WO2022237890A1 - Azepine-type fused ring compound and pharmaceutical use thereof - Google Patents

Azepine-type fused ring compound and pharmaceutical use thereof Download PDF

Info

Publication number
WO2022237890A1
WO2022237890A1 PCT/CN2022/092607 CN2022092607W WO2022237890A1 WO 2022237890 A1 WO2022237890 A1 WO 2022237890A1 CN 2022092607 W CN2022092607 W CN 2022092607W WO 2022237890 A1 WO2022237890 A1 WO 2022237890A1
Authority
WO
WIPO (PCT)
Prior art keywords
cycloalkyl
alkyl
ring
heteroaryl
heterocyclyl
Prior art date
Application number
PCT/CN2022/092607
Other languages
French (fr)
Chinese (zh)
Inventor
闫旭
刘国标
王国政
沙汉明
李斌
李建浩
辛丕明
刘延鑫
Original Assignee
中国医药研究开发中心有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国医药研究开发中心有限公司 filed Critical 中国医药研究开发中心有限公司
Priority to CN202280005442.8A priority Critical patent/CN115867557A/en
Publication of WO2022237890A1 publication Critical patent/WO2022237890A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to azapine condensed ring compounds and their medical application. Specifically, the present invention relates to an azepine fused ring compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing it, and as a receptor-interacting protein kinase 1 (RIP1) inhibitor, used Use for treating diseases associated with RIP1 activity.
  • azepine fused ring compound represented by general formula (I) a preparation method thereof, a pharmaceutical composition containing it, and as a receptor-interacting protein kinase 1 (RIP1) inhibitor, used Use for treating diseases associated with RIP1 activity.
  • RIP1 receptor-interacting protein kinase 1
  • Apoptosis and necrosis are two ways of cell death. Passive cell death and necrosis caused by environmental factors play an important role in pathological and physiological processes such as inflammation. RIP1 is at the interaction point of multiple inflammation and cell death-related signaling pathways, and participates in the regulation of TNF-activated NF- ⁇ B, apoptosis, necrosis and other downstream signaling pathways.
  • RIP1 can promote inflammatory response by mediating the NF- ⁇ B pathway, but it is worth noting that the activation of the NF- ⁇ B pathway and TNF-induced apoptosis do not require the kinase activity of RIP1, and RIP1 kinase inhibition has no effect on the TNF-induced NF- ⁇ B pathway Activation has no effect. However, the kinase activity of RIP1 can also promote the occurrence and development of inflammation through multiple pathways such as cell necrosis, inflammasome, and TNF production.
  • IL-1 ⁇ is also a key pro-inflammatory factor.
  • IL-1 ⁇ acts on synovial fibroblasts and chondrocytes to aggravate the destruction of cartilage, bone tissue, and soft tissue around the joint.
  • IL-1 ⁇ secretion requires the assistance of two pathways: first, pathways such as TLR4 and TNF promote the expression of IL-1 ⁇ /IL-18 precursors; secondly, the formed NLPR3 and other inflammasome platforms promote the maturation of IL-1 ⁇ /IL-18 precursors .
  • the inflammasome is closely related to the occurrence and development of autoimmune diseases such as RA and psoriasis. Activation of the inflammasome depends on RIP1 and RIP3 and their kinase activity. RIP1 and RIP3 can amplify the expression of IL-1 ⁇ , and this process is independent of necrosis.
  • RIP1 kinase-dependent mediation of IL-1 ⁇ production protein tyrosine phosphatase SHP-1 plays an important role in immune signaling pathways, and SHP-1 mutant mice produce a large number of inflammatory factors associated with inflammatory diseases such as arthritis, but the mechanism is unknown. Certain SHP-1 mutant mice develop spontaneous severe inflammation with symptoms similar to human neutrophilic dermatosis. In this model, RIP1 kinase is dependent on the production of IL-1 ⁇ , which mediates and amplifies inflammation and tissue damage, independent of the inflammasome, IL-1 ⁇ , and RIP3.
  • Inhibition of RIP1 kinase can prevent the occurrence of related inflammation and injury, and inhibition of NF- ⁇ B and ERK can alleviate the production of inflammatory factors mediated by RIP1. Therefore, the inflammation and tissue damage in SHP-1 mutant mice depend on the production of IL-1 ⁇ mediated by RIP1 kinase, and the mechanism is related to the regulation of NF- ⁇ B and ERK pathways by RIP1 kinase.
  • RIP1 kinase-dependent mediation of TNF ⁇ production cIAP can inhibit RIP1 activity through ubiquitination, and cIAP inhibitors such as Smac can induce TNF ⁇ production and cell death, but the mechanism is unknown. TNF ⁇ inhibition prevents cell death induced by caspase inhibition, suggesting that caspase e inhibition may induce TNF ⁇ production. RIP1 kinase inhibition prevents cell death induced by caspase inhibition, therefore, RIP1 may act as an upstream mechanism of TNF ⁇ production in the context of caspase inhibition.
  • RIP1 kinase can interact with EDD to induce JNK pathway activation and TNF ⁇ production, which specifically corresponds to caspase inhibition, indicating that RIP1 kinase activity not only regulates cell necrosis downstream of TNFR1, but also mediates TNF ⁇ production. play an important role.
  • RIP1 kinase inactivating mutations completely protect against multiorgan inflammatory phenotypes, especially skin inflammation; RIP1 kinase inhibition protects against ischemia-reperfusion-induced kidney injury in animal models of kidney transplantation; RIP1 kinase inhibitor Nec-1 prevents myocardial infarction and Cardiac hypoxia; RIP1 kinase inhibitor Nec-1 prevents cone cell death, dsRNA-induced retinal degeneration, and retinitis pigmentosa.
  • RIP1 causes animal death. Unlike RIP1 loss, RIP1 kinase-inactive mutant mice survive normally and are resistant to necrotic stimuli. Therefore, death caused by RIP1 loss is not related to kinase activity. Ripk1D138N/D138N and RipkK45A/K45A kinase inactivation mutant mice did not have significantly altered phenotypes, indicating that RIP1 kinase activity is a relatively safe target. In contrast, RIP3 kinase-inactive mutant mice lost weight faster and died.
  • RIP1 receptor-interacting protein kinase 1
  • the object of the present invention is to provide a compound represented by general formula (I) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt,
  • X is selected from -O-, -S(O) m -, -NR a -, -CR'R"-;
  • Y1 and Y2 are each independently selected from O or S;
  • Z 1 and Z 2 are each independently selected from C or N atoms
  • L is selected from single bond, -O-, -S(O) m -, -NR a -, -(CR a R b ) n -, -(CR a R b ) n O-, -(CR a R b ) n S- and -(CR a R b ) n NR a -;
  • Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally further substituted by one or more R9 ;
  • Ring B is an aromatic ring or an aromatic heterocyclic ring, which is optionally further substituted by one or more R 8 ;
  • Ring C is a nitrogen-containing heterocycle, which is optionally further substituted by one or more R 7 ;
  • R 1 and R 2 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group together with the atoms they are connected to, or R 2 and R 3 form a 5-membered heteroaryl group, a 5-membered heteroaryl group, or a 5-membered cycloalkyl group together with their connected atoms
  • a heterocyclic group or a 5-membered cycloalkyl group, or R 3 and R 4 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group with the atoms they are connected to, wherein the 5-membered heteroaryl group , 5-membered heterocyclyl or 5-membered cycloalkyl are optionally further substituted by one or more R 6 ;
  • R 3 and R 4 are each independently selected from R 6 ;
  • R 1 and R 4 are each independently selected from R 6 ;
  • R 3 and R 4 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group together with their connected atoms, R 1 and R 2 are each independently selected from R 6 ;
  • R is selected from hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl ;
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 , wherein the alkyl, alkoxy, ring Alkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, oxo, hydroxyl,
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester
  • R' and R" are each independently selected from hydrogen, halogen, alkyl, haloalkyl
  • R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1 or 2;
  • n is an integer of 0 to 3.
  • the compound represented by general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereoisomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof,
  • Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m
  • R 1 and R 2 are each independently selected from hydrogen, halogen, alkyl
  • R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, Ester group, oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group substitution by one or more groups;
  • R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1 or 2;
  • X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in general formula (I).
  • Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m
  • R 1 and R 4 are each independently selected from hydrogen, halogen, alkyl
  • R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1 or 2;
  • X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or Its mixture form, or its pharmaceutically acceptable salt it is the compound represented by general formula (IV), or its mesoform, racemate, enantiomer, diastereoisomer, or in the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m
  • R 3 and R 4 are each independently selected from hydrogen, halogen, alkyl
  • R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1 or 2;
  • X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in general formula (I).
  • R a and R b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally Further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups are substituted;
  • R a and R b form a 5-7 membered nitrogen-containing heterocyclic group together with the atoms they are connected to, and the 5-7 membered nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, One or more groups of oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted.
  • ring C is a 5- to 8-membered nitrogen-containing heterocycle, preferably piperidine ring, tetrahydropyrrole ring, piperazine ring , dihydropyrrole ring, tetrahydropyridine ring or homopiperazine ring, more preferably piperidine ring, which is optionally further substituted by one or more R 7 ;
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cyclic One or more groups of alkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1 or 2.
  • ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocycle, preferably a benzene ring, a pyridine ring, Pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring , more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further substituted by one or more R 8
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cyclic One or more groups of alkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1 or 2.
  • Y2 is selected from O or S
  • Z 1 and Z 2 are each independently selected from C or N atoms
  • Ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, Thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further replaced by one or more R 8 replace;
  • Each R 7 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy; or two adjacent R 7 are together with the atoms to which they are attached Form heterocyclyl or cycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, One or more groups of carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted; preferably R 7 is hydrogen;
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; p is 0, 1, 2, 3 or 4, preferably 0.
  • Y2 is selected from O or S
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups; preferably R is halogen;
  • q 0, 1 or 2.
  • X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined in general formula (I).
  • Ring A is selected from aryl and heteroaryl, preferably phenyl, wherein said aryl or heteroaryl is optionally further substituted by one or more R 9 ,
  • Each R is independently selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, alkane and alkoxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, One or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted.
  • L is selected from -NR a - and -(CR a R b ) n -, preferably -(CR a R b ) n -;
  • R a and R b are each independently selected from hydrogen and C 1-6 alkyl
  • n is an integer from 0 to 3, preferably 1;
  • L is more preferably -CH 2 -;
  • the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (II-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • X is -O- or -S-;
  • Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
  • R 1 and R 2 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl
  • R 5 is selected from hydrogen and C 1 -C 6 alkyl
  • R is selected from hydrogen and halogen
  • R9 is selected from hydrogen and halogen
  • R a is selected from C 1 -C 6 alkyl
  • p 0, 1 or 2.
  • the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (III-1) or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • X is -O- or -S-;
  • Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
  • R 1 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl
  • R 5 is selected from hydrogen and C 1 -C 6 alkyl
  • R is selected from hydrogen and halogen
  • R9 is selected from hydrogen and halogen
  • R a is selected from C 1 -C 6 alkyl
  • p 0, 1 or 2.
  • the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IV-1) or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • X is -O- or -S-;
  • Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
  • R 3 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl
  • R 5 is selected from hydrogen and C 1 -C 6 alkyl
  • R is selected from hydrogen and halogen
  • R9 is selected from hydrogen and halogen
  • R a is selected from C 1 -C 6 alkyl
  • p 0, 1 or 2.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention further provides a compound represented by the general formula (IA) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound IA-I undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (IA), and the catalyst is preferably trimethylaluminum;
  • X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined in general formula (IA).
  • the present invention further provides a compound represented by general formula (II-1) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or its
  • the preparation method of mixture form or its pharmaceutically acceptable salt it comprises the following steps:
  • the compound II-1a undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (II-1), and the catalyst is preferably trimethylaluminum;
  • X, ring D, R 1 , R 2 , R 5 , R 8 , R 9 , and p are as defined in general formula (II-1).
  • the present invention further provides a compound represented by general formula (III-1) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or its
  • the preparation method of mixture form or its pharmaceutically acceptable salt it comprises the following steps:
  • the compound III-1a undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (III-1), and the catalyst is preferably trimethylaluminum;
  • X, ring E, R 1 , R 4 , R 5 , R 8 , R 9 , and p are as defined in general formula (III-1).
  • the present invention further provides a compound represented by the general formula (IV-1) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or its
  • the preparation method of mixture form or its pharmaceutically acceptable salt it comprises the following steps:
  • the compound IV-1a undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (IV-1), and the catalyst is preferably trimethylaluminum;
  • the present invention further provides a pharmaceutical composition, which comprises the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) according to the present invention ) or a compound represented by (IV-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable carrier or excipient.
  • a pharmaceutical composition which comprises the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) according to the present invention ) or a compound represented by (IV-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable carrier or excipient.
  • the present invention further relates to the compound of general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention
  • the present invention further relates to the compound of general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention
  • the present invention further relates to a general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention ) or its mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, which Used as a receptor-interacting protein kinase 1 (RIP1) inhibitor.
  • RIP1 receptor-interacting protein kinase 1
  • the present invention further relates to a general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention ) or its mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, which
  • said diseases are preferably inflammatory diseases, autoimmune diseases or neurological diseases, said inflammatory diseases and autoimmune diseases such as rheumatoid arthritis, Ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus , Sjogren's syndrome,
  • the present invention further relates to a method of inhibiting receptor-interacting protein kinase 1 (RIP1), which comprises administering an effective amount of the general formula (I), (IA), (II) according to the present invention to a patient in need , (III), (IV), (II-1), (III-1) or the compound represented by (IV-1) or its mesoform, racemate, enantiomer, diastereomer An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • RIP1 receptor-interacting protein kinase 1
  • the present invention further relates to a method for preventing or treating diseases related to the activity of receptor-interacting protein kinase 1, which comprises administering a preventive or therapeutically effective amount of the general formula (I),
  • the inflammatory diseases and autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spinal Arthritis, gout, juvenile idiopathic arthritis, systemic lupus
  • the compound of the general formula of the present invention can form a pharmaceutically acceptable basic addition salt with a base.
  • the base includes inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension 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 can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • the compounds of this invention may 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 will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention can contain the compound of the general formula and its pharmaceutically acceptable salt, hydrate or solvate as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into a clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • 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-dimethyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, propynyl, butynyl and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls 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 rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • 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 does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • the present invention adopts the following synthetic scheme to prepare the compound of the present invention.
  • Step 1 In the presence of a catalyst, compound IAa is reacted with compound IAm to obtain compound IAb, the catalyst is preferably triphenylphosphine and DIAD, and the protecting group is preferably Boc and Trt;
  • Step 2 In the presence of a catalyst, compound IAb is hydrogenated to obtain compound IAc, the catalyst is preferably palladium carbon;
  • Step 3 In the presence of a catalyst, the compound IAc undergoes an intramolecular ring-closing reaction to obtain the compound IAd, and the catalyst is preferably trimethylaluminum;
  • Step 4 under basic conditions, compound IAd is reacted with R 5 I to obtain compound IAe, and the basic conditions are preferably cesium carbonate;
  • Step 5 Under acidic conditions, compound IAe is deprotected to obtain compound IAf, and the acidic conditions are preferably trifluoroacetic acid;
  • Step 6 under alkaline conditions, diethyl butynedioate is reacted with hydrazine compound IAg to obtain compound IAh, and the alkaline conditions are preferably potassium carbonate;
  • Step 7 In the presence of a catalyst, the compound IAh is subjected to the Vilsmeyer-Hacker reaction and chlorinated to obtain the compound IAi, the catalyst is preferably DMF and phosphorus oxychloride;
  • Step 8 under basic conditions, compound IAi is reacted with wittig reagent to obtain compound IAj, and the basic conditions are preferably potassium tert-butoxide;
  • Step 9 Under acidic conditions, compound IAj is hydrolyzed to obtain compound IAk, and the acidic conditions are preferably hydrochloric acid;
  • Step 10 Reductive amination reaction of compound IAk and compound IAf under catalyst conditions to obtain compound IA-I, the catalyst is preferably 2-picoline borane complex;
  • Step 11 In the presence of a catalyst, the compound IA-I undergoes an intramolecular ring closure reaction to obtain a compound of the general formula (IA), and the catalyst is preferably trimethylaluminum;
  • R is an amino protecting group
  • X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined in general formula (IA); preferably, X is -O-, Y 1 and Y 2 are O, and L is -CH 2 -.
  • the compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures.
  • the present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art.
  • Protecting Groups in Organic Preparations by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high-performance liquid chromatography or a combination of the above methods.
  • For its specific usage method please refer to the examples described in the present invention.
  • other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
  • the lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography.
  • Chromatographic column is DaisogelC18 10 ⁇ m 100A (30mm ⁇ 250mm), mobile phase: acetonitrile/water.
  • TLC Thin-layer chromatography
  • Silica gel column chromatography uses Qingdao ocean silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvents organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78°C and 200°C.
  • the reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent is according to the compound It can be adjusted according to the polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
  • Step 5 O-(1,3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-trityl Preparation of base-L-serine methyl ester (1e)
  • Step 7 N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- Preparation of 5-yl)-L-serine methyl ester (1g)
  • Step 8 O-(6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(tert-butoxy Preparation of methyl carbonyl)-L-serine (1h)
  • Step 9 (S)-(1,3-Dimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4',5': Preparation of tert-butyl 4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (1i)
  • Step 10 (S)-(1,3,9-Trimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4',5 Preparation of ':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate tert-butyl ester (1j)
  • diethyl butynedioate 4.4 g, 25.6 mmol
  • benzylhydrazine dihydrochloride 5 g, 25.6 mmol
  • anhydrous potassium carbonate 8.8 g, 64 mmol
  • the reaction solution was cooled to room temperature, and the reaction solution was stirred for 5 hours.
  • Add 300 mL of water and 150 mL of ethyl acetate wash the organic layer with 100 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • the residue was slurried with 10 mL of acetonitrile and filtered to obtain 2.2 g of the title compound as a yellow solid with a yield of 35%.
  • Step 14 Preparation of ethyl 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (1n)
  • Step 15 Preparation of ethyl 1-benzyl-5-chloro-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (1o)
  • Step 16 (S)-1-Benzyl-5-chloro-4-(2-((1,3,9-trimethyl-2,8-dioxo-2,3,6,7,8 ,9-Hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)- Preparation of ethyl 1H-pyrazole-3-carboxylate (1p)
  • Step 17 (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -yl)-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4',5':4,5]benzo[1,2-b][ Preparation of 1,4]oxazepine-2,8-dione (1)
  • benzo[d][1,3]dioxin-5-yl acetate (4.00g, 24.0mmol) was added to 40mL of acetic acid, stirred for 10 minutes, and nitric acid (2.80g , 26.0 mmol). After stirring at room temperature for 3 hours, the reaction solution was poured into crushed ice, allowed to stand for 30 minutes and then filtered. The filter cake was washed twice with water and dried to obtain 4.2 g of the title compound as a yellow solid with a yield of 83.9%.
  • 6-nitrobenzo[d][1,3]dioxin-5-yl acetate (4.20g, 18.7mmol) was added in 40mL of 20% sulfuric acid aqueous solution, stirred for 10 minutes and then heated to Stir at 80°C for 3 hours.
  • the reaction solution was poured into crushed ice, allowed to stand for 30 minutes and then filtered.
  • the filter cake was washed twice with water and dried to obtain 3.1 g of the title compound as a yellow solid with a yield of 90.7%.
  • Acetyl chloride (476 mg, 6.70 mmol) was added to a solution of 2-bromo-4-methoxy-5-nitroaniline (1.00 g, 4.07 mmol) and triethylamine (739 mg, 7.32 mmol) in DCM at 0 °C ( 20mL). Warm to room temperature and stir overnight. Add DCM to dilute, wash with water, saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 1.3 g of the title compound as a yellow solid, which is directly used in the next reaction.
  • N-(2-bromo-4-methoxy-5-nitrophenyl)acetamide (1.30g, 4.51mmol), potassium sulfide (1.49g, 13.5mmol) and CuI (85.8mg, 0.451 mmol) was dissolved in DMF (25ml), and the reaction solution was raised to 90°C and stirred for 1 hour.
  • step 5 The remaining steps are the same as in Example 1, except that 5-hydroxy-1,3-dimethyl in step 5 is replaced by 6-hydroxy-2-methyl-5-nitrobenzo[d]thiazole (3d) -6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to obtain the title compound 3.
  • Step 2 Preparation of N-(tert-butoxycarbonyl)-O-(2-methyl-7-nitrobenzo[d]thiazol-6-yl)-L-serine methyl ester (6b)
  • N-(2-bromo-4-methoxyphenyl)cyclopropanecarboxamide (7a) (5.00 g, 1.86 mmol) was dissolved in DMF (100 mL), and Cs 2 CO 3 (12.1 g, 37.2 mmol) was added , CuI (180mg, 0.930mmol), bipyridine (290mg, 1.86mmol), and react overnight at 120°C under a nitrogen atmosphere.
  • Step 5 Preparation of O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-N-trityl-L-serine methyl ester (7e)
  • Step 7 Preparation of N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7 g)
  • Step 8 Preparation of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (7h)
  • N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7g) (3.50 g, 8.31 mmol) was dissolved in 30 mL of methanol, and aqueous Pd/C (1 g) was added to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Celite was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 3.2 g of the title compound (crude product) as a yellow oil.
  • Step 9 Preparation of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i)
  • Step 10 (S)-(2-Cyclopropyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4',5':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-7-yl) tert-butyl carbamate (7j)
  • Step 11 (S)-(2-Cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4',5':4,5]benzo Preparation of tert-butyl [1,2-b][1,4]oxazepine-7-yl)carbamate (7k)
  • Step 12 (S)-7-Amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b Preparation of ][1,4]oxazepine-6(5H)-one (7l)
  • Step 2 Preparation of N-(tert-butoxycarbonyl)-O-(7-nitro-1H-indazol-6-yl)-D-serine methyl ester (8b)
  • Step 3 Preparation of O-(7-amino-1H-indazol-6-yl)-N-(tert-butoxycarbonyl)-D-serine methyl ester (8c)
  • N-(tert-butoxycarbonyl)-O-(7-nitro-1H-indazol-6-yl)-D-serine methyl ester (8b) (8.95 g, 23.6 mmol) was dissolved in 80 mL MeOH, Hydrous palladium on carbon (2.00 g) was added, and stirred overnight at room temperature under a hydrogen atmosphere. Filter, wash the filter cake (10mL x 3) with methanol, and concentrate the filtrate under reduced pressure to obtain 8.11g of the title compound as a reddish-brown solid, yield: 98.4%.
  • Step 4 (S)-(9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepine[2,3-g]indazol-8-yl) Preparation of tert-butyl carbamate (8d)
  • Step 5 (S)-(1,10-Dimethyl-9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepine[2,3-g Preparation of ]indazol-8-yl) tert-butyl carbamate (8e)
  • 4,5-dimethoxy-2-nitrobenzaldehyde (5.00g, 23.7mmol) was dissolved in 100mL DCM, m-CPBA (10.9g, 63.4mmol) was added at 0°C, under nitrogen atmosphere, TFA (1.76 mL) was added at 0°C and stirred at room temperature overnight.
  • TFA (1.76 mL) was added at 0°C and stirred at room temperature overnight.
  • 0°C add saturated sodium thiosulfate solution to quench, filter, wash the filter cake with DCM, wash the organic phase with saturated sodium bicarbonate solution (100mL x 1), wash with saturated brine (100mL x 1), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain a crude product.
  • the crude product was dissolved in 70 mL of methanol, 2 mol/L NaOH solution (30 mL) was added, and stirred at room temperature for 1 hour. Adjust the pH to 3-4 with 1 mol/L hydrochloric acid, filter, wash the filter cake with methanol, collect the filter cake, and dry to obtain 3.25 g of the title compound as a yellow solid, yield: 69.0%.
  • 4,5-dimethoxy-2-nitrophenol (9a) (3.25g, 12.3mmol), methyltrityl-L-serine (6.64g, 18.4mmol) and triphenyl Phosphine (6.45g, 24.5mmol) was dissolved in 150mL THF. Under nitrogen atmosphere, DIAD (4.95g, 24.5mmol) was added at 0°C, and stirred overnight at room temperature.
  • Step 4 Preparation of N-(tert-butoxycarbonyl)-O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9d)
  • Step 5 Preparation of O-(2-amino-4,5-dimethoxyphenyl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (9e)
  • Step 6 (S)-(7,8-Dimethoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine]-3- base) preparation of tert-butyl carbamate (9f)
  • Step 9 (S)-1-Benzyl-5-chloro-4-(2-((7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5- Preparation of ethyl tetrahydrobenzo[b][1,4]oxazepin-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylate (9i)
  • Step 10 (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 Preparation of -yl)-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9j)
  • Step 11 (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 Preparation of -yl)-7,8-dihydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9k)
  • Step 12 (7S)-7-(2-Benzyl-3-chloro)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-[1,3]dioxole[4',5':4,5]benzene
  • ethyl[1,2-b][1,4]oxazepine-2-carboxylate 9
  • Step 2 Preparation of ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate (10b).
  • Step 3 Preparation of ethyl 5-chloro-1-(2-fluorobenzyl)-4-(2-methoxyethenyl)-1H-pyrazole-3-carboxylate (10c)
  • Step 5 O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine (11e ) preparation
  • Step 6 (S)-2,2-Difluoro-7-(trityl)-6,7-dihydro-[1,3]dioxolo[4',5';4 ,5] Preparation of benzo[1,2-b][1,1,4]oxazepine-8(9H)-one (11f)
  • O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine (11e) ( 2.20g, 4.25mmol) was dissolved in 40mL DMF, added DIEA (1.64g, 12.7mmol), HATU (2.42g, 6.37mmol), and stirred at room temperature for 2 hours.
  • Step 7 (S)-2,2-Difluoro-9-methyl-7-(trityl)-6,7-dihydro-[1,3]dioxole[4' ,5'; 4,5]Benzo[1,2-b][1,4]oxazepine-8(9H)-one (11g)
  • Step 8 (S)-7-Amino-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxolo[4',5';4 ,5] Benzo[1,2-b][1,4]oxazepine-8(9H)-one (11h) preparation
  • Step 9 (S)-1-Benzyl-5-chloro-4-(2-((2,2-difluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro -[1,3]dioxole[4',5'; 4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl Base)-1H-pyrazole-3-carboxylic acid ethyl ester (11i) preparation
  • Step 10 (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -yl)-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxole[4',5'; 4,5]benzo[1 ,2-b][1,4]Oxazepine-8(9H)-one (11)
  • N-(2-Bromo-4-methoxy-5-nitrophenyl)pivalamide (12b) (5.75g, 17.4mmol) was dissolved in DMF (60mL), Cs 2 CO 3 (11.3g , 34.8mmol), CuI (166mg, 0.871mmol), bipyridine (272mg, 1.74mmol), and stirred overnight at 120°C under a nitrogen atmosphere.
  • Step 4 O-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl- Preparation of L-serine methyl ester (14d)
  • Step 5 O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L - Preparation of serine methyl ester (14e)
  • Step 6 O-(5-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L - Preparation of serine (14f)
  • Step 7 (S)-1-((2-(Trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7,8-tetrahydro- Preparation of 6H-[1,4]oxazepine[3,2-f]indazol-(5H)-one (14g)
  • Step 8 (S)-5-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7, Preparation of 8-tetrahydro-6H-[1,4]oxazepine[3,2-f]indazol-6-one (14h)
  • Step 10 (S)-1-Benzyl-5-chloro-4-(2-((5-methyl-6-oxo-1-((2-(trimethylsilyl)ethoxy) )methyl)-5,6,7,8-tetrahydro-1H-[1,4]oxazepine[3,2-f]indazol-7-yl)amino)ethyl)-1H- Preparation of ethyl pyrazole-3-carboxylate (14j)
  • Step 11 (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4]oxygen
  • (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4]oxygen Preparation of azazolo[3,2-f]indazol-6-one (14k)
  • Dissolve compound 14j (110 mg, 0.168 mmol) in 3 ml of chloroform at room temperature, add Al(CH 3 ) 3 solution (0.253 ml, 2M) to the reaction solution at 0°C under nitrogen atmosphere, and stir at 50°C for 3 hours .
  • Step 12 (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 Preparation of -yl)-5-methyl-1,5,7,8-tetrahydro-6H-[1,4]oxazepine[3,2-f]indazol-6-one (14)
  • N-(2-bromo-5-methoxyphenyl)cyclopropanecarboxamide (5.00 g, 1.86 mmol) was dissolved in DMF (100 mL) and Cs 2 CO 3 (12.1 g, 37.2 mmol) was added , CuI (180mg, 0.930mmol), bipyridine (290mg, 1.86mmol), and stirred overnight at 120°C under a nitrogen atmosphere.
  • Step 5 Preparation of O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-N-trityl-L-serine methyl ester (15e)
  • Step 7 Preparation of N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15 g)
  • Step 8 Preparation of O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (15h)
  • N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15g) (1.50 g, 3.05 mmol) was dissolved in 20 mL of methanol, and aqueous Pd/C (1.00 g) was added to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Filter through celite, add MeOH to wash the filter cake, and concentrate the filtrate under reduced pressure to obtain 1.6 g of the title compound (crude product) as a yellow oil.
  • Step 9 Preparation of O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine (15i)
  • Step 10 (S)-(2-Cyclopropyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-7-yl) tert-butyl carbamate (15j)
  • Step 11 (S)-(2-Cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo Preparation of tert-butyl [1,2-b][1,4]oxazepine-7-yl)carbamate (15k)
  • Step 12 (S)-7-Amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b Preparation of ][1,4]oxazepine-8(9H)-one (15l)
  • 2-bromo-5-methoxyaniline (5.00g, 25.0mmol) was dissolved in 100ml DCM, DIEA (9.60g, 75.0mmol) was added, and three Methylacetyl chloride (3.58g, 29.8mmol), stirred at room temperature for 2 hours.
  • N-(2-bromo-5-methoxyphenyl)pivalamide (16a) (5.00 g, 17.5 mmol) was dissolved in DMF (100 mL), and Cs 2 CO 3 (11.4 g, 35.1 mmol), CuI (333mg, 1.75mmol), bipyridine (546mg, 3.50mmol) were stirred overnight at 120°C under a nitrogen atmosphere.
  • N-(2-Bromo-4-methoxy-3-methylphenyl)cyclopropanecarboxamide (17c) was dissolved in DMF (100 mL) and Cs 2 CO 3 (11.9 g, 36.6mmol), CuI (340mg, 1.83mmol), bipyridine (570mg, 3.66mmol), and stirred overnight at 120°C under a nitrogen atmosphere.
  • N-(2-Bromo-4-methoxy-3-methylphenyl)pivalamide (19a) (1.00 g, 3.30 mmol) was dissolved in DMF (10 mL), Cs 2 CO 3 (2.18 g , 6.68mmol), CuI (30.0mg, 0.165mmol), bipyridine (50.0mg, 0.330mmol), and stirred overnight at 120°C under a nitrogen atmosphere.
  • N-(2-bromo-4-methoxyphenyl)cyclopropanethioamide (20a) (5.40 g, 18.9 mmol) was dissolved in DMF (60 mL), Cs 2 CO 3 (12.4 g, 37.9 mmol) was added ), CuI (180mg, 0.945mmol), bipyridine (295mg, 1.89mmol), and stirred overnight at 25°C under a nitrogen atmosphere.
  • N-(2-bromo-5-methoxyphenyl)cyclopropanethioamide (21a) (5.40 g, 18.9 mmol) was dissolved in DMF (60 mL), Cs 2 CO 3 (12.4 g, 37.9 mmol) was added ), CuI (180mg, 0.945mmol), bipyridine (295mg, 1.89mmol), and stirred overnight at 25°C under a nitrogen atmosphere.
  • Step 1 (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4' ,5':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyridine
  • ethyl azole-3-carboxylate 22a
  • Step 2 (S)-7-(3-Chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepine-6(5H)-one (22)
  • Step 1 (S)-5-Chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5' ,4':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyridine
  • azole-3-carboxylic acid ethyl ester (23a)
  • Step 2 (S)-7-(3-Chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepin-8(9H)-one (23)
  • Step 5 Preparation of ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate (24e)
  • Step 6 (E)-Ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (24f ) preparation
  • Step 7 Preparation of ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (24 g)
  • Step 8 (S)-5-Chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4' ,5':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)- Preparation of ethyl 1H-pyrazole-3-carboxylate (24h)
  • Step 9 (S)-7-(3-Chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-6(5H)-one (24)
  • Step 1 Preparation of ethyl 1-(4-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (25a)
  • Step 2 Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate (25b)
  • Step 3 Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (25c)
  • Step 4 Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (25d)
  • Step 5 (S)-5-Chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4' ,5':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyridine
  • azole-3-carboxylic acid ethyl ester 25e
  • Step 6 (S)-7-(3-Chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepine-6(5H)-one (25)
  • Step 4 Preparation of N-(tert-butoxycarbonyl)-S-(1-methyl-5-nitro-1H-indol-6-yl)-L-cysteine (26d)
  • 6-Fluoro-1-methyl-5-nitro-1H-indole (250mg, 1.28mmol) was dissolved in DMF (10mL), and Cs 2 CO 3 (2.50g, 7.73mmol) was added at 0°C ), (tert-butoxycarbonyl)-L-cysteine (849mg, 3.84mmol), stirred at 80°C for 12 hours.
  • Step 5 Preparation of (S)-(5-amino-1-methyl-1H-indol-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine (26e)
  • N-(tert-butoxycarbonyl)-S-(1-methyl-5-nitro-1H-indol-6-yl)-L-cysteine (26d) (450mg, 9.03mmol ) was dissolved in 10 mL of methanol, and aqueous Pd/C (100 mg) was added to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Filter through celite, add MeOH to wash the filter cake, and concentrate the filtrate under reduced pressure to obtain 460 mg of the title compound (crude product) as a yellow oil.
  • Step 7 Preparation of O-(5-nitrobenzofuran-6-yl)-N-triphenyl-L-serine methyl ester (27 g)
  • Step 1 Preparation of N-(tert-butoxycarbonyl)-S-(5-nitrobenzofuran-6-yl)-L-cysteine (28a)
  • Step 2 Preparation of (S)-(5-aminobenzofuran-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine (28b)
  • step 9 is replaced by S-(5-aminobenzofuran-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine (28b) O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i) in (7i), the title compound 28 was prepared.
  • Step 1 (S)-5-Chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5' ,4':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)- Preparation of ethyl 1H-pyrazole-3-carboxylate (29a)
  • Step 2 (S)-7-(3-Chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-8(9H)-one (29)
  • Step 1 (S)-5-Chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5' ,4':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyridine
  • azole-3-carboxylic acid ethyl ester (30a)
  • Step 2 (S)-7-(3-Chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepin-8(9H)-one (30)
  • 6-Fluoro-5-nitro-1H-indole (26b) (2.00g, 10.6mmol) was dissolved in THF (30mL), NaH (630mg, 15.7mmol) was added at 0°C, under nitrogen atmosphere, at 0 °C was stirred for 0.5 hours, and SEM-Cl (2.12 g, 12.8 mmol) was added dropwise to the reaction solution at 0 °C.
  • Test example 1 Analysis of the activity of the compound of the present invention to inhibit U937 cell necrosis in vitro
  • Activation of receptor-interacting protein kinase 1 can induce necrosis of human monocytic leukemia U937 cells, therefore, human monocytic leukemia U937 cells (CBP60277, CoBioer) were used to test the present invention through in vitro cell necrosis assays compound activity.

Abstract

An azepine-type fused ring compound and a pharmaceutical use thereof. Specifically, involved are an azepine-type fused ring compound shown in general formula (I), a preparation method therefor, a pharmaceutical composition comprising same, and a use thereof as a receptor-interacting protein kinase 1 (RIP1) inhibitor in treatment of diseases associated with RIP1 activity. The definition of each substituent in general formula (I) is the same as the definition in the description.

Description

氮杂卓类稠环化合物及其医药用途Azapine fused ring compounds and their medicinal uses 技术领域technical field
本发明涉及氮杂卓类稠环化合物及其医药用途。具体地，本发明涉及通式(I)所示的氮杂卓类稠环化合物，其制备方法，含有其的药物组合物，以及其作为受体相互作用蛋白激酶1(RIP1)抑制剂，用于治疗与RIP1活性相关的疾病的用途。The invention relates to azapine condensed ring compounds and their medical application. Specifically, the present invention relates to an azepine fused ring compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing it, and as a receptor-interacting protein kinase 1 (RIP1) inhibitor, used Use for treating diseases associated with RIP1 activity.
背景技术Background technique
凋亡和坏死是细胞死亡的2种方式。环境因素引起的被动性细胞死亡、细胞坏死在炎症反应等病理和生理过程中发挥重要作用。RIP1处于多条炎症和细胞死亡相关信号通路交互点，参与调节TNF激活的NF-κB、凋亡、坏死等多条下游信号通路。Apoptosis and necrosis are two ways of cell death. Passive cell death and necrosis caused by environmental factors play an important role in pathological and physiological processes such as inflammation. RIP1 is at the interaction point of multiple inflammation and cell death-related signaling pathways, and participates in the regulation of TNF-activated NF-κB, apoptosis, necrosis and other downstream signaling pathways.
RIP1可通过介导NF-κB通路促进炎症反应，但值得注意的是，NF-κB通路的激活以及TNF诱导的细胞凋亡不需要RIP1的激酶活性，RIP1激酶抑制对TNF诱导的NF-κB通路激活没有影响。但是，RIP1的激酶活性也可通过细胞坏死、炎症小体、TNF产生等多条途径促进炎症的发生发展。RIP1 can promote inflammatory response by mediating the NF-κB pathway, but it is worth noting that the activation of the NF-κB pathway and TNF-induced apoptosis do not require the kinase activity of RIP1, and RIP1 kinase inhibition has no effect on the TNF-induced NF-κB pathway Activation has no effect. However, the kinase activity of RIP1 can also promote the occurrence and development of inflammation through multiple pathways such as cell necrosis, inflammasome, and TNF production.
RIP1激酶介导的细胞坏死与炎症：发生凋亡的细胞可在细胞膜未破裂时就被机体快速清除，而坏死细胞清除较慢，细胞膜破裂后，细胞质内大量的危险内容物释放，并被机体视为病原体样物质，激活众多模式识别受体，严重增强炎症反应。细胞坏死也被认为是相关炎症疾病快速发展并发生严重症状的重要因素。Cell necrosis and inflammation mediated by RIP1 kinase: Apoptotic cells can be quickly cleared by the body when the cell membrane is not broken, while necrotic cells are cleared slowly. Treated as a pathogen-like substance, it activates numerous pattern recognition receptors and severely enhances the inflammatory response. Cell necrosis is also considered an important factor in the rapid development and severe symptoms of related inflammatory diseases.
RIP1激酶与炎症小体：同TNF-α一样，IL-1β也是关键的促炎症因子。例如，在RA的发生发展过程中，IL-1β通过作用于滑膜成纤维细胞和软骨细胞而加重软骨、骨组织以及关节周围软组织的破坏。IL-1β分泌需要2条通路协助：首先，TLR4和TNF等通路促IL-1β/IL-18前体表达；随后，形成的NLPR3等炎症小体平台促IL-1β/IL-18前体成熟。炎症小体与RA、银屑病等自身免疫性疾病的发生发展密切相关。炎症小体的活化依赖于RIP1和RIP3及其激酶活性。RIP1和RIP3可扩大IL-1β的表达，且该过程非依赖于细胞坏死。RIP1 Kinase and Inflammasome: Like TNF-α, IL-1β is also a key pro-inflammatory factor. For example, during the development of RA, IL-1β acts on synovial fibroblasts and chondrocytes to aggravate the destruction of cartilage, bone tissue, and soft tissue around the joint. IL-1β secretion requires the assistance of two pathways: first, pathways such as TLR4 and TNF promote the expression of IL-1β/IL-18 precursors; secondly, the formed NLPR3 and other inflammasome platforms promote the maturation of IL-1β/IL-18 precursors . The inflammasome is closely related to the occurrence and development of autoimmune diseases such as RA and psoriasis. Activation of the inflammasome depends on RIP1 and RIP3 and their kinase activity. RIP1 and RIP3 can amplify the expression of IL-1β, and this process is independent of necrosis.
RIP1激酶依赖性介导IL-1α产生：蛋白酪氨酸磷酸酶SHP-1在免疫信号通路中扮演重要角色，SHP-1突变小鼠产生大量炎症因子伴随关节炎等炎症疾病，但机制未知。特定SHP-1突变小鼠可自发严重炎症，症状与人嗜中性皮肤病相似。在该模型中，RIP1激酶依赖促IL-1α产生，后者可介导和扩大炎症以及组织损伤，这些都非依赖于炎症小体、IL-1β和RIP3。RIP1激酶抑制可防止相关炎症和损伤的发生，NF-κB和ERK抑制可缓解RIP1介导的炎症因子产生。因此，SHP-1突变小鼠的炎症及组织损伤依赖RIP1激酶介导的IL-1α产生，机制与RIP1激酶调控NF-κB和ERK通路有关。RIP1 kinase-dependent mediation of IL-1α production: protein tyrosine phosphatase SHP-1 plays an important role in immune signaling pathways, and SHP-1 mutant mice produce a large number of inflammatory factors associated with inflammatory diseases such as arthritis, but the mechanism is unknown. Certain SHP-1 mutant mice develop spontaneous severe inflammation with symptoms similar to human neutrophilic dermatosis. In this model, RIP1 kinase is dependent on the production of IL-1α, which mediates and amplifies inflammation and tissue damage, independent of the inflammasome, IL-1β, and RIP3. Inhibition of RIP1 kinase can prevent the occurrence of related inflammation and injury, and inhibition of NF-κB and ERK can alleviate the production of inflammatory factors mediated by RIP1. Therefore, the inflammation and tissue damage in SHP-1 mutant mice depend on the production of IL-1α mediated by RIP1 kinase, and the mechanism is related to the regulation of NF-κB and ERK pathways by RIP1 kinase.
RIP1激酶依赖性介导TNFα产生：cIAP可通过泛素化抑制RIP1活性，而Smac 等cIAP抑制剂可诱导TNFα产生和细胞死亡，但机制未知。TNFα抑制可防止半胱天冬酶抑制诱导的细胞死亡，说明半胱天冬酶e抑制可能诱导TNFα的产生。RIP1激酶抑制可防止半胱天冬酶抑制诱导的细胞死亡，因此，在半胱天冬酶抑制的情况下，RIP1可能作为TNFα产生的上游机制。近年研究表明，RIP1激酶可与EDD相互作用诱导JNK通路激活和TNFα产生，该通路特异性对应半胱天冬酶抑制，说明RIP1激酶活性不仅调控TNFR1下游的细胞坏死，而且在介导TNFα产生方面扮演重要角色。RIP1 kinase-dependent mediation of TNFα production: cIAP can inhibit RIP1 activity through ubiquitination, and cIAP inhibitors such as Smac can induce TNFα production and cell death, but the mechanism is unknown. TNFα inhibition prevents cell death induced by caspase inhibition, suggesting that caspase e inhibition may induce TNFα production. RIP1 kinase inhibition prevents cell death induced by caspase inhibition, therefore, RIP1 may act as an upstream mechanism of TNFα production in the context of caspase inhibition. Recent studies have shown that RIP1 kinase can interact with EDD to induce JNK pathway activation and TNFα production, which specifically corresponds to caspase inhibition, indicating that RIP1 kinase activity not only regulates cell necrosis downstream of TNFR1, but also mediates TNFα production. play an important role.
近年来，一些基因学证据(例如RIP1激酶失活突变)以及RIP1激酶抑制剂工具分子(例如Nec-1)的相关研究进一步证实RIP1激酶在一些炎症及多种组织损伤疾病的发生发展中扮演重要角色。RIP1激酶失活突变可完全防止多器官炎症表型，特别是皮肤炎症；RIP1激酶抑制可防止肾移植动物模型因缺血-再灌注导致的肾损伤；RIP1激酶抑制剂Nec-1防止心梗和心脏缺氧；RIP1激酶抑制剂Nec-1防止视锥细胞死亡，dsRNA导致的视网膜变性，以及色素性视网膜炎。In recent years, some genetic evidence (such as RIP1 kinase inactivating mutations) and research on RIP1 kinase inhibitor tool molecules (such as Nec-1) have further confirmed that RIP1 kinase plays an important role in the occurrence and development of some inflammatory and various tissue damage diseases. Role. RIP1 kinase inactivating mutations completely protect against multiorgan inflammatory phenotypes, especially skin inflammation; RIP1 kinase inhibition protects against ischemia-reperfusion-induced kidney injury in animal models of kidney transplantation; RIP1 kinase inhibitor Nec-1 prevents myocardial infarction and Cardiac hypoxia; RIP1 kinase inhibitor Nec-1 prevents cone cell death, dsRNA-induced retinal degeneration, and retinitis pigmentosa.
RIP1缺失导致动物死亡，与RIP1缺失不同，RIP1激酶失活突变小鼠可以正常存活，且抵抗坏死刺激，因此，RIP1缺失导致的死亡与激酶活性无关。Ripk1D138N/D138N和RipkK45A/K45A激酶失活突变小鼠没有明显改变的表型，说明RIP1激酶活性是相对比较安全的靶点。相比之下，RIP3激酶失活突变小鼠体重下降较快，且发生死亡。Loss of RIP1 causes animal death. Unlike RIP1 loss, RIP1 kinase-inactive mutant mice survive normally and are resistant to necrotic stimuli. Therefore, death caused by RIP1 loss is not related to kinase activity. Ripk1D138N/D138N and RipkK45A/K45A kinase inactivation mutant mice did not have significantly altered phenotypes, indicating that RIP1 kinase activity is a relatively safe target. In contrast, RIP3 kinase-inactive mutant mice lost weight faster and died.
鉴于RIP1激酶在炎症发生发展中扮演的重要角色，RIP1激酶抑制剂用于炎症疾病治疗受到全球领先药企的一定关注。其中，GSK代表化合物GSK2982772已开始临床II期研究；Roche也有分子处于临床前研究阶段。但至今尚无RIP1激酶抑制剂上市，研发人员还需要开发更多的RIP1激酶抑制剂分子，以便选择更好的化合物用于相关疾病及炎症的治疗。In view of the important role played by RIP1 kinase in the occurrence and development of inflammation, the use of RIP1 kinase inhibitors in the treatment of inflammatory diseases has attracted some attention from the world's leading pharmaceutical companies. Among them, GSK's representative compound GSK2982772 has begun clinical phase II research; Roche also has molecules in the preclinical research stage. However, there is no RIP1 kinase inhibitor on the market so far, and researchers still need to develop more RIP1 kinase inhibitor molecules in order to select better compounds for the treatment of related diseases and inflammation.
发明内容Contents of the invention
本发明人经过潜心研究，设计合成了一系列氮杂卓类稠环化合物，其显示出受体相互作用蛋白激酶1(RIP1)的抑制活性，可以被开发为预防或治疗与RIP1活性相关的疾病的药物。After painstaking research, the inventors designed and synthesized a series of azapine fused ring compounds, which exhibit inhibitory activity of receptor-interacting protein kinase 1 (RIP1), and can be developed to prevent or treat diseases related to RIP1 activity medicine.
因此，本发明的目的是提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt,
Figure PCTCN2022092607-appb-000001
Figure PCTCN2022092607-appb-000001
其中，in,
X选自-O-、-S(O) m-、-NR a-、-CR’R”-； X is selected from -O-, -S(O) m -, -NR a -, -CR'R"-;
Y 1和Y 2各自独立地选自O或S； Y1 and Y2 are each independently selected from O or S;
Z 1和Z 2各自独立地选自C或N原子； Z 1 and Z 2 are each independently selected from C or N atoms;
L选自单键、-O-、-S(O) m-、-NR a-、-(CR aR b) n-、-(CR aR b) nO-、-(CR aR b) nS-和-(CR aR b) nNR a-； L is selected from single bond, -O-, -S(O) m -, -NR a -, -(CR a R b ) n -, -(CR a R b ) n O-, -(CR a R b ) n S- and -(CR a R b ) n NR a -;
环A选自芳基、杂芳基、环烷基和杂环基，其中所述芳基、杂芳基、环烷基和杂环烷基任选进一步被一个或多个R 9取代； Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally further substituted by one or more R9 ;
环B为芳环或芳杂环，其任选进一步被一个或多个R 8取代； Ring B is an aromatic ring or an aromatic heterocyclic ring, which is optionally further substituted by one or more R 8 ;
环C为含氮杂环，其任选进一步被一个或多个R 7取代； Ring C is a nitrogen-containing heterocycle, which is optionally further substituted by one or more R 7 ;
R 1和R 2与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基，或者R 2和R 3与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基，或者R 3和R 4与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基，其中所述5元杂芳基、5元杂环基或5元环烷基任选进一步被一个或多个R 6取代； R 1 and R 2 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group together with the atoms they are connected to, or R 2 and R 3 form a 5-membered heteroaryl group, a 5-membered heteroaryl group, or a 5-membered cycloalkyl group together with their connected atoms A heterocyclic group or a 5-membered cycloalkyl group, or R 3 and R 4 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group with the atoms they are connected to, wherein the 5-membered heteroaryl group , 5-membered heterocyclyl or 5-membered cycloalkyl are optionally further substituted by one or more R 6 ;
其中：in:
当R 1和R 2与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基时，R 3和R 4各自独立地选自R 6；或者 When R 1 and R 2 form 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl together with their attached atoms, R 3 and R 4 are each independently selected from R 6 ; or
当R 2和R 3与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基时，R 1和R 4各自独立地选自R 6；或者 When R 2 and R 3 form 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl together with the atoms they are connected to, R 1 and R 4 are each independently selected from R 6 ; or
当R 3和R 4与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基时，R 1和R 2各自独立地选自R 6； When R 3 and R 4 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group together with their connected atoms, R 1 and R 2 are each independently selected from R 6 ;
R 5选自氢、烷基、卤代烷基、环烷基和卤代环烷基； R is selected from hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl ;
每个R 6各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2，其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 , wherein the alkyl, alkoxy, ring Alkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy One or more groups of radical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted;
每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、 -C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted;
每个R 9各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted;
R’和R”各自独立地选自氢、卤素、烷基、卤代烷基；R' and R" are each independently selected from hydrogen, halogen, alkyl, haloalkyl;
R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m为0、1或2；m is 0, 1 or 2;
n为0至3的整数。n is an integer of 0 to 3.
在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In a preferred embodiment, the compound represented by general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereoisomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022092607-appb-000002
Figure PCTCN2022092607-appb-000002
其中，in,
环D选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2的一个或多个基团取代； Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m One or more groups of R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 are substituted;
R 1和R 2各自独立地选自氢、卤素、烷基； R 1 and R 2 are each independently selected from hydrogen, halogen, alkyl;
R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, Ester group, oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group substitution by one or more groups;
或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m为0、1或2；m is 0, 1 or 2;
X、Y 1、Y 2、Z 1、Z 2、L、环A、环B、环C、R 5如通式(I)所定义。 X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in general formula (I).
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, it is a compound represented by general formula (III) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022092607-appb-000003
Figure PCTCN2022092607-appb-000003
其中，in,
环E选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2的一个或多个基团取代； Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m One or more groups of R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 are substituted;
R 1和R 4各自独立地选自氢、卤素、烷基； R 1 and R 4 are each independently selected from hydrogen, halogen, alkyl;
R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m为0、1或2；m is 0, 1 or 2;
X、Y 1、Y 2、Z 1、Z 2、L、环A、环B、环C、R 5如通式(I)所定义。 X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in general formula (I).
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or Its mixture form, or its pharmaceutically acceptable salt, it is the compound represented by general formula (IV), or its mesoform, racemate, enantiomer, diastereoisomer, or in the form of a mixture, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022092607-appb-000004
Figure PCTCN2022092607-appb-000004
其中：in:
环F选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2的一个或多个基团取代； Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m One or more groups of R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 are substituted;
R 3和R 4各自独立地选自氢、卤素、烷基； R 3 and R 4 are each independently selected from hydrogen, halogen, alkyl;
R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m为0、1或2；m is 0, 1 or 2;
X、Y 1、Y 2、Z 1、Z 2、L、环A、环B、环C、R 5如通式(I)所定义。 X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in general formula (I).
在一个优选的实施方案中，根据通式(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In a preferred embodiment, according to the compound represented by general formula (II), (III) and (IV) or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R a和R b各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基，其中所述烷基、烯基、炔基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R a and R b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally Further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups are substituted;
或者R a和R b与他们连接的原子一起形成5-7元含氮杂环基，所述5-7元含氮 杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Or R a and R b form a 5-7 membered nitrogen-containing heterocyclic group together with the atoms they are connected to, and the 5-7 membered nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, One or more groups of oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，X为-O-或-S-。In another preferred embodiment, according to the compounds represented by the general formula (I), (II), (III) and (IV) of the present invention or their mesomers, racemates, enantiomers Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein X is -O- or -S-.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环C为5至8元含氮杂环，优选哌啶环、四氢吡咯环、哌嗪环、二氢吡咯环、四氢吡啶环或高哌嗪环，更优选哌啶环，其任选进一步被一个或多个R 7取代； In another preferred embodiment, according to the compounds represented by the general formula (I), (II), (III) and (IV) of the present invention or their mesomers, racemates, enantiomers Isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring C is a 5- to 8-membered nitrogen-containing heterocycle, preferably piperidine ring, tetrahydropyrrole ring, piperazine ring , dihydropyrrole ring, tetrahydropyridine ring or homopiperazine ring, more preferably piperidine ring, which is optionally further substituted by one or more R 7 ;
每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted;
其中：in:
R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R a and R b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cyclic One or more groups of alkyl, heterocyclyl, aryl, heteroaryl are substituted;
或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m为0、1或2。m is 0, 1 or 2.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R 8取代； In another preferred embodiment, according to the compounds represented by the general formula (I), (II), (III) and (IV) of the present invention or their mesomers, racemates, enantiomers Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocycle, preferably a benzene ring, a pyridine ring, Pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring , more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further substituted by one or more R 8 ;
每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、 炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R 8为卤素； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted; preferably R 8 is halogen;
其中：in:
R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R a and R b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cyclic One or more groups of alkyl, heterocyclyl, aryl, heteroaryl are substituted;
或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m为0、1或2。m is 0, 1 or 2.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another preferred embodiment, according to the compounds represented by the general formula (I), (II), (III) and (IV) of the present invention or their mesomers, racemates, enantiomers isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein,
Figure PCTCN2022092607-appb-000005
选自：
Figure PCTCN2022092607-appb-000005
selected from:
Figure PCTCN2022092607-appb-000006
Figure PCTCN2022092607-appb-000006
其中，in,
Y 2选自O或S； Y2 is selected from O or S;
Z 1和Z 2各自独立地选自C或N原子； Z 1 and Z 2 are each independently selected from C or N atoms;
环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R 8取代； Ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, Thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further replaced by one or more R 8 replace;
每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基；或者两个相邻的R 7与他们连接的原子一起形成杂环基或环烷基，其中所述烷基、烷氧基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R 7为氢； Each R 7 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy; or two adjacent R 7 are together with the atoms to which they are attached Form heterocyclyl or cycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, One or more groups of carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted; preferably R 7 is hydrogen;
每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基；其中所述烷基、烷氧基、环烷 基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；p为0、1、2、3或4，优选0。 Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; p is 0, 1, 2, 3 or 4, preferably 0.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another preferred embodiment, according to the compounds represented by the general formula (I), (II), (III) and (IV) of the present invention or their mesomers, racemates, enantiomers isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein,
Figure PCTCN2022092607-appb-000007
选自：
Figure PCTCN2022092607-appb-000007
selected from:
Figure PCTCN2022092607-appb-000008
Figure PCTCN2022092607-appb-000009
优选
Figure PCTCN2022092607-appb-000010
Figure PCTCN2022092607-appb-000008
Figure PCTCN2022092607-appb-000009
preferred
Figure PCTCN2022092607-appb-000010
其中，in,
Y 2选自O或S； Y2 is selected from O or S;
每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R 8为卤素； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups; preferably R is halogen;
q为0、1或2。q is 0, 1 or 2.
在一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IA)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In a specific embodiment, the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IA) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022092607-appb-000011
Figure PCTCN2022092607-appb-000011
X、Y 1、Y 2、L、环A、R 1、R 2、R 3、R 4、R 5、R 8如通式(I)所定义。 X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined in general formula (I).
在另一个优选的实施方案中，根据本发明所述的通式(I)、(IA)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y 2为O。 In another preferred embodiment, according to the compounds represented by the general formulas (I), (IA), (II), (III) and (IV) of the present invention or their mesomers, racemic isomers, enantiomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y 2 is O.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(IA)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y 1为O。 In another preferred embodiment, according to the compounds represented by the general formulas (I), (IA), (II), (III) and (IV) of the present invention or their mesomers, racemic isomers, enantiomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y 1 is O.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(IA)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, according to the compounds represented by the general formulas (I), (IA), (II), (III) and (IV) of the present invention or their mesomers, racemic isomers, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
其中，in,
环A选自芳基和杂芳基，优选苯基，其中所述芳基或杂芳基任选进一步被一个或多个R 9取代， Ring A is selected from aryl and heteroaryl, preferably phenyl, wherein said aryl or heteroaryl is optionally further substituted by one or more R 9 ,
每个R 9各自独立地选自氢、卤素、氰基、羟基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基，优选氢、卤素、烷基和烷氧基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Each R is independently selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, alkane and alkoxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, One or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted.
在另一个优选的实施方案中，根据本发明所述的通式(I)、(IA)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, according to the compounds represented by the general formulas (I), (IA), (II), (III) and (IV) of the present invention or their mesomers, racemic isomers, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
其中，其中，L选自-NR a-和-(CR aR b) n-，优选-(CR aR b) n-； Wherein, L is selected from -NR a - and -(CR a R b ) n -, preferably -(CR a R b ) n -;
R a和R b各自独立地选自氢和C 1-6烷基； R a and R b are each independently selected from hydrogen and C 1-6 alkyl;
n为0至3的整数，优选1；n is an integer from 0 to 3, preferably 1;
L更优选-CH 2-； L is more preferably -CH 2 -;
在另一个优选的实施方案中，根据本发明所述的通式(I)、(IA)、(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R 5选自氢、C 1-6烷基和卤代C 1-6烷基，优选氢和C 1-6烷基。 In another preferred embodiment, according to the compounds represented by the general formulas (I), (IA), (II), (III) and (IV) of the present invention or their mesomers, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is selected from hydrogen, C 1-6 alkyl and halogenated C 1-6 alkyl , preferably hydrogen and C 1-6 alkyl.
在本发明一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In a specific embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022092607-appb-000012
Figure PCTCN2022092607-appb-000012
其中，in,
X为-O-或-S-；X is -O- or -S-;
环D选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、-C(O)OR a的一个或多个基团取代； Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
R 1和R 2各自独立地选自氢、卤素、C 1-C 6烷基； R 1 and R 2 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl;
R 5选自氢和C 1-C 6烷基； R 5 is selected from hydrogen and C 1 -C 6 alkyl;
R 8选自氢和卤素； R is selected from hydrogen and halogen;
R 9选自氢和卤素； R9 is selected from hydrogen and halogen;
R a选自C 1-C 6烷基； R a is selected from C 1 -C 6 alkyl;
p为0、1或2。p is 0, 1 or 2.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another specific embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III-1) or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022092607-appb-000013
Figure PCTCN2022092607-appb-000013
其中，in,
X为-O-或-S-；X is -O- or -S-;
环E选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、-C(O)OR a的一个或多个基团取代； Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
R 1和R 4各自独立地选自氢、卤素、C 1-C 6烷基； R 1 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl;
R 5选自氢和C 1-C 6烷基； R 5 is selected from hydrogen and C 1 -C 6 alkyl;
R 8选自氢和卤素； R is selected from hydrogen and halogen;
R 9选自氢和卤素； R9 is selected from hydrogen and halogen;
R a选自C 1-C 6烷基； R a is selected from C 1 -C 6 alkyl;
p为0、1或2。p is 0, 1 or 2.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another specific embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV-1) or its mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022092607-appb-000014
Figure PCTCN2022092607-appb-000014
其中，in,
X为-O-或-S-；X is -O- or -S-;
环F选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、-C(O)OR a的一个或多个基团取代； Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
R 3和R 4各自独立地选自氢、卤素、C 1-C 6烷基； R 3 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl;
R 5选自氢和C 1-C 6烷基； R 5 is selected from hydrogen and C 1 -C 6 alkyl;
R 8选自氢和卤素； R is selected from hydrogen and halogen;
R 9选自氢和卤素； R9 is selected from hydrogen and halogen;
R a选自C 1-C 6烷基； R a is selected from C 1 -C 6 alkyl;
p为0、1或2。p is 0, 1 or 2.
本发明的典型化合物，包括但不限于：Typical compounds of the invention include, but are not limited to:
Figure PCTCN2022092607-appb-000015
Figure PCTCN2022092607-appb-000015
Figure PCTCN2022092607-appb-000016
Figure PCTCN2022092607-appb-000016
Figure PCTCN2022092607-appb-000017
Figure PCTCN2022092607-appb-000017
Figure PCTCN2022092607-appb-000018
Figure PCTCN2022092607-appb-000018
Figure PCTCN2022092607-appb-000019
Figure PCTCN2022092607-appb-000019
Figure PCTCN2022092607-appb-000020
Figure PCTCN2022092607-appb-000020
Figure PCTCN2022092607-appb-000021
Figure PCTCN2022092607-appb-000021
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。or a mesoform, a racemate, an enantiomer, a diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
本发明进一步提供一种根据本发明所述的通式(IA)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further provides a compound represented by the general formula (IA) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2022092607-appb-000022
Figure PCTCN2022092607-appb-000022
在催化剂的存在下，将化合物IA-I发生分子内关环反应得到通式(IA)化合物，所述催化剂优选三甲基铝；In the presence of a catalyst, the compound IA-I undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (IA), and the catalyst is preferably trimethylaluminum;
其中，X、Y 1、Y 2、L、环A、R 1、R 2、R 3、R 4、R 5、R 8如通式(IA)所定义。 Wherein, X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined in general formula (IA).
本发明进一步提供一种根据本发明所述的通式(II-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further provides a compound represented by general formula (II-1) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or its The preparation method of mixture form or its pharmaceutically acceptable salt, it comprises the following steps:
Figure PCTCN2022092607-appb-000023
Figure PCTCN2022092607-appb-000023
在催化剂的存在下，将化合物II-1a发生分子内关环反应得到通式(II-1)化合物，所述催化剂优选三甲基铝；In the presence of a catalyst, the compound II-1a undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (II-1), and the catalyst is preferably trimethylaluminum;
其中，X、环D、R 1、R 2、R 5、R 8、R 9、p如通式(II-1)所定义。 Wherein, X, ring D, R 1 , R 2 , R 5 , R 8 , R 9 , and p are as defined in general formula (II-1).
本发明进一步提供一种根据本发明所述的通式(III-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further provides a compound represented by general formula (III-1) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or its The preparation method of mixture form or its pharmaceutically acceptable salt, it comprises the following steps:
Figure PCTCN2022092607-appb-000024
Figure PCTCN2022092607-appb-000024
在催化剂的存在下，将化合物III-1a发生分子内关环反应得到通式(III-1)化合物，所述催化剂优选三甲基铝；In the presence of a catalyst, the compound III-1a undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (III-1), and the catalyst is preferably trimethylaluminum;
其中，X、环E、R 1、R 4、R 5、R 8、R 9、p如通式(III-1)所定义。 Wherein, X, ring E, R 1 , R 4 , R 5 , R 8 , R 9 , and p are as defined in general formula (III-1).
本发明进一步提供一种根据本发明所述的通式(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further provides a compound represented by the general formula (IV-1) according to the present invention or its mesoform, racemate, enantiomer, diastereoisomer, or its The preparation method of mixture form or its pharmaceutically acceptable salt, it comprises the following steps:
Figure PCTCN2022092607-appb-000025
Figure PCTCN2022092607-appb-000025
在催化剂的存在下，将化合物IV-1a发生分子内关环反应得到通式(IV-1)化合物，所述催化剂优选三甲基铝；In the presence of a catalyst, the compound IV-1a undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (IV-1), and the catalyst is preferably trimethylaluminum;
其中，X、环F、R 3、R 4、R 5、R 8、R 9、p如通式(IV-1)所定义。 Wherein, X, ring F, R 3 , R 4 , R 5 , R 8 , R 9 , and p are as defined in general formula (IV-1).
本发明进一步提供一种药物组合物，其包含根据本发明所述的通式(I)、(IA)、 (II)、(III)、(IV)、(II-1)、(III-1)或(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体或赋形剂。The present invention further provides a pharmaceutical composition, which comprises the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) according to the present invention ) or a compound represented by (IV-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable carrier or excipient.
本发明进一步涉及根据本发明所述的通式(I)、(IA)、(II)、(III)、(IV)、(II-1)、(III-1)或(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物在制备受体相互作用蛋白激酶1(RIP1)抑制剂中的用途。The present invention further relates to the compound of general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention The indicated compound or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of receptor Use in inhibitors of interacting protein kinase 1 (RIP1).
本发明进一步涉及根据本发明所述的通式(I)、(IA)、(II)、(III)、(IV)、(II-1)、(III-1)或(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物在制备预防或治疗与受体相互作用蛋白激酶1活性相关的疾病的药物中的用途，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The present invention further relates to the compound of general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention The indicated compound or its mesomer, racemate, enantiomer, diastereoisomer, or its mixture form, or its pharmaceutically acceptable salt or the pharmaceutical composition containing it in the preparation of prophylaxis or Use in medicine for the treatment of diseases associated with receptor-interacting protein kinase 1 activity, preferably inflammatory diseases, autoimmune diseases or neurological diseases, said inflammatory diseases and autoimmune diseases such as rheumatoid arthritis , ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic erythema Lupus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, Nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, allergic disease, asthma, atopic skin disease, multiple sclerosis, type 1 diabetes mellitus, orbital necrotizing granulomatous disease, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, pulmonary chronic obstructive disease, tumor necrosis factor receptor-associated syndrome, or dental periarthritis; said neurological disease such as Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.
本发明进一步涉及一种根据本发明所述的通式(I)、(IA)、(II)、(III)、(IV)、(II-1)、(III-1)或(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物，其用作受体相互作用蛋白激酶1(RIP1)抑制剂。The present invention further relates to a general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention ) or its mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, which Used as a receptor-interacting protein kinase 1 (RIP1) inhibitor.
本发明进一步涉及一种根据本发明所述的通式(I)、(IA)、(II)、(III)、(IV)、(II-1)、(III-1)或(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物，其用于预防或治疗与受体相互作用蛋白激酶1活性相关的疾病，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺 血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The present invention further relates to a general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention ) or its mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, which For the prevention or treatment of diseases associated with the activity of receptor-interacting protein kinase 1, said diseases are preferably inflammatory diseases, autoimmune diseases or neurological diseases, said inflammatory diseases and autoimmune diseases such as rheumatoid arthritis, Ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus , Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis , celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, allergic disease, asthma, atopic skin disease, multiple sclerosis , type 1 diabetes mellitus, orbital necrotizing granulomatous disease, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, pulmonary chronic obstructive disease, tumor necrosis factor receptor-associated syndrome, or periodontal disease inflammation; said neurological disease such as Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.
本发明进一步涉及一种抑制受体相互作用蛋白激酶1(RIP1)的方法，其包括向有需要的患者施用有效量的根据本发明所述的通式(I)、(IA)、(II)、(III)、(IV)、(II-1)、(III-1)或(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，或包含其的药物组合物。The present invention further relates to a method of inhibiting receptor-interacting protein kinase 1 (RIP1), which comprises administering an effective amount of the general formula (I), (IA), (II) according to the present invention to a patient in need , (III), (IV), (II-1), (III-1) or the compound represented by (IV-1) or its mesoform, racemate, enantiomer, diastereomer An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
本发明进一步涉及一种预防或治疗与受体相互作用蛋白激酶1活性相关的疾病的方法，其包括向有需要的患者施用预防或治疗有效量的根据本发明所述的通式(I)、(IA)、(II)、(III)、(IV)、(II-1)、(III-1)或(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，或包含其的药物组合物；其中，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The present invention further relates to a method for preventing or treating diseases related to the activity of receptor-interacting protein kinase 1, which comprises administering a preventive or therapeutically effective amount of the general formula (I), The compound represented by (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) or its mesoform, racemate, para Enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them; wherein the disease is preferably an inflammatory disease, an autoimmune disease or a nervous system disease, The inflammatory diseases and autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spinal Arthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis , autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, Allergic disease, asthma, atopic skin disease, multiple sclerosis, type 1 diabetes, orbital necrotizing granulomatous disease, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, pulmonary Chronic obstructive disease, tumor necrosis factor receptor-related syndrome, or periodontitis; such neurological disease as Huntington's disease, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis.
按照本发明所属领域的常规方法，本发明通式化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。According to conventional methods in the field to which the present invention belongs, the compound of the general formula of the present invention can form a pharmaceutically acceptable basic addition salt with a base. The base includes inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或***胶；和润滑剂，例 如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time. For example, water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used. Soft gelatin capsules provide an oral formulation.
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和***胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural The resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners. Flavoring agents such as sucrose, saccharin, or aspartame.
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将 注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated in a mixture of water and glycerol to form a microemulsion. The injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。The pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension 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 can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are prepared as injectables.
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of this invention may 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 will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、***的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。It is well known to those skilled in the art that the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc. In addition, the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
本发明可以含有通式化合物及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗与酪氨酸激酶活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。The present invention can contain the compound of the general formula and its pharmaceutically acceptable salt, hydrate or solvate as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
发明的详细说明Detailed Description of the Invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙 基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl ylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl 2,2-diethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, propynyl, butynyl and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. 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 monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2022092607-appb-000026
Figure PCTCN2022092607-appb-000026
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2022092607-appb-000027
Figure PCTCN2022092607-appb-000027
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2022092607-appb-000028
Figure PCTCN2022092607-appb-000028
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环 杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclyls include:
Figure PCTCN2022092607-appb-000029
Figure PCTCN2022092607-appb-000029
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring The atom is carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2022092607-appb-000030
Figure PCTCN2022092607-appb-000030
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond. A pi-electron system of a yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2022092607-appb-000031
Figure PCTCN2022092607-appb-000031
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
Figure PCTCN2022092607-appb-000032
等。
Figure PCTCN2022092607-appb-000032
Wait.
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2022092607-appb-000033
Figure PCTCN2022092607-appb-000033
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2022092607-appb-000034
Figure PCTCN2022092607-appb-000034
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷 氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
术语“羟基”指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代基”指＝O。The term "oxo" refers to =O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“巯基”指-SH。The term "mercapto" refers to -SH.
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。The term "acyl" refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
本发明化合物的合成方法The synthetic method of compound of the present invention
为了完成本发明的目的，本发明采用如下合成方案制备本发明的化合物。In order to accomplish the object of the present invention, the present invention adopts the following synthetic scheme to prepare the compound of the present invention.
根据以下方案1合成本发明的通式(IA)所示的化合物：The compound shown in the general formula (IA) of the present invention is synthesized according to the following scheme 1:
Figure PCTCN2022092607-appb-000035
Figure PCTCN2022092607-appb-000035
方案1plan 1
步骤1：在催化剂的存在下，将化合物IAa与化合物IAm反应得到化合物IAb，所述催化剂优选三苯基膦和DIAD，所述保护基优选Boc和Trt；Step 1: In the presence of a catalyst, compound IAa is reacted with compound IAm to obtain compound IAb, the catalyst is preferably triphenylphosphine and DIAD, and the protecting group is preferably Boc and Trt;
步骤2：在催化剂的存在下，将化合物IAb发生氢化反应得到化合物IAc，所述催化剂优选钯碳；Step 2: In the presence of a catalyst, compound IAb is hydrogenated to obtain compound IAc, the catalyst is preferably palladium carbon;
步骤3：在催化剂的存在下，将化合物IAc发生分子内关环反应得到化合物IAd，所述催化剂优选三甲基铝；Step 3: In the presence of a catalyst, the compound IAc undergoes an intramolecular ring-closing reaction to obtain the compound IAd, and the catalyst is preferably trimethylaluminum;
步骤4：在碱性条件下，将化合物IAd与R 5I反应得到化合物IAe，所述碱性条件优选碳酸铯； Step 4: under basic conditions, compound IAd is reacted with R 5 I to obtain compound IAe, and the basic conditions are preferably cesium carbonate;
步骤5：在酸性条件下，将化合物IAe发生脱保护基反应得到化合物IAf，所述酸性条件优选三氟乙酸；Step 5: Under acidic conditions, compound IAe is deprotected to obtain compound IAf, and the acidic conditions are preferably trifluoroacetic acid;
步骤6：在碱性条件下，将丁炔二酸二乙酯与肼类化合物IAg反应得到化合物 IAh，所述碱性条件优选碳酸钾；Step 6: under alkaline conditions, diethyl butynedioate is reacted with hydrazine compound IAg to obtain compound IAh, and the alkaline conditions are preferably potassium carbonate;
步骤7：在催化剂的存在下，将化合物IAh发生维尔斯迈尔-哈克反应并氯化得到化合物IAi，所述催化剂优选DMF和三氯氧磷；Step 7: In the presence of a catalyst, the compound IAh is subjected to the Vilsmeyer-Hacker reaction and chlorinated to obtain the compound IAi, the catalyst is preferably DMF and phosphorus oxychloride;
步骤8：在碱性条件下，将化合物IAi与wittig试剂反应得到化合物IAj，所述碱性条件优选叔丁醇钾；Step 8: under basic conditions, compound IAi is reacted with wittig reagent to obtain compound IAj, and the basic conditions are preferably potassium tert-butoxide;
步骤9：在酸性条件下，将化合物IAj发生水解反应得到化合物IAk，所述酸性条件优选盐酸；Step 9: Under acidic conditions, compound IAj is hydrolyzed to obtain compound IAk, and the acidic conditions are preferably hydrochloric acid;
步骤10：在催化剂条件下，将化合物IAk与化合物IAf发生还原氨化反应得到化合物IA-I，所述催化剂优选2-甲基吡啶硼烷复合物；Step 10: Reductive amination reaction of compound IAk and compound IAf under catalyst conditions to obtain compound IA-I, the catalyst is preferably 2-picoline borane complex;
步骤11：在催化剂的存在下，将化合物IA-I发生分子内关环反应得到通式(IA)化合物，所述催化剂优选三甲基铝；Step 11: In the presence of a catalyst, the compound IA-I undergoes an intramolecular ring closure reaction to obtain a compound of the general formula (IA), and the catalyst is preferably trimethylaluminum;
其中，R为氨基保护基，X、Y 1、Y 2、L、环A、R 1、R 2、R 3、R 4、R 5、R 8如通式(IA)所定义；优选地，X为-O-，Y 1、Y 2为O，L为-CH 2-。 Wherein, R is an amino protecting group, X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined in general formula (IA); preferably, X is -O-, Y 1 and Y 2 are O, and L is -CH 2 -.
具体实施方式Detailed ways
进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。The compounds of the invention and their preparation are further understood by the examples, which illustrate some of the methods of making or using the compounds. However, it is to be understood that these examples do not limit the invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.
本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。The compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures. The present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。In addition, some protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, "Protecting Groups in Organic Preparations" by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析、制备薄层板色谱、制备高效液相色谱或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。The separation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high-performance liquid chromatography or a combination of the above methods. For its specific usage method, please refer to the examples described in the present invention. Of course, other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps 300型核磁仪，测定溶 剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts are given in units of 10 -6 (ppm). The determination of NMR is a Brukerdps 300 type nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl sulfoxide. trimethylsilane (TMS).
MS的测定用LC(Waters 2695)/MS(Quattro Premier xE)质谱仪(生产商：沃特世)(Photodiode Array Detector)。MS was determined by LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
制备液相色谱法使用lc6000高效液相色谱仪(生产商：创新通恒)。色谱柱为DaisogelC18 10μm 100A(30mm×250mm)，流动相：乙腈/水。The lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography. Chromatographic column is DaisogelC18 10μm 100A (30mm×250mm), mobile phase: acetonitrile/water.
薄层色谱法(TLC)使用青岛海洋化工GF254硅胶板，反应监测用薄层色谱法使用的硅胶板采用的规格是0.20mm～0.25mm，分离纯化用薄层色谱法使用的硅胶板采用的规格是0.5mm。Thin-layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica gel plate, the specification of the silica gel plate used for reaction monitoring TLC is 0.20mm ~ 0.25mm, and the specification of silica gel plate used for separation and purification TLC It is 0.5mm.
硅胶柱层析色谱法使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。Silica gel column chromatography uses Qingdao ocean silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得等公司。The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
实施例中无特殊说明，反应能够均在氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
反应溶剂，有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括，如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、***、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。Reaction solvents, organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.
本发明中所描述的化学反应一般在常压下进行。反应温度在-78℃至200℃之间。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和三氟乙酸等碱性或酸性试剂进行调节。The eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent is according to the compound It can be adjusted according to the polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention.
实施例Example
实施例1：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1,3,9-三甲基-3,6,7,9-四氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-2,8-二酮(1)的制备Example 1: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4',5':4,5]benzo[1,2-b] Preparation of [1,4]oxazepine-2,8-dione (1)
Figure PCTCN2022092607-appb-000036
Figure PCTCN2022092607-appb-000036
步骤1：5-甲氧基-1,3-二甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1a)的制备Step 1: Preparation of 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1a)
于室温，将4-甲氧基苯-1,2-二胺(3.00g，21.7mmol)和三乙胺(3.30g，32.7mmol)加入到二氯甲烷(30mL)中。于冰浴，加入三光气(6.50g，21.9mmol)，将反应液升至室温，搅拌6小时。向反应液中加水淬灭，用饱和碳酸钠溶液调PH到8，EA萃取(30mL x 2)，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：CH 2Cl 2/MeOH＝10:1)，得2g黄色固体状标题化合物，收率56％。 4-Methoxybenzene-1,2-diamine (3.00 g, 21.7 mmol) and triethylamine (3.30 g, 32.7 mmol) were added to dichloromethane (30 mL) at room temperature. In an ice bath, triphosgene (6.50 g, 21.9 mmol) was added, the reaction solution was raised to room temperature, and stirred for 6 hours. Add water to the reaction solution to quench, adjust the pH to 8 with saturated sodium carbonate solution, extract with EA (30mL x 2), wash with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: CH 2 Cl 2 /MeOH=10:1) to obtain 2 g of the title compound as a yellow solid, with a yield of 56%.
LC-MS：m/z 165.06[M+H] +。 LC-MS: m/z 165.06 [M+H] + .
步骤2：5-甲氧基-1,3-二甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1b)的制备Step 2: Preparation of 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1b)
于0℃，将5-甲氧基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1a)(2.00g，12.2mmol)溶于DMF(30mL)中，分批加入NaH(877mg，36.6mmol，60％)，搅拌20分钟，滴加CH 3I(15.6g，109mmol)，将反应液升至室温搅拌3小时。向反应液中 加水淬灭，EA(100mL x 2)萃取，饱和食盐水(100mLx 3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝1:100-100:1)，得1.5g黑色固体状标题化合物，收率：64.1％。 At 0°C, 5-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (1a) (2.00g, 12.2mmol) was dissolved in DMF (30mL) in batches NaH (877 mg, 36.6 mmol, 60%) was added, stirred for 20 minutes, CH 3 I (15.6 g, 109 mmol) was added dropwise, and the reaction solution was raised to room temperature and stirred for 3 hours. Add water to the reaction solution to quench, extract with EA (100mL x 2), wash with saturated brine (100mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE=1:100-100:1) to obtain 1.5 g of the title compound as a black solid, yield: 64.1%.
LC-MS：m/z 193.09[M+H] +。 LC-MS: m/z 193.09 [M+H] + .
步骤3：5-甲氧基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1c)的制备Step 3: Preparation of 5-methoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1c)
于0℃，将5-甲氧基-1,3-二甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1b)(1.50g，7.81mmol)溶于醋酸(7.50mL)中，滴加HNO 3(67％，1.50mL)，搅拌15分钟，将反应液加水(150mL)稀释，用DCM(100mL x 1)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相DCM/MeOH＝100:1-20:1)，得黄色固体状标题化合物1.3g，收率：72％。 At 0°C, 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1b) (1.50g, 7.81mmol) was dissolved in In acetic acid (7.50mL), add HNO 3 (67%, 1.50mL) dropwise, stir for 15 minutes, dilute the reaction solution with water (150mL), extract with DCM (100mL x 1), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase DCM/MeOH=100:1-20:1) to obtain 1.3 g of the title compound as a yellow solid, yield: 72%.
LC-MS：m/z 238.07[M+H] +。 LC-MS: m/z 238.07 [M+H] + .
步骤4：5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)的制备Step 4: Preparation of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d)
于0℃，将5-甲氧基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1c)(1.3g，5.14mmol)溶于DCM(50ml)中，滴加BBr 3(5.16g，20.5mmol)，将反应液升至室温搅拌1小时。加水淬灭，DCM(100mL x2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体状标题化合物1.00g，收率：87.1％。 At 0°C, 5-methoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1c) (1.3g, 5.14 mmol) was dissolved in DCM (50 ml), BBr 3 (5.16 g, 20.5 mmol) was added dropwise, and the reaction solution was raised to room temperature and stirred for 1 hour. It was quenched with water, extracted with DCM (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.00 g of the title compound as a yellow solid, yield: 87.1%.
LC-MS：m/z 224.06[M+H] +。 LC-MS: m/z 224.06 [M+H] + .
步骤5：O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-N-三苯甲基-L-丝氨酸甲酯(1e)的制备Step 5: O-(1,3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-trityl Preparation of base-L-serine methyl ester (1e)
于室温，将5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)(1.00g，4.48mmol)溶于50mL THF中，加入三苯甲基-L-丝氨酸甲酯(2.43g,6.72mmol)、三苯基膦((Ph) 3P)(2.35g，8.96mmol)。氮气氛下，在冰浴下，滴加DIAD(1.81g，8.96mmol)，加毕室温搅拌2小时。加入50mL水，用DCM萃取(100mL x 2)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:1)，得黄色油状标题化合物2.90g。 At room temperature, 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) (1.00g, 4.48mmol) Dissolved in 50 mL THF, added trityl-L-serine methyl ester (2.43 g, 6.72 mmol), triphenylphosphine ((Ph) 3 P) (2.35 g, 8.96 mmol). Under a nitrogen atmosphere, DIAD (1.81 g, 8.96 mmol) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 2 hours after the addition. Add 50 mL of water, extract with DCM (100 mL x 2), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:1) to obtain 2.90 g of the title compound as yellow oil.
LC-MS：m/z 566.61[M+H] +。 LC-MS: m/z 566.61 [M+H] + .
步骤6：O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-L-丝氨酸甲酯(1f)的制备Step 6: O-(1,3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester Preparation of (1f)
将O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-N-三苯甲基-L-丝氨酸甲酯(1e)(2.90g，5.11mmol)溶于50mL DCM中，加入HCl的二氧六环溶液(4M，10mL)，室温搅拌1小时。将反应液减压浓缩，残余物用EA/PE＝(1:1)打浆，抽滤，滤饼用EA/PE＝(1:1)洗涤，得浅黄色固体标题化合物1.4g。O-(1,3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-trityl- L-serine methyl ester (1e) (2.90 g, 5.11 mmol) was dissolved in 50 mL of DCM, HCl in dioxane (4 M, 10 mL) was added, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was slurried with EA/PE=(1:1), filtered with suction, and the filter cake was washed with EA/PE=(1:1) to obtain 1.4 g of the title compound as a pale yellow solid.
LC-MS：m/z 324.29[M+H] +。 LC-MS: m/z 324.29 [M+H] + .
步骤7：N-(叔丁氧基羰基)-O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d] 咪唑-5-基)-L-丝氨酸甲酯(1g)的制备Step 7: N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- Preparation of 5-yl)-L-serine methyl ester (1g)
将O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-L-丝氨酸甲酯(1f)(1.4g,4.36mmol)溶于DCM(50ml)中，加入TEA(1.32g，13.1mmol)，搅拌至反应液澄清。冰浴下加入(Boc) 2O(1.43g，6.55mmol)，室温搅拌3小时。加水(50mL)稀释，加入DCM(50 x 1)萃取，饱和食盐水洗涤(50mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:100)，得黄色固体状标题化合物1g，收率：60.2％。 O-(1,3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1f ) (1.4g, 4.36mmol) was dissolved in DCM (50ml), TEA (1.32g, 13.1mmol) was added and stirred until the reaction solution was clear. (Boc) 2 O (1.43 g, 6.55 mmol) was added under ice cooling, and stirred at room temperature for 3 hours. Dilute with water (50 mL), extract with DCM (50 x 1), wash with saturated brine (50 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:100) to obtain 1 g of the title compound as a yellow solid, yield: 60.2%.
LC-MS：m/z 424.16[M+H] +。 LC-MS: m/z 424.16 [M+H] + .
步骤8：O-(6-氨基-1,3-二甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-N-(叔丁氧基羰基)-L-丝氨酸甲酯(1h)的制备Step 8: O-(6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(tert-butoxy Preparation of methyl carbonyl)-L-serine (1h)
将N-(叔丁氧基羰基)-O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-L-丝氨酸甲酯(1g)(1.00g，2.36mmol)溶于30mL EA，加入Pd-C(260mg，0.236mmol)，在氢气氛下，室温搅拌2小时。反应液抽滤，滤液减压浓缩，得浅黄色固体的标题化合物650mg，收率：92.9％。N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- Base)-L-serine methyl ester (1g) (1.00g, 2.36mmol) was dissolved in 30mL EA, added Pd-C (260mg, 0.236mmol), and stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction solution was suction-filtered, and the filtrate was concentrated under reduced pressure to obtain 650 mg of the title compound as a light yellow solid, yield: 92.9%.
LC-MS：m/z 394.19[M+H] +。 LC-MS: m/z 394.19 [M+H] + .
步骤9：(S)-(1,3-二甲基-2,8-二氧代-2,3,6,7,8,9-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(1i)的制备Step 9: (S)-(1,3-Dimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4',5': Preparation of tert-butyl 4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (1i)
在冰浴下，将化合物1h(650mg，1.52mmol)溶于20mL氯仿。在氮气氛下，将Al(CH) 3(2.40mL，4.56mmol)滴加入反应液中，于50℃反应2小时。加入DCM(50mL)稀释，加甲醇淬灭，硅藻土抽滤，滤液减压浓缩，得浅黄色固体标题化合物600mg粗品。 Compound 1h (650 mg, 1.52 mmol) was dissolved in 20 mL of chloroform under ice bath. Under nitrogen atmosphere, Al(CH) 3 (2.40 mL, 4.56 mmol) was added dropwise into the reaction liquid, and reacted at 50°C for 2 hours. Add DCM (50 mL) to dilute, add methanol to quench, celite suction filtration, and the filtrate is concentrated under reduced pressure to obtain 600 mg of the title compound as a light yellow solid.
LC-MS：m/z 362.16[M+H] +。 LC-MS: m/z 362.16 [M+H] + .
步骤10：(S)-(1,3,9-三甲基-2,8-二氧代-2,3,6,7,8,9-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(1j)的制备Step 10: (S)-(1,3,9-Trimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4',5 Preparation of ':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate tert-butyl ester (1j)
在冰浴下，将化合物1i(600mg，1.66mmol)溶于10mL DMF，加入CS 2CO 3(809mg，2.28mmol)，最后滴加CH 3I(235mg，1.66mmol)。于室温反应2小时。加EA(100mL×1)稀释，用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:100)，得淡黄色固体状标题化合物320mg，收率：51.2％。 Under ice-cooling, compound 1i (600 mg, 1.66 mmol) was dissolved in 10 mL DMF, CS 2 CO 3 (809 mg, 2.28 mmol) was added, and finally CH 3 I (235 mg, 1.66 mmol) was added dropwise. React at room temperature for 2 hours. Add EA (100mL×1) to dilute, wash with saturated brine (50mL×3), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/ EA=100:1-1:100), to obtain 320 mg of the title compound as light yellow solid, yield: 51.2%.
LC-MS：m/z 376.17[M+H] +。 LC-MS: m/z 376.17 [M+H] + .
步骤11：(S)-7-氨基-1,3,9三甲基-3,6,7,9四氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1，4]氧氮杂卓-2,8-二酮(1k)的制备Step 11: (S)-7-Amino-1,3,9trimethyl-3,6,7,9tetrahydro-1H-imidazo[4',5':4,5]benzo[1, Preparation of 2-b][1,4]oxazepine-2,8-dione (1k)
于室温，将化合物1j(300mg,0.798mmol)溶于10ml DCM中，滴加HCl的二氧六环溶液(4M，5mL)，于室温搅拌1小时。加碳酸氢钠水溶液中和，DCM(50mL×1)萃取，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体状标题化合物120mg，收率：55.5％。Compound 1j (300mg, 0.798mmol) was dissolved in 10ml DCM at room temperature, HCl in dioxane (4M, 5mL) was added dropwise, and stirred at room temperature for 1 hour. Add aqueous sodium bicarbonate to neutralize, extract with DCM (50mL×1), wash with saturated brine (20mL×1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 120 mg of the title compound as a yellow solid, yield: 55.5%.
LC-MS：m/z 276.12[M+H] +。 LC-MS: m/z 276.12 [M+H] + .
步骤12：1-苄基-5-羟基-1H-吡唑-3-羧酸乙酯(1l)的制备Step 12: Preparation of ethyl 1-benzyl-5-hydroxy-1H-pyrazole-3-carboxylate (1l)
于0℃，将丁炔二酸二乙酯(4.4g，25.6mmol)、苄基肼二盐酸盐(5g,25.6mmol)和无水碳酸钾(8.8g，64mmol)加入到160mL无水乙醇中，加热回流搅拌过夜。将反应液降至室温，并继续反应液搅拌5小时。加入6N的盐酸调节PH值至3。加入300mL水与150mL乙酸乙酯，有机层用饱和食盐水100mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用10mL乙腈打浆，过滤，得到黄色固体状的标题化合物2.2g，收率35％。At 0° C., diethyl butynedioate (4.4 g, 25.6 mmol), benzylhydrazine dihydrochloride (5 g, 25.6 mmol) and anhydrous potassium carbonate (8.8 g, 64 mmol) were added to 160 mL of absolute ethanol , heated to reflux and stirred overnight. The reaction solution was cooled to room temperature, and the reaction solution was stirred for 5 hours. Add 6N hydrochloric acid to adjust the pH value to 3. Add 300 mL of water and 150 mL of ethyl acetate, wash the organic layer with 100 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was slurried with 10 mL of acetonitrile and filtered to obtain 2.2 g of the title compound as a yellow solid with a yield of 35%.
LC-MS：m/z 247.10[M+H] +。 LC-MS: m/z 247.10 [M+H] + .
步骤13：1-苄基-5-氯-4-甲酰基-1H-吡唑-3-羧酸乙酯(1m)的制备Step 13: Preparation of ethyl 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylate (1m)
于室温，将1-苄基-5-羟基-1H-吡唑-3-羧酸乙酯(0.5g，2.1mmol)加入到DMF0.65mL中，滴入三氯氧磷(1.6mL，16mmol)，升温至90℃搅拌4小时。将反应液缓慢倾入到冰的饱和碳酸氢钠溶液中，加入30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-5:1)，得白色固体状的标题化合物300mg，收率48.9％。At room temperature, 1-benzyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (0.5g, 2.1mmol) was added to DMF0.65mL, and phosphorus oxychloride (1.6mL, 16mmol) was added dropwise , heated to 90°C and stirred for 4 hours. The reaction solution was slowly poured into ice saturated sodium bicarbonate solution, 30 mL of ethyl acetate was added, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=10:1-5:1) to obtain 300 mg of the title compound as a white solid, with a yield of 48.9%.
LC-MS：m/z 293.06[M+H] +。 LC-MS: m/z 293.06 [M+H] + .
步骤14：1-苄基-5-氯-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(1n)的制备Step 14: Preparation of ethyl 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (1n)
于室温，将(甲氧基甲基)三苯基氯化鏻(1.6g，4.8mmol)溶于20mL无水四氢呋喃中。于0℃，滴入叔丁醇钾(0.5g，4.4mmol)溶于10mL无水四氢呋喃的溶液，搅拌10分钟后，滴入1-苄基-5-氯-4-甲酰基-1H-吡唑-3-羧酸乙酯(0.3g，1.1mmol)的10mL无水四氢呋喃溶液中，继续搅拌30分钟后升至室温并搅拌过夜。向反应液加入60mL水与40mL乙酸乙酯，有机相用饱和食盐水50mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝5:1-2:1)，得黄色固体状标题化合物200mg，收率56.8％。(Methoxymethyl)triphenylphosphonium chloride (1.6 g, 4.8 mmol) was dissolved in 20 mL of anhydrous THF at room temperature. At 0°C, a solution of potassium tert-butoxide (0.5 g, 4.4 mmol) dissolved in 10 mL of anhydrous tetrahydrofuran was added dropwise, and after stirring for 10 minutes, 1-benzyl-5-chloro-4-formyl-1H-pyridine was added dropwise In a solution of ethyl azole-3-carboxylate (0.3 g, 1.1 mmol) in 10 mL of anhydrous tetrahydrofuran, stirring was continued for 30 minutes, then warmed to room temperature and stirred overnight. 60 mL of water and 40 mL of ethyl acetate were added to the reaction solution, the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=5:1-2:1) to obtain 200 mg of the title compound as a yellow solid, with a yield of 56.8%.
LC-MS：m/z 321.09[M+H] +。 LC-MS: m/z 321.09 [M+H] + .
步骤15：1-苄基-5-氯-4-(2-氧代乙基)-1H-吡唑-3-羧酸乙酯(1o)的制备Step 15: Preparation of ethyl 1-benzyl-5-chloro-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (1o)
于室温，将1-苄基-5-氯-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(0.2g，0.63mmol)溶于10mL THF中，加入2mL 6N盐酸，升温至60℃，搅拌30钟。将反应液倾入到20mL饱和碳酸氢钠溶液中，加入30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得无色油状标题化合物190mg，收率98.6％。At room temperature, 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.2g, 0.63mmol) was dissolved in 10mL THF, added 2mL of 6N hydrochloric acid, heated to 60°C, stirred for 30 minutes. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution, 30 mL of ethyl acetate was added, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 190 mg of the title compound as a colorless oil. Yield 98.6%.
LC-MS：m/z 307.08[M+H] +。 LC-MS: m/z 307.08 [M+H] + .
步骤16：(S)-1-苄基-5-氯-4-(2-((1,3,9-三甲基-2,8-二氧代-2,3,6,7,8,9-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(1p)的制备Step 16: (S)-1-Benzyl-5-chloro-4-(2-((1,3,9-trimethyl-2,8-dioxo-2,3,6,7,8 ,9-Hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)- Preparation of ethyl 1H-pyrazole-3-carboxylate (1p)
于室温，将化合物1k(100mg，0.362mmol)溶于5mL甲醇，加入化合物1o(134mg，0.434mmol)，加入醋酸(0.5mL)，最后加入甲基硼烷(58.8mg，0.543mmol)，于室温反应1小时。加入EA(50mL×1)稀释，用饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:100)，得淡黄色固体状标题化合物30mg，收率：15.0％。At room temperature, compound 1k (100mg, 0.362mmol) was dissolved in 5mL of methanol, compound 1o (134mg, 0.434mmol) was added, acetic acid (0.5mL) was added, and finally methylborane (58.8mg, 0.543mmol) was added, and at room temperature React for 1 hour. Add EA (50mL×1) to dilute, wash with saturated brine (20mL×1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/ EA=100:1-1:100), to obtain 30 mg of the title compound as a pale yellow solid, yield: 15.0%.
LC-MS：m/z 566.20[M+H] +。 LC-MS: m/z 566.20 [M+H] + .
步骤17：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1,3,9-三甲基-3,6,7,9-四氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-2,8-二酮(1)的制备Step 17: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -yl)-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4',5':4,5]benzo[1,2-b][ Preparation of 1,4]oxazepine-2,8-dione (1)
在冰浴下，将化合物1p(30.0mg，0.035mmol)溶于1mL氯仿。在氮气氛下，将Al(CH 3) 3(0.06mL，0.105mmol)滴加入反应液中，于50℃反应2小时。加入DCM(10mL)稀释，加甲醇淬灭，硅藻土抽滤，滤液减压浓缩。残余物通过高压制备液相色谱法分离(色谱柱型号：XBRIDGE 3.5um 2.1×50mm，流动相：乙腈/水(0.05％甲酸)，梯度：10％-100％)，得白色固体状标题化合物9.30mg，收率：50.2％。 Compound 1p (30.0 mg, 0.035 mmol) was dissolved in 1 mL of chloroform under ice bath. Under nitrogen atmosphere, Al(CH 3 ) 3 (0.06 mL, 0.105 mmol) was added dropwise into the reaction liquid, and reacted at 50°C for 2 hours. Add DCM (10 mL) to dilute, add methanol to quench, celite suction filter, and the filtrate is concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (column model: XBRIDGE 3.5um 2.1×50mm, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 10%-100%), and the title compound 9.30 was obtained as a white solid mg, yield: 50.2%.
LC-MS：m/z 521.16[M+H] +。 LC-MS: m/z 521.16 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.44-7.32(m,3H),7.31-7.22(m,2H),6.82(s,2H),5.91-5.85(m,1H),5.49-5.48(s,2H),4.71-4.62(m,1H),4.49-4.48(m,1H),4.47-4.46(m,1H),3.65-3.55(m,1H),3.49-3.35(m,9H),3.15-3.10(m,1H),2.73-2.64(m,1H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.44-7.32(m,3H),7.31-7.22(m,2H),6.82(s,2H),5.91-5.85(m,1H),5.49-5.48 (s,2H),4.71-4.62(m,1H),4.49-4.48(m,1H),4.47-4.46(m,1H),3.65-3.55(m,1H),3.49-3.35(m,9H) ,3.15-3.10(m,1H),2.73-2.64(m,1H).
实施例2：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-9-甲基-6,7-二氢-[1,3]二氧杂环戊烯并[4'5':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(2)的制备Example 2: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-9-methyl-6,7-dihydro-[1,3]dioxole[4'5':4,5]benzo[1,2-b][1 ,4] Preparation of oxazepine-8(9H)-one (2)
Figure PCTCN2022092607-appb-000037
Figure PCTCN2022092607-appb-000037
步骤1：苯并[d][1,3]二噁英-5-基乙酸酯(2a)的制备Step 1: Preparation of benzo[d][1,3]dioxin-5-yl acetate (2a)
氮气氛下，将芝麻酚(4.00g，29.0mmol)溶于DCM 50mL中。于冰浴，加入DIPEA(12.0mL，87.0mmol)，搅拌下滴加溶于10mL DCM中的乙酰氯(3.00mL,43.5mmol)，升至室温并继续搅拌2h。加入100mL水，有机层用饱和食盐水 洗涤，干燥有机层，减压除去溶剂，得深黄色油状标题化合物4g，收率76.7％。Sesamol (4.00 g, 29.0 mmol) was dissolved in DCM 50 mL under nitrogen atmosphere. In an ice bath, DIPEA (12.0 mL, 87.0 mmol) was added, acetyl chloride (3.00 mL, 43.5 mmol) dissolved in 10 mL DCM was added dropwise with stirring, warmed to room temperature and continued stirring for 2 h. 100 mL of water was added, the organic layer was washed with saturated brine, the organic layer was dried, and the solvent was removed under reduced pressure to obtain 4 g of the title compound as a dark yellow oil with a yield of 76.7%.
LC-MS：m/z 181.04[M+H] +。 LC-MS: m/z 181.04 [M+H] + .
步骤2：6-硝基苯并[d][1,3]二噁英-5-基乙酸酯(2b)的制备Step 2: Preparation of 6-nitrobenzo[d][1,3]dioxin-5-yl acetate (2b)
于冰浴，将苯并[d][1,3]二噁英-5-基乙酸酯(4.00g，24.0mmol)加入40mL乙酸中，搅拌10分钟后向其中缓慢滴加硝酸(2.80g，26.0mmol)。于室温搅拌3小时后，将反应液倾入碎冰，静置30分钟后过滤，水洗滤饼两次，干燥，得黄色固体状标题化合物4.2g，收率83.9％。In an ice bath, benzo[d][1,3]dioxin-5-yl acetate (4.00g, 24.0mmol) was added to 40mL of acetic acid, stirred for 10 minutes, and nitric acid (2.80g , 26.0 mmol). After stirring at room temperature for 3 hours, the reaction solution was poured into crushed ice, allowed to stand for 30 minutes and then filtered. The filter cake was washed twice with water and dried to obtain 4.2 g of the title compound as a yellow solid with a yield of 83.9%.
LC-MS：m/z 226.03[M+H] +。 LC-MS: m/z 226.03 [M+H] + .
步骤3：6-硝基苯并[d][1,3]二噁英-5-醇(2c)的制备Step 3: Preparation of 6-nitrobenzo[d][1,3]dioxin-5-ol (2c)
于冰浴，将6-硝基苯并[d][1,3]二噁英-5-基乙酸酯(4.20g，18.7mmol)加入40mL 20％硫酸水溶液中，搅拌10分钟后升温至80℃搅拌3小时。将反应液倾入碎冰中，静置30分钟后过滤，水洗滤饼两次，干燥，得黄色固体状标题化合物3.1g，收率90.7％。In an ice bath, 6-nitrobenzo[d][1,3]dioxin-5-yl acetate (4.20g, 18.7mmol) was added in 40mL of 20% sulfuric acid aqueous solution, stirred for 10 minutes and then heated to Stir at 80°C for 3 hours. The reaction solution was poured into crushed ice, allowed to stand for 30 minutes and then filtered. The filter cake was washed twice with water and dried to obtain 3.1 g of the title compound as a yellow solid with a yield of 90.7%.
LC-MS：m/z 184.02[M+H] +。 LC-MS: m/z 184.02 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用6-硝基苯并[d][1,3]二噁英-5-醇(2c)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物2。The remaining steps are the same as in Example 1, except that 5-hydroxy-1,3-ol in step 5 is replaced by 6-nitrobenzo[d][1,3]dioxin-5-ol Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to give the title compound 2.
LC-MS：m/z 481.12[M+H] +。 LC-MS: m/z 481.12 [M+H] + .
1H NMR(300MHz,DMSO-d 6)δ8.23-8.01(m,1H),7.35-7.14(m,6H),5.96(s,2H),5.27(s,2H),4.50-4.34(m,3H),3.35-3.32(m,2H),3.21(s,3H),2.76-2.74(m,1H),2.73-2.68(m,1H)。 1 H NMR (300MHz,DMSO-d 6 )δ8.23-8.01(m,1H),7.35-7.14(m,6H),5.96(s,2H),5.27(s,2H),4.50-4.34(m ,3H), 3.35-3.32(m,2H), 3.21(s,3H), 2.76-2.74(m,1H), 2.73-2.68(m,1H).
实施例3：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2,5-二甲基-7,8-二氢噻唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(3)的制备Example 3: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2,5-dimethyl-7,8-dihydrothiazolo[4',5':4,5]benzo[1,2-b][1,4]oxazepine Preparation of -6(5H)-one (3)
Figure PCTCN2022092607-appb-000038
Figure PCTCN2022092607-appb-000038
步骤1：2-溴-4-甲氧基-5-硝基苯胺(3a)的制备Step 1: Preparation of 2-bromo-4-methoxy-5-nitroaniline (3a)
于0℃，将2-溴-4-甲氧基苯胺(5.00g，24.9mmol)加入到浓硫酸(25mL)中，分批加入硝酸钠(3.70g，27.3mmol)。于10℃搅拌10分钟。用20％氢氧化钠溶液调节PH值至9～10，用EA萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1)，得黄色固体状标题 化合物1.5g，收率24.5％。At 0°C, 2-bromo-4-methoxyaniline (5.00 g, 24.9 mmol) was added into concentrated sulfuric acid (25 mL), and sodium nitrate (3.70 g, 27.3 mmol) was added in portions. Stir at 10°C for 10 minutes. Adjust the pH value to 9-10 with 20% sodium hydroxide solution, extract with EA, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=10:1) to obtain 1.5 g of the title compound as a yellow solid with a yield of 24.5%.
LC-MS：m/z 246.96[M+H] +。 LC-MS: m/z 246.96 [M+H] + .
步骤2：N-(2-溴-4-甲氧基-5-硝基苯基)乙酰胺(3b)的制备Step 2: Preparation of N-(2-bromo-4-methoxy-5-nitrophenyl)acetamide (3b)
于0℃，将乙酰氯(476mg，6.70mmol)加入到2-溴-4-甲氧基-5-硝基苯胺(1.00g,4.07mmol)和三乙胺(739mg，7.32mmol)的DCM(20mL)中。升至室温搅拌过夜。加入DCM稀释，分别用水、饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体标题化合物1.3g，粗品，直接用于下一步反应。Acetyl chloride (476 mg, 6.70 mmol) was added to a solution of 2-bromo-4-methoxy-5-nitroaniline (1.00 g, 4.07 mmol) and triethylamine (739 mg, 7.32 mmol) in DCM at 0 °C ( 20mL). Warm to room temperature and stir overnight. Add DCM to dilute, wash with water, saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 1.3 g of the title compound as a yellow solid, which is directly used in the next reaction.
LC-MS：m/z 288.97[M+H] +。 LC-MS: m/z 288.97 [M+H] + .
步骤3：6-甲氧基-2-甲基-5-硝基苯并[d]噻唑(3c)的制备Step 3: Preparation of 6-methoxy-2-methyl-5-nitrobenzo[d]thiazole (3c)
于室温，将N-(2-溴-4-甲氧基-5-硝基苯基)乙酰胺(1.30g，4.51mmol)、硫化钾(1.49g，13.5mmol)和CuI(85.8mg，0.451mmol)溶于DMF(25ml)中，将反应液升至90℃搅拌1小时。将反应液加1N HCl淬灭，EA萃取，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法分离纯化(流动相：PE/EA＝3:1)，得黄色固体状标题化合物800mg，两步收率87.9％。At room temperature, N-(2-bromo-4-methoxy-5-nitrophenyl)acetamide (1.30g, 4.51mmol), potassium sulfide (1.49g, 13.5mmol) and CuI (85.8mg, 0.451 mmol) was dissolved in DMF (25ml), and the reaction solution was raised to 90°C and stirred for 1 hour. The reaction solution was quenched with 1N HCl, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA= 3:1), to obtain 800 mg of the title compound as a yellow solid, with a two-step yield of 87.9%.
LC-MS：m/z 225.03[M+H] +。 LC-MS: m/z 225.03 [M+H] + .
步骤4：6-羟基-2-甲基-5-硝基苯并[d]噻唑(3d)的制备Step 4: Preparation of 6-hydroxy-2-methyl-5-nitrobenzo[d]thiazole (3d)
于0℃，将三溴化硼的1N二氯甲烷溶液缓慢滴加到6-甲氧基-2-甲基-5-硝基苯并[d]噻唑(1.2g，5.36mmol)的DCM(10ml)溶液中，升至室温搅拌3h。加饱和碳酸氢钠溶液淬灭，DCM萃取(2x 20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法分离纯化(流动相：PE/EA＝4:1)得淡黄色固体油状标题化合物650mg，收率57.8％。At 0°C, a 1N solution of boron tribromide in dichloromethane was slowly added dropwise to a solution of 6-methoxy-2-methyl-5-nitrobenzo[d]thiazole (1.2 g, 5.36 mmol) in DCM ( 10ml) solution, raised to room temperature and stirred for 3h. Quenched by adding saturated sodium bicarbonate solution, extracted with DCM (2×20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=4: 1) 650 mg of the title compound was obtained as a pale yellow solid oil, with a yield of 57.8%.
LC-MS：m/z 211.01[M+H] +。 LC-MS: m/z 211.01 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用6-羟基-2-甲基-5-硝基苯并[d]噻唑(3d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物3。The remaining steps are the same as in Example 1, except that 5-hydroxy-1,3-dimethyl in step 5 is replaced by 6-hydroxy-2-methyl-5-nitrobenzo[d]thiazole (3d) -6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to obtain the title compound 3.
LC-MS：m/z 508.11[M+H] +。 LC-MS: m/z 508.11 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.91(s,1H),7.79(s,1H),7.32-7.22(m,5H),5.77-5.72(m,1H),5.41(s,2H),4.88-4.82(m,1H),4.42(t,1H),4.18-4.11(m,1H),3.66-3.63(m,1H),3.47(s,3H),2.95-2.91(m,1H),2.84(s,3H),2.77-2.68(m,1H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.91(s,1H),7.79(s,1H),7.32-7.22(m,5H),5.77-5.72(m,1H),5.41(s,2H ),4.88-4.82(m,1H),4.42(t,1H),4.18-4.11(m,1H),3.66-3.63(m,1H),3.47(s,3H),2.95-2.91(m,1H ), 2.84(s,3H), 2.77-2.68(m,1H).
实施例4：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4c]吡啶-6-基)-5-甲基-2-吗啉基-7,8-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(4)的制备Example 4: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4c]pyridine-6- Base)-5-methyl-2-morpholinyl-7,8-dihydrooxazolo[5',4':4,5]benzo[1,2-b][1,4]oxazone Preparation of hetero-6(5H)-one (4)
Figure PCTCN2022092607-appb-000039
Figure PCTCN2022092607-appb-000039
步骤1：5-甲氧基苯并[d]噁唑-2-硫醇(4a)的制备Step 1: Preparation of 5-methoxybenzo[d]oxazole-2-thiol (4a)
于室温，将2-氨基-4-甲氧基苯酚(2.00g，14.4mmol)溶于25ml乙醇中，加入二硫化碳(3.28g，43.2mmol)和氢氧化钾(967mg，17.3mmol)。封管中，于90℃搅拌过夜。1mol/L的盐酸调节PH至弱酸性，EA萃取(20mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得***固体状的标题化合物2.30g，收率：88.4％。At room temperature, 2-amino-4-methoxyphenol (2.00g, 14.4mmol) was dissolved in 25ml of ethanol, and carbon disulfide (3.28g, 43.2mmol) and potassium hydroxide (967mg, 17.3mmol) were added. In a sealed tube, stir overnight at 90 °C. 1mol/L hydrochloric acid to adjust the pH to weakly acidic, extracted with EA (20mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a purple solid 2.30 g, yield: 88.4%.
LC-MS：m/z 182.02[M+H] +。 LC-MS: m/z 182.02 [M+H] + .
步骤2：5-甲氧基-2-吗啉基苯并[d]噁唑(4b)的制备Step 2: Preparation of 5-methoxy-2-morpholinylbenzo[d]oxazole (4b)
于室温，将5-甲氧基苯并[d]噁唑-2-硫醇(2.20g，12.2mmol)溶于20ml吗啉中，于100℃搅拌2小时。加入30mL水，EA萃取(20mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-3:1)，得红棕色固体状的标题化合物1.84g，收率：77.6％。5-Methoxybenzo[d]oxazole-2-thiol (2.20 g, 12.2 mmol) was dissolved in morpholine 20 ml at room temperature, and stirred at 100° C. for 2 hours. Added 30mL of water, extracted with EA (20mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-3:1), to obtain 1.84 g of the title compound as a reddish-brown solid, yield: 77.6%.
LC-MS：m/z 235.10[M+H] +。 LC-MS: m/z 235.10 [M+H] + .
步骤3：5-甲氧基-2-吗啉基-6-硝基苯并[d]噁唑(4c)的制备Step 3: Preparation of 5-methoxy-2-morpholinyl-6-nitrobenzo[d]oxazole (4c)
于室温，将5-甲氧基-2-吗啉基苯并[d]噁唑(1.74g，7.44mmol)溶于15ml冰醋酸中。于0℃，加入浓硝酸(5mL)，于0℃搅拌1小时。反应液倒入冰水中，过滤，EA萃取(20mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体的标题化合物1.65g，收率：80.8％。5-Methoxy-2-morpholinylbenzo[d]oxazole (1.74 g, 7.44 mmol) was dissolved in 15 mL of glacial acetic acid at room temperature. At 0°C, concentrated nitric acid (5 mL) was added, and stirred at 0°C for 1 hour. The reaction solution was poured into ice water, filtered, extracted with EA (20mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.65g of the title compound as a yellow solid. Rate: 80.8%.
LC-MS：m/z 280.09[M+H] +。 LC-MS: m/z 280.09 [M+H] + .
步骤4：2-吗啉基-6-硝基苯并[d]噁唑-5-醇(4d)的制备Step 4: Preparation of 2-morpholino-6-nitrobenzo[d]oxazol-5-ol (4d)
将5-甲氧基-2-吗啉基-6-硝基苯并[d]噁唑(1.56g,5.59mmol)溶于20mL DCM中，氮气氛下，于0℃，加入BBr 3(1mol/L)(11.2mL)，于0℃搅拌2.5h。加入甲醇淬灭，DCM萃取(20mL x 3)，饱和食盐水洗涤(50mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体标题化合物1.53g(粗品)。 5-Methoxy-2-morpholinyl-6-nitrobenzo[d]oxazole (1.56g, 5.59mmol) was dissolved in 20mL DCM, and BBr 3 (1mol /L) (11.2mL), stirred at 0°C for 2.5h. It was quenched by adding methanol, extracted with DCM (20 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.53 g of the title compound as a yellow solid (crude product).
LC-MS：m/z 266.07[M+H] +。 LC-MS: m/z 266.07 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-吗啉基-6-硝基苯并[d]噁唑-5- 醇(4d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物4。The remaining steps are the same as in Example 1, except that 2-morpholino-6-nitrobenzo[d]oxazol-5-ol (4d) is used to replace 5-hydroxyl-1,3- Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to give the title compound 4.
LC-MS：m/z 563.17[M+H] +。 LC-MS: m/z 563.17 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.69(s,1H),7.40-7.26(m,3H),7.23-7.16(m,3H),5.57(dd,1H),5.43(s,2H),4.78(dd,1H),4.30(dd,1H),4.04(dt,1H),3.80-3.70(m,4H),3.65-3.55(m,5H),3.33(s,3H),2.88-2.75(m,1H),2.74-2.63(m,1H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.69(s,1H),7.40-7.26(m,3H),7.23-7.16(m,3H),5.57(dd,1H),5.43(s,2H ),4.78(dd,1H),4.30(dd,1H),4.04(dt,1H),3.80-3.70(m,4H),3.65-3.55(m,5H),3.33(s,3H),2.88- 2.75(m,1H),2.74-2.63(m,1H).
实施例5：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1,3-二异丙基-9-甲基-3,6,7,9-四氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-2,8-二酮(5)的制备Example 5: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1,3-diisopropyl-9-methyl-3,6,7,9-tetrahydro-1H-imidazo[4',5':4,5]benzo[1, Preparation of 2-b][1,4]oxazepine-2,8-dione (5)
Figure PCTCN2022092607-appb-000040
Figure PCTCN2022092607-appb-000040
与实施例1的制备方法相同，除了用碘代异丙烷代替步骤2中的碘甲烷，制得标题化合物5。The same preparation method as in Example 1, except that isopropane iodide was used instead of methyl iodide in step 2, to obtain the title compound 5.
LC-MS：m/z 577.10[M+H] +。 LC-MS: m/z 577.10 [M+H] + .
1H NMR(400MHz,CDCl 3)δ7.44(s,1H),7.38-7.27(m,3H),7.23(s,1H),7.21-7.16(m,2H),5.62-5.54(m,1H),5.43(s,2H),4.78(t,1H),4.67-4.53(m,2H),4.38-4.25(m,1H),4.10-4.00(m,1H),3.70-3.60(m,1H),3.37(s,3H),2.87-2.75(m,1H),2.73-2.64(m,1H),1.52-1.38(m,12H)。 1 H NMR (400MHz, CDCl 3 )δ7.44(s,1H),7.38-7.27(m,3H),7.23(s,1H),7.21-7.16(m,2H),5.62-5.54(m,1H ),5.43(s,2H),4.78(t,1H),4.67-4.53(m,2H),4.38-4.25(m,1H),4.10-4.00(m,1H),3.70-3.60(m,1H ), 3.37(s,3H), 2.87-2.75(m,1H), 2.73-2.64(m,1H), 1.52-1.38(m,12H).
实施例6：(S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2,10-二甲基-7,8-二氢噻唑并[5',4':3,4]苯并[1,2-b][1,4]氧氮杂卓-9(10H)-酮(6)的制备Example 6: (S)-8-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2,10-dimethyl-7,8-dihydrothiazolo[5',4':3,4]benzo[1,2-b][1,4]oxazepine Preparation of -9(10H)-ketone (6)
Figure PCTCN2022092607-appb-000041
Figure PCTCN2022092607-appb-000041
步骤1：2-甲基-6-羟基-7-硝基苯并噻唑(6a)的制备Step 1: Preparation of 2-methyl-6-hydroxy-7-nitrobenzothiazole (6a)
于0℃，将2-甲基-6-羟基苯并噻唑(5.00g，30mmol)加入30mL浓硫酸中，搅拌10分钟后，向其中加入硝酸钠(2.45g，30mmol)。将混合物升至室温，并继续搅拌3小时。将反应液倾入碎冰中，静置，过滤，滤饼用水淋洗，干燥，得黄色固体状的标题化合物4.20g，收率：66.7％。At 0°C, 2-methyl-6-hydroxybenzothiazole (5.00 g, 30 mmol) was added into 30 mL of concentrated sulfuric acid, and after stirring for 10 minutes, sodium nitrate (2.45 g, 30 mmol) was added thereto. The mixture was warmed to room temperature and stirring was continued for 3 hours. The reaction solution was poured into crushed ice, allowed to stand, filtered, the filter cake was rinsed with water, and dried to obtain 4.20 g of the title compound as a yellow solid, yield: 66.7%.
LC-MS：m/z 211.34[M+H] +。 LC-MS: m/z 211.34 [M+H] + .
步骤2：N-(叔丁氧基羰基)-O-(2-甲基-7-硝基苯并[d]噻唑-6-基)-L-丝氨酸甲酯(6b)的制备Step 2: Preparation of N-(tert-butoxycarbonyl)-O-(2-methyl-7-nitrobenzo[d]thiazol-6-yl)-L-serine methyl ester (6b)
于室温，将三苯基磷(6.30g，24mmol)溶于30mL THF中。于0℃，在氮气氛下，向其中滴加DIAD(4.85g，24mmol)，继续搅拌10分钟后，加入L-Boc-丝氨酸甲酯(4.38g，20mmol)，继续搅拌10分钟后，加入2-甲基-6-羟基-7-硝基苯并噻唑(4.20g，20mmol)。将混合物升至室温并搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝150:1-100:1)，得浅黄色固体状的标题化合物1.40g，收率：17.1％。Triphenylphosphine (6.30 g, 24 mmol) was dissolved in 30 mL THF at room temperature. At 0°C, under a nitrogen atmosphere, DIAD (4.85g, 24mmol) was added dropwise, and after stirring for 10 minutes, L-Boc-serine methyl ester (4.38g, 20mmol) was added, and after stirring for 10 minutes, 2 -Methyl-6-hydroxy-7-nitrobenzothiazole (4.20 g, 20 mmol). The mixture was warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=150:1-100:1) to obtain 1.40 g of the title compound as a light yellow solid, yield: 17.1%.
LC-MS:m/z 412.31[M+H] +。 LC-MS: m/z 412.31 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用N-(叔丁氧基羰基)-O-(2-甲基-7-硝基苯并[d]噻唑-6-基)-L-丝氨酸甲酯(6b)代替步骤8中的N-(叔丁氧基羰基)-O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-L-丝氨酸甲酯(1g)，制得标题化合物6。The remaining steps are the same as the preparation method of Example 1, except that N-(tert-butoxycarbonyl)-O-(2-methyl-7-nitrobenzo[d]thiazol-6-yl)-L-serine Methyl ester (6b) in place of N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H- Benzo[d]imidazol-5-yl)-L-serine methyl ester (1 g) to give the title compound 6.
LC-MS：m/z 508.11[M+H] +。 LC-MS: m/z 508.11 [M+H] + .
1HNMR(300MHz,DMSO-d 6)δ7.39-7.13(m,7H),5.33(s,2H),4.82-4.72(m,2H),4.62-4.60(m,1H),3.32(s,3H),2.83(s,3H)，3.78-3.55(m,2H),2.82-2.80(m,1H),2.78-2.75(m,1H)。 1 HNMR(300MHz,DMSO-d 6 )δ7.39-7.13(m,7H),5.33(s,2H),4.82-4.72(m,2H),4.62-4.60(m,1H),3.32(s, 3H), 2.83(s, 3H), 3.78-3.55(m, 2H), 2.82-2.80(m, 1H), 2.78-2.75(m, 1H).
实施例7：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6基)-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(7)的制备Example 7: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b][1,4]oxo Preparation of azepine-6(5H)-one (7)
Figure PCTCN2022092607-appb-000042
Figure PCTCN2022092607-appb-000042
Figure PCTCN2022092607-appb-000043
Figure PCTCN2022092607-appb-000043
步骤1：N-(2-溴-4-甲氧基苯基)环丙烷甲酰胺(7a)的制备Step 1: Preparation of N-(2-bromo-4-methoxyphenyl)cyclopropanecarboxamide (7a)
于室温，将2-溴-4-甲氧基苯胺(5.00g，25.0mmol)溶于100ml DCM中，加入DIEA(9.60g，75.0mmol)，氮气氛下，于0℃向反应液中加入环丙基酰氯(3.10g，29.8mmol)，室温搅拌2小时。加水淬灭，用DCM萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝4:1)，得无色透明液体的标题化合物6.50g，收率96.8％。At room temperature, 2-bromo-4-methoxyaniline (5.00g, 25.0mmol) was dissolved in 100ml of DCM, DIEA (9.60g, 75.0mmol) was added, and cycloheximide was added to the reaction solution at 0°C under a nitrogen atmosphere. Propyl chloride (3.10 g, 29.8 mmol), stirred at room temperature for 2 hours. Add water to quench, extract with DCM (200mL x 3), wash with saturated brine (200mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=4:1) to obtain 6.50 g of the title compound as a colorless transparent liquid with a yield of 96.8%.
LC-MS：m/z 270[M+H] +。 LC-MS: m/z 270 [M+H] + .
步骤2：2-环丙基-6-甲氧基苯并[d]噁唑(7b)的制备Step 2: Preparation of 2-cyclopropyl-6-methoxybenzo[d]oxazole (7b)
将N-(2-溴-4-甲氧基苯基)环丙烷甲酰胺(7a)(5.00g,1.86mmol)溶于DMF(100mL)中，加入Cs 2CO 3(12.1g，37.2mmol)、CuI(180mg，0.930mmol)、二联吡啶(290mg，1.86mmol)，氮气氛下，于120℃反应过夜。加入水淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物2.71g，收率77.1％。 N-(2-bromo-4-methoxyphenyl)cyclopropanecarboxamide (7a) (5.00 g, 1.86 mmol) was dissolved in DMF (100 mL), and Cs 2 CO 3 (12.1 g, 37.2 mmol) was added , CuI (180mg, 0.930mmol), bipyridine (290mg, 1.86mmol), and react overnight at 120°C under a nitrogen atmosphere. Water was added to quench, EA extracted (100mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1), to obtain 2.71 g of the title compound as a pale yellow solid, with a yield of 77.1%.
LC-MS：m/z 190[M+H] +。 LC-MS: m/z 190 [M+H] + .
步骤3：2-环丙基-6-甲氧基-5-硝基苯并[d]噁唑(7c)的制备Step 3: Preparation of 2-cyclopropyl-6-methoxy-5-nitrobenzo[d]oxazole (7c)
将2-环丙基-6-甲氧基苯并[d]噁唑(7b)(2.50g，13.2mmol)溶于TFA(24ml)中，氮气氛下，于0℃向反应液中滴加浓硝酸(8mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水淬灭，EA萃取(50mL x 3)，饱和食盐水洗涤(80mL x1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.5g，收率49.6％Dissolve 2-cyclopropyl-6-methoxybenzo[d]oxazole (7b) (2.50g, 13.2mmol) in TFA (24ml), and add dropwise to the reaction solution at 0°C under nitrogen atmosphere Concentrated nitric acid (8 mL), stirred at 0°C for 2 hours and at room temperature overnight. Quenched with water at 0°C, extracted with EA (50mL x 3), washed with saturated brine (80mL x1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile Phase PE/EA=3:1), the title compound was obtained as light yellow solid 1.5g, yield 49.6%
LC-MS：m/z 234[M+H] +。 LC-MS: m/z 234 [M+H] + .
步骤4：2-环丙基-5-硝基苯并[d]噁唑-6-醇(7d)的制备Step 4: Preparation of 2-cyclopropyl-5-nitrobenzo[d]oxazol-6-ol (7d)
将2-环丙基-6-甲氧基-5-硝基苯并[d]噁唑(7c)(3.20g，13.6mmol)溶于DCM(50ml)中，氮气氛下，于0℃向反应液中滴加BBr 3(27.2mL，1M)，于0℃搅 拌2小时。于0℃加甲醇淬灭，DCM萃取(60mL x 3)，饱和食盐水洗涤(80mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.8g，收率60.0％。 2-Cyclopropyl-6-methoxy-5-nitrobenzo[d]oxazole (7c) (3.20g, 13.6mmol) was dissolved in DCM (50ml), under nitrogen atmosphere, at 0°C to BBr 3 (27.2 mL, 1M) was added dropwise to the reaction solution, and stirred at 0°C for 2 hours. Quenched by adding methanol at 0°C, extracted with DCM (60mL x 3), washed with saturated brine (80mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 1.8 g of the title compound was obtained as a pale yellow solid, with a yield of 60.0%.
LC-MS：m/z 220[M+H] +。 LC-MS: m/z 220 [M+H] + .
步骤5：O-(2-环丙基-5-硝基苯并[d]噁唑-6-基)-N-三苯甲基-L-丝氨酸甲酯(7e)的制备Step 5: Preparation of O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-N-trityl-L-serine methyl ester (7e)
于室温，将2-环丙基-5-硝基苯并[d]噁唑-6-醇(7d)(2.30g，10.4mmol)，甲基三苯甲基-L-丝氨酸(5.66g,15.7mmol)溶于50mL THF中，氮气氛下，向反应液中加入PPh 3(5.47g，20.9mmol)、DIAD(偶氮二羧酸二异丙酯)(4.20g，20.9mmol)，室温搅拌过夜。加入水淬灭，用EA萃取(50mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝1:1)，得黄色半固体状标题化合物8.2g(粗品)。 At room temperature, 2-cyclopropyl-5-nitrobenzo[d]oxazol-6-ol (7d) (2.30g, 10.4mmol), methyltrityl-L-serine (5.66g, 15.7mmol) was dissolved in 50mL THF, under a nitrogen atmosphere, PPh 3 (5.47g, 20.9mmol), DIAD (diisopropyl azodicarboxylate) (4.20g, 20.9mmol) were added to the reaction solution, and stirred at room temperature overnight. Quenched by adding water, extracted with EA (50mL x 3), washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile Phase PE/EA=1:1) to obtain 8.2 g of the title compound (crude product) as a yellow semi-solid.
LC-MS：m/z 564[M+H] +。 LC-MS: m/z 564 [M+H] + .
步骤6：O-(2-环丙基-5-硝基苯并[d]噁唑-6-基)-L-丝氨酸甲酯(7f)制备Step 6: Preparation of O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7f)
于室温，将O-(2-环丙基-5-硝基苯并[d]噁唑-6-基)-N-三苯甲基-L-丝氨酸甲酯(7e)(7.50g，13.3mmol)溶于100mL DCM中，加入盐酸二氧六环溶液(13.3ml，4M)，室温搅拌3小时。减压浓缩，PE：EA＝5:1打浆(50mL x 1)，过滤，收集滤饼，得浅黄色固体标题化合物4.84g，收率75.4％。At room temperature, O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-N-trityl-L-serine methyl ester (7e) (7.50g, 13.3 mmol) was dissolved in 100mL of DCM, added dioxane hydrochloride solution (13.3ml, 4M), and stirred at room temperature for 3 hours. Concentrated under reduced pressure, PE: EA = 5:1 beating (50mL x 1), filtered, and the filter cake was collected to obtain 4.84g of the title compound as a light yellow solid, with a yield of 75.4%.
LC-MS：m/z 464[M+H] +。 LC-MS: m/z 464 [M+H] + .
步骤7：N-(叔丁氧基羰基)-O-(2-环丙基-5-硝基苯并[d]噁唑-6-基)-L-丝氨酸甲酯(7g)的制备Step 7: Preparation of N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7 g)
于室温，将O-(2-环丙基-5-硝基苯并[d]噁唑-6-基)-L-丝氨酸甲酯(7f)(4.50g,13.9mmol)溶于DCM(60ml)中，向反应液中加入DIEA(5.38g，41.7mmol),Boc 2O(4.52g，20.9mmol)，于室温搅拌过夜。加水稀释，DCM萃取(50mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝2:1)，得黄色油状标题化合物3.6g，收率58.6％。 At room temperature, O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7f) (4.50 g, 13.9 mmol) was dissolved in DCM (60 ml ), DIEA (5.38g, 41.7mmol), Boc 2 O (4.52g, 20.9mmol) were added to the reaction solution, and stirred overnight at room temperature. Diluted with water, extracted with DCM (50mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/ EA=2:1), to obtain 3.6 g of the title compound as a yellow oil, with a yield of 58.6%.
LC-MS：m/z 492.4[M+H] +。 LC-MS: m/z 492.4 [M+H] + .
步骤8：O-(5-氨基-2-环丙基苯并[d]噁唑-6-基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(7h)的制备Step 8: Preparation of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (7h)
于室温，将N-(叔丁氧基羰基)-O-(2-环丙基-5-硝基苯并[d]噁唑-6-基)-L-丝氨酸甲酯(7g)(3.50g，8.31mmol)溶于30mL甲醇中，向反应液中加入含水Pd/C(1g)，氢气氛下，室温搅拌过夜。硅藻土过滤，MeOH洗涤滤饼，滤液减压浓缩，得黄色油状的标题化合物3.2g(粗品)。At room temperature, N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7g) (3.50 g, 8.31 mmol) was dissolved in 30 mL of methanol, and aqueous Pd/C (1 g) was added to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Celite was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 3.2 g of the title compound (crude product) as a yellow oil.
LC-MS：m/z 462.4[M+H] +。 LC-MS: m/z 462.4 [M+H] + .
步骤9：O-(5-氨基-2-环丙基苯并[d]噁唑-6-基)-N-(叔丁氧羰基)-L-丝氨酸(7i)的制备Step 9: Preparation of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i)
将O-(5-氨基-2-环丙基苯并[d]噁唑-6-基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(7h)(3.20g，8.18mmol)溶于THF(30ml)中，加入氢氧化锂(282mg，12.3mmol)，水(5mL)，于室温搅拌30分钟，减压浓缩，得黑色油状标题化合物3.4g(粗品)。O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (7h) (3.20g, 8.18mmol) Dissolve in THF (30ml), add lithium hydroxide (282mg, 12.3mmol), water (5mL), stir at room temperature for 30 minutes, and concentrate under reduced pressure to obtain 3.4g of the title compound as a black oil (crude product).
LC-MS：m/z 378[M+H] +。 LC-MS: m/z 378 [M+H] + .
步骤10：(S)-(2-环丙基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(7j)的制备Step 10: (S)-(2-Cyclopropyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4',5':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-7-yl) tert-butyl carbamate (7j)
将O-(5-氨基-2-环丙基苯并[d]噁唑-6-基)-N-(叔丁氧羰基)-L-丝氨酸(7i)(3.20g，8.48mmol)溶于50mL DMF，加入DIEA(1.64g，12.8mmol)和HATU(4.54g，12.8mmol)，于室温搅拌1小时。加入20mL水，EA萃取(20mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:1)，得浅黄色固体的标题化合物710mg，收率：23.3％。O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i) (3.20 g, 8.48 mmol) was dissolved in 50mL DMF, added DIEA (1.64g, 12.8mmol) and HATU (4.54g, 12.8mmol), stirred at room temperature for 1 hour. Add 20mL of water, extract with EA (20mL x 3), wash with saturated brine (20mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:1), to obtain 710 mg of the title compound as a pale yellow solid, yield: 23.3%.
LC-MS：m/z 360[M+H] +。 LC-MS: m/z 360 [M+H] + .
步骤11：(S)-(2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(7k)的制备Step 11: (S)-(2-Cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4',5':4,5]benzo Preparation of tert-butyl [1,2-b][1,4]oxazepine-7-yl)carbamate (7k)
将(S)-(2-环丙基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(7j)(500mg，1.39mmol)溶于DMF(10ml)，加入Cs 2CO 3(680mg，2.09mmol)和碘甲烷(197mg，1.39mmol)，于室温搅拌2小时。加水稀释，EA萃取(15mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色油状标题化合物480mg，收率92.6％。 (S)-(2-Cyclopropyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4',5':4,5]benzo[1,2-b] [1,4]Oxazepin-7-yl) tert-butyl carbamate (7j) (500 mg, 1.39 mmol) was dissolved in DMF (10 ml), Cs 2 CO 3 (680 mg, 2.09 mmol) and iodomethane ( 197mg, 1.39mmol), stirred at room temperature for 2 hours. Diluted with water, extracted with EA (15mL x 3), washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/ EA=3:1), 480 mg of the title compound was obtained as a yellow oil, with a yield of 92.6%.
LC-MS：m/z 374[M+H] +。 LC-MS: m/z 374 [M+H] + .
步骤12：(S)-7-氨基-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(7l)的制备Step 12: (S)-7-Amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b Preparation of ][1,4]oxazepine-6(5H)-one (7l)
于室温，将(S)-(2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(7k)(200mg，0.536mmol)溶于2mL DCM中，向反应液中加入盐酸二氧六环溶液(0.4ml，4M)，室温搅拌2小时。加入10mL饱和NaHCO 3溶液，用DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物140mg(粗品)。 At room temperature, (S)-(2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4',5':4,5]benzene And[1,2-b][1,4]oxazepin-7-yl) tert-butyl carbamate (7k) (200 mg, 0.536 mmol) was dissolved in 2 mL of DCM, and dioxygen hydrochloride was added to the reaction solution Hexacyclic solution (0.4ml, 4M) was stirred at room temperature for 2 hours. Add 10 mL of saturated NaHCO 3 solution, extract with DCM (10 mL x 3), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 140 mg of the title compound as a yellow oil (crude product).
LC-MS：m/z 274[M+H] +。 LC-MS: m/z 274 [M+H] + .
其余步骤与实施例1的制备方法相同，除了(S)-7-氨基-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(7l)代替步骤11中的(S)-7-氨基-1,3,9三甲基-3,6,7,9四氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-2,8-二 酮(1k)，制得标题化合物7。The remaining steps are the same as the preparation method of Example 1, except (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5 ]benzo[1,2-b][1,4]oxazepine-6(5H)-one (7l) instead of (S)-7-amino-1,3,9trimethyl in step 11 -3,6,7,9 Tetrahydro-1H-imidazo[4',5':4,5]benzo[1,2-b][1,4]oxazepine-2,8-di Ketone (1k), yielding the title compound 7.
LC-MS：m/z 518.00[M+H] +。 LC-MS: m/z 518.00 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.80(s,1H),7.60(s,1H),7.39-7.25(m,3H),7.22-7.15(m,2H),5.55(dd,J＝12.0,8.0Hz,1H),5.42(s,2H),4.83(dd,J＝12.0,10.1Hz,1H),4.33(dd,J＝10.0,8.0Hz,1H),4.04(ddd,J＝12.3,7.0,5.1Hz,1H),3.63(ddd,J＝12.9,8.6,4.8Hz,1H),3.38(s,3H),2.80(ddd,J＝15.4,8.6,5.1Hz,1H),2.68(ddd,J＝15.5,6.9,4.8Hz,1H),2.29(tt,J＝8.2,4.9Hz,1H),1.26-1.10(m,4H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.80(s,1H),7.60(s,1H),7.39-7.25(m,3H),7.22-7.15(m,2H),5.55(dd,J =12.0,8.0Hz,1H),5.42(s,2H),4.83(dd,J=12.0,10.1Hz,1H),4.33(dd,J=10.0,8.0Hz,1H),4.04(ddd,J= 12.3,7.0,5.1Hz,1H),3.63(ddd,J＝12.9,8.6,4.8Hz,1H),3.38(s,3H),2.80(ddd,J＝15.4,8.6,5.1Hz,1H),2.68 (ddd, J=15.5, 6.9, 4.8Hz, 1H), 2.29(tt, J=8.2, 4.9Hz, 1H), 1.26-1.10(m, 4H).
实施例8：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1,8二甲基-1,3,4,8-四氢-2H-[1,4]氧氮杂卓并3,2-e]吲唑-2-酮(8)的制备Example 8: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1,8-dimethyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepine3,2-e]indazol-2-one (8) preparation of
Figure PCTCN2022092607-appb-000044
Figure PCTCN2022092607-appb-000044
步骤1：7-硝基-1H-吲唑-6-醇(8a)的制备Step 1: Preparation of 7-nitro-1H-indazol-6-ol (8a)
于室温，将1H-吲唑-6-醇(3.00g，22.4mmol)溶于30ml浓硫酸中，于0℃，加入硝酸钠(2.10g，24.7mmol)，室温搅拌2小时。反应液倒入冰水中，过滤，水洗滤饼(10mL x 3)，干燥，得黄色固体的标题化合物4.45g(粗品)。1H-Indazol-6-ol (3.00g, 22.4mmol) was dissolved in 30ml of concentrated sulfuric acid at room temperature, and sodium nitrate (2.10g, 24.7mmol) was added at 0°C, and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, filtered, the filter cake (10mL x 3) was washed with water, and dried to obtain 4.45g (crude product) of the title compound as a yellow solid.
LC-MS：m/z 180.0[M+H] +。 LC-MS: m/z 180.0 [M+H] + .
步骤2：N-(叔丁氧基羰基)-O-(7-硝基-1H-吲唑-6-基)-D-丝氨酸甲酯(8b)的制备Step 2: Preparation of N-(tert-butoxycarbonyl)-O-(7-nitro-1H-indazol-6-yl)-D-serine methyl ester (8b)
将7-硝基-1H-吲唑-6-醇(8a)(3.90g，19.6mmol)、(叔丁氧基羰基)-D-丝氨酸甲酯(5.89g，26.9mmol)和三苯基膦(11.7，44.8mmol)溶于200mL THF中，氮气氛下，于0℃，加入DIAD(9.05g，44.8mmol)，于室温搅拌过夜。加入100mL水淬灭，DCM萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:1)，得黄色固体标题化合物9.46g(粗品)。7-Nitro-1H-indazol-6-ol (8a) (3.90g, 19.6mmol), (tert-butoxycarbonyl)-D-serine methyl ester (5.89g, 26.9mmol) and triphenylphosphine (11.7, 44.8mmol) was dissolved in 200mL THF, under nitrogen atmosphere, DIAD (9.05g, 44.8mmol) was added at 0°C, and stirred overnight at room temperature. Add 100mL water to quench, DCM extraction (200mL x 3), saturated brine washing (200mL x 1), anhydrous sodium sulfate drying, filtration, the filtrate is concentrated under reduced pressure, the residue is separated and purified by silica gel column chromatography (mobile Phase: PE/EA=100:1-1:1), to obtain 9.46 g of the title compound (crude product) as a yellow solid.
LC-MS：m/z 381.13[M+H] +。 LC-MS: m/z 381.13 [M+H] + .
步骤3：O-(7-氨基-1H-吲唑-6-基)-N-(叔丁氧基羰基)-D-丝氨酸甲酯(8c)的 制备Step 3: Preparation of O-(7-amino-1H-indazol-6-yl)-N-(tert-butoxycarbonyl)-D-serine methyl ester (8c)
将N-(叔丁氧基羰基)-O-(7-硝基-1H-吲唑-6-基)-D-丝氨酸甲酯(8b)(8.95g，23.6mmol)溶于80mL MeOH中，加入含水钯炭(2.00g)，氢气氛下，室温搅拌过夜。过滤，甲醇洗涤滤饼(10mL x 3)，滤液减压浓缩，得红棕色固体标题化合物8.11g，收率：98.4％。N-(tert-butoxycarbonyl)-O-(7-nitro-1H-indazol-6-yl)-D-serine methyl ester (8b) (8.95 g, 23.6 mmol) was dissolved in 80 mL MeOH, Hydrous palladium on carbon (2.00 g) was added, and stirred overnight at room temperature under a hydrogen atmosphere. Filter, wash the filter cake (10mL x 3) with methanol, and concentrate the filtrate under reduced pressure to obtain 8.11g of the title compound as a reddish-brown solid, yield: 98.4%.
LC-MS：m/z 351.16[M+H] +。 LC-MS: m/z 351.16 [M+H] + .
步骤4：(S)-(9-氧代-7,8,9,10-四氢-1H-[1,4]氧氮杂卓并[2,3-g]吲唑-8-基)氨基甲酸叔丁酯(8d)的制备Step 4: (S)-(9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepine[2,3-g]indazol-8-yl) Preparation of tert-butyl carbamate (8d)
将O-(7-氨基-1H-吲唑-6-基)-N-(叔丁氧基羰基)-D-丝氨酸甲酯(8c)(4.05g，11.6mmol)溶于50ml CHCl 3中，氮气氛下，于0℃，向反应液中加入5mL三甲基铝溶液(2mol/L)，于50℃搅拌过夜。加入甲醇淬灭，过滤，DCM洗涤滤饼(10mL x 3)，滤液减压浓缩，得黄色固体状标题化合物4.71g(粗品)。 O-(7-Amino-1H-indazol-6-yl)-N-(tert-butoxycarbonyl)-D-serine methyl ester (8c) (4.05 g, 11.6 mmol) was dissolved in 50 ml CHCl 3 , Under a nitrogen atmosphere, 5 mL of trimethylaluminum solution (2 mol/L) was added to the reaction solution at 0°C, and stirred overnight at 50°C. It was quenched by adding methanol, filtered, the filter cake was washed with DCM (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain 4.71 g of the title compound (crude product) as a yellow solid.
LC-MS：m/z 319.13[M+H] +。 LC-MS: m/z 319.13 [M+H] + .
步骤5：(S)-(1,10-二甲基-9-氧代-7,8,9,10-四氢-1H-[1,4]氧氮杂卓并[2,3-g]吲唑-8-基)氨基甲酸叔丁酯(8e)的制备Step 5: (S)-(1,10-Dimethyl-9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepine[2,3-g Preparation of ]indazol-8-yl) tert-butyl carbamate (8e)
将(S)-(9-氧代-7,8,9,10-四氢-1H-[1,4]氧氮杂卓并[2,3-g]吲唑-8-基)氨基甲酸叔丁酯(8d)(1.41g，4.44mmol)溶于60mL DMF，加入碳酸铯(2.89g，8.88mmol)，于0℃，加入碘甲烷(1.26g，8.88mmol)，于0℃搅拌2小时。加入100mL水，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得浅黄色油状的标题化合物3.23g(粗品)。(S)-(9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepine[2,3-g]indazol-8-yl)carbamate Tert-butyl ester (8d) (1.41g, 4.44mmol) was dissolved in 60mL DMF, cesium carbonate (2.89g, 8.88mmol) was added, at 0°C, methyl iodide (1.26g, 8.88mmol) was added, stirred at 0°C for 2 hours . Added 100mL of water, extracted with EA (100mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3.23g of the title compound (crude product) as light yellow oil.
LC-MS：m/z 347.16[M+H] +。 LC-MS: m/z 347.16 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用(S)-(1,10-二甲基-9-氧代-7,8,9,10-四氢-1H-[1,4]氧氮杂卓并[2,3-g]吲唑-8-基)氨基甲酸叔丁酯(8e)代替步骤10中的(S)-(1,3,9-三甲基-2,8-二氧代-2,3,6,7,8,9-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(1j)，制得标题化合物8。The remaining steps are the same as the preparation method of Example 1, except that (S)-(1,10-dimethyl-9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxo Azepine[2,3-g]indazol-8-yl)carbamate tert-butyl ester (8e) instead of (S)-(1,3,9-trimethyl-2,8- Dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-b][1,4]oxazone tert-butyl carbamate (1j) to give the title compound 8.
LC-MS:m/z 491.15[M+H] +。 LC-MS: m/z 491.15 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ:8.49(s,1H),7.70(d,1H),7.39-7.26(m,3H),7.19(d,2H),6.96(d,J＝8.8Hz,1H),5.59(dd,1H),5.42(s,2H),4.91(t,1H),4.43(t,1H),4.20(s,3H),4.14-4.00(m,1H),3.74-3.58(m,1H),3.47(s,3H),2.90-2.76(m,1H),2.75-2.64(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ: 8.49(s, 1H), 7.70(d, 1H), 7.39-7.26(m, 3H), 7.19(d, 2H), 6.96(d, J=8.8 Hz,1H),5.59(dd,1H),5.42(s,2H),4.91(t,1H),4.43(t,1H),4.20(s,3H),4.14-4.00(m,1H),3.74 -3.58(m,1H),3.47(s,3H),2.90-2.76(m,1H),2.75-2.64(m,1H).
实施例9：(7S)-7-(2-苄基-3-氯)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-9-甲基-8-氧代-6,7,8,9-四氢-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-2-羧酸乙酯(9)的制备Example 9: (7S)-7-(2-Benzyl-3-chloro)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine -6-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-[1,3]dioxole[4',5':4,5] Preparation of ethyl benzo[1,2-b][1,4]oxazepine-2-carboxylate (9)
Figure PCTCN2022092607-appb-000045
Figure PCTCN2022092607-appb-000045
步骤1：4,5-二甲氧基-2-硝基苯酚(9a)的制备Step 1: Preparation of 4,5-dimethoxy-2-nitrophenol (9a)
于室温，将4,5-二甲氧基-2-硝基苯甲醛(5.00g，23.7mmol)溶于100mL DCM，于0℃加入m-CPBA(10.9g，63.4mmol)，氮气氛下，于0℃加入TFA(1.76mL)，室温搅拌过夜。于0℃，加入饱和硫代硫酸钠溶液淬灭，过滤，DCM洗涤滤饼，有机相用饱和碳酸氢钠溶液洗涤(100mL x 1)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品溶于70mL甲醇中，加入2mol/L的NaOH溶液(30mL)，于室温搅拌1小时。1mol/L的盐酸调节PH至3-4，过滤，甲醇洗涤滤饼，收集滤饼，干燥得黄色固体的标题化合物3.25g，收率：69.0％。At room temperature, 4,5-dimethoxy-2-nitrobenzaldehyde (5.00g, 23.7mmol) was dissolved in 100mL DCM, m-CPBA (10.9g, 63.4mmol) was added at 0°C, under nitrogen atmosphere, TFA (1.76 mL) was added at 0°C and stirred at room temperature overnight. At 0°C, add saturated sodium thiosulfate solution to quench, filter, wash the filter cake with DCM, wash the organic phase with saturated sodium bicarbonate solution (100mL x 1), wash with saturated brine (100mL x 1), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was dissolved in 70 mL of methanol, 2 mol/L NaOH solution (30 mL) was added, and stirred at room temperature for 1 hour. Adjust the pH to 3-4 with 1 mol/L hydrochloric acid, filter, wash the filter cake with methanol, collect the filter cake, and dry to obtain 3.25 g of the title compound as a yellow solid, yield: 69.0%.
LC-MS：m/z 200.0[M+H] +。 LC-MS: m/z 200.0 [M+H] + .
步骤2：O-(4,5-二甲氧基-2-硝基苯基)-N-三苯甲基-L-丝氨酸甲酯(9b)的制备Step 2: Preparation of O-(4,5-dimethoxy-2-nitrophenyl)-N-trityl-L-serine methyl ester (9b)
于室温，将4,5-二甲氧基-2-硝基苯酚(9a)(3.25g，12.3mmol)、甲基三苯甲基-L-丝氨酸(6.64g，18.4mmol)和三苯基膦(6.45g，24.5mmol)溶于150mL THF中，氮气氛下，于0℃，加入DIAD(4.95g，24.5mmol)，于室温搅拌过夜。加入100mL水淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(150mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-2:1)，得黄色油状标题化合物13.2g(粗品)。At room temperature, 4,5-dimethoxy-2-nitrophenol (9a) (3.25g, 12.3mmol), methyltrityl-L-serine (6.64g, 18.4mmol) and triphenyl Phosphine (6.45g, 24.5mmol) was dissolved in 150mL THF. Under nitrogen atmosphere, DIAD (4.95g, 24.5mmol) was added at 0°C, and stirred overnight at room temperature. Add 100mL water to quench, EA extract (100mL x 3), wash with saturated brine (150mL x 1), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile Phase: PE/EA=100:1-2:1), to obtain 13.2 g of the title compound (crude product) as a yellow oil.
步骤3：O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(9c)的制备Step 3: Preparation of O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9c)
将O-(4,5-二甲氧基-2-硝基苯基)-N-三苯甲基-L-丝氨酸甲酯(9b)(13.2g，21.7 mmol)溶于100ml DCM中，加入4mol/L的盐酸二氧六环溶液(20mL)，室温搅拌过夜。减压浓缩，打浆三次(EA/PE＝3:1)，过滤，滤饼干燥，得浅黄色固体标题化合物3.05g，收率：46.8％。Dissolve O-(4,5-dimethoxy-2-nitrophenyl)-N-trityl-L-serine methyl ester (9b) (13.2 g, 21.7 mmol) in 100 ml DCM, add 4 mol/L dioxane hydrochloride solution (20 mL), stirred overnight at room temperature. Concentrate under reduced pressure, beat three times (EA/PE=3:1), filter, and dry the filter cake to obtain 3.05 g of the title compound as a light yellow solid, yield: 46.8%.
LC-MS：m/z 301.10[M+H] +。 LC-MS: m/z 301.10 [M+H] + .
步骤4：N-(叔丁氧基羰基)-O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(9d)的制备Step 4: Preparation of N-(tert-butoxycarbonyl)-O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9d)
将O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(9c)(3.05g，10.2mmol)溶于50mL DCM中，加入DIEA(3.93g,30.5mmol)，室温搅拌20分钟，于0℃，分批加入Boc 2O(3.32g，15.2mmol)，室温搅拌过夜。加入100mL水，用DCM萃取(50mL x 2)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物5.01g(粗品)。 Dissolve O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9c) (3.05g, 10.2mmol) in 50mL DCM, add DIEA (3.93g, 30.5mmol ), stirred at room temperature for 20 minutes, added Boc 2 O (3.32 g, 15.2 mmol) in batches at 0° C., and stirred overnight at room temperature. Add 100 mL of water, extract with DCM (50 mL x 2), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 5.01 g of the title compound as a yellow oil (crude product).
LC-MS：m/z 401.15[M+H] +。 LC-MS: m/z 401.15 [M+H] + .
步骤5：O-(2-氨基-4,5-二甲氧基苯基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(9e)的制备Step 5: Preparation of O-(2-amino-4,5-dimethoxyphenyl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (9e)
将N-(叔丁氧基羰基)-O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(9d)(5.01g，12.5mmol)溶于50ml MeOH中，加入含水钯炭(2.50g)，氢气氛下，室温搅拌过夜。过滤，甲醇洗涤滤饼(10mL x 3)，滤液减压浓缩，得黑色油状标题化合物4.75g(粗品)。Dissolve N-(tert-butoxycarbonyl)-O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9d) (5.01 g, 12.5 mmol) in 50 ml MeOH , added hydrous palladium carbon (2.50 g), and stirred overnight at room temperature under a hydrogen atmosphere. Filter, wash the filter cake (10mL x 3) with methanol, and concentrate the filtrate under reduced pressure to obtain 4.75 g of the title compound as a black oil (crude product).
LC-MS：m/z 371.17[M+H] +。 LC-MS: m/z 371.17 [M+H] + .
步骤6：(S)-(7,8-二甲氧基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓]-3-基)氨基甲酸叔丁酯(9f)的制备Step 6: (S)-(7,8-Dimethoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine]-3- base) preparation of tert-butyl carbamate (9f)
将O-(2-氨基-4,5-二甲氧基苯基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(9e)(4.75g,12.5mmol)溶于CHCl 3(80ml)中，氮气氛下，于0℃向反应液中加入三甲基铝溶液(2.7mL，2mol/L)，50℃搅拌3小时。加入甲醇淬灭，减压浓缩，残余物用DCM/MeOH＝5:1(10mL x 5)打浆，过滤，收集滤液，减压浓缩，得黑色油状标题化合物2.65g，收率：62.8％。 Dissolve O-(2-amino-4,5-dimethoxyphenyl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (9e) (4.75g, 12.5mmol) in CHCl 3 (80ml ), under a nitrogen atmosphere, trimethylaluminum solution (2.7 mL, 2 mol/L) was added to the reaction solution at 0°C, and stirred at 50°C for 3 hours. Add methanol to quench and concentrate under reduced pressure. The residue was slurried with DCM/MeOH=5:1 (10 mL x 5), filtered, the filtrate was collected, and concentrated under reduced pressure to obtain 2.65 g of the title compound as a black oil, yield: 62.8%.
LC-MS：m/z 339.15[M+H] +。 LC-MS: m/z 339.15 [M+H] + .
步骤7：(S)-(7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓]-3-基)氨基甲酸叔丁基(9g)的制备Step 7: (S)-(7,8-Dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Preparation of tert-butyl carbamate (9g)
将(S)-(7,8-二甲氧基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓]-3-基)氨基甲酸叔丁酯(9f)(2.65g，7.84mmol)溶于35mL DMF，加入碳酸铯(3.83g，11.7mmol)，室温搅拌30min。于0℃加入碘甲烷(1.11g，7.82mmol)，于室温搅拌2h。加入50mL水，EA萃取(30mL x 3)，饱和食盐水洗涤(30mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-3:1)，得黄色油状标题化合物650mg，收率：23.6％。(S)-(7,8-dimethoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine]-3-yl) Tert-butyl carbamate (9f) (2.65g, 7.84mmol) was dissolved in 35mL DMF, cesium carbonate (3.83g, 11.7mmol) was added, and stirred at room temperature for 30min. Add iodomethane (1.11 g, 7.82 mmol) at 0° C. and stir at room temperature for 2 h. Add 50mL of water, extract with EA (30mL x 3), wash with saturated brine (30mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-3:1), to obtain 650 mg of the title compound as yellow oil, yield: 23.6%.
LC-MS：m/z 353.16[M+H] +。 LC-MS: m/z 353.16 [M+H] + .
步骤8：(S)-3-氨基-7,8-二甲氧基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(9h)的制备Step 8: (S)-3-Amino-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H) - Preparation of ketone (9h)
将(S)-(7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓]-3-基)氨基甲酸叔丁基(9g)(650mg，1.85mmol)溶于DCM(10ml)中，向反应液中加入4mol/L的盐酸二氧六环溶液(3mL)，于室温搅拌过夜。加入10mL饱和碳酸氢钠溶液，DCM萃取(10mL x 3)，饱和食盐水洗涤(15mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色半固体标题化合物380mg，收率：81.7％。(S)-(7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine] -3-yl) tert-butyl carbamate (9g) (650mg, 1.85mmol) was dissolved in DCM (10ml), and 4mol/L dioxane hydrochloride solution (3mL) was added to the reaction solution, and stirred overnight at room temperature . Add 10 mL of saturated sodium bicarbonate solution, extract with DCM (10 mL x 3), wash with saturated brine (15 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 380 mg of the yellow semi-solid title compound, yield: 81.7%.
LC-MS：m/z 253.27[M+H] +。 LC-MS: m/z 253.27 [M+H] + .
步骤9：(S)-1-苄基-5-氯-4-(2-((7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓-3-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(9i)的制备Step 9: (S)-1-Benzyl-5-chloro-4-(2-((7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5- Preparation of ethyl tetrahydrobenzo[b][1,4]oxazepin-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylate (9i)
将(S)-3-氨基-7,8-二甲氧基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(9h)(360mg，1.43mmol)、1-苄基-5-氯-4-甲酰基-1H-吡唑-3-羧酸乙酯(1m)(612mg，2.00mmol)溶于10mL甲醇，加入1mL冰醋酸和2-甲基吡啶硼烷复合物(214mg，2.00mmol)，室温搅拌2小时。加入20mL饱和碳酸氢钠溶液，用DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-2:3)，得红棕色色固体标题化合物400mg，收率：51.6％。(S)-3-amino-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9h) (360mg, 1.43mmol), ethyl 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylate (1m) (612mg, 2.00mmol) were dissolved in 10mL of methanol and added 1 mL of glacial acetic acid and 2-picoline borane complex (214 mg, 2.00 mmol), stirred at room temperature for 2 hours. Add 20mL saturated sodium bicarbonate solution, extract with DCM (10mL x 3), wash with saturated brine (20mL x 1), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated by silica gel column chromatography Purification (mobile phase: PE/EA=100:1-2:3) gave 400 mg of the title compound as a reddish-brown solid, yield: 51.6%.
LC-MS：m/z 543.19[M+H] +。 LC-MS: m/z 543.19 [M+H] + .
步骤10：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二甲氧基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(9j)的制备Step 10: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 Preparation of -yl)-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9j)
将(S)-1-苄基-5-氯-4-(2-((7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓-3-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(9i)(350mg，0.644mmol)溶于5ml甲苯中，氮气氛下，于0℃，加入Al(CH 3) 3甲苯溶液(0.97mL，2mol/L)，于90℃搅拌3小时。加10mL水淬灭，EA萃取(10mL x 3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:1)，得浅红色固体标题化合物330mg(粗品)。 (S)-1-benzyl-5-chloro-4-(2-((7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydro Benzo[b][1,4]oxazepin-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (9i) (350mg, 0.644mmol) was dissolved in 5ml of toluene , under a nitrogen atmosphere, Al(CH 3 ) 3 toluene solution (0.97 mL, 2 mol/L) was added at 0°C, and stirred at 90°C for 3 hours. Add 10 mL of water to quench, extract with EA (10 mL x 3), wash with saturated brine (10 mL x 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase : PE/EA=100:1-1:1), to obtain 330 mg of the title compound (crude product) as a light red solid.
LC-MS：m/z 496.29[M+H] +。 LC-MS: m/z 496.29 [M+H] + .
步骤11：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二羟基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(9k)的制备Step 11: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 Preparation of -yl)-7,8-dihydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9k)
于室温，将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二甲氧基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(9j)(250mg，0.503mmol)溶于6mL二氯甲烷，于0℃加入三溴化硼的二氯甲烷溶液(1M，3mL)，于室温搅拌2小时。于0℃滴加甲醇淬灭，DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩得红棕色色固体标题化合物270mg(粗品)。At room temperature, (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (9j)( 250mg, 0.503mmol) was dissolved in 6mL of dichloromethane, and a solution of boron tribromide in dichloromethane (1M, 3mL) was added at 0°C, and stirred at room temperature for 2 hours. Add dropwise methanol to quench at 0°C, extract with DCM (10mL x 3), wash with saturated brine (20mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 270mg of the title compound as a reddish-brown solid (crude product) .
步骤12：(7S)-7-(2-苄基-3-氯)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6- 基)-9-甲基-8-氧代-6,7,8,9-四氢-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-2-羧酸乙酯(9)的制备Step 12: (7S)-7-(2-Benzyl-3-chloro)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-[1,3]dioxole[4',5':4,5]benzene Preparation of ethyl[1,2-b][1,4]oxazepine-2-carboxylate (9)
将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二羟基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(9k)(300mg，0.641mmol)溶于10ml乙腈中，加入碳酸钾(265mg，1.92mmol)和2,2-二溴乙酸乙酯(234mg，0.960mmol)，于70℃搅拌过夜。加10mL水，EA萃取(10mL x 3)，饱和食盐水洗涤(10mL x 3)，无水硫酸钠干燥，过滤，减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物33mg，收率：9.32％。(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl )-7,8-dihydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9k) (300mg, 0.641mmol) Dissolve in 10ml of acetonitrile, add potassium carbonate (265mg, 1.92mmol) and ethyl 2,2-dibromoacetate (234mg, 0.960mmol), and stir overnight at 70°C. Add 10mL of water, extract with EA (10mL x 3), wash with saturated brine (10mL x 3), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is separated by high-pressure preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), the title compound was obtained as a white solid 33 mg, yield: 9.32%.
LC-MS：m/z 553.0[M+H] +。 LC-MS: m/z 553.0 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.38-7.28(m,4H),7.22-7.17(m,2H),7.01(d,J＝2.1Hz,1H),6.74(d,J＝6.7Hz,1H),5.55(dt,J＝11.9,7.8Hz,1H),5.43(s,2H),4.82-4.71(m,1H),4.38-4.21(m,3H),4.08-3.96(m,1H),3.66-3.56(m,1H),3.23(d,J＝1.8Hz,3H),2.84-2.74(m,1H),2.73-2.62(m,1H),1.29-1.22(m,3H)。 1 H NMR (400MHz, DMSO-d6) δ7.38-7.28(m, 4H), 7.22-7.17(m, 2H), 7.01(d, J=2.1Hz, 1H), 6.74(d, J=6.7Hz ,1H),5.55(dt,J＝11.9,7.8Hz,1H),5.43(s,2H),4.82-4.71(m,1H),4.38-4.21(m,3H),4.08-3.96(m,1H ), 3.66-3.56 (m, 1H), 3.23 (d, J=1.8Hz, 3H), 2.84-2.74 (m, 1H), 2.73-2.62 (m, 1H), 1.29-1.22 (m, 3H).
实施例10：(S)-8-(2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2,10-二甲基-7,8-二氢噻唑并[5',4':3,4]苯并[1,2-b][1,4]氧氮杂卓-9(10H)-酮(10)的制备Example 10: (S)-8-(2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine -6-yl)-2,10-dimethyl-7,8-dihydrothiazolo[5',4':3,4]benzo[1,2-b][1,4]oxazepine Preparation of Zol-9(10H)-one (10)
Figure PCTCN2022092607-appb-000046
Figure PCTCN2022092607-appb-000046
步骤1：1-(2-氟苄基)-5-羟基-1H-吡唑-3-羧酸乙酯(10a)的制备Step 1: Preparation of ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (10a)
于室温，将草酸二乙酯钠盐(10.0g，47.6mmol)溶于HAc(42.8g，714mmol)和二氧六环(100ml)中，室温搅拌0.5小时，加入(2-氟苯基)联胺(10.0g，71.4mmol)，于100℃搅拌2小时。加水淬灭，用EA萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分 离纯化(流动相PE/EA＝3:1)，得黄色半固体状标题化合物12.5g，收率44.2％。Dissolve diethyl oxalate sodium salt (10.0g, 47.6mmol) in HAc (42.8g, 714mmol) and dioxane (100ml) at room temperature, stir at room temperature for 0.5 hours, add (2-fluorophenyl) Amine (10.0 g, 71.4 mmol), stirred at 100°C for 2 hours. Quenched with water, extracted with EA (200mL x 3), washed with saturated brine (200mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain 12.5 g of the title compound as a yellow semi-solid, with a yield of 44.2%.
LC-MS：m/z 265[M+H] +。 LC-MS: m/z 265 [M+H] + .
步骤2：5-氯-1-(2-氟苄基)-4-甲酰基-1H-吡唑-3-羧酸乙酯(10b)的制备。Step 2: Preparation of ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate (10b).
将1-(2-氟苄基)-5-羟基-1H-吡唑-3-羧酸乙酯(10a)(7.50g，28.4mmol)溶于DMF(10.0mL，114mmol)中，于0℃加入POCl 3(24ml，228mmol)，于90℃搅拌2小时。将反应液加到冰水中，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得浅棕色油状标题化合物600mg，收率6.80％。 Dissolve ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (10a) (7.50g, 28.4mmol) in DMF (10.0mL, 114mmol) at 0°C POCl 3 (24ml, 228mmol) was added and stirred at 90°C for 2 hours. The reaction solution was added to ice water, extracted with EA (100mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 600 mg of the title compound was obtained as a light brown oil, with a yield of 6.80%.
LC-MS：m/z 311[M+H] +。 LC-MS: m/z 311 [M+H] + .
步骤3：5-氯-1-(2-氟苄基)-4-(2-甲氧乙烯基)-1H-吡唑-3-甲酸乙酯(10c)的制备Step 3: Preparation of ethyl 5-chloro-1-(2-fluorobenzyl)-4-(2-methoxyethenyl)-1H-pyrazole-3-carboxylate (10c)
将氯(甲氧甲基)三苯基磷(4.38g，12.8mmol)溶于THF(15mL)中，于0℃缓慢加入20％EtONa溶液(3.94ml，11.6mmol)，搅拌0.5小时，缓慢加入5-氯-1-(2-氟苄基)-4-甲酰基-1H-吡唑-3-羧酸乙酯(10b)(900mg，2.90mmol)的THF(15mL)溶液，于室温搅拌3小时，将反应液加到冰水中，EA萃取(30mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝5:1)，得黄色油状标题化合物600mg，收率55.0％。Dissolve chloro(methoxymethyl)triphenylphosphine (4.38g, 12.8mmol) in THF (15mL), slowly add 20% EtONa solution (3.94ml, 11.6mmol) at 0°C, stir for 0.5 hours, and slowly add 5-Chloro-1-(2-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (10b) (900mg, 2.90mmol) in THF (15mL) was stirred at room temperature for 3 After 1 hour, the reaction solution was added to ice water, extracted with EA (30mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=5:1) gave 600 mg of the title compound as a yellow oil with a yield of 55.0%.
LC-MS：m/z 338[M+H] +。 LC-MS: m/z 338 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用5-氯-1-(2-氟苄基)-4-(2-甲氧乙烯基)-1H-吡唑-3-甲酸乙酯(10c)代替1-苄基-5-氯-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(1n)，用N-(叔丁氧基羰基)-O-(2-甲基-7-硝基苯并[d]噻唑-6-基)-L-丝氨酸甲酯(6b)代替步骤8中的N-(叔丁氧基羰基)-O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-L-丝氨酸甲酯(1g)，制得标题化合物10。The remaining steps are the same as the preparation method of Example 1, except that ethyl 5-chloro-1-(2-fluorobenzyl)-4-(2-methoxyethenyl)-1H-pyrazole-3-carboxylate (10c ) instead of ethyl 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (1n), with N-(tert-butoxycarbonyl)-O -(2-Methyl-7-nitrobenzo[d]thiazol-6-yl)-L-serine methyl ester (6b) in place of N-(tert-butoxycarbonyl)-O-(1 , 3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1 g), the title Compound 10.
LC-MS：m/z 492.14[M+H] +。 LC-MS: m/z 492.14 [M+H] + .
1H NMR(400MHz,CD 3OD)δ:7.85(d,1H),7.57(s,1H),7.41(d,1H),7.28-7.26(m,1H),7.23-7.21(m,1H),7.13-7.08(m,2H),5.73(t,1H),5.41(s,2H),4.87(s,1H),4.43(t,1H),4.18-4.15(m,1H),3.41(s,3H),3.03-2.98(m,1H),2.86(s,3H),2.82-2.77(m,2H)。 1 H NMR (400MHz, CD 3 OD)δ:7.85(d,1H),7.57(s,1H),7.41(d,1H),7.28-7.26(m,1H),7.23-7.21(m,1H) ,7.13-7.08(m,2H),5.73(t,1H),5.41(s,2H),4.87(s,1H),4.43(t,1H),4.18-4.15(m,1H),3.41(s ,3H), 3.03-2.98(m,1H), 2.86(s,3H), 2.82-2.77(m,2H).
实施例11：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2,2-二氟-9-甲基-6,7-二氢-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(11)的制备Example 11: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxole[4',5':4,5]benzo[ Preparation of 1,2-b][1,4]oxazepine-8(9H)-one (11)
Figure PCTCN2022092607-appb-000047
Figure PCTCN2022092607-appb-000047
步骤1：5-溴-2,2-二氟-6-硝基苯并[d][1,3]二氧杂环戊烯(11a)的制备Step 1: Preparation of 5-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxole (11a)
于0℃，将5-溴-2,2-二氟苯并[d][1,3]二氧杂环戊烯(5.00g，21.2mmol)滴加至TFA(50mL)中，于0℃滴加浓HNO 3(2.94g，31.8mmol)，于室温搅拌2小时。反应液倒入冰水中，EA萃取(200mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝6:1)，得黄色油状标题化合物3.0g，收率50.3％。 At 0°C, 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (5.00g, 21.2mmol) was added dropwise to TFA (50mL), and at 0°C Concentrated HNO 3 (2.94 g, 31.8 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with EA (200mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Mobile phase PE/EA=6:1), to obtain 3.0 g of the title compound as a yellow oil, with a yield of 50.3%.
LC-MS：m/z 281.9[M+H] +。 LC-MS: m/z 281.9 [M+H] + .
步骤2：2,2-二氟-6-硝基苯并[d][1,3]二氧杂环戊烯-5-醇(11b)的制备Step 2: Preparation of 2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-ol (11b)
将5-溴-2,2-二氟-6-硝基苯并[d][1,3]二氧杂环戊烯(11a)(4.30g，15.3mmol)、联硼酸频哪醇酯(8.53g，22.9mmol)、Pd(dppf)Cl 2(2.24g，3.06mmol)、KOAc(2.96g，30.3mmol)溶于二氧六环(44ml)中，氮气氛下，于80℃下搅拌2小时。EA萃取(200mL x 3)，饱和食盐水洗涤(100mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黑色固体标题化合物8.9g(粗品)。 5-Bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxole (11a) (4.30 g, 15.3 mmol), pinacol diboronate ( 8.53g, 22.9mmol), Pd(dppf)Cl 2 (2.24g, 3.06mmol), KOAc (2.96g, 30.3mmol) were dissolved in dioxane (44ml), and stirred at 80°C for 2 Hour. Extracted with EA (200 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 8.9 g of the title compound as a black solid (crude product).
将粗品8.9g溶于DCM(43mL)与MeOH(43mL)中，于0℃下加入双氧 水(8.6mL)，室温搅拌过夜。减压浓缩，DCM(50mL×2)萃取，饱和食盐水洗涤(50mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝100:1),得棕色固体标题化合物2.5g，收率74.6％。8.9 g of the crude product was dissolved in DCM (43 mL) and MeOH (43 mL), hydrogen peroxide (8.6 mL) was added at 0°C, and stirred overnight at room temperature. Concentrated under reduced pressure, extracted with DCM (50mL×2), washed with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE /EA=100:1), to obtain 2.5 g of the title compound as a brown solid, with a yield of 74.6%.
LC-MS：m/z 218.0[M-H] -。 LC-MS: m/z 218.0 [MH] - .
步骤3：O-(2,2-二氟-6-硝基苯并[d][1,3]二氧杂环戊烯-5-基)-N-三苯甲基-L-丝氨酸甲酯(11c)的制备Step 3: O-(2,2-Difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine methyl Preparation of ester (11c)
于室温，将2,2-二氟-6-硝基苯并[d][1,3]二氧杂环戊烯-5-醇(11b)(2.40g，11.0mmol)、三苯甲基-L-丝氨酸甲酯(5.93g,16.4mmol)溶于50mL THF中，氮气氛下，向反应液中加入PPh 3(5.74g，21.9mmol)、DIAD(4.43g，21.9mmol)，室温搅拌过夜。加入水稀释，用EA萃取(200mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩,残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝9:1)，得黄色固体状标题化合物4.30g，收率69.8％。 At room temperature, 2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-ol (11b) (2.40g, 11.0mmol), trityl - L-serine methyl ester (5.93g, 16.4mmol) was dissolved in 50mL THF, under a nitrogen atmosphere, PPh 3 (5.74g, 21.9mmol), DIAD (4.43g, 21.9mmol) were added to the reaction solution, and stirred overnight at room temperature . Diluted with water, extracted with EA (200mL x 3), washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=9:1), to obtain 4.30 g of the title compound as a yellow solid, with a yield of 69.8%.
LC-MS：m/z 563.2[M+H] +。 LC-MS: m/z 563.2 [M+H] + .
步骤4：O-(6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-三苯甲基-L-丝氨酸甲酯(11d)的制备Step 4: O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine methyl ester Preparation of (11d)
于室温，将O-(2,2-二氟-6-硝基苯并[d][1,3]二氧杂环戊烯-5-基)-N-三苯甲基-L-丝氨酸甲酯(11c)(1.50g，2.67mmol)溶于20mL EA中，向反应液中加入含水Pd/C(800mg)，氢气氛下，室温搅拌3小时。硅藻土过滤，加EA洗涤滤饼，滤液减压浓缩，得黑色油状的标题化合物1.6g(粗品)。At room temperature, O-(2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine Methyl ester (11c) (1.50g, 2.67mmol) was dissolved in 20mL of EA, and aqueous Pd/C (800mg) was added to the reaction solution, and stirred at room temperature for 3 hours under hydrogen atmosphere. Filter through celite, add EA to wash the filter cake, and concentrate the filtrate under reduced pressure to obtain 1.6 g of the title compound (crude product) as a black oil.
LC-MS：m/z 533.2[M+H] +。 LC-MS: m/z 533.2 [M+H] + .
步骤5：O-(6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-三苯甲基-L-丝氨酸(11e)的制备Step 5: O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine (11e ) preparation
将O-(6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-三苯甲基-L-丝氨酸甲酯(11d)(1.50g，2.82mmol)溶于THF(15ml)中，加入氢氧化锂(355mg，8.46mmol)、水(4.2mL)，于80℃搅拌16小时，减压浓缩，得黑色固体标题化合物2.3g(粗品)。O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine methyl ester (11d ) (1.50g, 2.82mmol) was dissolved in THF (15ml), lithium hydroxide (355mg, 8.46mmol) and water (4.2mL) were added, stirred at 80°C for 16 hours, and concentrated under reduced pressure to give the title compound 2.3 as a black solid g (crude).
LC-MS：m/z 519.2[M+H] +。 LC-MS: m/z 519.2 [M+H] + .
步骤6：(S)-2,2-二氟-7-(三苯甲基)-6,7-二氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,1,4]氧氮杂卓-8(9H)-酮(11f)的制备Step 6: (S)-2,2-Difluoro-7-(trityl)-6,7-dihydro-[1,3]dioxolo[4',5';4 ,5] Preparation of benzo[1,2-b][1,1,4]oxazepine-8(9H)-one (11f)
将O-(6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-三苯甲基-L-丝氨酸(11e)(2.20g，4.25mmol)溶于40mL DMF，加入DIEA(1.64g，12.7mmol)、HATU(2.42g，6.37mmol)，于室温搅拌2小时。加入20mL水，EA萃取(200mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝4:1),得白色固体标题化合物740mg，收率：34.7％。O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine (11e) ( 2.20g, 4.25mmol) was dissolved in 40mL DMF, added DIEA (1.64g, 12.7mmol), HATU (2.42g, 6.37mmol), and stirred at room temperature for 2 hours. Add 20mL of water, extract with EA (200mL x 3), wash with saturated brine (50mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=4:1), to obtain 740 mg of the title compound as a white solid, yield: 34.7%.
LC-MS：m/z 501.2[M+H] +。 LC-MS: m/z 501.2 [M+H] + .
步骤7：(S)-2,2-二氟-9-甲基-7-(三苯甲基)-6,7-二氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(11g)的制备Step 7: (S)-2,2-Difluoro-9-methyl-7-(trityl)-6,7-dihydro-[1,3]dioxole[4' ,5'; 4,5]Benzo[1,2-b][1,4]oxazepine-8(9H)-one (11g)
将(S)-2,2-二氟-7-(三苯甲基)-6,7-二氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,1,4]氧氮杂卓-8(9H)-酮(11f)(700mg，1.40mmol)溶于DMF(7ml),加入K 2CO 3(386mg，2.80mmol)、碘甲烷(199mg，1.40mmol)，于室温搅拌16小时。加水稀释，EA萃取(50mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝4:1)，得白色固体状标题化合物640mg，收率88.9％。 (S)-2,2-difluoro-7-(trityl)-6,7-dihydro-[1,3]dioxole[4',5'; 4,5 ]Benzo[1,2-b][1,1,4]oxazepine-8(9H)-one (11f) (700mg, 1.40mmol) was dissolved in DMF (7ml), added K 2 CO 3 ( 386mg, 2.80mmol), iodomethane (199mg, 1.40mmol), and stirred at room temperature for 16 hours. Diluted with water, extracted with EA (50mL x 3), washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/ EA=4:1), 640 mg of the title compound was obtained as a white solid, with a yield of 88.9%.
LC-MS：m/z 515.2[M+H] +。 LC-MS: m/z 515.2 [M+H] + .
步骤8：(S)-7-氨基-2,2-二氟-9-甲基-6,7-二氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(11h)制备Step 8: (S)-7-Amino-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxolo[4',5';4 ,5] Benzo[1,2-b][1,4]oxazepine-8(9H)-one (11h) preparation
于室温，(S)-2,2-二氟-9-甲基-7-(三苯甲基)-6,7-二氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(11g)(300mg，0.584mmol)溶于6mL DCM中，向反应液中加入TFA(200mg，1.75mmol)，室温搅拌2小时。加入冰水4mL淬灭，用DCM(10mL x 3)萃取，用1M NaOH溶液调节pH至弱碱性，用DCM(10mL x 3)萃取，饱和食盐水洗涤(4mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得白色固体标题化合物160mg(粗品)。At room temperature, (S)-2,2-difluoro-9-methyl-7-(trityl)-6,7-dihydro-[1,3]dioxole[4' ,5'; 4,5]benzo[1,2-b][1,4]oxazepine-8(9H)-one (11 g) (300 mg, 0.584 mmol) was dissolved in 6 mL of DCM and charged to the reaction TFA (200mg, 1.75mmol) was added to the solution and stirred at room temperature for 2 hours. Add ice water 4mL to quench, extract with DCM (10mL x 3), adjust pH to weak alkaline with 1M NaOH solution, extract with DCM (10mL x 3), wash with saturated brine (4mL x 2), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain 160 mg of the title compound (crude product) as a white solid.
LC-MS：m/z 273.1[M+H] +。 LC-MS: m/z 273.1 [M+H] + .
步骤9：(S)-1-苄基-5-氯-4-(2-((2,2-二氟-9-甲基-8-氧代-6,7,8,9-四氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(11i)制备Step 9: (S)-1-Benzyl-5-chloro-4-(2-((2,2-difluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro -[1,3]dioxole[4',5'; 4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl Base)-1H-pyrazole-3-carboxylic acid ethyl ester (11i) preparation
于室温，将(S)-7-氨基-2,2-二氟-9-甲基-6,7-二氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(11h)(160mg，0.588mmol)、1-苄基-5-氯-4-(2-甲酰基)-1H-吡唑-3-羧酸甲酯(1m)(270mg，0.882mmol)溶于5mL甲醇，向反应液中加入2-甲基吡啶硼烷复合物(94.0mg，0.882mmol)，室温搅拌16小时。EA萃取(20mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝2:1),得白色固体标题化合物110mg，收率33.5％。At room temperature, (S)-7-amino-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxole[4',5'; 4,5]benzo[1,2-b][1,4]oxazepine-8(9H)-one (11h) (160mg, 0.588mmol), 1-benzyl-5-chloro-4- (2-Formyl)-1H-pyrazole-3-carboxylic acid methyl ester (1m) (270 mg, 0.882 mmol) was dissolved in 5 mL of methanol, and 2-picoline borane complex (94.0 mg, 0.882mmol), stirred at room temperature for 16 hours. EA extracted (20mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=2:1), to obtain 110 mg of the title compound as a white solid, yield 33.5%.
LC-MS：m/z 563.1[M+H] +。 LC-MS: m/z 563.1 [M+H] + .
步骤10：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2,2-二氟-9-甲基-6,7-二氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(11)的制备Step 10: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -yl)-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxole[4',5'; 4,5]benzo[1 ,2-b][1,4]Oxazepine-8(9H)-one (11)
于室温，将(S)-1-苄基-5-氯-4-(2-((2,2-二氟-9-甲基-8-氧代-6,7,8,9-四氢-[1,3]二氧杂环戊烯并[4',5'；4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(11i)(90.0mg,0.174mmol)溶于3ml氯仿中，氮气氛下，于0℃向反应 液中加入Al(CH 3) 3(0.26mL，2M)，于50℃搅拌16小时。加甲醇淬灭，用DCM萃取(20mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得白色固体状标题化合物38.0mg，收率42.3％。 At room temperature, (S)-1-benzyl-5-chloro-4-(2-((2,2-difluoro-9-methyl-8-oxo-6,7,8,9-tetra Hydrogen-[1,3]dioxole[4',5'; 4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino) Ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (11i) (90.0mg, 0.174mmol) was dissolved in 3ml of chloroform, under a nitrogen atmosphere, Al(CH 3 ) 3 ( 0.26mL, 2M), stirred at 50°C for 16 hours. Quenched with methanol, extracted with DCM (20mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by high-pressure preparative liquid chromatography (column Model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), to obtain 38.0mg of the title compound as a white solid, with a yield of 42.3%.
LC-MS：m/z 516.8[M+H] +。 LC-MS: m/z 516.8 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.73(s,1H),7.46(s,1H),7.38-7.26(m,3H),7.22-7.16(m,2H),5.55(dd,J＝11.8,8.0Hz,1H),5.43(s,2H),4.85(dd,J＝11.9,10.2Hz,1H),4.38(dd,J＝10.1,8.0Hz,1H),4.00(ddd,J＝12.3,7.0,5.0Hz,1H),3.63(ddd,J＝12.8,8.4,4.8Hz,1H),3.28(s,3H),2.80(ddd,J＝15.6,8.4,5.1Hz,1H),2.68(ddd,J＝15.6,7.0,4.8Hz,1H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.73(s,1H),7.46(s,1H),7.38-7.26(m,3H),7.22-7.16(m,2H),5.55(dd,J =11.8,8.0Hz,1H),5.43(s,2H),4.85(dd,J=11.9,10.2Hz,1H),4.38(dd,J=10.1,8.0Hz,1H),4.00(ddd,J= 12.3,7.0,5.0Hz,1H),3.63(ddd,J＝12.8,8.4,4.8Hz,1H),3.28(s,3H),2.80(ddd,J＝15.6,8.4,5.1Hz,1H),2.68 (ddd, J=15.6, 7.0, 4.8Hz, 1H).
实施例12：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-(叔丁基)-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(12)的制备Example 12: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-(tert-butyl)-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b][1, 4] Preparation of Oxazepine-6(5H)-one (12)
Figure PCTCN2022092607-appb-000048
Figure PCTCN2022092607-appb-000048
步骤1：2-溴-4-甲氧基-5-硝基苯胺(12a)的制备Step 1: Preparation of 2-bromo-4-methoxy-5-nitroaniline (12a)
于0℃，将2-溴-4-甲氧基苯胺(3.88g，19.3mmol)溶于19.4mL H 2SO 4中，加入NaNO 3(1.80g，21.2mmol)，于0℃搅拌10分钟，用2M NaOH冰溶液(100mL)淬灭反应，用EA萃取(200mL x 3)，饱和食盐水洗涤(100mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝5:1)，得红色固体状标题化合物4.4g，收率92.6％。 At 0°C, 2-bromo-4-methoxyaniline (3.88g, 19.3mmol) was dissolved in 19.4mL H 2 SO 4 , NaNO 3 (1.80g, 21.2mmol) was added, stirred at 0°C for 10 minutes, The reaction was quenched with 2M NaOH ice solution (100 mL), extracted with EA (200 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=5:1) to obtain 4.4 g of the title compound as a red solid, with a yield of 92.6%.
LC-MS：m/z 247.0[M+H] +。 LC-MS: m/z 247.0 [M+H] + .
步骤2：N-(2-溴-4-甲氧基-5-硝基苯基)新戊酰胺(12b)的制备Step 2: Preparation of N-(2-bromo-4-methoxy-5-nitrophenyl)pivalamide (12b)
于室温，将2-溴-4-甲氧基-5-硝基苯胺(12a)(4.20g，17.0mmol)溶于42mL DCM中，加入DIEA(6.60g，51.2mmol)。氮气保护下，于0℃向反应液中加入 三甲基乙酰氯(2.46g，20.4mmol)，室温搅拌16小时。加水淬灭，用DCM萃取(200mL x 3)，饱和食盐水洗涤(100mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得棕色固体状标题化合物6.1g(粗品)。2-Bromo-4-methoxy-5-nitroaniline (12a) (4.20 g, 17.0 mmol) was dissolved in 42 mL DCM at room temperature and DIEA (6.60 g, 51.2 mmol) was added. Under nitrogen protection, trimethylacetyl chloride (2.46 g, 20.4 mmol) was added to the reaction solution at 0°C, and stirred at room temperature for 16 hours. Quenched with water, extracted with DCM (200mL x 3), washed with saturated brine (100mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6.1g (crude) as a brown solid.
LC-MS：m/z 331.0[M+H] +。 LC-MS: m/z 331.0 [M+H] + .
步骤3：2-(叔丁基)-6-甲氧基-5-硝基苯并[d]噁唑(12c)的制备Step 3: Preparation of 2-(tert-butyl)-6-methoxy-5-nitrobenzo[d]oxazole (12c)
将N-(2-溴-4-甲氧基-5-硝基苯基)新戊酰胺(12b)(5.75g,17.4mmol)溶于DMF(60mL)中，加入Cs 2CO 3(11.3g，34.8mmol)、CuI(166mg，0.871mmol)、二联吡啶(272mg，1.74mmol)，氮气氛下，于120℃搅拌过夜。加入水淬灭，EA萃取(500mL x 3)，饱和食盐水洗涤(100mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝5:1)，得淡黄色固体标题化合物2.3g，两步收率54.1％。 N-(2-Bromo-4-methoxy-5-nitrophenyl)pivalamide (12b) (5.75g, 17.4mmol) was dissolved in DMF (60mL), Cs 2 CO 3 (11.3g , 34.8mmol), CuI (166mg, 0.871mmol), bipyridine (272mg, 1.74mmol), and stirred overnight at 120°C under a nitrogen atmosphere. Water was added to quench, EA extracted (500mL x 3), washed with saturated brine (100mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=5:1), to obtain 2.3 g of the title compound as a light yellow solid, with a two-step yield of 54.1%.
LC-MS：m/z 251.1[M+H] +。 LC-MS: m/z 251.1 [M+H] + .
步骤4：2-(叔丁基)-5-硝基苯并[d]噁唑-6-醇(12d)的制备Step 4: Preparation of 2-(tert-butyl)-5-nitrobenzo[d]oxazol-6-ol (12d)
将2-(叔丁基)-6-甲氧基-5-硝基苯并[d]噁唑(12c)(2.28g，9.12mmol)溶于DCM(23ml)中，氮气氛下，于0℃向反应液中滴加BBr 3(1M)(18.2mL，18.2mmol)，于0℃搅拌0.5小时。将反应液滴加到冰水中淬灭，DCM萃取(60mL x3)，饱和食盐水洗涤(30mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝5:1)，得淡黄色固体标题化合物1.98g，收率92％。 2-(tert-butyl)-6-methoxy-5-nitrobenzo[d]oxazole (12c) (2.28g, 9.12mmol) was dissolved in DCM (23ml), under nitrogen atmosphere, at 0 °C, BBr 3 (1M) (18.2 mL, 18.2 mmol) was added dropwise to the reaction solution, and stirred at 0 °C for 0.5 hour. The reaction solution was added dropwise to ice water to quench, extracted with DCM (60mL x 3), washed with saturated brine (30mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography After separation and purification (mobile phase PE/EA=5:1), 1.98 g of the title compound was obtained as a pale yellow solid, with a yield of 92%.
LC-MS：m/z 237.1[M+H] +。 LC-MS: m/z 237.1 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-(叔丁基)-5-硝基苯并[d]噁唑-6-醇(12d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物12。The remaining steps are the same as the preparation method of Example 1, except that 5-hydroxy-1 in step 5 is replaced by 2-(tert-butyl)-5-nitrobenzo[d]oxazol-6-ol (12d), 3-Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to give the title compound 12.
LC-MS：m/z 533.9[M+H] +。 LC-MS: m/z 533.9 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.90(s,1H),7.67(s,1H),7.39-7.27(m,3H),7.24-7.14(m,2H),5.57(dd,J＝12.0,8.0Hz,1H),5.42(s,2H),4.84(dd,J＝12.0,10.0Hz,1H),4.34(dd,J＝10.0,8.0Hz,1H),4.04(ddd,J＝12.0,6.9,5.2Hz,1H),3.64(ddd,J＝12.8,8.4,4.8Hz,1H),3.35(s,3H),2.81(ddd,J＝15.2,8.6,5.2Hz,1H),2.74-2.63(m,1H),1.44(s,9H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.90(s,1H),7.67(s,1H),7.39-7.27(m,3H),7.24-7.14(m,2H),5.57(dd,J =12.0,8.0Hz,1H),5.42(s,2H),4.84(dd,J=12.0,10.0Hz,1H),4.34(dd,J=10.0,8.0Hz,1H),4.04(ddd,J= 12.0, 6.9, 5.2Hz, 1H), 3.64 (ddd, J＝12.8, 8.4, 4.8Hz, 1H), 3.35 (s, 3H), 2.81 (ddd, J＝15.2, 8.6, 5.2Hz, 1H), 2.74 -2.63(m,1H),1.44(s,9H).
实施例13：(S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-3,10-二甲基-3,7,8,10-四氢-9H-咪唑并[4',5':3,4]苯并[1,2-b][1,4]氧氮杂卓-9-酮(13)的制备Example 13: (S)-8-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-3,10-dimethyl-3,7,8,10-tetrahydro-9H-imidazo[4',5':3,4]benzo[1,2-b][1 ,4] Preparation of oxazepin-9-one (13)
Figure PCTCN2022092607-appb-000049
Figure PCTCN2022092607-appb-000049
步骤1：4-甲氧基-N 1-甲基苯-1,2-二胺(13a)的制备 Step 1: Preparation of 4-methoxy-N 1 -methylbenzene-1,2-diamine (13a)
将4-甲氧基-N-甲基-2-硝基苯胺(2.50g，13.7mmol)溶于35mL EtOH中，加入含水钯炭(146mg)，氢气氛下，50℃搅拌2小时。过滤，乙醇洗涤滤饼(10mL x 3)，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1-10:1)，得红棕色固体的标题化合物2.00g，收率：99％。4-Methoxy-N-methyl-2-nitroaniline (2.50 g, 13.7 mmol) was dissolved in 35 mL of EtOH, and aqueous palladium on carbon (146 mg) was added, and stirred at 50° C. for 2 hours under a hydrogen atmosphere. Filtration, washing the filter cake with ethanol (10mL x 3), the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1-10:1) to obtain a reddish-brown solid 2.00 g of the title compound, yield: 99%.
LC-MS：m/z 153[M+H] +。 LC-MS: m/z 153 [M+H] + .
步骤2：5-甲氧基-1-甲基-1H-苯并[d]咪唑(13b)的制备Step 2: Preparation of 5-methoxy-1-methyl-1H-benzo[d]imidazole (13b)
于室温，将4-甲氧基-N 1-甲基苯-1,2-二胺(13a)(1.90g，12.5mmol)溶于甲酸(30mL)，于封管100℃搅拌2小时。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝5:1-1:1)，得棕色固体的标题化合物2.10g(粗品)。 4-Methoxy-N 1 -methylbenzene-1,2-diamine (13a) (1.90 g, 12.5 mmol) was dissolved in formic acid (30 mL) at room temperature, and stirred at 100°C in a sealed tube for 2 hours. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=5:1-1:1) to obtain 2.10 g of the title compound as a brown solid (crude product).
LC-MS：m/z 163[M+H] +。 LC-MS: m/z 163 [M+H] + .
步骤3：5-甲氧基-1-甲基-4-硝基-1H-苯并[d]咪唑(13c)的制备Step 3: Preparation of 5-methoxy-1-methyl-4-nitro-1H-benzo[d]imidazole (13c)
于室温，将5-甲氧基-1-甲基-1H-苯并[d]咪唑(13b)溶于10ml浓硝酸和10ml TFA中，于0℃加入浓硫酸(0.5mL)，于50℃搅拌2小时。反应液倒入冰水中，饱和碳酸氢钠溶液调PH至8，EA萃取(50mL x 3)，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1-10:1)，得黄色固体的标题化合物3.20g，收率：86.4％。Dissolve 5-methoxy-1-methyl-1H-benzo[d]imidazole (13b) in 10ml of concentrated nitric acid and 10ml of TFA at room temperature, add concentrated sulfuric acid (0.5mL) at 0°C, and Stir for 2 hours. The reaction solution was poured into ice water, adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with EA (50mL x 3), concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20: 1-10:1), to obtain 3.20 g of the title compound as a yellow solid, yield: 86.4%.
LC-MS：m/z 208[M+H]+。LC-MS: m/z 208 [M+H]+.
步骤4：1-甲基-4-硝基-1H-苯并[d]咪唑-5-羟基(13d)的制备Step 4: Preparation of 1-methyl-4-nitro-1H-benzo[d]imidazole-5-hydroxyl (13d)
于室温，将5-甲氧基-1-甲基-4-硝基-1H-苯并[d]咪唑(13c)(4.70g，22.7mmol)溶于50ml氢溴酸中，于封管100℃搅拌过夜，饱和碳酸氢钠溶液调PH至8，DCM洗涤水相(50mL x 3)，水相减压浓缩,DCM：MeOH＝10：1洗滤饼，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1-10:1)，得淡黄色固体的标题化合物5.00g(粗品)。At room temperature, dissolve 5-methoxy-1-methyl-4-nitro-1H-benzo[d]imidazole (13c) (4.70g, 22.7mmol) in 50ml hydrobromic acid, and seal the tube at 100 Stir overnight at ℃, adjust the pH to 8 with saturated sodium bicarbonate solution, wash the aqueous phase with DCM (50mL x 3), concentrate the aqueous phase under reduced pressure, wash the filter cake with DCM:MeOH=10:1, filter, and concentrate the filtrate under reduced pressure. Separation and purification by silica gel column chromatography (mobile phase: DCM/MeOH=20:1-10:1) gave 5.00 g of the title compound as a pale yellow solid (crude product).
LC-MS：m/z 194[M+H] +。 LC-MS: m/z 194 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用1-甲基-4-硝基-1H-苯并[d]咪唑-5-羟基(13d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物13。The remaining steps are the same as in Example 1, except that 1-methyl-4-nitro-1H-benzo[d]imidazole-5-hydroxyl (13d) is used instead of 5-hydroxyl-1,3 in step 5 -Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to give the title compound 13.
LC-MS：m/z 491[M+H] +。 LC-MS: m/z 491 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ8.30(s,1H),7.53(d,1H),7.34-7.27(m,3H),7.21-7.17(m,3H),5.58(dd,1H),5.42(s,2H),4.88-4.82(m,1H),4.34(dd,1H),4.24-4.06(m,1H),3.84(s,3H),3.75-3.60(m,1H),3.52(s,3H),2.86-2.81(m,1H),2.80-2.65(m,1H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.30(s,1H),7.53(d,1H),7.34-7.27(m,3H),7.21-7.17(m,3H),5.58(dd,1H ),5.42(s,2H),4.88-4.82(m,1H),4.34(dd,1H),4.24-4.06(m,1H),3.84(s,3H),3.75-3.60(m,1H), 3.52 (s, 3H), 2.86-2.81 (m, 1H), 2.80-2.65 (m, 1H).
实施例14：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(14)的制备Example 14: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-1,5,7,8-tetrahydro-6H-[1,4]oxazepine[3,2-f]indazol-6-one (14) preparation
Figure PCTCN2022092607-appb-000050
Figure PCTCN2022092607-appb-000050
步骤1：6-氟-5-硝基-1H-吲唑(14a)的制备Step 1: Preparation of 6-fluoro-5-nitro-1H-indazole (14a)
于0℃，将6-氟-1H-吲唑(10.0g，73.5mmol)溶于浓H 2SO 4(100ml)中，氮气氛下，于0℃向反应液中加入NaNO 3(7.40g，87.6mmol)，于0℃搅拌1小时。于0℃加水(500mL)淬灭，EA萃取(300mL x 3)，饱和食盐水洗涤(600mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝2:1)，得淡黄色固体标题化合物3.4g，收率25.7％。 Dissolve 6-fluoro-1H-indazole (10.0g, 73.5mmol) in concentrated H 2 SO 4 (100ml) at 0°C, and add NaNO 3 (7.40g, 87.6 mmol), stirred at 0°C for 1 hour. Quenched by adding water (500mL) at 0°C, extracted with EA (300mL x 3), washed with saturated brine (600mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=2:1) gave 3.4 g of the title compound as a pale yellow solid, with a yield of 25.7%.
LC-MS：m/z 182[M+H] +。 LC-MS: m/z 182 [M+H] + .
步骤2：6-氟-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑(14b)的 制备Step 2: Preparation of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (14b)
将6-氟-5-硝基-1H-吲唑(14a)(3.10g，17.1mmol)溶于THF(30mL)中，于0℃加入NaH(1.03g，25.7mmol)，氮气氛下，于0℃搅拌0.5小时，于0℃向反应液中滴加SEM-Cl(3.41g，20.5mmol)，室温搅拌过夜，加水(100mL)淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1),得淡黄色固体标题化合物3.81g，收率70.8％。6-Fluoro-5-nitro-1H-indazole (14a) (3.10g, 17.1mmol) was dissolved in THF (30mL), NaH (1.03g, 25.7mmol) was added at 0°C, under nitrogen atmosphere, in Stir at 0°C for 0.5 hours, add SEM-Cl (3.41g, 20.5mmol) dropwise to the reaction solution at 0°C, stir overnight at room temperature, add water (100mL) to quench, extract with EA (100mL x 3), wash with saturated brine ( 100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain 3.81 g of the title compound as a light yellow solid, Yield 70.8%.
LC-MS：m/z 312[M+H] +。 LC-MS: m/z 312 [M+H] + .
步骤3：5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-醇(14c)的制备Step 3: Preparation of 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ol (14c)
于室温，将(叔丁氧羰基)-L-丝氨酸(659mg，3.22mmol)溶于DMF(10ml)中，氮气氛下，于0℃向反应液中滴加NaH(258mg，6.44mmol)，于0℃搅拌0.5小时，分批加入6-氟-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑(14b)(500mg，1.61mmol)，室温搅拌过夜。于0℃加水(30mL)淬灭，EA萃取(30mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物210mg，收率42.1％。Dissolve (tert-butoxycarbonyl)-L-serine (659mg, 3.22mmol) in DMF (10ml) at room temperature, and add NaH (258mg, 6.44mmol) dropwise to the reaction solution at 0°C under a nitrogen atmosphere. Stir at 0°C for 0.5 hours, add 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (14b) (500 mg, 1.61 mmol), stirred overnight at room temperature. Quenched by adding water (30mL) at 0°C, extracted with EA (30mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 210 mg of the title compound as a pale yellow solid, with a yield of 42.1%.
LC-MS：m/z 310[M+H] +。 LC-MS: m/z 310 [M+H] + .
步骤4：O-(5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)-N-三苯甲基-L-丝氨酸甲酯(14d)的制备Step 4: O-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl- Preparation of L-serine methyl ester (14d)
于室温，将5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-醇(14c)(230mg，0.744mmol)，三苯甲基-L-丝氨酸甲酯(403mg,1.16mmol)溶于4mL THF中，氮气氛下，加入PPh 3(390mg，1.48mmol)、DIAD(300mg，1.48mmol)，室温搅拌过夜。加水(20mL)淬灭，用EA萃取(30mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩,残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色半固体状标题化合物800mg(粗品)。 At room temperature, 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ol (14c) (230mg, 0.744mmol), tri Benzyl-L-serine methyl ester (403mg, 1.16mmol) was dissolved in 4mL THF. Under nitrogen atmosphere, PPh 3 (390mg, 1.48mmol) and DIAD (300mg, 1.48mmol) were added, and stirred overnight at room temperature. Add water (20mL) to quench, extract with EA (30mL x 3), wash with saturated brine (20mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 800 mg of the title compound (crude product) was obtained as a yellow semi-solid.
LC-MS：m/z 653[M+H] +。 LC-MS: m/z 653 [M+H] + .
步骤5：O-(5-氨基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)-N-三苯甲基-L-丝氨酸甲酯(14e)制备Step 5: O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L - Preparation of serine methyl ester (14e)
于室温，将O-(5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)-N-三苯甲基-L-丝氨酸甲酯(500mg，0.765mmol)溶于10mL甲醇中，向反应液中加入含水Pd/C(250mg)，氢气氛下，室温搅拌过夜。硅藻土过滤，MeOH洗涤滤饼，滤液减压浓缩，得黄色油状的标题化合物460mg(粗品)。At room temperature, O-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl - L-serine methyl ester (500 mg, 0.765 mmol) was dissolved in 10 mL of methanol, aqueous Pd/C (250 mg) was added to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Celite was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 460 mg of the title compound (crude product) as a yellow oil.
LC-MS：m/z 623[M+H] +。 LC-MS: m/z 623 [M+H] + .
步骤6：O-(5-氨基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)-N-三苯甲基-L-丝氨酸(14f)的制备Step 6: O-(5-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L - Preparation of serine (14f)
将O-(5-氨基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)-N-三苯甲基-L-丝氨酸甲酯(14e)(200mg，0.320mmol)溶于EtOH(3ml)中，加入氢氧化锂(21.0mg，0.963mmol)、水(0.5mL)，于80℃搅拌2小时，减压浓缩，得黑色油状标题化合物320mg(粗品)。O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine Methyl ester (14e) (200mg, 0.320mmol) was dissolved in EtOH (3ml), lithium hydroxide (21.0mg, 0.963mmol) and water (0.5mL) were added, stirred at 80°C for 2 hours, and concentrated under reduced pressure to obtain black 320 mg (crude product) of the title compound in the form of oil.
LC-MS：m/z 609[M+H] +。 LC-MS: m/z 609 [M+H] + .
步骤7：(S)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-(三苯甲基氨基)-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-(5H)-酮(14g)的制备Step 7: (S)-1-((2-(Trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7,8-tetrahydro- Preparation of 6H-[1,4]oxazepine[3,2-f]indazol-(5H)-one (14g)
将O-(5-氨基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)-N-三苯甲基-L-丝氨酸(1.00g，1.64mmol)溶于10mL DMF，加入DIEA(367mg，2.47mmol)和HATU(937mg，2.47mmol)，于室温搅拌1小时。加入10mL水，EA萃取(20mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:1)，得浅黄色固体的标题化合物560mg，收率：58.7％。O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine (1.00g, 1.64mmol) was dissolved in 10mL DMF, DIEA (367mg, 2.47mmol) and HATU (937mg, 2.47mmol) were added, and stirred at room temperature for 1 hour. Add 10mL of water, extract with EA (20mL x 3), wash with saturated brine (20mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:1), to obtain 560 mg of the title compound as a pale yellow solid, yield: 58.7%.
LC-MS：m/z 591[M+H] +。 LC-MS: m/z 591 [M+H] + .
步骤8：(S)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-(三苯甲基氨基)-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(14h)的制备Step 8: (S)-5-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7, Preparation of 8-tetrahydro-6H-[1,4]oxazepine[3,2-f]indazol-6-one (14h)
将(S)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-(三苯甲基氨基)-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-(5H)-酮(14g)(600mg，1.02mmol)溶于DMF(10ml)，加入Cs 2CO 3(663mg，2.04mmol)、碘甲烷(217mg，1.53mmol)，于室温搅拌2小时。加20mL水稀释，EA萃取(20mL x 3)，饱和食盐水洗涤(10mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色油状标题化合物540mg，收率87.2％。 (S)-1-((2-(trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7,8-tetrahydro-6H- [1,4]Oxazepine[3,2-f]indazol-(5H)-one (14g) (600mg, 1.02mmol) was dissolved in DMF (10ml), Cs 2 CO 3 (663mg, 2.04 mmol), methyl iodide (217 mg, 1.53 mmol), and stirred at room temperature for 2 hours. Add 20mL of water to dilute, extract with EA (20mL x 3), wash with saturated brine (10mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1), to obtain 540 mg of the title compound as a yellow oil, with a yield of 87.2%.
LC-MS：m/z 605[M+H] +。 LC-MS: m/z 605 [M+H] + .
步骤9：(S)-7-氨基-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(14i)的制备Step 9: (S)-7-Amino-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H Preparation of -[1,4]oxazepine[3,2-f]indazol-6-one (14i)
于室温，将(S)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-(三苯甲基氨基)-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(310mg，0.513mmol)溶于5mL DCM中，向反应液中加入4mol/L的盐酸二氧六环溶液(0.4ml)，室温搅拌2小时。加入50mL饱和NaHCO 3溶液，用DCM萃取(30mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物140mg(粗品)。 At room temperature, (S)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7 , 8-tetrahydro-6H-[1,4]oxazepine[3,2-f]indazol-6-one (310mg, 0.513mmol) was dissolved in 5mL DCM, and 4mol/ L of dioxane hydrochloride solution (0.4ml), stirred at room temperature for 2 hours. Add 50 mL of saturated NaHCO 3 solution, extract with DCM (30 mL x 3), wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 140 mg of the title compound as a yellow oil (crude product).
LC-MS：m/z 363[M+H] +。 LC-MS: m/z 363 [M+H] + .
步骤10：(S)-1-苄基-5-氯-4-(2-((5-甲基-6-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-5,6,7,8-四氢-1H-[1,4]氧氮杂卓并[3,2-f]吲唑-7-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(14j)制备Step 10: (S)-1-Benzyl-5-chloro-4-(2-((5-methyl-6-oxo-1-((2-(trimethylsilyl)ethoxy) )methyl)-5,6,7,8-tetrahydro-1H-[1,4]oxazepine[3,2-f]indazol-7-yl)amino)ethyl)-1H- Preparation of ethyl pyrazole-3-carboxylate (14j)
于室温，将(S)-7-氨基-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5,7,8-四氢 -6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(14i)(120mg，0.330mmol)、1-苄基-5-氯-4-甲酰基-1H-吡唑-3-羧酸乙酯(1m)(122mg，0.398mmol)溶于3mL甲醇，向反应液中加入2-甲基吡啶硼烷(53.0mg，0.496mmol)，室温搅拌1小时。加入5mL饱和NaHCO 3溶液，DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝1:1)，得淡黄色油体状标题化合物140mg，收率65.1％。 At room temperature, (S)-7-amino-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro- 6H-[1,4]oxazepine[3,2-f]indazol-6-one (14i) (120mg, 0.330mmol), 1-benzyl-5-chloro-4-formyl-1H - Ethyl pyrazole-3-carboxylate (1m) (122 mg, 0.398 mmol) was dissolved in 3 mL of methanol, 2-picoline borane (53.0 mg, 0.496 mmol) was added to the reaction solution, and stirred at room temperature for 1 hour. Add 5mL of saturated NaHCO3 solution, extract with DCM (10mL x 3), wash with saturated brine (20mL x1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (flow Phase PE/EA=1:1), to obtain 140 mg of the title compound in the form of pale yellow oil, with a yield of 65.1%.
LC-MS:m/z 653[M+H] +。 LC-MS: m/z 653 [M+H] + .
步骤11：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(14k)的制备Step 11: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4]oxygen Preparation of azazolo[3,2-f]indazol-6-one (14k)
于室温，将化合物14j(110mg，0.168mmol)溶于3ml氯仿中，氮气氛下，于0℃向反应液中加入Al(CH 3) 3溶液(0.253ml，2M)，于50℃搅拌3小时。加饱和碳酸氢钠溶液(1mL)淬灭，搅拌半小时，过滤，用DCM(20mL x 3)洗涤滤饼，无水硫酸钠干燥，过滤，滤液减压浓缩，得类白色固体状标题化合物粗品100mg。 Dissolve compound 14j (110 mg, 0.168 mmol) in 3 ml of chloroform at room temperature, add Al(CH 3 ) 3 solution (0.253 ml, 2M) to the reaction solution at 0°C under nitrogen atmosphere, and stir at 50°C for 3 hours . Add saturated sodium bicarbonate solution (1 mL) to quench, stir for half an hour, filter, wash the filter cake with DCM (20 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of the title compound as an off-white solid 100 mg.
LC-MS：m/z 607[M+H] +。 LC-MS: m/z 607 [M+H] + .
步骤12：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(14)的制备Step 12: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 Preparation of -yl)-5-methyl-1,5,7,8-tetrahydro-6H-[1,4]oxazepine[3,2-f]indazol-6-one (14)
于室温，将(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5,7,8-四氢-6H-[1,4]氧氮杂卓并[3,2-f]吲唑-6-酮(14k)(110mg，0.181mmol)溶于4mol/L盐酸二氧六环溶液(3ml)中，氮气氛下，于25℃搅拌12小时，减压浓缩，加氨水(6mL)继续搅拌2小时，减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸)，得类白色固体状标题化合物15mg，收率17.4％。At room temperature, (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4] Oxazepine[3,2-f]indazol-6-one (14k) (110mg, 0.181mmol) was dissolved in 4mol/L dioxane hydrochloride solution (3ml), under nitrogen atmosphere, at 25°C Stir for 12 hours, concentrate under reduced pressure, add ammonia water (6mL) and continue stirring for 2 hours, concentrate under reduced pressure, and the residue is separated by high pressure preparative liquid chromatography (column model: Daisogei30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile /water, gradient: 10%-50%, 0.05% formic acid), to obtain 15 mg of the title compound as an off-white solid, with a yield of 17.4%.
LC-MS:m/z 476.9[M+H] +。 LC-MS: m/z 476.9 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ13.18(s,1H),8.11(s,1H),7.89(s,1H),7.40-7.25(m,4H),7.18(d,J＝7.0Hz,2H),5.59(dd,J＝11.9,7.9Hz,1H),5.42(s,2H),4.86-4.76(m,1H),4.36-4.27(m,1H),4.05(dt,J＝12.1,5.6Hz,1H),3.69-3.58(m,1H),3.36(s,3H),2.87-2.75(m,1H),2.74-2.64(m,1H)。 1 H NMR (400MHz,DMSO-d 6 )δ13.18(s,1H),8.11(s,1H),7.89(s,1H),7.40-7.25(m,4H),7.18(d,J=7.0 Hz,2H),5.59(dd,J=11.9,7.9Hz,1H),5.42(s,2H),4.86-4.76(m,1H),4.36-4.27(m,1H),4.05(dt,J= 12.1,5.6Hz,1H),3.69-3.58(m,1H),3.36(s,3H),2.87-2.75(m,1H),2.74-2.64(m,1H).
实施例15：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(15)的制备Example 15: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b][1,4] Preparation of Oxazepine-8(9H)-one (15)
Figure PCTCN2022092607-appb-000051
Figure PCTCN2022092607-appb-000051
步骤1：N-(2-溴-5-甲氧基苯基)环丙烷甲酰胺(15a)的制备Step 1: Preparation of N-(2-bromo-5-methoxyphenyl)cyclopropanecarboxamide (15a)
于室温，将2-溴-5-甲氧基苯胺(5.00g，25.0mmol)溶于100ml DCM中，加入DIEA(9.60g，75.0mmol)，氮气氛下，于0℃向反应液中加入环丙基酰氯(3.10g，29.8mmol)，室温搅拌2小时。加水淬灭，用DCM萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝4:1)，得无色透明液体的标题化合物6.3g，收率94.2％。At room temperature, 2-bromo-5-methoxyaniline (5.00g, 25.0mmol) was dissolved in 100ml of DCM, DIEA (9.60g, 75.0mmol) was added, and ring was added to the reaction solution at 0°C under a nitrogen atmosphere. Propyl chloride (3.10 g, 29.8 mmol), stirred at room temperature for 2 hours. Add water to quench, extract with DCM (200mL x 3), wash with saturated brine (200mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=4:1) to obtain 6.3 g of the title compound as a colorless transparent liquid with a yield of 94.2%.
LC-MS：m/z 270[M+H] +。 LC-MS: m/z 270 [M+H] + .
步骤2：2-环丙基-5-甲氧基苯并[d]噁唑(15b)的制备Step 2: Preparation of 2-cyclopropyl-5-methoxybenzo[d]oxazole (15b)
将N-(2-溴-5-甲氧基苯基)环丙烷甲酰胺(15a)(5.00g，1.86mmol)溶于DMF(100mL)中，加入Cs 2CO 3(12.1g，37.2mmol)、CuI(180mg，0.930mmol)、二联吡啶(290mg，1.86mmol)，氮气氛下，于120℃搅拌过夜。加入水淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物2.4g，收率75.1％。 N-(2-bromo-5-methoxyphenyl)cyclopropanecarboxamide (15a) (5.00 g, 1.86 mmol) was dissolved in DMF (100 mL) and Cs 2 CO 3 (12.1 g, 37.2 mmol) was added , CuI (180mg, 0.930mmol), bipyridine (290mg, 1.86mmol), and stirred overnight at 120°C under a nitrogen atmosphere. Water was added to quench, EA extracted (100mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1), to obtain 2.4 g of the title compound as a light yellow solid, with a yield of 75.1%.
LC-MS：m/z 190[M+H] +。 LC-MS: m/z 190 [M+H] + .
步骤3：2-环丙基-5-甲氧基-6-硝基苯并[d]噁唑(15c)的制备Step 3: Preparation of 2-cyclopropyl-5-methoxy-6-nitrobenzo[d]oxazole (15c)
将2-环丙基-5-甲氧基苯并[d]噁唑(15b)(2.50g，13.2mmol)溶于TFA(24ml)中，氮气氛下，于0℃向反应液中滴加浓HNO 3(8mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水淬灭，EA萃取(50mL x 3)，饱和食盐水洗涤(80mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.5g，收率49.6％。 Dissolve 2-cyclopropyl-5-methoxybenzo[d]oxazole (15b) (2.50g, 13.2mmol) in TFA (24ml), and add dropwise to the reaction solution at 0°C under nitrogen atmosphere Concentrated HNO 3 (8 mL), stirred at 0°C for 2 hours and at room temperature overnight. Quenched with water at 0°C, extracted with EA (50mL x 3), washed with saturated brine (80mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Mobile phase PE/EA=3:1), to obtain 1.5 g of the title compound as a pale yellow solid, with a yield of 49.6%.
LC-MS：m/z 234[M+H] +。 LC-MS: m/z 234 [M+H] + .
步骤4：2-环丙基-6-硝基苯并[d]噁唑-5-醇(15d)的制备Step 4: Preparation of 2-cyclopropyl-6-nitrobenzo[d]oxazol-5-ol (15d)
将2-环丙基-5-甲氧基-6-硝基苯并[d]噁唑(15c)(3.20g，13.6mmol)溶于 DCM(50ml)中，氮气氛下，于0℃向反应液中滴加BBr 3溶液(27.2mL，1M)，于0℃搅拌2小时。于0℃加甲醇淬灭，DCM萃取(60mL x 3)，饱和食盐水洗涤(80mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.8g，收率60.0％。 2-Cyclopropyl-5-methoxy-6-nitrobenzo[d]oxazole (15c) (3.20g, 13.6mmol) was dissolved in DCM (50ml), under nitrogen atmosphere, at 0°C to BBr 3 solution (27.2 mL, 1M) was added dropwise to the reaction solution, and stirred at 0°C for 2 hours. Quenched by adding methanol at 0°C, extracted with DCM (60mL x 3), washed with saturated brine (80mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 1.8 g of the title compound was obtained as a pale yellow solid, with a yield of 60.0%.
LC-MS：m/z 220[M+H] +。 LC-MS: m/z 220 [M+H] + .
步骤5：O-(2-环丙基-6-硝基苯并[d]噁唑-5-基)-N-三苯甲基-L-丝氨酸甲酯(15e)的制备Step 5: Preparation of O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-N-trityl-L-serine methyl ester (15e)
于室温，将2-环丙基-6-硝基苯并[d]噁唑-5-醇(15d)(2.30g，10.4mmol)，三苯甲基-L-丝氨酸甲酯(5.66g，15.7mmol)溶于50mL THF中，氮气氛下，向反应液中加入PPh 3(5.47g，20.9mmol)、DIAD(4.20g，20.9mmol)，室温搅拌过夜。加水稀释，用EA萃取(50mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝1:1)，得黄色半固体状标题化合物7.8g(粗品)。 At room temperature, 2-cyclopropyl-6-nitrobenzo[d]oxazol-5-ol (15d) (2.30g, 10.4mmol), trityl-L-serine methyl ester (5.66g, 15.7 mmol) was dissolved in 50 mL THF, under nitrogen atmosphere, PPh 3 (5.47 g, 20.9 mmol) and DIAD (4.20 g, 20.9 mmol) were added to the reaction liquid, and stirred overnight at room temperature. Diluted with water, extracted with EA (50mL x 3), washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE /EA=1:1) to obtain 7.8 g of the title compound (crude product) as a yellow semi-solid.
LC-MS：m/z 564[M+H] +。 LC-MS: m/z 564 [M+H] + .
步骤6：O-(2-环丙基-6-硝基苯并[d]噁唑-5-基)-L-丝氨酸甲酯(15f)制备Step 6: Preparation of O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15f)
于室温，将O-(2-环丙基-6-硝基苯并[d]噁唑-5-基)-N-三苯甲基-L-丝氨酸甲酯(15e)(7.50g，13.3mmol)溶于100mL DCM中，向反应液中加入盐酸二氧六环(13.3ml)，室温搅拌3小时。减压浓缩，PE：EA＝5:1打浆，过滤，收集滤饼，得浅黄色固体标题化合物3.65g，收率65.4％。At room temperature, O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-N-trityl-L-serine methyl ester (15e) (7.50g, 13.3 mmol) was dissolved in 100mL of DCM, and dioxane hydrochloride (13.3ml) was added to the reaction solution, stirred at room temperature for 3 hours. Concentrate under reduced pressure, beat PE:EA=5:1, filter, and collect the filter cake to obtain 3.65 g of the title compound as a light yellow solid, with a yield of 65.4%.
LC-MS：m/z 322[M+H] +。 LC-MS: m/z 322 [M+H] + .
步骤7：N-(叔丁氧基羰基)-O-(2-环丙基-6-硝基苯并[d]噁唑-5-基)-L-丝氨酸甲酯(15g)的制备Step 7: Preparation of N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15 g)
于室温，将O-(2-环丙基-6-硝基苯并[d]噁唑-5-基)-L-丝氨酸甲酯(15f)(2.25g，7.00mmol)溶于DCM(30ml)中，向反应液中加入DIEA(2.70g，20.7mmol)、Boc 2O(2.26g，10.9mmol)，于室温搅拌过夜。加水稀释，DCM萃取(30mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝2:1)，得黄色油状标题化合物1.6g，收率53.2％。 O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15f) (2.25 g, 7.00 mmol) was dissolved in DCM (30 ml ), DIEA (2.70 g, 20.7 mmol) and Boc 2 O (2.26 g, 10.9 mmol) were added to the reaction solution, and stirred overnight at room temperature. Diluted with water, extracted with DCM (30mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/ EA=2:1), to obtain 1.6 g of the title compound as a yellow oil, with a yield of 53.2%.
LC-MS：m/z 422[M+H] +。 LC-MS: m/z 422 [M+H] + .
步骤8：O-(6-氨基-2-环丙基苯并[d]噁唑-5-基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(15h)的制备Step 8: Preparation of O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (15h)
于室温，将N-(叔丁氧基羰基)-O-(2-环丙基-6-硝基苯并[d]噁唑-5-基)-L-丝氨酸甲酯(15g)(1.50g，3.05mmol)溶于20mL甲醇中，向反应液中加入含水Pd/C(1.00g)，氢气氛下，室温搅拌过夜。硅藻土过滤，加MeOH洗涤滤饼，滤液减压浓缩，得黄色油状的标题化合物1.6g(粗品)。At room temperature, N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15g) (1.50 g, 3.05 mmol) was dissolved in 20 mL of methanol, and aqueous Pd/C (1.00 g) was added to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Filter through celite, add MeOH to wash the filter cake, and concentrate the filtrate under reduced pressure to obtain 1.6 g of the title compound (crude product) as a yellow oil.
LC-MS：m/z 392[M+H] +。 LC-MS: m/z 392 [M+H] + .
步骤9：O-(6-氨基-2-环丙基苯并[d]噁唑-5-基)-N-(叔丁氧羰基)-L-丝氨酸(15i)的制备Step 9: Preparation of O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine (15i)
将O-(6-氨基-2-环丙基苯并[d]噁唑-5-基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(15h)(1.60g，4.08mmol)溶于THF(30ml)中，加入氢氧化锂(141mg，6.12mmol)、水(5mL)，于室温搅拌30分钟，减压浓缩，得黑色油状标题化合物1.9g(粗品)。O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (15h) (1.60g, 4.08mmol) Dissolve in THF (30ml), add lithium hydroxide (141mg, 6.12mmol) and water (5mL), stir at room temperature for 30 minutes, and concentrate under reduced pressure to give the title compound 1.9g (crude product) as a black oil.
LC-MS：m/z 378[M+H] +。 LC-MS: m/z 378 [M+H] + .
步骤10：(S)-(2-环丙基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(15j)的制备Step 10: (S)-(2-Cyclopropyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-7-yl) tert-butyl carbamate (15j)
将O-(6-氨基-2-环丙基苯并[d]噁唑-5-基)-N-(叔丁氧羰基)-L-丝氨酸(15i)(1.80g，4.76mmol)溶于30mL DMF，加入DIEA(1.84g，14.3mmol)和HATU(4.54g，12.8mmol)，于室温搅拌1小时。加入20mL水，EA萃取(20mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:1),得浅黄色固体的标题化合物360mg，收率：26.2％。O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine (15i) (1.80 g, 4.76 mmol) was dissolved in 30mL of DMF, added DIEA (1.84g, 14.3mmol) and HATU (4.54g, 12.8mmol), stirred at room temperature for 1 hour. Add 20mL of water, extract with EA (20mL x 3), wash with saturated brine (20mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:1), to obtain 360 mg of the title compound as a light yellow solid, yield: 26.2%.
LC-MS：m/z 360[M+H] +。 LC-MS: m/z 360 [M+H] + .
步骤11：(S)-(2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(15k)的制备Step 11: (S)-(2-Cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo Preparation of tert-butyl [1,2-b][1,4]oxazepine-7-yl)carbamate (15k)
将(S)-(2-环丙基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(15j)(300mg，0.830mmol)溶于DMF(10ml),加入Cs 2CO 3(408mg，1.25mmol)、碘甲烷(139mg，0.996mmol)，于室温搅拌2小时。加水稀释，EA萃取(15mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色油状标题化合物260mg，收率83.8％。 (S)-(2-Cyclopropyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1,2-b] [1,4]Oxazepine-7-yl) tert-butyl carbamate (15j) (300mg, 0.830mmol) was dissolved in DMF (10ml), and Cs 2 CO 3 (408mg, 1.25mmol), iodomethane ( 139 mg, 0.996 mmol), stirred at room temperature for 2 hours. Diluted with water, extracted with EA (15mL x 3), washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/ EA=3:1), to obtain 260 mg of the title compound as a yellow oil, with a yield of 83.8%.
LC-MS：m/z 374[M+H] +。 LC-MS: m/z 374 [M+H] + .
步骤12：(S)-7-氨基-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(15l)的制备Step 12: (S)-7-Amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b Preparation of ][1,4]oxazepine-8(9H)-one (15l)
于室温，将(S)-(2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基甲酸叔丁酯(15k)(200mg，0.536mmol)溶于2mL DCM中，向反应液中加入4mol/L的盐酸二氧六环溶液(4ml)，室温搅拌2小时。加入10mL饱和NaHCO 3溶液，用DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物150mg(粗品)。 At room temperature, (S)-(2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzene And[1,2-b][1,4]oxazepin-7-yl) tert-butyl carbamate (15k) (200mg, 0.536mmol) was dissolved in 2mL DCM, and 4mol/L was added to the reaction solution dioxane hydrochloride solution (4ml), stirred at room temperature for 2 hours. Add 10 mL of saturated NaHCO 3 solution, extract with DCM (10 mL x 3), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 150 mg of the title compound as a yellow oil (crude product).
LC-MS：m/z 274[M+H] +。 LC-MS: m/z 274 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用(S)-7-氨基-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(15l)代替步骤11中的(S)-7-氨基-1,3,9三甲基-3,6,7,9四氢-1H-咪唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-2,8-二 酮(1k)，制得标题化合物15。The remaining steps are the same as the preparation method of Example 1, except that (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4, 5] Benzo[1,2-b][1,4]oxazepine-8(9H)-one (15l) instead of (S)-7-amino-1,3,9trimethyl in step 11 Base-3,6,7,9tetrahydro-1H-imidazo[4',5':4,5]benzo[1,2-b][1,4]oxazepine-2,8- Diketone (1k), yielding the title compound 15.
LC-MS：m/z 518.0[M+H] +。 LC-MS: m/z 518.0 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.49(s,1H),7.37-7.29(m,3H),7.21-7.16(m,2H),5.55(dd,J＝11.9,8.1Hz,1H),5.42(s,2H),4.82(dd,J＝11.9,10.1Hz,1H),4.33(dd,J＝10.1,8.1Hz,1H),4.03(ddd,J＝12.3,7.0,5.1Hz,1H),3.64(ddd,J＝12.8,8.5,4.8Hz,1H),3.38(s,3H),2.80(ddd,J＝15.5,8.5,5.0Hz,1H),2.75-2.62(m,1H),2.34-2.26(m,1H),1.25-1.19(m,4H)。 1 H NMR (400MHz, DMSO-d6) δ7.89(s, 1H), 7.49(s, 1H), 7.37-7.29(m, 3H), 7.21-7.16(m, 2H), 5.55(dd, J= 11.9,8.1Hz,1H),5.42(s,2H),4.82(dd,J=11.9,10.1Hz,1H),4.33(dd,J=10.1,8.1Hz,1H),4.03(ddd,J=12.3 ,7.0,5.1Hz,1H),3.64(ddd,J=12.8,8.5,4.8Hz,1H),3.38(s,3H),2.80(ddd,J=15.5,8.5,5.0Hz,1H),2.75- 2.62 (m, 1H), 2.34-2.26 (m, 1H), 1.25-1.19 (m, 4H).
实施例16：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-(叔-丁基)-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(16)的制备Example 16: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-(tert-butyl)-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b][1 ,4] Preparation of oxazepine-8(9H)-one (16)
Figure PCTCN2022092607-appb-000052
Figure PCTCN2022092607-appb-000052
步骤1：N-(2-溴-5-甲氧基苯基)新戊酰胺(16a)的制备Step 1: Preparation of N-(2-bromo-5-methoxyphenyl)pivalamide (16a)
于室温，将2-溴-5-甲氧基苯胺(5.00g，25.0mmol)溶于100ml DCM中，加入DIEA(9.60g，75.0mmol)，氮气氛下，于0℃向反应液中加入三甲基乙酰氯(3.58g，29.8mmol)，室温搅拌2小时。加水淬灭，用DCM萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝4:1)，得无色透明油状的标题化合物6.1g，收率85.9％。At room temperature, 2-bromo-5-methoxyaniline (5.00g, 25.0mmol) was dissolved in 100ml DCM, DIEA (9.60g, 75.0mmol) was added, and three Methylacetyl chloride (3.58g, 29.8mmol), stirred at room temperature for 2 hours. Quenched with water, extracted with DCM (200mL x 3), washed with saturated brine (200mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=4:1), to obtain 6.1 g of the title compound as a colorless transparent oil, with a yield of 85.9%.
LC-MS：m/z 286[M+H] +。 LC-MS: m/z 286 [M+H] + .
步骤2：2-(叔丁基)-5-甲氧基苯并[d]噁唑(16b)的制备Step 2: Preparation of 2-(tert-butyl)-5-methoxybenzo[d]oxazole (16b)
将N-(2-溴-5-甲氧基苯基)新戊酰胺(16a)(5.00g，17.5mmol)溶于DMF(100mL)中，加入Cs 2CO 3(11.4g，35.1mmol)、CuI(333mg，1.75mmol)、二联吡啶(546mg，3.50mmol)，氮气氛下，于120℃搅拌过夜。加入水淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物2.1g，收率58.3％。 N-(2-bromo-5-methoxyphenyl)pivalamide (16a) (5.00 g, 17.5 mmol) was dissolved in DMF (100 mL), and Cs 2 CO 3 (11.4 g, 35.1 mmol), CuI (333mg, 1.75mmol), bipyridine (546mg, 3.50mmol) were stirred overnight at 120°C under a nitrogen atmosphere. Water was added to quench, EA extracted (100mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1), to obtain 2.1 g of the title compound as a pale yellow solid, with a yield of 58.3%.
LC-MS：m/z 206[M+H] +。 LC-MS: m/z 206 [M+H] + .
步骤3：2-(叔丁基)-5-甲氧基-6-硝基苯并[d]噁唑(16c)的制备Step 3: Preparation of 2-(tert-butyl)-5-methoxy-6-nitrobenzo[d]oxazole (16c)
将2-(叔丁基)-5-甲氧基苯并[d]噁唑(16b)(2.00g，9.71mmol)溶于TFA(20ml)中，氮气氛下，于0℃滴加浓HNO 3(7mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水淬灭，EA萃取(50mL x 3)，饱和食盐水洗涤(80mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.3g，收率54.2％。 2-(tert-butyl)-5-methoxybenzo[d]oxazole (16b) (2.00g, 9.71mmol) was dissolved in TFA (20ml), and concentrated HNO was added dropwise at 0°C under a nitrogen atmosphere 3 (7 mL), stirred at 0°C for 2 hours and at room temperature overnight. Quenched with water at 0°C, extracted with EA (50mL x 3), washed with saturated brine (80mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Mobile phase PE/EA=3:1), to obtain 1.3 g of the title compound as a pale yellow solid, with a yield of 54.2%.
LC-MS：m/z 251[M+H] +。 LC-MS: m/z 251 [M+H] + .
步骤4：2-(叔丁基)-6-硝基苯并[d]噁唑-5-醇(16d)的制备Step 4: Preparation of 2-(tert-butyl)-6-nitrobenzo[d]oxazol-5-ol (16d)
将2-(叔丁基)-5-甲氧基-6-硝基苯并[d]噁唑(16c)(1.20g，4.78mmol)溶于DCM(50ml)中，氮气氛下，于0℃滴加BBr 3(9.6mL，1M)，于0℃搅拌2小时。于0℃加甲醇淬灭，DCM萃取(60mL x 3)，饱和食盐水洗涤(80mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物840mg，收率86％。 2-(tert-Butyl)-5-methoxy-6-nitrobenzo[d]oxazole (16c) (1.20g, 4.78mmol) was dissolved in DCM (50ml), under nitrogen atmosphere, at 0 BBr 3 (9.6 mL, 1M) was added dropwise at °C, and stirred at 0°C for 2 hours. Quenched by adding methanol at 0°C, extracted with DCM (60mL x 3), washed with saturated brine (80mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 840 mg of the title compound was obtained as a light yellow solid, with a yield of 86%.
LC-MS：m/z 237[M+H] +。 LC-MS: m/z 237 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-环丙基-6-硝基苯并[d]噁唑-5-醇(16d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物16。The remaining steps are the same as the preparation method of Example 1, except that 5-hydroxyl-1,3- Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d), yielding the title compound 16.
LC-MS：m/z 534.0[M+H] +。 LC-MS: m/z 534.0 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.59(s,1H),7.38-7.26(m,3H),7.22-7.15(m,2H),5.56(dd,J＝11.9,8.1Hz,1H),5.42(s,2H),4.83(dd,J＝11.9,10.1Hz,1H),4.33(dd,J＝10.1,8.1Hz,1H),4.04(dt,J＝12.3,5.9Hz,1H),3.65(ddd,J＝12.8,8.4,4.8Hz,1H),3.35(s,3H),2.81(ddd,J＝13.8,8.5,5.1Hz,1H),2.68(ddd,J＝15.6,6.9,4.8Hz,1H),1.45(s,9H)。 1 H NMR (400MHz, DMSO-d6) δ7.96(s, 1H), 7.59(s, 1H), 7.38-7.26(m, 3H), 7.22-7.15(m, 2H), 5.56(dd, J= 11.9,8.1Hz,1H),5.42(s,2H),4.83(dd,J=11.9,10.1Hz,1H),4.33(dd,J=10.1,8.1Hz,1H),4.04(dt,J=12.3 ,5.9Hz,1H),3.65(ddd,J=12.8,8.4,4.8Hz,1H),3.35(s,3H),2.81(ddd,J=13.8,8.5,5.1Hz,1H),2.68(ddd, J=15.6, 6.9, 4.8Hz, 1H), 1.45(s, 9H).
实施例17：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5,10-二甲基-7,8-二氢噁唑[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(17)的制备Example 17: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-cyclopropyl-5,10-dimethyl-7,8-dihydrooxazol[4',5':4,5]benzo[1,2-b][1, 4] Preparation of Oxazepine-6(5H)-one (17)
Figure PCTCN2022092607-appb-000053
Figure PCTCN2022092607-appb-000053
步骤1：2-溴-4-甲氧基-3-甲基-1-硝基苯(17a)的制备Step 1: Preparation of 2-bromo-4-methoxy-3-methyl-1-nitrobenzene (17a)
将1-溴-3-甲氧基-2-甲基苯(15.00g，75.0mmol)溶于TFA(150ml)中，氮气氛下，于0℃向反应液中滴加HNO 3(50mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水淬灭，EA萃取(200mL x 3)，饱和食盐水洗涤(80mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品10.6g。 1-Bromo-3-methoxy-2-methylbenzene (15.00 g, 75.0 mmol) was dissolved in TFA (150 ml), and HNO 3 (50 mL) was added dropwise to the reaction solution at 0°C under a nitrogen atmosphere, Stir at 0°C for 2 hours and at room temperature overnight. Add water to quench at 0°C, extract with EA (200mL x 3), wash with saturated brine (80mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 10.6g of crude product.
LC-MS：m/z 246[M+H] +。 LC-MS: m/z 246 [M+H] + .
步骤2：2-溴-4-甲氧基-3-甲基苯胺(17b)的制备Step 2: Preparation of 2-bromo-4-methoxy-3-methylaniline (17b)
将2-溴-4-甲氧基-3-甲基-1-硝基苯(17a)(10.0g，0.0408mmol)溶于THF/H 2O(100mL/100mL)中，加入NH 4Cl(11.1g，0.204mmol)，于0℃加入锌粉(13.3g，0.204mmol)，于室温搅拌过夜。加入水(200mL)淬灭，EA萃取(200mL x 3)，饱和食盐水洗涤(100mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物8.2g，收率77％。 2-Bromo-4-methoxy-3-methyl-1-nitrobenzene (17a) (10.0 g, 0.0408 mmol) was dissolved in THF/H 2 O (100 mL/100 mL), NH 4 Cl was added ( 11.1g, 0.204mmol), zinc powder (13.3g, 0.204mmol) was added at 0°C, and stirred overnight at room temperature. Add water (200mL) to quench, extract with EA (200mL x 3), wash with saturated brine (100mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 8.2 g of the title compound was obtained as a pale yellow solid, with a yield of 77%.
LC-MS：m/z 216[M+H] +。 LC-MS: m/z 216 [M+H] + .
步骤3：N-(2-溴-4-甲氧基-3-甲基苯基)环丙烷甲酰胺(17c)的制备Step 3: Preparation of N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanecarboxamide (17c)
于室温，将2-溴-4-甲氧基-3-甲基苯胺(17b)(5.00g，23.1mmol)溶于100ml DCM中，加入DIEA(8.95g，69.4mmol)。氮气氛下，于0℃向反应液中加入环丙基乙酰氯(3.61g，34.7mmol)，室温搅拌2小时。加水(100mL)淬灭，用DCM萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝4:1)，得白色固体的标题化合物5.6g，收率85.9％。2-Bromo-4-methoxy-3-methylaniline (17b) (5.00 g, 23.1 mmol) was dissolved in 100 ml DCM at room temperature and DIEA (8.95 g, 69.4 mmol) was added. Under a nitrogen atmosphere, cyclopropylacetyl chloride (3.61 g, 34.7 mmol) was added to the reaction solution at 0° C., and stirred at room temperature for 2 hours. Add water (100mL) to quench, extract with DCM (200mL x 3), wash with saturated brine (200mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=4:1) to obtain 5.6 g of the title compound as a white solid, with a yield of 85.9%.
LC-MS：m/z 284[M+H] +。 LC-MS: m/z 284 [M+H] + .
步骤4：2-环丙基-6-甲氧基-7-甲基苯并[d]噁唑(17d)的制备Step 4: Preparation of 2-cyclopropyl-6-methoxy-7-methylbenzo[d]oxazole (17d)
将N-(2-溴-4-甲氧基-3-甲基苯基)环丙烷甲酰胺(17c)(5.20g，18.3mmol)溶于DMF(100mL)中，加入Cs 2CO 3(11.9g，36.6mmol)、CuI(340mg，1.83mmol)、二联吡啶(570mg，3.66mmol)，氮气氛下，于120℃搅拌过夜。加入水(200mL)淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.8g，收率48.6％。 N-(2-Bromo-4-methoxy-3-methylphenyl)cyclopropanecarboxamide (17c) (5.20 g, 18.3 mmol) was dissolved in DMF (100 mL) and Cs 2 CO 3 (11.9 g, 36.6mmol), CuI (340mg, 1.83mmol), bipyridine (570mg, 3.66mmol), and stirred overnight at 120°C under a nitrogen atmosphere. Add water (200mL) to quench, extract with EA (100mL x 3), wash with saturated brine (100mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 1.8 g of the title compound was obtained as a pale yellow solid, with a yield of 48.6%.
LC-MS：m/z 204[M+H] +。 LC-MS: m/z 204 [M+H] + .
步骤5：2-环丙基-6-甲氧基-7-甲基-5-硝基苯并[d]噁唑(17e)的制备Step 5: Preparation of 2-cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (17e)
将2-环丙基-6-甲氧基-7-甲基苯并[d]噁唑(17d)(1.50g，7.39mmol)溶于TFA(15ml)中，氮气氛下，于0℃向反应液中去滴加HNO 3(5mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水(30mL)淬灭，EA萃取(30mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.1g，收率61.1％ 2-Cyclopropyl-6-methoxy-7-methylbenzo[d]oxazole (17d) (1.50g, 7.39mmol) was dissolved in TFA (15ml), under nitrogen atmosphere, at 0°C to HNO 3 (5 mL) was added dropwise to the reaction solution, stirred at 0°C for 2 hours, and stirred at room temperature overnight. Quenched by adding water (30mL) at 0°C, extracted with EA (30mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 1.1 g of the title compound as a pale yellow solid, yield 61.1%
LC-MS：m/z 249[M+H] +。 LC-MS: m/z 249 [M+H] + .
步骤6：2-环丙基-7-甲基-5-硝基苯并[d]噁唑-6-醇(17f)的制备Step 6: Preparation of 2-cyclopropyl-7-methyl-5-nitrobenzo[d]oxazol-6-ol (17f)
将2-环丙基-6-甲氧基-7-甲基-5-硝基苯并[d]噁唑(17e)(1.00g，4.03mmol)溶于DCM(15ml)中，氮气氛下，于0℃向反应液中滴加BBr 3(8.1mL，1M)，于0℃搅拌2小时，于0℃加甲醇淬灭，DCM萃取(60mL x 3)，饱和食盐水洗涤(80mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1),得淡黄色固体标题化合物720mg，收率76.6％。 2-Cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (17e) (1.00 g, 4.03 mmol) was dissolved in DCM (15 ml) under nitrogen atmosphere , added BBr 3 (8.1mL, 1M) dropwise to the reaction solution at 0°C, stirred at 0°C for 2 hours, quenched with methanol at 0°C, extracted with DCM (60mL x 3), washed with saturated brine (80mL x 1 ), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain 720 mg of the title compound as a pale yellow solid, with a yield of 76.6% .
LC-MS：m/z 235[M+H] +。 LC-MS: m/z 235 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-环丙基-6-硝基苯并[d]噁唑-5-醇(17e)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物17。The remaining steps are the same as the preparation method of Example 1, except that 5-hydroxyl-1,3- Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d), yielding the title compound 17.
LC-MS：m/z 532.2[M+H] +。 LC-MS: m/z 532.2 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.42-7.27(m,3H),7.27-7.11(m,2H),5.58-5.48(m,1H),5.42(s,2H),4.83(dd,J＝11.9,10.1Hz,1H),4.36(dd,J＝10.1,8.1Hz,1H),4.04(ddd,J＝12.4,7.2,5.1Hz,1H),3.64(ddd,J＝12.8,8.4,4.7Hz,1H),3.33(s,3H),2.81(ddd,J＝15.4,8.3,4.9Hz,1H),2.74-2.63(m,1H),2.40(s,3H),2.35-2.24(m,1H),1.27-1.10(m,4H)。 1 H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.42-7.27(m,3H),7.27-7.11(m,2H),5.58-5.48(m,1H),5.42(s, 2H), 4.83(dd, J=11.9, 10.1Hz, 1H), 4.36(dd, J=10.1, 8.1Hz, 1H), 4.04(ddd, J=12.4, 7.2, 5.1Hz, 1H), 3.64(ddd ,J=12.8,8.4,4.7Hz,1H),3.33(s,3H),2.81(ddd,J=15.4,8.3,4.9Hz,1H),2.74-2.63(m,1H),2.40(s,3H ), 2.35-2.24(m,1H), 1.27-1.10(m,4H).
实施例18：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5,10-二甲基-7,8-二氢噻唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(18)的制备Example 18: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-cyclopropyl-5,10-dimethyl-7,8-dihydrothiazolo[4',5':4,5]benzo[1,2-b][1, 4] Preparation of oxazepine-6(5H)-one (18)
Figure PCTCN2022092607-appb-000054
Figure PCTCN2022092607-appb-000054
步骤1：N-(2-溴-4-甲氧基-3-甲基苯基)环丙烷硫代酰胺(18a)的制备Step 1: Preparation of N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanethioamide (18a)
将N-(2-溴-4-甲氧基-3-甲基苯基)环丙烷甲酰胺(3.20g，11.3mmol)溶于甲苯(50ml)中，氮气氛下，于0℃向反应液中加入劳森试剂(9.13g，22.6mmol)，于80℃搅拌2小时。于室温过滤，用甲苯(10mL x 3)洗涤滤饼，合并有机相，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物2.8g，收率82％。Dissolve N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanecarboxamide (3.20g, 11.3mmol) in toluene (50ml), and add to the reaction solution at 0°C under nitrogen atmosphere Add Lawson's reagent (9.13g, 22.6mmol) to it, and stir at 80°C for 2 hours. Filter at room temperature, wash the filter cake with toluene (10mL x 3), combine the organic phases, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain light yellow 2.8 g of the solid title compound, yield 82%.
LC-MS：m/z 300[M+H] +。 LC-MS: m/z 300 [M+H] + .
步骤2：2-环丙基-6-甲氧基-7-甲基苯并[d]噻唑(18b)的制备Step 2: Preparation of 2-cyclopropyl-6-methoxy-7-methylbenzo[d]thiazole (18b)
将N-(2-溴-4-甲氧基-3-甲基苯基)环丙烷硫代酰胺(18a)(2.50g，8.36mmol)溶于DMF(30mL)中，加入Cs 2CO 3(5.45g，16.7mmol)、CuI(79.4mg，0.418mmol)、二联吡啶(130mg，0.836mmol)，氮气氛下，于25℃搅拌过夜。加入水(100mL)淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.23g，收率68.2％。 N-(2-Bromo-4-methoxy-3-methylphenyl)cyclopropanethioamide (18a) (2.50 g, 8.36 mmol) was dissolved in DMF (30 mL), and Cs 2 CO 3 ( 5.45g, 16.7mmol), CuI (79.4mg, 0.418mmol), bipyridine (130mg, 0.836mmol), and stirred overnight at 25°C under a nitrogen atmosphere. Add water (100mL) to quench, EA extract (100mL x 3), wash with saturated brine (100mL x 1), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 1.23 g of the title compound was obtained as a light yellow solid, with a yield of 68.2%.
LC-MS：m/z 220[M+H] +。 LC-MS: m/z 220 [M+H] + .
步骤3：2-环丙基-6-甲氧基-7-甲基-5-硝基苯并[d]噻唑(18c)的制备Step 3: Preparation of 2-cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]thiazole (18c)
于室温，将2-环丙基-6-甲氧基-7-甲基苯并[d]噻唑(18b)(1.10g，5.02mmol)溶于TFA(9ml)中，氮气氛下，于0℃向反应液中滴加HNO 3(3mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水(30mL)淬灭，EA萃取(30mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物800mg，收率61.1％。 At room temperature, 2-cyclopropyl-6-methoxy-7-methylbenzo[d]thiazole (18b) (1.10g, 5.02mmol) was dissolved in TFA (9ml), under nitrogen atmosphere, at 0 °C, HNO 3 (3 mL) was added dropwise to the reaction solution, stirred at 0 °C for 2 hours, and stirred at room temperature overnight. Quenched by adding water (30mL) at 0°C, extracted with EA (30mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 800 mg of the title compound as a light yellow solid with a yield of 61.1%.
LC-MS：m/z 265[M+H] +。 LC-MS: m/z 265 [M+H] + .
步骤4：2-环丙基-7-甲基-5-硝基苯并[d]噻唑-6-醇(18d)的制备Step 4: Preparation of 2-cyclopropyl-7-methyl-5-nitrobenzo[d]thiazol-6-ol (18d)
将2-环丙基-6-甲氧基-7-甲基-5-硝基苯并[d]噻唑(18c)(700mg，2.65mmol)溶于DCM(15ml)中，氮气氛下，于0℃向反应液中滴加BBr 3(10.6mL，1M)，于0℃搅拌0.5小时。于0℃加甲醇(40mL)淬灭，DCM萃取(50mL x 3)，饱和食盐水洗涤(80mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1),得淡黄色固体标题化合物210mg，收率32.8％。 2-Cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]thiazole (18c) (700mg, 2.65mmol) was dissolved in DCM (15ml), under nitrogen atmosphere, at BBr 3 (10.6 mL, 1M) was added dropwise to the reaction solution at 0°C, and stirred at 0°C for 0.5 hour. Quenched by adding methanol (40mL) at 0°C, extracted with DCM (50mL x 3), washed with saturated brine (80mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) to obtain 210 mg of the title compound as a light yellow solid with a yield of 32.8%.
LC-MS：m/z 251[M+H] +。 LC-MS: m/z 251 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-环丙基-7-甲基-5-硝基苯并[d]噻唑-6-醇(18d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物18。The remaining steps are the same as the preparation method of Example 1, except that 5-hydroxy- 1,3-Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to give the title compound 18.
LC-MS：m/z 548.2[M+H] +。 LC-MS: m/z 548.2 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.44-7.24(m,3H),7.23-7.15(m,2H),5.54(dd,J＝11.9,8.0Hz,1H),5.42(s,2H),4.85(dd,J＝11.9,10.1Hz,1H),4.38(dd,J＝10.0,8.0Hz,1H),4.04(ddd,J＝12.4,7.1,5.0Hz,1H),3.64(ddd,J＝12.8,8.3,4.8Hz,1H),3.36(s,3H),2.81(ddd,J＝15.4,8.4,5.0Hz,1H),2.68(ddd,J＝15.6,7.2,4.9Hz,1H),2.55(dt,J＝6.7,4.1Hz,1H),2.44(s,3H),1.25(dt,J＝7.6,3.0Hz,2H),1.15(dt,J＝4.7,3.1Hz,2H)。 1 H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.44-7.24(m,3H),7.23-7.15(m,2H),5.54(dd,J＝11.9,8.0Hz,1H) ,5.42(s,2H),4.85(dd,J=11.9,10.1Hz,1H),4.38(dd,J=10.0,8.0Hz,1H),4.04(ddd,J=12.4,7.1,5.0Hz,1H ), 3.64(ddd, J＝12.8, 8.3, 4.8Hz, 1H), 3.36(s, 3H), 2.81(ddd, J＝15.4, 8.4, 5.0Hz, 1H), 2.68(ddd, J＝15.6, 7.2 ,4.9Hz,1H),2.55(dt,J=6.7,4.1Hz,1H),2.44(s,3H),1.25(dt,J=7.6,3.0Hz,2H),1.15(dt,J=4.7, 3.1Hz, 2H).
实施例19：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6- 基)-2-(叔-丁基)-5,10-二甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(19)的制备Example 19: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-(tert-butyl)-5,10-dimethyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b Preparation of ][1,4]oxazepine-6(5H)-one (19)
Figure PCTCN2022092607-appb-000055
Figure PCTCN2022092607-appb-000055
步骤1：N-(2-溴-4-甲氧基-3-甲基苯基)新戊酰胺(19a)的制备Step 1: Preparation of N-(2-bromo-4-methoxy-3-methylphenyl)pivalamide (19a)
于室温，将2-溴-4-甲氧基-3-甲基苯胺(17b)(7.40g，34.4mmol)溶于100ml DCM中，加入DIEA(13.0g，103mmol)，氮气氛下，于0℃向反应液中加入新戊酰氯(6.19g，51.6mmol)，室温搅拌2小时。加水(100mL)淬灭，用DCM萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝4:1)，得白色固体的标题化合物7.9g，收率78.6％。At room temperature, 2-bromo-4-methoxy-3-methylaniline (17b) (7.40g, 34.4mmol) was dissolved in 100ml DCM, DIEA (13.0g, 103mmol) was added, under nitrogen atmosphere, at 0 °C, pivaloyl chloride (6.19 g, 51.6 mmol) was added to the reaction liquid, and stirred at room temperature for 2 hours. Add water (100mL) to quench, extract with DCM (200mL x 3), wash with saturated brine (200mL x 1), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (Mobile phase PE/EA=4:1), 7.9 g of the title compound was obtained as a white solid, with a yield of 78.6%.
LC-MS：m/z 300[M+H] +。 LC-MS: m/z 300 [M+H] + .
步骤2：2-叔丁基-6-甲氧基-7-甲基苯并[d]噁唑(19b)的制备Step 2: Preparation of 2-tert-butyl-6-methoxy-7-methylbenzo[d]oxazole (19b)
将N-(2-溴-4-甲氧基-3-甲基苯基)新戊酰胺(19a)(1.00g，3.30mmol)溶于DMF(10mL)中，加入Cs 2CO 3(2.18g，6.68mmol)、CuI(30.0mg，0.165mmol)、二联吡啶(50.0mg，0.330mmol)，氮气氛下，于120℃搅拌过夜。加水(20mL)淬灭，EA萃取(20mL x 3)，饱和食盐水洗涤(40mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1),得淡黄色固体标题化合物550mg，收率75.3％。 N-(2-Bromo-4-methoxy-3-methylphenyl)pivalamide (19a) (1.00 g, 3.30 mmol) was dissolved in DMF (10 mL), Cs 2 CO 3 (2.18 g , 6.68mmol), CuI (30.0mg, 0.165mmol), bipyridine (50.0mg, 0.330mmol), and stirred overnight at 120°C under a nitrogen atmosphere. Water (20mL) was added to quench, EA extracted (20mL x 3), washed with saturated brine (40mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Mobile phase PE/EA=3:1), to obtain 550 mg of the title compound as a pale yellow solid, with a yield of 75.3%.
LC-MS：m/z 220[M+H] +。 LC-MS: m/z 220 [M+H] + .
步骤3：2-叔丁基-6-甲氧基-7-甲基-5-硝基苯并[d]噁唑(19c)的制备Step 3: Preparation of 2-tert-butyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (19c)
将2-叔丁基-6-甲氧基-7-甲基苯并[d]噁唑(19b)(1.50g，6.85mmol)溶于TFA(15ml)中，氮气氛下，于0℃向反应液中滴加浓HNO 3(5mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水(30mL)淬灭，EA萃取(30mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物900mg，收率51.1％。 2-tert-butyl-6-methoxy-7-methylbenzo[d]oxazole (19b) (1.50g, 6.85mmol) was dissolved in TFA (15ml), under nitrogen atmosphere, at 0°C to Concentrated HNO 3 (5 mL) was added dropwise to the reaction solution, stirred at 0°C for 2 hours and at room temperature overnight. Quenched by adding water (30mL) at 0°C, extracted with EA (30mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 900 mg of the title compound as a pale yellow solid, with a yield of 51.1%.
LC-MS：m/z 265[M+H] +。 LC-MS: m/z 265 [M+H] + .
步骤4：2-叔丁基-7-甲基-5-硝基苯并[d]噁唑-6-醇(19d)的制备Step 4: Preparation of 2-tert-butyl-7-methyl-5-nitrobenzo[d]oxazol-6-ol (19d)
将2-叔丁基-6-甲氧基-7-甲基-5-硝基苯并[d]噁唑(19c)(1.00g，3.79mmol)溶于DCM(15ml)中，氮气氛下，于0℃向反应液中滴加BBr 3(7.6mL，1M)，于0℃搅拌2小时。于0℃加甲醇淬灭，DCM萃取(60mL x 3)，饱和食盐水洗涤(80mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物640mg，收率67.3％ 2-tert-Butyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (19c) (1.00 g, 3.79 mmol) was dissolved in DCM (15 ml) under nitrogen atmosphere , BBr 3 (7.6 mL, 1M) was added dropwise to the reaction solution at 0°C, and stirred at 0°C for 2 hours. Quenched by adding methanol at 0°C, extracted with DCM (60mL x 3), washed with saturated brine (80mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), to obtain 640 mg of the title compound as a pale yellow solid, yield 67.3%
LC-MS：m/z 251[M+H] +。 LC-MS: m/z 251 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-叔丁基-7-甲基-5-硝基苯并[d]噁唑-6-醇(19d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物19。The remaining steps are the same as in Example 1, except that 2-tert-butyl-7-methyl-5-nitrobenzo[d]oxazol-6-ol (19d) is used to replace the 5-hydroxyl in step 5 -1,3-Dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) to obtain the title compound 19.
LC-MS：m/z 548.2[M+H] +。 LC-MS: m/z 548.2 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.39-7.28(m,3H),7.23-7.13(m,2H),5.54(dd,J＝11.9,8.1Hz,1H),5.42(s,2H),4.83(dd,J＝11.9,10.1Hz,1H),4.38(dd,J＝10.1,8.1Hz,1H),4.05(ddd,J＝12.4,7.1,5.1Hz,1H),3.64(ddd,J＝12.8,8.5,4.7Hz,1H),3.34(s,3H),2.81(ddd,J＝15.3,8.3,5.0Hz,1H),2.68(ddd,J＝15.6,7.0,4.7Hz,1H),2.42(s,3H),1.45(s,9H)。 1 H NMR (400MHz, DMSO-d6) δ7.71(s, 1H), 7.39-7.28(m, 3H), 7.23-7.13(m, 2H), 5.54(dd, J=11.9, 8.1Hz, 1H) ,5.42(s,2H),4.83(dd,J=11.9,10.1Hz,1H),4.38(dd,J=10.1,8.1Hz,1H),4.05(ddd,J=12.4,7.1,5.1Hz,1H ), 3.64(ddd, J＝12.8, 8.5, 4.7Hz, 1H), 3.34(s, 3H), 2.81(ddd, J＝15.3, 8.3, 5.0Hz, 1H), 2.68(ddd, J＝15.6, 7.0 ,4.7Hz,1H),2.42(s,3H),1.45(s,9H).
实施例20：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噻唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(20)的制备Example 20: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrothiazolo[5',4':4,5]benzo[1,2-b][1,4]oxy Preparation of azepine-8(9H)-one (20)
Figure PCTCN2022092607-appb-000056
Figure PCTCN2022092607-appb-000056
步骤1：N-(2-溴-4-甲氧基苯基)环丙烷硫代酰胺(20a)的制备Step 1: Preparation of N-(2-bromo-4-methoxyphenyl)cyclopropanethioamide (20a)
将N-(2-溴-4-甲氧基苯基)环丙烷甲酰胺(7a)(6.10g，22.6mmol)溶于甲苯(100ml)中，氮气氛下，于0℃向反应液中加入劳森试剂(18.4g，45.3mmol)，于80℃搅拌2小时。于室温过滤，用甲苯(20mL x 3)洗涤滤饼，合并有机相，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物5.8g，收率81.4％。Dissolve N-(2-bromo-4-methoxyphenyl)cyclopropanecarboxamide (7a) (6.10g, 22.6mmol) in toluene (100ml), and add Lawson's reagent (18.4g, 45.3mmol), stirred at 80°C for 2 hours. Filter at room temperature, wash the filter cake with toluene (20mL x 3), combine the organic phases, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain light yellow The solid title compound was 5.8 g, yield 81.4%.
LC-MS：m/z 286[M+H] +。 LC-MS: m/z 286 [M+H] + .
步骤2：2-环丙基-6-甲氧基苯并[d]噻唑(20b)的制备Step 2: Preparation of 2-cyclopropyl-6-methoxybenzo[d]thiazole (20b)
将N-(2-溴-4-甲氧基苯基)环丙烷硫代酰胺(20a)(5.40g，18.9mmol)溶于DMF(60mL)中，加入Cs 2CO 3(12.4g，37.9mmol)、CuI(180mg，0.945mmol)、二联吡啶(295mg，1.89mmol)，氮气氛下，于25℃搅拌过夜。加入水(100mL)淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物3.20g，收率82.1％。 N-(2-bromo-4-methoxyphenyl)cyclopropanethioamide (20a) (5.40 g, 18.9 mmol) was dissolved in DMF (60 mL), Cs 2 CO 3 (12.4 g, 37.9 mmol) was added ), CuI (180mg, 0.945mmol), bipyridine (295mg, 1.89mmol), and stirred overnight at 25°C under a nitrogen atmosphere. Add water (100mL) to quench, EA extract (100mL x 3), wash with saturated brine (100mL x 1), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 3.20 g of the title compound was obtained as a pale yellow solid, with a yield of 82.1%.
LC-MS：m/z 206[M+H] +。 LC-MS: m/z 206 [M+H] + .
步骤3：2-环丙基-6-甲氧基-5-硝基苯并[d]噻唑(20c)的制备Step 3: Preparation of 2-cyclopropyl-6-methoxy-5-nitrobenzo[d]thiazole (20c)
于室温，将2-环丙基-6-甲氧基苯并[d]噻唑(20b)(3.20g，15.6mmol)溶于TFA(30ml)中，氮气氛下，于0℃向反应液中滴加浓HNO 3(10mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水(50mL)淬灭，EA萃取(50mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物800mg，收率20.5％。 Dissolve 2-cyclopropyl-6-methoxybenzo[d]thiazole (20b) (3.20g, 15.6mmol) in TFA (30ml) at room temperature, and add to the reaction solution at 0°C under nitrogen atmosphere Concentrated HNO 3 (10 mL) was added dropwise, stirred at 0° C. for 2 hours and at room temperature overnight. Quenched by adding water (50mL) at 0°C, extracted with EA (50mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 800 mg of the title compound as a pale yellow solid, with a yield of 20.5%.
LC-MS：m/z 251[M+H] +。 LC-MS: m/z 251 [M+H] + .
步骤4：2-环丙基-5-硝基苯并[d]噻唑-6-醇(20d)的制备Step 4: Preparation of 2-cyclopropyl-5-nitrobenzo[d]thiazol-6-ol (20d)
将2-环丙基-6-甲氧基-5-硝基苯并[d]噻唑(20c)(700mg，2.80mmol)溶于DCM(15ml)中，氮气氛下，于0℃向反应液中滴加BBr 3(11.2mL，1M)，于0℃搅拌0.5小时。于0℃加水(40mL)淬灭，DCM萃取(50mL x 3)，饱和食盐水洗涤(80mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物420mg，收率63.3％。 Dissolve 2-cyclopropyl-6-methoxy-5-nitrobenzo[d]thiazole (20c) (700mg, 2.80mmol) in DCM (15ml), and add to the reaction solution at 0°C under nitrogen atmosphere BBr 3 (11.2 mL, 1M) was added dropwise to the mixture, and stirred at 0°C for 0.5 hours. Quenched by adding water (40mL) at 0°C, extracted with DCM (50mL x 3), washed with saturated brine (80mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 420 mg of the title compound as a pale yellow solid, with a yield of 63.3%.
LC-MS：m/z 237[M+H] +。 LC-MS: m/z 237 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-环丙基-5-硝基苯并[d]噻唑-6-醇(20d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物20。The remaining steps are the same as in Example 1, except that 2-cyclopropyl-5-nitrobenzo[d]thiazol-6-ol (20d) is used instead of 5-hydroxyl-1,3-di Methyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d), yielding the title compound 20.
LC-MS:m/z 534.1[M+H] +。 LC-MS: m/z 534.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.92(s,1H),7.43-7.27(m,3H),7.19(dd,J＝6.9,1.8Hz,2H),5.58(dd,J＝11.9,7.9Hz,1H),5.42(s,2H),4.85(dd,J＝12.0,10.1Hz,1H),4.34(dd,J＝10.1,7.9Hz,1H),4.04(ddd,J＝12.2,6.9,5.0Hz,1H),3.64(ddd,J＝12.9,8.6,4.8Hz,1H),3.37(s,3H),2.81(ddd,J＝15.5,8.6,5.0Hz,1H),2.68(ddd,J＝15.7,7.0,4.8Hz,1H),2.61-2.57(m,1H),1.24(dt,J＝8.0,3.3Hz,2H),1.19-1.10(m,2H)。 1 H NMR (400MHz, DMSO-d6)δ8.01(s,1H),7.92(s,1H),7.43-7.27(m,3H),7.19(dd,J＝6.9,1.8Hz,2H),5.58 (dd, J=11.9,7.9Hz,1H),5.42(s,2H),4.85(dd,J=12.0,10.1Hz,1H),4.34(dd,J=10.1,7.9Hz,1H),4.04( ddd,J=12.2,6.9,5.0Hz,1H), 3.64(ddd,J=12.9,8.6,4.8Hz,1H),3.37(s,3H),2.81(ddd,J=15.5,8.6,5.0Hz, 1H), 2.68(ddd, J＝15.7, 7.0, 4.8Hz, 1H), 2.61-2.57(m, 1H), 1.24(dt, J＝8.0, 3.3Hz, 2H), 1.19-1.10(m, 2H) .
实施例21：(S)-7-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噻唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(21)的制备Example 21: (S)-7-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrothiazolo[5',4':4,5]benzo[1,2-b][1,4]oxy Preparation of azepine-8(9H)-one (21)
Figure PCTCN2022092607-appb-000057
Figure PCTCN2022092607-appb-000057
步骤1：N-(2-溴-5-甲氧基苯基)环丙烷硫代酰胺(21a)的制备Step 1: Preparation of N-(2-bromo-5-methoxyphenyl)cyclopropanethioamide (21a)
将N-(2-溴-5-甲氧基苯基)环丙烷甲酰胺(15a)(6.10g，22.6mmol)溶于甲苯(100ml)中，氮气氛下，于0℃向反应液中加入劳森试剂(18.4g，45.3mmol)，于80℃搅拌2小时。于室温过滤，用甲苯(20mL x 3)洗涤滤饼，合并有机相，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物5.8g，收率81.4％。Dissolve N-(2-bromo-5-methoxyphenyl)cyclopropanecarboxamide (15a) (6.10g, 22.6mmol) in toluene (100ml), and add Lawson's reagent (18.4g, 45.3mmol), stirred at 80°C for 2 hours. Filter at room temperature, wash the filter cake with toluene (20mL x 3), combine the organic phases, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain light yellow The solid title compound was 5.8 g, yield 81.4%.
LC-MS：m/z 286[M+H] +。 LC-MS: m/z 286 [M+H] + .
步骤2：2-环丙基-5-甲氧基苯并[d]噻唑(21b)的制备Step 2: Preparation of 2-cyclopropyl-5-methoxybenzo[d]thiazole (21b)
将N-(2-溴-5-甲氧基苯基)环丙烷硫代酰胺(21a)(5.40g，18.9mmol)溶于DMF(60mL)中，加入Cs 2CO 3(12.4g，37.9mmol)、CuI(180mg，0.945mmol)、二联吡啶(295mg，1.89mmol)，氮气氛下，于25℃搅拌过夜。加入水(100mL)淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物3.20g，收率82.1％。 N-(2-bromo-5-methoxyphenyl)cyclopropanethioamide (21a) (5.40 g, 18.9 mmol) was dissolved in DMF (60 mL), Cs 2 CO 3 (12.4 g, 37.9 mmol) was added ), CuI (180mg, 0.945mmol), bipyridine (295mg, 1.89mmol), and stirred overnight at 25°C under a nitrogen atmosphere. Add water (100mL) to quench, EA extract (100mL x 3), wash with saturated brine (100mL x 1), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 3.20 g of the title compound was obtained as a pale yellow solid, with a yield of 82.1%.
LC-MS：m/z 206[M+H] +。 LC-MS: m/z 206 [M+H] + .
步骤3：2-环丙基-5-甲氧基-6-硝基苯并[d]噻唑(21c)的制备Step 3: Preparation of 2-cyclopropyl-5-methoxy-6-nitrobenzo[d]thiazole (21c)
于室温，将2-环丙基-5-甲氧基苯并[d]噻唑(21b)(3.20g，15.6mmol)溶于TFA(30ml)中，氮气氛下，于0℃向反应液中滴加浓HNO 3(10mL)，于0℃搅拌2小时，于室温搅拌过夜。于0℃加水(50mL)淬灭，EA萃取(50mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物800mg，收率20.5％。 Dissolve 2-cyclopropyl-5-methoxybenzo[d]thiazole (21b) (3.20g, 15.6mmol) in TFA (30ml) at room temperature, and add to the reaction solution at 0°C under nitrogen atmosphere Concentrated HNO 3 (10 mL) was added dropwise, stirred at 0° C. for 2 hours and at room temperature overnight. Quenched by adding water (50mL) at 0°C, extracted with EA (50mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 800 mg of the title compound as a pale yellow solid, with a yield of 20.5%.
LC-MS：m/z 251[M+H] +。 LC-MS: m/z 251 [M+H] + .
步骤4：2-环丙基-6-硝基苯并[d]噻唑-5-醇(21d)的制备Step 4: Preparation of 2-cyclopropyl-6-nitrobenzo[d]thiazol-5-ol (21d)
将2-环丙基-5-甲氧基-6-硝基苯并[d]噻唑(21c)(700mg，2.80mmol)溶于DCM(15ml)中，氮气氛下，于0℃向反应液中滴加BBr 3溶液(11.2mL，1M)，于0℃搅拌0.5小时。于0℃加水(40mL)淬灭，DCM萃取(50mL x 3)，饱和 食盐水洗涤(80mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物420mg，收率63.3％。 Dissolve 2-cyclopropyl-5-methoxy-6-nitrobenzo[d]thiazole (21c) (700mg, 2.80mmol) in DCM (15ml), and add to the reaction solution at 0°C under nitrogen atmosphere BBr 3 solution (11.2 mL, 1 M) was added dropwise to the mixture, and stirred at 0° C. for 0.5 hours. Quenched by adding water (40mL) at 0°C, extracted with DCM (50mL x 3), washed with saturated brine (80mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 420 mg of the title compound as a pale yellow solid, with a yield of 63.3%.
LC-MS：m/z 237[M+H] +。 LC-MS: m/z 237 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用2-环丙基-6-硝基苯并[d]噻唑-5-醇(21d)代替步骤5中的5-羟基-1,3-二甲基-6-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(1d)，制得标题化合物21。The remaining steps are the same as in Example 1, except that 2-cyclopropyl-6-nitrobenzo[d]thiazol-5-ol (21d) is used instead of 5-hydroxy-1,3-di Methyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d), yielding the title compound 21.
LC-MS：m/z 534.1[M+H] +。 LC-MS: m/z 534.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.70(s,1H),7.39-7.25(m,3H),7.22-7.15(m,2H),5.56(dd,J＝12.0,8.0Hz,1H),5.42(s,2H),4.85(dd,J＝12.0,10.1Hz,1H),4.36(dd,J＝10.1,8.0Hz,1H),4.03(ddd,J＝12.2,7.0,5.0Hz,1H),3.65(ddd,J＝12.8,8.5,4.8Hz,1H),3.35(s,3H),2.81(ddd,J＝15.4,8.5,5.0Hz,1H),2.74-2.64(m,1H),2.54(s,1H),1.30-1.21(m,2H),1.15(tq,J＝6.9,4.7Hz,2H)。 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.70(s,1H),7.39-7.25(m,3H),7.22-7.15(m,2H),5.56(dd,J= 12.0,8.0Hz,1H),5.42(s,2H),4.85(dd,J=12.0,10.1Hz,1H),4.36(dd,J=10.1,8.0Hz,1H),4.03(ddd,J=12.2 ,7.0,5.0Hz,1H),3.65(ddd,J=12.8,8.5,4.8Hz,1H),3.35(s,3H),2.81(ddd,J=15.4,8.5,5.0Hz,1H),2.74- 2.64 (m, 1H), 2.54 (s, 1H), 1.30-1.21 (m, 2H), 1.15 (tq, J=6.9, 4.7Hz, 2H).
实施例22：(S)-7-(3-氯-2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(22)的制备Example 22: (S)-7-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4 -c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b] Preparation of [1,4]oxazepine-6(5H)-one (22)
Figure PCTCN2022092607-appb-000058
Figure PCTCN2022092607-appb-000058
步骤1：(S)-5-氯-4-(2-((2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(22a)的制备Step 1: (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4' ,5':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyridine Preparation of ethyl azole-3-carboxylate (22a)
于室温，将(S)-7-氨基-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(7l)(80.0mg，0.310mmol)、5-氯-1-(2-氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-甲酸乙酯(10d)(145mg，0.450mmol)、钛酸四乙酯(106mg，0.470mmol)溶于THF(8mL)，室温搅拌1小时，加入甲醇(4mL)、氰基硼氢化钠(38.9mg，0.620mmol)，室温搅拌5小时。加入10mL饱和碳酸氢钠溶液，用EA萃取(30mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物20.0mg，收率11.1％。At room temperature, (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2- b] [1,4]oxazepine-6(5H)-one (7l) (80.0mg, 0.310mmol), 5-chloro-1-(2-fluorobenzyl)-4-(2-oxo Ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (10d) (145mg, 0.450mmol), tetraethyl titanate (106mg, 0.470mmol) were dissolved in THF (8mL), stirred at room temperature for 1 hour, and methanol ( 4 mL), sodium cyanoborohydride (38.9 mg, 0.620 mmol), and stirred at room temperature for 5 hours. Add 10mL saturated sodium bicarbonate solution, extract with EA (30mL x 3), wash with saturated brine (50mL x 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by high-pressure preparative liquid chromatography (Column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), obtain 20.0mg of off-white solid shape title compound, yield 11.1 %.
LC-MS：m/z 582[M+H] +。 LC-MS: m/z 582 [M+H] + .
步骤2：(S)-7-(3-氯-2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(22)的制备Step 2: (S)-7-(3-Chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepine-6(5H)-one (22)
于0℃，将(S)-5-氯-4-(2-((2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(22a)(20.0mg，0.0340mmol)溶于1ml氯仿中，氮气氛下，向反应液中加入Al(CH 3) 3(0.09ml，2M)，于50℃搅拌3小时。加水淬灭，用EA萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物15mg，收率55.5％。 At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[ 4',5':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H -Pyrazole-3-carboxylic acid ethyl ester (22a) (20.0mg, 0.0340mmol) was dissolved in 1ml of chloroform, and under a nitrogen atmosphere, Al(CH 3 ) 3 (0.09ml, 2M) was added to the reaction solution, and the °C and stirred for 3 hours. Quenched with water, extracted with EA (10mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by high-pressure preparative liquid chromatography (column type : Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), to obtain 15 mg of the title compound as off-white solid, yield 55.5%.
LC-MS:m/z 536.0[M+H] +。 LC-MS: m/z 536.0 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.60(s,1H),7.39-7.37(m,1H),7.25-7.12(m,3H),5.57-5.52(m,1H),5.47(s,2H),4.86-4.80(m,1H),4.35-4.30(m,1H),4.03(m,1H),3.64-3.62(m,1H),3.34(s,3H),2.77-2.71(m,2H),2.29-2.21(m,1H),1.23-1.14(m,4H)。 1 H NMR (400MHz,DMSO-d6)δ7.80(s,1H),7.60(s,1H),7.39-7.37(m,1H),7.25-7.12(m,3H),5.57-5.52(m, 1H),5.47(s,2H),4.86-4.80(m,1H),4.35-4.30(m,1H),4.03(m,1H),3.64-3.62(m,1H),3.34(s,3H) ,2.77-2.71(m,2H),2.29-2.21(m,1H),1.23-1.14(m,4H).
实施例23：(S)-7-(3-氯-2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(23)的制备Example 23: (S)-7-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4 -c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b] Preparation of [1,4]oxazepine-8(9H)-one (23)
Figure PCTCN2022092607-appb-000059
Figure PCTCN2022092607-appb-000059
步骤1：(S)-5-氯-4-(2-((2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(23a)制备Step 1: (S)-5-Chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5' ,4':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyridine Preparation of azole-3-carboxylic acid ethyl ester (23a)
于室温，将(S)-7-氨基-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(15l)(92.0mg，0.360mmol)、5-氯-1-(2-氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-甲酸乙酯(10d)(127mg，0.390mmol)、钛酸四乙酯(123mg，0.540mmol)溶于THF(5mL)，室温搅拌2小时，加入甲醇(2.5mL)、氰基硼氢化钠(45.2mg，0.720mmol)，室温搅拌过夜。加入10mL饱和碳酸氢钠溶液， 用EA萃取(30mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物120mg，收率52.4％。At room temperature, (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2- b] [1,4]oxazepine-8(9H)-one (15l) (92.0mg, 0.360mmol), 5-chloro-1-(2-fluorobenzyl)-4-(2-oxo Ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (10d) (127mg, 0.390mmol), tetraethyl titanate (123mg, 0.540mmol) were dissolved in THF (5mL), stirred at room temperature for 2 hours, and methanol ( 2.5 mL), sodium cyanoborohydride (45.2 mg, 0.720 mmol), and stirred overnight at room temperature. Add 10mL saturated sodium bicarbonate solution, extract with EA (30mL x 3), wash with saturated brine (50mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated by high-pressure preparative liquid chromatography (Column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), and 120 mg of the title compound was obtained as an off-white solid with a yield of 52.4%.
LC-MS：m/z 582[M+H] +。 LC-MS: m/z 582 [M+H] + .
步骤2：(S)-7-(3-氯-2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(23)的制备Step 2: (S)-7-(3-Chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepin-8(9H)-one (23)
于0℃，将(S)-5-氯-4-(2-((2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(23a)(100mg，0.170mmol)溶于1ml氯仿中，氮气氛下，向反应液中加入Al(CH 3) 3(0.27ml，2M)，于50℃搅拌2小时。加水淬灭，用EA萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物30.0mg，收率27.3％。 At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[ 5',4':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H -Pyrazole-3-carboxylic acid ethyl ester (23a) (100mg, 0.170mmol) was dissolved in 1ml of chloroform, and under a nitrogen atmosphere, Al(CH 3 ) 3 (0.27ml, 2M) was added to the reaction solution, and the Stir for 2 hours. Quenched with water, extracted with EA (10mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by high-pressure preparative liquid chromatography (column type : Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), to obtain 30.0mg of the title compound as off-white solid, yield 27.3%.
LC-MS：m/z 536.0[M+H] +。 LC-MS: m/z 536.0 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.49(s,1H),7.36(s,1H),7.23-7.10(m,3H),5.57-5.52(m,1H),5.47(s,2H),4.84-4.79(m,1H),4.35-4.30(dd,J＝10.0,8.2Hz,1H),4.04-4.00(dt,J＝12.2,5.9Hz,1H),3.67-3.61(m,1H),3.34(s,3H),2.78-2.77(m,1H),2.72-2.65(m,1H),2.33-2.26(ddd,J＝13.0,8.2,4.9Hz,1H),1.22-1.13(m,4H)。 1 H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.49(s,1H),7.36(s,1H),7.23-7.10(m,3H),5.57-5.52(m,1H) ,5.47(s,2H),4.84-4.79(m,1H),4.35-4.30(dd,J=10.0,8.2Hz,1H),4.04-4.00(dt,J=12.2,5.9Hz,1H),3.67 -3.61(m,1H),3.34(s,3H),2.78-2.77(m,1H),2.72-2.65(m,1H),2.33-2.26(ddd,J＝13.0,8.2,4.9Hz,1H) ,1.22-1.13(m,4H).
实施例24：(S)-7-(3-氯-2-(3,5-二氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(24)的制备Example 24: (S)-7-(3-chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[ 3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2 -b] Preparation of [1,4]oxazepine-6(5H)-one (24)
Figure PCTCN2022092607-appb-000060
Figure PCTCN2022092607-appb-000060
Figure PCTCN2022092607-appb-000061
Figure PCTCN2022092607-appb-000061
步骤1：(E)-2-(3,5-二氟苯亚甲基)联胺-1-羧酸叔丁酯(24a)的制备Step 1: Preparation of (E)-tert-butyl 2-(3,5-difluorobenzylidene)hydrazine-1-carboxylate (24a)
于室温，将3,5-二氟苯甲醛(10.0g，70.4mmol)溶于DCM(100ml)中，加入联胺羧酸叔丁酯(9.29g，70.4mmol)，于室温搅拌过夜。减压浓缩，得类白色固体状标题化合物18.0g，收率98.5％。Dissolve 3,5-difluorobenzaldehyde (10.0 g, 70.4 mmol) in DCM (100 ml) at room temperature, add tert-butyl hydrazinecarboxylate (9.29 g, 70.4 mmol), and stir overnight at room temperature. Concentration under reduced pressure afforded 18.0 g of the title compound as an off-white solid with a yield of 98.5%.
LC-MS：m/z 257[M+H] +。 LC-MS: m/z 257 [M+H] + .
步骤2：2-(3,5-二氟苯甲基)联胺-1-羧酸叔丁酯(24b)的制备Step 2: Preparation of tert-butyl 2-(3,5-difluorobenzyl)hydrazine-1-carboxylate (24b)
将(E)-2-(3,5-二氟苯亚甲基)联胺-1-羧酸叔丁酯(24a)(5.00g，19.5mmol)溶于EtOH(30mL)中，于室温加入含水Pd/C(2.07g)，氢气氛下，于50℃搅拌过夜。过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝5:1)，得类白色固体状标题化合物4.90g，收率97.4％。Dissolve (E)-2-(3,5-difluorobenzylidene)hydrazine-1-carboxylate tert-butyl ester (24a) (5.00 g, 19.5 mmol) in EtOH (30 mL) and add Aqueous Pd/C (2.07g) was stirred overnight at 50°C under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=5:1) to obtain 4.90 g of the title compound as an off-white solid, with a yield of 97.4%.
LC-MS：m/z 259[M+H] +。 LC-MS: m/z 259 [M+H] + .
步骤3：(3,5-二氟苯甲基)联胺(24c)的制备Step 3: Preparation of (3,5-difluorobenzyl)hydrazine (24c)
将2-(3,5-二氟苯甲基)联胺-1-羧酸叔丁酯(24b)(5.00g，19.4mmol)溶于MeOH(25mL)中，于室温加入浓盐酸(8ml)，于40℃搅拌过夜。饱和碳酸氢钠溶液调PH至10，EA萃取(50mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝5:1)，得黄色油状标题化合物1.60g，收率53.3％。Dissolve tert-butyl 2-(3,5-difluorobenzyl)hydrazine-1-carboxylate (24b) (5.00g, 19.4mmol) in MeOH (25mL), add concentrated hydrochloric acid (8ml) at room temperature , and stirred overnight at 40°C. Adjust the pH to 10 with saturated sodium bicarbonate solution, extract with EA (50mL x 3), wash with saturated brine (100mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=5:1) gave 1.60 g of the title compound as a yellow oil, with a yield of 53.3%.
步骤4：1-(3,5-二氟苯甲基)-5-羟基-1H-吡唑-3-羧酸乙酯(24d)的制备Step 4: Preparation of ethyl 1-(3,5-difluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (24d)
于室温，将草酸二乙酯钠盐(8.77g，41.8mmol)溶于HAc(34.2g，570mmol)和二氧六环(180ml)中，室温搅拌0.5小时，加入(3,5-二氟苯甲基)联胺(24c)(6.00g，38.0mmol)，于100℃搅拌2小时。加水淬灭，用EA萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色半固体状标题化合物5.50g，收率51.4％。Dissolve diethyl oxalate sodium salt (8.77g, 41.8mmol) in HAc (34.2g, 570mmol) and dioxane (180ml) at room temperature, stir at room temperature for 0.5 hours, add (3,5-difluorobenzene Methyl)hydrazine (24c) (6.00g, 38.0mmol), stirred at 100°C for 2 hours. Quenched with water, extracted with EA (200mL x 3), washed with saturated brine (200mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain 5.50 g of the title compound as a yellow semi-solid, with a yield of 51.4%.
LC-MS：m/z 283[M+H] +。 LC-MS: m/z 283 [M+H] + .
步骤5：5-氯-1-(3,5-二氟苯甲基)-4-甲酰基-1H-吡唑-3-羧酸乙酯(24e)的制备Step 5: Preparation of ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate (24e)
将1-(3,5-二氟苯甲基)-5-羟基-1H-吡唑-3-羧酸乙酯(24d)(1.00g，3.55mmol) 溶于DMF(2.8mL，28.4mmol)中，于0℃加入POCl 3(5.6ml，56.8mmol)，于90℃搅拌过夜。将反应液倒入冰水中，饱和碳酸氢钠调节PH至10，EA萃取(30mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝1:1)，得黄色半固体状标题化合物590mg，收率：50.6％。 Ethyl 1-(3,5-difluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (24d) (1.00 g, 3.55 mmol) was dissolved in DMF (2.8 mL, 28.4 mmol) , POCl 3 (5.6ml, 56.8mmol) was added at 0°C, and stirred at 90°C overnight. The reaction solution was poured into ice water, adjusted to pH 10 with saturated sodium bicarbonate, extracted with EA (30mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue Separation and purification by silica gel column chromatography (mobile phase PE/EA=1:1) gave 590 mg of the title compound as yellow semi-solid, yield: 50.6%.
LC-MS：m/z 329[M+H] +。 LC-MS: m/z 329 [M+H] + .
步骤6：(E)-5-氯-1-(3,5-二氟苯甲基)-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(24f)的制备Step 6: (E)-Ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (24f ) preparation
将氯(甲氧甲基)三苯基磷(1.38g，4.02mmol)溶于THF(5mL)中，于0℃加入t-BuOK(408mg，3.64mmol)的THF溶液(2mL)，搅拌0.5小时。缓慢加入5-氯-1-(3,5-二氟苯甲基)-4-甲酰基-1H-吡唑-3-羧酸乙酯(24e)(300mg，0.910mmol)的THF溶液(2mL)，于室温搅拌过夜。将反应液加到冰水中，EA萃取(30mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色油状标题化合物350mg，收率67.1％。Dissolve chloro(methoxymethyl)triphenylphosphine (1.38g, 4.02mmol) in THF (5mL), add t-BuOK (408mg, 3.64mmol) in THF solution (2mL) at 0°C, and stir for 0.5 hours . A THF solution (2 mL ), stirred overnight at room temperature. The reaction solution was added to ice water, extracted with EA (30mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), 350 mg of the title compound was obtained as a yellow oil, with a yield of 67.1%.
LC-MS：m/z 357[M+H] +。 LC-MS: m/z 357 [M+H] + .
步骤7：5-氯-1-(3,5-二氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-羧酸乙酯(24g)的制备Step 7: Preparation of ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (24 g)
将(E)-5-氯-1-(3,5-二氟苯甲基)-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(24f)(350mg，0.980mmol)溶于THF(5ml)中，滴加盐酸(6M)(8.2mL，49.2mmol)，于60℃搅拌1小时。于0℃，用2mol/L的NaOH溶液调节PH至10，EA萃取(10mL x 3)，饱和食盐水洗涤(30mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物409mg(粗品)。(E)-5-Chloro-1-(3,5-difluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (24f) ( 350mg, 0.980mmol) was dissolved in THF (5ml), hydrochloric acid (6M) (8.2mL, 49.2mmol) was added dropwise, and stirred at 60°C for 1 hour. At 0°C, adjust the pH to 10 with 2mol/L NaOH solution, extract with EA (10mL x 3), wash with saturated brine (30mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oil The title compound 409 mg (crude product).
LC-MS：m/z 343[M+H] +。 LC-MS: m/z 343 [M+H] + .
步骤8：(S)-5-氯-4-(2-((2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(3,5-二氟苄基)-1H-吡唑-3-羧酸乙酯(24h)制备Step 8: (S)-5-Chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4' ,5':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)- Preparation of ethyl 1H-pyrazole-3-carboxylate (24h)
于室温，将(S)-7-氨基-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(7l)(138mg，0.530mmol)、5-氯-1-(3,5-二氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-羧酸乙酯(24g)(200mg，0.580mmol)、钛酸四乙酯(181mg，0.800mmol)溶于THF(10mL)，室温搅拌0.5小时，加入甲醇(5mL)、氰基硼氢化钠(66.6mg，1.06mmol)，室温搅拌过夜。加入10mL饱和碳酸氢钠溶液，用EA萃取(30mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物200mg，收率63.1％。At room temperature, (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2- b] [1,4]oxazepine-6(5H)-one (7l) (138mg, 0.530mmol), 5-chloro-1-(3,5-difluorobenzyl)-4-(2- Oxoethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (24g) (200mg, 0.580mmol), tetraethyl titanate (181mg, 0.800mmol) were dissolved in THF (10mL), stirred at room temperature for 0.5 hours, Add methanol (5 mL), sodium cyanoborohydride (66.6 mg, 1.06 mmol), and stir at room temperature overnight. Add 10mL saturated sodium bicarbonate solution, extract with EA (30mL x 3), wash with saturated brine (50mL x 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by high-pressure preparative liquid chromatography (Column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), to obtain 200 mg of the title compound as off-white solid, yield 63.1% .
LC-MS：m/z 600[M+H] +。 LC-MS: m/z 600 [M+H] + .
步骤9：(S)-7-(3-氯-2-(3,5-二氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(24)的制备Step 9: (S)-7-(3-Chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-6(5H)-one (24)
于0℃，将(S)-5-氯-4-(2-((2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(3,5-二氟苯甲基)-1H-吡唑-3-羧酸乙酯(24h)(180mg，0.300mmol)溶于2ml氯仿中，氮气氛下，向反应液中加入Al(CH 3) 3(0.45ml，2M)，于50℃搅拌3小时。加水淬灭，用EA萃取(10mL x3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物61.3mg，收率：37.3％。 At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[ 4',5':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl Base)-1H-pyrazole-3-carboxylic acid ethyl ester (24h) (180mg, 0.300mmol) was dissolved in 2ml of chloroform, under nitrogen atmosphere, Al(CH 3 ) 3 (0.45ml, 2M) was added to the reaction solution , stirred at 50°C for 3 hours. Quenched with water, extracted with EA (10mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), to obtain 61.3mg of the title compound as off-white solid, yield: 37.3%.
LC-MS:m/z 554[M+H] +。 LC-MS: m/z 554 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.60(s,1H),7.21(tt,J＝9.4,2.3Hz,1H),6.85-6.77(m,2H),5.59-5.54(dd,J＝11.9,8.0Hz,1H),5.48(s,2H),4.87-4.82(m,1H),4.37-4.32(m,1H),4.09-4.02(m,1H),3.67-3.62(m,1H),3.35(s,3H),2.80(ddd,J＝13.7,8.6,5.0Hz,1H),2.73-2.66(dt,J＝11.6,4.9Hz,1H),2.33-2.26(ddd,J＝12.9,8.2,5.0Hz,1H),1.23-1.13(m,4H)。 1 H NMR (400MHz, DMSO-d6) δ7.80(s,1H),7.60(s,1H),7.21(tt,J=9.4,2.3Hz,1H),6.85-6.77(m,2H),5.59 -5.54(dd,J＝11.9,8.0Hz,1H),5.48(s,2H),4.87-4.82(m,1H),4.37-4.32(m,1H),4.09-4.02(m,1H),3.67 -3.62(m,1H),3.35(s,3H),2.80(ddd,J＝13.7,8.6,5.0Hz,1H),2.73-2.66(dt,J＝11.6,4.9Hz,1H),2.33-2.26 (ddd, J = 12.9, 8.2, 5.0 Hz, 1H), 1.23-1.13 (m, 4H).
实施例25：(S)-7-(3-氯-2-(4-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(25)的制备Example 25: (S)-7-(3-chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4 -c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b] Preparation of [1,4]oxazepine-6(5H)-one (25)
Figure PCTCN2022092607-appb-000062
Figure PCTCN2022092607-appb-000062
步骤1：1-(4-氟苄基)-5-羟基-1H-吡唑-3-甲酸乙酯(25a)的制备Step 1: Preparation of ethyl 1-(4-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (25a)
于室温，将草酸二乙酯钠盐(6.56g，31.2mmol)溶于HAc(10mL)和二氧六环(80ml)中，室温搅拌0.5小时，加入(4-氟苄基)肼盐酸盐(5.00g，28.4mmol)， 于100℃搅拌2小时。加水淬灭，用EA萃取(200mL x 3)，饱和食盐水洗涤(200mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色半固体状标题化合物3.49g，收率46.1％。Dissolve diethyl oxalate sodium salt (6.56g, 31.2mmol) in HAc (10mL) and dioxane (80ml) at room temperature, stir at room temperature for 0.5 hours, add (4-fluorobenzyl)hydrazine hydrochloride (5.00 g, 28.4 mmol), stirred at 100°C for 2 hours. Quenched with water, extracted with EA (200mL x 3), washed with saturated brine (200mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain 3.49 g of the title compound as a yellow semi-solid, with a yield of 46.1%.
LC-MS：m/z 265[M+H] +。 LC-MS: m/z 265 [M+H] + .
步骤2：5-氯-1-(4-氟苄基)-4-甲酰基-1H-吡唑-3-甲酸乙酯(25b)的制备Step 2: Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate (25b)
将1-(4-氟苄基)-5-羟基-1H-吡唑-3-甲酸乙酯(25a)(3.00g，11.4mmol)溶于DMF(9mL)中，于0℃加入POCl 3(18ml)，于90℃搅拌过夜。将反应液加到冰水中，饱和碳酸氢钠调节PH至10，EA萃取(30mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝1:1)，得黄色半固体状标题化合物1.7g，收率48.1％。 1-(4-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (25a) (3.00g, 11.4mmol) was dissolved in DMF (9mL), and POCl 3 was added at 0°C ( 18ml), stirred overnight at 90°C. Add the reaction solution to ice water, adjust the pH to 10 with saturated sodium bicarbonate, extract with EA (30mL x 3), wash with saturated brine (100mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the residue Separation and purification by silica gel column chromatography (mobile phase PE/EA=1:1) gave 1.7 g of the title compound as a yellow semi-solid, with a yield of 48.1%.
LC-MS：m/z 311[M+H] +。 LC-MS: m/z 311 [M+H] + .
步骤3：5-氯-1-(4-氟苄基)-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(25c)的制备Step 3: Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (25c)
将氯(甲氧甲基)三苯基磷(7.30g，21.3mmol)溶于THF(20mL)中，于0℃加入t-BuOK(2.17g，19.4mmol)的THF溶液(5mL)，搅拌0.5小时。缓慢加入5-氯-1-(4-氟苄基)-4-甲酰基-1H-吡唑-3-甲酸乙酯(25b)(1.50g，4.84mmol)的THF溶液(5mL)，于室温搅拌过夜。将反应液加到冰水中，EA萃取(30mL x3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色油状标题化合物500mg，收率：30.4％。Dissolve chloro(methoxymethyl)triphenylphosphine (7.30g, 21.3mmol) in THF (20mL), add a THF solution (5mL) of t-BuOK (2.17g, 19.4mmol) at 0°C, and stir for 0.5 Hour. Slowly add 5-chloro-1-(4-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (25b) (1.50g, 4.84mmol) in THF solution (5mL), at room temperature Stir overnight. The reaction solution was added to ice water, extracted with EA (30mL x3), washed with saturated brine (100mL x1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Mobile phase PE/EA=3:1), to obtain 500 mg of the title compound as yellow oil, yield: 30.4%.
LC-MS：m/z 339[M+H] +。 LC-MS: m/z 339 [M+H] + .
步骤4：5-氯-1-(4-氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-甲酸乙酯(25d)的制备Step 4: Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (25d)
将(E)-5-氯-1-(4-氟苄基)-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(25c)(500mg，1.48mmol)溶于THF(5ml)中，滴加盐酸(8mL，6M)，于60℃搅拌1小时。于0℃，用2mol/L的NaOH溶液调PH至10，EA萃取(10mL x 3)，饱和食盐水洗涤(30mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物600mg(粗品)。(E)-5-Chloro-1-(4-fluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (25c) (500mg, 1.48mmol ) was dissolved in THF (5ml), hydrochloric acid (8mL, 6M) was added dropwise, and stirred at 60°C for 1 hour. At 0°C, adjust the pH to 10 with 2mol/L NaOH solution, extract with EA (10mL x 3), wash with saturated brine (30mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oil The title compound 600 mg (crude product).
LC-MS：m/z 325[M+H] +。 LC-MS: m/z 325 [M+H] + .
步骤5：(S)-5-氯-4-(2-((2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(4-氟苄基)-1H-吡唑-3-羧酸乙酯(25e)制备Step 5: (S)-5-Chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4' ,5':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyridine Preparation of azole-3-carboxylic acid ethyl ester (25e)
于室温，将(S)-7-氨基-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(7l)(92.0mg，0.360mmol)、5-氯-1-(4-氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-甲酸乙酯(25d)(127mg，0.390mmol)、钛酸四乙酯(123mg，0.540mmol)溶于THF(5mL)，室温搅拌2小时，加入甲醇(2.5mL)、氰基硼氢化钠(45.2mg，0.720mmol)，室温搅拌过夜。加入10mL饱和碳酸氢钠 溶液，用EA萃取(30mL x 3)，饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物120mg，收率52.4％。At room temperature, (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2- b] [1,4]oxazepine-6(5H)-one (7l) (92.0mg, 0.360mmol), 5-chloro-1-(4-fluorobenzyl)-4-(2-oxo Ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (25d) (127mg, 0.390mmol), tetraethyl titanate (123mg, 0.540mmol) were dissolved in THF (5mL), stirred at room temperature for 2 hours, and methanol ( 2.5 mL), sodium cyanoborohydride (45.2 mg, 0.720 mmol), and stirred overnight at room temperature. Add 10mL saturated sodium bicarbonate solution, extract with EA (30mL x 3), wash with saturated brine (50mL x 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by high-pressure preparative liquid chromatography (Column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), to obtain 120mg of the title compound as off-white solid, yield 52.4% .
LC-MS：m/z 582[M+H] +。 LC-MS: m/z 582 [M+H] + .
步骤6：(S)-7-(3-氯-2-(4-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-5-甲基-7,8-二氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-6(5H)-酮(25)的制备Step 6: (S)-7-(3-Chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4',5':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepine-6(5H)-one (25)
于0℃，将(S)-5-氯-4-(2-((2-环丙基-5-甲基-6-氧代-5,6,7,8-四氢噁唑并[4',5':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(4-氟苄基)-1H-吡唑-3-羧酸乙酯(25e)(60.0mg，0.103mmol)溶于2ml氯仿中，氮气氛下，向反应液中加入Al(CH 3) 3(0.15ml,2M)，于50℃搅拌2小时。加水淬灭，用EA萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物59.0mg，收率91.6％。 At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[ 4',5':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H -Pyrazole-3-carboxylic acid ethyl ester (25e) (60.0mg, 0.103mmol) was dissolved in 2ml of chloroform, and under a nitrogen atmosphere, Al(CH 3 ) 3 (0.15ml, 2M) was added to the reaction solution, and the °C and stirred for 2 hours. Quenched with water, extracted with EA (10mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by high-pressure preparative liquid chromatography (column type : Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), and obtained 59.0 mg of the title compound as off-white solid, with a yield of 91.6%.
LC-MS：m/z 536.0[M+H] +。 LC-MS: m/z 536.0 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.60(s,1H),7.26-7.16(m,4H),5.56(dd,J＝11.9,8.0,1H),5.42(s,2H),4.84(dd,J＝11.7,10.3,1H),4.34(dd,J＝10.0,8.1Hz,1H),4.04(dt,J＝12.2,5.3Hz,1H),3.65-3.60(m,1H),3.34(s,3H),2.79-2.77(m,1H),2.70-2.64(m,1H),2.29(ddd,J＝12.9,8.2,4.9Hz,1H),1.23-1.13(m,4H)。 1 H NMR (400MHz, DMSO-d6) δ7.80(s, 1H), 7.60(s, 1H), 7.26-7.16(m, 4H), 5.56(dd, J=11.9, 8.0, 1H), 5.42( s,2H),4.84(dd,J=11.7,10.3,1H),4.34(dd,J=10.0,8.1Hz,1H),4.04(dt,J=12.2,5.3Hz,1H),3.65-3.60( m,1H),3.34(s,3H),2.79-2.77(m,1H),2.70-2.64(m,1H),2.29(ddd,J＝12.9,8.2,4.9Hz,1H),1.23-1.13( m, 4H).
实施例26：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1,7-二甲基-1,3,4,7-四氢-2H-[1,4]硫氮杂卓并[3,2-f]吲哚-2-酮(26)的制备Example 26: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1,7-dimethyl-1,3,4,7-tetrahydro-2H-[1,4]thiazepine[3,2-f]indol-2-one ( 26) Preparation
Figure PCTCN2022092607-appb-000063
Figure PCTCN2022092607-appb-000063
步骤1：6-氟-5-硝基二氢吲哚-2,3-二酮(26a)的制备Step 1: Preparation of 6-fluoro-5-nitroindoline-2,3-dione (26a)
于0℃，将6-氟二氢吲哚-2,3-二酮(10.0g，60.6mmol)溶于浓H 2SO 4(100ml)中，氮气氛下，于0℃向反应液中加入NaNO 3(6.18g，72.7mmol)，于0℃搅拌1 小时。反应液倒入冰水中，EA萃取(300mL x 3)，饱和食盐水洗涤(600mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得淡黄色固体标题化合物6.8g(粗品)。 Dissolve 6-fluoroindoline-2,3-dione (10.0g, 60.6mmol) in concentrated H 2 SO 4 (100ml) at 0°C, and add NaNO 3 (6.18g, 72.7mmol), stirred at 0°C for 1 hour. The reaction solution was poured into ice water, extracted with EA (300mL x 3), washed with saturated brine (600mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6.8g of the title compound as a light yellow solid (crude).
LC-MS：m/z 211[M+H] +。 LC-MS: m/z 211 [M+H] + .
步骤2：6-氟-5-硝基-1H-吲哚(26b)的制备Step 2: Preparation of 6-fluoro-5-nitro-1H-indole (26b)
将6-氟-5-硝基二氢吲哚-2,3-二酮(26a)(2.00g，9.52mmol)溶于THF(30ml)中，氮气氛下，于0℃向反应液中加入硼烷四氢呋喃溶液(28.6mL，28.6mmol)，于室温搅拌4小时。于0℃加水(50mL)淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1),得淡黄色固体标题化合物1.1g(粗品)。Dissolve 6-fluoro-5-nitroindoline-2,3-dione (26a) (2.00g, 9.52mmol) in THF (30ml), and add Borane tetrahydrofuran solution (28.6 mL, 28.6 mmol) was stirred at room temperature for 4 hours. Quenched by adding water (50mL) at 0°C, extracted with EA (100mL x 3), washed with saturated brine (50mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography After separation and purification (mobile phase PE/EA=3:1), 1.1 g of the title compound (crude product) was obtained as a light yellow solid.
LC-MS：m/z 181[M+H] +。 LC-MS: m/z 181 [M+H] + .
步骤3：6-氟-1-甲基-5-硝基-1H-吲哚(26c)的制备Step 3: Preparation of 6-fluoro-1-methyl-5-nitro-1H-indole (26c)
于0℃，将6-氟-5-硝基-1H-吲哚(26b)(500mg，2.78mmol)溶于DMF(10ml)中，氮气氛下，于0℃向反应液中加入Cs 2CO 3(1.36g，4.17mmol)，于0℃加入CH 3I，于室温搅拌12小时。于0℃加水(50mL)淬灭，EA萃取(30mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物450mg，收率：84.9％。 Dissolve 6-fluoro-5-nitro-1H-indole (26b) (500mg, 2.78mmol) in DMF (10ml) at 0°C, add Cs 2 CO to the reaction solution at 0°C under nitrogen atmosphere 3 (1.36 g, 4.17 mmol), CH 3 I was added at 0°C, and stirred at room temperature for 12 hours. Quenched by adding water (50mL) at 0°C, extracted with EA (30mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 450 mg of the title compound as a pale yellow solid, yield: 84.9%.
LC-MS：m/z 195[M+H] +。 LC-MS: m/z 195 [M+H] + .
步骤4：N-(叔丁氧羰基)-S-(1-甲基-5-硝基-1H-吲哚-6-基)-L-半胱氨酸(26d)的制备Step 4: Preparation of N-(tert-butoxycarbonyl)-S-(1-methyl-5-nitro-1H-indol-6-yl)-L-cysteine (26d)
将6-氟-1-甲基-5-硝基-1H-吲哚(26c)(250mg，1.28mmol)溶于DMF(10mL)中，于0℃加入Cs 2CO 3(2.50g，7.73mmol)、(叔丁氧羰基)-L-半胱氨酸(849mg，3.84mmol)，于80℃搅拌12小时。于0℃加水(50mL)淬灭，EA萃取(30mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得淡黄色固体标题化合物450mg(粗品)。 6-Fluoro-1-methyl-5-nitro-1H-indole (26c) (250mg, 1.28mmol) was dissolved in DMF (10mL), and Cs 2 CO 3 (2.50g, 7.73mmol) was added at 0°C ), (tert-butoxycarbonyl)-L-cysteine (849mg, 3.84mmol), stirred at 80°C for 12 hours. Quenched by adding water (50 mL) at 0°C, extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 450 mg of the title compound as a pale yellow solid (crude ).
LC-MS：m/z 396[M+H] +。 LC-MS: m/z 396 [M+H] + .
步骤5：(S)-(5-氨基-1-甲基-1H-吲哚-6-基)-N-(叔丁氧羰基)-L-半胱氨酸(26e)的制备Step 5: Preparation of (S)-(5-amino-1-methyl-1H-indol-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine (26e)
于室温，将N-(叔丁氧羰基)-S-(1-甲基-5-硝基-1H-吲哚-6-基)-L-半胱氨酸(26d)(450mg，9.03mmol)溶于10mL甲醇中，向反应液中加入含水Pd/C(100mg)，氢气氛下，室温搅拌过夜。硅藻土过滤，加MeOH洗涤滤饼，滤液减压浓缩，得黄色油状的标题化合物460mg(粗品)。At room temperature, N-(tert-butoxycarbonyl)-S-(1-methyl-5-nitro-1H-indol-6-yl)-L-cysteine (26d) (450mg, 9.03mmol ) was dissolved in 10 mL of methanol, and aqueous Pd/C (100 mg) was added to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Filter through celite, add MeOH to wash the filter cake, and concentrate the filtrate under reduced pressure to obtain 460 mg of the title compound (crude product) as a yellow oil.
LC-MS：m/z 366[M+H] +。 LC-MS: m/z 366 [M+H] + .
其余步骤与实施例7的制备方法相同，除了用(S)-(5-氨基-1-甲基-1H-吲哚-6-基)-N-(叔丁氧羰基)-L-半胱氨酸(26e)代替步骤9中的O-(5-氨基-2-环丙基苯并[d] 噁唑-6-基)-N-(叔丁氧羰基)-L-丝氨酸(7i)，制得标题化合物26。The remaining steps are the same as the preparation method of Example 7, except that (S)-(5-amino-1-methyl-1H-indol-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine amino acid (26e) in place of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i) in step 9 , The title compound 26 was obtained.
LC-MS：m/z 506.1[M+H] +。 LC-MS: m/z 506.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.73(s,1H),7.66(s,1H),7.43(d,1H),7.29-7.24(m,3H),7.11-7.09(m,2H),6.45(s,1H),5.34(br,2H),5.25-5.20(m,1H),4.12-4.06(m,1H),3.77(s,3H),3.62-3.56(m,1H),3.45-3.39(m,1H),3.35(s,3H),2.73-2.57(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.73(s,1H),7.66(s,1H),7.43(d,1H),7.29-7.24(m,3H),7.11 -7.09(m,2H),6.45(s,1H),5.34(br,2H),5.25-5.20(m,1H),4.12-4.06(m,1H),3.77(s,3H),3.62-3.56 (m,1H), 3.45-3.39(m,1H), 3.35(s,3H), 2.73-2.57(m,2H).
实施例27：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4-二氢苯并呋喃并[6,5-b][1,4]氧氮杂卓-2(1H)-酮(27)的制备Example 27: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H pyrazolo[3,4-c]pyridine-6 Preparation of -yl)-1-methyl-3,4-dihydrobenzofuro[6,5-b][1,4]oxazepin-2(1H)-one (27)
Figure PCTCN2022092607-appb-000064
Figure PCTCN2022092607-appb-000064
步骤1：1-(4-氟-2-羟基-5-硝基苯基)乙烷-1-酮(27a)的制备Step 1: Preparation of 1-(4-fluoro-2-hydroxy-5-nitrophenyl)ethan-1-one (27a)
于0℃，将1-(4-氟-2-羟基苯基)乙烷-1-酮(10.0g，64.9mmol)溶于浓H 2SO 4(100ml)中，氮气氛下，于0℃向反应液中加入NaNO 3(7.40g，87.6mmol)，于0℃搅拌1小时。于0℃加水(500mL)淬灭，EA萃取(300mL x 3)，饱和食盐水洗涤(600mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1),得淡黄色固体标题化合物7.2g，收率55.3％。 At 0°C, 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one (10.0g, 64.9mmol) was dissolved in concentrated H 2 SO 4 (100ml), under nitrogen atmosphere, at 0°C NaNO 3 (7.40 g, 87.6 mmol) was added to the reaction liquid, and stirred at 0° C. for 1 hour. Quenched by adding water (500mL) at 0°C, extracted with EA (300mL x 3), washed with saturated brine (600mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography After separation and purification (mobile phase PE/EA=3:1), 7.2 g of the title compound was obtained as a pale yellow solid, with a yield of 55.3%.
LC-MS：m/z 200[M+H] +。 LC-MS: m/z 200 [M+H] + .
步骤2：2-溴-1-(4-氟-2-羟基-5-硝基苯基)乙烷-1-酮(27b)的制备Step 2: Preparation of 2-bromo-1-(4-fluoro-2-hydroxy-5-nitrophenyl)ethan-1-one (27b)
将1-(4-氟-2-羟基-5-硝基苯基)乙烷-1-酮(27a)(3.80g，19.1mmol)溶于EtOH(50mL)中，于0℃加入CuBr 2(8.86g，40.1mmol)，氮气氛下，于70℃搅拌2小时。加水(100mL)淬灭，EA萃取(100mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物4.50g，收率83.2％。 1-(4-Fluoro-2-hydroxy-5-nitrophenyl)ethan-1-one (27a) (3.80 g, 19.1 mmol) was dissolved in EtOH (50 mL), and CuBr 2 ( 8.86 g, 40.1 mmol), stirred at 70° C. for 2 hours under nitrogen atmosphere. Water (100mL) was added to quench, EA extracted (100mL x 3), washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Mobile phase PE/EA=3:1), to obtain 4.50 g of the title compound as a light yellow solid, with a yield of 83.2%.
LC-MS：m/z 278[M+H] +。 LC-MS: m/z 278 [M+H] + .
步骤3：6-氟-5-硝基苯并呋喃-3(2H)-酮(27c)的制备Step 3: Preparation of 6-fluoro-5-nitrobenzofuran-3(2H)-one (27c)
于室温，将2-溴-1-(4-氟-2-羟基-5-硝基苯基)乙烷-1-酮(27b)(2.50g，9.03mmol)溶于THF(30ml)中，氮气氛下，于0℃向反应液中滴加DIEA(1.39g，10.8mmol)，于室温搅拌过夜。于0℃加水(30mL)淬灭，EA萃取(30mL x 3)，饱和食盐 水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物1.32g，收率72.2％。2-Bromo-1-(4-fluoro-2-hydroxy-5-nitrophenyl)ethan-1-one (27b) (2.50 g, 9.03 mmol) was dissolved in THF (30 ml) at room temperature, Under a nitrogen atmosphere, DIEA (1.39 g, 10.8 mmol) was added dropwise to the reaction solution at 0° C., and stirred overnight at room temperature. Quenched by adding water (30mL) at 0°C, extracted with EA (30mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 1.32 g of the title compound as a pale yellow solid, with a yield of 72.2%.
LC-MS：m/z 198[M+H] +。 LC-MS: m/z 198 [M+H] + .
步骤4：6-氟-5-硝基-2,3-二氢苯并呋喃-3-醇(27d)的制备Step 4: Preparation of 6-fluoro-5-nitro-2,3-dihydrobenzofuran-3-ol (27d)
于室温，将6-氟-5-硝基苯并呋喃-3(2H)-酮(27c)(200mg，1.01mmol)溶于THF(4mL)中，氮气氛下，于0℃向反应液中加入NaBH 4(115mg，3.03mmol),室温搅拌1小时。加入水(5mL)稀释，用EA萃取(30mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色标题化合物150mg(粗品)。 Dissolve 6-fluoro-5-nitrobenzofuran-3(2H)-one (27c) (200mg, 1.01mmol) in THF (4mL) at room temperature, and add to the reaction solution at 0°C under nitrogen atmosphere NaBH 4 (115 mg, 3.03 mmol) was added and stirred at room temperature for 1 hour. It was diluted with water (5 mL), extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 150 mg of the yellow title compound (crude product).
LC-MS：m/z 200[M+H] +。 LC-MS: m/z 200 [M+H] + .
步骤5：6-氟-5-硝基苯并呋喃(27e)的制备Step 5: Preparation of 6-fluoro-5-nitrobenzofuran (27e)
于室温，将6-氟-5-硝基-2,3-二氢苯并呋喃-3-醇(27d)(1.60g，8.04mmol)，溶于CAN(20mL)中，氮气氛下，于0℃向反应液中加入4N盐酸(5mL)，于60℃搅拌5h。加入水(30mL)稀释，用EA萃取(30mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-4:1)，得黄色标题化合物720mg，收率：49.8％。At room temperature, 6-fluoro-5-nitro-2,3-dihydrobenzofuran-3-ol (27d) (1.60g, 8.04mmol) was dissolved in CAN (20mL), under nitrogen atmosphere, in 4N hydrochloric acid (5 mL) was added to the reaction solution at 0°C, and stirred at 60°C for 5h. Add water (30mL) to dilute, extract with EA (30mL x 3), wash with saturated brine (20mL x 2), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (Mobile phase: PE/EA=100:1-4:1) to obtain 720 mg of the yellow title compound, yield: 49.8%.
LC-MS：m/z 182[M+H] +。 LC-MS: m/z 182 [M+H] + .
步骤6：5-硝基苯并呋喃-6-醇(27f)的制备Step 6: Preparation of 5-nitrobenzofuran-6-ol (27f)
于室温，将(叔丁氧羰基)-L-丝氨酸(906mg，4.42mmol)溶于DMF(10ml)中，氮气氛下，于0℃向反应液中滴加NaH(354mg，8.84mmol)，于0℃搅拌0.5小时，分批加入6-氟-5-硝基苯并呋喃(27e)(400mg，2.21mmol)，于室温搅拌过夜。于0℃加水(30mL)淬灭，EA萃取(30mL x 3)，饱和食盐水洗涤(60mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物210mg，收率42.1％Dissolve (tert-butoxycarbonyl)-L-serine (906mg, 4.42mmol) in DMF (10ml) at room temperature, and add NaH (354mg, 8.84mmol) dropwise to the reaction solution at 0°C under a nitrogen atmosphere. Stir at 0°C for 0.5 hour, add 6-fluoro-5-nitrobenzofuran (27e) (400 mg, 2.21 mmol) in batches, and stir at room temperature overnight. Quenched by adding water (30mL) at 0°C, extracted with EA (30mL x 3), washed with saturated brine (60mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase PE/EA=3:1) gave 210 mg of the title compound as a pale yellow solid, yield 42.1%
LC-MS：m/z 180[M+H] +。 LC-MS: m/z 180 [M+H] + .
步骤7：O-(5-硝基苯并呋喃-6-基)-N-三苯基-L-丝氨酸甲酯(27g)的制备Step 7: Preparation of O-(5-nitrobenzofuran-6-yl)-N-triphenyl-L-serine methyl ester (27 g)
于室温，将5-硝基苯并呋喃-6-醇(27f)(250mg，1.39mmol)、甲基三苯甲基-L-丝氨酸(756mg，2.09mmol)溶于10mL THF中，氮气氛下，向反应液中加入PPh 3(728mg，2.78mmol)、DIAD(561mg，2.78mmol)，室温搅拌过夜。加入水(10mL)稀释，用EA萃取(30mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩,残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得黄色半固体状标题化合物1.20g(粗品)。 At room temperature, 5-nitrobenzofuran-6-ol (27f) (250mg, 1.39mmol), methyltrityl-L-serine (756mg, 2.09mmol) were dissolved in 10mL THF, under nitrogen atmosphere , PPh 3 (728mg, 2.78mmol) and DIAD (561mg, 2.78mmol) were added to the reaction solution, and stirred overnight at room temperature. Added water (10mL) to dilute, extracted with EA (30mL x 3), washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Mobile phase PE/EA=3:1), the title compound 1.20 g (crude product) was obtained as a yellow semi-solid.
LC-MS：m/z 523[M+H] +。 LC-MS: m/z 523 [M+H] + .
其余步骤与实施例1的制备方法相同，除了用O-(5-硝基苯并呋喃-6-基)-N-三 苯基-L-丝氨酸甲酯(27g)代替步骤5中的O-(1,3-二甲基-6-硝基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-N-三苯甲基-L-丝氨酸甲酯(1e)，制得标题化合物27。The remaining steps are the same as the preparation method of Example 1, except that O-(5-nitrobenzofuran-6-yl)-N-triphenyl-L-serine methyl ester (27g) is used to replace O- (1,3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-trityl-L-serine Methyl ester (1e), the title compound 27 was obtained.
LC-MS：m/z 477.1[M+H] +。 LC-MS: m/z 477.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.07(d,J＝2.2Hz,1H),7.79(s,1H),7.56(s,1H),7.42-7.26(m,3H),7.25-7.14(m,2H),7.00(d,J＝2.2Hz,1H),5.57(dd,J＝12.0,8.0Hz,1H),5.42(s,2H),4.83(dd,J＝12.0,10.1Hz,1H),4.33(dd,J＝10.1,8.0Hz,1H),4.05(ddd,J＝12.3,7.0,5.1Hz,1H),3.64(ddd,J＝12.9,8.6,4.8Hz,1H),3.35(s,3H),2.81(ddd,J＝15.4,8.5,5.0Hz,1H),2.68(ddd,J＝15.5,7.0,4.8Hz,1H)。 1 H NMR (400MHz, DMSO-d6) δ8.07 (d, J = 2.2Hz, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42-7.26 (m, 3H), 7.25-7.14 (m,2H),7.00(d,J=2.2Hz,1H),5.57(dd,J=12.0,8.0Hz,1H),5.42(s,2H),4.83(dd,J=12.0,10.1Hz, 1H), 4.33(dd, J=10.1, 8.0Hz, 1H), 4.05(ddd, J=12.3, 7.0, 5.1Hz, 1H), 3.64(ddd, J=12.9, 8.6, 4.8Hz, 1H), 3.35 (s, 3H), 2.81 (ddd, J=15.4, 8.5, 5.0Hz, 1H), 2.68 (ddd, J=15.5, 7.0, 4.8Hz, 1H).
实施例28：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4-二氢苯并呋喃并[6,5-b][1,4]硫氮杂卓-2(1H)-酮(28)的制备Example 28: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- Preparation of 6-yl)-1-methyl-3,4-dihydrobenzofuro[6,5-b][1,4]thiazepine-2(1H)-one (28)
Figure PCTCN2022092607-appb-000065
Figure PCTCN2022092607-appb-000065
步骤1：N-(叔丁氧基羰基)-S-(5-硝基苯并呋喃-6-基)-L-半胱氨酸(28a)的制备Step 1: Preparation of N-(tert-butoxycarbonyl)-S-(5-nitrobenzofuran-6-yl)-L-cysteine (28a)
于室温，将(叔丁氧羰基)-L-半胱氨酸(732mg，3.31mmol)溶于DMF(10mL)中，氮气氛下，向反应液中加入Cs 2CO 3(2.16g，6.64mmol)、6-氟-5-硝基苯并呋喃(27e)(300mg，1.66mmol)，80℃搅拌过夜。加入水(30mL)稀释，用EA萃取(30mL x 3)，饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色标题化合物620mg(粗品)。 Dissolve (tert-butoxycarbonyl)-L-cysteine (732mg, 3.31mmol) in DMF (10mL) at room temperature, and add Cs 2 CO 3 (2.16g, 6.64mmol) to the reaction solution under a nitrogen atmosphere ), 6-fluoro-5-nitrobenzofuran (27e) (300mg, 1.66mmol), stirred overnight at 80°C. It was diluted with water (30 mL), extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 620 mg of the yellow title compound (crude product).
LC-MS：m/z 383[M+H] +。 LC-MS: m/z 383 [M+H] + .
步骤2：(S)-(5-氨基苯并呋喃-6-基)-N-(叔丁氧基羰基)-L-半胱氨酸(28b)制备Step 2: Preparation of (S)-(5-aminobenzofuran-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine (28b)
于室温，将N-(叔丁氧基羰基)-S-(5-硝基苯并呋喃-6-基)-L-半胱氨酸(28a)(550mg，1.44mmol)溶于10mL甲醇中，向反应液中加入含水Pd/C(250mg)，氢气氛下，室温搅拌过夜。硅藻土过滤，加MeOH洗涤滤饼，滤液减压浓缩，得黄色油状的标题化合物460mg(粗品)。Dissolve N-(tert-butoxycarbonyl)-S-(5-nitrobenzofuran-6-yl)-L-cysteine (28a) (550 mg, 1.44 mmol) in 10 mL of methanol at room temperature , added aqueous Pd/C (250 mg) to the reaction solution, and stirred overnight at room temperature under a hydrogen atmosphere. Filter through celite, add MeOH to wash the filter cake, and concentrate the filtrate under reduced pressure to obtain 460 mg of the title compound (crude product) as a yellow oil.
LC-MS：m/z 353[M+H] +。 LC-MS: m/z 353 [M+H] + .
其余步骤与实施例7的制备方法相同，除了用S-(5-氨基苯并呋喃-6-基)-N-(叔丁氧基羰基)-L-半胱氨酸(28b)代替步骤9中的O-(5-氨基-2-环丙基苯并[d]噁唑-6-基)-N-(叔丁氧羰基)-L-丝氨酸(7i)，制得标题化合物28。The remaining steps are the same as in Example 7, except that step 9 is replaced by S-(5-aminobenzofuran-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine (28b) O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i) in (7i), the title compound 28 was prepared.
LC-MS：m/z 473.1[M+H] +。 LC-MS: m/z 473.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝2.2Hz,1H),7.96(s,1H),7.89(s,1H),7.32(ddd,J＝13.3,7.9,6.2Hz,3H),7.20-7.14(m,2H),7.07(d,J＝2.2Hz,1H),5.41(s,2H),5.25(dd,J＝12.5,6.9Hz,1H),4.12(ddd,J＝12.5,7.3,5.1Hz,1H),3.67(ddd,J＝12.8,8.0,5.1Hz,1H),3.57(t,J＝11.9Hz,1H),3.39(dd,J＝11.3,7.0Hz,1H),3.32(s,3H),2.81-2.64(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ8.16 (d, J = 2.2Hz, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.32 (ddd, J = 13.3, 7.9, 6.2Hz ,3H),7.20-7.14(m,2H),7.07(d,J=2.2Hz,1H),5.41(s,2H),5.25(dd,J=12.5,6.9Hz,1H),4.12(ddd, J=12.5,7.3,5.1Hz,1H), 3.67(ddd,J=12.8,8.0,5.1Hz,1H),3.57(t,J=11.9Hz,1H),3.39(dd,J=11.3,7.0Hz ,1H), 3.32(s,3H), 2.81-2.64(m,2H).
实施例29：(S)-7-(3-氯-2-(3,5-二氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(29)的制备Example 29: (S)-7-(3-chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[ 3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2 -b] Preparation of [1,4]oxazepine-8(9H)-one (29)
Figure PCTCN2022092607-appb-000066
Figure PCTCN2022092607-appb-000066
步骤1：(S)-5-氯-4-(2-((2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(3,5-二氟苄基)-1H-吡唑-3-羧酸乙酯(29a)制备Step 1: (S)-5-Chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5' ,4':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)- Preparation of ethyl 1H-pyrazole-3-carboxylate (29a)
于室温，将(S)-7-氨基-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(15l)(70.0mg，0.256mmol)、5-氯-1-(3,5-二氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-羧酸乙酯(24g)(131mg，0.384mmol)溶于1mL甲醇，向反应液中加入2-甲基吡啶硼烷(38.0mg，0.358mmol)，室温搅拌过夜。加入5mL饱和NaHCO 3溶液，DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝1:1)，得淡黄色油体状标题化合物90mg，收率：58.7％。 At room temperature, (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2- b] [1,4]oxazepine-8(9H)-one (15l) (70.0mg, 0.256mmol), 5-chloro-1-(3,5-difluorobenzyl)-4-(2 -Oxoethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (24g) (131mg, 0.384mmol) was dissolved in 1mL methanol, and 2-picoline borane (38.0mg, 0.358mmol ), stirred overnight at room temperature. Add 5mL of saturated NaHCO3 solution, extract with DCM (10mL x 3), wash with saturated brine (20mL x 1), dry over anhydrous sodium sulfate, filter, and the residue is separated and purified by silica gel column chromatography (mobile phase PE/EA =1:1), 90 mg of the title compound was obtained as light yellow oil, yield: 58.7%.
LC-MS：m/z 600.1[M+H] +。 LC-MS: m/z 600.1 [M+H] + .
步骤2：(S)-7-(3-氯-2-(3,5-二氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(29)的制备Step 2: (S)-7-(3-Chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2- b] Preparation of [1,4]oxazepine-8(9H)-one (29)
于室温，将(S)-5-氯-4-(2-((2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(3,5-二氟苄基)-1H-吡唑-3-羧酸乙酯(29a)(70.0mg，0.116mmol)溶于2ml氯仿中，氮气氛下，于0℃向反应液中加入Al(CH 3) 3(0.18ml，2M)，于50℃搅拌3小时。加饱和碳酸氢钠溶液淬灭，硅藻土过滤，DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，过滤，减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号： Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物7.9mg，收率：12.8％。 At room temperature, (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5 ',4':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl) -1H-Pyrazole-3-carboxylic acid ethyl ester (29a) (70.0mg, 0.116mmol) was dissolved in 2ml of chloroform, under a nitrogen atmosphere, Al(CH 3 ) 3 (0.18ml, 2M), stirred at 50°C for 3 hours. Quenched by adding saturated sodium bicarbonate solution, filtered with celite, extracted with DCM (10mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was prepared by high-pressure liquid Separation by phase chromatography (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min) to obtain 7.9mg of the title compound as off-white solid , Yield: 12.8%.
LC-MS：m/z 554[M+H] +。 LC-MS: m/z 554 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.50(s,1H),7.21(tt,J＝9.4,2.4Hz,1H),6.96-6.82(m,2H),5.56(dd,J＝11.9,8.1Hz,1H),5.48(s,2H),4.82(dd,J＝11.9,10.1Hz,1H),4.34(dd,J＝10.1,8.0Hz,1H),4.04(ddd,J＝12.2,7.0,5.1Hz,1H),3.65(ddd,J＝12.8,8.7,4.8Hz,1H),3.34(s,3H),2.82(ddd,J＝15.5,8.6,5.1Hz,1H),2.73-2.63(m,1H),2.34-2.23(m,1H),1.28-1.15(m,4H)。 1 H NMR (400MHz, DMSO-d6) δ7.89(s,1H),7.50(s,1H),7.21(tt,J=9.4,2.4Hz,1H),6.96-6.82(m,2H),5.56 (dd, J=11.9,8.1Hz,1H),5.48(s,2H),4.82(dd,J=11.9,10.1Hz,1H),4.34(dd,J=10.1,8.0Hz,1H),4.04( ddd,J=12.2,7.0,5.1Hz,1H),3.65(ddd,J=12.8,8.7,4.8Hz,1H),3.34(s,3H),2.82(ddd,J=15.5,8.6,5.1Hz, 1H), 2.73-2.63(m, 1H), 2.34-2.23(m, 1H), 1.28-1.15(m, 4H).
实施例30：(S)-7-(3-氯-2-(4-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(30)的制备Example 30: (S)-7-(3-Chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4 -c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b] Preparation of [1,4]oxazepine-8(9H)-one (30)
Figure PCTCN2022092607-appb-000067
Figure PCTCN2022092607-appb-000067
步骤1：(S)-5-氯-4-(2-((2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(4-氟苄基)-1H-吡唑-3-羧酸乙酯(30a)制备Step 1: (S)-5-Chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5' ,4':4,5]benzo[1,2-b][1,4]oxazepine-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyridine Preparation of azole-3-carboxylic acid ethyl ester (30a)
于室温，将(S)-7-氨基-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(15l)(30.0mg，0.110mmol)、5-氯-1-(4-氟苄基)-4-(2-氧代乙基)-1H-吡唑-3-甲酸乙酯(25d)(39.2mg，0.120mmol)、钛酸四乙酯(37.6mg，0.174mmol)溶于THF(1mL)，室温搅拌1小时，加入甲醇(0.2mL)、氰基硼氢化钠(13.8mg，0.220mmol)，室温搅拌过夜。加入10mL饱和碳酸氢钠溶液，用EA萃取(15mL x 3)，饱和食盐水洗涤(10mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物10.0mg，收率15.6％。At room temperature, (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2- b] [1,4]oxazepine-8(9H)-one (15l) (30.0mg, 0.110mmol), 5-chloro-1-(4-fluorobenzyl)-4-(2-oxo Ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (25d) (39.2mg, 0.120mmol), tetraethyl titanate (37.6mg, 0.174mmol) were dissolved in THF (1mL), stirred at room temperature for 1 hour, added Methanol (0.2 mL), sodium cyanoborohydride (13.8 mg, 0.220 mmol), stirred overnight at room temperature. Add 10mL saturated sodium bicarbonate solution, extract with EA (15mL x 3), wash with saturated brine (10mL x 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by high-pressure preparative liquid chromatography (Column model: Daisogei30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), the title compound was obtained as off-white solid 10.0mg, yield 15.6% .
LC-MS：m/z 582[M+H] +。 LC-MS: m/z 582 [M+H] + .
步骤2：(S)-7-(3-氯-2-(4-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-2-环丙基-9-甲基-6,7-二氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-8(9H)-酮(30)的制备Step 2: (S)-7-(3-Chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepin-8(9H)-one (30)
于0℃，将(S)-5-氯-4-(2-((2-环丙基-9-甲基-8-氧代-6,7,8,9-四氢噁唑并[5',4':4,5]苯并[1,2-b][1,4]氧氮杂卓-7-基)氨基)乙基)-1-(4-氟苄基)-1H-吡唑-3-羧酸乙酯(30a) (10.0mg，0.0170mmol)溶于1ml氯仿中，氮气氛下，向反应液中加入Al(CH 3) 3(0.03ml，2M)，于50℃搅拌2小时。加水淬灭，用DCM萃取(10mL x 3)，饱和食盐水洗涤(20mL x 1)，无水硫酸钠干燥，减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-50％,0.05％甲酸，30min)，得类白色固体状标题化合物1mg，收率10.8％。 At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[ 5',4':4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H -Pyrazole-3-carboxylic acid ethyl ester (30a) (10.0mg, 0.0170mmol) was dissolved in 1ml of chloroform, and under nitrogen atmosphere, Al(CH 3 ) 3 (0.03ml, 2M) was added to the reaction solution, and the °C and stirred for 2 hours. Quenched with water, extracted with DCM (10mL x 3), washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30mm *250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30min), the title compound was obtained as off-white solid 1mg, yield 10.8%.
LC-MS：m/z 536.1[M+H] +。 LC-MS: m/z 536.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.49(s,1H),7.25-7.18(m,4H),5.57-5.52(m,1H),5.42(s,2H),4.84-4.79(m,1H),4.33-4.29(m,1H),4.06-3.99(m,1H),3.65-3.60(m,1H),3.33(s,3H),2.81-2.76(m,1H),2.70-2.64(m,1H),2.33-2.26(ddd,J＝13.1,6.2,3.5Hz,1H),1.24-1.15(m,4H)。 1 H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.49(s,1H),7.25-7.18(m,4H),5.57-5.52(m,1H),5.42(s,2H) ,4.84-4.79(m,1H),4.33-4.29(m,1H),4.06-3.99(m,1H),3.65-3.60(m,1H),3.33(s,3H),2.81-2.76(m, 1H), 2.70-2.64 (m, 1H), 2.33-2.26 (ddd, J=13.1, 6.2, 3.5Hz, 1H), 1.24-1.15 (m, 4H).
实施例31：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-1,3,4,7-四氢-2H-[1,4]氧氮杂卓[3,2-f]吲哚-2-酮(31)的制备Example 31: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- Preparation of 6-yl)-1-methyl-1,3,4,7-tetrahydro-2H-[1,4]oxazepine[3,2-f]indol-2-one (31)
Figure PCTCN2022092607-appb-000068
Figure PCTCN2022092607-appb-000068
步骤1：6-氟-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚(31a)的制备Step 1: Preparation of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (31a)
将6-氟-5-硝基-1H-吲哚(26b)(2.00g，10.6mmol)溶于THF(30mL)中，于0℃加入NaH(630mg，15.7mmol)，氮气氛下，于0℃搅拌0.5小时，于0℃向反应液中滴加SEM-Cl(2.12g，12.8mmol)。加水(50mL)淬灭，EA萃取(50mL x 3)，饱和食盐水洗涤(100mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝3:1)，得淡黄色固体标题化合物2.20g，收率63.9％。6-Fluoro-5-nitro-1H-indole (26b) (2.00g, 10.6mmol) was dissolved in THF (30mL), NaH (630mg, 15.7mmol) was added at 0°C, under nitrogen atmosphere, at 0 °C was stirred for 0.5 hours, and SEM-Cl (2.12 g, 12.8 mmol) was added dropwise to the reaction solution at 0 °C. Add water (50mL) to quench, EA extract (50mL x 3), wash with saturated brine (100mL x 1), dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography ( Mobile phase PE/EA=3:1), to obtain 2.20 g of the title compound as a pale yellow solid, with a yield of 63.9%.
LC-MS：m/z 311[M+H] +。 LC-MS: m/z 311 [M+H] + .
其余步骤与实施例14的制备方法相同，除了用6-氟-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚(31a)代替步骤2中的6-氟-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑(14b)，制得标题化合物31。The remaining steps are the same as the preparation method of Example 14, except that 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (31a ) in place of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (14b) in step 2, yielding the title compound 31 .
LC-MS：m/z 476.1[M+H] +。 LC-MS: m/z 476.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.2(s,1H),7.64(s,1H),7.42(s,1H),7.38-7.18(m，6H),6.47(s,1H),5.63-5.58(m,1H),5.42(s,2H),4.77-4.72(m,1H),4.29-4.25(m,1H),4.10-4.05(m,1H),3.65-3.60(m,1H),3.33(s,3H),2.81-2.76(m,1H),2.70-2.64(m,1H)。 1 H NMR(400MHz,DMSO-d6)δ11.2(s,1H),7.64(s,1H),7.42(s,1H),7.38-7.18(m,6H),6.47(s,1H),5.63 -5.58(m,1H),5.42(s,2H),4.77-4.72(m,1H),4.29-4.25(m,1H),4.10-4.05(m,1H),3.65-3.60(m,1H) ,3.33(s,3H),2.81-2.76(m,1H),2.70-2.64(m,1H).
生物学试验biological test
试验例1：本发明化合物体外抑制U937细胞坏死活性的分析Test example 1: Analysis of the activity of the compound of the present invention to inhibit U937 cell necrosis in vitro
受体相互作用蛋白激酶1(RIP1)活化可诱导人类单核细胞性白血病U937细胞坏死，因此，利用人类单核细胞性白血病U937细胞(CBP60277，CoBioer)，通过体外细胞坏死测定实验来测试本发明化合物的活性。Activation of receptor-interacting protein kinase 1 (RIP1) can induce necrosis of human monocytic leukemia U937 cells, therefore, human monocytic leukemia U937 cells (CBP60277, CoBioer) were used to test the present invention through in vitro cell necrosis assays compound activity.
ATP腺嘌呤核苷三磷酸参与生物体内多种酶促反应，是活细胞新陈代谢的一个指标，其含量直接反应了细胞的数量及细胞状态。向细胞培养基中加入相应体积的CellTiter-Glo TM试剂(Promega)，测量发光值，发光值与ATP量成正比，而ATP又与活细胞数正相关，通过检测ATP含量从而测定细胞活力。 ATP adenosine triphosphate participates in various enzymatic reactions in organisms, and is an indicator of the metabolism of living cells, and its content directly reflects the number and state of cells. Add corresponding volume of CellTiter-Glo TM reagent (Promega) to the cell culture medium, measure the luminescence value, the luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells, and the cell viability is determined by detecting the ATP content.
试验方法：experiment method:
a.细胞培养在补充有10％胎牛血清(10099141，Gibco)、100U/mL青霉素和100μg/mL链霉素(15140122，Invitrogen)的RPMI 1640培养基(31800-500，Solarbio)中。测定时，将细胞以5×10 5个细胞/mL悬浮于补充有1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基内。将细胞悬液加入384孔板(3570，Corning)中，每孔35μL，即U937细胞17500个/孔。 a. Cells were cultured in RPMI 1640 medium (31800-500, Solarbio) supplemented with 10% fetal bovine serum (10099141, Gibco), 100 U/mL penicillin and 100 μg/mL streptomycin (15140122, Invitrogen). For measurement, the cells were suspended in RPMI 1640 medium supplemented with 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin at 5×10 5 cells/mL. The cell suspension was added to a 384-well plate (3570, Corning), 35 μL per well, that is, 17500 U937 cells per well.
b.将10mM QVD(Q-VD-OPh)(货号：551476，EMD Millipore Corp)储液(QVD溶于100％的DMSO配制成10mM储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基稀释40倍至250μM，取5μL QVD加入相应的细胞孔中，反应终体系为50μL，QVD的终浓度为25μM。b. Prepare 10mM QVD (Q-VD-OPh) (product number: 551476, EMD Millipore Corp) stock solution (QVD is dissolved in 100% DMSO to make 10mM stock solution) with 1% fetal bovine serum, 100U/mL penicillin, RPMI 1640 medium with 100 μg/mL streptomycin was diluted 40 times to 250 μM, 5 μL QVD was added to the corresponding cell well, the final reaction system was 50 μL, and the final concentration of QVD was 25 μM.
c.将10mM本发明化合物储液作为起始浓度(本发明化合物溶于100％的DMSO配制成10mM储液)，在96孔稀释板中(249944，Nunc)以1：3进行等比稀释，化合物的梯度浓度为10000μM、3333.33μM、1111.11μM、370.37μM、123.46μM、41.15μM、13.72μM、4.57μM、0μM。c. 10 mM stock solution of the compound of the present invention is used as the initial concentration (the compound of the present invention is dissolved in 100% DMSO to prepare a 10 mM stock solution), and is equally diluted with 1:3 in a 96-well dilution plate (249944, Nunc), The gradient concentration of the compound was 10000 μM, 3333.33 μM, 1111.11 μM, 370.37 μM, 123.46 μM, 41.15 μM, 13.72 μM, 4.57 μM, 0 μM.
d.将上述经过100％DMSO等比稀释的化合物用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基稀释100倍。d. Dilute the above-mentioned compound diluted 100 times with RPMI 1640 medium containing 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin.
e.取步骤d中经过稀释的化合物5μL加入384孔板的细胞中，化合物的终浓度为10000nM、3333.33nM、1111.11nM、370.37nM、123.46nM、41.15nM、13.72nM、4.57nM、0nM。e. Take 5 μL of the compound diluted in step d and add it to cells in a 384-well plate. The final concentrations of the compound are 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, OnM.
f.在37℃，5％CO 2培养箱中培养30分钟。 f. Incubate in a 37°C, 5% CO 2 incubator for 30 minutes.
g.培养后，将TNFα(PHC3016，Gibco)储液(TNFα溶于无菌水配制成100μg/mL储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基稀释100倍至1μg/mL，取5μL TNFα加入相应的细胞孔中，反应终体系为50μL，TNFα的终浓度为100ng/mL。g. After culturing, the TNFα (PHC3016, Gibco) stock solution (TNFα was dissolved in sterile water to prepare 100 μg/mL stock solution) was treated with RPMI containing 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin The 1640 medium was diluted 100 times to 1 μg/mL, and 5 μL of TNFα was added to the corresponding cell wells. The final reaction system was 50 μL, and the final concentration of TNFα was 100 ng/mL.
h.将细胞培养板放置培养箱中，37℃，5％CO 2培养过夜。 h. Place the cell culture plate in the incubator, culture overnight at 37°C, 5% CO 2 .
i.将384孔板细胞取出，室温平衡30分钟。i. Remove the cells from the 384-well plate and equilibrate at room temperature for 30 minutes.
j.向每个试验孔中加入30μLCellTiter-Glo TM试剂，振荡混匀，室温孵育10分钟。 j. Add 30 μL CellTiter-Glo TM reagent to each test well, shake and mix well, and incubate at room temperature for 10 minutes.
k.用Cytation 3检测化学发光信号。k. Detection of chemiluminescent signal with Cytation 3.
用GraphPad Prism 5软件，利用以下非线性拟合公式得到化合物的IC 50： Using GraphPad Prism 5 software, the IC 50 of the compound was obtained using the following nonlinear fitting formula:
Y＝Bottom+(Top–Bottom)/(1+10^((Log IC 50–X)×Hillslope))， Y＝Bottom+(Top–Bottom)/(1+10^((Log IC 50 –X)×Hillslope)),
其中，X为化合物浓度的对数值，Y为化合物抑制细胞坏死的效能；Top和Bottom为曲线最高及最低平台期的Y值；Hillslope为希尔常数。Among them, X is the logarithmic value of the compound concentration, Y is the potency of the compound to inhibit cell necrosis; Top and Bottom are the Y values of the highest and lowest plateau of the curve; Hillslope is the Hill constant.
本发明化合物抑制U937细胞坏死的活性见下表1。The activity of the compounds of the present invention in inhibiting necrosis of U937 cells is shown in Table 1 below.
在表1中，A是指化合物抑制细胞坏死的IC 50<10nM；B是指10nM<IC 50<100nM；C是指100nM<IC 50<500nM；D是指IC 50>500nM。 In Table 1, A refers to the IC 50 <10nM of the compound inhibiting cell necrosis; B refers to 10nM<IC 50 <100nM; C refers to 100nM<IC 50 <500nM; D refers to IC 50 >500nM.
表1 本发明化合物抑制U937细胞坏死的IC 50值 Table 1 IC50 values of compounds of the present invention inhibiting necrosis of U937 cells
实施例Example IC 50(nM) IC 50 (nM)
11 AA
22 AA
33 AA
44 AA
55 BB
66 AA
77 AA
88 BB
99 CC
1010 AA
1111 AA
1212 BB
1313 BB
1414 AA
1515 AA
1616 AA
1717 AA
1818 BB
1919 BB
2020 AA
21twenty one AA
22twenty two AA
23twenty three AA
24twenty four AA
2525 AA
2626 AA
2727 AA
2828 AA
2929 AA
3030 BB
3131 AA
结论：本发明化合物能够有效抑制U937细胞坏死。Conclusion: the compound of the present invention can effectively inhibit the necrosis of U937 cells.
试验例2：本发明化合物体外抑制L929细胞坏死活性的分析Test example 2: analysis of the compound of the present invention inhibiting L929 cell necrosis activity in vitro
本发明化合物的作用可以利用L929细胞(南京科佰)，通过体外细胞坏死测定实验来测试。The effect of the compounds of the present invention can be tested by using L929 cells (Nanjing Kebai) through in vitro cell necrosis assay.
ATP腺嘌呤核苷三磷酸参与生物体内多种酶促反应，是活细胞新陈代谢的一个指标，其含量直接反应了细胞的数量及细胞状态。向细胞培养基中加入相应体积的CellTiter-Glo TM试剂(Promega)，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，通过检测ATP含量从而测定细胞活力。 ATP adenosine triphosphate participates in various enzymatic reactions in organisms, and is an indicator of the metabolism of living cells, and its content directly reflects the number and state of cells. Add the corresponding volume of CellTiter-Glo TM reagent (Promega) to the cell culture medium, measure the luminescence value, the luminescence value is proportional to the amount of ATP, and ATP is positively correlated with the number of living cells, and the cell viability is determined by detecting the ATP content.
试验方法：experiment method:
a.细胞培养在补充有10％胎牛血清(10099141，Gibco)、100U/mL青霉素和100μg/mL链霉素(15140122，invitrogen)的MEM培养基(11095-080，Invitrogen)中。测定时，将细胞以5×10 4个细胞/mL悬浮于补充有1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基内。将细胞悬液加入384孔板(3570，Corning)中，每孔35μL，即L929细胞1750个/孔。 a. Cells were cultured in MEM medium (11095-080, Invitrogen) supplemented with 10% fetal bovine serum (10099141, Gibco), 100 U/mL penicillin and 100 μg/mL streptomycin (15140122, invitrogen). For measurement, the cells were suspended at 5×10 4 cells/mL in MEM medium supplemented with 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. The cell suspension was added to a 384-well plate (3570, Corning), 35 μL per well, that is, 1750 L929 cells per well.
b.将30mM本发明化合物储液作为起始浓度(本发明化合物溶于100％的DMSO配制成30mM储液)在96孔稀释板中(249944，Nunc)以1：3进行等比稀释，化合物的梯度浓度为30000μM、10000μM、3333.33μM、1111.11μM、370.37μM、123.46μM、41.15μM、13.72μM、4.57μM、0μM。b. The 30mM stock solution of the compound of the present invention is used as the initial concentration (the compound of the present invention is dissolved in 100% DMSO to prepare a 30mM stock solution) in a 96-well dilution plate (249944, Nunc) and is diluted 1:3, the compound The gradient concentrations are 30000 μM, 10000 μM, 3333.33 μM, 1111.11 μM, 370.37 μM, 123.46 μM, 41.15 μM, 13.72 μM, 4.57 μM, 0 μM.
c.将上述经过100％DMSO等比稀释的化合物用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基稀释100倍。c. Dilute the compound diluted 100% in DMSO by 100 times with MEM medium containing 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin.
d.取步骤c中经过稀释的化合物5μL加入384孔板的细胞中，反应总体系为50μL，化合物的终浓度为30000nM、10000nM、3333.33nM、1111.11nM、370.37nM、123.46nM、41.15nM、13.72nM、4.57nM、0nM。d. Take 5 μL of the compound diluted in step c and add it to cells in a 384-well plate. The total reaction system is 50 μL, and the final concentration of the compound is 30000 nM, 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57nM, OnM.
e.在37℃，5％CO 2培养箱中培养30分钟。 e. Incubate in a 37°C, 5% CO 2 incubator for 30 minutes.
f.将10mM QVD(551476，EMD)储液(QVD溶于100％的DMSO配制成10mM储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基稀释40倍至250μM。f. Dilute 10mM QVD (551476, EMD) stock solution (QVD is dissolved in 100% DMSO to prepare 10mM stock solution) with MEM medium containing 1% fetal bovine serum, 100U/mL penicillin, 100μg/mL streptomycin 40-fold to 250 μM.
g.将mTNFα(50349-MNAE，义翘神州)储液(TNFα溶于无菌水配制成590μg/mL储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基稀释590倍至1μg/mL。g. Use mTNFα (50349-MNAE, Yiqiao Shenzhou) stock solution (TNFα is dissolved in sterile water to prepare 590 μg/mL stock solution) with 1% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin MEM medium was diluted 590 times to 1 μg/mL.
h.将中间稀释的QVD和mTNFα以1：1混合均匀。h. Mix the intermediate diluted QVD and mTNFα at a ratio of 1:1.
i.取10μlQVD和mTNFα的混合物加入相应的细胞孔中。反应终体系为50μl，QVD终浓度为25μM，mTNFα终浓度为100ng/mL。i. Add 10 μl of the mixture of QVD and mTNFα to the corresponding cell wells. The final reaction system was 50 μl, the final concentration of QVD was 25 μM, and the final concentration of mTNFα was 100 ng/mL.
j.将细胞培养板放置培养箱中，37℃，5％CO 2培养48h。 j. Place the cell culture plate in an incubator, culture at 37°C, 5% CO 2 for 48h.
k.将384孔板细胞取出，室温平衡30分钟。k. Take out the cells from the 384-well plate and equilibrate at room temperature for 30 minutes.
l.向每个试验孔加入30μL CellTiter-Glo TM试剂，振荡混匀，室温孵育10分钟。 l. Add 30 μL CellTiter-Glo TM reagent to each test well, shake and mix well, and incubate at room temperature for 10 minutes.
m.用Cytation 3检测化学发光信号。m. Chemiluminescent signal was detected with Cytation 3.
用GraphPad Prism 5软件，利用以下非线性拟合公式来得到化合物的IC 50： Using GraphPad Prism 5 software, the following nonlinear fitting formula was used to obtain the IC 50 of the compound:
Y＝Bottom+(Top–Bottom)/(1+10^((Log IC 50–X)×Hillslope))， Y＝Bottom+(Top–Bottom)/(1+10^((Log IC 50 –X)×Hillslope)),
其中，X为化合物浓度的对数值，Y为化合物抑制细胞坏死的效能；Top和Bottom为曲线最高及最低平台期的Y值；Hillslope为希尔常数。Among them, X is the logarithmic value of the compound concentration, Y is the potency of the compound to inhibit cell necrosis; Top and Bottom are the Y values of the highest and lowest plateau of the curve; Hillslope is the Hill constant.
本发明化合物抑制L929细胞坏死的活性见下表2。The activity of the compounds of the present invention in inhibiting the necrosis of L929 cells is shown in Table 2 below.
在表2中，A是指化合物抑制细胞坏死的IC 50<50nM；B是指50nM<IC 50<100nM；C是指100nM<IC 50<500nM；D是指IC 50>500nM。 In Table 2, A refers to the IC 50 <50nM of the compound inhibiting cell necrosis; B refers to 50nM<IC 50 <100nM; C refers to 100nM<IC 50 <500nM; D refers to IC 50 >500nM.
表2 本发明化合物抑制L929细胞坏死的IC 50值 Table 2 IC50 values of compounds of the present invention inhibiting L929 cell necrosis
实施例Example IC 50(nM) IC 50 (nM)
11 BB
22 AA
33 AA
44 AA
55 BB
66 AA
77 AA
88 CC
99 --
1010 BB
1111 AA
1212 AA
1313 DD.
1414 AA
1515 AA
1616 AA
1717 CC
1818 CC
1919 CC
2020 AA
21twenty one AA
22twenty two AA
23twenty three AA
24twenty four AA
2525 AA
2626 AA
2727 AA
2828 AA
2929 AA
3030 AA
3131 AA
结论：本发明化合物能够抑制L929细胞坏死。Conclusion: the compound of the present invention can inhibit the necrosis of L929 cells.
试验例3：本发明化合物的肝微粒体稳定性测试Test Example 3: Liver microsomal stability test of compounds of the present invention
分别用体系为400μL的人、小鼠和大鼠肝微粒体(452117，corning；452701，corning；452501，corning)进行代谢稳定性孵育。体系中肝微粒体终浓度为0.5mg/mL，NADPH(2646-7H，solarbio)终浓度为1mM，受试化合物终浓度为2μM。以2μM盐酸维拉帕米(100223-200102，中国药品生物制品鉴定所)为阳性对照。分别在0、15、30、45、60分钟时，分别取出50μL反应样品，加入200μL含有终浓度为200nM拉贝洛尔(100484-201001，中国药品生物制品鉴定所)的乙腈终止反应。样品混匀后10000rpm离心10分钟，取100μL上清液加100μL超纯水混匀，用于HPLC-MS/MS分析，通过测定化合物的相对减少量计算化合物的代谢稳定性。用化合物剩余百分数的自然对数和孵育时间绘制曲线，得到斜率k，体外半衰期T 1/2＝-(0.693/k)。 Metabolic stability incubation was performed with human, mouse and rat liver microsomes (452117, corning; 452701, corning; 452501, corning) with a system of 400 μL, respectively. The final concentration of liver microsomes in the system was 0.5 mg/mL, the final concentration of NADPH (2646-7H, solarbio) was 1 mM, and the final concentration of the test compound was 2 μM. 2 μM verapamil hydrochloride (100223-200102, China National Institute of Pharmaceutical and Biological Products) was used as a positive control. At 0, 15, 30, 45, and 60 minutes, 50 μL of reaction samples were taken out, and 200 μL of acetonitrile containing a final concentration of 200 nM labetalol (100484-201001, China National Institute of Pharmaceutical and Biological Products) was added to terminate the reaction. After the sample was mixed, it was centrifuged at 10,000 rpm for 10 minutes, and 100 μL supernatant was mixed with 100 μL ultrapure water for HPLC-MS/MS analysis. The metabolic stability of the compound was calculated by determining the relative reduction of the compound. The natural logarithm of the remaining percentage of the compound was plotted against the incubation time to obtain the slope k and the in vitro half-life T 1/2 =-(0.693/k).
本发明化合物在人、小鼠和大鼠肝微粒体中的代谢稳定性如下表3。The metabolic stability of the compounds of the present invention in human, mouse and rat liver microsomes is shown in Table 3 below.
表3 本发明化合物在人、小鼠和大鼠肝微粒体中的代谢稳定性Table 3 Metabolic stability of compounds of the present invention in human, mouse and rat liver microsomes
Figure PCTCN2022092607-appb-000069
Figure PCTCN2022092607-appb-000069
结论：本发明化合物在人、小鼠和大鼠肝微粒体中有较好的稳定性。Conclusion: the compound of the present invention has good stability in liver microsomes of human, mouse and rat.
试验例4：本发明化合物的肝细胞代谢稳定性测试Test Example 4: Hepatocyte metabolic stability test of the compound of the present invention
使用人、小鼠和大鼠原代肝细胞(HPCH10，xenotech；M005052，BioreclamationIVT；M00005，BioreclamationIVT)孵育化合物，肝细胞密度为1.0×10 6 个细胞/mL。用煮沸灭活5分钟的肝细胞作为阴性对照。转移198μL活细胞或者灭活细胞的混悬液到96孔深孔板，将深孔板置于涡旋仪上于孵箱中预热10分钟。每孔加入2μL，100μM受试物或盐酸维拉帕米(100223-200102，中国药品生物制品鉴定所)进行反应起始，化合物终浓度为1μM，将深孔板放回孵箱涡旋器上，分别于0、15、30、60、90、120分钟时，取25μL混悬液，加入150μL含500nM拉贝洛尔(100484-201001，中国药品生物制品鉴定所)的乙腈终止反应。涡旋10分钟，于3220g，4℃条件离心30分钟，转移100μL上清液到进样板，加入100μL纯水混匀，用于UPLC-MS/MS分析。通过测定化合物的相对减少量计算化合物的代谢稳定性。用化合物剩余百分数的自然对数和孵育时间绘制曲线，得到斜率k，体外半衰期T 1/2＝-(0.693/k)。 Human, mouse and rat primary hepatocytes (HPCH10, xenotech; M005052, BioreclamationIVT; M00005, BioreclamationIVT ) were used to incubate compounds at a hepatocyte density of 1.0 x 106 cells/mL. Hepatocytes inactivated by boiling for 5 min were used as a negative control. Transfer 198 μL of live cell or inactivated cell suspension to a 96-well deep-well plate, place the deep-well plate on a vortexer and preheat it in an incubator for 10 minutes. Add 2 μL, 100 μM test substance or verapamil hydrochloride (100223-200102, National Institute of Pharmaceutical and Biological Products, China) to each well to start the reaction, the final concentration of the compound is 1 μM, and put the deep well plate back on the incubator vortexer , respectively at 0, 15, 30, 60, 90, and 120 minutes, 25 μL of the suspension was taken, and 150 μL of acetonitrile containing 500 nM labetalol (100484-201001, China National Institute of Pharmaceutical and Biological Products) was added to terminate the reaction. Vortex for 10 minutes, centrifuge at 3220g, 4°C for 30 minutes, transfer 100 μL of supernatant to the sample plate, add 100 μL of pure water and mix well for UPLC-MS/MS analysis. The metabolic stability of a compound is calculated by determining the relative reduction of the compound. The natural logarithm of the remaining percentage of the compound was plotted against the incubation time to obtain the slope k and the in vitro half-life T 1/2 =-(0.693/k).
本发明化合物在人、小鼠和大鼠肝细胞中的代谢稳定性如下表4。The metabolic stability of the compounds of the present invention in human, mouse and rat hepatocytes is shown in Table 4 below.
表4 本发明化合物在人、小鼠和大鼠肝细胞中的代谢稳定性Table 4 Metabolic stability of compounds of the present invention in human, mouse and rat hepatocytes
Figure PCTCN2022092607-appb-000070
Figure PCTCN2022092607-appb-000070
结论：本发明化合物在人、小鼠和大鼠肝细胞中有较好的稳定性。Conclusion: the compound of the present invention has good stability in human, mouse and rat hepatocytes.
试验例5：本发明化合物在ICR小鼠体内药代动力学评价Test Example 5: Pharmacokinetic evaluation of compounds of the present invention in ICR mice
对雄性7周龄ICR小鼠(北京市维通利华实验动物技术有限公司)口服给予2mg/kg本发明化合物，化合物浓度为0.2mg/mL。分别于给药前和给药后，在0、0.167、0.25、0.50、1.00、2.00、4.00、6.00、8.00和24.00h从眼眦静脉丛采血，血液经肝素钠抗凝，于4℃，3500rpm离心10分钟，获取血浆并在-80℃保存直至测试。取10μL血浆样品加入100μL含5ng/mL维拉帕米(100223-200102，中国药品生物制品鉴定所)乙腈工作溶液，涡旋剧烈震荡5min，在4℃条件下以4000rpm离心10min。取上清液50μL，加入200μL乙腈混匀，在4℃条件下以4000rpm离心10min，取上清液，置于96孔进样盘中，经LC/MS(Waters，Waters UPLC I Class、TQ-S micro)分析得出血药浓度，并通过MassLynx V4.2SCN977数据处理软件分析药代动力学参数。Male 7-week-old ICR mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were orally administered 2 mg/kg of the compound of the present invention, and the concentration of the compound was 0.2 mg/mL. At 0, 0.167, 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00 and 24.00 hours before and after administration, blood was collected from the canthus venous plexus, anticoagulated by sodium heparin, at 4°C, 3500rpm Plasma was obtained by centrifugation for 10 min and stored at -80°C until assayed. Take 10 μL of plasma sample and add 100 μL of acetonitrile working solution containing 5 ng/mL verapamil (100223-200102, China National Institute of Pharmaceutical and Biological Products), vortex vigorously for 5 min, and centrifuge at 4000 rpm for 10 min at 4 °C. Take 50 μL of the supernatant, add 200 μL of acetonitrile and mix well, centrifuge at 4000 rpm for 10 min at 4°C, take the supernatant, put it in a 96-well sample tray, and run through LC/MS (Waters, Waters UPLC I Class, TQ- S micro) was analyzed to obtain the blood drug concentration, and the pharmacokinetic parameters were analyzed by MassLynx V4.2SCN977 data processing software.
本发明化合物口服给药后药代动力学实验数据见下表5。The pharmacokinetic experimental data of the compounds of the present invention after oral administration are shown in Table 5 below.
在表中，A是指化合物的AUC 0-t(μg/L*h)<500；B是指500<AUC 0-t(μg/L*h)<1000；C是指1000<AUC 0-t(μg/L*h)<5000；D是指5000<AUC 0-t(μg/L*h)<10000。a是指化合物的半衰期1h＜T 1/2Z＜2h，b是指化合物的半衰期2h＜T 1/2Z＜3h，c是指化合物的半衰期3h＜T 1/2Z。 In the table, A means AUC 0-t (μg/L*h)<500 of the compound; B means 500<AUC 0-t (μg/L*h)<1000; C means 1000<AUC 0- t (μg/L*h)<5000; D means 5000<AUC 0-t (μg/L*h)<10000. a refers to the half-life of the compound 1h<T 1/2Z <2h, b refers to the half-life of the compound 2h<T 1/2Z <3h, and c refers to the half-life of the compound 3h<T 1/2Z .
表5 单次口服给予雄性ICR小鼠本发明化合物的药动学参数Table 5 single oral administration of the pharmacokinetic parameters of the compound of the present invention in male ICR mice
Figure PCTCN2022092607-appb-000071
Figure PCTCN2022092607-appb-000071
结论：本发明化合物在小鼠体内有较好的药代动力学性质。Conclusion: the compound of the present invention has better pharmacokinetic properties in mice.
试验例6：本发明化合物在C57BL/6J小鼠体内血脑屏障透过率测试Test Example 6: Blood-brain barrier permeability test of the compound of the present invention in C57BL/6J mice
对雄性6周龄C57BL/6小鼠(北京市维通利华实验动物技术有限公司)口服给予本发明化合物。分别于给药前和给药后，在0、0.25、1.00和4.00h采集小鼠血液和脑组织。取脑组织前，从小鼠左心室灌流10mL生理盐水。血液样品经肝素钠抗凝，于4℃，3500rpm离心10分钟，获取血浆并在-80℃保存直至测试。脑组织称量重量后，转移至EP管中。根据脑组织重量加生理盐水匀浆(脑重：生理盐水体积＝1:2)，整个过程在低温下进行。精密量取脑组织匀浆液样品50μL，转移至1.5mL EP管中，向其中加入400μL含有5ng/mL盐酸维拉帕米(100223-200102，中国药品生物制品鉴定所)的乙腈工作液，涡旋剧烈震荡1min，16000rpm离心10min。取上清液，用0.22μm有机膜(AS081320-T，Agela Technologies)过滤，加入进样小瓶中待测。经LC/MS(Waters，Waters UPLC I Class、TQ-S micro)分析得出血药浓度和脑组织药物浓度。The compound of the present invention was orally administered to male 6-week-old C57BL/6 mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.). The blood and brain tissue of mice were collected at 0, 0.25, 1.00 and 4.00 hours before and after administration, respectively. Before taking the brain tissue, 10 mL of normal saline was perfused from the left ventricle of the mouse. Blood samples were anticoagulated with sodium heparin, centrifuged at 3500 rpm for 10 minutes at 4°C, and plasma was obtained and stored at -80°C until testing. After the brain tissue was weighed, it was transferred to an EP tube. Add physiological saline homogenate according to brain tissue weight (brain weight: normal saline volume = 1:2), and the whole process is carried out at low temperature. Accurately measure 50 μL of the brain tissue homogenate sample, transfer it to a 1.5 mL EP tube, add 400 μL of acetonitrile working solution containing 5 ng/mL verapamil hydrochloride (100223-200102, China Institute for the Identification of Pharmaceutical and Biological Products) to it, vortex Shake vigorously for 1 min, and centrifuge at 16000 rpm for 10 min. The supernatant was taken, filtered with a 0.22 μm organic membrane (AS081320-T, Agela Technologies), and added to a sample injection vial for testing. Blood drug concentration and brain tissue drug concentration were analyzed by LC/MS (Waters, Waters UPLC I Class, TQ-S micro).
本发明化合物口服给药后血脑屏障透过率见表6。Table 6 shows the blood-brain barrier permeability of the compound of the present invention after oral administration.
在表中，A是指化合物的Cb/Cp<0.3；B是指Cb/Cp>0.3。In the table, A refers to the compound with Cb/Cp<0.3; B refers to Cb/Cp>0.3.
表6 单次口服给予雄性C57BL/6J小鼠本发明化合物的血脑屏障透过率Table 6 Single oral administration of the blood-brain barrier permeability of the compound of the present invention in male C57BL/6J mice
实施例Example C b/C p，1h C b /C p , 1h
77 AA
1111 BB
1212 AA
1616 AA
2020 AA
2525 AA
注：C b(ng/g)：脑组织中药物浓度，C p(ng/mL)：血浆中药物浓度。 Note: C b (ng/g): drug concentration in brain tissue, C p (ng/mL): drug concentration in plasma.
结论：本发明化合物能透过小鼠血脑屏障。Conclusion: the compound of the present invention can pass through the mouse blood-brain barrier.
试验例7：本发明化合物作用于hERG钾离子通道的安全性测试Test Example 7: Safety test of compounds of the present invention acting on hERG potassium ion channels
使用手动膜片钳方法测试化合物对hERG钾通道电流的影响。The effect of compounds on hERG potassium channel currents was tested using the manual patch clamp method.
试验方法：experiment method:
a.细胞准备a. Cell preparation
稳定表达hERG离子通道的HEK293细胞株(K1236，Invitrogen)，按照5×10 5的密度培养在6cm培养皿中，加入1μg/mL强力霉素(D9891，sigma)诱导48小时，然后将细胞进行消化，接种在玻片上以备后续的手动膜片钳的实验。 HEK293 cell line (K1236, Invitrogen) stably expressing hERG ion channel was cultured in a 6 cm dish at a density of 5×10 5 , added 1 μg/mL doxycycline (D9891, sigma) for induction for 48 hours, and then the cells were digested , inoculated on glass slides for subsequent manual patch clamp experiments.
b.溶液配制b. Solution preparation
细胞外液(以mM为单位)：132NaCl，4KCl，3CaCl 2，0.5MgCl 2，11.1葡萄糖和10HEPES，用NaOH将pH调至7.35。 Extracellular fluid (in mM): 132 NaCl, 4KCl, 3CaCl2 , 0.5MgCl2 , 11.1 glucose and 10HEPES, pH adjusted to 7.35 with NaOH.
细胞内液(以mM为单位)：140KCl，2MgCl 2，10EGTA，5ATP-Mg和10HEPES，用KOH将pH调至7.35。 Intracellular fluid (in mM): 140KCl, 2MgCl 2 , 10EGTA, 5ATP-Mg and 10HEPES, pH adjusted to 7.35 with KOH.
c.待测化合物溶液配制c. Preparation of test compound solution
待测化合物用DMSO溶解并配制成终浓度为3.33mM的储备液，用细胞外液将待测化合物稀释333.33倍，配制成10μM的工作液，DMSO在该工作溶液中的含量为0.3％。The compound to be tested was dissolved in DMSO and prepared as a stock solution with a final concentration of 3.33mM. The compound to be tested was diluted 333.33 times with extracellular fluid to prepare a 10 μM working solution. The content of DMSO in the working solution was 0.3%.
d.电生理记录过程d. Electrophysiological recording process
将培养皿中载有HEK293细胞的小玻片放置于显微操作台的灌流槽中，在倒置显微镜下使电极慢慢接近细胞，当快接近细胞时，转换为×40倍物镜进行观察，通过微操纵器微调档，使电极逐渐接近细胞的表面，给予负压，使电极尖与细胞膜之间形成电阻高于1GΩ的封接，在电压钳模式下对瞬时电容电流C fast进行补偿。然后重复给予短促的负压进行破膜，最终形成全细胞记录模式。在膜电位钳制于-60mV的条件下，对缓慢电容电流C slow，细胞膜电容(Cm)和输入膜电阻(Ra)分别进行补偿。细胞稳定后，将钳制电压改为-90mV，采样频率设置为50kHz，过滤频率为10kHz。漏电流在检测条件为钳制电压-80mV，时程500ms。施加4.8秒去极化命令电压将膜电位从-80mV去极化至+30mV，然后瞬间施加5.2秒的复极化电压使膜电位降至-50mV以去除通道失活，从而得以观察到hERG尾电流。首先将 在正常细胞外液中测定得到的hERG电流作为检测基线。在hERG电流保持稳定至少5分钟后，采用ALA公司8通道重力给药***，将含有待测化合物的溶液灌注于细胞周围。每次灌流结束后等待约5分钟以使化合物充分作用于细胞并同步记录hERG电流。待记录电流趋于稳定后记录最后5个hERG电流值，并取其平均值作为其最终在特定浓度下的电流值。 Place the small slides containing HEK293 cells in the culture dish in the perfusion tank of the micromanipulator, and slowly approach the cells under the inverted microscope. The micromanipulator fine-tunes the gear to make the electrode gradually approach the surface of the cell, and applies negative pressure to form a seal with a resistance higher than 1GΩ between the electrode tip and the cell membrane. In the voltage clamp mode, the instantaneous capacitive current C fast is compensated. Then repeated brief negative pressure was applied to permeate the membrane, and finally the whole-cell recording mode was formed. Under the condition that the membrane potential was clamped at -60mV, the slow capacitive current C slow , the cell membrane capacitance (Cm) and the input membrane resistance (Ra) were compensated respectively. After the cells are stable, change the clamping voltage to -90mV, set the sampling frequency to 50kHz, and filter frequency to 10kHz. The detection condition of the leakage current is the clamp voltage -80mV, and the duration is 500ms. A 4.8-s depolarization command voltage was applied to depolarize the membrane potential from -80 mV to +30 mV, followed by a 5.2-s repolarization voltage momentarily applied to lower the membrane potential to -50 mV to remove channel inactivation, allowing the hERG tail to be observed current. First, the hERG current measured in normal extracellular fluid was used as the detection baseline. After the hERG current remained stable for at least 5 minutes, the solution containing the compound to be tested was perfused around the cells using an 8-channel gravity drug delivery system from ALA Company. Wait about 5 minutes after each perfusion to allow the compound to fully act on the cells and simultaneously record the hERG current. After the recorded current tends to be stable, record the last 5 hERG current values, and take the average value as the final current value at a specific concentration.
尾电流抑制率＝(1-尾电流大小 化合物/尾电流大小 空白)×100％ Tail current inhibition rate=(1-tail current size compound /tail current size blank )×100%
本发明化合物作用于hERG钾离子通道的安全性测试结果如下表7。The safety test results of the compound of the present invention acting on the hERG potassium ion channel are shown in Table 7 below.
在表中，A是指化合物对hERG钾离子通道电流抑制率<35％；B是指化合物对hERG钾离子通道电流抑制率>35％。In the table, A means that the inhibitory rate of the compound on the current of hERG potassium ion channel is <35%; B means that the inhibitory rate of the compound on the current of hERG potassium ion channel is >35%.
表7 本发明化合物对hERG钾离子通道电流的抑制Table 7 Compounds of the present invention inhibit hERG potassium ion channel current
实施例Example 抑制率，10μMInhibition rate, 10μM
1111 BB
1515 AA
21twenty one AA
23twenty three AA
2929 AA
结论：本发明化合物对hERG钾离子通道电流抑制作用弱，心脏毒性风险较低。Conclusion: the compound of the present invention has a weak inhibitory effect on hERG potassium ion channel current, and the risk of cardiotoxicity is low.
试验例8：本发明化合物在全身炎症反应综合症模型中的药效Test Example 8: The efficacy of the compound of the present invention in the systemic inflammatory response syndrome model
利用TNFα驱动的全身炎症反应综合症模型评价化合物在小鼠体内的药效。实验设计包括模型组、受试化合物低剂量组(3mg/kg)和受试化合物高剂量组(10mg/kg)。受试化合物溶于DMSO后，加入羟丙基β环糊精溶液，配制成浓度为0.3mg/mL和1mg/mL的化合物溶液，其中DMSO的终浓度为3％，羟丙基β环糊精的终浓度为20％。雄性6周龄C57BL/6小鼠(北京维通利华实验动物技术有限公司)，口服给予溶媒(3％DMSO,20％羟丙基β环糊精溶液)或受试化合物，15分钟后每只小鼠静脉注射20μg TNFα(50349-MNAE，sinobiological)，小鼠体温损失通过高精度温度计(AZ8856，台湾衡欣)直肠探测测量，分别于静脉注射TNFα后1、2、3、4、5、6和24小时检测小鼠体温，并计算6小时时的小鼠体温下降抑制率。The TNFα-driven systemic inflammatory response syndrome model was used to evaluate the efficacy of compounds in mice. The experimental design includes model group, test compound low dose group (3mg/kg) and test compound high dose group (10mg/kg). After the test compound was dissolved in DMSO, hydroxypropyl β-cyclodextrin solution was added to prepare compound solutions with a concentration of 0.3 mg/mL and 1 mg/mL, wherein the final concentration of DMSO was 3%, and hydroxypropyl β-cyclodextrin The final concentration was 20%. Male 6-week-old C57BL/6 mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.), orally administered vehicle (3% DMSO, 20% hydroxypropyl β-cyclodextrin solution) or test compound, 15 minutes after each Each mouse was intravenously injected with 20 μg TNFα (50349-MNAE, sinobiological), and the body temperature loss of the mice was measured by rectal detection with a high-precision thermometer (AZ8856, Hengxin, Taiwan). The body temperature of the mice was detected at 6 and 24 hours, and the inhibition rate of the temperature drop of the mice at 6 hours was calculated.
抑制率％＝1-(模型组体温下降值-受试化合物组体温下降值)/模型组体温下降值。Inhibition rate%=1-(the drop in body temperature of the model group-the drop in body temperature of the test compound group)/the drop in body temperature of the model group.
表8 本发明化合物抑制全身炎症反应综合症模型中小鼠体温下降的药效Table 8 The efficacy of the compounds of the present invention in inhibiting the drop in body temperature of mice in the systemic inflammatory response syndrome model
实施例Example 剂量(mg/kg)Dose (mg/kg) 抑制率％Inhibition rate% 剂量(mg/kg)Dose (mg/kg) 抑制率％Inhibition rate%
1111 33 44.544.5 1010 61.861.8
1515 33 55.555.5 1010 62.762.7
21twenty one 33 37.337.3 1010 51.851.8
23twenty three 33 63.663.6 1010 59.159.1
2929 33 56.456.4 1010 63.663.6
结论：本发明化合物能够抑制全身炎症反应综合症模型中的小鼠体温下降。Conclusion: the compound of the present invention can inhibit the decrease of body temperature of mice in the systemic inflammatory response syndrome model.

Claims (24)

  1. 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，A compound represented by general formula (I) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022092607-appb-100001
    Figure PCTCN2022092607-appb-100001
    其中，in,
    X选自-O-、-S(O) m-、-NR a-、-CR’R”-； X is selected from -O-, -S(O) m -, -NR a -, -CR'R"-;
    Y 1和Y 2各自独立地选自O或S； Y1 and Y2 are each independently selected from O or S;
    Z 1和Z 2各自独立地选自C或N原子； Z 1 and Z 2 are each independently selected from C or N atoms;
    L选自单键、-O-、-S(O) m-、-NR a-、-(CR aR b) n-、-(CR aR b) nO-、-(CR aR b) nS-和-(CR aR b) nNR a-； L is selected from single bond, -O-, -S(O) m -, -NR a -, -(CR a R b ) n -, -(CR a R b ) n O-, -(CR a R b ) n S- and -(CR a R b ) n NR a -;
    环A选自芳基、杂芳基、环烷基和杂环基，其中所述芳基、杂芳基、环烷基和杂环烷基任选进一步被一个或多个R 9取代； Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally further substituted by one or more R9 ;
    环B为芳环或芳杂环，其任选进一步被一个或多个R 8取代； Ring B is an aromatic ring or an aromatic heterocyclic ring, which is optionally further substituted by one or more R 8 ;
    环C为含氮杂环，其任选进一步被一个或多个R 7取代； Ring C is a nitrogen-containing heterocycle, which is optionally further substituted by one or more R 7 ;
    R 1和R 2与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基，或者R 2和R 3与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基，或者R 3和R 4与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基，其中所述5元杂芳基、5元杂环基或5元环烷基任选进一步被一个或多个R 6取代； R 1 and R 2 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group together with the atoms they are connected to, or R 2 and R 3 form a 5-membered heteroaryl group, a 5-membered heteroaryl group, or a 5-membered cycloalkyl group together with their connected atoms A heterocyclic group or a 5-membered cycloalkyl group, or R 3 and R 4 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group with the atoms they are connected to, wherein the 5-membered heteroaryl group , 5-membered heterocyclyl or 5-membered cycloalkyl are optionally further substituted by one or more R 6 ;
    其中：in:
    当R 1和R 2与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基时，R 3和R 4各自独立地选自R 6；或者 When R 1 and R 2 form 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl together with their attached atoms, R 3 and R 4 are each independently selected from R 6 ; or
    当R 2和R 3与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基时，R 1和R 4各自独立地选自R 6；或者 When R 2 and R 3 form 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl together with the atoms they are connected to, R 1 and R 4 are each independently selected from R 6 ; or
    当R 3和R 4与他们连接的原子一起形成5元杂芳基、5元杂环基或5元环烷基时，R 1和R 2各自独立地选自R 6； When R 3 and R 4 form a 5-membered heteroaryl group, a 5-membered heterocyclic group or a 5-membered cycloalkyl group together with their connected atoms, R 1 and R 2 are each independently selected from R 6 ;
    R 5选自氢、烷基、卤代烷基、环烷基和卤代环烷基； R is selected from hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl ;
    每个R 6各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2，其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步 被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 , wherein the alkyl, alkoxy, ring Alkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy One or more groups of radical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
    每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic One or more groups of radical, aryl, heteroaryl are substituted;
    每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic One or more groups of radical, aryl, heteroaryl are substituted;
    每个R 9各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic One or more groups of radical, aryl, heteroaryl are substituted;
    R’和R”各自独立地选自氢、卤素、烷基、卤代烷基；R' and R" are each independently selected from hydrogen, halogen, alkyl, haloalkyl;
    R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
    或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    m为0、1或2；m is 0, 1 or 2;
    n为0至3的整数。n is an integer of 0 to 3.
  2. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物 形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or its druggable A salt, which is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,
    Figure PCTCN2022092607-appb-100002
    Figure PCTCN2022092607-appb-100002
    其中，in,
    环D选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2的一个或多个基团取代； Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m One or more groups of R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 are substituted;
    R 1和R 2各自独立地选自氢、卤素、烷基； R 1 and R 2 are each independently selected from hydrogen, halogen, alkyl;
    R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, Ester group, oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group substitution by one or more groups;
    或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    m为0、1或2；m is 0, 1 or 2;
    X、Y 1、Y 2、Z 1、Z 2、L、环A、环B、环C、R 5如权利要求1所定义。 X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in claim 1.
  3. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or its druggable A salt, which is a compound represented by general formula (III) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,
    Figure PCTCN2022092607-appb-100003
    Figure PCTCN2022092607-appb-100003
    其中，in,
    环E选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其 任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2的一个或多个基团取代； Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m One or more groups of R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 are substituted;
    R 1和R 4各自独立地选自氢、卤素、烷基； R 1 and R 4 are each independently selected from hydrogen, halogen, alkyl;
    R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
    或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    m为0、1或2；m is 0, 1 or 2;
    X、Y 1、Y 2、Z 1、Z 2、L、环A、环B、环C、R 5如权利要求1所定义。 X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in claim 1.
  4. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or its druggable A salt, which is a compound represented by general formula (IV) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,
    Figure PCTCN2022092607-appb-100004
    Figure PCTCN2022092607-appb-100004
    其中：in:
    环F选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a和-P(O)(R a) 2的一个或多个基团取代； Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m One or more groups of R a , -S(O) m NR a R b , -NHS(O) m R a and -P(O)(R a ) 2 are substituted;
    R 3和R 4各自独立地选自氢、卤素、烷基； R 3 and R 4 are each independently selected from hydrogen, halogen, alkyl;
    R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
    或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    m为0、1或2；m is 0, 1 or 2;
    X、Y 1、Y 2、Z 1、Z 2、L、环A、环B、环C、R 5如权利要求1所定义。 X, Y 1 , Y 2 , Z 1 , Z 2 , L, ring A, ring B, ring C, and R 5 are as defined in claim 1.
  5. 根据权利要求2至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 2 to 4 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,
    R a和R b各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基，其中所述烷基、烯基、炔基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R a and R b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally Further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups are substituted;
    或者R a和R b与他们连接的原子一起形成5-7元含氮杂环基，所述5-7元含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Or R a and R b form a 5-7 membered nitrogen-containing heterocyclic group together with the atoms they are connected to, and the 5-7 membered nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, One or more groups of oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted.
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，X为-O-或-S-。The compound represented by the general formula (I) according to any one of claims 1 to 5 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein X is -O- or -S-.
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 1 to 6 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,
    环C为5至8元含氮杂环，优选哌啶环、四氢吡咯环、哌嗪环、二氢吡咯环、四氢吡啶环或高哌嗪环，更优选哌啶环，其任选进一步被一个或多个R 7取代； Ring C is a 5 to 8-membered nitrogen-containing heterocyclic ring, preferably a piperidine ring, a tetrahydropyrrole ring, a piperazine ring, a dihydropyrrole ring, a tetrahydropyridine ring or a homopiperazine ring, more preferably a piperidine ring, which is optionally further substituted by one or more R7 ;
    每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted;
    其中：in:
    R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R a and R b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cyclic One or more groups of alkyl, heterocyclyl, aryl, heteroaryl are substituted;
    或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环 基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    m为0、1或2。m is 0, 1 or 2.
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 1 to 7 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,
    环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R 8取代； Ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, Thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further replaced by one or more R 8 replace;
    每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR aR b、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、和-NHS(O) mR a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R 8为卤素； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , - S(O) m R a , -S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted; preferably R 8 is halogen;
    其中：in:
    R a和R b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R a and R b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cyclic One or more groups of alkyl, heterocyclyl, aryl, heteroaryl are substituted;
    或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, Substitution by one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    m为0、1或2。m is 0, 1 or 2.
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 1 to 8 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,
    Figure PCTCN2022092607-appb-100005
    选自：
    Figure PCTCN2022092607-appb-100005
    selected from:
    Figure PCTCN2022092607-appb-100006
    Figure PCTCN2022092607-appb-100006
    其中，in,
    Y 2选自O或S； Y2 is selected from O or S;
    Z 1和Z 2各自独立地选自C或N原子； Z 1 and Z 2 are each independently selected from C or N atoms;
    环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R 8取代； Ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, Thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further replaced by one or more R 8 replace;
    每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基；或者两个相邻的R 7与他们连接的原子一起形成杂环基或环烷基，其中所述烷基、烷氧基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R 7为氢； Each R 7 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy; or two adjacent R 7 are together with the atoms to which they are attached Form heterocyclyl or cycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, One or more groups of carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted; preferably R 7 is hydrogen;
    每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R 8为卤素； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups; preferably R is halogen;
    p为0、1、2、3或4，优选0。p is 0, 1, 2, 3 or 4, preferably 0.
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 1 to 9 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,
    Figure PCTCN2022092607-appb-100007
    选自：
    Figure PCTCN2022092607-appb-100007
    selected from:
    Figure PCTCN2022092607-appb-100008
    Figure PCTCN2022092607-appb-100009
    优选
    Figure PCTCN2022092607-appb-100010
    Figure PCTCN2022092607-appb-100008
    Figure PCTCN2022092607-appb-100009
    preferred
    Figure PCTCN2022092607-appb-100010
    其中，in,
    Y 2选自O或S； Y2 is selected from O or S;
    每个R 8各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R 8为卤素； Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups; preferably R is halogen;
    q为0、1或2。q is 0, 1 or 2.
  11. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IA)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or its druggable A salt, which is a compound represented by the general formula (IA) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,
    Figure PCTCN2022092607-appb-100011
    Figure PCTCN2022092607-appb-100011
    X、Y 1、Y 2、L、环A、R 1、R 2、R 3、R 4、R 5、R 8如权利要求1所定义。 X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 are as defined in claim 1.
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y 2为O。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein Y 2 is O.
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y 1为O。 The compound represented by the general formula (I) according to any one of claims 1 to 12 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein Y 1 is O.
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 13 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof,
    其中，in,
    环A选自芳基和杂芳基，优选苯基，其中所述芳基或杂芳基任选进一步被一个或多个R 9取代， Ring A is selected from aryl and heteroaryl, preferably phenyl, wherein said aryl or heteroaryl is optionally further substituted by one or more R 9 ,
    每个R 9各自独立地选自氢、卤素、氰基、羟基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基，优选氢、卤素、烷基和烷氧基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Each R is independently selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, alkane and alkoxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, One or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted.
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 14 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof,
    其中，L选自-NR a-和-(CR aR b) n-，优选-(CR aR b) n-； Wherein, L is selected from -NR a - and -(CR a R b ) n -, preferably -(CR a R b ) n -;
    R a和R b各自独立地选自氢和C 1-6烷基； R a and R b are each independently selected from hydrogen and C 1-6 alkyl;
    n为0至3的整数，优选1；n is an integer from 0 to 3, preferably 1;
    L更优选-CH 2-。 L is more preferably -CH 2 -.
  16. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 15 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof,
    其中，R 5选自氢、C 1-6烷基和卤代C 1-6烷基，优选氢和C 1-6烷基。 Wherein, R 5 is selected from hydrogen, C 1-6 alkyl and halogenated C 1-6 alkyl, preferably hydrogen and C 1-6 alkyl.
  17. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 16 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022092607-appb-100012
    Figure PCTCN2022092607-appb-100012
    其中，in,
    X为-O-或-S-；X is -O- or -S-;
    环D选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、-C(O)OR a的一个或多个基团取代； Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
    R 1和R 2各自独立地选自氢、卤素、C 1-C 6烷基； R 1 and R 2 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl;
    R 5选自氢和C 1-C 6烷基； R 5 is selected from hydrogen and C 1 -C 6 alkyl;
    R 8选自氢和卤素； R is selected from hydrogen and halogen;
    R 9选自氢和卤素； R9 is selected from hydrogen and halogen;
    R a选自C 1-C 6烷基； R a is selected from C 1 -C 6 alkyl;
    p为0、1或2。p is 0, 1 or 2.
  18. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 16 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022092607-appb-100013
    Figure PCTCN2022092607-appb-100013
    其中，in,
    X为-O-或-S-；X is -O- or -S-;
    环E选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、-C(O)OR a的一个或多个基团取代； Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
    R 1和R 4各自独立地选自氢、卤素、C 1-C 6烷基； R 1 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl;
    R 5选自氢和C 1-C 6烷基； R 5 is selected from hydrogen and C 1 -C 6 alkyl;
    R 8选自氢和卤素； R is selected from hydrogen and halogen;
    R 9选自氢和卤素； R9 is selected from hydrogen and halogen;
    R a选自C 1-C 6烷基； R a is selected from C 1 -C 6 alkyl;
    p为0、1或2。p is 0, 1 or 2.
  19. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 16 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022092607-appb-100014
    Figure PCTCN2022092607-appb-100014
    其中，in,
    X为-O-或-S-；X is -O- or -S-;
    环F选自5元杂芳基、5元杂环基或5元环烷基，优选咪唑基、二氢咪唑基、吡唑基、二氢吡唑基、二氧杂环戊烯基、噻唑基、噁唑基、吡咯基、呋喃基；其任选进一步被选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、-C(O)OR a的一个或多个基团取代； Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclic group or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazole Base, oxazolyl, pyrrolyl, furyl; It is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(O)OR a One or more groups are substituted;
    R 3和R 4各自独立地选自氢、卤素、C 1-C 6烷基； R 3 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl;
    R 5选自氢和C 1-C 6烷基； R 5 is selected from hydrogen and C 1 -C 6 alkyl;
    R 8选自氢和卤素； R is selected from hydrogen and halogen;
    R 9选自氢和卤素； R9 is selected from hydrogen and halogen;
    R a选自C 1-C 6烷基； R a is selected from C 1 -C 6 alkyl;
    p为0、1或2。p is 0, 1 or 2.
  20. 根据权利要求1至19中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中所述化合物选自：The compound represented by the general formula (I) according to any one of claims 1 to 19 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
    Figure PCTCN2022092607-appb-100015
    Figure PCTCN2022092607-appb-100015
    Figure PCTCN2022092607-appb-100016
    Figure PCTCN2022092607-appb-100016
  21. 一种通式(II-1)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：A compound represented by general formula (II-1) or its mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Preparation method, it comprises the following steps:
    Figure PCTCN2022092607-appb-100017
    Figure PCTCN2022092607-appb-100017
    在催化剂的存在下，将化合物IA-I发生分子内关环反应得到通式(IA)化合物，所述催化剂优选三甲基铝；In the presence of a catalyst, the compound IA-I undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (IA), and the catalyst is preferably trimethylaluminum;
    其中，X、Y 1、Y 2、L、环A、R 1、R 2、R 3、R 4、R 5、R 8如权利要求11所定义。 Wherein, X, Y 1 , Y 2 , L, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined in claim 11.
  22. 一种药物组合物，其包含根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体或赋形剂。A pharmaceutical composition comprising the compound represented by the general formula (I) according to any one of claims 1 to 20 or its mesoform, racemate, enantiomer, diastereomer An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  23. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求22所述的药物组合物在制备受体相互作用蛋白激酶1(RIP1)抑制剂中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 20 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22 in the preparation of a receptor-interacting protein kinase 1 (RIP1) inhibitor.
  24. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求22所述的药物组合物在制备预防或治疗与受体相互作用蛋白激酶1活性相关的疾病的药物中的用途，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The compound represented by the general formula (I) according to any one of claims 1 to 20 or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for the prevention or treatment of diseases associated with receptor-interacting protein kinase 1 activity, the diseases are preferably inflammatory diseases, autoimmune Immunological or neurological diseases, the inflammatory and autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatic atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic Steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis syndrome, systemic inflammatory response syndrome, allergic disease, asthma, atopic skin disease, multiple sclerosis, type 1 diabetes, orbital necrotizing granulomatous disease, pulmonary sarcoidosis, Behcet's disease, interleukin-1 Convertase-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated syndrome, or periodontitis; such neurological disorders as Huntington's disease, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral hardening.
PCT/CN2022/092607 2021-05-14 2022-05-13 Azepine-type fused ring compound and pharmaceutical use thereof WO2022237890A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280005442.8A CN115867557A (en) 2021-05-14 2022-05-13 Azepine fused ring compounds and medical application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110526950.8 2021-05-14
CN202110526950 2021-05-14

Publications (1)

Publication Number Publication Date
WO2022237890A1 true WO2022237890A1 (en) 2022-11-17

Family

ID=84028185

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/092607 WO2022237890A1 (en) 2021-05-14 2022-05-13 Azepine-type fused ring compound and pharmaceutical use thereof

Country Status (3)

Country Link
CN (1) CN115867557A (en)
TW (1) TW202311261A (en)
WO (1) WO2022237890A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021228173A1 (en) * 2020-05-14 2021-11-18 中国医药研究开发中心有限公司 Azepine fused ring compounds and medical uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108431004A (en) * 2015-10-23 2018-08-21 武田药品工业株式会社 Heterocyclic compound
CN110642874A (en) * 2018-06-26 2020-01-03 中国科学院上海有机化学研究所 Cell necrosis inhibitor and preparation method and application thereof
CN112079839A (en) * 2019-06-15 2020-12-15 察略盛医药科技(上海)有限公司 Lactam derivative, preparation method and medical application thereof
CN112384510A (en) * 2018-05-03 2021-02-19 里格尔药品股份有限公司 RIP1 inhibiting compounds and methods of making and using the same
WO2021046437A1 (en) * 2019-09-06 2021-03-11 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same
WO2021228173A1 (en) * 2020-05-14 2021-11-18 中国医药研究开发中心有限公司 Azepine fused ring compounds and medical uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108431004A (en) * 2015-10-23 2018-08-21 武田药品工业株式会社 Heterocyclic compound
CN112384510A (en) * 2018-05-03 2021-02-19 里格尔药品股份有限公司 RIP1 inhibiting compounds and methods of making and using the same
CN110642874A (en) * 2018-06-26 2020-01-03 中国科学院上海有机化学研究所 Cell necrosis inhibitor and preparation method and application thereof
CN112079839A (en) * 2019-06-15 2020-12-15 察略盛医药科技(上海)有限公司 Lactam derivative, preparation method and medical application thereof
WO2021046437A1 (en) * 2019-09-06 2021-03-11 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same
WO2021228173A1 (en) * 2020-05-14 2021-11-18 中国医药研究开发中心有限公司 Azepine fused ring compounds and medical uses thereof

Also Published As

Publication number Publication date
CN115867557A (en) 2023-03-28
TW202311261A (en) 2023-03-16

Similar Documents

Publication Publication Date Title
WO2020108590A1 (en) Pyrimidine and five-membered nitrogen heterocycle derivative, preparation method therefor, and medical uses thereof
JP2021508703A (en) IRAK Degradants and Their Use
CN112135824A (en) Heterocyclic compounds as immunomodulators
WO2020259679A1 (en) Pyrimidine five-membered nitrogen heterocyclic derivative, preparation method thereof and pharmaceutical use thereof
JP6800885B2 (en) Imidazopyrazine and pyrazolopyrimidine, and their use as AMPA receptor regulators
TW202012412A (en) A pharmaceutical composition containing amide derivatives, its preparation method and application thereof
CN103476768A (en) 6,5-heterocyclic propargylic alcohol compounds and uses therefor
CN103038233A (en) Pyridone and aza-pyridone compounds and methods of use
CN114423753A (en) Heterobicyclic amides as CD38 inhibitors
WO2021249519A1 (en) Pyridine-pyrimidine derivative, preparation method therefor and pharmaceutical use thereof
TW202102505A (en) A pyrroloheterocyclic derivative and preparation method and medical use thereof
WO2021228173A1 (en) Azepine fused ring compounds and medical uses thereof
CN106432246B (en) Heteroaromatic compounds and their use in medicine
TW202128690A (en) A pyrazolo heteroaryl derivative, a preparation method thereof, and a medical use thereof
TW202110848A (en) A substituted fused bicyclic derivative, a preparation method thereof, and medical applications thereof
JP2022527744A (en) Thieno Heterocyclic Derivatives, Preparation Methods for This Derivative and Use of This Derivative in Medicine
WO2022236058A1 (en) Cdk2 degraders and uses thereof
WO2022237890A1 (en) Azepine-type fused ring compound and pharmaceutical use thereof
WO2021027647A1 (en) Bridged heterocyclyl-substituted pyrimidine compound, preparation method therefor, and pharmaceutical use thereof
TW202128686A (en) A fused heteroaryl derivative, a preparation method and medical use thereof
WO2022002243A1 (en) Imidazopyrimidine derivative, preparation method therefor and medical use thereof
CN113912608B (en) Pyrimidopyrimidinone derivatives, preparation method thereof and application thereof in medicines
WO2023109540A1 (en) Heterocyclic compound with akt kinase inhibitory activity, preparation method therefor and medical use thereof
WO2022166810A1 (en) Fused azatricyclic derivative, preparation method therefor, and application thereof in medicine
TW202237101A (en) Ctla-4 small molecule inhibitor and its application

Legal Events

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

Ref document number: 22806852

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE