WO2022017339A1 - Dérivé pyridazinique condensé, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé pyridazinique condensé, son procédé de préparation et son utilisation pharmaceutique 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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Chinese (zh)
Inventor
李心
陈阳
王斌
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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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.

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Abstract

L'invention concerne un dérivé pyridazinique condensé tel que représenté par la formule générale (I), un procédé de préparation de celui-ci, une composition pharmaceutique contenant ledit dérivé et son utilisation en tant qu'agent thérapeutique, en particulier son utilisation en tant qu'inhibiteur de SOS1 et son utilisation dans la préparation d'un médicament pour le traitement d'états ou de troubles qui sont améliorés par l'inhibition de SOS1.
PCT/CN2021/107220 2020-07-20 2021-07-20 Dérivé pyridazinique condensé, son procédé de préparation et son utilisation pharmaceutique Ceased WO2022017339A1 (fr)

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CN114621186A (zh) * 2022-05-12 2022-06-14 上海维申医药有限公司 作为ras信号通路调控剂的杂环化合物
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022214594A1 (fr) 2021-04-09 2022-10-13 Boehringer Ingelheim International Gmbh Thérapie anticancéreuse
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023280317A1 (fr) * 2021-07-09 2023-01-12 南京明德新药研发有限公司 Composé benzylamino tricyclique et son utilisation
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2023135260A1 (fr) 2022-01-14 2023-07-20 Jazz Pharmaceuticals Ireland Limited Nouveaux phtalazines à substitution amine et dérivés utilisés comme inhibiteurs de sos1
WO2023180345A1 (fr) * 2022-03-22 2023-09-28 Jazz Pharmaceuticals Ireland Limited Phtalazines tricycliques et leurs dérivés utilisés comme inhibiteurs de sos1
WO2024022507A1 (fr) * 2022-07-29 2024-02-01 江苏恒瑞医药股份有限公司 Composition pharmaceutique comprenant un inhibiteur de kras g12d
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US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
CN119451960A (zh) * 2022-08-05 2025-02-14 上海艾力斯医药科技股份有限公司 一种稠环化合物、其制备方法及其应用
WO2025070947A1 (fr) * 2023-09-27 2025-04-03 한미약품 주식회사 Nouveau composé dérivé de phtalazine en tant qu'inhibiteur de sos1, et son utilisation
TWI880239B (zh) * 2022-06-13 2025-04-11 大陸商上海優理惠生醫藥有限公司 一種噠嗪類化合物、其藥物組合物及應用
US12281113B2 (en) 2020-09-11 2025-04-22 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12336995B2 (en) 2018-09-10 2025-06-24 Mirati Therapeutics, Inc. Combination therapies
US12377101B2 (en) 2018-12-05 2025-08-05 Mirati Therapeutics, Inc. Combination therapies
US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
US12485122B2 (en) 2018-09-10 2025-12-02 Mirati Therapeutics, Inc. Combination of palbociclib and adagrasib for lung cancer
US12527795B2 (en) 2018-09-10 2026-01-20 Mirati Therapeutics, Inc. Compositions of adagrasib and mTOR inhibitors and methods of treatment therewith

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US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12336995B2 (en) 2018-09-10 2025-06-24 Mirati Therapeutics, Inc. Combination therapies
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
US12527795B2 (en) 2018-09-10 2026-01-20 Mirati Therapeutics, Inc. Compositions of adagrasib and mTOR inhibitors and methods of treatment therewith
US12485122B2 (en) 2018-09-10 2025-12-02 Mirati Therapeutics, Inc. Combination of palbociclib and adagrasib for lung cancer
US12377101B2 (en) 2018-12-05 2025-08-05 Mirati Therapeutics, Inc. Combination therapies
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US12304915B2 (en) 2019-12-20 2025-05-20 Mirati Therapeutics, Inc. SOS1 inhibitors
US12281113B2 (en) 2020-09-11 2025-04-22 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12286431B2 (en) 2020-09-11 2025-04-29 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
WO2022214594A1 (fr) 2021-04-09 2022-10-13 Boehringer Ingelheim International Gmbh Thérapie anticancéreuse
WO2023280317A1 (fr) * 2021-07-09 2023-01-12 南京明德新药研发有限公司 Composé benzylamino tricyclique et son utilisation
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
WO2023135260A1 (fr) 2022-01-14 2023-07-20 Jazz Pharmaceuticals Ireland Limited Nouveaux phtalazines à substitution amine et dérivés utilisés comme inhibiteurs de sos1
WO2023180345A1 (fr) * 2022-03-22 2023-09-28 Jazz Pharmaceuticals Ireland Limited Phtalazines tricycliques et leurs dérivés utilisés comme inhibiteurs de sos1
CN114621186A (zh) * 2022-05-12 2022-06-14 上海维申医药有限公司 作为ras信号通路调控剂的杂环化合物
TWI880239B (zh) * 2022-06-13 2025-04-11 大陸商上海優理惠生醫藥有限公司 一種噠嗪類化合物、其藥物組合物及應用
WO2024022507A1 (fr) * 2022-07-29 2024-02-01 江苏恒瑞医药股份有限公司 Composition pharmaceutique comprenant un inhibiteur de kras g12d
EP4563151A4 (fr) * 2022-07-29 2025-11-05 Jiangsu Hengrui Pharmaceuticals Co Ltd Composition pharmaceutique comprenant un inhibiteur de kras g12d
CN119451960A (zh) * 2022-08-05 2025-02-14 上海艾力斯医药科技股份有限公司 一种稠环化合物、其制备方法及其应用
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
WO2025070947A1 (fr) * 2023-09-27 2025-04-03 한미약품 주식회사 Nouveau composé dérivé de phtalazine en tant qu'inhibiteur de sos1, et son utilisation
TWI905898B (zh) * 2023-09-27 2025-11-21 南韓商韓美藥品股份有限公司 作為ｓｏｓ１抑制劑的新穎呔衍生化合物及其用途

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