversion. This transformation is regulated by the guanine nucleotide exchange factor (GEF) and GTPases activating protein (GAP).
  • GEF guanine nucleotide exchange factor
  • GAP GTPases activating protein
  • SOS sinless son
  • Ras-GRF Ras-GRF
  • Ras-GRP Ras-GRP. The latter two types are only expressed in neurons and leukocytes. Only SOS is widely expressed in a variety of tissues and is considered to be Play a leading role in the activation of RAS.
  • SOS1 Since the expression level of SOS1 is higher than that of SOS2, and the activity is stronger than 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 combine with GTP to form active KRAS-GTP.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form, or its pharmaceutically acceptable salt:
  • Ring A is aryl or heteroaryl
  • Ring B is a 5-6 membered heterocyclic group or heteroaryl group
  • R 9 and R 11 are the same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, -(CH 2 ) q NR 6 R 7 , cycloalkyl and heterocyclyl;
  • the alkyl group, cycloalkyl group and heterocyclic group are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, and carboxy;
  • R 10 is selected from hydrogen, alkyl, hydroxyalkyl, hydroxyl, -(CH 2 ) q NR 6 R 7 , cycloalkyl and heterocyclic group; the alkyl, cycloalkyl and heterocyclic group are each independently Optionally substituted by one or more substituents selected from alkyl, alkoxy, cyano, and carboxy;
  • R 1 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
  • R 2 is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are each independently optionally It is substituted by one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;
  • R 3 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxy Substituted by one or more substituents of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -NR 6 R 7 ;
  • R 5 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , Cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -NR 6 R 7 , cyano and nitro, wherein the alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and -NR 6 R 7 Substituted by one or more substituents;
  • R 8 is the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, -(CH 2 ) q NR 6 R 7 , Nitro, 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 selected from hydroxyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -(CH 2 ) q NR 6 R 7 , cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;
  • R 6 and R 7 are the same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • p 0, 1, 2, 3, 4 or 5;
  • q 0, 1, or 2
  • n 0, 1, 2, 3, 4 or 5;
  • t 0, 1, 2, 3, 4, or 5.
  • R 9 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, -(CH 2 ) q NR 6 R 7 , cycloalkyl and heterocyclic group;
  • R 8 is the same or different, and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, -(CH 2 ) q NR 6 R 7 , nitro , Hydroxy, hydroxyalkyl, -S (O) 2 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl are each independently optionally selected from hydroxyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -(CH 2 ) q NR 6 R 7 , one or more substituents in cycloalkyl, heterocyclic, aryl and heteroaryl;
  • R 6 , R 7 and q are as defined in the general formula (I).
  • a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a five-membered or six-membered heterocyclic group, preferably a five-membered heterocyclic group.
  • a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Structure, or its mixture form, or its pharmaceutically acceptable salt which is a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • G 1 , G 2 and G 3 are the same or different, and are each independently selected from a carbon atom, an oxygen atom, a nitrogen atom and a sulfur atom, provided that G 1 , G 2 and G 3 are not carbon atoms at the same time;
  • r is 0 or 1; preferably, r is 0;
  • Ring A, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the dashed line represents a single bond.
  • a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein: G 1 and G 2 are carbon atoms, G 3 is an oxygen atom; or G 2 and G 3 are carbon atoms, and G 1 is an oxygen atom; or G 1 and G 3 are each independently an oxygen atom or a nitrogen atom, and G 2 is a carbon atom.
  • a compound represented by general formula (I) and (II) or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are of general formula (III), general formula (IV), general formula (V), general formula (VI) or general formula (VII)
  • Ring A, R 0 , R 1 , R 2 , R 4 , R 5 , R 8 , p and n are as defined in general formula (I) and (II) (R 5 in general formula (VI) can be optionally substituted On N).
  • a compound represented by general formula (I) and (II) or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are of general formula (III-1), general formula (IV-1), general formula (V-1), general formula (VI- 1) Or the compound represented by the general formula (VII-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Or its pharmaceutically acceptable salt:
  • Ring A, R 0 , R 1 , R 2 , R 4 , R 5 , R 8 , p and n are as defined in general formulas (I) and (II) (R 5 in general formula (VI-1) Can be optionally substituted on N).
  • ring A is selected from phenyl, thienyl, pyrrolyl and furyl.
  • the groups are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S(O) 2 R 9 and -C (O) One or more substituents in R 9 are substituted; wherein R 9 is selected from hydrogen, alkyl, haloalkyl, -(CH 2 ) q
  • R 0 is selected from C 1-6 alkoxy, five-membered heterocyclyloxy and six-membered heterocyclyl, said five-membered heterocyclyloxy and six-membered heterocyclyl are each independently optionally Ground is substituted by one or more substituents in -C(O)R 9 and hydroxyl, wherein R 9 is C 1-6 alkyl or -(CH 2 ) q NR 6 R 7 , R 6 and R 7 are the same or Different, each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.
  • R 0 is selected from the group consisting of tetrahydrofuranyloxy, C 1-6 alkoxy, hydrogenated pyridyl and hydrogenated pyranyl, and said hydrogenated pyridyl and hydrogenated pyranyl are each independently optionally substituted by -C( O) One or more substituents in R 9 and/or hydroxy, wherein R 9 is C 1-6 alkyl or -(CH 2 ) q NR 6 R 7 , R 6 and R 7 are the same or different, each Independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.
  • R 0 is selected from tetrahydrofuranyloxy, C 1-6 alkoxy, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl and dihydropyranyl, the piperidinyl, tetrahydropyranyl Pyridyl, tetrahydropyranyl, and dihydropyranyl are each independently optionally substituted with one or more substituents in hydroxy and/or -C(O)R 9 , wherein R 9 is C 1-6 Alkyl group or -(CH 2 ) q NR 6 R 7 , R 6 and R 7 are the same or different, and are each independently selected from hydrogen, alkyl and haloalkyl, and q is 1 or 2;
  • R 0 is selected from tetrahydrofuranyloxy or tetrahydropyridyl, and said tetrahydropyridyl is optionally substituted by -C(O)R 9 , wherein R 9 is C 1-6 alkyl.
  • R 0 is selected from 3-6 membered cycloalkyl, which is optionally substituted by halogen, C 1-6 alkyl and hydroxy.
  • 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, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, a nitro group, a cyano group , -S(O) 2 R 9 , -(CH 2 ) t C(O)R 9 and -NHC(O)R 11 ;
  • 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 and R 11 are as general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1).
  • R 13a , R 13b and R 13c are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, a nitro group, a cyano group , -S(O) 2 R 9 , -(CH 2 ) t C(O)R 9 and -NHC(O)R 11 ;
  • v 0, 1, 2 or 3;
  • R 9 and R 11 are as general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1).
  • R 13a is -(CH 2 ) t -C(O)R 9 ;
  • R 9 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl and -( CH 2 ) q NR 6 R 7 , the C 1-6 alkyl group may be optionally substituted by a C 1-6 alkoxy group and a cyano group;
  • R 6 and R 7 are the same or different, and are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 hydroxyalkyl; t is 0 or 1; q is 0 or 1;
  • R 13a is -(CH 2 ) t -C(O)R 9 ; R 9 is selected from C 1-6 alkyl; t is zero.
  • R 13c is -(CH 2 ) t -C(O)R 9 ;
  • R 9 is selected from hydroxyl, -(CH 2 ) q NR 6 R 7 and 3-6 membered heterocyclic groups; the 3-6 The membered heterocyclic group is optionally substituted by C 1-6 alkyl;
  • R 6 and R 7 are the same or different, and are each independently selected from C 1-6 alkyl and C 1-6 hydroxyalkyl; t is 0; q is 0.
  • R 8 are the same or different, and are each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) q NR 6 R 7 , C 1-6 hydroxyalkyl and C 6-10 aryl group, wherein the C 1-6 haloalkyl group is optionally substituted by one or more hydroxyl groups, and the C 6-10 aryl group is optionally substituted by one or more -(CH 2 ) q is substituted by NR 6 R 7 ; R 6 and R 7 are selected from hydrogen or C 1-6 alkyl, and q is 0, 1, or 2.
  • R 1 is selected from hydrogen, C 1-6 alkyl and halogen.
  • R 1 is a methyl group.
  • R 2 is selected from hydrogen and C 1-6 alkyl.
  • R 2 is methyl
  • R 3 is selected from hydrogen and C 1-6 alkyl.
  • R 4 is hydrogen
  • R 5 is hydrogen or methyl, more preferably hydrogen.
  • R 6 and R 7 are the same or different, and are each independently selected from hydrogen and C 1-6 alkyl.
  • R 10 is -(CH 2 ) q NR 6 R 7 , R 6 and R 7 are the same or different, and each independently is a methyl group, and q is 1.
  • R 11 is cyclopropyl or -(CH 2 ) q NR 6 R 7 , R 6 and R 7 are the same or different, and are each independently a methyl group, and q is 1.
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:
  • R 1 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;
  • Ring B, R 0 , R 4 , R 5 and p are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:
  • G 1 is an oxygen atom or a sulfur atom
  • Ring A, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:
  • X is halogen
  • Ring A, ring B, R 1 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:
  • the dashed line, G 1 -G 3 , R 0 -R 1 , R 4 -R 5 , p, and r are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:
  • the dashed line, ring A, G 1 -G 3 , R 1 -R 5 , R 8 , p, r, and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to compounds represented by general formulas (IIIA-1), (IVA-1), (VA-1), (VIA-1) or (VIIA-1) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or salt thereof:
  • R 0 -R 1 , R 4 -R 5 and p are as defined in the general formula (III), (IV), (V), (VI) or (VII).
  • Another aspect of the present disclosure relates to compounds represented by general formula (IIIA-2) or (IVA-2) or tautomers, mesosomes, racemates, enantiomers, and non-pairs thereof Enantiomers, or their mixture forms or their salts:
  • ring A, R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as defined in general formula (III) or (IV).
  • Another aspect of the present disclosure relates to compounds represented by general formulas (IIIA-3), (IVA-3), (VA-3), (VIA-3) or (VIIA-3) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or salt thereof:
  • Ring A, R 1 -R 2 , R 4 -R 5 , R 8 , p and n are as defined in the general formula (III), (IV), (V), (VI) or (VII).
  • Another aspect of the present disclosure relates to compounds represented by general formulas (IIIA-4), (IVA-4), (VA-4), (VIA-4) or (VIIA-4) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or salt thereof:
  • R 0 -R 1 , R 4 -R 5 , and p are as defined in the general formula (III-1), (IV-1), (V-1), (VI-1) or (VII-1) .
  • Another aspect of the present disclosure relates to compounds represented by general formula (IIIA-5) or (IVA-5) or tautomers, mesosomes, racemates, enantiomers, and non-pairs thereof Enantiomers, or their mixture forms or their salts:
  • ring A, R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as defined in the general formula (III-1) or (IV-1).
  • Another aspect of the present disclosure relates to compounds represented by general formulas (IIIA-6), (IVA-6), (VA-6), (VIA-6) or (VIIA-6) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or salt thereof:
  • Ring A, R 1 -R 2 , R 4 -R 5 , R 8 , p and n are as general formula (III-1), (IV-1), (V-1), (VI-1) or (VII -1) as defined in.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIaA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof Form or its salt:
  • Q 1 , Q 2 and Q 3 are the same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;
  • j 0 or 1
  • k 0, 1, 2, 3, 4 or 5;
  • R 1 -R 5 , G 1 -G 3 , R 8 , R 9 , R 11 , p, r, n, and t are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to compounds represented by general formula (IIIaA) or (III-1aA) or tautomers, mesosomes, racemates, enantiomers, and diastereomers thereof Structure, or its mixture form or its salt:
  • Q 1 , Q 2 and Q 3 are the same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;
  • j 0 or 1
  • k 0, 1, 2, 3, 4 or 5;
  • R 1 -R 2 , R 4 -R 5 , R 8 , R 9 , R 11 , p, n, and t are as defined in the general formula (III).
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method includes the following steps:
  • the compound of general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its salt and general formula (IB) The compound or its salt (preferably the hydrochloride) is reacted to obtain the compound of the general formula (I) or its tautomer, meso, racemate, enantiomer, and non-pair Enantiomers, or mixtures thereof or pharmaceutically acceptable salts thereof,
  • ring A, ring B, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer
  • the method for preparing a phytosome, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method includes the following steps:
  • G 1 is an oxygen atom or a sulfur atom
  • Ring A, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method includes the following steps:
  • reaction Use salt Take the compound of the general formula (IA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its salt as raw material
  • the compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its medicine is prepared by reaction Use salt; this reaction can be cross-coupling with transition metal catalysis such as Suzuki or Herck coupling, metal halide addition such as Grignard addition, nucleophilic substitution, Ullmann reaction, etc. to introduce R 0 , preferably via Ullmann reaction, Suzuki Reaction or Grignard reaction,
  • Ring A, ring B, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the general formulas (I), (II), (III), (IV), (V), (VI), (VII) of the present disclosure , (III-1), (IV-1), (V-1), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, meso, The racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or its mixture form, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, in the preparation of a medicament for inhibiting SOS1.
  • the present disclosure further relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for the treatment and/or prevention of SOS1 mediated diseases.
  • the present disclosure further relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), and multiple spots Noonan Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Heart-Facial-Skin Syndrome (CFC), Legus Syndrome, Genetics Use in drugs for gingival fibromatosis or other proliferative diseases, preferably cancer; the cancer is preferably melanoma, skin cancer, liver cancer, hepatocellular carcinoma, kidney cancer, lung cancer, na
  • the present disclosure also relates to a method for inhibiting SOS1, which comprises administering to a desired patient an effective amount of general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and Table A or the compounds shown in or tautomers, meso, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and Table A or the compounds shown in or tautomers, meso, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method for the treatment and/or prevention of SOS1-mediated diseases, which comprises administering to a patient a therapeutically effective amount of general formulas (I), (II), (III), (IV), (V) , (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and the compounds shown in Table A or their mutual variation Constructs, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • 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), heart-face-skin syndrome (CFC), Legers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably methods of treating cancer , Which includes the general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV- 1), (V-1), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers , Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, hepatocellular carcinoma, renal cancer , Lung cancer, n
  • the present disclosure further relates to a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V -1), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers Body, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.
  • the present disclosure also relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an SOS1 inhibitor.
  • the present disclosure also relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for the treatment and/or prevention of SOS1 mediated diseases.
  • the present disclosure also relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), and disease with multiple spots South Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Heart-Facial-Skin Syndrome (CFC), Legacy Syndrome, Hereditary Gingival fibromatosis, or other proliferative diseases, are preferably used for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, hepato
  • the SOS1-mediated diseases described in the present disclosure are selected from cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), heart-face-skin syndrome (CFC), Legus syndrome, hereditary gingival fibromatosis, or other proliferative diseases; preferably cancer; the Said cancer is preferably selected from melanoma, skin cancer, liver cancer, hepatocellular carcinoma, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, colon cancer, rectal cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma Epithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumors, prostate cancer, seminoma
  • the active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (for example, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation administration.
  • the compounds of the present disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound of the present disclosure is preferably in the form of a unit dose, or a form in which the patient can self-administer in a single dose.
  • the expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.
  • a suitable unit dose can be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients, which may be selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients ⁇ etc.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants.
  • These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and suitable excipients for mixing to prepare aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. 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.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickeners. Sweetening and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, or mineral oil, or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion can be injected into the patient's bloodstream by local mass injection.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • 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 that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by adding water to prepare water-suspended dispersible powders and granules.
  • These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent, or one or more preservatives.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, and the health of the patient. Condition, patient’s behavior, patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode, such as the mode of treatment, the daily dosage of the compound, or the type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight line containing 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms.
  • the chain or branched group is preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 (for example, 1, 2, 3, 4, 5, or 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 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, and sec-butyl.
  • Alkyl groups can be substituted or unsubstituted.
  • the substituents are preferably independently selected from the group consisting of D atom, halogen, alkyl, and alkoxy. Group, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl One or more substituents of.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbons Atom, more preferably an alkylene group containing 1 to 6 (for example, 1, 2, 3, 4, 5, or 6) carbon atoms.
  • alkylene groups 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 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from alkenyl, alkynyl, and alkoxy.
  • substituents in the group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo are substituents in the group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.
  • alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above.
  • Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy
  • alkynyl refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (E.g. 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group that shares one carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group 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 Multiple double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed 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 Five-membered and six-membered/6-membered bicyclic alkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, non-limiting examples include Etc.; preferably
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of D atom, halogen, alkoxy, halogenated alkyl, and halogenated alkoxy Group, 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, which contains 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or sulfur,
  • 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 hetero Atom; more preferably contains 3 to 8 ring atoms (such as 3, 4, 5, 6, 7 and 8), of which 1-3 (such as 1, 2 and 3) are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, in which one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen or sulfur.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group 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.
  • 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 5-membered 5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent
  • the structures linked together are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl.
  • the aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is an aryl ring, and non-limiting examples thereof include :
  • Aryl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkanes Or Multiple substituents.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms (such as 1, 2, 3, or 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl include residues derived from the removal of one hydrogen atom from the parent ring atom, or the removal of two hydrogen atoms from the same or two different ring atoms of the parent.
  • Derivative residues namely "divalent cycloalkyl", “divalent heterocyclic group", “arylene”, “heteroarylene”.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, where aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, where heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • cycloalkylcarbonyl refers to cycloalkyl-C(O)-, where cycloalkyl is as defined above.
  • heterocyclylcarbonyl refers to heterocyclyl -C(O)-, wherein heterocyclyl is as defined above.
  • carboxylate group refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O ) O-, wherein alkyl and cycloalkyl are as defined above.
  • hydrogenated refers to the number of double bonds in the ring, which can be dihydro, tetrahydro, hexahydro, etc., such as hydrogenated pyridyl, including dihydropyridyl, tetrahydropyridyl and hexahydropyridyl (ie piper (Pyridyl), as for hydrogenated pyranyl, includes dihydropyranyl and tetrahydropyranyl.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • 18 F-fluorine label 18 F isotope
  • 11 C-, 13 C-, or 14 C-rich Compounds in which collective carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present 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 diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • the present disclosure also includes formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1) in various deuterated forms , (V-1), (VI-1), (VII-1) and Table A compounds.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • Deuterated reagents include but are not limited to deuterium Borane, tri-deuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present.
  • the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents.
  • substituents Those skilled in the art can determine possible or impossible substitutions (through experiments or theory) without making too much effort.
  • an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredients and then exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity.
  • the salt can be prepared separately during the final isolation and purification of the compound, 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 sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • solvate refers to the physical combination 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 into the crystal lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • Prodrug refers to a compound that can be transformed in the body under physiological conditions, such as by hydrolysis in the blood, to produce an active prodrug compound.
  • pharmaceutically acceptable refers to these compounds, materials, compositions and/or dosage forms, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or Other problems or complications have a reasonable benefit/risk ratio and are effective for the intended use.
  • the preparation method of medicinal salt includes the following steps:
  • the compound of general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its salt and general formula (IB) The compound or its salt (preferably hydrochloride) is reacted in the presence of a base and a condensing agent to obtain a compound of the general formula (I) or its tautomer, meso, racemate, and Enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof,
  • ring A, ring B, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • the preparation method of its pharmaceutically acceptable salt includes the following steps:
  • G 1 is an oxygen atom or a sulfur atom; preferably an oxygen atom;
  • Ring A, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • the preparation method of medicinal salt includes the following steps:
  • Ring A, ring B, R 0 -R 5 , R 8 , p and n are as defined in the general formula (I).
  • the preparation method of medicinal salt includes the following steps:
  • the compound of formula (IB) or its salt (preferably hydrochloride) is reacted in the presence of a base and a condensing agent to obtain a compound of general formula (II) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • the dotted line, ring A, G 1 -G 3 , R 0 -R 5 , R 8 , p, r, and n are as defined in the general formula (II).
  • the preparation method of medicinal salt includes the following steps:
  • the dashed line, ring A, R 0 -R 5 , R 8 , p, r, and n are as defined in the general formula (II).
  • ring A, R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as defined in general formula (III), (IV), (V), (VI) or (VII).
  • ring A, R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as defined in general formula (III) or (IV).
  • transition metals can be used for this reaction Catalytic cross-coupling such as Suzuki or Herck coupling, etc., metal halide addition such as Grignard addition, nucleophilic substitution, Ullmann reaction, etc. introduce R 0 ,
  • Ring A, R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as defined in general formula (III), (IV), (V), (VI) or (VII).
  • R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as general formula (III-1), (IV-1), (V-1), (VI-1) or ( As defined in VII-1).
  • ring A, R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as defined in the general formula (III-1) or (IV-1).
  • Ring A, R 0 -R 2 , R 4 -R 5 , R 8 , p and n are as in the general formula (III-1), (IV-1), (V-1), (VI-1) or (VII -1) as defined in.
  • Q 1 , Q 2 and Q 3 are the same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;
  • j 0 or 1
  • k 0, 1, 2, 3, 4 or 5; wherein R 9- R 11 and t are as defined in the general formula (I).
  • the preparation method is:
  • the general formula (IIaA) is prepared by oxidation reaction to obtain the general formula (IIa),
  • Q 1 , Q 2 and Q 3 are the same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;
  • j 0 or 1
  • k 0, 1, 2, 3, 4 or 5;
  • R 1 -R 5 , G 1 -G 3 , R 8 -R 9 , R 11 , p, r, n, and t are as defined in the general formula (II).
  • the preparation method is:
  • the general formula (IIIaA) or (III-1aA) is prepared by oxidation reaction to obtain the general formula (IIIa) or (III-1a),
  • Q 1 , Q 2 and Q 3 are the same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;
  • j 0 or 1
  • k 0, 1, 2, 3, 4 or 5;
  • R 1 -R 2 , R 4 -R 5 , R 8 -R 9 , R 11 , p, n, and t are as defined in the general formula (III).
  • Q 1 , Q 2 and Q 3 are the same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;
  • j 0 or 1
  • k 0, 1, 2, 3, 4 or 5;
  • R 9- R 11 and t are as defined in the general formula (I).
  • the preparation method is:
  • Q 1 , Q 2 and Q 3 are the same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;
  • j 0 or 1
  • k 0, 1, 2, 3, 4 or 5;
  • R 1 -R 5 , G 1 -G 3 , R 8 -R 9 , R 11 , p, r, n, and t are as defined in the general formula (II).
  • the condensing agent described in the above reaction includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N ,N'-Diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole Nitrozole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate, benzotriazo
  • the Ullmann reaction can be carried out in the presence of a metal catalyst/ligand/base.
  • the metal catalyst includes but is not limited to cuprous iodide, cuprous chloride, cuprous bromide, Cu(OTf) 2 PhH, Cu, CuO, Cu 2 O, Cu(OAc) 2 , preferably cuprous iodide;
  • ligands include but are not limited to 1,10-phenanthroline, 4,7-dichlorophenanthroline, 4,7-dichlorophenanthroline Methoxyphenanthroline, tetramethylphenanthroline, TEMDA (CAS registration number 110-18-9), N,N'-dimethyl-1,2-ethylenediamine, TMHD (CAS registration number 1118- 71-4), cyclohexyl-1,2-diamine, N,N'-dimethylcyclohexyl-1,2-diamine, salicylaldoxime, N-diethyl salicylamide, 8-hydroxyquinoline Etc., preferably
  • the bases mentioned in the above reaction include organic bases and inorganic bases.
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamino.
  • the inorganic bases include but are 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 or 1,8-dinitrogen Heterocyclic [5,4,0]undec-7-ene.
  • the catalyst used in the above reduction reaction includes but is not limited to palladium on carbon, iron powder, Raney nickel, zinc powder, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzyl Phosphorus)dichlorodipentyl iron palladium, tris(dibenzylideneacetone)dipalladium, etc., preferably palladium on carbon.
  • the reducing agent used includes but is not limited to hydrogen, dilute hydrochloric acid, acetic acid or dilute sulfuric acid, preferably hydrogen.
  • the catalyst system used in the above 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 Compound/NaBH 4 (or Pt-H 2 ), tetraphenylporphyrin cobalt(II) complex/NaBH 4 (or EtNBH 4 ), (bis(salicylic- ⁇ -iminopropyl)methylamine)cobalt (II)/primary alcohol, Co(acac) 2 , Co(salen), Co(acacen), BH 3, etc.; the oxidants used include but are not limited to oxygen, air, hydrogen peroxide, etc., where Mn(dpm) 2 is Bis(2,2,6,6-tetramethyl-3,5-heptanedione) manganese, Mn(dpm) 3 is tri
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, isopropanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Methyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, N,N-dimethylacetamide or N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR is measured with Bruker AVANCE-400 nuclear magnetometer or Bruker AVANCE NEO 500M, and the solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ,
  • the internal standard is tetramethylsilane (TMS).
  • MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole 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 analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatograph.
  • HPLC preparative chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • 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 thin layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by 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 Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses 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 examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of silica gel column chromatography used to purify the compound, and the developing solvent system of thin layer chromatography.
  • TLC thin layer chromatography
  • 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 can also be added Adjust with alkaline or acidic reagents such as triethylamine and acetic acid.
  • Chloral hydrate 9b (5.60g, 33.0mmol, Shanghai Titan Technology Co., Ltd.) and anhydrous sodium sulfate (27.76g, 195.4mmol) were dissolved in 50mL of water, followed by the addition of the compound benzo[d][1,3] two Oxolane-4-amine 9a (4g, 29.2mmol, Shanghai Shaoyuan Reagent Co., Ltd.), hydroxylamine sulfate (24.9g, 151.7mmol), concentrated hydrochloric acid (3.1mL). Stir at room temperature for 10 minutes, then heat to 60°C to react for 1.5 hours, and finally return to room temperature to react overnight. A solid precipitated out during the reaction, which was filtered after standing, and the filter cake was sucked dry to obtain the title compound 9c (4.5 g). Yield: 74.1%.
  • Dissolve compound 9d (3.76g, 19.7mmol) and sodium hydroxide (6.3g, 157.5mmol) in 45mL water in turn, slowly add 30% hydrogen peroxide (22.3g, 196.7mmol, 24mL) in an ice bath, and stir for 30 minutes .
  • 2M diluted hydrochloric acid was added to neutralize the pH to about 7, and the system precipitated solid. After standing, it was filtered and washed with water. The filter cake was drained to obtain the title compound 9e (2.33g). Yield: 65.4%.
  • Dissolve compound 15c (0.7g, 3.19mmol), hydroxylamine sulfate (2.6g, 15.84mmol) in water (15mL), add concentrated hydrochloric acid (0.32mL), 2,2,2-trichloroethane-1,1 -Diol (792mg, 4.79mmol), anhydrous sodium sulfate (3.2g, 22.5mmol), first heat to 60°C and stir for 1.5 hours, then cool to room temperature and continue to stir and react for 16 hours. The reaction solution is filtered and the filter cake is collected. The title compound 15d (0.8g) was obtained, and the yield was 86.3%.
  • Example 12 Using the synthetic route in Example 12, the first step raw material compound 10b was replaced with compound 9j, and the second step raw material compound 1j was replaced with compound 3a to obtain the title compound 16 (50 mg), yield: 44%.
  • the compound 2-amino-5-bromo-4-methoxybenzoic acid 17a (5g, 23mmol, Shanghai Bi De Pharmaceutical Co., Ltd.) was dissolved in 2 mL of acetic anhydride, and reacted under reflux for 8 hours. After cooling and standing overnight, it precipitated out after a little stirring. A large amount of solids are filtered, and the filter cake is washed with a small amount of acetic anhydride.
  • Example 11 Using the synthetic route in Example 11, the seventh step raw material compound 3a was replaced by compound 1j and the eighth step raw material compound 1-acetylpiperidin-4-one was replaced by the compound tetrahydropyrone to obtain the title compound 22 (3mg), yield: 10.5%.
  • HPLC analysis retention time 10.47 minutes, purity: 98.5% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23% -42%).
  • HPLC analysis retention time 11.52 minutes, purity: 97.2% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23% -42%).
  • HPLC analysis retention time 11.28 minutes, purity: 98.5% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -55%).
  • HPLC analysis retention time 13.11 minutes, purity: 99.3% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -55%).
  • Example 11 Using the synthetic route in Example 11, the seventh step raw material compound 3a was replaced with compound 2a, and the eighth step raw material compound 1-acetylpiperidin-4-one was replaced with compound tetrahydropyrone to obtain compound 32 (13 mg ), yield: 5.5%.

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Abstract

L'invention concerne un dérivé de quinazoline condensé, son procédé de préparation et une application de celui-ci en médecine. Plus précisément, la présente invention concerne un dérivé de quinazoline condensé représenté par la formule générale (I), un procédé de préparation de celui-ci, une composition pharmaceutique contenant le dérivé et une utilisation de celui-ci en tant qu'agent thérapeutique, en particulier une utilisation de celui-ci en tant qu'inhibiteur de SOS1 et son utilisation dans la préparation d'un médicament pour le traitement de maladies ou d'états qui peuvent être améliorés par l'inhibition de SOS1.
PCT/CN2021/099351 2020-06-10 2021-06-10 Dérivé de quinazoline condensé, son procédé de préparation et son application en médecine WO2021249475A1 (fr)

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WO2023134374A1 (fr) * 2022-01-12 2023-07-20 如东凌达生物医药科技有限公司 Composé pyrimido-hétérocyclique, procédé de préparation et utilisation
WO2024027762A1 (fr) * 2022-08-05 2024-02-08 上海艾力斯医药科技股份有限公司 Composé à cycles fusionnés, son procédé de préparation et son utilisation

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WO2024027762A1 (fr) * 2022-08-05 2024-02-08 上海艾力斯医药科技股份有限公司 Composé à cycles fusionnés, son procédé de préparation et son utilisation

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