WO2018130174A1 - Pyrrolo[2,3-c]pyridine derivative, preparation method therefor, and use thereof in medicine - Google Patents

Pyrrolo[2,3-c]pyridine derivative, preparation method therefor, and use thereof in medicine Download PDF

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Publication number
WO2018130174A1
WO2018130174A1 PCT/CN2018/072204 CN2018072204W WO2018130174A1 WO 2018130174 A1 WO2018130174 A1 WO 2018130174A1 CN 2018072204 W CN2018072204 W CN 2018072204W WO 2018130174 A1 WO2018130174 A1 WO 2018130174A1
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group
cycloalkyl
alkyl
methyl
haloalkyl
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PCT/CN2018/072204
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French (fr)
Chinese (zh)
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苏熠东
古鹏
陈晓坡
刘磊
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN201880006265.9A priority Critical patent/CN110167939B/en
Publication of WO2018130174A1 publication Critical patent/WO2018130174A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of medicine, and relates to pyrrolo[2,3-c]pyridine derivatives, a preparation method thereof and a pharmaceutical composition containing the same, which are disclosed as a BRD4 inhibitor.
  • cardiovascular diseases such as cancer, inflammation, chronic liver disease, diabetes, dyslipidemia, and related diseases such as AIDS.
  • Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries.
  • the incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%.
  • Ageing, urbanization, industrialization and lifestyle changes In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.
  • Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The natural defense mechanism of the host or the naturally occurring highly targeted substance is obtained to obtain an anti-tumor effect.
  • Bromostructured protein 4 (BRD4) is a member of the bromodomain and extraterminal domain (BET) family, and BRD4 recruits different transcriptional regulators such as Mediator, positive transcription elongation factor b (positive transcription elongation factor b) , P-TEFb) to regulate the expression of the target gene.
  • BET bromodomain and extraterminal domain
  • P-TEFb transcriptional regulators
  • BRD4 shRNA or BET inhibitor can induce cell cycle arrest, apoptosis and cell differentiation of the above tumors, and exhibits strong antitumor activity.
  • BET protein is expected to be a new therapeutic target for these and even other tumors.
  • studies by the tool compound JQ1 and the like have found that BRD4 inhibitors may be widely used in various diseases such as viral infection, diabetes, metabolic diseases, liver diseases and Alzheimer's disease.
  • Patent applications for the disclosed selective BRD4 inhibitors include WO2013097052, WO2013158952, WO2014165127, WO2014206345, WO2016077378 and WO2015081189, and the like.
  • BRD4 inhibitors have good application prospects in the pharmaceutical industry as pharmaceuticals. Currently, there are no listed drugs. In order to achieve better therapeutic effects and meet market demand, we hope to develop a new generation of highly efficient and low toxicity selective BRD4. Inhibitor.
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:
  • M is CH or N
  • L is selected from O, NR v , C(O), -(CH 2 ) n -, S(O) m , -O(CR 6 R 7 ) n - or -NR v (CR 6 R 7 ) n -;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • Ra is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, an oxo group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group.
  • heteroaryl -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -NR 9 (CH 2 ) n R 10 And -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, The cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(
  • R 2 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group.
  • alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally selected Further selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR
  • R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, an alkene, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group.
  • R 2 and R 3 are bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m
  • R 10 Substituted by
  • R 2 and R 3 are each independently bonded to R 6 , R 7 or R v on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkene, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, an alkenyl group, a nitro group, a hydroxyl group, a hydroxymethyl group, a cyano group, Cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, olefin, cycloalkyl group, heterocyclic group
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R v is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 6 and R 7 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkane.
  • R 6 and R 7 may form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy.
  • R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cyclo Alkyl, heterocyclic, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 ,- Substituting one or more substituent
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 11 , -C(O)R.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy Substituted by one or more substituents of a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 11 and R 12 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;
  • n is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • x is an integer of 0 or 1.
  • the compound of the formula (I) is a compound of the formula (II):
  • L is selected from S, -(CH 2 ) n -, -O(CR 6 R 7 ) n - or -NR v (CR 6 R 7 ) n -;
  • R v is a hydrogen atom or a C 1-8 alkyl group
  • R 2 is selected from C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, cyano, C 3-8 cycloalkyl, 3-10 membered hetero a cyclic group, a 6-10 membered aryl group and a 5-10 membered heteroaryl group; wherein said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 alkoxy group, C 1-8 haloalkoxy group
  • the base, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally further selected from C 1-8 alkyl, C 1-8 haloalkane.
  • Base halogen, cyano, hydroxy, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, 6 -10-membered aryl, 5-10 membered heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 ,- Substituting one or more substituents of C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
  • R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, -S(O) m R 8 and -C(O)R 8 ;
  • R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ;
  • R 5 is a hydrogen atom or a C 1-8 alkyl group
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom or a C 1-8 alkyl group
  • Ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein said C 3-8 cycloalkyl, 3-10
  • the heterocyclic group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally further selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and C 1- 8 alkoxy group, one or more C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl substituted Substituted by
  • Ra is the same or different and is independently selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkoxy group.
  • Base halogen, hydroxyl, cyano and -OR 8 ;
  • Y is an integer of 0, 1, 2, 3 or 4;
  • z is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • R 8 to R 12 are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (III):
  • L is -O(CH 2 ) n - or -NR v (CR 6 R 7 ) n -;
  • R v is a hydrogen atom or a C 1-8 alkyl group
  • R 2 is C 1-8 alkyl or C 1-8 haloalkyl
  • R 3 is C 1-8 alkyl or C 1-8 haloalkyl
  • R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ; preferably a hydrogen atom;
  • R 5 is a hydrogen atom or a C 1-8 alkyl group; preferably a methyl group;
  • Ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein said C 3-8 cycloalkyl, 3-10
  • the heterocyclic group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally further selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and an oxo group.
  • Ra is the same or different and is independently selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkoxy group.
  • Base halogen, hydroxyl, cyano and -OR 8 ;
  • Y is an integer of 0, 1, 2, 3 or 4;
  • z is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2 or 3.
  • the compound of the formula (I) is a compound of the formula (IIA) and (IIB):
  • Ring A, R 2 to R 5 , R a , M, L, X and Y are as defined in the general formula (I).
  • the compound of the formula (II) is a compound of the formula (IV) and (IVA):
  • n is an integer of 0, 1, or 2;
  • Rings A, R 2 , R 3 , R 4 , R a , R v and y are as defined in formula (II).
  • the compounds of the formulae (IV) and (IVA) are compounds of the formulae (V), (VA) and (VB):
  • u, p, q are each the same or different, and each is independently selected from an integer of 0, 1, 2 or 3;
  • Rings A, R 2 , R 3 , R 4 , R a , R v and n are as defined in the general formulae (IV) and (IVA).
  • the compound of the formula (I) is a compound of the formula (VI):
  • L is selected from O and NR v ; preferably O or NH;
  • R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an oxo group, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, and a C 1-8 haloalkoxy group; preferably a hydrogen atom or a halogen , oxo, hydroxy, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen, halogen, hydroxy, C 1-3 alkyl or C 1-3 haloalkyl;
  • any two R a form a C 3-8 cycloalkyl or a 3-10 membered heterocyclic group, wherein the C 3-8 cycloalkyl or 3-10 membered heterocyclic group is optionally further selected Substituted from one or more substituents of C 1-8 alkyl, halo, hydroxy, amino, nitro, cyano, C 1-8 alkoxy or C 1-8 hydroxyalkyl;
  • R 2 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl or 6-10 membered aryl
  • the group is optionally further selected from a C 1-8 alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a C 1-8 alkoxy group, a C 3-8 cycloalkyl group or a C 1-8 hydroxyalkyl group.
  • substituents preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano substituted C 3 8 -cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl Most preferred are methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl, cyano substituted cyclopropyl and their progeny;
  • R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, a cyano substituted C 3-8 cycloalkyl, -S(O) m R 8 and -C(O)R 8 ; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 ring An alkyl or cyano substituted C 3-6 cycloalkyl; most preferably a methyl, ethyl, iso
  • R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a —C(O)OR 8 , a —C(O)NR 9 R 10 or a C 1-8 haloalkyl group;
  • C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are optionally further selected from C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1- Substituted by one or more substituents in the 8 -alkoxy group or the C 1-8 hydroxyalkyl group, preferably a C 1-6 alkyl group or a C 1-6 haloalkyl group; more preferably a C 1-3 alkyl group or a C 1- 3- haloalkyl;
  • z is an integer of 0 or 1;
  • p is an integer of 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound of the formula (VII):
  • L is selected from O and NR v ; preferably O or NH;
  • R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an amino group, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group or a C 1-8 hydroxyalkyl group; preferably a hydrogen atom, a halogen, C a 1-6 alkyl group or a C 1-6 hydroxyalkyl group; more preferably a hydrogen atom, a halogen, or a C 1-3 hydroxyalkyl group;
  • R 2 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aryl
  • the group is optionally further selected from the group consisting of C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1-8 alkoxy, C 3-8 cycloalkyl and C 1-8 hydroxyalkyl Substituted by one or more substituents; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano substituted C 3 8 -cyclo
  • R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, a cyano substituted C 3-8 cycloalkyl, -S(O) m R 8 and -C(O)R 8 ; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 ring An alkyl or cyano substituted C 3-6 cycloalkyl; most preferably a methyl, ethyl, iso
  • R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 1-8 haloalkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ;
  • C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are optionally further selected from C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1- Substituted by one or more substituents in the 8 -alkoxy group or the C 1-8 hydroxyalkyl group; preferably a C 1-6 alkyl group or a C 1-6 haloalkyl group; more preferably a C 1-3 alkyl group or a C 1- 3- haloalkyl;
  • z is an integer of 0 or 1;
  • p is an integer of 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (VI) is a compound of the formula (VIII):
  • R 2 to R 4 , L, R a and p are as defined in the formula (VI).
  • the compound of the formula (VII) is a compound of the formula (IX):
  • R 2 to R 4 , L, R a and p are as defined in the formula (VII).
  • the compound of the formula (I) to (IX) wherein the ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclic group and 6 -10 membered aryl; preferably phenyl, cyclopropyl, cyclohexyl or pyranyl.
  • the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof includes a compound selected from the group consisting of:
  • G and G' are halogen
  • Pg is an amino protecting group selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), allylcarbonyl (Alloc), fluorenylmethoxycarbonyl (Fmoc), methoxycarbonyl, ethoxycarbonyl, trimethyl Silicon ethoxycarbonyl (Teoc), phthaloyl (Pht), p-toluenesulfonyl (Ts), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), pivaloyl, Benzoyl, trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn), preferably p-toluenesulfonyl (Ts) ;
  • Ring A, R 2 to R 4 , y, z, R a and L are as defined in the formula (II).
  • a compound of formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof is prepared.
  • a method of salt in the form of a mixture the method comprising:
  • the compound of the formula (I-1) is subjected to deamination of a protecting group to give a compound of the formula (I);
  • R 1 to R 5 , R a , M, L, X and Y are as defined in the formula (I).
  • a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof is prepared.
  • a method of salt in the form of a mixture the method comprising:
  • Ring A, R 1 to R 4 , R a , L, z and y are as defined in the formula (II).
  • Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I) to formula (IX) or a tautomer thereof, a mesogen, and an external Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a process for the preparation of the above composition which comprises the compounds of the general formula or their tautomers, meso, racemate, enantiomers, diastereomers
  • the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the prophylaxis and/or treatment of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS as a BRD4 inhibitor.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or The use of a pharmaceutically acceptable salt, a pharmaceutical composition, for the preparation of a BRD4 inhibitor drug.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, pharmaceutical composition for use in the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
  • the present invention also relates to a method of treating a disease preventing and/or treating a BRD4-mediated pathological feature comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof. , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Diseases in which BRD4 is mediated by pathology include cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
  • Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • Another aspect of the invention relates to a method of treating inflammation comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • Another aspect of the invention relates to a method of treating chronic liver disease, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, or an external Racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • the cancer of the present invention includes, but is not limited to, breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, Lymphoma, myeloma, and non-small cell lung cancer.
  • the chronic liver disease according to the present invention is selected from the group consisting of primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy.
  • PBC primary sclerosis
  • CX cerebral xanthoma
  • PSC primary sclerosing cholecystitis
  • drug-induced cholestasis drug-induced cholestasis
  • intrahepatic cholestasis of pregnancy intrahepatic cholestasis of pregnancy.
  • parenteral absorption related cholestasis PNAC
  • bacterial overgrowth or sepsis cholestasis autoimmune hepatitis
  • chronic viral hepatitis alcoholic liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • liver graft-related graft-versus-host disease live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis, Wilson's disease , Gaucher's disease, hemochromatosis and ⁇ 1 -anti-membrane protease deficiency.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” means -(CH 2 ) 4 - and the like.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the polycyclic cycloalkyl group includes a spiro ring, a fused ring, and a bridged cycloalkyl group, preferably a cyclopropyl group, a cyclohexyl group, and a cyclopentyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, and non-limiting examples include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group 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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably morpholinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be 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, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl,
  • a pyrimidinyl group, a thiadiazole, a pyrazinyl group or the like is preferably an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, or a thiazolyl group; and a pyrimidyl group is more preferred.
  • the heteroaryl group 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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group 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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • benzyloxycarbonyl refers to Cbz.
  • tert-butoxycarbonyl refers to Boc
  • allylcarbonyl refers to Alloc.
  • fluorenylmethoxycarbonyl refers to Fmoc.
  • trimethylsilyloxycarbonyl refers to Teoc.
  • phthaloyl refers to Pht.
  • p-toluenesulfonyl refers to Ts.
  • trifluoroacetyl refers to Tfa.
  • o(p-nitrophenyl)sulfonyl refers to Ns.
  • Trt trityl
  • benzyl refers to Bn.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the preparation method of the salt used includes the following steps:
  • the compound of the formula (II-1) is subjected to a coupling reaction with a compound of the formula (IIA-9) under the conditions of a basic and a phosphine-palladium catalyst to obtain a compound of the formula (XA); the obtained product has the formula (XA) Further reacting with a compound of the formula (IIA-2) under basic conditions to obtain a compound of the formula (XI); the obtained compound of the formula (XI) is deprotected under basic conditions to give a compound of the formula (II);
  • the compound of the formula (X) is subjected to a coupling reaction with a compound of the formula (IIA-9) under the conditions of a basic and a phosphine-palladium catalyst to obtain a compound of the formula (XI); Deprotection under basic conditions to give a compound of formula (II);
  • the preparation method of the salt used includes the following steps:
  • the reagent providing basic conditions is preferably cesium carbonate
  • the compound of the formula (IIA-1) is reacted with the compound of the formula (IIA-2) to obtain a compound of the formula (IIA-3);
  • the compound of the formula (IIA-3) is subjected to a reduction reaction under basic conditions (a reagent providing a basic condition is preferably NaBH 4 ) to obtain a compound of the formula (IIA-4); and the obtained compound of the formula (IIA-4) Reaction with PBr 3 under low temperature conditions to obtain a compound of the formula (IIA-5);
  • the obtained compound of the formula (IIA-5) is reacted with R 2 SNa to obtain a compound of the formula (IIA-6);
  • the compound is oxidized under low temperature conditions (the reagent providing oxidizing conditions is preferably m-chloroperoxybenzoic acid) to give the formula (IIA-7); the compound of the formula (IIA-
  • the reagent providing basic conditions is preferably sodium hydroxide
  • the compound of the formula (IIA-a) is reacted with a halogenated alkane compound to give a compound of the formula (IIA-c);
  • the compound of the formula (IIA-c) obtained by the above two methods is oxidized under low temperature conditions (the reagent providing the oxidizing condition is preferably m-chloroperoxybenzoic acid) to obtain the formula (IIA-d); (IIA-d)
  • the compound is reacted with sodium azide under acidic conditions to give a compound of the formula (IIA-e); the obtained compound of the formula (IIA-e) is basic (the reagent for providing basic conditions is preferably Under the conditions of sodium carbonate and phosphine palladium catalyst, a coupling reaction with a compound of the formula (IIA-9) is carried out to obtain a compound of the formula (IIA-10); and the obtained product of the formula (IIA-10) is optionally further
  • the halogenated product of R 3 , boric acid or boric acid ester is reacted to obtain a compound of the formula (IIA-11); the obtained product of the formula (IIA-10) & the
  • the preparation method of the salt used includes the following steps:
  • the reagent providing basic conditions is preferably cesium carbonate
  • the compound of the formula (IIB-2) is reacted with the compound of the formula (IIA-2) to give a compound of the formula (IIB-3);
  • the compound is reduced (the reagent providing the reducing condition is preferably iron powder) to obtain the compound of the formula (IIB-4);
  • the obtained compound of the formula (IIB-4) is subjected to a low temperature condition with sodium nitrite or potassium iodide.
  • the reaction is carried out to obtain a compound of the formula (IIB-5); the obtained compound of the formula (IIB-5) is reacted with an R 2 -substituted sulfanone to give a compound of the formula (IIB-6); -6)
  • the compound is subjected to a coupling reaction with a compound of the formula (IIA-9) under basic conditions (a reagent providing a basic condition is preferably sodium carbonate) and a phosphine palladium catalyst to obtain a formula (IIB-7).
  • a reagent providing a basic condition is preferably sodium carbonate
  • a phosphine palladium catalyst to obtain a formula (IIB-7).
  • Compound; the obtained product of the formula (IIB-7) is deprotected under basic conditions to give a compound of the formula (IIB-1).
  • the reagents for the alkaline conditions involved in the first to the fifth embodiments include an organic base and an inorganic base
  • the organic base includes, but not limited to, triethylamine, N,N-diisopropylethylamine, and n-butyl a lithium base, lithium diisopropylamide, potassium acetate, sodium t-butoxide or potassium t-butoxide
  • the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate;
  • the phosphine palladium catalysts involved include, but are not limited to, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, ( ⁇ )-2,2'-bis-(diphenylphosphino)-1 , 1'-binaphthyl, tris(dibenzylideneacetone)dipalladium, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine, tetra ( Triphenylphosphine)palladium;
  • the B involved is boric acid or boric acid ester
  • the G and G' involved are halogen
  • the Pg involved is an amino protecting group selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), allylcarbonyl (Alloc), fluorenylmethoxycarbonyl (Fmoc), methoxycarbonyl, ethoxycarbonyl, Trimethylsilyloxycarbonyl (Teoc), phthaloyl (Pht), p-toluenesulfonyl (Ts), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), special Valeronyl, benzoyl, trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn), preferably p-toluenesulfonyl (Ts);
  • Ring A, R 2 to R 5 , R a , L, X, y and z are as defined in the formula (I).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • chemical shifts are given in units of 10 -6 (ppm).
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for separation and purification of thin layer chromatography is 0.4mm. ⁇ 0.5mm silica gel plate.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the temperature of the reaction was room temperature unless otherwise specified.
  • Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
  • Step 5 2-Bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfinyl ⁇ sulfinyl)methyl)benzene
  • Step 6 (3-Bromo-4-(2,4-difluorophenoxy)benzyl)(ethyl)(imino)- ⁇ 6 -thione
  • Step 7 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1-toluenesulfonyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 8 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
  • EtOAc (EtOAc (EtOAc) N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2, 3-c]pyridin-4-yl)benzyl)(ethyl)(carbonyl)- ⁇ 6-sulfaninyl)cyclopropanesulfonamide (32.0 mg, yield 42.2%).
  • Second step 4-(2-(2,4-difluorophenoxy)-5-((N-methylethylsulfimidoyl)methyl)phenyl)-6-methyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 5 4-(2-(2,4-Difluorophenoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
  • the third step preparation of (3-chloro-4-fluorophenyl)(imino)(isopropyl)-sulfanone
  • Step 5 4-(2-(cyclopropylmethoxy)-5-(propan-2-ylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
  • the compound of the fifth step of Example 5 is obtained to obtain the compound 4-(2-((4,4-) Difluorocyclohexyl)oxo)-5-(propan-2-ylsulfoimine phenyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone (yield 19%).
  • reaction liquid is evaporated to dryness, and toluene and dilute hydrochloric acid are added to the reaction system, and the toluene phase is washed with dilute hydrochloric acid, water and saturated brine, and the organic phase is dried and evaporated to dryness, and the residue is subjected to distillation under reduced pressure to collect steam temperature 60-70 ° C. 3-bromo-4-fluorophenyl)(ethyl)sulfane (15 g, pale yellow oil, yield 63%).
  • Step 5 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one
  • 2,4-Difluorophenol 800 mg, 0.6 mmol was dissolved in 1-methylpyrrolidone (1.5 ml), sodium hydride (60% in mine oil, 25 mg, 0.6 mmol) was added to the reaction system, and stirred at room temperature for 10 minutes. Then 4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3- c] Pyridine-7-one (50 mg, 0.1 mmol). The reaction system was sealed and placed under microwave conditions of 180 ° C for half an hour, and then cooled to room temperature.
  • Second step Preparation of 2-bromo-1-fluoro-4-(methylsulfinyl ⁇ sulfinyl>)benzene
  • Step 5 4-(2-(cyclopropylmethoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
  • the third step preparation of 3-bromo-4-phenoxyaniline
  • Step 6 4-(5-((Dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1-toluenesulfonyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 7 4-(5-((Dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1-toluenesulfonyl-1,6 -dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Example 19 Using 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene as the starting material, the third step of Example 19 was followed by column chromatography to give 3-bromo-4-(cyclopropylmethoxy). Aniline (2.7 g, yield 50%).
  • the fourth step ((3-bromo-4-(cyclopropylmethoxy)phenyl)imino)dimethyl- ⁇ 6-sulfanone
  • Step 5 4-(2-(Cyclopropylmethoxy)-5-((dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)phenyl)-6-methyl-1-toluene Acyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 6 4-(2-(cyclopropylmethoxy)-5-((dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)phenyl)-6-methyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • the fourth step ((3-bromo-4-(2,4-difluorophenoxy)phenyl)imino)dimethyl- ⁇ 6-sulfanone
  • Step 5 4-(2-(2,4-Difluorophenoxy)-5-((dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)phenyl)-6-methyl-1 -toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 6 4-(2-(2,4-Difluorophenoxy)-5-((dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)phenyl)-6-methyl-1 ,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • the fourth step ((3-bromo-4-(cyclohexanetrienoxy)phenyl)imino)dimethyl- ⁇ 6-sulfanone
  • Step 6 4-(2-(Cyclohexatrienoxy)-5-((dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)phenyl)-6-methyl-1,6 -dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • 4-(2-(cyclohexanetrienoxy)-5-((dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)phenyl)-6-methyl-1-toluenesulfonyl -1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one is the starting material of the reaction, and the eighth step of the reference example 1 is carried out to obtain 4-(2-(cyclohexanetriene) -5-((dimethyl(carbonyl)- ⁇ 6-sulfaninyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one (28%).
  • Example 23 The first step of Example 23 was carried out to obtain 4-(2- ((cyclopropylmethyl)amino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one (yield 33%).
  • the product of the fourth step of the reaction of the fourth step of Example 14 4-(2-fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one and trans 4-methylcyclohexylamine were used as starting materials, and the first step of Example 23 was carried out to obtain 6-methyl-4-(2-( (trans-4-methylcyclohexyl)amino)-5-(S-methylsulfimidoyl)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (yield 50%).
  • the product of the fourth step of the reaction of the fourth step of Example 14 4-(2-fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one is used as a starting material, and trans-heptylamine is substituted for trans 4-methylcyclohexylamine.
  • the first step of Example 23 is carried out to obtain 4-(2-(cyclo). Heptylamino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ( Yield 50%).
  • the product of the fourth step of the reaction of the fourth step of Example 5 is 4-(2-fluoro-5-(propan-2-ylsulfanilidinoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one was used as a starting material, and trans-4-methylcyclohexylamine was replaced by cyclopropylmethylamine.
  • Example 23 The first step of Example 23 was carried out to obtain 4-( 2-((cyclopropylmethyl)amino)-5-(propan-2-ylsulfoimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one (yield 46%).
  • the first step the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
  • the second step the preparation of 3-bromo-4-fluorobenzenethiol
  • 1,2-bis(3-bromo-4-fluorophenyl)disulfane 42 g, 101.9 mmol
  • methanol 300 mL
  • tetrahydrofuran 1 L
  • sodium hydroxide 10.3 g, 257.5
  • Sodium borohydride (11.1 g, 293.6 mmol) was added in five portions at room temperature. After 1 hour of reaction, the mixture was concentrated.
  • EtOAc EtOAc m The aqueous phase was added dropwise to hydrochloric acid (800 mL, 3 mol/L) and the system temperature was maintained at 0-5 °C.
  • the reaction mixture was extracted with EtOAc (EtOAc)EtOAc.
  • the third step the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
  • the fourth step the preparation of (3-bromo-4-fluorophenyl) (cyclopropyl) sulane.
  • 1,2-bis(3-bromo-4-fluorophenyl)disulfane 8 g, 19.4 mmol
  • tetrahydrofuran 40 mL
  • Cyclopropylmagnesium bromide 60 mL, 1 M, 60 mmol
  • the fifth step the preparation of 2-bromo-4-(cyclopropylsulfinyl ⁇ sulfinyl)-1-fluorobenzene.
  • Step 6 Preparation of (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)- ⁇ 6 -sulfanone
  • Step 7 4-(5-(Cyclopropioni)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
  • Step 8 4-(5-(Cyclopropioni)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro Preparation of -7H-pyrrolo[2,3-c]pyridine-7-one
  • the product of the seventh step of Example 33 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one as a starting material, using cycloheptylamine in place of trans 4-methylcyclohexylamine.
  • the first step of Example 23 is carried out to obtain 4-(2-(cycloheptylamino). 5-(- propyl sulfanimidyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 45%).
  • the first step the preparation of 2-bromo-4-((1-chlorocyclopropyl)sulfinyl ⁇ sulfinyl>)-1-fluorobenzene.
  • the second step (3-bromo-4-fluorophenyl) (1-chlorocyclopropyl) (imino)- ⁇ 6 -sulfanone preparation.
  • the third step the preparation of (3-bromo-4-(2,4-difluorophenoxy)phenyl)(1-chlorocyclopropyl)(imino)- ⁇ 6 -sulfanone.
  • Step 5 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6- Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
  • Second step 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-1 -Preparation of tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
  • Example 41 The product of the second step of Example 41 (3-bromo-4-fluorophenyl)(1-chlorocyclopropyl)(imino)- ⁇ 6 -sulfanone was used as the starting material, and the first step of Example 42 was obtained ( 3-Bromo-4-(cycloheptylamino)phenyl)(1-chlorocyclopropyl)(imino)- ⁇ 6 -sulfanone (yield 76%).
  • Second step 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(cycloheptylamino)phenyl)-6-methyl-1-toluenesulfonyl-1,6 -Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
  • the third step 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(cycloheptylamino)phenyl)-6-methyl-1,6-dihydro-7H- Preparation of pyrrolo[2,3-c]pyridine-7-one
  • the product of the seventh step of Example 33 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one was used as a starting material, and trans-4-methylcyclohexylamine was replaced by cyclohexylamine.
  • the first step of Example 23 was carried out to obtain 4-(2-(cyclohexylamino). -5-(cyclopropaneimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (11 mg, white solid, Yield 22%).
  • Methyltriphenylphosphonium bromide (22.9 g, 64 mmol) was dissolved in tetrahydrofuran (200 mL). Potassium tert-butoxide (7.2 g, 64 mmol) was added portionwise at 0 ° C under nitrogen, and the mixture was stirred at 0 ° C for 1 hour. . 1,4-Dioxaspiro[4.5]decane-8-one (5 g, 32 mmol) was dissolved in tetrahydrofuran (50 mL), and the mixture was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc.
  • the crude product was purified by column chromatography ( petroleum ether / petroleum ether / ethyl acetate: 10/1) to give 8-methylene-1,4-dioxaspiro[4.5] decane (3.4 g, colorless liquid , yield: 69%).
  • Step 2 Preparation of 7,10-dioxaspiro[2.2.4 6 .2 3 ]dodecane
  • Step 6 Preparation of (3-bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(cyclopropyl)(imino)- ⁇ 6 -sulfanone
  • the crude product was purified by column chromatography ( petroleum ether / ethyl acetate: 20/1 - petroleum ether / ethyl acetate: 3/1) (3-bromo-4-(spiro[2.5] octane-6-yl. Amino)phenyl)(cyclopropyl)(imino)- ⁇ 6 -sulfanone (100 mg, colorless solid, yield: 65%).
  • Step 7 4-(5-(cyclopropaneimido)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6-methyl-1-toluenesulfonyl-1, Preparation of 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 8 4-(5-(Cyclopropioni)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6-methyl-1,6-dihydro-7H -Preparation of pyrrolo[2,3-c]pyridine-7-one
  • Example 42 Using (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)- ⁇ 6 -sulfanone as the starting material, the first step of Example 42 was obtained (3-bromo-4-((2, 4-Difluorophenyl)amino)phenyl)(cyclopropyl)(imino)- ⁇ 6 -sulfanone (yield 50%).
  • Second step 4-(5-(cyclopropaneimido)-2-((2,4-difluorophenyl)amino)phenyl)-6-methyl-1-toluenesulfonyl-1, Preparation of 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • N-Benzyl-4-(trifluoromethyl)cyclohexane-1-amine (5.0 g, 19.5 mmol) was dissolved in tetrahydrofuran (50 mL) and ethanol (50 mL). Hydrogen displacement and protection, stirring at 25 ° C for 16 hours, diatomaceous earth filtration, spin dry, column purification to obtain trans-4-(trifluoromethyl)cyclohexane-1-amine (2g).
  • Step 5 4-(5-(Cyclopropioni)-2-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)-6-methyl-1,6-di Preparation of hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one
  • 6-Methyl-4-(5-(S-methylsulfimidoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (40 mg, 0.07 mmol) was dissolved in tert-butanol (5 mL) and water (1 mL). The reaction was stirred at 60 ° C for 18 hours. . The reaction mixture was poured with water (10 mL), EtOAc (EtOAc)EtOAc.
  • Example 23 4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction.
  • the first step of Example 23 is followed by substituting R-phenylethylamine for trans-4-methylcyclohexylamine to give 6-methyl-4-(5-(S -methylsulfamimidoyl-2-((R)-1-phenylethyl)amino)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (yield 25%).
  • Example 23 4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction.
  • the first step of Example 23 is followed by substituting cyclohexylamine for trans-4-methylcyclohexylamine to give 4-(2-(cyclohexylamino)-5-( S-methylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 33%).
  • Example 10 4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material, and 2,4-dimethylphenol was replaced with 2-aminopyridine.
  • the fifth step of Example 10 was carried out to obtain 4-(5-(ethylsulfanimidoyl)-2-( Pyridin-2-ylamino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (white solid, yield 38%).
  • the third step 4-bromo-2-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 5 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl- 1,6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one.
  • the sixth step (3-bromo-4-((trans--4-methylcyclohexyl)amino)phenyl) (cyclopropyl) (imino)- ⁇ 6 -sulfanone preparation.
  • Example 33 Product (3-Bromo-4-fluorophenyl)(cyclopropyl)(imino)- ⁇ 6 -sulfanone (500 mg, 1.75 mmol) and trans-4-methylcyclohexane
  • the alkylamine 5.0 mL was placed in a 25 mL three-necked flask, heated to 90 ° C in an oil bath under nitrogen atmosphere, reacted for 5 hours, cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with saturated aqueous ammonium chloride (25 mL ⁇ 2) ), dried over anhydrous sodium sulfate and filtered.
  • Step 7 4-(5-(Cyclopropioni)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1-toluene Preparation of acyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
  • Step 8 4-(5-(Cyclopropioni)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6- Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
  • Second step 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfanilino)phenyl)-1- Preparation of tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one

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Abstract

Disclosed are a pyrrolo[2,3-c]pyridine derivative, a preparation method therefor, and use thereof in medicine. Specifically, disclosed are a pyrrolo[2,3-c]pyridine derivative as represented by general formula (1), a preparation method therefor, a pharmaceutical composition comprising the derivative, as well as use thereof as a BRD4 inhibitor in the treatment of related diseases such as cancers, inflammations, chronic liver diseases, diabetes, cardiovascular diseases and AIDS, each substituent in general formula (I) being same as defined in the description.

Description

吡咯并[2,3-c]吡啶类衍生物、其制备方法及其在医药上的应用Pyrrolo[2,3-c]pyridine derivatives, preparation method thereof and application thereof in medicine 技术领域Technical field
本发明属于医药领域，涉及吡咯并[2,3-c]吡啶类衍生物、其制备方法及含有该衍生物的药物组合物在医药研究上的应用，本发明公开了其作为BRD4抑制剂在治疗癌症、炎症、、慢性肝病、糖尿病、血脂异常等心血管疾病和AIDS等相关疾病的用途。The present invention belongs to the field of medicine, and relates to pyrrolo[2,3-c]pyridine derivatives, a preparation method thereof and a pharmaceutical composition containing the same, which are disclosed as a BRD4 inhibitor. The use of cardiovascular diseases such as cancer, inflammation, chronic liver disease, diabetes, dyslipidemia, and related diseases such as AIDS.
背景技术Background technique
肿瘤是严重危害人类生命的重大疾病之一，一半以上发生在发展中国家。我国恶性肿瘤发病率总体呈上升趋势，发病率以年均3％～5％的速度递增，预计到2020年，我国将有400万人发生癌症，300万人死于癌症，其主要原因是：老龄化、城镇化、工业化及生活习惯改变。在中国医院用药市场，抗肿瘤药物的销售规模近几年来一直稳步增长，2012年达到了664.2亿元，同比增长了13.07％，预计到2017年，抗肿瘤药物的市场规模将达到1055.7亿元，同比增长7.57％。Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries. The incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die of cancer. The main reasons are: Ageing, urbanization, industrialization and lifestyle changes. In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.
由于恶性肿瘤的无限制生长与浸润、转移，现今临床采用的三大常规治疗方法(手术、放疗和化疗)无法完全切除或彻底杀灭肿瘤细胞，因此常出现肿瘤转移或复发。肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法，因其安全、有效、不良反应低等特点，成为继手术、放疗、化疗之后肿瘤治疗的第四种模式，其通过调动宿主的天然防御机制或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。Due to the unrestricted growth and infiltration and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The natural defense mechanism of the host or the naturally occurring highly targeted substance is obtained to obtain an anti-tumor effect.
溴结构蛋白4(BRD4)是溴结构域和超末端结构(bromodomain and extraterminal domain，BET)家族成员，BRD4通过招募不同的转录调节因子，如Mediator、正性转录延伸因子b(positive transcription elongation factor b，P-TEFb)来调节靶基因的表达。作为一种在哺乳动物中广泛表达的染色质“适配器，reader”，可以在整个有丝分裂过程中识别乙酰化的蛋白结合到染色体上，募集不同的染色质修饰蛋白，广泛调控基因的表达，从而在调控细胞周期进程、转录、炎症等方面发挥重要作用。最近的研究表明BRD4的表达水平失调或功能紊乱与睾丸核蛋白中线癌(midline carcinoma with rearrangement of the nuclear protein intestis gene，NMC)、黑色素瘤、急性髓系白血病、结肠癌、乳腺癌等的发生有关。BRD4shRNA或BET抑制剂可以诱导上述肿瘤发生细胞周期阻滞、凋亡及细胞分化，显示出强大的抗肿瘤活性。这些发现表明，BET蛋白有望成为上述肿瘤甚至其他肿瘤新的治疗靶点。另外，通过工具化合物JQ1等研究发现，BRD4的抑制剂在病毒感染，糖尿病，代谢性疾病，肝脏疾病和老年痴呆症等多种疾病均可能有较广泛的运用。公开的选择性BRD4抑制剂的专利申请包括WO2013097052、WO2013158952、 WO2014165127、WO2014206345、WO2016077378和WO2015081189等。Bromostructured protein 4 (BRD4) is a member of the bromodomain and extraterminal domain (BET) family, and BRD4 recruits different transcriptional regulators such as Mediator, positive transcription elongation factor b (positive transcription elongation factor b) , P-TEFb) to regulate the expression of the target gene. As a chromatin "reader" widely expressed in mammals, it can recognize acetylated proteins to bind to chromosomes throughout mitosis, recruit different chromatin-modifying proteins, and widely regulate gene expression. It plays an important role in regulating cell cycle progression, transcription, and inflammation. Recent studies have shown that dysregulation or dysfunction of BRD4 is associated with the occurrence of midline carcinoma with rearrangement of the nuclear protein intestis gene (NMC), melanoma, acute myeloid leukemia, colon cancer, breast cancer, etc. . BRD4 shRNA or BET inhibitor can induce cell cycle arrest, apoptosis and cell differentiation of the above tumors, and exhibits strong antitumor activity. These findings suggest that BET protein is expected to be a new therapeutic target for these and even other tumors. In addition, studies by the tool compound JQ1 and the like have found that BRD4 inhibitors may be widely used in various diseases such as viral infection, diabetes, metabolic diseases, liver diseases and Alzheimer's disease. Patent applications for the disclosed selective BRD4 inhibitors include WO2013097052, WO2013158952, WO2014165127, WO2014206345, WO2016077378 and WO2015081189, and the like.
BRD4抑制剂作为药物在医药行业具有良好的应用前景，目前还没有上市的药物，为了达到更好的治疗效果的目的和满足市场需求，我们希望能开发出新一代的高效低毒的选择性BRD4抑制剂。BRD4 inhibitors have good application prospects in the pharmaceutical industry as pharmaceuticals. Currently, there are no listed drugs. In order to achieve better therapeutic effects and meet market demand, we hope to develop a new generation of highly efficient and low toxicity selective BRD4. Inhibitor.
发明内容Summary of the invention
本发明的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中通式(I)所示的化合物结构如下：The object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:
Figure PCTCN2018072204-appb-000001
Figure PCTCN2018072204-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
M为CH或N；M is CH or N;
L选自O、NR v、C(O)、-(CH 2) n-、S(O) m、-O(CR 6R 7) n-或-NR v(CR 6R 7) n-； L is selected from O, NR v , C(O), -(CH 2 ) n -, S(O) m , -O(CR 6 R 7 ) n - or -NR v (CR 6 R 7 ) n -;
X、Y各自独立的选自N、NR v、-(CR 6R 7) n-或-(CR 6R 7) nN(R v) x-，且X、Y至少有一个与S原子形成S＝N； X and Y are each independently selected from N, NR v , -(CR 6 R 7 ) n - or -(CR 6 R 7 ) n N(R v ) x -, and at least one of X and Y forms with S atom S=N;
R 1选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Base, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are described. Optionally further selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C Substituting one or more substituents of (O) R 12 and -NR 11 S(O) m R 12 ;
Ra选自氢原子、烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氧代基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-NR 9(CH 2) nR 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烷氧基、羟烷基、环烷基、杂环基、 芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； Ra is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, an oxo group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group. , heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -NR 9 (CH 2 ) n R 10 And -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, The cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , Substituting one or more substituents of -C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
R 2选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯烃、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 2 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally selected Further selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C(O Substituting one or more substituents of R 12 and -NR 11 S(O) m R 12 ;
R 3选自氢原子、氘原子、烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烯烃、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, an alkene, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group. Aryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, olefin, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C(O)R 12 And one or more substituents of -NR 11 S(O) m R 12 are substituted;
或者，R 2和R 3连接形成一个杂环基或杂芳基；其中所述的杂环基和杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代； Alternatively, R 2 and R 3 are bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substitutions in R 10 Substituted by
再或者，R 2、R 3各自独立的与X基团上的R 6、R 7或R v连接形成一个杂环基或杂芳基；其中所述的杂环基和杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代； Further, R 2 and R 3 are each independently bonded to R 6 , R 7 or R v on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
R 4选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、烯基、硝基、羟基、羟基甲基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烯烃、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、 -C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkene, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, an alkenyl group, a nitro group, a hydroxyl group, a hydroxymethyl group, a cyano group, Cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, olefin, cycloalkyl group, heterocyclic group The aryl and heteroaryl groups are optionally further selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 Substituting one or more substituents of R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
R 5选自氢原子、烷基、卤代烷基、羟烷基、氘代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基； R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
R v选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基； R v is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
R 6和R 7相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10； R 6 and R 7 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkane. Base, heterocyclic group, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C (O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
或者，R 6和R 7可以形成环烷基或杂环基，其中所述环烷基或杂环基任选进一步被选自烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代； Alternatively, R 6 and R 7 may form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy. , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substitutions in R 10 Substituted by
R 8选自氢原子、烷基、卤代烷基、烯基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、烯基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cyclo Alkyl, heterocyclic, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 ,- Substituting one or more substituents of C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
R 9和R 10相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 11 , -C(O)R. 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S( O) m R 12 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy Substituted by one or more substituents of a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
R 11和R 12相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 11 and R 12 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;
m为0、1或2的整数；m is an integer of 0, 1, or 2;
n为0、1、2、3、4或5的整数；且n is an integer of 0, 1, 2, 3, 4 or 5;
x为0或1的整数。x is an integer of 0 or 1.
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(II)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (II):
Figure PCTCN2018072204-appb-000002
Figure PCTCN2018072204-appb-000002
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
L选自S、-(CH 2) n-、-O(CR 6R 7) n-或-NR v(CR 6R 7) n-； L is selected from S, -(CH 2 ) n -, -O(CR 6 R 7 ) n - or -NR v (CR 6 R 7 ) n -;
R v为氢原子或C 1-8烷基； R v is a hydrogen atom or a C 1-8 alkyl group;
R 2选自C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、氰基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基；其中所述的C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基任选进一步被选自C 1-8烷基、C 1-8卤代烷基、卤素、氰基、羟基、C 1-8烷氧基、C 1-8卤代烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 2 is selected from C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, cyano, C 3-8 cycloalkyl, 3-10 membered hetero a cyclic group, a 6-10 membered aryl group and a 5-10 membered heteroaryl group; wherein said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 alkoxy group, C 1-8 haloalkoxy group The base, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally further selected from C 1-8 alkyl, C 1-8 haloalkane. Base, halogen, cyano, hydroxy, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, 6 -10-membered aryl, 5-10 membered heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 ,- Substituting one or more substituents of C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
R 3选自氢原子、氘原子、C 1-8烷基、C 1-8卤代烷基、氰基、-S(O) mR 8和-C(O)R 8； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, -S(O) m R 8 and -C(O)R 8 ;
R 4选自氢原子、C 1-8烷基、-C(O)OR 8和-C(O)NR 9R 10； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ;
R 5为氢原子或C 1-8烷基； R 5 is a hydrogen atom or a C 1-8 alkyl group;
R 6和R 7相同或不同，且各自独立地选自氢原子或C 1-8烷基； R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom or a C 1-8 alkyl group;
环A选自C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基，其中所述的C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基任选进一步被选自氢原子、C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基中的一个或多个取代基所取代； Ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein said C 3-8 cycloalkyl, 3-10 The heterocyclic group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally further selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and C 1- 8 alkoxy group, one or more C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl substituted Substituted by
Ra相同或不同，其各自独立的选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8羟烷基、C 1-8卤代烷氧基、卤素、羟基、氰基和-OR 8； Ra is the same or different and is independently selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkoxy group. Base, halogen, hydroxyl, cyano and -OR 8 ;
y为0、1、2、3或4的整数；Y is an integer of 0, 1, 2, 3 or 4;
z为0、1、2或3的整数；z is an integer of 0, 1, 2 or 3;
n为0、1、2、3、4或5的整数；且n is an integer of 0, 1, 2, 3, 4 or 5;
R 8～R 12如通式(I)中所定义。 R 8 to R 12 are as defined in the formula (I).
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(III)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (III):
Figure PCTCN2018072204-appb-000003
Figure PCTCN2018072204-appb-000003
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
L为-O(CH 2) n-或-NR v(CR 6R 7) n-； L is -O(CH 2 ) n - or -NR v (CR 6 R 7 ) n -;
R v为氢原子或C 1-8烷基； R v is a hydrogen atom or a C 1-8 alkyl group;
R 2为C 1-8烷基或C 1-8卤代烷基； R 2 is C 1-8 alkyl or C 1-8 haloalkyl;
R 3为C 1-8烷基或C 1-8卤代烷基； R 3 is C 1-8 alkyl or C 1-8 haloalkyl;
R 4选自氢原子、C 1-8烷基、-C(O)OR 8和-C(O)NR 9R 10；优选氢原子； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ; preferably a hydrogen atom;
R 5为氢原子或C 1-8烷基；优选甲基； R 5 is a hydrogen atom or a C 1-8 alkyl group; preferably a methyl group;
环A选自C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基，其中所述的C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基任选进一步被选自氢原子、C 1-8烷基、卤素、氨基、硝基、羟基、氰基、氧代基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基中的一个或多个取代基所取代； Ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein said C 3-8 cycloalkyl, 3-10 The heterocyclic group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally further selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and an oxo group. One of a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 3-8 cycloalkyl group, a 3-10 membered heterocyclic group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group. Substituted by a plurality of substituents;
Ra相同或不同，其各自独立的选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8羟烷基、C 1-8卤代烷氧基、卤素、羟基、氰基和-OR 8； Ra is the same or different and is independently selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkoxy group. Base, halogen, hydroxyl, cyano and -OR 8 ;
y为0、1、2、3或4的整数；Y is an integer of 0, 1, 2, 3 or 4;
z为0、1、2或3的整数；且z is an integer of 0, 1, 2 or 3;
n为0、1、2或3的整数。n is an integer of 0, 1, 2 or 3.
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(IIA)和(IIB)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (IIA) and (IIB):
Figure PCTCN2018072204-appb-000004
Figure PCTCN2018072204-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：环A、R 2～R 5、R a、M、L、X和Y如通式(I)中所定义。在本发明的一个优选实施例方案中，所述的通式(II)所示的化合物，其为通式(IV)和(IVA)所示的化合物： Wherein: Ring A, R 2 to R 5 , R a , M, L, X and Y are as defined in the general formula (I). In a preferred embodiment of the invention, the compound of the formula (II) is a compound of the formula (IV) and (IVA):
Figure PCTCN2018072204-appb-000005
Figure PCTCN2018072204-appb-000005
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
n为0、1或2的整数；且n is an integer of 0, 1, or 2;
环A、R 2、R 3、R 4、R a、R v和y如通式(II)中所定义。 Rings A, R 2 , R 3 , R 4 , R a , R v and y are as defined in formula (II).
在本发明的一个优选实施例方案中，所述的通式(IV)和(IVA)所示的化合物，其为通式(V)、(VA)和(VB)所示的化合物：In a preferred embodiment of the invention, the compounds of the formulae (IV) and (IVA) are compounds of the formulae (V), (VA) and (VB):
Figure PCTCN2018072204-appb-000006
Figure PCTCN2018072204-appb-000006
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
u、p、q各自相同或不同，各自独立的选自0、1、2或3的整数；u, p, q are each the same or different, and each is independently selected from an integer of 0, 1, 2 or 3;
环A、R 2、R 3、R 4、R a、R v和n如通式(IV)和(IVA)中所定义。 Rings A, R 2 , R 3 , R 4 , R a , R v and n are as defined in the general formulae (IV) and (IVA).
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(VI)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (VI):
Figure PCTCN2018072204-appb-000007
Figure PCTCN2018072204-appb-000007
其中：among them:
L选自O和NR v；优选O或NH； L is selected from O and NR v ; preferably O or NH;
R a选自氢原子、卤素、羟基、氧代基、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基和C 1-8卤代烷氧基；优选氢原子、卤素、氧代基、羟基、C 1-6烷基和C 1-6卤代烷基；更优选氢原子、卤素、羟基、C 1-3烷基或C 1-3卤代烷基； R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an oxo group, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, and a C 1-8 haloalkoxy group; preferably a hydrogen atom or a halogen , oxo, hydroxy, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen, halogen, hydroxy, C 1-3 alkyl or C 1-3 haloalkyl;
或者任意两个R a形成一个C 3-8环烷基或3-10元的杂环基，其中所述的C 3-8环烷基或3-10元的杂环基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基或C 1-8羟烷基中的一个或多个取代基所取代； Or any two R a form a C 3-8 cycloalkyl or a 3-10 membered heterocyclic group, wherein the C 3-8 cycloalkyl or 3-10 membered heterocyclic group is optionally further selected Substituted from one or more substituents of C 1-8 alkyl, halo, hydroxy, amino, nitro, cyano, C 1-8 alkoxy or C 1-8 hydroxyalkyl;
R 2选自C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基或6-10元芳基，其中所述的C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基和6-10元芳基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基、C 3-8环烷基或C 1-8羟烷基中的一个或多个取代基所取代；优选C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、卤代C 3-8环烷基或氰基取代的C 3-8环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基、氰基取代的环丙基及其氘代物； R 2 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl or 6-10 membered aryl Wherein C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl and 6-10 membered aromatic The group is optionally further selected from a C 1-8 alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a C 1-8 alkoxy group, a C 3-8 cycloalkyl group or a C 1-8 hydroxyalkyl group. Substituted by one or more substituents; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano substituted C 3 8 -cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl Most preferred are methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl, cyano substituted cyclopropyl and their progeny;
R 3选自氢原子、氘原子、C 1-8烷基、C 1-8卤代烷基、氰基、C 3-8环烷基、卤代C 3-8环烷基、氰基取代的C 3-8环烷基、-S(O) mR 8和-C(O)R 8；优选C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基或氰基取代的环丙基； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, a cyano substituted C 3-8 cycloalkyl, -S(O) m R 8 and -C(O)R 8 ; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 ring An alkyl or cyano substituted C 3-6 cycloalkyl; most preferably a methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl or cyano substituted cyclopropyl;
R 4选自氢原子、C 1-8烷基、C 3-8环烷基、-C(O)OR 8、-C(O)NR 9R 10或C 1-8卤代烷基；其中所述的C 1-8烷基、C 3-8环烷基和C 1-8卤代烷基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基或C 1-8羟烷基中的一个或多个取代基所取代，优选C 1-6烷基或C 1-6卤代烷基；更优选C 1-3烷基或C 1-3卤代烷基； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a —C(O)OR 8 , a —C(O)NR 9 R 10 or a C 1-8 haloalkyl group; C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are optionally further selected from C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1- Substituted by one or more substituents in the 8 -alkoxy group or the C 1-8 hydroxyalkyl group, preferably a C 1-6 alkyl group or a C 1-6 haloalkyl group; more preferably a C 1-3 alkyl group or a C 1- 3- haloalkyl;
z为0或1的整数；且z is an integer of 0 or 1;
p为0、1、2、3、4或5的整数。p is an integer of 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(VII)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (VII):
Figure PCTCN2018072204-appb-000008
Figure PCTCN2018072204-appb-000008
其中：among them:
L选自O和NR v；优选O或NH； L is selected from O and NR v ; preferably O or NH;
R a选自氢原子、卤素、羟基、氨基、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基或C 1-8羟烷基；优选氢原子、卤素、C 1-6烷基或C 1-6羟烷基；更优选氢原子、卤素、或C 1-3羟烷基； R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an amino group, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group or a C 1-8 hydroxyalkyl group; preferably a hydrogen atom, a halogen, C a 1-6 alkyl group or a C 1-6 hydroxyalkyl group; more preferably a hydrogen atom, a halogen, or a C 1-3 hydroxyalkyl group;
R 2选自C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基和6-10元芳基，其中所述的C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基和6-10元芳基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基、C 3-8环烷基和C 1-8羟烷基中的一个或多个取代基所取代；优选C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、卤代C 3-8环烷基或氰基取代的C 3-8环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基、氰基取代的环丙基及其氘代物； R 2 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aryl Wherein C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl and 6-10 membered aromatic The group is optionally further selected from the group consisting of C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1-8 alkoxy, C 3-8 cycloalkyl and C 1-8 hydroxyalkyl Substituted by one or more substituents; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano substituted C 3 8 -cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl Most preferred are methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl, cyano substituted cyclopropyl and their progeny;
R 3选自氢原子、氘原子、C 1-8烷基、C 1-8卤代烷基、氰基、C 3-8环烷基、卤代C 3-8环烷基、氰基取代的C 3-8环烷基、-S(O) mR 8和-C(O)R 8；优选C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基或氰基取代的环丙基； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, a cyano substituted C 3-8 cycloalkyl, -S(O) m R 8 and -C(O)R 8 ; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 ring An alkyl or cyano substituted C 3-6 cycloalkyl; most preferably a methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl or cyano substituted cyclopropyl;
R 4选自氢原子、C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、-C(O)OR 8和-C(O)NR 9R 10；其中所述的C 1-8烷基、C 3-8环烷基和C 1-8卤代烷基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基或C 1-8羟烷基中的一个或多个取代基所取代；优选C 1-6烷基或C 1-6卤代烷基；更优选C 1-3烷基或C 1-3卤代烷基； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 1-8 haloalkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ; C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are optionally further selected from C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1- Substituted by one or more substituents in the 8 -alkoxy group or the C 1-8 hydroxyalkyl group; preferably a C 1-6 alkyl group or a C 1-6 haloalkyl group; more preferably a C 1-3 alkyl group or a C 1- 3- haloalkyl;
z为0或1的整数；且z is an integer of 0 or 1;
p为0、1、2、3、4或5的整数。p is an integer of 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例方案中，所述的通式(VI)所示的化合物，其为通式(VIII)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (VI) is a compound of the formula (VIII):
Figure PCTCN2018072204-appb-000009
Figure PCTCN2018072204-appb-000009
其中：among them:
R 2～R 4、L、R a和p如通式(VI)中所定义。 R 2 to R 4 , L, R a and p are as defined in the formula (VI).
在本发明的一个优选实施例方案中，所述的通式(VII)所示的化合物，其为通式(IX)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (VII) is a compound of the formula (IX):
Figure PCTCN2018072204-appb-000010
Figure PCTCN2018072204-appb-000010
其中：among them:
R 2～R 4、L、R a和p如通式(VII)中所定义。 R 2 to R 4 , L, R a and p are as defined in the formula (VII).
在本发明的一个优选实施例方案中，所述的通式(I)～(IX)所示的化合物，其中L选自O、S、NRv、-O(CH 2) n-和-NH(CH 2) n-；优选O、-OCH 2-、NH或-NHCH 2-。 In a preferred embodiment of the invention, the compound of the formula (I) to (IX), wherein L is selected from the group consisting of O, S, NRv, -O(CH 2 ) n - and -NH ( CH 2 ) n -; preferably O, -OCH 2 -, NH or -NHCH 2 -.
在本发明的一个优选实施例方案中，所述的通式(I)～(IX)所示的化合物，其中环A选自C 3-8环烷基、3-10元杂环基和6-10元芳基；优选苯基、环丙基、环已基或吡喃基。 In a preferred embodiment of the invention, the compound of the formula (I) to (IX) wherein the ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclic group and 6 -10 membered aryl; preferably phenyl, cyclopropyl, cyclohexyl or pyranyl.
在本发明的一个优选实施例方案中，所述的通式(I)～(IX)所示的化合物，其中R 2选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基和6-10元芳基，其中所述的C 1-8烷基、C 1-8卤代烷基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基和6-10元芳基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、氰基、C 3-8环烷基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基和3-10元杂环基中的一个或多个取代基所取代；优选氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-8羟烷基、氰基取代的C 1-6烷基、C 3-6环烷基、卤代C 3-6环烷基、氰基取代的C 3-6环烷基、C 3-6羟基基取代的环烷基、4-6元杂环基或苯基。 In a preferred embodiment of the invention, the compound of the formula (I) to (IX), wherein R 2 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 hydroxyalkyl group, a C 3-8 cycloalkyl group, a 3-10 membered heterocyclic group, and a 6-10 membered aryl group, wherein said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl and 6-10 membered aryl are optionally further selected from C 1-8 alkyl, halogen, hydroxy, amino, cyano Substituting one or more substituents of a C 3-8 cycloalkyl group, a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 3-8 cycloalkyl group, and a 3-10 membered heterocyclic group Preferred as a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-8 hydroxyalkyl group, a cyano substituted C 1-6 alkyl group, a C 3-6 cycloalkyl group, a halogenated C 3 -6 cycloalkyl, cyano substituted C 3-6 cycloalkyl, C 3-6 hydroxy substituted cycloalkyl, 4-6 membered heterocyclyl or phenyl.
在本发明的一个优选实施例方案中，所述的通式(I)～(IX)所示的化合物，其中R 3选自氢原子、C 1-8烷基、C 1-8卤代烷基、氰基、-S(O) mR 8和-C(O)R 8；R 8选自C 1-8烷基、C 2-8烯基和C 3-8环烷基；R 3优选氢原子、C 1-6烷基、氰基、-S(O) mR 8或-C(O)R 8，R 8优选C 1-6烷基、C 2-4烯基或C 3-6环烷基。 In a preferred embodiment of the invention, the compound of the formula (I) to (IX), wherein R 3 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, Cyano, -S(O) m R 8 and -C(O)R 8 ; R 8 is selected from C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; R 3 is preferably hydrogen Atom, C 1-6 alkyl, cyano, -S(O) m R 8 or -C(O)R 8 , R 8 is preferably C 1-6 alkyl, C 2-4 alkenyl or C 3-6 Cycloalkyl.
在本发明的一个优选实施例方案中，所述的通式(I)～(IX)所示的化合物，其中R 4选自氢原子、C 1-8烷基、-C(O)OR 8和-C(O)NR 9R 10；优选氢原子、C 1-6烷基、-C(O)OR 8或-C(O)NR 9R 10，更优选氢原子或甲基。 In a preferred embodiment of the invention, the compound of the formula (I) to (IX), wherein R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, and a -C(O)OR 8 And -C(O)NR 9 R 10 ; preferably a hydrogen atom, a C 1-6 alkyl group, -C(O)OR 8 or -C(O)NR 9 R 10 , more preferably a hydrogen atom or a methyl group.
在本发明的一个优选实施例方案中，所示的式(I)化合物、其立体异构体或其药学上可接受的盐，包括选自如下化合物：In a preferred embodiment of the invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, includes a compound selected from the group consisting of:
Figure PCTCN2018072204-appb-000011
Figure PCTCN2018072204-appb-000011
Figure PCTCN2018072204-appb-000012
Figure PCTCN2018072204-appb-000012
Figure PCTCN2018072204-appb-000013
Figure PCTCN2018072204-appb-000013
Figure PCTCN2018072204-appb-000014
Figure PCTCN2018072204-appb-000014
Figure PCTCN2018072204-appb-000015
Figure PCTCN2018072204-appb-000015
Figure PCTCN2018072204-appb-000016
Figure PCTCN2018072204-appb-000016
Figure PCTCN2018072204-appb-000017
Figure PCTCN2018072204-appb-000017
Figure PCTCN2018072204-appb-000018
Figure PCTCN2018072204-appb-000018
Figure PCTCN2018072204-appb-000019
Figure PCTCN2018072204-appb-000019
Figure PCTCN2018072204-appb-000020
Figure PCTCN2018072204-appb-000020
Figure PCTCN2018072204-appb-000021
Figure PCTCN2018072204-appb-000021
在本发明的一个优选实施例方案中，所示的通式(I)化合物、其立体异构体或其药学上可接受的盐的中间体，其为通式(X)、通式(X-A)和通式(XI)所示的化合物：In a preferred embodiment of the invention, the intermediate of the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is represented by the formula (X), formula (XA) And a compound of the formula (XI):
Figure PCTCN2018072204-appb-000022
Figure PCTCN2018072204-appb-000022
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof,
其中：among them:
G和G’为卤素；G and G' are halogen;
Pg为氨基保护基，选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)、烯丙基羰基(Alloc)、笏甲氧羰基(Fmoc)、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基(Teoc)、邻苯二甲酰基(Pht)、对甲苯磺酰基(Ts)、三氟乙酰基(Tfa)、邻(对)硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲 氧基苄基(PMB)或苄基(Bn)，优选对甲苯磺酰基(Ts)；Pg is an amino protecting group selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), allylcarbonyl (Alloc), fluorenylmethoxycarbonyl (Fmoc), methoxycarbonyl, ethoxycarbonyl, trimethyl Silicon ethoxycarbonyl (Teoc), phthaloyl (Pht), p-toluenesulfonyl (Ts), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), pivaloyl, Benzoyl, trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn), preferably p-toluenesulfonyl (Ts) ;
环A、R 2～R 4、y、z、R a和L如通式(II)中所定义。 Ring A, R 2 to R 4 , y, z, R a and L are as defined in the formula (II).
在本发明的一个优选实施例方案中，一种制备通式(I)化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式的盐的方法，该方法包括：In a preferred embodiment of the invention, a compound of formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof is prepared. Or a method of salt in the form of a mixture, the method comprising:
Figure PCTCN2018072204-appb-000023
Figure PCTCN2018072204-appb-000023
通式(I-1)化合物经脱去氨基保护基，得到通式(I)化合物；The compound of the formula (I-1) is subjected to deamination of a protecting group to give a compound of the formula (I);
其中：R 1～R 5、R a、M、L、X和Y如通式(I)中所定义。 Wherein: R 1 to R 5 , R a , M, L, X and Y are as defined in the formula (I).
在本发明的一个优选实施例方案中，一种制备通式(II)化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式的盐的方法，该方法包括：In a preferred embodiment of the invention, a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof is prepared. Or a method of salt in the form of a mixture, the method comprising:
Figure PCTCN2018072204-appb-000024
Figure PCTCN2018072204-appb-000024
通式(XI)化合物脱去氨基保护基，得到通式(II)化合物；Deprotecting a compound of formula (XI) to give a compound of formula (II);
其中：among them:
环A、R 1～R 4、R a、L、z和y如通式(II)中所定义。本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的通式(I)～通式(IX)任一所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明还涉及一种制备上述组合物的方法，其包括将各通式所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。 Ring A, R 1 to R 4 , R a , L, z and y are as defined in the formula (II). Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I) to formula (IX) or a tautomer thereof, a mesogen, and an external Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present invention also relates to a process for the preparation of the above composition which comprises the compounds of the general formula or their tautomers, meso, racemate, enantiomers, diastereomers The isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is mixed with a pharmaceutically acceptable carrier, diluent or excipient.
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于预防和/或治疗预防作为BRD4抑制剂在治疗癌症、炎症、慢性肝病、糖尿病、心血管疾病或AIDS的药物中的用途。The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the prophylaxis and/or treatment of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS as a BRD4 inhibitor.
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，药物组合 物在制备BRD4抑制剂药物中的应用。The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or The use of a pharmaceutically acceptable salt, a pharmaceutical composition, for the preparation of a BRD4 inhibitor drug.
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，药物组合物在制备治疗癌症、炎症、慢性肝病、糖尿病、心血管疾病或AIDS的药物中的应用。The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, pharmaceutical composition for use in the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
本发明还涉及一种治疗预防和/或治疗预防BRD4介导的病理学特征的疾病的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。其中BRD4介导的病理学特征的疾病包括癌症、炎症、慢性肝病、糖尿病、心血管疾病或AIDS的疾病，The present invention also relates to a method of treating a disease preventing and/or treating a BRD4-mediated pathological feature comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof. , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Diseases in which BRD4 is mediated by pathology include cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
本发明另一方面涉及一种治疗癌症的方法，该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。该方法显示出突出的疗效和较少的副作用。Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.
本发明另一方面涉及一种治疗炎症的方法，该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。该方法显示出突出的疗效和较少的副作用。Another aspect of the invention relates to a method of treating inflammation comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.
本发明另一方面涉及一种治疗慢性肝病的方法，该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。该方法显示出突出的疗效和较少的副作用。Another aspect of the invention relates to a method of treating chronic liver disease, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, or an external Racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.
本发明所述的癌症包括但不限于乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。The cancer of the present invention includes, but is not limited to, breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, Lymphoma, myeloma, and non-small cell lung cancer.
本发明所述的慢性肝病选自原发性硬化(PBC)、脑脏性黄瘤症(CTX)、原发性硬化性胆囊炎(PSC)、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积(PNAC)、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病和α 1-抗膜蛋白酶缺乏症。 The chronic liver disease according to the present invention is selected from the group consisting of primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. , parenteral absorption related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis ( NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis, Wilson's disease , Gaucher's disease, hemochromatosis and α 1 -anti-membrane protease deficiency.
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。Terms used in the specification and claims have the following meanings unless stated to the contrary.
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8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3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。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 from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms. The alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。 The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene" refers to -CH 2 -, "ethylene" refers to -(CH 2 ) 2 -, "propylene" Refers to -(CH 2 ) 3 -, "butylene" means -(CH 2 ) 4 - and the like.
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。The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
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8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，优选环丙基、环己基和环戊基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene The polycyclic cycloalkyl group includes a spiro ring, a fused ring, and a bridged cycloalkyl group, preferably a cyclopropyl group, a cyclohexyl group, and a cyclopentyl group.
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电子系统。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 that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2018072204-appb-000025
Figure PCTCN2018072204-appb-000025
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：Also included are spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, and non-limiting examples include:
Figure PCTCN2018072204-appb-000026
Figure PCTCN2018072204-appb-000026
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, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group 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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
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；更优选包含3至8个环原子；最优选包含3至6个环原子。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，优选吗啉基和吡喃基。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 containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. The base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably morpholinyl and pyranyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
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, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
Figure PCTCN2018072204-appb-000027
等。
Figure PCTCN2018072204-appb-000027
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。The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
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 ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
Figure PCTCN2018072204-appb-000028
Figure PCTCN2018072204-appb-000028
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。The aryl group may be 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, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
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，更优选为5元或6元，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、吡唑基或嘧啶基、噻唑基；更有选嘧啶基。The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, A pyrimidinyl group, a thiadiazole, a pyrazinyl group or the like is preferably an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, or a thiazolyl group; and a pyrimidyl group is more preferred.
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。The heteroaryl group 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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
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 groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group 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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
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 by one or more halogens, 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 by one or more halogens, wherein alkoxy is as defined above.
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
术语“羟基”指-OH基团。The term "hydroxy" refers to an -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" means fluoro, chloro, bromo or iodo.
术语“氨基”指-NH 2。 The term "amino" means -NH 2.
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO 2 .
术语“氧代基”指＝O。The term "oxo" refers to =0.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“苄氧羰基”指Cbz。The term "benzyloxycarbonyl" refers to Cbz.
术语“叔丁氧羰基”指Boc。The term "tert-butoxycarbonyl" refers to Boc.
术语“烯丙基羰基”指Alloc。The term "allylcarbonyl" refers to Alloc.
术语“笏甲氧羰基”指Fmoc。The term "fluorenylmethoxycarbonyl" refers to Fmoc.
术语“三甲基硅乙氧羰基”指Teoc。The term "trimethylsilyloxycarbonyl" refers to Teoc.
术语“邻苯二甲酰基”指Pht。The term "phthaloyl" refers to Pht.
术语“对甲苯磺酰基”指Ts。The term "p-toluenesulfonyl" refers to Ts.
术语“三氟乙酰基”指Tfa。The term "trifluoroacetyl" refers to Tfa.
术语“邻(对)硝基苯磺酰基”指Ns。The term "o(p-nitrophenyl)sulfonyl" refers to Ns.
术语“三苯甲基”指Trt。The term "trityl" refers to Trt.
术语“2,4-二甲氧基苄基”指Dmb。The term "2,4-dimethoxybenzyl" refers to Dmb.
术语“甲氧基苄基”指PMB。The term "methoxybenzyl" refers to PMB.
术语“苄基”指Bn。The term "benzyl" refers to Bn.
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基如上所定义。The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
术语“酰卤”指含有-C(O)-卤素的基团的化合物。The term "acyl halide" refers to a compound containing a -C(O)-halogen group.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" and the like are expressed in the same language. Meaning, that is, X can be any one or several of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.
“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 environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .
“取代的”指基团中的一个或多个氢原子，优选为最多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" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) 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 comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts 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 a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
本发明化合物的合成方法Method for synthesizing the compound of the present invention
为了完成本发明的目的，本发明采用如下技术方案：In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:
本发明通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：a compound of the formula (II) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a drug thereof The preparation method of the salt used includes the following steps:
Figure PCTCN2018072204-appb-000029
Figure PCTCN2018072204-appb-000029
方案一Option One
通式(II-1)化合物在碱性和膦钯类催化剂的条件下，与通式(IIA-9)化合物发生偶联反应，得到通式(X-A)化合物；得到的产物通式(X-A)进一步与通式(IIA-2)化合物在碱性条件下反应得到通式(XI)化合物；得到的通式(XI)化合物在碱性条件下脱保护，得到通式(II)化合物；The compound of the formula (II-1) is subjected to a coupling reaction with a compound of the formula (IIA-9) under the conditions of a basic and a phosphine-palladium catalyst to obtain a compound of the formula (XA); the obtained product has the formula (XA) Further reacting with a compound of the formula (IIA-2) under basic conditions to obtain a compound of the formula (XI); the obtained compound of the formula (XI) is deprotected under basic conditions to give a compound of the formula (II);
Figure PCTCN2018072204-appb-000030
Figure PCTCN2018072204-appb-000030
方案二Option II
通式(X)化合物在碱性和膦钯类催化剂的条件下，与通式(IIA-9)化合物发生偶联反应，得到通式(XI)化合物；得到的产物通式(XI)化合物在碱性条件下脱保护，得到通式(II)化合物；The compound of the formula (X) is subjected to a coupling reaction with a compound of the formula (IIA-9) under the conditions of a basic and a phosphine-palladium catalyst to obtain a compound of the formula (XI); Deprotection under basic conditions to give a compound of formula (II);
本发明通式(IIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：a compound of the formula (IIA) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable drug thereof The preparation method of the salt used includes the following steps:
Figure PCTCN2018072204-appb-000031
Figure PCTCN2018072204-appb-000031
方案三third solution
在高温碱性条件下(提供碱性条件的试剂优选为碳酸铯)，通式(IIA-1)化合物与通式(IIA-2)化合物发生反应，得到通式(IIA-3)化合物；通式(IIA-3)化合物在碱性条件下(提供碱性条件的试剂优选为NaBH 4)，发生还原反应，得到通式(IIA-4)化合物；将得到的通式(IIA-4)化合物在低温条件下与PBr 3反应，得到通式(IIA-5)化合物；得到的通式(IIA-5)化合物与R 2SNa发生反应，得到通式(IIA-6)化合物；得到的通式(IIA-6)化合物在低温条件下，被氧化(提供氧化条件的试剂优选为间氯过氧苯甲酸)得到通式(IIA-7)；通式(IIA-7)化合物在氨基甲酸铵和二乙酸碘苯的作用下，得到通式(IIA-8)化合物；得到的通式(IIA-8)化合物在碱性(提供碱性条件的试剂优选为碳酸钠)和膦钯类催化剂的条件下，与通式(IIA-9)化合物发生偶联反应，得到通式(IIA-10)化合物；得到的产物通式(IIA-10)任选进一步与R 3的卤代物、硼酸或者硼酸酯反应得到通式(IIA-11)化合物；得到的产物通式(IIA-10)&通式(IIA-11)化合物在碱性条件下脱保护，得到通式(IIA)化合物。 Under high temperature alkaline conditions (the reagent providing basic conditions is preferably cesium carbonate), the compound of the formula (IIA-1) is reacted with the compound of the formula (IIA-2) to obtain a compound of the formula (IIA-3); The compound of the formula (IIA-3) is subjected to a reduction reaction under basic conditions (a reagent providing a basic condition is preferably NaBH 4 ) to obtain a compound of the formula (IIA-4); and the obtained compound of the formula (IIA-4) Reaction with PBr 3 under low temperature conditions to obtain a compound of the formula (IIA-5); the obtained compound of the formula (IIA-5) is reacted with R 2 SNa to obtain a compound of the formula (IIA-6); (IIA-6) The compound is oxidized under low temperature conditions (the reagent providing oxidizing conditions is preferably m-chloroperoxybenzoic acid) to give the formula (IIA-7); the compound of the formula (IIA-7) is in the ammonium carbamate and Under the action of iodobenzene diacetate, a compound of the formula (IIA-8) is obtained; the obtained compound of the formula (IIA-8) is in a basic condition (a reagent providing a basic condition is preferably sodium carbonate) and a phosphine palladium catalyst. Coupling reaction with a compound of the formula (IIA-9) to obtain a compound of the formula (IIA-10); the obtained product of the formula (IIA-10) is optionally further halogenated with R 3 Reaction with a boronic acid or a boronic ester to give a compound of the formula (IIA-11); the obtained product of the formula (IIA-10) & the compound of the formula (IIA-11) is deprotected under basic conditions to give the formula (IIA) ) compound.
Figure PCTCN2018072204-appb-000032
Figure PCTCN2018072204-appb-000032
方案四Option four
在碱性条件下(提供碱性条件的试剂优选为氢氧化钠)，通式(IIA-a)化合物与卤代烷化合物发生反应，得到通式(IIA-c)化合物；Under basic conditions (the reagent providing basic conditions is preferably sodium hydroxide), the compound of the formula (IIA-a) is reacted with a halogenated alkane compound to give a compound of the formula (IIA-c);
或者通式(IIA-b)化合物在加热条件下与含R 2取代的硫烷发生还原反应，得到通式(IIA-c)化合物； Or the compound of the formula (IIA-b) is subjected to a reduction reaction with a R 2 -substituted sulfane under heating to obtain a compound of the formula (IIA-c);
将上述两种方法得到的通式(IIA-c)化合物在低温条件下，被氧化(提供氧化条件的试剂优选为间氯过氧苯甲酸)得到通式(IIA-d)；得到的通式(IIA-d)化合物在酸性条件下，与叠氮化钠反应，得到通式(IIA-e)化合物；得到的通式(IIA-e)化合物在碱性(提供碱性条件的试剂优选为碳酸钠)和膦钯类催化剂的条件下，与通式(IIA-9)化合物发生偶联反应，得到通式(IIA-10)化合物；得到的产物通式(IIA-10)任选进一步与R 3的卤代物、硼酸或者硼酸酯反应得到通式(IIA-11)化合物；得到的产物通式(IIA-10)&通式(IIA-11)化合物在碱性条件下脱保护，得到通式(IIA)化合物。 The compound of the formula (IIA-c) obtained by the above two methods is oxidized under low temperature conditions (the reagent providing the oxidizing condition is preferably m-chloroperoxybenzoic acid) to obtain the formula (IIA-d); (IIA-d) The compound is reacted with sodium azide under acidic conditions to give a compound of the formula (IIA-e); the obtained compound of the formula (IIA-e) is basic (the reagent for providing basic conditions is preferably Under the conditions of sodium carbonate and phosphine palladium catalyst, a coupling reaction with a compound of the formula (IIA-9) is carried out to obtain a compound of the formula (IIA-10); and the obtained product of the formula (IIA-10) is optionally further The halogenated product of R 3 , boric acid or boric acid ester is reacted to obtain a compound of the formula (IIA-11); the obtained product of the formula (IIA-10) & the compound of the formula (IIA-11) is deprotected under basic conditions to obtain a compound of the formula (IIA).
本发明通式(IIB)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：a compound of the formula (IIB) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a drug thereof The preparation method of the salt used includes the following steps:
Figure PCTCN2018072204-appb-000033
Figure PCTCN2018072204-appb-000033
方案五Option five
在碱性条件下(提供碱性条件的试剂优选为碳酸铯)，通式(IIB-2)化合物与通式(IIA-2)化合物发生反应，得到通式(IIB-3)化合物；通式(IIB-3)化合物被还原(提供还原条件的试剂优选为铁粉)得到通式(IIB-4)化合物；将得到的通式(IIB-4)化合物在低温条件下与亚硝酸钠、碘化钾反应，得到通式(IIB-5)化合物；得到的通式(IIB-5)化合物与含R 2取代的硫烷酮发生反应，得到通式(IIB-6)化合物；得到的通式(IIB-6)化合物在碱性(提供碱性条件的试剂优选为碳酸钠)和膦钯类催化剂的条件下，与通式(IIA-9)化合物发生偶联反应，得到通式(IIB-7)化合物；得到的产物通式(IIB-7)化合物在碱性条件下脱保护，得到通式(IIB-1)化合物。 Under basic conditions (the reagent providing basic conditions is preferably cesium carbonate), the compound of the formula (IIB-2) is reacted with the compound of the formula (IIA-2) to give a compound of the formula (IIB-3); (IIB-3) The compound is reduced (the reagent providing the reducing condition is preferably iron powder) to obtain the compound of the formula (IIB-4); the obtained compound of the formula (IIB-4) is subjected to a low temperature condition with sodium nitrite or potassium iodide. The reaction is carried out to obtain a compound of the formula (IIB-5); the obtained compound of the formula (IIB-5) is reacted with an R 2 -substituted sulfanone to give a compound of the formula (IIB-6); -6) The compound is subjected to a coupling reaction with a compound of the formula (IIA-9) under basic conditions (a reagent providing a basic condition is preferably sodium carbonate) and a phosphine palladium catalyst to obtain a formula (IIB-7). Compound; the obtained product of the formula (IIB-7) is deprotected under basic conditions to give a compound of the formula (IIB-1).
其中：方案一至方案五中涉及到的碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾或碳酸铯；Wherein: the reagents for the alkaline conditions involved in the first to the fifth embodiments include an organic base and an inorganic base, and the organic base includes, but not limited to, triethylamine, N,N-diisopropylethylamine, and n-butyl a lithium base, lithium diisopropylamide, potassium acetate, sodium t-butoxide or potassium t-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate;
涉及到的膦钯类催化剂包括但不限于2-二环己基膦-2,4,6-三异丙基联苯、(±)-2,2’-双-(二苯基膦)-1,1’-联萘、三(二亚苄基丙酮)二钯、醋酸钯、[1,1'-双(二苯基磷)二茂铁]二氯化钯、三苯基膦、四(三苯基膦)钯；The phosphine palladium catalysts involved include, but are not limited to, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, (±)-2,2'-bis-(diphenylphosphino)-1 , 1'-binaphthyl, tris(dibenzylideneacetone)dipalladium, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine, tetra ( Triphenylphosphine)palladium;
涉及到的B为硼酸或者硼酸酯；The B involved is boric acid or boric acid ester;
涉及到的G、G’为卤素；The G and G' involved are halogen;
涉及到的Pg为氨基保护基，选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)、烯丙基羰基(Alloc)、笏甲氧羰基(Fmoc)、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基 (Teoc)、邻苯二甲酰基(Pht)、对甲苯磺酰基(Ts)、三氟乙酰基(Tfa)、邻(对)硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)或苄基(Bn)，优选对甲苯磺酰基(Ts)；The Pg involved is an amino protecting group selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), allylcarbonyl (Alloc), fluorenylmethoxycarbonyl (Fmoc), methoxycarbonyl, ethoxycarbonyl, Trimethylsilyloxycarbonyl (Teoc), phthaloyl (Pht), p-toluenesulfonyl (Ts), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), special Valeronyl, benzoyl, trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn), preferably p-toluenesulfonyl (Ts);
环A、R 2～R 5、R a、L、X、y和z如通式(I)中所定义。 Ring A, R 2 to R 5 , R a , L, X, y and z are as defined in the formula (I).
具体实施方式detailed description
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The invention is further described in the following examples, which are not intended to limit the scope of the invention.
实施例Example
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-400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)，化学位移是以10 -6(ppm)作为单位给出。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four. Methylsilane (TMS), chemical shifts are given in units of 10 -6 (ppm).
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo,型号：Finnigan LCQ advantage MAX)。The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 The average value of 50 measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产物采用的规格是0.4mm～0.5mm硅胶板。The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for separation and purification of thin layer chromatography is 0.4mm. ~0.5mm silica gel plate.
柱层析一般使用烟台黄海200～300目硅胶为载体。Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a 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ABCR GmbH&Co.KG，Acros Organnics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。In the examples, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
实施例中如无特殊说明，反应中的溶液是指水溶液。In the examples, the solution in the reaction means an aqueous solution unless otherwise specified.
实施例中如无特殊说明，反应的温度为室温。In the examples, the temperature of the reaction was room temperature unless otherwise specified.
室温为最适宜的反应温度，温度范围是20℃～30℃。Room temperature is the most suitable reaction temperature, and the temperature range is from 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：正己烷和乙酸乙酯体系，C：石油醚和乙酸 乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on 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的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：正己烷、乙酸乙酯和二氯甲烷体系，D：石油醚和乙酸乙酯体系，E：乙酸乙酯，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酸性或碱性试剂等进行调节。The system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
实施例1Example 1
4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000034
Figure PCTCN2018072204-appb-000034
第一步：3-溴-4-(2,4-二氟苯氧基)苯甲醛First step: 3-bromo-4-(2,4-difluorophenoxy)benzaldehyde
Figure PCTCN2018072204-appb-000035
Figure PCTCN2018072204-appb-000035
100mL三口瓶中依次加入2,4-二氟苯酚(1.47g,11.33mmol),3-溴-4-氟苯甲醛(2.30g,11.33mmol)，碳酸铯(4.05g,12.46mmol)，二甲基亚砜(10mL)。油浴加热升温至100℃，反应1小时后冷却至室温，反应液用乙酸乙酯(30mL)稀释后用饱和食盐水洗涤(10mLx3)，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚/乙酸乙酯：5/1)纯化得到3-溴-4-(2,4-二氟苯氧基)苯甲醛(2.60g,淡黄色油状物，产率：47％)。In a 100 mL three-necked flask, 2,4-difluorophenol (1.47 g, 11.33 mmol), 3-bromo-4-fluorobenzaldehyde (2.30 g, 11.33 mmol), cesium carbonate (4.05 g, 12.46 mmol), dimethyl Sulfone (10 mL). The mixture was heated to 100 ° C in an oil bath, and the mixture was stirred for 1 hour, then cooled to room temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with brine (10 mL×3). The crude product was purified by column chromatography (EtOAc/EtOAc:EtOAc:EtOAc) Rate: 47%).
第二步：3-溴-4-(2,4-二氟苯氧基)苯甲醇Second step: 3-bromo-4-(2,4-difluorophenoxy)benzyl alcohol
Figure PCTCN2018072204-appb-000036
Figure PCTCN2018072204-appb-000036
3-溴-4-(2,4-二氟苯氧基)苯甲醛(2.60g，8.31mmol)溶于甲醇(10mL)与四氢呋喃(10mL)混合溶剂中，室温下搅拌2-3分钟后，加入硼氢化钠(0.095g，2.49mmol)，加毕室温条件下搅拌2小时，反应结束。将反应混合液旋干，残留物用乙酸乙酯(30mL)溶解，饱和食盐水(10mL×3)洗涤，有机相经无水硫酸钠干燥，过滤，旋干，得到粗产物3-溴-4-(2,4-二氟苯氧基)苯甲醇(2.6g，白色固体)，直接用于下一步。3-bromo-4-(2,4-difluorophenoxy)benzaldehyde (2.60 g, 8.31 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). Sodium borohydride (0.095 g, 2.49 mmol) was added, and the mixture was stirred at room temperature for 2 hours, and the reaction was completed. The reaction mixture was dried with EtOAc (3 mL). -(2,4-Difluorophenoxy)benzyl alcohol (2.6 g, white solid) was used directly in the next step.
第三步：2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯The third step: 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene
Figure PCTCN2018072204-appb-000037
Figure PCTCN2018072204-appb-000037
3-溴-4-(2,4-二氟苯氧基)苯甲醇(2.60g,8.25mmol)溶于二氯甲烷(20mL)中，冰浴冷却至0～5℃，滴加三溴化磷(2.46g,9.08mmol)，加毕自然升温至室温，搅拌3小时反应结束。将反应液缓慢倒入冰水中，滴加饱和碳酸钠溶液中和，分液，水相用二氯甲烷萃取(15mLx3)，合并有机相，有机相用饱和食盐水(15mL×2)洗涤，无水硫酸钠干燥，过滤，旋干，得到2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(2.60g,白色固体)，直接用于下一步反应。3-Bromo-4-(2,4-difluorophenoxy)benzyl alcohol (2.60 g, 8.25 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 to 5 ° C, and tribromide was added dropwise. Phosphorus (2.46 g, 9.08 mmol) was heated to room temperature after the addition, and the reaction was completed after stirring for 3 hours. The reaction solution was slowly poured into ice water, neutralized with a saturated sodium carbonate solution, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (15 mL×3). The organic phase was combined and the organic phase was washed with saturated brine (15 mL×2). Drying with sodium sulfate, filtered, and dried to give 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.60 g, white solid) reaction.
第四步：3-溴-4-(2,4-二氟苯氧基)苄基乙基硫烷Fourth step: 3-bromo-4-(2,4-difluorophenoxy)benzylethylsulfane
Figure PCTCN2018072204-appb-000038
Figure PCTCN2018072204-appb-000038
100mL三口瓶中依次加入2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(2.40g,6.35mmol)，乙硫醇钠(0.53g,6.35mmol)，N,N-二甲基甲酰胺(40mL)，室温搅拌4小时反应结束。反应液用乙酸乙酯(50mL)稀释,经饱和食盐水洗涤(10mLx5)，有机相用无水硫酸钠干燥，过滤，旋干，柱层析分离(石油醚/乙酸乙酯：5/1)，得到：3-溴-4-(2,4-二氟苯氧基)苄基乙基硫烷(1.30g，油状物，收率57％)。2-Bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.40 g, 6.35 mmol) and sodium ethanethiolate (0.53 g, 6.35 mmol) were sequentially added to a 100 mL three-necked flask. N,N-dimethylformamide (40 mL) was stirred at room temperature for 4 hours and the reaction was completed. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Yield: 3-bromo-4-(2,4-difluorophenoxy)benzylethylsulfane (1.30 g, oil, yield 57%).
第五步：2-溴-1-(2,4-二氟苯氧基)-4-((乙基亚硫酰基<亚磺酰>)甲基)苯Step 5: 2-Bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfinyl <sulfinyl)methyl)benzene
Figure PCTCN2018072204-appb-000039
Figure PCTCN2018072204-appb-000039
(3-溴-4-(2,4-二氟苯氧基)苯甲基)(乙基)硫烷(1.3g，3.6mmol)溶于二氯甲烷(20mL)中，干冰/乙酸乙酯浴冷却到-20℃,分批加入间氯过氧苯甲酸(0.69g,4.0mmol)，加毕撤去冰浴自然升至室温后，搅拌30分钟。LC-MS监测反应完全，向反应溶液中加入饱和碳酸钠溶液(50mL)，然后用乙酸乙酯萃取(50mLx2)，混合有机相，用饱和氯化钠溶液(80mL x2)洗涤,无水硫酸钠干燥，减压浓缩得到2-溴-1-(2,4-二氟苯氧基)-4-((乙基亚硫酰基<亚磺酰>)甲基)苯(1.3g,96％)。(3-Bromo-4-(2,4-difluorophenoxy)benzyl)(ethyl)sulfane (1.3 g, 3.6 mmol) dissolved in dichloromethane (20 mL) The bath was cooled to -20 ° C, and m-chloroperoxybenzoic acid (0.69 g, 4.0 mmol) was added portionwise, and the mixture was stirred and cooled to room temperature, and then stirred for 30 minutes. The reaction was completed by LC-MS. EtOAc (50 mL), EtOAc (EtOAc (EtOAc) Dry and concentrate under reduced pressure to give 2-bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfinyl <sulfinyl)methyl)benzene (1.3 g, 96%) .
MS m/z(ESI):375.0/377.0(50/50)[M+H]+.MS m/z (ESI): 375.0/377.0 (50/50) [M+H]+.
第六步：(3-溴-4-(2,4-二氟苯氧基)苯甲基)(乙基)(亚氨基)-λ 6-硫烷酮 Step 6: (3-Bromo-4-(2,4-difluorophenoxy)benzyl)(ethyl)(imino)-λ 6 -thione
Figure PCTCN2018072204-appb-000040
Figure PCTCN2018072204-appb-000040
2-溴-1-(2,4-二氟苯氧基)-4-((乙基亚硫酰基<亚磺酰>)甲基)苯(300mg,0.78mmol)溶于甲醇(20mL)，依次加入氨基甲酸铵(252mg,3.24mmol)和二乙酸碘苯(753mg,2.34mmol)，室温条件下搅拌1小时。停止反应，加入水(50mL)淬灭反应,用乙酸乙酯(50mLx2)萃取，合并有机相。有机相经饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到(3-溴-4-(2,4-二氟苯氧基)苯甲基)(乙基)(亚氨基)-λ
Figure PCTCN2018072204-appb-000041
6-硫烷酮(300mg,95％)。 2-Bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfinyl <sulfinyl)methyl)benzene (300 mg, 0.78 mmol) was dissolved in methanol (20 mL). Ammonium carbamate (252 mg, 3.24 mmol) and iodobenzene diacetate (753 mg, 2.34 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched and quenched with water (50 mL)EtOAcEtOAc The organic phase was washed with EtOAc (EtOAc m. (imino)-λ
Figure PCTCN2018072204-appb-000041
6-sulfanone (300 mg, 95%).
MS m/z(ESI):390.0/392.0(50/50)M+H] +. MS m/z (ESI): 390.0 / 392.0 (50 / 50) M+H] + .
第七步：4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 7: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1-toluenesulfonyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000042
Figure PCTCN2018072204-appb-000042
在20mL微波管中将(3-溴-4-(2,4-二氟苯氧基)苯甲基)(乙基)(亚氨基)-λ6-硫烷酮(100mg,0.26mmol)，中间体Im(6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮)(109mg,0.26mmol)，四(三苯基膦)钯(44mg,0.04mmol)，碳酸钠(68mg,0.64mmol)溶于DME/H2O(4mL/4mL)，氮气吹扫1-2分钟后，微波120℃下反应30分钟。停止反应，加入水(30mL)淬灭反应，用乙酸乙酯(30mL×2)萃取，合并有机相用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩后制备薄层析分离得到4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(38mg,33％)。(3-Bromo-4-(2,4-difluorophenoxy)benzyl)(ethyl)(imino)-λ6-sulfanone (100 mg, 0.26 mmol) in a 20 mL microwave tube Im (6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one) (109 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (44 mg, 0.04 mmol), sodium carbonate (68 mg, 0.64 mmol) Dissolved in DME/H2O (4 mL / 4 mL), nitrogen purged for 1-2 minutes, and microwaved at 120 ° C for 30 minutes. The reaction was quenched, EtOAc (EtOAc) (EtOAc (EtOAc) 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfimidomethyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (38 mg, 33%).
MS m/z(ESI):612.1[M+H] +. MS m/z (ESI): 6121. [M+H] + .
第八步：4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 8: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000043
Figure PCTCN2018072204-appb-000043
4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(30.0mg，0.05mmol)溶于乙醇(10mL)中，加入3mol/L的NaOH(3mL),室温条件下搅拌3h。停止反应，加入饱和碳酸氢钠溶液(30mL)，用乙酸乙酯(30mLX2)萃取，合并有机相用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩，用制备硅胶板分离，二氯甲烷/甲醇(10/1)，得4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(16.6mg，产率72.6％)。4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-Pyro[2,3-c]pyridin-7-one (30.0 mg, 0.05 mmol) was dissolved in ethanol (10 mL), 3 mol/L NaOH (3 mL) was added and stirred at room temperature for 3 h. The reaction was quenched, and aq. EtOAc EtOAc (EtOAc m. , dichloromethane / methanol (10/1), 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl -1,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (16.6 mg, yield 72.6%).
MS m/z(ESI):458.0[M+H] +. MS m/z (ESI): 458.0 [M+H] + .
1H NMR(400MHz,CDCl 3)δ10.52(s,1H),7.62(d,J＝2.0Hz,1H),7.33-7.31(dd,J＝8.4Hz,2.0Hz,1H),7.25(d,J＝2.8Hz,1H),7.17(s,1H),7.00-6.88(m,2H),6.86-6.79(m,2H),6.43(t,J＝2.0Hz,1H),4.41(d,J＝12.8Hz,1H),4.30(d,J＝12.8Hz,1H),3.68(s,3H),3.18(q,J＝7.6Hz,2H),1.48(t,J＝7.6Hz,3H)； 1 H NMR (400MHz, CDCl 3 ) δ10.52 (s, 1H), 7.62 (d, J = 2.0Hz, 1H), 7.33-7.31 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.25 (d , J = 2.8 Hz, 1H), 7.17 (s, 1H), 7.00-6.88 (m, 2H), 6.86-6.79 (m, 2H), 6.43 (t, J = 2.0 Hz, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.30 (d, J = 12.8 Hz, 1H), 3.68 (s, 3H), 3.18 (q, J = 7.6 Hz, 2H), 1.48 (t, J = 7.6 Hz, 3H) ;
实施例2Example 2
N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ 6-硫烷亚基)环丙磺酰胺 N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 4-yl)benzyl)(ethyl)(carbonyl)-λ 6 -sulfane subunit)cyclopropanesulfonamide
Figure PCTCN2018072204-appb-000044
Figure PCTCN2018072204-appb-000044
第一步：N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ 6-硫烷亚基)环丙磺酰胺 First step: N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrole And [2,3-c]pyridin-4-yl)benzyl)(ethyl)(carbonyl)-λ 6 -sulfaninyl)cyclopropanesulfonamide
Figure PCTCN2018072204-appb-000045
Figure PCTCN2018072204-appb-000045
4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(65.0mg，0.11mmol)溶于吡啶(2mL)，加入环丙基磺酰氯(200mg，1.42mmol),DMAP(12mg，0.1mmol)在室温条件下搅拌过夜。停止反应，加入1N盐酸溶液(30mL),用乙酸乙酯(30mLX2)萃取，合并有机相用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩，用制备硅胶板分离，得N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ6-硫烷亚基)环丙磺酰胺(32.0mg，产率42.2％)。4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridin-7-one (65.0 mg, 0.11 mmol) was dissolved in pyridine (2 mL). EtOAc (EtOAc, EtOAc, ) Stir overnight at room temperature. The reaction was quenched, and aq. EtOAc (EtOAc (EtOAc) N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2, 3-c]pyridin-4-yl)benzyl)(ethyl)(carbonyl)-λ6-sulfaninyl)cyclopropanesulfonamide (32.0 mg, yield 42.2%).
MS m/z(ESI):716.0[M+H] +. MS m/z (ESI): 716.0 [M+H] + .
第二步：N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ 6-硫烷亚基)环丙磺酰胺 Second step: N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3- c]pyridin-4-yl)benzyl)(ethyl)(carbonyl)-λ 6 -sulfaninyl)cyclopropanesulfonamide
Figure PCTCN2018072204-appb-000046
Figure PCTCN2018072204-appb-000046
以N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ6-硫烷亚基)环丙磺酰胺为起始原料，参照实施例1第八步得到N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并 [2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ6-硫烷亚基)环丙磺酰胺。N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2] , 3-c]pyridin-4-yl)benzyl)(ethyl)(carbonyl)-λ6-sulfaninyl)cyclopropanesulfonamide as starting material, and N-(in the eighth step of Example 1 is obtained. (4-(2,4-Difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl Benzyl)(ethyl)(carbonyl)-λ6-sulfaninyl)cyclopropanesulfonamide.
MS m/z(ESI):562.0[M+H] +. MS m/z (ESI): 562.0 [M+H] + .
1H NMR(400MHz,CDCl 3)δ11.01(s,1H),7.69(d,J＝2.0Hz,1H),7.37-7.34(dd,J＝8.4Hz,2.4Hz,1H),7.30(d,J＝2.8Hz,1H),7.25(s,1H),7.02-6.90(m,2H),6.84-6.80(m,2H),6.42(t,J＝2.0Hz,1H),4.78(d,J＝14.4Hz,1H),4.70(d,J＝14.4Hz,1H),3.73(s,3H),3.18(q,J＝7.6Hz,2H),2.67-2.63(m,1H),1.48-1.45(t,J＝7.6Hz,3H),1.28-1.24(m,2H),1.02-0.98(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 11.01 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.37-7.34 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.30 (d) , J=2.8 Hz, 1H), 7.25 (s, 1H), 7.02-6.90 (m, 2H), 6.84-6.80 (m, 2H), 6.42 (t, J = 2.0 Hz, 1H), 4.78 (d, J=14.4 Hz, 1H), 4.70 (d, J = 14.4 Hz, 1H), 3.73 (s, 3H), 3.18 (q, J = 7.6 Hz, 2H), 2.67-2.63 (m, 1H), 1.48- 1.45 (t, J = 7.6 Hz, 3H), 1.28-1.24 (m, 2H), 1.02-0.98 (m, 2H).
实施例3Example 3
4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亚胺酰基)甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-Difluorophenoxy)-5-((N-methylethylsulfimido)methyl)phenyl)-6-methyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000047
Figure PCTCN2018072204-appb-000047
第一步：4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亚胺酰基)甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮First step: 4-(2-(2,4-difluorophenoxy)-5-((N-methylethylsulfimidoyl)methyl)phenyl)-6-methyl-1- Tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000048
Figure PCTCN2018072204-appb-000048
4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(100mg,0.16mmol)，三甲基氧鎓四氟硼酸(121mg,0.82mmol)，二氯甲烷(5mL)置反应瓶中，室温下搅拌15分钟后，加入碳酸钠(104mg,0.98mmol),室温反应过夜。停止反应，加入水(20mL),用乙酸乙酯(30mLx2)萃取，合并有机相用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝10/1；洗脱剂：乙酸乙酯/甲醇＝10/1)得4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亚胺酰基)甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(32.0mg，产率42.2％)。4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonimidomethyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 0.16 mmol), trimethyloxonium tetrafluoroboric acid (121 mg, 0.82 mmol), dichloromethane (5 mL), After stirring at room temperature for 15 minutes, sodium carbonate (104 mg, 0.98 mmol). The reaction was quenched, and water (20 mL) was evaporated, evaporated, evaporated, evaporated, evaporated. Agent: dichloromethane/methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to give 4-(2-(2,4-difluorophenoxy)-5-((N- Methyl ethylsulfonimido)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (32.0 mg, yield 42.2%).
MS m/z(ESI):626.0[M+H] +. MS m/z (ESI): 626.0 [M+H] + .
第二步：4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亚胺酰基)甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Second step: 4-(2-(2,4-difluorophenoxy)-5-((N-methylethylsulfimidoyl)methyl)phenyl)-6-methyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000049
Figure PCTCN2018072204-appb-000049
以4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亚胺酰基)甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为起始原料，参照实施例1第八步水解得到4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亚胺酰基)甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。4-(2-(2,4-difluorophenoxy)-5-((N-methylethylsulfimidoyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl -1,6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one as a starting material, which was hydrolyzed according to the eighth step of Example 1, to give 4-(2-(2,4-difluoro) Phenoxy)-5-((N-methylethylsulfimidoyl)methyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one.
MS m/z(ESI):472.0[M+H]+.MS m/z (ESI): 472.0 [M+H]+.
1H NMR(400MHz,CDCl 3)δ10.54(s,1H),7.56(d,J＝2.4Hz,1H),7.32-7.29(dd,J＝8.4Hz,2.0Hz,1H),7.27(d,J＝2.8Hz,1H),7.00(s,1H),6.98-6.88(m,2H),6.85-6.77(m,2H),6.44(t,J＝2.4Hz,1H),4.36(s,2H),3.69(s,3H),3.03(q,J＝7.6Hz,2H),2.84(s,3H),1.41(t,J＝7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.54 (s, 1H), 7.56 (d, J = 2.4Hz, 1H), 7.32-7.29 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.27 (d , J = 2.8 Hz, 1H), 7.00 (s, 1H), 6.98-6.88 (m, 2H), 6.85-6.77 (m, 2H), 6.44 (t, J = 2.4 Hz, 1H), 4.36 (s, 2H), 3.69 (s, 3H), 3.03 (q, J = 7.6 Hz, 2H), 2.84 (s, 3H), 1.41 (t, J = 7.6 Hz, 3H).
实施例4Example 4
4-(2-(2,4-二氟苯氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-difluorophenoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000050
Figure PCTCN2018072204-appb-000050
第一步：(3-氯-4-氟苯基)(甲基)硫烷First step: (3-chloro-4-fluorophenyl) (methyl) sulane
Figure PCTCN2018072204-appb-000051
Figure PCTCN2018072204-appb-000051
3-氯-4-氟苯硫醇(1g，6.2mmol)和氢氧化钠(246mg，6.2mmol)溶于甲醇(15ml)和水(1.5ml)，加入碘甲烷(873mg，6.2mmol)，反应在室温搅拌下过夜。反应液蒸干，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥蒸干，得到(3-氯-4-氟苯基)(甲基)硫烷(720mg，产率66％)。3-Chloro-4-fluorobenzenethiol (1 g, 6.2 mmol) and sodium hydroxide (246 mg, 6.2 mmol) were dissolved in methanol (15 ml) and water (1.5 ml), and iodomethane (873 mg, 6.2 mmol) was added. Stir at room temperature overnight. The reaction mixture was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
1H NMR(400MHz,CDCl 3):δ7.29(dd,J＝6.7Hz,2.3Hz,1H),7.13(m,1H),7.06(t,J＝8.7Hz,1H),2.47(s,3H)； 1 H NMR (400MHz, CDCl 3 ): δ7.29 (dd, J = 6.7Hz, 2.3Hz, 1H), 7.13 (m, 1H), 7.06 (t, J = 8.7Hz, 1H), 2.47 (s, 3H);
第二步：2-氯-1-氟-4-(甲基亚硫酰基<亚磺酰>)苯Second step: 2-chloro-1-fluoro-4-(methylsulfinyl <sulfinyl>)benzene
Figure PCTCN2018072204-appb-000052
Figure PCTCN2018072204-appb-000052
(3-氯-4-氟苯基)(甲基)硫烷(690mg，3.9mmol)溶于二氯甲烷(10ml)中，在-30℃下加入间氯过氧苯甲酸(75％w/w，900mg，3.9mmol)的二氯甲烷(3ml)溶液。反应在-20℃下搅拌2小时，然后碳酸氢钠饱和水溶液洗涤，二氯甲烷萃取。有机相分离，干燥，蒸干得到2-氯-1-氟-4-(甲基亚硫酰基<亚磺酰>)苯(620mg，产率86％)。(3-Chloro-4-fluorophenyl)(methyl)sulfane (690 mg, 3.9 mmol) was dissolved in dichloromethane (10 ml), and m-chloroperoxybenzoic acid (75% w/) was added at -30 °C. w, 900 mg, 3.9 mmol) in dichloromethane (3 ml). The reaction was stirred at -20 ° C for 2 hours, then washed with a saturated aqueous solution of sodium hydrogen carbonate and dichloromethane. The organic phase was separated, dried and evaporated to dryness to give crystals of 2-chloro-1-fluoro-4-(methylsulfamoyl <sulfinyl)benzene (620 mg, yield 86%).
1H NMR(400MHz,CDCl3):δ7.75(dd,J＝6.7Hz,2.2Hz,1H),7.56–7.50(m, 1H),7.32(t,J＝8.5Hz,1H),2.75(s,3H)； 1 H NMR (400MHz, CDCl3) : δ7.75 (dd, J = 6.7Hz, 2.2Hz, 1H), 7.56-7.50 (m, 1H), 7.32 (t, J = 8.5Hz, 1H), 2.75 (s , 3H);
第三步：(3-氯-4-氟苯基)(亚氨基)(甲基)-λ 6-硫烷酮 The third step: (3-chloro-4-fluorophenyl) (imino) (methyl)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000053
Figure PCTCN2018072204-appb-000053
2-氯-1-氟-4-(甲基亚硫酰基<亚磺酰>)苯(500mg，2.6mmol)和叠氮化钠(338mg，5.2mmol)悬浮于氯仿(10ml)中，然后加入浓硫酸(0.85ml，15.6mmol)。反应液在45℃下搅拌16小时，然后冷却到室温，二氯甲烷萃取，饱和碳酸氢钠水溶液洗涤，有机相干燥，蒸干，柱分离(石油醚：乙酸乙酯＝10:1)得到(3-氯-4-氟苯基)(亚氨基)(甲基)-λ6-硫烷酮(300mg，产率55％)。2-Chloro-1-fluoro-4-(methylsulfinyl <sulfinyl>)benzene (500 mg, 2.6 mmol) and sodium azide (338 mg, 5.2 mmol) were suspended in chloroform (10 ml) and then added Concentrated sulfuric acid (0.85 ml, 15.6 mmol). The reaction mixture was stirred at 45 ° C for 16 hours, then cooled to room temperature, extracted with methylene chloride, washed with saturated aqueous sodium hydrogen sulfate, and then dried and evaporated to dryness. 3-Chloro-4-fluorophenyl)(imino)(methyl)-λ6-sulfanone (300 mg, yield 55%).
MS m/z(ESI):208.0[M+H] +。 MS m/z (ESI): 208.0 [M+H] + .
1H NMR(400MHz,CDCl3):δ8.04(dd,J＝6.7Hz,2.3Hz,1H),7.90–7.82(m,1H),7.25(t,J＝8.5Hz,1H),3.06(s,3H),2.64-2.70(br,1H). 1 H NMR (400MHz, CDCl3) : δ8.04 (dd, J = 6.7Hz, 2.3Hz, 1H), 7.90-7.82 (m, 1H), 7.25 (t, J = 8.5Hz, 1H), 3.06 (s , 3H), 2.64-2.70 (br, 1H).
第四步：4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Fourth step: 4-(2-Fluoro-5-(S-methylsulfaminynoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000054
Figure PCTCN2018072204-appb-000054
将(3-氯-4-氟苯基)(亚氨基)(甲基)-λ 6-硫烷酮(100mg，0.48mmol)，中间体Im(250mg，0.58mmol)和碳酸钾(200mg，1.44mmol)溶于乙醇，甲苯，水(v/v 9:3:1，5ml)，然后加入四三苯基膦钯(56mg，48umol)。反应在120℃微波氮气保护下搅拌0.5小时。反应液浓缩，柱分离(二氯甲烷：甲醇＝98:2)得到4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(80mg，产率35％)。 (3-Chloro-4-fluorophenyl)(imino)(methyl)-λ 6 -thione (100 mg, 0.48 mmol), intermediate Im (250 mg, 0.58 mmol) and potassium carbonate (200 mg, 1.44) Methyl) was dissolved in ethanol, toluene, water (v/v 9:3:1, 5 ml), then tetratriphenylphosphine palladium (56 mg, 48 umol). The reaction was stirred at 120 ° C under microwave nitrogen for 0.5 hours. The reaction mixture was concentrated and purified by column (dichloromethane:methanol=98:2) to afford 4-(2-fluoro-5-(S-methylsulfanimidyl)phenyl)-6-methyl-1-toluene Acyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (80 mg, yield 35%).
MS m/z(ESI):474.0[M+H] +。 MS m/z (ESI): 474.0 [M+H] + .
第五步：4-(2-(2,4-二氟苯氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 5: 4-(2-(2,4-Difluorophenoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000055
Figure PCTCN2018072204-appb-000055
4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(30mg，63.4umol)和2,4-二氟苯酚(20mg，152umol)溶于二甲基亚砜(1.5ml)，然后加入碳酸钾(26mg，190umol)。反应在120℃氮气保 护下搅拌16小时，然后冷却到室温。二氯甲烷萃取，饱和食盐水洗涤。有机相干燥蒸干，粗品反相处层析分离(水：乙腈＝3:2)，得到4-(2-(2,4-二氟苯氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(2.5mg，产率9％)。4-(2-Fluoro-5-(S-methylsulfanilino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3- c] Pyridin-7-one (30 mg, 63.4 umol) and 2,4-difluorophenol (20 mg, 152 umol) were dissolved in dimethyl sulfoxide (1.5 ml), then potassium carbonate (26 mg, 190 umol) was added. The reaction was stirred under nitrogen at 120 ° C for 16 hours and then cooled to room temperature. Extract with dichloromethane and wash with saturated brine. The organic phase is dried and evaporated to dryness, and the crude product is separated by chromatography (water: acetonitrile = 3:2) to give 4-(2-(2,4-difluorophenoxy)-5-(S-methylsulfonimide). Acyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (2.5 mg, yield 9%).
MS m/z(ESI):430.1[M+H] +。 MS m/z (ESI): 430.1 [M+H] + .
1H NMR(400MHz,CDCl3):δ10.44-10.57(s,1H),8.15-8.09(m,1H),7.94-7.88(m,1H),7.31-7.26(m,1H),7.15(s,1H),7.10-7.02(m,1H),7.01-6.94(m,1H),6.91-6.83(m,2H),6.40-6.37(m,1H),3.71(s,3H),3.20(s,3H)； 1 H NMR (400MHz, CDCl3) : δ10.44-10.57 (s, 1H), 8.15-8.09 (m, 1H), 7.94-7.88 (m, 1H), 7.31-7.26 (m, 1H), 7.15 (s , 1H), 7.10-7.02 (m, 1H), 7.01-6.94 (m, 1H), 6.91-6.83 (m, 2H), 6.40-6.37 (m, 1H), 3.71 (s, 3H), 3.20 (s , 3H);
实施例5Example 5
4-(2-(环丙基甲氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cyclopropylmethoxy)-5-(propan-2-ylsulfoimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, Preparation of 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000056
Figure PCTCN2018072204-appb-000056
第一步：(3-氯-4-氟苯基)(异丙基)硫烷First step: (3-chloro-4-fluorophenyl) (isopropyl) sulane
Figure PCTCN2018072204-appb-000057
Figure PCTCN2018072204-appb-000057
以3-氯-4-氟苯硫醇(900mg,5.55mmol)为反应原料，参考实施例4第一步，用2-碘丙烷代替碘甲烷，得到化合物(3-氯-4-氟苯基)(异丙基)硫烷(产率66％)。3-chloro-4-fluorobenzenethiol (900 mg, 5.55 mmol) was used as the starting material of the reaction, and the first step of Example 4 was followed, and 2-iodopropane was used instead of methyl iodide to obtain a compound (3-chloro-4-fluorophenyl). (isopropyl)sulfane (yield 66%).
第二步：2-氯-1-氟-4-(异丙基亚硫酰基<亚磺酰>)苯Second step: 2-chloro-1-fluoro-4-(isopropylsulfinyl <sulfinyl>)benzene
Figure PCTCN2018072204-appb-000058
Figure PCTCN2018072204-appb-000058
以(3-氯-4-氟苯基)(异丙基)硫烷为反应原料，参考实施例4第二步，得到化合物2-氯-1-氟-4-(异丙基亚硫酰基<亚磺酰>)苯(产率93％)。Using (3-chloro-4-fluorophenyl)(isopropyl)sulfane as the starting material, referring to the second step of Example 4, the compound 2-chloro-1-fluoro-4-(isopropylsulfinyl) was obtained. <Sulfuryl>) benzene (yield 93%).
第三步：(3-氯-4-氟苯基)(亚氨基)(异丙基)-硫烷酮的制备The third step: preparation of (3-chloro-4-fluorophenyl)(imino)(isopropyl)-sulfanone
Figure PCTCN2018072204-appb-000059
Figure PCTCN2018072204-appb-000059
2-氯-1-氟-4-(异丙基亚硫酰基<亚磺酰>)苯(900.m g,4.09mmol)，溶于甲醇(15 mL)，室温下加氨基甲酸胺(1.27g,16.36mmol)，醋酸碘苯(3.95g,12.27mmol)，反应在室温下搅拌半个小时，反应完全，将反应液浓缩，用乙酸乙酯(20ml)萃取，然后用水(20mL*2)和饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，浓缩后柱层析(二氯甲烷:甲醇＝20:1)得到化合物(3-氯-4-氟苯基)(亚氨基)(异丙基)-硫烷酮(680mg，产率72％)。2-Chloro-1-fluoro-4-(isopropylsulfinyl <sulfinyl>)benzene (900.m g, 4.09 mmol), dissolved in methanol (15 mL), EtOAc (1. g, 16.36 mmol), iodobenzene acetate (3.95 g, 12.27 mmol), the reaction was stirred at room temperature for half an hour, the reaction was completed, the reaction mixture was concentrated, ethyl acetate (20 ml), and then water (20mL*2) It was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Isopropyl)-sulfanone (680 mg, yield 72%).
MS m/z(ESI):236.06[M+H] +。 MS m/z (ESI): 236.06 [M+H] + .
第四步：4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Fourth step: 4-(2-Fluoro-5-(propan-2-ylsulfinylamido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000060
Figure PCTCN2018072204-appb-000060
以(3-氯-4-氟苯基)(亚氨基)(异丙基)-硫烷酮为反应原料，参考实施例4第四步，得到化合物4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率33％)。Using (3-chloro-4-fluorophenyl)(imino)(isopropyl)-sulfanone as the starting material, referring to the fourth step of Example 4, the compound 4-(2-fluoro-5-(propane) was obtained. -2- sulfoimidinoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 33%).
MS m/z(ESI):502.1[M+H] +。 MS m/z (ESI): 5021. [M+H] + .
第五步：4-(2-(环丙基甲氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5: 4-(2-(cyclopropylmethoxy)-5-(propan-2-ylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000061
Figure PCTCN2018072204-appb-000061
4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(64.0mg,0.12mmol)，溶于DMF(2mL)中,加入环丙基甲醇(17.2mg,0.24mmol)，冰浴下加入钠氢(10.0mg,0.24mmol)，0℃下搅拌十分钟，然后45℃搅拌过夜，将反应用乙酸乙酯(10ml)萃取，然后用水(10mL*2)和饱和食盐水(10mL)洗涤，并用无水硫酸钠干燥，浓缩后柱层析(二氯甲烷:甲醇＝20:1)得到化合物4-(2-(环丙基甲氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(23.5mg,产率49％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one (64.0 mg, 0.12 mmol) in EtOAc (2 mL). The mixture was stirred for 10 minutes at 0 ° C, then stirred at 45 ° C overnight. The mixture was extracted with ethyl acetate (10 mL), then washed with water (10 mL*2) and brine (10 mL) Column chromatography (dichloromethane:methanol = 20:1) gave compound 4-(2-(cyclopropylmethoxy)-5-(propan-2-ylsulfimidoyl)phenyl)-6- Base-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (23.5 mg, yield 49%).
MS m/z(ESI):400.1[M+H] +； MS m/z (ESI): 400.1 [M+H] +
1H NMR(400MHz,MeOD)δ7.95(d,J＝2.4Hz,1H),7.92(dd,J＝8.6Hz,2.5Hz,1H),7.40–7.34(m,2H),7.31(d,J＝8.7Hz,1H),6.28(d,J＝2.9Hz,1H),4.01(d,J＝6.8Hz,2H),3.73(s,3H),3.45–3.36(m,1H),1.33(d,J＝6.8Hz,3H),1.30(d,J＝6.8Hz,3H),1.26–1.11(m,1H),0.60–0.49(m,2H),0.37–0.26(m,2H). 1 H NMR (400MHz, MeOD) δ7.95 (d, J = 2.4Hz, 1H), 7.92 (dd, J = 8.6Hz, 2.5Hz, 1H), 7.40-7.34 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 6.28 (d, J = 2.9 Hz, 1H), 4.01 (d, J = 6.8 Hz, 2H), 3.73 (s, 3H), 3.45 - 3.36 (m, 1H), 1.33 ( d, J = 6.8 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H), 1.26 - 1.11 (m, 1H), 0.60 - 0.49 (m, 2H), 0.37 - 0.26 (m, 2H).
实施例6Example 6
4-(2-(2,4-二氟苯氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000062
Figure PCTCN2018072204-appb-000062
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用2,4-二氟苯酚取代环丙基甲醇，参考实施例5第五步，得到化合物4-(2-(2,4-二氟苯氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率39％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one as a starting material, replacing cyclopropylmethanol with 2,4-difluorophenol, and referring to the fifth step of Example 5, the compound 4-(2-(2,4-difluorophenoxy) was obtained. -5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one The rate is 39%).
MS m/z(ESI):458.1[M+H] +。 MS m/z (ESI): 458.1 [M+H] + .
1H NMR(400MHz,CDCl 3):δ8.21(s,1H),8.12(s,1H),7.52(m,1H),7.42(d,J＝8.7Hz,1H),7.35(s,1H),7.21(t,J＝9.4Hz,2H),7.08(d,J＝2.9Hz,1H),6.40(s,1H),4.40-4.19(m,1H),3.76(s,3H),1.59(d,J＝6.8Hz,3H),1.47(d,J＝6.8Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ8.21 (s, 1H), 8.12 (s, 1H), 7.52 (m, 1H), 7.42 (d, J = 8.7Hz, 1H), 7.35 (s, 1H ), 7.21 (t, J = 9.4 Hz, 2H), 7.08 (d, J = 2.9 Hz, 1H), 6.40 (s, 1H), 4.40 - 4.19 (m, 1H), 3.76 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H).
实施例7Example 7
4-(2-(环己三烯并氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cyclohexanetrienoxy)-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 , 3-c]pyridine-7-one preparation
Figure PCTCN2018072204-appb-000063
Figure PCTCN2018072204-appb-000063
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环己基甲醇取代环丙基甲醇，参考实施例5第五步，得到化合物4-(2-(环己三烯并氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率35％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one as a starting material, substituting cyclopropylmethanol with cyclopropylmethanol, and referring to the fifth step of Example 5, the compound 4-(2-(cyclohexanetrienoxy)-5-( Propane-2-ylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 35%).
MS m/z(ESI):428.1[M+H] +； MS m/z (ESI): 428.1 [M+H] +
1H NMR(400MHz,CDCl 3)δ10.47(s,1H),7.99(d,J＝2.4Hz,1H),7.88(dd,J＝8.7Hz,2.4Hz,1H),7.26(s,1H),7.13(s,1H),7.09(d,J＝8.9Hz,1H),6.28(t,J＝2.4Hz,1H),4.51–4.37(m,1H),3.71(s,3H),3.42–3.30(m,1H),1.95–1.84(m,2H),1.70–1.57(m,2H),1.57–1.44(m,2H),1.43–1.15(m,10H). 1 H NMR (400MHz, CDCl 3 ) δ10.47 (s, 1H), 7.99 (d, J = 2.4Hz, 1H), 7.88 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.26 (s, 1H ), 7.13 (s, 1H), 7.09 (d, J = 8.9 Hz, 1H), 6.28 (t, J = 2.4 Hz, 1H), 4.51 - 4.37 (m, 1H), 3.71 (s, 3H), 3.42 –3.30 (m, 1H), 1.95–1.84 (m, 2H), 1.70–1.57 (m, 2H), 1.57–1.44 (m, 2H), 1.43–1.15 (m, 10H).
实施例8Example 8
6-甲基-4-(2-苯氧基-5-(丙烷-2-基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备6-Methyl-4-(2-phenoxy-5-(propan-2-ylsulfinylimido)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine Preparation of -7-ketone
Figure PCTCN2018072204-appb-000064
Figure PCTCN2018072204-appb-000064
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，用苯酚取代环丙基甲醇，参考实施例5第五步，得到化合物6-甲基-4-(2-苯氧基-5-(丙烷-2-基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(7.9mg,产率22％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one is the starting material for the reaction, and cyclopropylmethanol is substituted with phenol. Referring to the fifth step of Example 5, the compound 6-methyl-4-(2-phenoxy-5-(propane-) is obtained. 2-Hydroxyimino)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (7.9 mg, yield 22%).
MS m/z(ESI):422.1[M+H] +； MS m/z (ESI): 4221. [M+H] +
1H NMR(400MHz,CDCl3)δ10.48(br,1H),8.11(d,J＝2.4Hz,1H),7.85(dd,J＝8.7Hz,2.4Hz,1H),7.41–7.31(m,2H),7.30–7.27(m,1H),7.23–7.11(m,2H),7.08–6.93(m,3H),6.42–6.30(m,1H),3.68(s,3H),3.48–3.33(m,1H),1.40(d,J＝6.8Hz,3H),1.35(d,J＝6.8Hz,3H). 1 H NMR (400MHz, CDCl3) δ10.48 (br, 1H), 8.11 (d, J = 2.4Hz, 1H), 7.85 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.41-7.31 (m, 2H), 7.30–7.27 (m, 1H), 7.23–7.11 (m, 2H), 7.08–6.93 (m, 3H), 6.42–6.30 (m, 1H), 3.68 (s, 3H), 3.48–3.33 ( m, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.35 (d, J = 6.8 Hz, 3H).
实施例9Example 9
4-(2-((4,4-二氟环己基)氧代)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-((4,4-difluorocyclohexyl)oxo)-5-(propan-2-ylsulfinimidyl)phenyl)-6-methyl-1,6-dihydro-7H -Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000065
Figure PCTCN2018072204-appb-000065
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，用4,4-二氟环己基甲醇取代环丙基甲醇，参考实施例5第五步，得到化合物4-(2-((4,4-二氟环己基)氧代)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率19％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one is the starting material of the reaction, and cyclopropylmethanol is replaced by 4,4-difluorocyclohexylmethanol. The compound of the fifth step of Example 5 is obtained to obtain the compound 4-(2-((4,4-) Difluorocyclohexyl)oxo)-5-(propan-2-ylsulfoimine phenyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone (yield 19%).
MS m/z(ESI):464.1[M+H] +。 MS m/z (ESI): 464.1 [M+H] + .
1H NMR(400MHz,CDCl3)δ10.49(br,1H),8.17–7.80(m,2H),7.79–7.67(m,1H),7.58–7.45(m,1H),7.21–6.96(m,1H),6.30–6.12(m,1H),4.71–4.57(m,1H),3.70(s,3H),3.61–3.42(m,1H),1.85-1.70(m,8H),1.42(d,J＝6.3Hz,3H),1.36(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl3) δ10.49 (br, 1H), 8.17-7.80 (m, 2H), 7.79-7.67 (m, 1H), 7.58-7.45 (m, 1H), 7.21-6.96 (m, 1H), 6.30–6.12 (m, 1H), 4.71–4.57 (m, 1H), 3.70 (s, 3H), 3.61–3.42 (m, 1H), 1.85-1.70 (m, 8H), 1.42 (d, J = 6.3 Hz, 3H), 1.36 (d, J = 6.6 Hz, 3H).
实施例10Example 10
4-(2-(2,4-二氟苯氧基)-5-(S-乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-difluorophenoxy)-5-(S-ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000066
Figure PCTCN2018072204-appb-000066
第一步：(3-溴-4-氟苯基)(乙基)硫烷First step: (3-bromo-4-fluorophenyl) (ethyl) sulane
Figure PCTCN2018072204-appb-000067
Figure PCTCN2018072204-appb-000067
3-溴-4-氟苯胺(19g，0.1mol)和铜粉(0.96g，15mmol)溶于1,2-二乙基二硫烷(50ml)，将反应体系加热至80摄氏度。缓慢的滴入亚硝酸异戊酯(15g,0.15mmol)以保持反应的内部温度不高于90℃。滴加完毕反应在九90℃下搅拌两小时。反应液蒸干，甲苯和稀盐酸加入反应体系，分液，甲苯相分别使用稀盐酸，水和饱和食盐水洗涤，有机相干燥蒸干，残留物通过减压蒸馏，收集蒸汽温度60-70℃的馏分来得到的3-溴-4-氟苯基)(乙基)硫烷(15g，淡黄色油状，产率63％)。3-Bromo-4-fluoroaniline (19 g, 0.1 mol) and copper powder (0.96 g, 15 mmol) were dissolved in 1,2-diethyldisulfane (50 ml), and the reaction was heated to 80 °C. Isoamyl nitrite (15 g, 0.15 mmol) was slowly added dropwise to maintain the internal temperature of the reaction not higher than 90 °C. The reaction was completed and the mixture was stirred at 90 ° C for two hours. The reaction liquid is evaporated to dryness, and toluene and dilute hydrochloric acid are added to the reaction system, and the toluene phase is washed with dilute hydrochloric acid, water and saturated brine, and the organic phase is dried and evaporated to dryness, and the residue is subjected to distillation under reduced pressure to collect steam temperature 60-70 ° C. 3-bromo-4-fluorophenyl)(ethyl)sulfane (15 g, pale yellow oil, yield 63%).
1H NMR(400MHz,CDCl3):δ7.53(dd,J＝6.4Hz，2.0Hz,1H),7.27-7.23(m,1H),7.04(t,J＝8.4Hz,1H),2.90(q,J＝7.6Hz,2H),1.29(t,J＝7.6Hz,3H)； 1 H NMR (400MHz, CDCl3) : δ7.53 (dd, J = 6.4Hz, 2.0Hz, 1H), 7.27-7.23 (m, 1H), 7.04 (t, J = 8.4Hz, 1H), 2.90 (q , J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H);
第二步：2-溴-1-氟-4-(乙基亚硫酰基<亚磺酰>)苯Second step: 2-bromo-1-fluoro-4-(ethylsulfinyl <sulfinyl>)benzene
Figure PCTCN2018072204-appb-000068
Figure PCTCN2018072204-appb-000068
以(3-溴-4-氟苯基)(乙基)硫烷为反应原料，参考实施例4第二步，得到2-溴-1-氟-4-(乙基亚硫酰基<亚磺酰>)苯(产率86％)。Using (3-bromo-4-fluorophenyl)(ethyl)sulfane as the starting material, referring to the second step of Example 4, 2-bromo-1-fluoro-4-(ethylsulfinyl <sulfinated sulfinate was obtained. Acyl>) benzene (yield 86%).
第三步：(3-溴-4-氟苯基)(亚氨基)(乙基)-λ 6-硫烷酮 Third step: (3-bromo-4-fluorophenyl)(imino)(ethyl)-λ 6 -thiol ketone
Figure PCTCN2018072204-appb-000069
Figure PCTCN2018072204-appb-000069
以2-溴-1-氟-4-(乙基亚硫酰基<亚磺酰>)苯为反应原料，参考实施例5第三步，得到(3-溴-4-氟苯基)(亚氨基)(乙基)-λ6-硫烷酮(收率78％)。Using 2-bromo-1-fluoro-4-(ethylsulfinyl <sulfinyl>)benzene as the starting material, referring to the third step of Example 5, (3-bromo-4-fluorophenyl) (Asian) Amino)(ethyl)-λ6-sulfanone (yield 78%).
MS m/z(ESI):265.9/267.9(50/50)[M+H] +. MS m/z (ESI): 265.9 / 267.9 (50 / 50) [M+H] + .
第四步：4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Fourth step: 4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000070
Figure PCTCN2018072204-appb-000070
(3-溴-4-氟苯基)(亚氨基)(乙基)-λ 6-硫烷酮(266mg，1mmol)，中间体Im(428mg，1mmol)和碳酸钾(270mg，2mmol)溶于1,4-二氧六环和水(v/v 9:1，10ml),然后加入[1,1'-二(二苯基膦基)二茂铁]二氯钯(II)(140mg，0.2mmol)。反应在100℃氮气保护下搅拌15小时。反应液浓缩，柱分离(石油醚：乙酸乙酯＝1:1～0:1) 得到4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(160mg，产率30％)。 (3-Bromo-4-fluorophenyl)(imino)(ethyl)-λ 6 -sulfanone (266 mg, 1 mmol), intermediate Im (428 mg, 1 mmol) and potassium carbonate (270 mg, 2 mmol) 1,4-dioxane and water (v/v 9:1, 10 ml), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg, 0.2 mmol). The reaction was stirred at 100 ° C under nitrogen for 15 hours. The reaction solution was concentrated, and the residue was separated (EtOAc (EtOAc: EtOAc = 1:1 to 0:1) to give 4-(5-(ethylsulfanimidyl)-2-fluorophenyl)-6-methyl-1 -toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (160 mg, yield 30%).
MS m/z(ESI):488.1[M+H] +. MS m/z (ESI): 488.1 [M+H] + .
第五步：4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 5: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000071
Figure PCTCN2018072204-appb-000071
2,4-二氟苯酚(800mg，0.6mmol)溶于1-甲基吡咯烷酮(1.5ml)，将氢化钠(60％in mine oil，25mg,0.6mmol)加入反应体系中，室温下搅拌10分钟之后加入4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(50mg，0.1mmol)。反应体系密封之后置于180摄氏度的微波条件下反应半个小时，然后冷却到室温。乙酸乙酯萃取，饱和食盐水洗涤。有机相干燥蒸干，粗品制备板分离(二氯甲烷：甲醇＝＝10:1)，得到4-(2-(2,4-二氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(30mg，产率67％)。2,4-Difluorophenol (800 mg, 0.6 mmol) was dissolved in 1-methylpyrrolidone (1.5 ml), sodium hydride (60% in mine oil, 25 mg, 0.6 mmol) was added to the reaction system, and stirred at room temperature for 10 minutes. Then 4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3- c] Pyridine-7-one (50 mg, 0.1 mmol). The reaction system was sealed and placed under microwave conditions of 180 ° C for half an hour, and then cooled to room temperature. Extract with ethyl acetate and wash with saturated brine. The organic phase is dried and evaporated to dryness. The crude material is purified (dichloromethane:methanol == 10:1) to give 4-(2-(2,4-difluorophenoxy)-5- (ethyl sulfanilide) Phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (30 mg, yield 67%).
MS m/z(ESI):444.1[M+H] +； MS m/z (ESI): 444.1 [M+H] +
1H NMR(400MHz,d4-MeOD):δ7.97(d,J＝2.4Hz,1H),7.81(dd,J＝8.8Hz,2.4Hz,1H),7.24-7.27(m,2H),7.10-7.12(m,2H),6.84-6.93(m,2H),6.27(d,J＝2.8Hz,1H),3.60(s,3H),3.19(q,J＝8.0Hz,2H),1.16(t,J＝8.0Hz,3H)。 1 H NMR (400MHz, d4- MeOD): δ7.97 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.24-7.27 (m, 2H), 7.10 -7.12 (m, 2H), 6.84-6.93 (m, 2H), 6.27 (d, J = 2.8 Hz, 1H), 3.60 (s, 3H), 3.19 (q, J = 8.0 Hz, 2H), 1.16 ( t, J = 8.0 Hz, 3H).
实施例11Example 11
4-(2-(环己三烯并氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]4-(2-(cyclohexanetrienoxy)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3- c]
吡啶-7-酮Pyridine-7-one
Figure PCTCN2018072204-appb-000072
Figure PCTCN2018072204-appb-000072
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用环己醇取代2,4-二氟苯酚得到4-(2-(环己三烯并氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率21％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting cyclohexanol for 2,4-difluorophenol gives 4-(2-(cyclohexanetrienoxy)-5-(B Sulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 21%).
MS m/z(ESI):414.1[M+H] +； MS m/z (ESI): 414.1 [M+H] +
1H NMR(400MHz,d4-MeOD):δ7.82-7.86(m,2H),7.23-7.24(m,2H),7.20(s,1H),6.16(d,J＝2.8Hz,1H),4.47-4.48(m,1H),3.61(s,3H),3.24(q,J＝7.2Hz,2H),1.79-1.82(m,2H),1.37-1.52(m,5H),1.24-1.33(m,3H),1.17(t,J＝7.2Hz,3H). 1 H NMR (400MHz, d4- MeOD): δ7.82-7.86 (m, 2H), 7.23-7.24 (m, 2H), 7.20 (s, 1H), 6.16 (d, J = 2.8Hz, 1H), 4.47-4.48 (m, 1H), 3.61 (s, 3H), 3.24 (q, J = 7.2 Hz, 2H), 1.79-1.82 (m, 2H), 1.37-1.52 (m, 5H), 1.24-1.33 ( m, 3H), 1.17 (t, J = 7.2 Hz, 3H).
实施例12Example 12
4-(2-((4,4-二氟环己基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((4,4-difluorocyclohexyl)oxo)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000073
Figure PCTCN2018072204-appb-000073
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用4,4-二氟环己醇取代2,4-二氟苯酚，得到4-(2-((4,4-二氟环己基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率33％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting 4,4-difluorocyclohexanol for 2,4-difluorophenol gives 4-(2-((4,4-) Fluorocyclohexyl)oxo-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Yield 33%).
MS m/z(ESI):450.1[M+H] +； MS m/z (ESI): 450.1 [M+H] +
1H NMR(400MHz,d4-MeOD):δ7.86-7.89(m,2H),7.30(d,J＝9.6Hz,1H),7.25(d,J＝2.8Hz,1H),7.18(s,1H),6.15(d,J＝3.2Hz,1H),4.69-4.70(m,1H),3.61(s,3H),3.24(q,J＝7.2Hz,2H),1.55-1.84(m,8H),1.17(t,J＝7.2Hz,3H)。 1 H NMR (400MHz, d4- MeOD): δ7.86-7.89 (m, 2H), 7.30 (d, J = 9.6Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.18 (s, 1H), 6.15 (d, J = 3.2 Hz, 1H), 4.69-4.70 (m, 1H), 3.61 (s, 3H), 3.24 (q, J = 7.2 Hz, 2H), 1.55-1.84 (m, 8H) ), 1.17 (t, J = 7.2 Hz, 3H).
实施例13Example 13
4-(5-(乙基磺亚胺酰基)-2-((4-甲氧基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-((4-methoxycyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000074
Figure PCTCN2018072204-appb-000074
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用对甲氧基环己醇取代2,4-二氟苯酚，得到4-(5-(乙基磺亚胺酰基)-2-((4-甲氧基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率33％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting p-methoxycyclohexanol for 2,4-difluorophenol gives 4-(5-(ethylsulfimidoyl)- 2-((4-Methoxycyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 33%).
MS m/z(ESI):444.1[M+H] +。 MS m/z (ESI): 444.1 [M+H] + .
1H NMR(400MHz,d6-DMSO):δ12.05(s,1H),7.84(dd,J＝9.6Hz,2.4Hz,1H),7.78(d,J＝8.8Hz,1H),7.29-7.36(m,3H),6.15(dt,J＝2.4,9.6Hz,1H),4.56-4.62(m,1H),4.05(s,1H),3.56(s,3H),3.09-3.22(m,5H),1.93-1.97(m,1H),1.58-1.78(m,4H),1.33-1.45(m,3H),1.10(t,J＝7.2Hz,3H). 1 H NMR (400MHz, d6- DMSO): δ12.05 (s, 1H), 7.84 (dd, J = 9.6Hz, 2.4Hz, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.29-7.36 (m,3H), 6.15 (dt, J=2.4, 9.6 Hz, 1H), 4.56-4.62 (m, 1H), 4.05 (s, 1H), 3.56 (s, 3H), 3.09-3.22 (m, 5H) ), 1.93-1.97 (m, 1H), 1.58-1.78 (m, 4H), 1.33-1.45 (m, 3H), 1.10 (t, J = 7.2 Hz, 3H).
实施例14Example 14
4-(2-(环丙基甲氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cyclopropylmethoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]Preparation of pyridin-7-one
Figure PCTCN2018072204-appb-000075
Figure PCTCN2018072204-appb-000075
第一步：(3-溴-4-氟苯基)(甲基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(methyl)sulfane
Figure PCTCN2018072204-appb-000076
Figure PCTCN2018072204-appb-000076
以3-溴-4-氟苯胺为反应原料，参考实施例10第一步，用二甲基二硫烷取代1,2-二乙基二硫烷，得到的(3-溴-4-氟苯基)(甲基)硫烷(淡黄色油状物，产率63％)。Using 3-bromo-4-fluoroaniline as the starting material for the reaction, referring to the first step of Example 10, substituting dimethyl disulfane for 1,2-diethyldisulfane, the obtained (3-bromo-4-fluoro group) Phenyl)(methyl)sulfane (light yellow oil, yield 63%).
1H NMR(400MHz,CDCl3):δ7.46–7.38(m,1H),7.21–7.12(m,1H),7.08–6.99(m,1H),2.46(s,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.46 - 7.38 (m, 1H), 7.21. - 7.12 (m, 1H), 7.08 - 6.99 (m, 1H), 2.46 (s, 3H).
第二步：2-溴-1-氟-4-(甲基亚硫酰基<亚磺酰>)苯的制备Second step: Preparation of 2-bromo-1-fluoro-4-(methylsulfinyl <sulfinyl>)benzene
Figure PCTCN2018072204-appb-000077
Figure PCTCN2018072204-appb-000077
以(3-溴-4-氟苯基)(甲基)硫烷为反应原料，参考实施例4第二步，得到2-溴-1-氟-4-(甲基亚硫酰基<亚磺酰>)苯(产率85％)。Using (3-bromo-4-fluorophenyl)(methyl)sulfane as the starting material, referring to the second step of Example 4, 2-bromo-1-fluoro-4-(methylsulfinyl <sulfinyl] was obtained. Acyl>) benzene (yield 85%).
MS m/z(ESI):237.0[M+H] +,238.9[M+2+H] +。 MS m / z (ESI): 237.0 [M + H] +, 238.9 [M + 2 + H] +.
第三步：(3-溴-4-氟苯基)(亚氨基)(甲基)-λ 6-硫烷酮的制备 Third step: Preparation of (3-bromo-4-fluorophenyl)(imino)(methyl)-λ 6 -thione
Figure PCTCN2018072204-appb-000078
Figure PCTCN2018072204-appb-000078
以2-溴-1-氟-4-(甲基亚硫酰基<亚磺酰>)苯为原料，参考实施例5第三步，得到(3-溴-4-氟苯基)(亚氨基)(甲基)-λ6-硫烷酮(产率90％)。Using 2-bromo-1-fluoro-4-(methylsulfinyl <sulfinyl>)benzene as the starting material, referring to the third step of Example 5, (3-bromo-4-fluorophenyl) (imino group was obtained. (Methyl)-λ6-sulfanone (yield 90%).
MS m/z(ESI):251.9/253.9(50/50)[M+H] +. MS m/z (ESI): 251.9 / 253.9 (50 / 50) [M+H] + .
第四步：4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Fourth step: 4-(2-Fluoro-5-(S-methylsulfaminynoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000079
Figure PCTCN2018072204-appb-000079
以(3-溴-4-氟苯基)(亚氨基)(甲基)-λ6-硫烷酮为原料，参考实施例4第四步得到4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c] 吡啶-7-酮(产率58％)。Using (3-bromo-4-fluorophenyl)(imino)(methyl)-λ6-sulfanone as the starting material, refer to the fourth step of Example 4 to obtain 4-(2-fluoro-5-(S-A) Sulfimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 58%) .
MS m/z(ESI):474.1[M+H] +。 MS m/z (ESI): 474.1 [M+H] + .
第五步：4-(2-(环丙基甲氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 5: 4-(2-(cyclopropylmethoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000080
Figure PCTCN2018072204-appb-000080
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用环丙基甲醇取代2,4-二氟苯酚，得到4-(2-(环丙基甲氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, the 2,4-difluorophenol is replaced with cyclopropylmethanol to give 4-(2-(cyclopropylmethoxy)-5. -(S-Methylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.
MS m/z(ESI):372.1[M+H] +。 MS m/z (ESI): 3721. [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.33(s,1H),8.08(d,J＝2.4Hz,1H),7.99(dd,J＝8.7Hz,2.4Hz,1H),7.31(t,J＝2.7Hz,1H),7.11(d,J＝8.8Hz,1H),7.05(s,1H),6.24(t,J＝2.4Hz,1H),4.62(s,1H),3.91(d,J＝8Hz,2H),3.73(s,3H),3.20(s,3H),1.24–1.31(m,1H),0.58–0.49(m,2H),0.31–0.24(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ11.33 (s, 1H), 8.08 (d, J = 2.4Hz, 1H), 7.99 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.05 (s, 1H), 6.24 (t, J = 2.4 Hz, 1H), 4.62 (s, 1H), 3.91 (d, J=8 Hz, 2H), 3.73 (s, 3H), 3.20 (s, 3H), 1.24–1.31 (m, 1H), 0.58–0.49 (m, 2H), 0.31–0.24 (m, 2H).
实施例15Example 15
4-(2-(4,4-二氟环己氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(4,4-Difluorocyclohexyloxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000081
Figure PCTCN2018072204-appb-000081
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用4,4-二氟环己醇取代2,4-二氟苯酚，得到4-(2-(4,4-二氟环己氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one as the starting material for the reaction, referring to the fifth step of Example 10, substituting 4,4-difluorocyclohexanol for 2,4-difluorophenol to obtain 4-(2-(4,4-) Difluorocyclohexyloxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7 -ketone.
MS m/z(ESI):436.1[M+H] +。 MS m/z (ESI): 436.1 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.08(s,1H),8.06(d,J＝2.4Hz,1H),8.00(dd,J＝8.7Hz,2.4Hz,1H),7.30(t,J＝2.7Hz,1H),7.11(d,J＝8.8Hz,1H),7.05(s,1H),6.24(t,J＝2.4Hz,1H),4.62-4.61(m,1H),3.73(s,3H),3.20(s,3H),2.04–1.70(m,8H). 1 H NMR (400MHz, CDCl 3 ): δ11.08 (s, 1H), 8.06 (d, J = 2.4Hz, 1H), 8.00 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.30 (t, J = 2.7 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.05 (s, 1H), 6.24 (t, J = 2.4 Hz, 1H), 4.62-4.61 (m, 1H), 3.73 ( s, 3H), 3.20 (s, 3H), 2.04–1.70 (m, 8H).
实施例16Example 16
4-(2-(环己氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cyclohexyloxy)-5-(S-methylsulfaminynoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one
Figure PCTCN2018072204-appb-000082
Figure PCTCN2018072204-appb-000082
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用环己醇取代2,4-二氟苯酚，得到标题化合物4-(2-(环己氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material of the reaction, and the title compound 4-(2-(cyclohexyloxy)-5- is obtained by substituting cyclohexanol for 2,4-difluorophenol with reference to the fifth step of Example 10. (S-Methylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.
MS m/z(ESI):400.1[M+H] + MS m/z (ESI): 400.1 [M+H] +
1H NMR(400MHz,CDCl 3):δ11.17(s,1H),8.05(d,J＝2.4Hz,1H),7.95(dd,J＝8.7Hz,2.4Hz,1H),7.30(t,J＝2.6Hz,1H),7.12(s,1H),7.09(d,J＝8.8Hz,1H),6.28(t,J＝2.2Hz,1H),4.42-4.41(m,1H),3.73(s,3H),3.17(s,3H),1.90-1.88(m,2H),1.61-1.60(m,2H),1.49-1.48(m,2H),1.34-1.32(m,4H). 1 H NMR (400MHz, CDCl 3 ): δ11.17 (s, 1H), 8.05 (d, J = 2.4Hz, 1H), 7.95 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.30 (t, J = 2.6 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.28 (t, J = 2.2 Hz, 1H), 4.42-4.41 (m, 1H), 3.73 ( s, 3H), 3.17 (s, 3H), 1.90-1.88 (m, 2H), 1.61-1.60 (m, 2H), 1.49-1.48 (m, 2H), 1.34-1.32 (m, 4H).
实施例17Example 17
N-((4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(甲基)(羰基)-λ 6-硫烷亚基)环丙磺酰胺的制备 N-((4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Preparation of phenyl)(methyl)(carbonyl)-λ 6 -sulfane subunit)cyclopropanesulfonamide
Figure PCTCN2018072204-appb-000083
Figure PCTCN2018072204-appb-000083
以4-(2-(环丙基甲氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为起始原料，参考实施例2第一步，得到标题化合物N-((4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(甲基)(羰基)-λ 6-硫烷亚基)环丙磺酰胺。 4-(2-(cyclopropylmethoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one was used as the starting material. The title compound N-((4-(cyclopropylmethoxy)-3-(6-methyl-7-) Carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)(methyl)(carbonyl)-λ 6 -sulfaninyl)cyclopropanesulfonamide.
MS m/z(ESI):476.1[M+H] + MS m/z (ESI): 476.1 [M+H] +
1H NMR(400MHz,CDCl 3)δ10.62(s,1H),8.00(d,J＝2.5Hz,1H),7.94(dd,J＝8.8Hz,2.4Hz,1H),7.20(s,1H),7.14(s,1H),7.06(d,J＝8.8Hz,1H),6.25(d,J＝2.2Hz,1H),3.89(d,J＝6.7Hz,2H),3.71(s,3H),3.37(s,3H),2.71–2.57(m,1H),1.24–1.18(m,4H),1.15–1.04(m,1H),1.00–0.90(m,2H),0.52–0.47(m,2H),0.23–0.19(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ10.62 (s, 1H), 8.00 (d, J = 2.5Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.20 (s, 1H ), 7.14 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 2.2 Hz, 1H), 3.89 (d, J = 6.7 Hz, 2H), 3.71 (s, 3H) ), 3.37 (s, 3H), 2.71–2.57 (m, 1H), 1.24–1.18 (m, 4H), 1.15–1.04 (m, 1H), 1.00–0.90 (m, 2H), 0.52–0.47 (m) , 2H), 0.23–0.19 (m, 2H).
实施例18Example 18
4-(2-(3-氨基苯氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(3-Aminophenoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]Preparation of pyridin-7-one
Figure PCTCN2018072204-appb-000084
Figure PCTCN2018072204-appb-000084
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用3-氨基苯酚取代2,4-二氟苯酚，得到4-(2-(3-氨基苯氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, the 2,4-difluorophenol is substituted with 3-aminophenol to obtain 4-(2-(3-aminophenoxy)-5. -(S-Methylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.
MS m/z(ESI):409.1[M+H] + MS m/z (ESI): 409.1 [M+H] +
1H NMR(400MHz,DMSO-d 6):δ12.16(s,1H),8.24(d,J＝2.6Hz,1H),8.11(dd,J＝8.9Hz,2.6Hz,1H),7.52(s,1H),7.47(t,J＝8.0Hz,1H),7.32(t,J＝2.8Hz,1H),7.24(d,J＝8.9Hz,1H),7.13(d,J＝7.7Hz,1H),7.06(s,1H),7.00(d,J＝8.0Hz,1H),6.50–6.22(m,1H),4.01(s,3H),3.59(s,3H). 1 H NMR (400MHz, DMSO- d 6): δ12.16 (s, 1H), 8.24 (d, J = 2.6Hz, 1H), 8.11 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.52 ( s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 2.8 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.06 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.50 - 6.22 (m, 1H), 4.01 (s, 3H), 3.59 (s, 3H).
实施例19Example 19
4-(5-((二甲基(羰基)-λ6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-((Dimethyl(carbonyl)-λ6-sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000085
Figure PCTCN2018072204-appb-000085
第一步：亚氨基二甲基-λ6-硫烷酮First step: iminodimethyl-λ6-sulfanone
Figure PCTCN2018072204-appb-000086
Figure PCTCN2018072204-appb-000086
将二甲亚砜(5g，64mmol)溶于二氯甲烷(40mL)，0℃下加入叠氮化钠(4.4g，68mmol)，滴加浓硫酸(13mL)。反应在35℃下搅拌过夜，将反应液倒入冰水中(100g)，分出水层，水相旋干，加入乙醇(100mL)打浆30分钟，过滤，滤液旋干，加入二氯甲烷(100mL)打浆30分钟，过滤，滤液旋干得到亚氨基二甲基-λ6-硫烷酮(5.2g，产率87％)。Dimethyl sulfoxide (5 g, 64 mmol) was dissolved in dichloromethane (40 mL) and sodium azide (4.4 g, The reaction was stirred at 35 ° C overnight, the reaction solution was poured into ice water (100 g), the aqueous layer was separated, and the aqueous phase was evaporated to dryness, and the mixture was stirred in ethanol (100 mL) for 30 minutes, filtered, and the filtrate was evaporated to dryness. It was beaten for 30 minutes, filtered, and the filtrate was dried to give iminodimethyl-[lambda]6-sulfanone (5.2 g, yield 87%).
1H NMR(400MHz,CDCl 3)δ3.09(s,6H),2.68(brs,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.09 (s, 6H), 2.68 (brs, 1H).
第二步：2-溴-4-硝基-1-苯氧基苯的制备The second step: preparation of 2-bromo-4-nitro-1-phenoxybenzene
Figure PCTCN2018072204-appb-000087
Figure PCTCN2018072204-appb-000087
将2-溴-1-氟-4硝基苯(2g，9mmol)，苯酚(0.9g，10mmol)溶于二甲亚砜 (20mL)中，加入碳酸铯(3.3g，10mmol)。反应在100℃搅拌过夜，反应完全后，在25℃下加入水(50mL)，用乙酸乙酯(50mL)萃取，再用饱和氯化钠水溶液(20mL)洗涤，分出乙酸乙酯，减压脱除乙酸乙酯得到2-溴-4-硝基-1-苯氧基苯(2.7g，产率100％)。2-Bromo-1-fluoro-4-nitrobenzene (2 g, 9 mmol), phenol (0.9 g, 10 mmol) was dissolved in dimethyl sulfoxide (20 mL) and EtOAc (3 g, The reaction was stirred at 100 ° C overnight. After the reaction was completed, water (50 mL) was evaporated. Ethyl acetate was removed to give 2-bromo-4-nitro-1-phenoxybenzene (2.7 g, yield 100%).
第三步：3-溴-4-苯氧基苯胺的制备The third step: preparation of 3-bromo-4-phenoxyaniline
Figure PCTCN2018072204-appb-000088
Figure PCTCN2018072204-appb-000088
将2-溴-4-硝基-1-苯氧基苯(2.7g，9mmol)溶于乙醇(20mL)、四氢呋喃(20mL)、水(10mL)，加入铁粉(2.5g，45mmol)、氯化铵(2.4g，45mmol)。升温至75℃,搅拌1.5小时，经硅藻土过滤，滤液脱除溶剂，加入二氯甲烷萃取，分层，干燥，减压脱除二氯甲烷得到3-溴-4-苯氧基苯胺(2.0g，产率83％)。2-Bromo-4-nitro-1-phenoxybenzene (2.7 g, 9 mmol) was dissolved in ethanol (20 mL), tetrahydrofuran (20 mL), water (10 mL), and iron powder (2.5 g, 45 mmol) Ammonium (2.4 g, 45 mmol). The mixture was heated to 75 ° C, stirred for 1.5 hours, filtered through celite, and the solvent was evaporated. 2.0 g, yield 83%).
MS m/z(ESI):264.0/266.0(50/50)[M+H] +. MS m/z (ESI): 264.0 / 266.0 (50 / 50) [M+H] + .
第四步：2-溴-4-碘-1-苯氧基苯The fourth step: 2-bromo-4-iodo-1-phenoxybenzene
Figure PCTCN2018072204-appb-000089
Figure PCTCN2018072204-appb-000089
将3-溴-4-苯氧基苯胺(0.8g，3mmol)溶于乙腈(30mL)、水(5mL)，加入对甲苯磺酸一水合物(1.8g，10mmol)，在0℃下，滴加亚硝酸钠(0.4g，6mmol)与碘化钾(1.3g，8mmol)的水溶液(5mL)，在25℃下反应3小时，加入亚硫酸钠饱和溶液(20mL)，蒸除有机溶剂，加入乙酸乙酯(100mL)萃取，乙酸乙酯旋干柱层析得到2-溴-4-碘-1-苯氧基苯(678mg，产率58％)。3-Bromo-4-phenoxyaniline (0.8 g, 3 mmol) was dissolved in acetonitrile (30 mL), water (5 mL), and p-toluenesulfonic acid monohydrate (1.8 g, 10 mmol) was added at 0 ° C Add sodium nitrite (0.4 g, 6 mmol) and potassium iodide (1.3 g, 8 mmol) in an aqueous solution (5 mL), and react at 25 ° C for 3 hours, add a saturated solution of sodium sulfite (20 mL), evaporate the organic solvent, and add ethyl acetate ( Extraction with 100 mL), EtOAc EtOAc EtOAc.
第五步：((3-溴-4-苯氧基苯基)亚氨基)二甲基-λ6-硫烷酮Step 5: ((3-Bromo-4-phenoxyphenyl)imino)dimethyl-λ6-sulfanone
Figure PCTCN2018072204-appb-000090
Figure PCTCN2018072204-appb-000090
将2-溴-4-碘-1-苯氧基苯(300mg，0.8mmol)，亚氨基二甲基-λ6-硫烷酮(88mg，0.9mmol)溶于二氧六环(5mL)中，再加入碳酸铯(359mg，1.1mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(34mg，0.06mmol)、三(二亚苄基丙酮)二钯(22mg，0.02mmol)，氮气置换并保护。在100℃搅拌3小时，加入硅胶旋干柱层析得((3-溴-4-苯氧基苯基)亚氨基)二甲基-λ6-硫烷酮(160mg，产率59％)。2-Bromo-4-iodo-1-phenoxybenzene (300 mg, 0.8 mmol), iminodimethyl-λ6-sulfanone (88 mg, 0.9 mmol) was dissolved in dioxane (5 mL). Additional cesium carbonate (359 mg, 1.1 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (34 mg, 0.06 mmol), tris(dibenzylideneacetone) dipalladium (22 mg) , 0.02 mmol), replaced with nitrogen and protected. After stirring at 100 ° C for 3 hours, it was added to a silica gel spin-purified column to give ((3-bromo-4-phenoxyphenyl)imino) dimethyl-[lambda]6-sulfanone (160 mg, yield 59%).
第六步：4-(5-((二甲基(羰基)-λ6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 6: 4-(5-((Dimethyl(carbonyl)-λ6-sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1-toluenesulfonyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000091
Figure PCTCN2018072204-appb-000091
将((3-溴-4-苯氧基苯基)亚氨基)二甲基-λ6-硫烷酮(160mg，0.5mmol)，中间体Im(262mg，0.6mmol)溶于二氧六环(5mL)与水(1mL)中，加入碳酸钾(137mg，0.6mmol)，[1,1'-二(二苯基膦基)二茂铁]二氯钯(II)(40mg，0.05mmol)，氮气置换并保护，在100℃下搅拌3小时，加入硅胶旋干柱层析得4-(5-((二甲基(羰基)-λ6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(100mg，产率38％)。((3-Bromo-4-phenoxyphenyl)imino)dimethyl-λ6-sulfanone (160 mg, 0.5 mmol), Intermediate Im (262 mg, 0.6 mmol) was dissolved in dioxane ( 5 mL) and water (1 mL), potassium carbonate (137 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.05 mmol), Displaced and protected with nitrogen, stirred at 100 ° C for 3 hours, and added to a silica gel spin-dry column to give 4-(5-((dimethyl(carbonyl))-[lambda]6-sulfaninyl)amino)-2-phenoxy Phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, yield 38%).
MS m/z(ESI):562.1[M+H] +. MS m/z (ESI): 5621. [M+H] + .
第七步 4-(5-((二甲基(羰基)-λ6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 7 4-(5-((Dimethyl(carbonyl)-λ6-sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1-toluenesulfonyl-1,6 -dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000092
Figure PCTCN2018072204-appb-000092
以4-(5-((二甲基(羰基)-λ6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为起始原料，参考实施例1第八步水解，得到4-(5-((二甲基(羰基)-λ6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率17％)。4-(5-((Dimethyl(carbonyl)-λ6-sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one is used as a starting material, and is hydrolyzed according to the eighth step of Example 1, to obtain 4-(5-((dimethyl(carbonyl))-[lambda]6-sulfur Alkylene)amino)-2-phenoxyphenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Yield 17%).
MS m/z(ESI):408.1[M+H] +. MS m/z (ESI): 408.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ11.98(br,1H),7.19-7.26(m,4H),7.07(s,1H),6.93-6.95(m,3H),6.78(d,J＝8Hz,2H),6.24(s,1H),3.47(s,3H),3.23(s,6H)。 1 H NMR (400MHz, DMSO- d6): δ11.98 (br, 1H), 7.19-7.26 (m, 4H), 7.07 (s, 1H), 6.93-6.95 (m, 3H), 6.78 (d, J = 8 Hz, 2H), 6.24 (s, 1H), 3.47 (s, 3H), 3.23 (s, 6H).
实施例20Example 20
4-(2-(环丙基甲氧基)-5-((二甲基(羰基)-l6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cyclopropylmethoxy)-5-((dimethyl(carbonyl)-l6-sulfaninyl)amino)phenyl)-6-methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000093
Figure PCTCN2018072204-appb-000093
第一步 2-溴-1-(环丙基甲氧基)-4-硝基苯First step 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene
Figure PCTCN2018072204-appb-000094
Figure PCTCN2018072204-appb-000094
将2-溴-1-氟-4-硝基苯(5g，22.7mmol)、环丙基甲醇(2g，27.3mmol)溶于N,N-二甲基甲酰胺(20mL)中，在0℃下分批加入钠氢(1.2g，29.5mmol)，搅拌2小时。加入水(60mL)，加入乙酸乙酯(100mL)萃取，减压除去乙酸乙酯得2-溴-1-(环丙基甲氧基)-4-硝基苯(6g，产率96％)。2-Bromo-1-fluoro-4-nitrobenzene (5g, 22.7mmol), cyclopropylmethanol (2g, 27.3mmol) was dissolved in N,N-dimethylformamide (20mL) at 0°C Sodium hydrogen (1.2 g, 29.5 mmol) was added portionwise and stirred for 2 hours. Water (60 mL) was added, and ethyl acetate (100 mL) was added and evaporated, and ethyl acetate was evaporated to give 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene (6 g, yield 96%) .
第二步 3-溴-4-(环丙基甲氧基)苯胺The second step 3-bromo-4-(cyclopropylmethoxy)aniline
Figure PCTCN2018072204-appb-000095
Figure PCTCN2018072204-appb-000095
以2-溴-1-(环丙基甲氧基)-4-硝基苯为反应原料，参考实施例19第三步，柱层析得3-溴-4-(环丙基甲氧基)苯胺(2.7g，产率50％)。Using 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene as the starting material, the third step of Example 19 was followed by column chromatography to give 3-bromo-4-(cyclopropylmethoxy). Aniline (2.7 g, yield 50%).
第三步 2-溴-1-(环丙基甲氧基)-4-碘苯The third step 2-bromo-1-(cyclopropylmethoxy)-4-iodobenzene
Figure PCTCN2018072204-appb-000096
Figure PCTCN2018072204-appb-000096
以3-溴-4-(环丙基甲氧基)苯胺为反应原料，参考实施例19第四步，柱层析得2-溴-1-(环丙基甲氧基)-4-碘苯(266mg，产率61％)。3-bromo-4-(cyclopropylmethoxy)-4-iodide was obtained by column chromatography according to the fourth step of Example 19 using 3-bromo-4-(cyclopropylmethoxy)aniline as the starting material. Benzene (266 mg, yield 61%).
第四步 ((3-溴-4-(环丙基甲氧基)苯基)亚氨基)二甲基-λ6-硫烷酮The fourth step ((3-bromo-4-(cyclopropylmethoxy)phenyl)imino)dimethyl-λ6-sulfanone
Figure PCTCN2018072204-appb-000097
Figure PCTCN2018072204-appb-000097
以2-溴-1-(环丙基甲氧基)-4-碘苯为反应原料，操作参考实施例19第五步，柱层析得((3-溴-4-(环丙基甲氧基)苯基)亚氨基)二甲基-λ6-硫烷酮(产率46％)。Using 2-bromo-1-(cyclopropylmethoxy)-4-iodobenzene as the starting material, the fifth step of Reference Example 19 was carried out and column chromatography ((3-bromo-4-(cyclopropyl)) Oxy)phenyl)imino)dimethyl-λ6-sulfanone (yield 46%).
第五步 4-(2-(环丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 5 4-(2-(Cyclopropylmethoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1-toluene Acyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000098
Figure PCTCN2018072204-appb-000098
以((3-溴-4-(环丙基甲氧基)苯基)亚氨基)二甲基-λ6-硫烷酮与中间体Im为反应原料，操作参考实施例19第六步，得4-(2-(环丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。Taking ((3-bromo-4-(cyclopropylmethoxy)phenyl)imino)dimethyl-λ6-sulfanone and the intermediate Im as the starting materials, the sixth step of the reference example 19 is obtained. 4-(2-(cyclopropylmethoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1-toluenesulfonyl-1 , 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one.
MS m/z(ESI):540.1[M+H] +. MS m/z (ESI): 540.1 [M+H] + .
第六步 4-(2-(环丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 6 4-(2-(cyclopropylmethoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000099
Figure PCTCN2018072204-appb-000099
以4-(2-(环丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，操作参考实施例1第八步水解，得4-(2-(环丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。4-(2-(cyclopropylmethoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1-toluenesulfonyl- 1,6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one is the starting material for the reaction, and the hydrolysis is carried out in the eighth step of Reference Example 1, to obtain 4-(2-(cyclopropylmethoxy). -5-((Dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone.
MS m/z(ESI):386.1[M+H] +. MS m/z (ESI): 386.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ11.95(br,1H),7.26(t,J＝2.4Hz,1H),7.24(s,1H),6.91-6.95(m,2H),6.83-6.86(m,1H),6.15(t,J＝2.4Hz,1H),3.73(d,J＝6.8,Hz2H),3.55(s,3H),3.16(s,6H),0.99-1.08(m,1H),0.39-0.44(m,2H),0.16-0.20(m,2H). 1 H NMR (400MHz, DMSO- d6): δ11.95 (br, 1H), 7.26 (t, J = 2.4Hz, 1H), 7.24 (s, 1H), 6.91-6.95 (m, 2H), 6.83- 6.86(m,1H), 6.15(t,J=2.4Hz,1H),3.73(d,J=6.8,Hz2H),3.55(s,3H),3.16(s,6H),0.99-1.08(m, 1H), 0.39-0.44 (m, 2H), 0.16-0.20 (m, 2H).
实施例21Example 21
4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)-l6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-difluorophenoxy)-5-((dimethyl(carbonyl)-l6-sulfaninyl)amino)phenyl)-6-methyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000100
Figure PCTCN2018072204-appb-000100
第一步 2-溴-1-(2,4-二氟苯氧基)-4-硝基苯First step 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene
Figure PCTCN2018072204-appb-000101
Figure PCTCN2018072204-appb-000101
用2,4-二氟苯酚取代苯酚，反应操作参考实施例19第二步，以2,4-二氟苯酚取代苯酚，得2-溴-1-(2,4-二氟苯氧基)-4-硝基苯(产率100％)。Substituting 2,4-difluorophenol for phenol, the reaction is carried out in the second step of Reference Example 19, substituting 2,4-difluorophenol for phenol to give 2-bromo-1-(2,4-difluorophenoxy) 4-nitrobenzene (yield 100%).
第二步 3-溴-4-(2,4-二氟苯氧基)苯胺The second step 3-bromo-4-(2,4-difluorophenoxy)aniline
Figure PCTCN2018072204-appb-000102
Figure PCTCN2018072204-appb-000102
以2-溴-1-(2,4-二氟苯氧基)-4-硝基苯为反应原料，操作参考实施例19第三步，得3-溴-4-(2,4-二氟苯氧基)苯胺(收率100％)。Using 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene as the starting material, the third step of Reference Example 19 was operated to obtain 3-bromo-4-(2,4-di). Fluorophenoxy)aniline (yield 100%).
MS m/z(ESI):300.0[M+H] +. MS m/z (ESI): 300.0 [M+H] + .
第三步 2-溴-1-(2,4-二氟苯氧基)-4-碘苯The third step 2-bromo-1-(2,4-difluorophenoxy)-4-iodobenzene
Figure PCTCN2018072204-appb-000103
Figure PCTCN2018072204-appb-000103
以3-溴-4-(2,4-二氟苯氧基)苯胺为反应原料，操作参考实施例19第四步，得2-溴-1-(2,4-二氟苯氧基)-4-碘苯。Using 4-bromo-4-(2,4-difluorophenoxy)aniline as the starting material, the fourth step of Reference Example 19 was carried out to obtain 2-bromo-1-(2,4-difluorophenoxy). 4-iodobenzene.
第四步 ((3-溴-4-(2,4-二氟苯氧基)苯基)亚氨基)二甲基-λ6-硫烷酮The fourth step ((3-bromo-4-(2,4-difluorophenoxy)phenyl)imino)dimethyl-λ6-sulfanone
Figure PCTCN2018072204-appb-000104
Figure PCTCN2018072204-appb-000104
以2-溴-1-(2,4-二氟苯氧基)-4-碘苯为反应原料，操作参考实施例19第五步，得((3-溴-4-(2,4-二氟苯氧基)苯基)亚氨基)二甲基-λ6-硫烷酮。Using 2-bromo-1-(2,4-difluorophenoxy)-4-iodobenzene as the starting material, the fifth step of Reference Example 19 was carried out to obtain ((3-bromo-4-(2,4-) Difluorophenoxy)phenyl)imino)dimethyl-λ6-sulfanone.
第五步 4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 5 4-(2-(2,4-Difluorophenoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1 -toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000105
Figure PCTCN2018072204-appb-000105
以((3-溴-4-(2,4-二氟苯氧基)苯基)亚氨基)二甲基-λ6-硫烷酮与中间体Im为反应原料，操作参考实施例19第六步，得4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。Taking ((3-bromo-4-(2,4-difluorophenoxy)phenyl)imino)dimethyl-λ6-sulfanone and the intermediate Im as a reaction raw material, operation reference example 19 sixth Step: 4-(2-(2,4-difluorophenoxy)-5-((dimethyl(carbonyl)λ6-sulfaninyl)amino)phenyl)-6-methyl-1- Tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one.
MS m/z(ESI):598.1[M+H] +. MS m/z (ESI): 598.1 [M+H] + .
第六步 4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 6 4-(2-(2,4-Difluorophenoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1 ,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000106
Figure PCTCN2018072204-appb-000106
以4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，操作参考实施例1第八步水解，得4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)-λl-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(7mg，产率47％)。4-(2-(2,4-difluorophenoxy)-5-((dimethyl(carbonyl)λ6-sulfaninyl)amino)phenyl)-6-methyl-1-toluene Acyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one is the starting material of the reaction, and the hydrolysis is carried out in the eighth step of Reference Example 1, to obtain 4-(2-(2,4-) Difluorophenoxy)-5-((dimethyl(carbonyl)-λl-sulfaninyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one (7 mg, yield 47%).
MS m/z(ESI):444.1[M+H] +. MS m/z (ESI): 444.1 [M+H] + .
1H NMR(400MHz,CDCl3):δ10.06(br,1H),7.21(m,2H),7.10(s,1H),7.02(d,J＝6.4Hz,1H),6.76-6.83(m,3H),6.66-6.68(m,1H),6.42(s,1H),3.63(s,3H),3.16(s, 6H). 1 H NMR (400MHz, CDCl3) : δ10.06 (br, 1H), 7.21 (m, 2H), 7.10 (s, 1H), 7.02 (d, J = 6.4Hz, 1H), 6.76-6.83 (m, 3H), 6.66-6.68 (m, 1H), 6.42 (s, 1H), 3.63 (s, 3H), 3.16 (s, 6H).
实施例22Example 22
4-(2-(环己三烯并氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cyclohexanetrienoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000107
Figure PCTCN2018072204-appb-000107
第一步 2-溴-1-(环己三烯并氧基)-4-硝基苯First step 2-bromo-1-(cyclohexanetrienoxy)-4-nitrobenzene
Figure PCTCN2018072204-appb-000108
Figure PCTCN2018072204-appb-000108
以环己醇取代环丙基甲醇，反应操作参考实施例20第二步，以环己醇取代环丙基甲醇，得标题化合物2-溴-1-(环己三烯并氧基)-4-硝基苯。Replacing cyclopropylmethanol with cyclohexanol, the reaction was carried out in the second step of Reference Example 20, substituting cyclohexanol with cyclopropylmethanol to give the title compound 2-bromo-1-(cyclohexanetrienoxy)-4. - Nitrobenzene.
第二步 3-溴-4-(环己三烯并氧基)苯胺The second step 3-bromo-4-(cyclohexanetrienoxy)aniline
Figure PCTCN2018072204-appb-000109
Figure PCTCN2018072204-appb-000109
以2-溴-1-(环己三烯并氧基)-4-硝基苯为反应原料，操作参考实施例19第三步，得3-溴-4-(环己三烯并氧基)苯胺(产率100％)。Using 2-bromo-1-(cyclohexanetrienoxy)-4-nitrobenzene as the starting material, the third step of Reference Example 19 was carried out to obtain 3-bromo-4-(cyclohexanetrienoxy). Aniline (yield 100%).
MS m/z(ESI):270.0/272.0(50/50)[M+H] +. MS m/z (ESI): 270.0 / 272.0 (50 / 50) [M+H] + .
第三步 2-溴-1-(环己三烯并氧基)-4-碘苯The third step 2-bromo-1-(cyclohexanetrienoxy)-4-iodobenzene
Figure PCTCN2018072204-appb-000110
Figure PCTCN2018072204-appb-000110
以3-溴-4-(环己三烯并氧基)苯胺为反应原料，操作同实施例19第四步，得2-溴-1-(环己三烯并氧基)-4-碘苯(产率35％)。Using 4-bromo-4-(cyclohexanetrienoxy)aniline as the starting material, the same procedure as in the fourth step of Example 19 was carried out to obtain 2-bromo-1-(cyclohexanetrienoxy)-4-iodine. Benzene (yield 35%).
第四步 ((3-溴-4-(环己三烯并氧基)苯基)亚氨基)二甲基-λ6-硫烷酮The fourth step ((3-bromo-4-(cyclohexanetrienoxy)phenyl)imino)dimethyl-λ6-sulfanone
Figure PCTCN2018072204-appb-000111
Figure PCTCN2018072204-appb-000111
以2-溴-1-(环己三烯并氧基)-4-碘苯为反应原料，操作参考实施例19第五步，得((3-溴-4-(环己三烯并氧基)苯基)亚氨基)二甲基-λ6-硫烷酮(产率100％)。Using 2-bromo-1-(cyclohexanetrienoxy)-4-iodobenzene as the starting material, the fifth step of Reference Example 19 was carried out to obtain ((3-bromo-4-(cyclohexanetriene) Phenyl)imino)dimethyl-λ6-sulfanone (yield 100%).
MS m/z(ESI):346.0/347.0(50/50)[M+H]+.第五步 4-(2-(环己三烯并氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡 啶-7-酮MS m/z (ESI): 346.0/347.0 (50/50) [M+H]+. Step 5 4-(2-(cyclohexanetrienoxy)-5-((dimethyl (carbonyl) )-λ6-sulfane subunit)amino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000112
Figure PCTCN2018072204-appb-000112
以((3-溴-4-(环己三烯并氧基)苯基)亚氨基)二甲基-λ6-硫烷酮与中间体Im为反应原料，操作参考实施例19第六步，得4-(2-(环己三烯并氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(284mg，产率61％)。Taking ((3-bromo-4-(cyclohexanetrienoxy)phenyl)imino)dimethyl-λ6-sulfanone and the intermediate Im as a reaction raw material, the sixth step of the reference example 19 is operated. 4-(2-(cyclohexanetrienoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1-toluenesulfonyl -1,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (284 mg, yield 61%).
MS m/z(ESI):568.1[M+H] +. MS m/z (ESI): 568.1 [M+H] + .
第六步 4-(2-(环己三烯并氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 6 4-(2-(Cyclohexatrienoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1,6 -dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000113
Figure PCTCN2018072204-appb-000113
以4-(2-(环己三烯并氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，操作参考实施例1第八步，得4-(2-(环己三烯并氧基)-5-((二甲基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(28％)。4-(2-(cyclohexanetrienoxy)-5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1-toluenesulfonyl -1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one is the starting material of the reaction, and the eighth step of the reference example 1 is carried out to obtain 4-(2-(cyclohexanetriene) -5-((dimethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one (28%).
MS m/z(ESI):414.1[M+H] +。 MS m/z (ESI): 414.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ11.95(br,1H),7.26(t,J＝2.4Hz,1H),7.24(s,1H),6.94-6.97(m,2H),6.83-6.86(m,1H),6.17(t,J＝2.4Hz,1H),4.09-4.13(m,1H),3.55(s,3H),3.10(s,6H),1.72-1.75(m,2H),1.49-1.59(m,2H),1.15-1.40(m,6H). 1 H NMR (400MHz, DMSO- d6): δ11.95 (br, 1H), 7.26 (t, J = 2.4Hz, 1H), 7.24 (s, 1H), 6.94-6.97 (m, 2H), 6.83- 6.86(m,1H), 6.17(t,J=2.4Hz,1H),4.09-4.13(m,1H),3.55(s,3H),3.10(s,6H),1.72-1.75(m,2H) , 1.49-1.59 (m, 2H), 1.15 - 1.40 (m, 6H).
实施例23Example 23
4-(5-(乙基磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(ethylsulfimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000114
Figure PCTCN2018072204-appb-000114
以实施例10第四步反应的产物4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(49mg，0.1mmol)与反式4-甲基环己胺(1.0mL)反应体系密封之后置于150℃的封管条件下反应12小时。冷却到 室温。乙酸乙酯(10.0mL)稀释，饱和食盐水洗涤。有机相干燥蒸干，粗品液相制备分离得到4-(5-(乙基磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(15.4mg，产率36％)。The product of the reaction of the fourth step of Example 10 4-(5-(ethylsulfanimidoyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H - pyrrolo[2,3-c]pyridine-7-one (49 mg, 0.1 mmol) and trans 4-methylcyclohexylamine (1.0 mL) were sealed and placed under a sealed condition at 150 ° C. hour. Cool to room temperature. Ethyl acetate (10.0 mL) was diluted and washed with brine. The organic phase is dried and evaporated to dryness to give 4-(5-(ethylsulfanimidyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl. -1,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (15.4 mg, yield 36%).
MS m/z(ESI):427.2[M+H] +。 MS m/z (ESI): 427.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.78(dd,J＝8.8Hz,2.4Hz,1H),7.63(d,J＝2.4Hz,1H),7.36(d,J＝2.8Hz,1H),7.22(s,1H),6.91(d,J＝9.0Hz,1H),6.13(d,J＝2.8Hz,1H),3.71(s,3H),3.40(m,1H),3.23(q,J＝7.4Hz,2H),2.02(s,2H),1.72(s,2H),1.36(s,1H),1.25(t,J＝7.4Hz,3H),1.16–1.03(m,4H),0.92(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ7.78 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.63 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.22 (s, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.13 (d, J = 2.8 Hz, 1H), 3.71 (s, 3H), 3.40 (m, 1H), 3.23 (q, J = 7.4 Hz, 2H), 2.02 (s, 2H), 1.72 (s, 2H), 1.36 (s, 1H), 1.25 (t, J = 7.4 Hz, 3H), 1.16 - 1.03 (m, 4H), 0.92 ( d, J = 6.5 Hz, 3H).
实施例24Example 24
4-(2-(环庚基氨基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cycloheptylamino)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine Preparation of -7-ketone
Figure PCTCN2018072204-appb-000115
Figure PCTCN2018072204-appb-000115
以实施例10第四步反应的产物4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为起始原料，用环庚胺代替反式4-甲基环己胺参考实施例23第一步得到4-(2-(环庚基氨基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率19％)。The product of the reaction of the fourth step of Example 10 4-(5-(ethylsulfanimidoyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one as starting material, using cycloheptylamine in place of trans 4-methylcyclohexylamine. Reference Example 23, first step, 4-(2-(cycloheptane) Benzyl)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 19 %).
MS m/z(ESI):427.2[M+H] +。 MS m/z (ESI): 427.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.69(dd,J＝8.8Hz,2.4Hz,1H),7.53(d,J＝2.4Hz,1H),7.26(d,J＝2.8Hz,1H),7.12(s,1H),6.71(d,J＝9.0Hz,1H),6.02(d,J＝2.8Hz,1H),3.60(s,3H),3.57-3.50(m,1H),3.11(q,J＝7.4Hz,2H),1.82(s,2H),1.65-1.23(m,10H),1.13(t,J＝7.4Hz,3H). 1 H NMR (400MHz, MeOD) : δ7.69 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.12 (s, 1H), 6.71 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 3.60 (s, 3H), 3.57-3.50 (m, 1H), 3.11 (q) , J = 7.4 Hz, 2H), 1.82 (s, 2H), 1.65-1.23 (m, 10H), 1.13 (t, J = 7.4 Hz, 3H).
实施例25Example 25
4-(2-((环丙基甲基)氨基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((cyclopropylmethyl)amino)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one
Figure PCTCN2018072204-appb-000116
Figure PCTCN2018072204-appb-000116
以实施例10第四步反应的产物4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为起始原料，用环丙基甲胺代替反式4-甲基环己胺，参考实施例23第一步得到4-(2-((环丙基甲基)氨基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(35mg，产率63％)。The product of the reaction of the fourth step of Example 10 4-(5-(ethylsulfanimidoyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one as starting material, replacing trans 4-methylcyclohexylamine with cyclopropylmethylamine, and obtaining 4-(2-) with reference to the first step of Example 23. ((cyclopropylmethyl)amino)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (35 mg, yield 63%).
MS m/z(ESI):385.2[M+H] +. MS m/z (ESI): 385.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.90(dd,J＝9.2Hz,2.8Hz,1H),7.72(d,J＝2.4Hz,1H),7.38(d,J＝3.2Hz,1H),7.28(s,1H),7.07(d,J＝9.2Hz,1H),6.15(d,J＝2.8Hz,1H),3.84(q,J＝7.2Hz,2H),3.72(s,3H),3.16(d,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H),1.09-1.06(m,1H),0.51-0.46(m,2H),0.23-0.19(m,2H). 1 H NMR (400MHz, MeOD) : δ7.90 (dd, J = 9.2Hz, 2.8Hz, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.38 (d, J = 3.2Hz, 1H), 7.28(s,1H),7.07(d,J=9.2Hz,1H), 6.15(d,J=2.8Hz,1H),3.84(q,J=7.2Hz,2H),3.72(s,3H), 3.16 (d, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.09-1.06 (m, 1H), 0.51 - 0.46 (m, 2H), 0.23-0.19 (m, 2H) .
实施例26Example 26
4-(2-((4,4-二甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-((4,4-Dimethylcyclohexyl)amino)-5-(S-methylsulfimido)phenyl)-6-methyl-1,6-dihydro-7H- Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000117
Figure PCTCN2018072204-appb-000117
以实施例10第四步反应的产物4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用4,4二甲基环己胺代替反式4-甲基环己胺，参考实施例23第一步，得到4-(2-((4,4-二甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率46％)。The product of the reaction of the fourth step of Example 10 4-(5-(ethylsulfanimidoyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one as a starting material, using 4,4 dimethylcyclohexylamine in place of trans 4-methylcyclohexylamine, referring to the first step of Example 23, to give 4- (2-((4,4-Dimethylcyclohexyl)amino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one (yield 46%).
MS m/z(ESI):441.2[M+H] +. MS m/z (ESI): 441.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.78(dd,J＝9.1Hz,2.5Hz,1H),7.60(d,J＝2.5Hz,1H),7.27(d,J＝2.8Hz,1H),7.17(s,1H),6.95(d,J＝9.2Hz,1H),6.02(d,J＝2.8Hz,1H),3.78(q,J＝7.3Hz,2H),3.60(s,3H),3.46–3.32(m,1H),1.28(t,J＝7.3Hz,3H),1.27–1.16(m,8H),0.83(s,3H),0.75(s,3H). 1 H NMR (400MHz, MeOD) δ7.78 (dd, J = 9.1Hz, 2.5Hz, 1H), 7.60 (d, J = 2.5Hz, 1H), 7.27 (d, J = 2.8Hz, 1H), 7.17 (s, 1H), 6.95 (d, J = 9.2 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 3.78 (q, J = 7.3 Hz, 2H), 3.60 (s, 3H), 3.46 –3.32 (m, 1H), 1.28 (t, J = 7.3 Hz, 3H), 1.27–1.16 (m, 8H), 0.83 (s, 3H), 0.75 (s, 3H).
实施例27Example 27
4-(5-(乙基磺亚胺酰基)-2-(哌啶-1-基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(ethylsulfanimidoyl)-2-(piperidin-1-yl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Preparation of pyridin-7-one
Figure PCTCN2018072204-appb-000118
Figure PCTCN2018072204-appb-000118
以实施例10第四步反应的产物4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用哌啶代替反式4-甲基环己胺参考实施例23第一步，得到4-(5-(乙基磺亚胺酰基)-2-(哌啶-1-基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率44％)。The product of the reaction of the fourth step of Example 10 4-(5-(ethylsulfanimidoyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one as starting material, using piperidine instead of trans 4-methylcyclohexylamine. Refer to the first step of Example 23 to obtain 4-(5-(ethylsulfonate) Aminoacyl)-2-(piperidin-1-yl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 44 %).
MS m/z(ESI):399.2[M+H] +. MS m/z (ESI): 399.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.86(dd,J＝8.6Hz,2.4Hz,1H),7.82(d,J＝2.4Hz,1H),7.42(s,1H),7.35(d,J＝2.8Hz,1H),7.26(d,J＝8.6Hz,1H),6.28(d,J＝2.9Hz,1H),3.74(s,3H),3.25(q,J＝7.4Hz,2H),3.05–2.90(m,4H),1.40–1.31(m,6H),1.25(t,J＝7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ7.86 (dd, J = 8.6Hz, 2.4Hz, 1H), 7.82 (d, J = 2.4Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.28 (d, J = 2.9 Hz, 1H), 3.74 (s, 3H), 3.25 (q, J = 7.4 Hz, 2H), 3.05 – 2.90 (m, 4H), 1.40–1.31 (m, 6H), 1.25 (t, J = 7.4 Hz, 3H).
实施例28Example 28
4-(2-(环辛基氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cyclooctylamino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Preparation of pyridin-7-one
Figure PCTCN2018072204-appb-000119
Figure PCTCN2018072204-appb-000119
以实施例14第四步反应的产物4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环辛胺代替反式4-甲基环己胺参考实施例23第一步，得到4-(2-(环辛基氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率18％)。The product of the fourth step of the reaction of the fourth step of Example 14 4-(2-fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridin-7-one as starting material, replacing cyclo-4-octylamine with trans 4-methylcyclohexylamine. Referring to the first step of Example 23, 4-(2-(cyclo) was obtained. Octylamino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ( Yield 18%).
MS m/z(ESI):427.2[M+H] +. MS m/z (ESI): 427.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.86(d,J＝8.2Hz,1H),7.68(s,1H),7.28(d,J＝2.4Hz,1H),7.19(s,1H),6.86(d,J＝9.0Hz,1H),6.01(d,J＝2.3Hz,1H),3.66(s,3H),3.61(s,3H),3.60–3.54(m,1H),1.78–1.64(m,2H),1.40–1.54(m,12H). 1 H NMR (400MHz, MeOD) : δ7.86 (d, J = 8.2Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.19 (s, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.01 (d, J = 2.3 Hz, 1H), 3.66 (s, 3H), 3.61 (s, 3H), 3.60 - 3.54 (m, 1H), 1.78 - 1.64 ( m, 2H), 1.40–1.54 (m, 12H).
实施例29Example 29
4-(2-((环丙基甲基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-((cyclopropylmethyl)amino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 , 3-c]pyridine-7-one preparation
Figure PCTCN2018072204-appb-000120
Figure PCTCN2018072204-appb-000120
以实施例14第四步反应的产物4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环丙基甲胺代替反式4-甲基环己胺参考实施例23第一步，得到4-(2-((环丙基甲基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率33％)。The product of the fourth step of the reaction of the fourth step of Example 14 4-(2-fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one was used as a starting material, and cyclopropylmethylamine was used instead of trans 4-methylcyclohexylamine. The first step of Example 23 was carried out to obtain 4-(2- ((cyclopropylmethyl)amino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one (yield 33%).
MS m/z(ESI):371.2[M+H] +. MS m/z (ESI): 371.2 [M+H] + .
1H NMR(400MHz,DMSO)δ7.81(dd,J＝9.0Hz,2.5Hz,1H),7.66(d,J＝2.5Hz,1H),7.31(s,1H),7.24(s,1H),6.13(s,1H),6.04(s,1H),3.73(s,3H),3.57(s,3H),3.10(d,J＝5.7Hz,2H),1.09–0.95(m,1H),0.41-0.38(m,2H),0.23–0.12(m,2H). 1 H NMR (400MHz, DMSO) δ7.81 (dd, J = 9.0Hz, 2.5Hz, 1H), 7.66 (d, J = 2.5Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H) , 6.13 (s, 1H), 6.04 (s, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 3.10 (d, J = 5.7 Hz, 2H), 1.09 - 0.95 (m, 1H), 0.41-0.38 (m, 2H), 0.23–0.12 (m, 2H).
实施例30Example 30
6-甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备6-Methyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfimido)phenyl)-1,6-dihydro-7H- Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000121
Figure PCTCN2018072204-appb-000121
以实施例14第四步反应的产物4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与反式4-甲基环己胺为原料，参考实施例23第一步，得到6-甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率50％)。The product of the fourth step of the reaction of the fourth step of Example 14 4-(2-fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one and trans 4-methylcyclohexylamine were used as starting materials, and the first step of Example 23 was carried out to obtain 6-methyl-4-(2-( (trans-4-methylcyclohexyl)amino)-5-(S-methylsulfimidoyl)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (yield 50%).
MS m/z(ESI):413.2[M+H] +. MS m/z (ESI): 413.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.72(dd,J＝8.8,2.4Hz,1H),7.57(d,J＝2.4Hz,1H),7.25(d,J＝2.8Hz,1H),7.11(s,1H),6.78(d,J＝9.0Hz,1H),6.02(d,J＝2.8Hz,1H),3.59(s,3H),3.32–3.23(m,1H),3.03(s,3H),1.95–1.85(m,2H),1.65–1.58(m,2H),1.26–1.24(m,1H),1.08–0.87(m,4H),0.80(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ7.72 (dd, J = 8.8,2.4Hz, 1H), 7.57 (d, J = 2.4Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.11 ( s, 1H), 6.78 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.32 - 3.23 (m, 1H), 3.03 (s, 3H) ), 1.95–1.85 (m, 2H), 1.65–1.58 (m, 2H), 1.26–1.24 (m, 1H), 1.08–0.87 (m, 4H), 0.80 (d, J=6.5 Hz, 3H).
实施例31Example 31
4-(2-(环庚基氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cycloheptylamino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Preparation of pyridin-7-one
Figure PCTCN2018072204-appb-000122
Figure PCTCN2018072204-appb-000122
以实施例14第四步反应的产物4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环庚胺代替反式4-甲基环己胺参考实施例23第一步，得到4-(2-(环庚基氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率50％)。The product of the fourth step of the reaction of the fourth step of Example 14 4-(2-fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one is used as a starting material, and trans-heptylamine is substituted for trans 4-methylcyclohexylamine. The first step of Example 23 is carried out to obtain 4-(2-(cyclo). Heptylamino)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ( Yield 50%).
MS m/z(ESI):413.2[M+H] +. MS m/z (ESI): 413.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.86(d,J＝8.2Hz,1H),7.68(s,1H),7.28(d,J＝2.4Hz,1H),7.19(s,1H),6.86(d,J＝9.0Hz,1H),6.01(d,J＝2.3Hz,1H),3.72(s,3H),3.70–3.62(m,1H),3.15(s,3H),2.10–2.02(m,2H),1.70–1.46(m,10H). 1 H NMR (400MHz, MeOD) : δ7.86 (d, J = 8.2Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.19 (s, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.01 (d, J = 2.3 Hz, 1H), 3.72 (s, 3H), 3.70 - 3.62 (m, 1H), 3.15 (s, 3H), 2.10 - 2.02 ( m, 2H), 1.70–1.46 (m, 10H).
实施例32Example 32
4-(2-((环丙基甲基)氨基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-((cyclopropylmethyl)amino)-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ Preparation of 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000123
Figure PCTCN2018072204-appb-000123
以实施例5第四步反应的产物4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环丙基甲胺代替反式4-甲基环己胺，参考实施例23第一步，得到4-(2-((环丙基甲基)氨基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率46％)。The product of the fourth step of the reaction of the fourth step of Example 5 is 4-(2-fluoro-5-(propan-2-ylsulfanilidinoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one was used as a starting material, and trans-4-methylcyclohexylamine was replaced by cyclopropylmethylamine. The first step of Example 23 was carried out to obtain 4-( 2-((cyclopropylmethyl)amino)-5-(propan-2-ylsulfoimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one (yield 46%).
MS m/z(ESI):399.2[M+H] +. MS m/z (ESI): 399.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.66(dd,J＝9.1Hz,2.5Hz,1H),7.45(d,J＝2.5Hz,1H),7.16(d,J＝2.8Hz,1H),7.05(s,1H),6.87(d,J＝9.1Hz,1H),5.93(d,J＝2.8Hz,1H),3.95–3.75(m,1H),3.50(s,3H),2.94(d,J＝6.9Hz,2H),1.29(d,J＝6.7Hz,3H),1.21(d,J＝6.8Hz,3H),0.85(dd,J＝12.4,7.4Hz,1H),0.27(dd,J＝8.0,1.3Hz,2H),-0.00(dd,J＝7.6,2.7Hz,2H). 1 H NMR (400MHz, MeOD) δ7.66 (dd, J = 9.1Hz, 2.5Hz, 1H), 7.45 (d, J = 2.5Hz, 1H), 7.16 (d, J = 2.8Hz, 1H), 7.05 (s, 1H), 6.87 (d, J = 9.1 Hz, 1H), 5.93 (d, J = 2.8 Hz, 1H), 3.95 - 3.75 (m, 1H), 3.50 (s, 3H), 2.94 (d, J = 6.9 Hz, 2H), 1.29 (d, J = 6.7 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 0.85 (dd, J = 12.4, 7.4 Hz, 1H), 0.27 (dd, J = 8.0, 1.3 Hz, 2H), -0.00 (dd, J = 7.6, 2.7 Hz, 2H).
实施例33Example 33
4-(5-(环丙磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropaneimidoyl)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000124
Figure PCTCN2018072204-appb-000124
第一步：1,2-二(3-溴-4-氟苯基)二硫烷的制备.The first step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
Figure PCTCN2018072204-appb-000125
Figure PCTCN2018072204-appb-000125
3L三口瓶中依次加入3-溴-4-氟苯胺(60g,315.6mmol),乙腈(600mL)，水(600mL)，浓盐酸(300mL)。冰浴冷却至0-5℃，滴加亚硝酸钠(23.4g，316mmol)的水(300mL)溶液，维持体系温度在0-5℃。反应1小时后加入尿素(3.6g，60mmol)淬灭多余的亚硝酸钠，搅拌10分钟。1L的三口瓶中依次加入九水硫化钠(100.8g，420mmol)，硫磺粉(13.2g，420mmol)，NaOH(17.4g，432mmol)，水(300mL)。油浴加热至75℃反应1小时至溶液变澄清。将澄清溶液冷却至室温滴加到上述反应液中，并维持体系温度为0-5℃。滴加完毕后，反应液用乙酸乙酯(1Lx2)萃取，过滤，无水硫酸钠干燥，旋干得到粗品1,2-二(3-溴-4-氟苯基)二硫烷(42g，黄色油状物，产率64％)。3-Bromo-4-fluoroaniline (60 g, 315.6 mmol), acetonitrile (600 mL), water (600 mL), and concentrated hydrochloric acid (300 mL). The mixture was cooled to 0-5 ° C in an ice bath, and a solution of sodium nitrite (23.4 g, 316 mmol) in water (300 mL) was added dropwise, maintaining the system temperature at 0-5 °C. After 1 hour of reaction, urea (3.6 g, 60 mmol) was added to quench excess sodium nitrite and stirred for 10 minutes. Sodium sulfide nonahydrate (100.8 g, 420 mmol), sulfur powder (13.2 g, 420 mmol), NaOH (17.4 g, 432 mmol), water (300 mL) were sequentially added to a 1 L three-necked flask. The oil bath was heated to 75 ° C for 1 hour until the solution became clear. The clear solution was cooled to room temperature and added dropwise to the above reaction liquid, and the temperature of the system was maintained at 0 to 5 °C. After the completion of the dropwise addition, the reaction mixture was extracted with ethyl acetate (1 L.sub.2), filtered, dried over anhydrous sodium sulfate. Yellow oil, yield 64%).
第二步：3-溴-4-氟苯硫醇的制备The second step: the preparation of 3-bromo-4-fluorobenzenethiol
Figure PCTCN2018072204-appb-000126
Figure PCTCN2018072204-appb-000126
3L三口瓶中依次加入1,2-二(3-溴-4-氟苯基)二硫烷(42g，101.9mmol)，甲醇(300mL)，四氢呋喃(1L)，氢氧化钠(10.3g，257.5mmol)的水(300mL)溶液。室温下分五批加入硼氢化钠(11.1g，293.6mmol)。反应1小时后浓缩，加入氢氧化钠(35g，875.0mmol)的水(300mL)溶液，用甲基叔丁基醚(500mLx2)洗。水相滴加到盐酸(800mL，3mol/L)中，并维持体系温度为0-5℃。反应液用甲基叔丁基醚(500mLx3)萃取，无水硫酸钠干燥，旋干得到3-溴-4-氟苯硫醇(16g，黄色油状物，产率38％)。1,2-bis(3-bromo-4-fluorophenyl)disulfane (42 g, 101.9 mmol), methanol (300 mL), tetrahydrofuran (1 L), sodium hydroxide (10.3 g, 257.5) were sequentially added to a 3L three-necked flask. A solution of mmol (300 mL) of water. Sodium borohydride (11.1 g, 293.6 mmol) was added in five portions at room temperature. After 1 hour of reaction, the mixture was concentrated. EtOAc EtOAc m. The aqueous phase was added dropwise to hydrochloric acid (800 mL, 3 mol/L) and the system temperature was maintained at 0-5 °C. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl 3):δ7.50(dd,J＝6.3,2.3Hz,1H),7.23–7.16(m,1H),7.00(t,J＝8.4Hz,1H),3.48(s,1H). 1 H NMR (400MHz, CDCl 3 ): δ7.50 (dd, J = 6.3,2.3Hz, 1H), 7.23-7.16 (m, 1H), 7.00 (t, J = 8.4Hz, 1H), 3.48 (s , 1H).
第三步：1,2-二(3-溴-4-氟苯基)二硫烷的制备.The third step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
Figure PCTCN2018072204-appb-000127
Figure PCTCN2018072204-appb-000127
500mL三口瓶中依次加入3-溴-4-氟苯硫醇(14g,68.0mmol),乙腈(200mL)。室温下分五批加入碘苯二乙酸(21.9g，68.0mmol)。室温反应1小时后加水(100mL)淬灭，浓缩，乙酸乙酯(100mL x2)萃取，无水硫酸钠干燥,柱分离(石油醚)得到1,2-二(3-溴-4-氟苯基)二硫烷(14g,黄色油状物，产率100％)。3-Bromo-4-fluorobenzenethiol (14 g, 68.0 mmol), acetonitrile (200 mL) was added to a 500 mL three-necked flask. Iodophthalic acid (21.9 g, 68.0 mmol) was added in five portions at room temperature. After reacting at room temperature for 1 hour, it was quenched with water (100 mL), concentrated, ethyl acetate (100 mL×2), and dried over anhydrous sodium sulfate. Disulfane (14 g, yellow oil, yield 100%).
1H NMR(400MHz,CDCl 3):δ7.72–7.63(m,1H),7.39–7.28(m,1H),7.13–7.04(m,1H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.72 - 7.63 (m, 1H), 7.39 - 7.28 (m, 1H), 7.13 - 7.04 (m, 1H).
第四步：(3-溴-4-氟苯基)(环丙基)硫烷的制备.The fourth step: the preparation of (3-bromo-4-fluorophenyl) (cyclopropyl) sulane.
Figure PCTCN2018072204-appb-000128
Figure PCTCN2018072204-appb-000128
250mL三口瓶中依次加入1,2-二(3-溴-4-氟苯基)二硫烷(8g,19.4mmol),四氢呋喃(40mL)。氮气保护下于零下70℃滴加环丙基溴化镁(60mL，1M，60mmol)。反应1小时后加饱和NH 4Cl(100mL)淬灭，乙酸乙酯(100mL x2)萃取，无水硫酸钠干燥,柱分离(石油醚)得到(3-溴-4-氟苯基)(环丙基)硫烷(4.3g,黄色油状物，产率51％)。 1,2-bis(3-bromo-4-fluorophenyl)disulfane (8 g, 19.4 mmol) and tetrahydrofuran (40 mL) were sequentially added to a 250 mL three-necked flask. Cyclopropylmagnesium bromide (60 mL, 1 M, 60 mmol) was added dropwise at 70 ° C under nitrogen. After 1 hour the reaction was added saturated NH 4 Cl (100mL) was quenched with ethyl acetate (100mL x2) and extracted, dried over anhydrous sodium sulfate, and separated by column (petroleum ether) to give (3-bromo-4-fluorophenyl) (cyclo Propyl)sulfane (4.3 g, yellow oil, yield 51%).
1H NMR(400MHz,DMSO):δ7.65(m,1H),7.40–7.31(m,2H),2.35(m,4.3Hz,1H),1.13–1.06(m,2H),0.63–0.56(m,2H). 1 H NMR (400MHz, DMSO) : δ7.65 (m, 1H), 7.40-7.31 (m, 2H), 2.35 (m, 4.3Hz, 1H), 1.13-1.06 (m, 2H), 0.63-0.56 ( m, 2H).
第五步：2-溴-4-(环丙基亚硫酰基<亚磺酰>)-1-氟苯的制备.The fifth step: the preparation of 2-bromo-4-(cyclopropylsulfinyl <sulfinyl)-1-fluorobenzene.
Figure PCTCN2018072204-appb-000129
Figure PCTCN2018072204-appb-000129
以(3-溴-4-氟苯基)(环丙基)硫烷为反应原料，参考实施例4第二步，得到2-溴-4-(环丙基亚硫酰基<亚磺酰>)-1-氟苯(产率47％)。Using (3-bromo-4-fluorophenyl)(cyclopropyl)sulfane as the starting material, referring to the second step of Example 4, 2-bromo-4-(cyclopropylsulfinyl <sulfinyl> was obtained. )-1-fluorobenzene (yield 47%).
1H NMR(400MHz,DMSO):δ8.01(dd,J＝6.5,2.1Hz,1H),7.76(m,1H),7.61(t,J＝8.6Hz,1H),2.55(m,1H),1.04–0.90(m,3H),0.88–0.80(m,1H). 1 H NMR (400MHz, DMSO) : δ8.01 (dd, J = 6.5,2.1Hz, 1H), 7.76 (m, 1H), 7.61 (t, J = 8.6Hz, 1H), 2.55 (m, 1H) , 1.04–0.90 (m, 3H), 0.88–0.80 (m, 1H).
第六步：(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮的制备 Step 6: Preparation of (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000130
Figure PCTCN2018072204-appb-000130
以2-溴-4-(环丙基亚硫酰基<亚磺酰>)-1-氟苯为原料，参考实施例5第三步，得到(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(产率100％)。 Using 2-bromo-4-(cyclopropylsulfinyl <sulfinyl)-1-fluorobenzene as the starting material, referring to the third step of Example 5, (3-bromo-4-fluorophenyl) (cyclo) was obtained. Propyl)(imino)-λ 6 -thione (yield 100%).
MS m/z(ESI):278.0/280.0(50/50)[M+H] +. MS m/z (ESI): 278.0 / 280.0 (50 / 50) [M+H] + .
第七步：4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Step 7: 4-(5-(Cyclopropioni)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000131
Figure PCTCN2018072204-appb-000131
以(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮为原料，参考实施例4第四步得到4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率47％) Using (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone as the starting material, refer to the fourth step of Example 4 to obtain 4-(5-(cyclopropaneimine). Acyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 47%)
MS m/z(ESI):500.1[M+H] + MS m/z (ESI): 500.1 [M+H] +
第八步：4-(5-(环丙磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 8: 4-(5-(Cyclopropioni)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro Preparation of -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000132
Figure PCTCN2018072204-appb-000132
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与反式-4-甲基环己烷-1-胺为反应原料。参考实施例23第一步，得到4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H- 吡咯并[2,3-c]吡啶-7-酮(产率34％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one and trans-4-methylcyclohexane-1-amine are the starting materials for the reaction. Referring to the first step of Example 23, 4-(5-(cyclopropylsulfinyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-1 was obtained. 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 34%).
MS m/z(ESI):439.2[M+H] + MS m/z (ESI): 439.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.79(dd,J＝8.8Hz,2.4Hz,1H),7.64(d,J＝2.4Hz,1H),7.37(d,J＝2.8Hz,1H),7.22(s,1H),6.89(d,J＝9.2Hz,1H),6.14(d,J＝2.8Hz,1H),3.71(s,3H),3.44-3.37(m,1H),2.74–2.63(m,1H),2.08-1.97(m,2H),1.77-1.69(m,2H),1.36-1.28(m,2H),1.27–1.20(m,1H),1.15–1.05(m,5H),0.99–0.94(m,1H),0.92(d,J＝6.4Hz,3H). 1 H NMR (400MHz, MeOD) δ7.79 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.22 (s, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 3.71 (s, 3H), 3.44 - 3.37 (m, 1H), 2.74 - 2.63 ( m,1H), 2.08-1.97 (m, 2H), 1.77-1.69 (m, 2H), 1.36-1.28 (m, 2H), 1.27–1.20 (m, 1H), 1.15–1.05 (m, 5H), 0.99–0.94 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).
实施例34Example 34
(S)-4-(5-(环丙磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与(R)-4-(5-(环丙磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与的制备(S)-4-(5-(cyclopropaneimidoyl)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one and (R)-4-(5-(cyclopropaneimidoyl)-2-((trans--4-methylcyclohexyl) Of amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000133
Figure PCTCN2018072204-appb-000133
将4-(5-(环丙磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(30mg)手性制备得到(S)-4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(13mg)和(R)-4-(5-(环丙磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(13mg)。4-(5-(Cyclopropioni)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H- Chiral preparation of pyrrolo[2,3-c]pyridin-7-one (30 mg) affords (S)-4-(5-(cyclopropaneimidoyl)-2-((trans-4-methyl) Cyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (13 mg) and (R)-4-(5- (cyclopropaneimido)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one (13 mg).
手型制备条件：Hand preparation conditions:
柱型Column type CHIRALPAK IGCHIRALPAK IG
柱尺寸Column size 5.0cm I.D.×25cm L5.0cm I.D.×25cm L
流动相Mobile phase MeOH/CH 3CN＝90/10(V/V MeOH/CH 3 CN=90/10 (V/V
流速Flow rate 60ml/min60ml/min
检测波长Detection wavelength UV 254nmUV 254nm
柱温Column temperature 35℃35°C
(S)-构型化合物：t R＝4.832min.MS m/z(ESI):439.2[M+H] + (S)-Construction Compound: t R = 4.832 min. MS m/z (ESI): 439.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.79(dd,J＝8.8Hz,2.4Hz,1H),7.64(d,J＝2.4Hz,1H),7.37(d,J＝2.8Hz,1H),7.22(s,1H),6.89(d,J＝9.2Hz,1H),6.14(d,J＝2.8Hz,1H),3.71(s,3H),3.44-3.37(m,1H),2.74–2.63(m,1H),2.08-1.97(m,2H),1.77-1.69(m,2H),1.36-1.28(m,2H),1.27–1.20(m,1H),1.15–1.05(m,5H),0.99–0.94(m,1H),0.92(d,J＝6.4Hz,3H). 1 H NMR (400MHz, MeOD) δ7.79 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.22 (s, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 3.71 (s, 3H), 3.44 - 3.37 (m, 1H), 2.74 - 2.63 ( m,1H), 2.08-1.97 (m, 2H), 1.77-1.69 (m, 2H), 1.36-1.28 (m, 2H), 1.27–1.20 (m, 1H), 1.15–1.05 (m, 5H), 0.99–0.94 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).
(R)-构型化合物：t R＝6.201min.MS m/z(ESI):439.2[M+H] + (R) - configuration compound: t R = 6.201min.MS m / z (ESI): 439.2 [M + H] +
1H NMR(400MHz,MeOD)δ7.79(dd,J＝8.8,2.4Hz,1H),7.64(d,J＝2.4Hz,1H),7.37(d,J＝2.8Hz,1H),7.22(s,1H),6.89(d,J＝9.2Hz,1H),6.14(d,J＝2.8Hz,1H),3.71(s,3H),3.44-3.37(m,1H),2.74–2.63(m,1H),2.08-1.97(m,2H),1.77-1.69 (m,2H),1.36-1.28(m,2H),1.27–1.20(m,1H),1.15–1.05(m,5H),0.99–0.94(m,1H),0.92(d,J＝6.4Hz,3H). 1 H NMR (400 MHz, MeOD) δ 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 2.8 Hz, 1H), 7.22 ( s, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 3.71 (s, 3H), 3.44 - 3.37 (m, 1H), 2.74 - 2.63 (m , 1H), 2.08-1.97 (m, 2H), 1.77-1.69 (m, 2H), 1.36-1.28 (m, 2H), 1.27–1.20 (m, 1H), 1.15–1.05 (m, 5H), 0.99 –0.94 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).
实施例35Example 35
4-(2-(环庚基氨基)-5-(环丙磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cycloheptylamino)-5-(cyclopropylsulfinyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine Preparation of -7-ketone
Figure PCTCN2018072204-appb-000134
Figure PCTCN2018072204-appb-000134
以实施例33第七步产物4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环庚胺代替反式4-甲基环己胺参考实施例23第一步，得到4-(2-(环庚基氨基)-5-(环丙磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率45％)。The product of the seventh step of Example 33, 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one as a starting material, using cycloheptylamine in place of trans 4-methylcyclohexylamine. The first step of Example 23 is carried out to obtain 4-(2-(cycloheptylamino). 5-(- propyl sulfanimidyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 45%).
MS m/z(ESI):439.2[M+H] +. MS m/z (ESI): 439.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.68(dd,J＝8.8Hz,2.4Hz,1H),7.53(d,J＝2.4Hz,1H),7.26(d,J＝2.8Hz,1H),7.11(s,1H),6.69(d,J＝9.0Hz,1H),6.02(d,J＝2.8Hz,1H),3.60(s,3H),2.59-2.53(m,1H),1.85–1.76(m,2H),1.59–1.26(m,8H),1.21(m,3H),1.18-1.10(m,1H),0.99-0.95(m,2H),0.92–0.73(m,1H). 1 H NMR (400MHz, MeOD) : δ7.68 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.11(s,1H), 6.69 (d, J=9.0Hz, 1H), 6.02 (d, J=2.8Hz, 1H), 3.60(s,3H), 2.59-2.53(m,1H),1.85–1.76 (m, 2H), 1.59–1.26 (m, 8H), 1.21 (m, 3H), 1.18-1.10 (m, 1H), 0.99-0.95 (m, 2H), 0.92–0.73 (m, 1H).
实施例36Example 36
4-(5-(环丙磺亚胺酰基)-2-(甲基(反式-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropaneimidoyl)-2-(methyl(trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H- Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000135
Figure PCTCN2018072204-appb-000135
以实施例33第七步产物4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用N-甲基反式4-甲基环己胺代替反式4-甲基环己胺，参考实施例23第一步，得到4-(5-(环丙磺亚胺酰基)-2-(甲基(反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率47％)。The product of the seventh step of Example 33, 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridin-7-one as a raw material, using N-methyl trans 4-methylcyclohexylamine in place of trans 4-methylcyclohexylamine, referring to the first step of Example 23, 4-(5-(cyclopropaneimidoyl)-2-(methyl(trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H Pyrrolo[2,3-c]pyridine-7-one (yield 47%).
MS m/z(ESI):453.2[M+H] +. MS m/z (ESI): 453.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.83(dd,J＝8.7Hz,2.5Hz,1H),7.77(d,J＝2.4Hz,1H),7.37(d,J＝2.8Hz,1H),7.27(s,1H),7.21(d,J＝8.8Hz,1H),6.20(d,J＝2.8Hz,1H),3.72(s,3H),3.25-3.15(m,1H),2.77–2.66(m,4H),1.58-1.51m,2H),1.46-1.37(m,2H),1.31–1.07(m,6H),1.02–0.95(m,1H),0.73(d,J＝4.0Hz,3H),0.52-0.43(m,2H). 1 H NMR (400MHz, MeOD) δ7.83 (dd, J = 8.7Hz, 2.5Hz, 1H), 7.77 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.27 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.20 (d, J = 2.8 Hz, 1H), 3.72 (s, 3H), 3.25-3.15 (m, 1H), 2.77 - 2.66 ( m,4H),1.58-1.51m,2H),1.46-1.37(m,2H),1.31–1.07(m,6H),1.02–0.95(m,1H),0.73(d,J=4.0Hz,3H ), 0.52-0.43 (m, 2H).
实施例37Example 37
4-(5-(环丙磺亚胺酰基)-2-((环丙基甲基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropaneimidoyl)-2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]Preparation of pyridin-7-one
Figure PCTCN2018072204-appb-000136
Figure PCTCN2018072204-appb-000136
以实施例33第七步产物4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环丙基甲基胺代替反式4-甲基环己胺，参考实施例23第一步，得到4-(5-(环丙磺亚胺酰基)-2-((环丙基甲基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备(产率40％)。The product of the seventh step of Example 33, 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridin-7-one as a raw material, using cyclopropylmethylamine instead of trans 4-methylcyclohexylamine, referring to the first step of Example 23, to obtain 4-(5-(cyclo) Propionimino)-2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Preparation of ketone (yield 40%).
MS m/z(ESI):397.17[M+H] +. MS m/z (ESI): 397.17 [M+H] + .
1HNMR(400MHz,MeOD)δ7.61(dd,J＝9.2Hz,2.4Hz,1H),7.47(d,J＝2.0Hz,1H),7.18(d,J＝2.8Hz,1H),7.05(s,1H),6.70(d,J＝8.8Hz,1H),5.98(d,J＝2.8Hz,1H),3.53(s,3H),2.90(d,J＝6.8Hz,2H),1.86-1.85(m,1H),1.45-1.43(m,1H),0.91-0.85(m,2H),0.75-0.71(m,2H),0.27-0.25(m,2H),0.17-0.15(m,2H). 1 H NMR (400 MHz, MeOD) δ 7.61 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.05 ( s, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.98 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H), 2.90 (d, J = 6.8 Hz, 2H), 1.86- 1.85 (m, 1H), 1.45-1.43 (m, 1H), 0.91-0.85 (m, 2H), 0.75-0.71 (m, 2H), 0.27-0.25 (m, 2H), 0.17-0.15 (m, 2H) ).
实施例38Example 38
4-(5-(环丙磺亚胺酰基)-2-((4,4-二甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropanesulfonyl)-2-((4,4-dimethylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000137
Figure PCTCN2018072204-appb-000137
以实施例33第七步产物4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用4,4-二甲基环己基胺代替反式4-甲基环己胺，参考实施例23第一步，得到4-(5-(环丙磺亚胺酰基)-2-((4,4-二甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率24％)。The product of the seventh step of Example 33, 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one as a starting material, and 4,4-dimethylcyclohexylamine was used instead of trans 4-methylcyclohexylamine. Referring to the first step of Example 23, 4-( 5-(cyclopropaneimido)-2-((4,4-dimethylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one (yield 24%).
MS m/z(ESI):453.2[M+H] +. MS m/z (ESI): 453.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.69(dd,J＝8.8Hz,2.4Hz,1H),7.55(d,J＝2.4Hz,1H),7.26(d,J＝2.8Hz,1H),7.12(s,1H),6.79(d,J＝9.0Hz,1H),6.04(d,J＝2.8Hz,1H),3.60(s,3H),3.36-3.27(m,1H),2.72–2.64(m,1H),1.72-1.65(m,2H),1.37–1.13(m,7H),1.11-0.95(m,2H),0.93-0.88(m,1H),0.83(s,3H),0.75(s,3H). 1 H NMR (400MHz, MeOD) : δ7.69 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.12(s,1H), 6.79(d,J=9.0Hz,1H),6.04(d,J=2.8Hz,1H), 3.60(s,3H),3.36-3.27(m,1H),2.72–2.64 (m, 1H), 1.72-1.65 (m, 2H), 1.37–1.13 (m, 7H), 1.11-0.95 (m, 2H), 0.93-0.88 (m, 1H), 0.83 (s, 3H), 0.75 (s, 3H).
实施例39Example 39
4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropionimido)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, Preparation of 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000138
Figure PCTCN2018072204-appb-000138
以实施例33第七步产物4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与2,4-二氟苯酚为原料，参考实施例4第四步，得到4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率44％)。The product of the seventh step of Example 33, 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridin-7-one and 2,4-difluorophenol as raw materials, referring to the fourth step of Example 4, to obtain 4-(5-(cyclopropaneimidoyl)-2-( 2,4-Difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 44%).
MS m/z(ESI):456.2[M+H] + MS m/z (ESI): 456.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.98(d,J＝2.4Hz,1H),7.81(dd,J＝8.7Hz,2.4Hz,1H),7.27(s,1H),7.25(d,J＝2.9Hz,1H),7.08-7.05(m,2H),6.89(dd,J＝15.1,5.4Hz,2H),6.28(d,J＝2.9Hz,1H),3.60(s,3H),2.67-2.64(m,1H),1.28–1.12(m,1H),1.04-0.98(m,2H),0.91-0.86(m,1H). 1 H NMR (400MHz, MeOD) δ7.98 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.08-7.05 (m, 2H), 6.89 (dd, J = 15.1, 5.4 Hz, 2H), 6.28 (d, J = 2.9 Hz, 1H), 3.60 (s, 3H), 2.67- 2.64 (m, 1H), 1.28–1.12 (m, 1H), 1.04-0.98 (m, 2H), 0.91-0.86 (m, 1H).
实施例40Example 40
(S)-4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮和(R)-4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备(S)-4-(5-(cyclopropanesulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one and (R)-4-(5-(cyclopropylsulfinyl)-2-(2,4-difluorophenoxy)phenyl)-6 -Preparation of methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000139
Figure PCTCN2018072204-appb-000139
将4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(60.0mg)以手性制备得(S)-4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(24mg)和(S)-4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(22mg)。4-(5-(Cyclopropioni)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one (60.0 mg) was obtained by chirality to give (S)-4-(5-(cyclopropylsulfinyl)-2-(2,4-difluorophenoxy)phenyl)- 6-Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (24 mg) and (S)-4-(5-(cyclopropaneimidoyl)- 2-(2,4-Difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (22 mg).
手型制备条件：Hand preparation conditions:
柱型Column type CHIRALPAK IGCHIRALPAK IG
柱尺寸Column size 5.0cm I.D.×25cm L5.0cm I.D.×25cm L
流动相Mobile phase EtOH/CH 3CN＝90/10(V/V) EtOH/CH 3 CN=90/10(V/V)
流速Flow rate 60ml/min60ml/min
检测波Detection wave UV 254nmUV 254nm
柱温Column temperature 35℃35°C
(S)-构型化合物：t R＝11.2min.MS m/z(ESI):456.2[M+H] +. (S) - configuration of the compounds: t R = 11.2min.MS m / z (ESI): 456.2 [M + H] +.
1H NMR(400MHz,MeOD)δ7.98(d,J＝2.4Hz,1H),7.81(dd,J＝8.7Hz,2.4Hz,1H),7.27(s,1H),7.25(d,J＝2.9Hz,1H),7.08-7.05(m,2H),6.89(dd,J＝15.1,5.4Hz,2H),6.28(d,J＝2.9Hz,1H),3.60(s,3H),2.67-2.64(m,1H),1.28–1.12(m, 1H),1.04-0.98(m,2H),0.91-0.86(m,1H). 1 H NMR (400MHz, MeOD) δ7.98 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.08-7.05 (m, 2H), 6.89 (dd, J = 15.1, 5.4 Hz, 2H), 6.28 (d, J = 2.9 Hz, 1H), 3.60 (s, 3H), 2.67- 2.64 (m, 1H), 1.28–1.12 (m, 1H), 1.04-0.98 (m, 2H), 0.91-0.86 (m, 1H).
(R)-构型化合物：t R＝11.6min.MS m/z(ESI):456.2[M+H] +. (R) - configuration compound: t R = 11.6min.MS m / z (ESI): 456.2 [M + H] +.
1H NMR(400MHz,MeOD)δ7.98(d,J＝2.4Hz,1H),7.81(dd,J＝8.7,2.4Hz,1H),7.27(s,1H),7.25(d,J＝2.9Hz,1H),7.08-7.05(m,2H),6.89(dd,J＝15.1,5.4Hz,2H),6.28(d,J＝2.9Hz,1H),3.60(s,3H),2.67-2.64(m,1H),1.28–1.12(m,1H),1.04-0.98(m,2H),0.91-0.86(m,1H). 1 H NMR (400MHz, MeOD) δ7.98 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.7,2.4Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.08-7.05 (m, 2H), 6.89 (dd, J = 15.1, 5.4 Hz, 2H), 6.28 (d, J = 2.9 Hz, 1H), 3.60 (s, 3H), 2.67-2.64 (m, 1H), 1.28–1.12 (m, 1H), 1.04-0.98 (m, 2H), 0.91-0.86 (m, 1H).
实施例41Example 41
4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H -Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000140
Figure PCTCN2018072204-appb-000140
第一步：2-溴-4-((1-氯环丙基)亚硫酰基<亚磺酰>)-1-氟苯的制备.The first step: the preparation of 2-bromo-4-((1-chlorocyclopropyl)sulfinyl <sulfinyl>)-1-fluorobenzene.
Figure PCTCN2018072204-appb-000141
Figure PCTCN2018072204-appb-000141
25mL单口瓶中依次加入实施例33第五步产物2-溴-4-(环丙基亚硫酰基<亚磺酰>)-1-氟苯(260mg,1.0mmol),四氯化碳(5mL)。室温下加入N-氯代丁二酰亚胺(150mg，1.1mmol)。油浴加热到60℃反应12小时后过滤，滤液浓缩柱分离(石油醚/乙酸乙酯＝5/1)得到2-溴-4-((1-氯环丙基)亚硫酰基<亚磺酰>)-1-氟苯(220mg,黄色油状物，产率74％)。The product of the fifth step of Example 33, 2-bromo-4-(cyclopropylsulfinyl <sulfinyl)-1-fluorobenzene (260 mg, 1.0 mmol), carbon tetrachloride (5 mL) was added to a 25 mL single-necked flask. ). N-chlorosuccinimide (150 mg, 1.1 mmol) was added at room temperature. The oil bath was heated to 60 ° C for 12 hours, filtered, and the filtrate was concentrated on a column (petroleum ether / ethyl acetate = 5 / 1) to give 2-bromo-4-((1-chlorocyclopropyl)sulfinyl <sulfin Acyl>)-1-fluorobenzene (220 mg, yellow oil, yield 74%).
MS m/z(ESI):296.9/298.9(50/50)[M+H]+.MS m/z (ESI): 296.9/298.9 (50/50) [M+H]+.
1H NMR(400MHz,CDCl 3)δ7.92(dd,J＝6.3,2.1Hz,1H),7.64(m,1H),7.28(dd,J＝13.0,4.5Hz,1H),1.67(dd,J＝4.0,2.8Hz,2H),1.44–1.37(m,1H),1.28–1.22(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.92 (dd, J = 6.3,2.1Hz, 1H), 7.64 (m, 1H), 7.28 (dd, J = 13.0,4.5Hz, 1H), 1.67 (dd, J=4.0, 2.8 Hz, 2H), 1.44–1.37 (m, 1H), 1.28–1.22 (m, 1H).
第二步：(3-溴-4-氟苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮的制备. The second step: (3-bromo-4-fluorophenyl) (1-chlorocyclopropyl) (imino)-λ 6 -sulfanone preparation.
Figure PCTCN2018072204-appb-000142
Figure PCTCN2018072204-appb-000142
以2-溴-4-((1-氯环丙基)亚硫酰基<亚磺酰>)-1-氟苯为原料，参考实施例5第三步，得到(3-溴-4-氟苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮(产率65％)。 Using 2-bromo-4-((1-chlorocyclopropyl)sulfinyl <sulfinyl>)-1-fluorobenzene as the starting material, referring to the third step of Example 5, (3-bromo-4-fluoro) Phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -thione (yield 65%).
MS m/z(ESI):311.9/313.9(50/50)[M+H] +. MS m/z (ESI): 311.9 / 313.9 (50 / 50) [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.27(dd,J＝6.3,2.3Hz,1H),8.00(m,1H),7.31(dd,J＝8.6,8.0Hz,1H),2.05–1.88(m,2H),1.55–1.38(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (dd, J = 6.3, 2.3 Hz, 1H), 8.00 (m, 1H), 7.31 (dd, J = 8.6, 8.0 Hz, 1H), 2.05 - 1.88 ( m, 2H), 1.55–1.38 (m, 2H).
第三步：(3-溴-4-(2,4-二氟苯氧基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮的制备. The third step: the preparation of (3-bromo-4-(2,4-difluorophenoxy)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone.
Figure PCTCN2018072204-appb-000143
Figure PCTCN2018072204-appb-000143
25mL单口瓶中依次加入(3-溴-4-氟苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮(150mg,0.48mmol),2,4-二氟苯酚(195mg,1.5mmol),碳酸铯(490mg,1.5mmol),二甲基亚砜(5mL)。油浴加热到80℃反应6小时后过滤，滤液浓缩柱分离(石油醚/乙酸乙酯＝3/1)得到(3-溴-4-(2,4-二氟苯氧基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮(150mg,黄色油状物，产率74％)。 (3-Bromo-4-fluorophenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone (150 mg, 0.48 mmol), 2,4-difluorophenol was added to a 25 mL single-mouth bottle (195 mg, 1.5 mmol), cesium carbonate (490 mg, 1.5 mmol), dimethyl sulfoxide (5 mL). The oil bath was heated to 80 ° C for 6 hours, filtered, and the filtrate was concentrated on a column (petroleum ether / ethyl acetate = 3 / 1) to give (3-bromo-4-(2,4-difluorophenoxy)phenyl) (1-Chlorocyclopropyl)(imino)-λ 6 -sulfanone (150 mg, yellow oil, yield 74%).
MS m/z(ESI):421.9/423.9(50/50)[M+H] +. MS m/z (ESI): 421.9 / 423.9 (50 / 50) [M+H] + .
第四步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Fourth step: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-toluene Preparation of acyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000144
Figure PCTCN2018072204-appb-000144
以(3-溴-4-(2,4-二氟苯氧基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮为原料，参考实施例4第四步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率43％)。 Taking (3-bromo-4-(2,4-difluorophenoxy)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone as a raw material, refer to Example 4 Step 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-toluenesulfonyl- 1,6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 43%).
MS m/z(ESI):644.1[M+H] +. MS m/z (ESI): 644.1 [M+H] + .
第五步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6- Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000145
Figure PCTCN2018072204-appb-000145
以4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率47％)。4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-toluenesulfonyl-1 , 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting material, and the eighth step of the first embodiment is obtained as 4-(5-(1-chlorocyclopropane-1-sulfinimide). Acyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one The rate is 47%).
MS m/z(ESI):490.0[M+H] +。 MS m / z (ESI): 490.0 [M + H] +.
1H NMR(400MHz,MeOD)δ8.05(d,J＝2.4Hz,1H),7.87(dd,J＝8.8Hz,2.4Hz,1H),7.32-7.23(m,2H),7.18-7.01(m,2H),6.96-6.84(m,2H),6.30(d,J＝2.9Hz,1H),3.61(s,3H),1.92-1.79(m,2H),1.45-1.37(m,1H),1.36-1.29(m,1H). 1 H NMR (400 MHz, MeOD) δ 8.05 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.18 - 7.01 ( m, 2H), 6.96-6.84 (m, 2H), 6.30 (d, J = 2.9 Hz, 1H), 3.61 (s, 3H), 1.92-1.79 (m, 2H), 1.45-1.37 (m, 1H) , 1.36-1.29 (m, 1H).
实施例42Example 42
4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6- Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000146
Figure PCTCN2018072204-appb-000146
第一步：(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮的制备 First step: Preparation of (3-bromo-4-((trans--4-methylcyclohexyl)amino)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000147
Figure PCTCN2018072204-appb-000147
氮气保护下，25mL单口瓶中依次加入实施例41第二步产物(3-溴-4-氟苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮(100mg,0.32mmol),反式-4-甲基环己胺(1.0mL)。油浴加热到80℃反应6小时后过滤，滤液浓缩柱分离(石油醚/乙酸乙酯＝3/1)得到(3-溴-4-((反式-4-甲基环己基)氨基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮(100mg,黄色油状物,产率77％)。 Under the protection of nitrogen, the product of the second step of Example 41 (3-bromo-4-fluorophenyl)(1-chlorocyclopropyl)(imino)-λ 6 -thione (100 mg, was added in a 25 mL single-necked flask. 0.32 mmol), trans-4-methylcyclohexylamine (1.0 mL). The oil bath was heated to 80 ° C for 6 hours, filtered, and the filtrate was concentrated on a column (petroleum ether / ethyl acetate = 3 / 1) to give (3-bromo-4-((trans-4-methylcyclohexyl)amino) Phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone (100 mg, yellow oil, yield 77%).
MS m/z(ESI):405.0/407(50/50)[M+H] +. MS m/z (ESI): 405.0 / 407 (50 / 50) [M+H] + .
第二步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Second step: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-1 -Preparation of tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000148
Figure PCTCN2018072204-appb-000148
以(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮为原料，参考实施例4第四步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率58％)。 Using (3-bromo-4-((trans--4-methylcyclohexyl)amino)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone as a raw material, refer to the implementation Example 4, step 4, 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl 1-Toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 58%).
MS m/z(ESI):627.1[M+H] +. MS m/z (ESI): 627.1 [M+H] + .
第三步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式--4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Third step: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans--4-methylcyclohexyl)amino)phenyl)-6-methyl- Preparation of 1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000149
Figure PCTCN2018072204-appb-000149
以4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-)-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(52mg,产率76％)。4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-1-toluene Acetyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one was used as the starting material, and the eighth step of Example 1 was obtained to obtain 4-(5-(1-chlorocyclopropane-1- Sulfimido)-2-((trans-)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one (52 mg, yield 76%).
MS m/z(ESI):473.1[M+H] +. MS m/z (ESI): 473.1 [M+H] + .
1H NMR(400MHz,MeOD):δ7.84(dd,J＝8.9Hz,2.4Hz,1H),7.70(d,J＝2.4Hz,1H),7.37(d,J＝2.8Hz,1H),7.22(s,1H),6.91(d,J＝9.0Hz,1H),6.17(d,J＝2.8Hz,1H),3.72(s,3H),3.45-3.38(m,1H),2.07-1.98(m,2H),1.94–1.85(m,2H),1.74(d,J＝7.7Hz,2H),1.50–1.30(m,3H),1.19–1.05(m,4H),0.92(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) : δ7.84 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.70 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.22 (s, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.17 (d, J = 2.8 Hz, 1H), 3.72 (s, 3H), 3.45-3.38 (m, 1H), 2.07-1.98 (m, 2H), 1.94–1.85 (m, 2H), 1.74 (d, J = 7.7 Hz, 2H), 1.50–1.30 (m, 3H), 1.19–1.05 (m, 4H), 0.92 (d, J) =6.5Hz, 3H).
实施例43Example 43
4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(环庚基氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(cycloheptylamino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 ,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000150
Figure PCTCN2018072204-appb-000150
第一步：(3-溴-4-(环庚基氨基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮的制备 First step: Preparation of (3-bromo-4-(cycloheptylamino)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000151
Figure PCTCN2018072204-appb-000151
以实施例41第二步产物(3-溴-4-氟苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮为原料，参考实施例42第一步得(3-溴-4-(环庚基氨基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮(产率76％)。 The product of the second step of Example 41 (3-bromo-4-fluorophenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone was used as the starting material, and the first step of Example 42 was obtained ( 3-Bromo-4-(cycloheptylamino)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone (yield 76%).
MS m/z(ESI):405.0/407.2(50/50)[M+H] +. MS m/z (ESI): 405.0 / 407.2 (50 / 50) [M+H] + .
第二步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(环庚基氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Second step: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(cycloheptylamino)phenyl)-6-methyl-1-toluenesulfonyl-1,6 -Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000152
Figure PCTCN2018072204-appb-000152
以(3-溴-4-(环庚基氨基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮为原料，参考实 施例4第四步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(环庚基氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率65％)。 Using (3-bromo-4-(cycloheptylamino)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone as the starting material, refer to the fourth step of Example 4 to obtain 4-( 5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(cycloheptylamino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one (yield 65%).
MS m/z(ESI):627.1[M+H] +. MS m/z (ESI): 627.1 [M+H] + .
第三步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(环庚基氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备The third step: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(cycloheptylamino)phenyl)-6-methyl-1,6-dihydro-7H- Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000153
Figure PCTCN2018072204-appb-000153
以4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(环庚基氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-(环庚基氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(52mg,产率76％)。4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-(cycloheptylamino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one was used as the starting material, and 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2- was obtained according to the eighth step of Example 1. (Cycloheptylamino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (52 mg, yield 76%).
MS m/z(ESI):473.2[M+H] +. MS m/z (ESI): 473.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.74(dd,J＝8.8Hz,2.4Hz,1H),7.60(d,J＝2.4Hz,1H),7.26(d,J＝2.8Hz,1H),7.11(s,1H),6.71(d,J＝9.0Hz,1H),6.05(d,J＝2.8Hz,1H),3.61(s,3H),3.59–3.49(m,1H),1.92–1.76(m,4H),1.57–1.23(m,12H). 1 H NMR (400MHz, MeOD) δ7.74 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.60 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.11 (s, 1H), 6.71 (d, J = 9.0 Hz, 1H), 6.05 (d, J = 2.8 Hz, 1H), 3.61 (s, 3H), 3.59 - 3.49 (m, 1H), 1.92 - 1.76 ( m, 4H), 1.57–1.23 (m, 12H).
实施例44Example 44
4-(2-(环己基氨基)-5-(环丙磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cyclohexylamino)-5-(cyclopropylsulfinyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone
Figure PCTCN2018072204-appb-000154
Figure PCTCN2018072204-appb-000154
以实施例33第七步产物4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用环己胺替代反式-4-甲基环己胺，参考实施例23第一步，得到4-(2-(环己基氨基)-5-(环丙磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(11mg,白色固体，产率22％)。The product of the seventh step of Example 33, 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one was used as a starting material, and trans-4-methylcyclohexylamine was replaced by cyclohexylamine. The first step of Example 23 was carried out to obtain 4-(2-(cyclohexylamino). -5-(cyclopropaneimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (11 mg, white solid, Yield 22%).
MS m/z(ESI):425.2[M+H] +。 MS m/z (ESI): 425.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.67(dd,J＝8.8Hz,2.4Hz,1H),7.54(d,J＝2.4Hz,1H),7.26(d,J＝2.8Hz,1H),7.11(s,1H),6.78(d,J＝9.2Hz,1H),6.04(d,J＝2.8Hz,1H),3.60(s,3H),3.41-3.33(m,1H),2.60-2.53(m,1H),1.90-1.81(m,2H),1.62–1.47(m,3H),1.37–1.26(m,2H),1.15–1.08(m,2H),1.06–0.93(m,4H),0.89–0.82(m,1H). 1 H NMR (400MHz, MeOD) δ7.67 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.54 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.11 (s, 1H), 6.78 (d, J = 9.2 Hz, 1H), 6.04 (d, J = 2.8 Hz, 1H), 3.60 (s, 3H), 3.41-3.33 (m, 1H), 2.60-2.53 ( m,1H), 1.90-1.81 (m, 2H), 1.62–1.47 (m, 3H), 1.37–1.26 (m, 2H), 1.15–1.08 (m, 2H), 1.06–0.93 (m, 4H), 0.89–0.82 (m, 1H).
实施例45Example 45
4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropaneimido)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ Preparation of 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000155
Figure PCTCN2018072204-appb-000155
第一步：8-亚甲基-1,4-二氧杂螺[4.5]癸烷的制备First step: Preparation of 8-methylene-1,4-dioxaspiro[4.5]decane
Figure PCTCN2018072204-appb-000156
Figure PCTCN2018072204-appb-000156
溴化甲基三苯基磷(22.9g,64mmol)溶于四氢呋喃(200mL)中，在0℃氮气保护下分批加入叔丁醇钾(7.2g，64mmol)，反应液在0℃搅拌1小时。1,4-二氧杂螺[4.5]癸烷-8-酮(5g，32mmol)溶于四氢呋喃(50mL)中，缓慢滴加入上述反应液中，反应缓慢升至室温，搅拌18小时。反应液用水(100mL)淬灭，水相用乙酸乙酯(100mL×3)萃取，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚～石油醚/乙酸乙酯：10/1)纯化得到8-亚甲基-1,4-二氧杂螺[4.5]癸烷(3.4g,无色液体，产率：69％)。Methyltriphenylphosphonium bromide (22.9 g, 64 mmol) was dissolved in tetrahydrofuran (200 mL). Potassium tert-butoxide (7.2 g, 64 mmol) was added portionwise at 0 ° C under nitrogen, and the mixture was stirred at 0 ° C for 1 hour. . 1,4-Dioxaspiro[4.5]decane-8-one (5 g, 32 mmol) was dissolved in tetrahydrofuran (50 mL), and the mixture was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The crude product was purified by column chromatography ( petroleum ether / petroleum ether / ethyl acetate: 10/1) to give 8-methylene-1,4-dioxaspiro[4.5] decane (3.4 g, colorless liquid , yield: 69%).
1H NMR(400MHz,CDCl 3)δ4.67(s,2H),3.96(s,4H),2.32-2.24(m,4H),1.75-1.67(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 4.67 (s, 2H), 3.96 (s, 4H), 2.32 - 2.24 (m, 4H), 1.75-1.67 (m, 4H).
第二步：7,10-二氧杂二螺[2.2.4 6.2 3]十二烷的制备 Step 2: Preparation of 7,10-dioxaspiro[2.2.4 6 .2 3 ]dodecane
Figure PCTCN2018072204-appb-000157
Figure PCTCN2018072204-appb-000157
8-亚甲基-1,4-二氧杂螺[4.5]癸烷(3.4g，22.1mmol)溶于甲苯(7mL)中，在-40℃氮气保护下滴加二乙基锌(55.2mL，55.2mmol)。反应在-40℃下搅拌10分钟，然后缓慢加入二碘甲烷(29.4g，110mmol)，反应液在室温下搅拌18小时。反应液倒入冰镇的饱和氯化铵水溶液(30mL)淬灭，水相用乙酸乙酯(30mL×3)萃取，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚～石油醚/乙酸乙酯：20/1)纯化得到7,10-二氧杂二螺[2.2.4 6.2 3]十二烷(2.8g,无色液体，产率：82％)。 8-Methylene-1,4-dioxaspiro[4.5]decane (3.4 g, 22.1 mmol) was dissolved in toluene (7 mL), and diethylzinc (55.2 mL) was added dropwise under a nitrogen atmosphere at -40 °C. , 55.2 mmol). The reaction was stirred at -40 °C for 10 minutes, then diiodomethane (29.4 g, 110 mmol) was slowly added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was poured into EtOAc EtOAc (EtOAc)EtOAc. The crude product was purified by column chromatography ( petroleum ether / petroleum ether / ethyl acetate: 20/1) to give 7,10-dioxaspiro[2.2.4 6 . 2 3 ]dodecane (2.8 g, Color liquid, yield: 82%).
1H NMR(400MHz,CDCl 3)δ3.97(s,4H),2.32-2.24(m,4H),1.75-1.67(m,4H),0.28(s,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 3.97 (s, 4H), 2.32 - 2.24 (m, 4H), 1.75-1.67 (m, 4H), 0.28 (s, 4H).
第三步：螺[2.5]辛烷-6-酮的制备The third step: preparation of spiro[2.5]octane-6-one
Figure PCTCN2018072204-appb-000158
Figure PCTCN2018072204-appb-000158
7,10-二氧杂二螺[2.2.4 6.2 3]十二烷(2.8g，16.7mmol)溶于四氢呋喃(8mL)和水(8mL)中，加入三氟乙酸(3mL)。反应在室温下搅拌2小时。反应液用2M的氢氧化钠水溶液调pH至7。水相用甲基叔丁基醚(30mL×2)萃取，有机相经无水硫酸钠干燥，过滤，低温旋干得到螺[2.5]辛烷-6-酮(1.8g,无色液体，产率：87％)。 7,10-Dioxaspiro[2.2.4 6 .2 3 ]dodecane (2.8 g, 16.7 mmol) was dissolved in tetrahydrofuran (8 mL) and water (8 mL). The reaction was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 7 with a 2M aqueous sodium hydroxide solution. The aqueous phase was extracted with methyl tert-butyl ether (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness Rate: 87%).
第四步：N-(4-甲氧苄基)螺[2.5]辛烷-6-胺的制备The fourth step: preparation of N-(4-methoxybenzyl)spiro[2.5]octane-6-amine
Figure PCTCN2018072204-appb-000159
Figure PCTCN2018072204-appb-000159
螺[2.5]辛烷-6-酮(0.2g，1.6mmol)和(4-甲氧苯基)甲胺(0.24g，1.8mmol)溶于1，2二氯乙烷(10mL)，在0℃氮气保护下加入乙酸(125mg，2.1mmol)。反应在0℃下搅拌十分钟，加入三乙酰氧基硼氢化钠(1.1g，5.3mmol)。反应在室温下搅拌18小时。反应液用饱和碳酸氢钠水溶液(20mL)淬灭，水相用二氯甲烷(30mL×3)萃取，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚～石油醚/乙酸乙酯：1/1)纯化得到N-(4-甲氧苄基)螺[2.5]辛烷-6-胺(220mg,无色液体，产率：56％)。Spiro[2.5]octane-6-one (0.2 g, 1.6 mmol) and (4-methoxyphenyl)methylamine (0.24 g, 1.8 mmol) were dissolved in 1,2 dichloroethane (10 mL) at 0 Acetic acid (125 mg, 2.1 mmol) was added under a nitrogen atmosphere. The reaction was stirred at 0 ° C for ten minutes and sodium triacetoxyborohydride (1.1 g, 5.3 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with EtOAc EtOAc. The crude product was purified by column chromatography ( petroleum ether / petroleum ether / ethyl acetate: 1 / 1) to give N-(4-methoxybenzyl)spiro[2.5]octane-6-amine (220 mg, colorless liquid , yield: 56%).
1H NMR(400MHz,CDCl3)δ7.25(d,J＝7.6Hz,2H),6.86(d,J＝8.7Hz,2H),3.80(s,3H),3.77(s,2H),2.60–2.52(m,1H),1.91–1.84(m,2H),1.70–1.63(m,2H),1.40–1.29(m,2H),1.00–0.92(m,2H),0.30–0.25(m,2H),0.23–0.16(m,2H). 1 H NMR (400MHz, CDCl3) δ7.25 (d, J = 7.6Hz, 2H), 6.86 (d, J = 8.7Hz, 2H), 3.80 (s, 3H), 3.77 (s, 2H), 2.60- 2.52 (m, 1H), 1.91–1.84 (m, 2H), 1.70–1.63 (m, 2H), 1.40–1.29 (m, 2H), 1.00–0.92 (m, 2H), 0.30–0.25 (m, 2H) ), 0.23–0.16 (m, 2H).
第五步：螺[2.5]辛烷-6-胺的制备Step 5: Preparation of spiro[2.5]octane-6-amine
Figure PCTCN2018072204-appb-000160
Figure PCTCN2018072204-appb-000160
N-(4-甲氧苄基)螺[2.5]辛烷-6-胺(1.1g，4.5mmol)和钯碳(500mg)溶于甲醇(20mL)，在室温氢气球下搅拌18小时。反应液过滤，滤饼用甲醇(10mL x5)洗，有机相旋干得到螺[2.5]辛烷-6-胺(450mg g,无色液体，产率：80％)。N-(4-Methoxybenzyl)spiro[2.5]octane-6-amine (1.1 g, 4.5 mmol) and palladium carbon (500 mg) were dissolved in methanol (20 mL) The reaction mixture was filtered, and the filter cake was washed with methanol (10 mL, EtOAc),
1H NMR(400MHz,CDCl3)δ2.79-2.68(m,1H),2.09(brs,2H),1.85-1.76(m,2H),1.76-1.64(m,2H),1.35-1.23(m,2H),0.96-0.89(m,2H),0.34-0.24(m,2H),0.24-0.16(m,2H). 1 H NMR (400MHz, CDCl3) δ2.79-2.68 (m, 1H), 2.09 (brs, 2H), 1.85-1.76 (m, 2H), 1.76-1.64 (m, 2H), 1.35-1.23 (m, 2H), 0.96-0.89 (m, 2H), 0.34-0.24 (m, 2H), 0.24-0.16 (m, 2H).
第六步：(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮的制备 Step 6: Preparation of (3-bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000161
Figure PCTCN2018072204-appb-000161
(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(110mg，0.4mmol)，螺[2.5]辛烷-6-胺(148mg，1.2mmol)和碳酸铯(325mg,1mmol)溶于二甲亚砜(10mL)，反应在80℃下搅拌18小时。反应液加水(50mL)，水相用乙酸乙酯(30mL×2)萃取，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚/乙酸乙酯：20/1～石油醚/乙酸乙酯：3/1)纯化得到(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(100mg,无色固体，产率：65％)。 (3-Bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (110 mg, 0.4 mmol), spiro[2.5]octane-6-amine (148 mg, 1.2 mmol) The cesium carbonate (325 mg, 1 mmol) was dissolved in dimethyl sulfoxide (10 mL), and the reaction was stirred at 80 ° C for 18 hours. Water (50 mL) was added to the mixture. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate: 20/1 - petroleum ether / ethyl acetate: 3/1) (3-bromo-4-(spiro[2.5] octane-6-yl. Amino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (100 mg, colorless solid, yield: 65%).
MS m/z(ESI):383.0/385.0(50/50)[M+H] +. MS m/z (ESI): 383.0 / 385.0 (50 / 50) [M+H] + .
第七步：4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 7: 4-(5-(cyclopropaneimido)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6-methyl-1-toluenesulfonyl-1, Preparation of 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000162
Figure PCTCN2018072204-appb-000162
(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(50mg，0.13mmol)，6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(112mg，0.26mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(19mg，0.026mmol)和碳酸钾(45mg,0.33mmol)溶于1,4-二氧六环/水(5/1，2mL)，氮气置换并保护，反应在90℃下搅拌2小时。反应液加水(10mL)，水相用乙酸乙酯(10mL×3)萃取，有机相经无水硫酸钠干燥，过滤，浓缩后用制备硅胶板分离(乙酸乙酯)，得到4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(30mg,棕色胶体，产率：38％)。 (3-Bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (50 mg, 0.13 mmol), 6-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one (112 mg, 0.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19 mg, 0.026 mmol) and potassium carbonate (45 mg, 0.33 mmol) was dissolved in 1,4-dioxane/water (5/1, 2 mL), and replaced with nitrogen, and the reaction was stirred at 90 ° C for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. (cyclopropionimido)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one (30 mg, brown colloid, yield: 38%).
MS m/z(ESI):605.2[M+H] + MS m/z (ESI): 605.2 [M+H] +
第八步：4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 8: 4-(5-(Cyclopropioni)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6-methyl-1,6-dihydro-7H -Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000163
Figure PCTCN2018072204-appb-000163
4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(30mg，0.05mmol)溶于乙醇(5mL)，加入2M氢氧化钠水溶液(5mL)，反应在30℃下搅拌0.5小时。反应液浓缩，旋干后用高效液相色谱柱分离，得到4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(6mg,白色固体，产率：27％)。4-(5-(cyclopropaneimidoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro -7H-Pyro[2,3-c]pyridin-7-one (30 mg, 0.05 mmol) was dissolved in ethanol (5 mL), and 2M aqueous sodium hydroxide (5 mL) was added, and the mixture was stirred at 30 ° C for 0.5 hour. The reaction solution was concentrated, dried, and then subjected to high-performance liquid chromatography to give 4-(5-(cyclopropylsulfinyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-6. Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (6 mg, white solid, yield: 27%).
MS m/z(ESI):451.2[M+H] + MS m/z (ESI): 451.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.78(dd,J＝8.8Hz,2.3Hz,1H),7.64(d,J＝2.4 Hz,1H),7.36(d,J＝2.8Hz,1H),7.22(s,1H),6.90(d,J＝9.0Hz,1H),6.15(d,J＝2.8Hz,1H),3.70(s,3H),3.56–3.48(m,1H),2.72–2.61(m,1H),2.00–1.88(m,2H),1.79–1.67(m,2H),1.36–1.24(m,4H),1.12–1.03(m,2H),1.00–0.94(m,2H),0.32–0.24(m,2H),0.21–0.13(m,2H). 1 H NMR (400MHz, MeOD) δ7.78 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.22 (s, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.15 (d, J = 2.8 Hz, 1H), 3.70 (s, 3H), 3.56 - 3.48 (m, 1H), 2.72 - 2.61 ( m,1H), 2.00–1.88 (m, 2H), 1.79–1.67 (m, 2H), 1.36–1.24 (m, 4H), 1.12–1.03 (m, 2H), 1.00–0.94 (m, 2H), 0.32–0.24 (m, 2H), 0.21–0.13 (m, 2H).
实施例46Example 46
4-(5-(环丙磺亚胺酰基)-2-((2,4-二氟苯基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropanesulfonyl)-2-((2,4-difluorophenyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000164
Figure PCTCN2018072204-appb-000164
第一步：(3-溴-4-((2,4-二氟苯基)氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮的制备 First step: Preparation of (3-bromo-4-((2,4-difluorophenyl)amino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000165
Figure PCTCN2018072204-appb-000165
以(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮为原料，参考实施例42第一步得(3-溴-4-((2,4-二氟苯基)氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(产率50％)。 Using (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone as the starting material, the first step of Example 42 was obtained (3-bromo-4-((2, 4-Difluorophenyl)amino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (yield 50%).
MS m/z(ESI):386.9[M+H] +,388.9[M+2+H] +. MS m/z (ESI): 386.9 [M+H] + , 388.9 [M+2+H] + .
第二步：4-(5-(环丙磺亚胺酰基)-2-((2,4-二氟苯基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Second step: 4-(5-(cyclopropaneimido)-2-((2,4-difluorophenyl)amino)phenyl)-6-methyl-1-toluenesulfonyl-1, Preparation of 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000166
Figure PCTCN2018072204-appb-000166
以(3-溴-4-((2,4-二氟苯基)氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮为原料，参考实施例4第四步得4-(5-(环丙磺亚胺酰基)-2-((2,4-二氟苯基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率65％)。 Taking (3-bromo-4-((2,4-difluorophenyl)amino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone as a raw material, refer to the fourth step of Example 4. 4-(5-(cyclopropanesulfonyl)-2-((2,4-difluorophenyl)amino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one (yield 65%).
MS m/z(ESI):609.1[M+H] +. MS m/z (ESI): 609.1 [M+H] + .
第三步：4-(5-(环丙磺亚胺酰基)-2-((2,4-二氟苯基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Third step: 4-(5-(cyclopropaneimidoyl)-2-((2,4-difluorophenyl)amino)phenyl)-6-methyl-1,6-dihydro-7H -Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000167
Figure PCTCN2018072204-appb-000167
以4-(5-(环丙磺亚胺酰基)-2-((2,4-二氟苯基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得4-(5-(环丙磺亚胺酰基)-2-((2,4-二氟苯基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率65％)。4-(5-(cyclopropanesulfonyl)-2-((2,4-difluorophenyl)amino)phenyl)-6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one was used as the starting material, and 4-(5-(cyclopropaneimidoyl)-2-((2,4) was obtained according to the eighth step of Example 1. -Difluorophenyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 65%).
MS m/z(ESI):455.1[M+H] +。 MS m/z (ESI): 455.1 [M+H] + .
1H NMR(400MHz,MeOD)δ7.69(d,J＝2.4Hz,1H),7.65(m,1H),7.24(d,J＝2.8Hz,1H),7.21(s,1H),7.18–7.11(m,1H),6.95–6.89(m,1H),6.83(d,J＝9.2Hz,1H),6.74(m,1H),6.17(d,J＝2.8Hz,1H),3.61(s,3H),2.63-2.59(m,1H),1.17–1.12(m,1H),1.04–0.98(m,2H),0.88(m,1H). 1 H NMR (400MHz, MeOD) δ7.69 (d, J = 2.4Hz, 1H), 7.65 (m, 1H), 7.24 (d, J = 2.8Hz, 1H), 7.21 (s, 1H), 7.18- 7.11 (m, 1H), 6.95 - 6.89 (m, 1H), 6.83 (d, J = 9.2 Hz, 1H), 6.74 (m, 1H), 6.17 (d, J = 2.8 Hz, 1H), 3.61 (s) , 3H), 2.63-2.59 (m, 1H), 1.17–1.12 (m, 1H), 1.04–0.98 (m, 2H), 0.88 (m, 1H).
实施例47Example 47
4-(5-(环丙磺亚胺酰基)-2-((反-4-(三氟甲基)环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropaneimidoyl)-2-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000168
Figure PCTCN2018072204-appb-000168
第一步 N-苯甲基-4-(三氟甲基)环己烷-1-胺的制备First step Preparation of N-benzyl-4-(trifluoromethyl)cyclohexane-1-amine
Figure PCTCN2018072204-appb-000169
Figure PCTCN2018072204-appb-000169
将4-(三氟甲基)环己烷-1-酮(9.7g，58.4mmol)溶于四氢呋喃(100mL)中，加入苄胺(6.3g，58.4mmol)，分批加入三乙酰氧基硼氢化钠(13.6g，64.2mmol)，在25℃搅拌16小时，加入饱和氯化铵水溶液(50mL)，乙酸乙酯(10mL)萃取，分出乙酸乙酯旋干，过柱纯化得到N-苯甲基-4-(三氟甲基)环己烷-1-胺(10g)。4-(Trifluoromethyl)cyclohexane-1-one (9.7 g, 58.4 mmol) was dissolved in tetrahydrofuran (100 mL), benzylamine (6.3 g, 58.4 mmol) was added, and triacetoxy boron was added in portions. Sodium hydride (13.6 g, 64.2 mmol) was stirred at 25 ° C for 16 h, then aq. Methyl-4-(trifluoromethyl)cyclohexane-1-amine (10 g).
MS m/z(ESI):258.1M+H] +. MS m/z (ESI): 258.1 M+H] + .
1H NMR(400MHz,DMSO-d6):δ7.28-7.35(m,4H),3.66(s,2H),2.73-2.75(m,1H),2.19-2.22(m,1H),1.95(br,1H),1.65-1.78(m,4H),1.38-1.54(m,4H)； 1 H NMR (400MHz, DMSO- d6): δ7.28-7.35 (m, 4H), 3.66 (s, 2H), 2.73-2.75 (m, 1H), 2.19-2.22 (m, 1H), 1.95 (br , 1H), 1.65-1.78 (m, 4H), 1.38-1.54 (m, 4H);
第二步 反-4-(三氟甲基)环己烷-1-胺的制备Second step Preparation of trans-4-(trifluoromethyl)cyclohexane-1-amine
Figure PCTCN2018072204-appb-000170
Figure PCTCN2018072204-appb-000170
将N-苯甲基-4-(三氟甲基)环己烷-1-胺(5.0g，19.5mmol)溶于四氢呋喃(50mL)与乙醇(50mL)中，加入钯炭(0.65g)，氢气置换并保护，在25℃搅拌16小时，硅藻土过滤，旋干，过柱纯化得到反-4-(三氟甲基)环己烷-1-胺(2g).N-Benzyl-4-(trifluoromethyl)cyclohexane-1-amine (5.0 g, 19.5 mmol) was dissolved in tetrahydrofuran (50 mL) and ethanol (50 mL). Hydrogen displacement and protection, stirring at 25 ° C for 16 hours, diatomaceous earth filtration, spin dry, column purification to obtain trans-4-(trifluoromethyl)cyclohexane-1-amine (2g).
MS m/z(ESI):168.1[M+H] +. MS m/z (ESI): 168.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ3.06-3.09(m,1H),2.11-2.21(m,1H),1.67-1.78(m,2H),1.45-1.57(m,6H)； 1 H NMR (400MHz, DMSO- d6): δ3.06-3.09 (m, 1H), 2.11-2.21 (m, 1H), 1.67-1.78 (m, 2H), 1.45-1.57 (m, 6H);
第三步 (3-溴-4-((反-4-(三氟甲基)环己基)氨基)苯基)(环丙基)(亚氨基)-λ6-硫烷酮的制备Third step (Preparation of 3-bromo-4-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)(cyclopropyl)(imino)-λ6-sulfanone
Figure PCTCN2018072204-appb-000171
Figure PCTCN2018072204-appb-000171
将实施例33第六步产物(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(140mg，0.5mmol)与反-4-(三氟甲基)环己胺-1-甲胺(1.0g)，在150℃下3小时后，柱层析得到(3-溴-4-((反-4-(三氟甲基)环己基)氨基)苯基)(环丙基)(亚氨基)-λ6-硫烷酮(0.12g，收率56.6％)。 The product of the sixth step of Example 33 (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (140 mg, 0.5 mmol) and trans-4-(trifluoromethyl) Cyclohexylamine-1-methylamine (1.0 g), after 3 hours at 150 ° C, column chromatography gave (3-bromo-4-((trans-4-(trifluoromethyl)cyclohexyl)amino) Phenyl)(cyclopropyl)(imino)-λ6-sulfanone (0.12 g, yield 56.6%).
MS m/z(ESI):425.0/427.0(50/50)[M+H] +. MS m/z (ESI): 425.0 / 427.0 (50 / 50) [M+H] + .
第四步 4-(5-(环丙磺亚胺酰基)-2-((反-4-(三氟甲基)环己基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Fourth step 4-(5-(cyclopropaneimido)-2-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)-6-methyl-1-toluenesulfonyl Of -1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000172
Figure PCTCN2018072204-appb-000172
将(3-溴-4-((反-4-(三氟甲基)环己基)氨基)苯基)(环丙基)(亚氨基)-λ6-硫烷酮替代实施例45第六步产物(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮，参考实施例45第七步，得到4-(5-(环丙磺亚胺酰基)-2-((反-4-(三氟甲基)环己基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率48.6％)。 Substituting (3-bromo-4-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)(cyclopropyl)(imino)-λ6-sulfanone for the sixth step of Example 45 The product (3-bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone was obtained in the seventh step of Example 45. 4-(5-(cyclopropaneimido)-2-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)-6-methyl-1-toluenesulfonyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 48.6%).
MS m/z(ESI):647.1[M+H] +. MS m/z (ESI): 647.1 [M+H] + .
第五步 4-(5-(环丙磺亚胺酰基)-2-((反-4-(三氟甲基)环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5 4-(5-(Cyclopropioni)-2-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)-6-methyl-1,6-di Preparation of hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000173
Figure PCTCN2018072204-appb-000173
将4-(5-(环丙磺亚胺酰基)-2-((反-4-(三氟甲基)环己基)氨基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为起始原料，参考实施例45第八步得到4-(5-(环丙磺亚胺酰基)-2-((反-4-(三氟甲基)环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮，收率86.6％)。4-(5-(Cyclopropioni)-2-((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)-6-methyl-1-toluenesulfonyl-1 , 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one as the starting material, and the 4-step of Example 45 was obtained to obtain 4-(5-(cyclopropaneimidoyl)-2. -((trans-4-(trifluoromethyl)cyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one , yield 86.6%).
MS m/z(ESI):493.1[M+H] +. MS m/z (ESI): 493.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ12.17(br,1H),7.67(dd,J＝8.8Hz,2.4Hz,1H),7.57(d,J＝2.4Hz，1H),7.28-7.26(m,2H),6.83(d,J＝8.8Hz,1H),6.07(t,J＝2.0Hz,1H),4.75(d,J＝6.4Hz,1H),3.78(s,1H),3.55(s,3H),2.61-2.55(m,1H),1.86-1.76(m,2H),1.64-1.54(m,4H),1.28-1.14(m,2H),1.10-1.00(m,2H),0.94-0.82(m,2H). 1 H NMR (400MHz, DMSO- d6): δ12.17 (br, 1H), 7.67 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.57 (d, J = 2.4Hz, 1H), 7.28-7.26 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.07 (t, J = 2.0 Hz, 1H), 4.75 (d, J = 6.4 Hz, 1H), 3.78 (s, 1H), 3.55 (s, 3H), 2.61-2.55 (m, 1H), 1.86-1.76 (m, 2H), 1.64-1.54 (m, 4H), 1.28-1.14 (m, 2H), 1.10-1.00 (m, 2H) , 0.94-0.82 (m, 2H).
实施例48Example 48
4-(5-(环丙磺亚胺酰基)-2-(4-(三氟甲氧基)苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropanesulfonyl)-2-(4-(trifluoromethoxy)phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000174
Figure PCTCN2018072204-appb-000174
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例4第四步，用4-三氟甲氧基苯酚取代2,4-二氟苯酚，得到4-(5-(环丙磺亚胺酰基)-2-(4-(三氟甲氧基)苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率44％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material, and in the fourth step of Example 4, 2,4-difluorophenol was replaced with 4-trifluoromethoxyphenol to give 4-(5-(cyclopropaneimidoyl)- 2-(4-(Trifluoromethoxy)phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Rate 44%).
MS m/z(ESI):504.1[M+H] +. MS m/z (ESI): 504.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.10(d,J＝2.4Hz,1H),7.96(dd,J＝8.7Hz,2.4Hz,1H),7.34(d,J＝2.9Hz,1H),7.31(s,1H),7.21(dd,J＝8.5Hz,4.3Hz,3H),7.04–6.98(m,2H),6.35(d,J＝2.9Hz,1H),3.65(s,3H),2.83–2.70(m,1H),1.21–1.07(m,2H),1.07–0.96(m,1H),0.95-0.85(m,1H). 1 H NMR (400MHz, MeOD) δ8.10 (d, J = 2.4Hz, 1H), 7.96 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.34 (d, J = 2.9Hz, 1H), 7.31 (s, 1H), 7.21 (dd, J = 8.5 Hz, 4.3 Hz, 3H), 7.04 - 6.98 (m, 2H), 6.35 (d, J = 2.9 Hz, 1H), 3.65 (s, 3H), 2.83 – 2.70 (m, 1H), 1.21–1.07 (m, 2H), 1.07–0.96 (m, 1H), 0.95-0.85 (m, 1H).
实施例49Example 49
6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(4-(三氟甲氧基)苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮6-Methyl-4-(5-(S-methylsulfimidoyl)-2-(4-(trifluoromethoxy)phenoxy)phenyl)-1,6-dihydro-7H- Pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000175
Figure PCTCN2018072204-appb-000175
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例4第五步，用4-三氟甲氧基苯酚取代2,4-二氟苯酚，得到标题化合物6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(4-(三氟甲氧基)苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率43％)。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one as a starting material, substituting 4-trifluoromethoxyphenol for 2,4-difluorophenol according to the fifth step of Example 4 to give the title compound 6-methyl-4-(5- (S-methanesulfonimido)-2-(4-(trifluoromethoxy)phenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone (yield 43%).
MS m/z(ESI):478.1[M+H] +. MS m/z (ESI): 478.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.17(d,J＝2.4Hz,1H),8.04(dd,J＝8.7Hz,2.5Hz,1H),7.36(d,J＝2.9Hz,1H),7.33(s,1H),7.24(t,J＝8.6Hz,3H),7.06–6.99(m,2H),6.38(d,J＝2.9Hz,1H),3.67(s,3H),3.24(s,3H). 1 H NMR (400MHz, MeOD) δ8.17 (d, J = 2.4Hz, 1H), 8.04 (dd, J = 8.7Hz, 2.5Hz, 1H), 7.36 (d, J = 2.9Hz, 1H), 7.33 (s, 1H), 7.24 (t, J = 8.6 Hz, 3H), 7.06 - 6.99 (m, 2H), 6.38 (d, J = 2.9 Hz, 1H), 3.67 (s, 3H), 3.24 (s, 3H).
实施例50Example 50
6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备6-Methyl-4-(5-(S-methylsulfimidoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000176
Figure PCTCN2018072204-appb-000176
第一步：(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(亚氨基)(甲基)-λ 6-硫烷酮的制备 First step: Preparation of (3-bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(imino)(methyl)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000177
Figure PCTCN2018072204-appb-000177
以(3-溴-4-氟苯基)(亚氨基)(甲基)-λ 6-硫烷酮(100mg,0.4mmol)为反应原料，参考实施例47第六步，得到化合物(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(亚氨基)(甲基)-λ 6-硫烷酮(40mg,产率28％)。 Using (3-bromo-4-fluorophenyl)(imino)(methyl)-λ 6 -thiol ketone (100 mg, 0.4 mmol) as the starting material of the reaction, the compound was obtained with reference to the step Bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(imino)(methyl)-λ 6 -sulfanone (40 mg, yield 28%).
MS m/z(ESI):357.0/359.0(50/50)[M+H]+.第二步：6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备MS m/z (ESI): 357.0/359.0 (50/50) [M+H]+. Step 2: 6-Methyl-4-(5-(S-methylsulfimidoyl)-2- Preparation of (spiro[2.5]octane-6-ylamino)phenyl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000178
Figure PCTCN2018072204-appb-000178
以(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(亚氨基)(甲基)-λ 6-硫烷酮(40mg,0.11mmol)为反应原料，参考实施例45第七步，得到化合物6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(40mg,产率63％)。 (3-Bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(imino)(methyl)-λ 6 -thione (40 mg, 0.11 mmol) as the starting material, The fourth step of Example 45 gave the compound 6-methyl-4-(5-(S-methylsulfimidoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-1 -toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (40 mg, yield 63%).
MS m/z(ESI):579.2[M+H] + MS m/z (ESI): 579.2 [M+H] +
第三步：6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-1,6-二氢 -7H-吡咯并[2,3-c]吡啶-7-酮的制备The third step: 6-methyl-4-(5-(S-methylsulfimidoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-1,6-dihydrogen Preparation of -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000179
Figure PCTCN2018072204-appb-000179
6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(40mg，0.07mmol)溶于叔丁醇(5mL)和水(1mL)，加入氢氧化钾(39mg，0.7mmol)，反应在60℃下搅拌18小时。。反应液加水(10mL)，水相用乙酸乙酯(20mL)萃取，有机相经无水硫酸钠干燥，过滤，旋干后用高效液相色谱柱分离，得到6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(2.2mg,白色固体，产率：7.6％)。6-Methyl-4-(5-(S-methylsulfimidoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (40 mg, 0.07 mmol) was dissolved in tert-butanol (5 mL) and water (1 mL). The reaction was stirred at 60 ° C for 18 hours. . The reaction mixture was poured with water (10 mL), EtOAc (EtOAc)EtOAc. -(S-methylsulfamidinoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone (2.2 mg, white solid, yield: 7.6%).
MS m/z(ESI):425.2[M+H] + MS m/z (ESI): 425.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.83(dd,J＝8.8Hz,2.4Hz,1H),7.68(d,J＝2.4Hz,1H),7.36(d,J＝2.8Hz,1H),7.23(s,1H),6.91(d,J＝9.0Hz,1H),6.14(d,J＝2.8Hz,1H),3.70(s,3H),3.57-3.46(m,1H),3.13(s,3H),2.07-2.00(m,1H),1.98-1.90(m,2H),1.78-1.68(m,2H),1.64-1.57(m,1H),1.01-0.93(m,2H),0.34-0.26(m,2H),0.20-0.15(m,2H). 1 H NMR (400MHz, MeOD) δ7.83 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.68 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.23 (s, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 3.70 (s, 3H), 3.57-3.46 (m, 1H), 3.13 (s, 3H), 2.07-2.00 (m, 1H), 1.98-1.90 (m, 2H), 1.78-1.68 (m, 2H), 1.64-1.57 (m, 1H), 1.01-0.93 (m, 2H), 0.34- 0.26 (m, 2H), 0.20-0.15 (m, 2H).
实施例51Example 51
6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(((R)-1-苯基乙基)氨基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮6-Methyl-4-(5-(S-methylsulfimidoyl)-2-(((R)-1-phenylethyl)amino)phenyl)-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000180
Figure PCTCN2018072204-appb-000180
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例23第一步，用R-苯乙胺取代反-4-甲基环己胺，得到6-甲基-4-(5-(S-甲基磺亚胺酰基)-2-(((R)-1-苯基乙基)氨基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率25％)。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction. The first step of Example 23 is followed by substituting R-phenylethylamine for trans-4-methylcyclohexylamine to give 6-methyl-4-(5-(S -methylsulfamimidoyl-2-((R)-1-phenylethyl)amino)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (yield 25%).
MS m/z(ESI):421.2[M+H] +. MS m/z (ESI): 421.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ8.08(d,J＝2.4Hz,1H),7.99(dd,J＝8.7Hz,2.4Hz,1H),7.28-7.36(m,5H),7.31(t,J＝2.7Hz,1H),7.11(d,J＝8.8Hz,1H),7.05(s,1H),6.24(t,J＝2.4Hz,1H),4.01-3.95(m,1H),3.73(s,3H),3.20(s,3H),1.41(d,J＝2.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ8.08 (d, J = 2.4Hz, 1H), 7.99 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.28-7.36 (m, 5H), 7.31 ( t, J = 2.7 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.05 (s, 1H), 6.24 (t, J = 2.4 Hz, 1H), 4.01-3.95 (m, 1H), 3.73 (s, 3H), 3.20 (s, 3H), 1.41 (d, J = 2.4 Hz, 3H).
实施例52Example 52
4-(2-(环己基氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c] 吡啶-7-酮4-(2-(cyclohexylamino)-5-(S-methylsulfamidinoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one
Figure PCTCN2018072204-appb-000181
Figure PCTCN2018072204-appb-000181
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例23第一步，用环己胺取代反-4-甲基环己胺，得到4-(2-(环己基氨基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率33％)。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction. The first step of Example 23 is followed by substituting cyclohexylamine for trans-4-methylcyclohexylamine to give 4-(2-(cyclohexylamino)-5-( S-methylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 33%).
MS m/z(ESI):399.2[M+H] +. MS m/z (ESI): 399.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.86(d,J＝8.2Hz,1H),7.68(s,1H),7.28(d,J＝2.4Hz,1H),7.19(s,1H),6.86(d,J＝9.0Hz,1H),6.01(d,J＝2.3Hz,1H),3.66(s,3H),3.61(s,3H),2.60-2.41(m,1H),1.56-1.42(m,10H). 1 H NMR (400MHz, MeOD) : δ7.86 (d, J = 8.2Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.19 (s, 1H), 6.86 (d, J=9.0 Hz, 1H), 6.01 (d, J=2.3 Hz, 1H), 3.66 (s, 3H), 3.61 (s, 3H), 2.60-2.41 (m, 1H), 1.56-1.42 ( m, 10H).
实施例53Example 53
4-(5-(乙基磺亚胺酰基)-2-(吡啶-2-氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfamidinoyl)-2-(pyridin-2-amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one
Figure PCTCN2018072204-appb-000182
Figure PCTCN2018072204-appb-000182
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用2-氨基吡啶取代2,4-二甲基苯酚，参考实施例10第五步，得到4-(5-(乙基磺亚胺酰基)-2-(吡啶-2-基氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(白色固体，产率38％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material, and 2,4-dimethylphenol was replaced with 2-aminopyridine. The fifth step of Example 10 was carried out to obtain 4-(5-(ethylsulfanimidoyl)-2-( Pyridin-2-ylamino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (white solid, yield 38%).
MS m/z(ESI):408.1[M+H] +. MS m/z (ESI): 408.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.18(d,J＝8.8Hz,1H),8.05(d,J＝4.0Hz,1H),7.84-7.74(m,2H),7.50-7.42(m,1H),7.23-7.14(m,2H),6.79-6.73(m,1H),6.69(d,J＝8.4Hz,1H),6.03(d,J＝2.8Hz,1H),3.61(s,3H),3.18(q,J＝7.4Hz,2H),1.17(t,J＝7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ8.18 (d, J = 8.8Hz, 1H), 8.05 (d, J = 4.0Hz, 1H), 7.84-7.74 (m, 2H), 7.50-7.42 (m, 1H ), 7.23 - 7.14 (m, 2H), 6.79 - 6.73 (m, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.03 (d, J = 2.8 Hz, 1H), 3.61 (s, 3H) , 3.18 (q, J = 7.4 Hz, 2H), 1.17 (t, J = 7.4 Hz, 3H).
实施例54Example 54
4-(5-(乙基磺亚胺酰基)-2-(吡啶-2-羟基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-(pyridin-2-hydroxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one
Figure PCTCN2018072204-appb-000183
Figure PCTCN2018072204-appb-000183
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用2-羟基吡啶取代2,4-二甲基苯酚，参考实施例10第五步，得到4-(5-(乙基磺亚胺酰基)-2-(吡啶-2-羟基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(白色固体，产率3％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material, and 2,4-dimethylphenol was replaced with 2-hydroxypyridine. The fifth step of Example 10 was followed to obtain 4-(5-(ethylsulfanilinoyl)-2-( Pyridine-2-hydroxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (white solid, 3% yield).
MS m/z(ESI):409.1[M+H] +。 MS m/z (ESI): 409.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.11-8.00(m,2H),7.67(d,J＝8.4Hz,1H),7.34(d,J＝9.2Hz,2H),7.16(d,J＝2.8Hz,1H),6.98(s,1H),6.40(d,J＝9.2Hz,1H),6.16-6.11(m,2H),3.48(s,3H),3.30-3.26(m,2H),1.21(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, MeOD) δ 8.11 - 8.00 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 9.2 Hz, 2H), 7.16 (d, J = 2.8 Hz, 1H), 6.98 (s, 1H), 6.40 (d, J = 9.2 Hz, 1H), 6.16-6.11 (m, 2H), 3.48 (s, 3H), 3.30-3.26 (m, 2H), 1.21. (t, J = 7.4 Hz, 3H).
实施例55Example 55
4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropaneimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6-dihydro-7H -Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000184
Figure PCTCN2018072204-appb-000184
第一步：4-溴-7-甲氧基-2-甲基-1H-吡咯并[2,3-c]吡啶First step: 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine
Figure PCTCN2018072204-appb-000185
Figure PCTCN2018072204-appb-000185
5-溴-2-甲氧基-3-硝基吡啶(15g，64.3mmol)溶于四氢呋喃(150mL)中，在-78℃氮气保护下慢慢滴加异烯丙基溴化镁(385mL，192.9mmol，0.5M)。反应液在-78℃搅拌3小时，反应液用饱和氯化铵水溶液(100mL)淬灭，溶液用乙酸乙酯(100mL×2)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。有机相干燥旋干，柱分离(石油醚/乙酸乙酯＝5/1)得到4-溴-7-甲氧基-2-甲基-1H-吡咯并[2,3-c]吡啶(5.5g，黄色油状物，35％)。5-bromo-2-methoxy-3-nitropyridine (15 g, 64.3 mmol) was dissolved in tetrahydrofuran (150 mL), and isoallyl magnesium bromide (385 mL) was slowly added dropwise under nitrogen at -78 °C. 192.9 mmol, 0.5 M). The reaction mixture was stirred at -78 °C for 3 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc) Sodium is dry. The organic phase was dried and dried, and then purified by column chromatography ( petroleum ether / ethyl acetate = 5 / 1) to give 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (5.5 g, yellow oil, 35%).
1H NMR(400MHz,CDCl 3)δ7.80(d,J＝5.6Hz,1H),7.26(s,1H),4.06(s,3H),2.48(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.80 (d, J = 5.6Hz, 1H), 7.26 (s, 1H), 4.06 (s, 3H), 2.48 (s, 3H).
第二步：4-溴-7-甲氧基-2-甲基-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶Second step: 4-bromo-7-methoxy-2-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine
Figure PCTCN2018072204-appb-000186
Figure PCTCN2018072204-appb-000186
4-溴-7-甲氧基-2-甲基-1H-吡咯并[2,3-c]吡啶(2.6g，11mmol)溶于N,N-二甲基甲酰胺(20mL)中，在0℃氮气保护下分批加入氢化钠(640mL，16mmol)。反应在室温下搅拌15分钟，然后在0℃氮气保护下分批加入对甲基本磺酰氯(3.04g，16mmol)，反应液在室温下搅拌16小时。反应液用饱和氯化铵水溶液(20mL)淬灭，溶液用乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥。有机相干燥旋干，柱分离(石油醚/乙酸乙酯＝10/1)得到4-溴-7-甲氧基-2-甲基-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶(1.6g，黄色固体，37.5％)。4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (2.6 g, 11 mmol) was dissolved in N,N-dimethylformamide (20 mL) Sodium hydride (640 mL, 16 mmol) was added portion wise under nitrogen. The reaction was stirred at room temperature for 15 minutes, then p-methylsulfonyl chloride (3.04 g, 16 mmol). The reaction mixture was diluted with EtOAc EtOAc EtOAc. The organic phase was dried and dried, and then purified by column ( petroleum ether / ethyl acetate = 10/1) to give 4-bromo-7-methoxy-2-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3 -c]pyridine (1.6 g, yellow solid, 37.5%).
MS m/z(ESI):394.9/397.0(50/50)[M+H] +. MS m/z (ESI): 394.9 / 397.0 (50 / 50) [M+H] + .
第三步：4-溴-2-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮The third step: 4-bromo-2-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000187
Figure PCTCN2018072204-appb-000187
4-溴-7-甲氧基-2-甲基-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶(1.6g，4.1mmol)二氧六环(20mL)中，在室温下加入盐酸(20mL，4M)。反应在40℃下搅拌16小时。反应液浓缩，用二氯甲烷(20mL×2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。有机相干燥旋干，柱分离(石油醚/乙酸乙酯＝2/1)得到4-溴-2-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(1.4g，白色固体，90.7％)。4-bromo-7-methoxy-2-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (1.6 g, 4.1 mmol) in dioxane (20 mL) Hydrochloric acid (20 mL, 4 M) was added at room temperature. The reaction was stirred at 40 ° C for 16 hours. The reaction mixture was concentrated and evaporated with m~~~~~ The organic phase was dried and dried, and then purified by column chromatography ( petroleum ether / ethyl acetate = 2 / 1) to give 4-bromo-2-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one (1.4 g, white solid, 90.7%).
MS m/z(ESI):380.9/382.9(50/50)[M+H] +. MS m/z (ESI): 380.9 / 382.9 (50 / 50) [M+H] + .
1H NMR(400MHz,CDCl 3)δ7.94(d,J＝8.4Hz,2H),7.29(d,J＝8.1Hz,2H),7.14(s,1H),6.34(d,J＝0.9Hz,1H),2.79(d,J＝0.7Hz,3H),2.41(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 6.34 (d, J = 0.9 Hz) , 1H), 2.79 (d, J = 0.7 Hz, 3H), 2.41 (s, 3H).
第四步：4-溴-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Fourth step: 4-bromo-2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000188
Figure PCTCN2018072204-appb-000188
4-溴-2-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(1.4g，3.7mmol)溶于N,N-二甲基甲酰胺(20mL)中，在0℃氮气保护下分批加入氢化钠(180mL，4.5mmol，60％)。反应在室温下搅拌15分钟，然后在0℃氮气保护下分批加入碘甲烷(620mg，4.5mmol)，反应液在室温下搅拌3小时。反应液用饱和氯化铵水溶液(20mL)淬灭，溶液用乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥。有机相干燥旋干，柱分离(石油醚/乙酸乙酯＝2/1)得到4-溴-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(1.4g，黄色 固体，96.5％)。4-bromo-2-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (1.4 g, 3.7 mmol) was dissolved in N, N In a solution of dimethylformamide (20 mL), sodium hydride (180 mL, 4.5 mmol, 60%) The reaction was stirred at room temperature for 15 minutes, then iodomethane (620 mg, 4.5 mmol) The reaction mixture was diluted with EtOAc EtOAc EtOAc. The organic phase was dried and dried, and the column was separated ( petroleum ether / ethyl acetate = 2 / 1) to give 4-bromo-2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole. [2,3-c]pyridine-7-one (1.4 g, yellow solid, 96.5%).
MS m/z(ESI):394.9/397.0[M+H] +. MS m/z (ESI): 394.9 / 397.0 [M+H] + .
1H NMR(400MHz,CDCl 3)δ7.99(d,J＝8.4Hz,2H),7.31(d,J＝8.1Hz,2H),7.18(s,1H),6.26(d,J＝0.9Hz,1H),3.48(s,3H),2.76(d,J＝0.8Hz,3H),2.41(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.18 (s, 1H), 6.26 (d, J = 0.9 Hz) , 1H), 3.48 (s, 3H), 2.76 (d, J = 0.8 Hz, 3H), 2.41 (s, 3H).
第五步：2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮.Step 5: 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl- 1,6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one.
Figure PCTCN2018072204-appb-000189
Figure PCTCN2018072204-appb-000189
4-溴-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(1.4g，3.5mmol)，频哪醇硼酸酯(1.8g，7.0mmol)，三(二亚苄基丙酮)二钯(84mg，0.091mmol)，乙酸钾(877mg，8.75mmol)，2-二环己基磷-2,4,6-三异丙基联苯(166mg，0.35mmol)溶于二氧六环(30mL)中，在90℃氮气保护下搅拌2小时。反应液过滤，溶液用乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。有机相干燥旋干，柱分离(石油醚/乙酸乙酯＝1/1)得到2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(1.4g，黄色油状物，89％)。4-bromo-2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (1.4 g, 3.5 mmol), frequency Polyol borate (1.8g, 7.0mmol), tris(dibenzylideneacetone)dipalladium (84mg, 0.091mmol), potassium acetate (877mg, 8.75mmol), 2-dicyclohexylphosphine-2,4, 6-Triisopropylbiphenyl (166 mg, 0.35 mmol) was dissolved in dioxane (30 mL) and stirred for 2 hours under nitrogen at 90 °C. The reaction mixture was filtered, and EtOAc EtOAc m. The organic phase is dried and dried, and the column is separated (petrole ether / ethyl acetate = 1 / 1) to give 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (1.4g, yellow oil, 89% ).
MS m/z(ESI):443.2[M+H] +。 MS m/z (ESI): 443.2 [M+H] + .
第六步：(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮的制备. The sixth step: (3-bromo-4-((trans--4-methylcyclohexyl)amino)phenyl) (cyclopropyl) (imino)-λ 6 -sulfanone preparation.
Figure PCTCN2018072204-appb-000190
Figure PCTCN2018072204-appb-000190
实施例33第六步产物(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(500mg,1.75mmol)与反式-4-甲基环己烷胺(5.0mL)置25mL三口瓶中，氮气保护下油浴加热到90℃，反应5小时后冷却至室温，用乙酸乙酯(50mL)稀释，经饱和氯化铵水溶液洗涤(25mL×2)，无水硫酸钠干燥，过滤。滤液浓缩后经柱层析纯化(石油醚/乙酸乙酯＝3/1)得到(3-溴-4-((反式-4-甲基环己基)氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(500mg,黄色油状物,产率75％)。 Example 33 Step 6 Product (3-Bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (500 mg, 1.75 mmol) and trans-4-methylcyclohexane The alkylamine (5.0 mL) was placed in a 25 mL three-necked flask, heated to 90 ° C in an oil bath under nitrogen atmosphere, reacted for 5 hours, cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with saturated aqueous ammonium chloride (25 mL×2) ), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography (peel ether / ethyl acetate = 3 / 1) to give (3-bromo-4-((trans-4-methylcyclohexyl)amino)phenyl) (cyclopropyl) (Imino)-λ 6 -sulfanone (500 mg, yellow oil, yield 75%).
MS m/z(ESI):370.9/372.9(50/50)[M+H] +. MS m/z (ESI): 370.9 / 372.9 (50 / 50) [M+H] + .
第七步：4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 7: 4-(5-(Cyclopropioni)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1-toluene Preparation of acyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000191
Figure PCTCN2018072204-appb-000191
(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮与2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例4第四步得4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率62％)。 (3-Bromo-4-((trans--4-methylcyclohexyl)amino)phenyl)(cyclopropyl)(imino)-λ 6 -thione and 2,6-dimethyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one is the starting material of the reaction, and 4-(5-(cyclopropaneimidoyl)-2-((trans-4-methylcyclohexyl) is obtained according to the fourth step of Example 4. Amino)phenyl)-2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 62%) .
MS m/z(ESI):607.1[M+H] +. MS m/z (ESI): 607.1 [M+H] + .
第八步：4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 8: 4-(5-(Cyclopropioni)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6- Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000192
Figure PCTCN2018072204-appb-000192
以4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率35％)。4-(5-(Cyclopropionimido)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1-toluenesulfonyl-1 , 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as a starting material, and the fourth step of Example 1 is obtained to obtain 4-(5-(cyclopropaneimidoyl)-2-( (trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Rate 35%).
MS m/z(ESI):453.2[M+H] +。 MS m/z (ESI): 453.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.65(dd,J＝8.8Hz,2.3Hz,1H),7.50(d,J＝2.3Hz,1H),7.06(s,1H),6.75(d,J＝8.9Hz,1H),5.73(s,1H),3.57(s,3H),3.26(d,J＝3.9Hz,1H),2.59–2.51(m,1H),2.29(s,3H),1.93-1.89(m,2H),1.64-1.60(m,2H),1.23-1.20(m,2H),1.16–1.09(m,1H),1.04–0.93(m,5H),0.85-0.83(m,1H),0.81(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) : δ7.65 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.50 (d, J = 2.3Hz, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.73 (s, 1H), 3.57 (s, 3H), 3.26 (d, J = 3.9 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.29 (s, 3H), 1.93 -1.89 (m, 2H), 1.64-1.60 (m, 2H), 1.23-1.20 (m, 2H), 1.16 - 1.09 (m, 1H), 1.04 - 0.93 (m, 5H), 0.85 - 0.83 (m, 1H), 0.81 (d, J = 6.5 Hz, 3H).
实施例56Example 56
4-(5-((S)-环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮和4-(5-((R)-环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-((S)-cyclopropylsulfinyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one and 4-(5-((R)-cyclopropanesulfinyl)-2-((trans-4-methyl) Preparation of hexyl)amino)phenyl)-2,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000193
Figure PCTCN2018072204-appb-000193
以4-(5-(环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，经拆分得4-(5-((S)-环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率40％)和4-(5-((R)-环丙磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率40％)。4-(5-(cyclopropanesulfonyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one is used as a raw material, and is obtained by dissolving 4-(5-((S)-cyclopropylsulfinyl)-2-((trans-4-) Methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 40%) and 4 -(5-((R)-cyclopropanesulfonyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1,6-di Hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one (yield 40%).
手型制备条件：Hand preparation conditions:
柱型Column type CHIRALPAK IGCHIRALPAK IG
柱尺寸Column size 2.5cm I.D.×25cm L2.5cm I.D.×25cm L
流动相Mobile phase MeOH＝100％MeOH=100%
流速Flow rate 30.0ml/min30.0ml/min
检测波Detection wave UV 254nmUV 254nm
柱温Column temperature 35℃35°C
(S)-构型化合物：MS m/z(ESI):453.2[M+H] +。 (S)-Construction Compound: MS m/z (ESI): 453.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.65(dd,J＝8.8Hz,2.4Hz,1H),7.50(d,J＝2.4Hz,1H),7.06(s,1H),6.75(d,J＝8.9Hz,1H),5.73(s,1H),3.57(s,3H),3.26(d,J＝3.6Hz,1H),2.59–2.51(m,1H),2.29(s,3H),1.93-1.89(m,2H),1.64-1.60(m,2H),1.23-1.20(m,2H),1.16–1.09(m,1H),1.04–0.93(m,5H),0.85-0.83(m,1H),0.81(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ7.65 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.50 (d, J = 2.4Hz, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.73 (s, 1H), 3.57 (s, 3H), 3.26 (d, J = 3.6 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.29 (s, 3H), 1.93 1.89 (m, 2H), 1.64-1.60 (m, 2H), 1.23-1.20 (m, 2H), 1.16–1.09 (m, 1H), 1.04–0.93 (m, 5H), 0.85-0.83 (m, 1H) ), 0.81 (d, J = 6.5 Hz, 3H).
t R＝7.054min(色谱柱：CHIRALPAK IG 0.46×15cm；流动相：100％MeOH；柱温：35℃；流速：1.0ml/min) t R =7.054 min (column: CHIRALPAK IG 0.46 x 15 cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0 ml/min)
(R)-构型化合物：MS m/z(ESI):453.2[M+H] +。 (R)-Construction Compound: MS m/z (ESI): 453.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.65(dd,J＝8.8Hz,2.3Hz,1H),7.50(d,J＝2.3Hz,1H),7.06(s,1H),6.75(d,J＝8.9Hz,1H),5.73(s,1H),3.57(s,3H),3.26(d,J＝3.9Hz,1H),2.59–2.51(m,1H),2.29(s,3H),1.93-1.89(m,2H),1.64-1.60(m,2H),1.23-1.20(m,2H),1.16–1.09(m,1H),1.04–0.93(m,5H),0.85-0.83(m,1H),0.81(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ7.65 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.50 (d, J = 2.3Hz, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.73 (s, 1H), 3.57 (s, 3H), 3.26 (d, J = 3.9 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.29 (s, 3H), 1.93 1.89 (m, 2H), 1.64-1.60 (m, 2H), 1.23-1.20 (m, 2H), 1.16–1.09 (m, 1H), 1.04–0.93 (m, 5H), 0.85-0.83 (m, 1H) ), 0.81 (d, J = 6.5 Hz, 3H).
t R＝9.953min(色谱柱：CHIRALPAK IG 0.46×15cm；流动相：100％MeOH；柱温：35℃；流速：1.0ml/min) t R = 9.953 min (column: CHIRALPAK IG 0.46 x 15 cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0 ml/min)
实施例57Example 57
2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备2,6-Dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfanilino)phenyl)-1,6-dihydro Preparation of -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000194
Figure PCTCN2018072204-appb-000194
第一步：(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(甲基)(亚氨基)-λ 6-硫烷酮的制备 First step: Preparation of (3-bromo-4-((trans--4-methylcyclohexyl)amino)phenyl)(methyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000195
Figure PCTCN2018072204-appb-000195
以实施例14第三步产物(3-溴-4-氟苯基)(亚氨基)(甲基)-λ 6-硫烷酮与反式-4-甲基环己胺为起始原料，参考实施例57的第六步反应条件，得到(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(甲基)(亚氨基)-λ 6-硫烷酮(产率92％)。 Taking the product of the third step of Example 14 (3-bromo-4-fluorophenyl)(imino)(methyl)-λ 6 -sulfanone and trans-4-methylcyclohexylamine as starting materials, Referring to the reaction conditions of the sixth step of Example 57, (3-bromo-4-((trans--4-methylcyclohexyl)amino)phenyl)(methyl)(imino)-λ 6 -sulfurate was obtained. Alkanone (yield 92%).
MS m/z(ESI):345.1/347.1(50/50)[M+H] +. MS m/z (ESI): 345. 1 / 347.1 (50 / 50) [M+H] + .
第二步：2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Second step: 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfanilino)phenyl)-1- Preparation of tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000196
Figure PCTCN2018072204-appb-000196
以(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(甲基)(亚氨基)-λ 6-硫烷酮代替(3-溴-4-((反式-4-甲基环己基)氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮，与2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮反应，参考实施例55第七步，得2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率63％)。 Replaced by (3-bromo-4-((trans--4-methylcyclohexyl)amino)phenyl)(methyl)(imino)-λ 6 -sulfanone (3-bromo-4-() (trans-4-methylcyclohexyl)amino)phenyl)(cyclopropyl)(imino)-λ 6 -thiol ketone with 2,6-dimethyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone reaction, referring to the seventh step of Example 55, to obtain 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfonate) Imidyl)phenyl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 63%).
MS m/z(ESI):581.2[M+H] +。 MS m/z (ESI): 581.2 [M+H] + .
第三步：2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Third step: 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfanilino)phenyl)-1, Preparation of 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000197
Figure PCTCN2018072204-appb-000197
以2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得2,6- 二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率80％)。2,6-Dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfimido)phenyl)-1-toluenesulfonyl -1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as a starting material, and the second step of the first step of Example 1 is obtained 2,6-dimethyl-4-(2-(( Trans-4-methylcyclohexyl)amino)-5-(S-methylsulfimidoyl)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7 - Ketone (yield 80%).
MS m/z(ESI):427.2[M+H] +. MS m/z (ESI): 427.2 [M+H] + .
1H NMR(400MHz,DMSO)δ7.78(dd,J＝9.0Hz,2.4Hz,1H),7.62(d,J＝2.5Hz,1H),7.20(s,1H),6.99(d,J＝9.2Hz,1H),5.73(s,1H),3.71(s,3H),3.51(s,3H),3.29–3.22(m,1H),2.29(s,3H),2.06–1.94(m,1H),1.89-1.82(m,2H),1.69-1.61(m,2H),1.17-1.10(m,4H),0.86(d,J＝6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ7.78 (dd, J = 9.0Hz, 2.4Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.29 - 3.22 (m, 1H), 2.29 (s, 3H), 2.06 - 1.94 (m, 1H) ), 1.89-1.82 (m, 2H), 1.69-1.61 (m, 2H), 1.7-1.10 (m, 4H), 0.86 (d, J = 6.5 Hz, 3H).
实施例58Example 58
2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-((S)-S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮和2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-((R)-S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮2,6-Dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-((S)-S-methylsulfimido)phenyl)-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)- 5-((R)-S-methylsulfimidoyl)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000198
Figure PCTCN2018072204-appb-000198
将2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(98mg)以手性制备得2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-((S)-S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(48mg，收率49％)和2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-((R)-S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(43mg，收率44％)。2,6-Dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(S-methylsulfimido)phenyl)-1,6-di Hydrogen-7H-pyrrolo[2,3-c]pyridin-7-one (98 mg) was obtained by chirality to give 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)) Amino)-5-((S)-S-methylsulfimidoyl)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (48 mg, Yield 49%) and 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-((R)-S-methylsulfimidoyl) Phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (43 mg, yield 44%).
手型制备条件：Hand preparation conditions:
柱型Column type CHIRALPAK IGCHIRALPAK IG
柱尺寸Column size 2.5cm I.D.×25cm L2.5cm I.D.×25cm L
流动相Mobile phase MeOH/CH 3CN＝100％ MeOH/CH 3 CN=100%
流速Flow rate 30.0ml/min30.0ml/min
检测波Detection wave UV 254nmUV 254nm
柱温Column temperature 35℃35°C
(S)-构型化合物：MS m/z(ESI):427.2[M+H] +. (S)-Construction Compound: MS m/z (ESI): 427.2 [M+H] + .
1H NMR(400MHz,DMSO)δ7.78(dd,J＝9.0Hz,2.4Hz,1H),7.62(d,J＝2.5Hz,1H),7.20(s,1H),6.99(d,J＝9.2Hz,1H),5.73(s,1H),3.71(s,3H),3.51(s,3H),3.29–3.22(m,1H),2.29(s,3H),2.06–1.94(m,1H),1.89-1.82(m,2H),1.69-1.61(m,2H),1.17-1.10(m,4H),0.86(d,J＝6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ7.78 (dd, J = 9.0Hz, 2.4Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.29 - 3.22 (m, 1H), 2.29 (s, 3H), 2.06 - 1.94 (m, 1H) ), 1.89-1.82 (m, 2H), 1.69-1.61 (m, 2H), 1.7-1.10 (m, 4H), 0.86 (d, J = 6.5 Hz, 3H).
t R＝6.803min(色谱柱：CHIRALPAK IG 0.46×15cm；流动相：100％MeOH；柱温：35℃；流速：1.0ml/min) t R = 6.803 min (column: CHIRALPAK IG 0.46 x 15 cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0 ml/min)
(R)-构型化合物：MS m/z(ESI):427.2[M+H] +. (R)-Construction Compound: MS m/z (ESI): 427.2 [M+H] + .
1H NMR(400MHz,DMSO)δ7.78(dd,J＝9.0Hz,2.4Hz,1H),7.62(d,J＝2.5Hz,1H),7.20(s,1H),6.99(d,J＝9.2Hz,1H),5.73(s,1H),3.71(s,3H),3.51(s,3H),3.29 –3.22(m,1H),2.29(s,3H),2.06–1.94(m,1H),1.89-1.82(m,2H),1.69-1.61(m,2H),1.17-1.10(m,4H),0.86(d,J＝6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ7.78 (dd, J = 9.0Hz, 2.4Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.29 - 3.22 (m, 1H), 2.29 (s, 3H), 2.06 - 1.94 (m, 1H) ), 1.89-1.82 (m, 2H), 1.69-1.61 (m, 2H), 1.7-1.10 (m, 4H), 0.86 (d, J = 6.5 Hz, 3H).
t R＝9.284min(色谱柱：CHIRALPAK IG 0.46×15cm；流动相：100％MeOH；柱温：35℃；流速：1.0ml/min). t R = 9.284 min (column: CHIRALPAK IG 0.46 x 15 cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0 ml/min).
实施例59Example 59
4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropanesulfonyl)-2-(2,4-difluorophenoxy)phenyl)-2,6-dimethyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000199
Figure PCTCN2018072204-appb-000199
第一步:(3-溴-4-(2,4-二氟苯氧基))(环丙基)(亚氨基)-λ6-硫烷酮的制备First step: Preparation of (3-bromo-4-(2,4-difluorophenoxy))(cyclopropyl)(imino)-λ6-sulfanone
Figure PCTCN2018072204-appb-000200
Figure PCTCN2018072204-appb-000200
以实施例33第六步产物(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮为起始原料，参考实施例4第五步反应，得到(3-溴-4-(2,4-二氟苯氧基))(环丙基)(亚氨基)-λ6-硫烷酮(收率76.8％). Taking the product of the sixth step of Example 33 (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone as the starting material, the reaction of the fifth step of Example 4 is obtained. (3-Bromo-4-(2,4-difluorophenoxy))(cyclopropyl)(imino)-λ6-sulfanone (yield 76.8%).
MS m/z(ESI):388.0/390.0(50/50)[M+H]+.第二步：2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(环丙磺亚胺酰基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备MS m/z (ESI): 388.0/390.0 (50/50) [M+H]+. Step 2: 2,6-dimethyl-4-(2-((trans-4-methyl) Preparation of hexyl)amino)-5-(cyclopropaneimido)phenyl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000201
Figure PCTCN2018072204-appb-000201
(3-溴-4-(2,4-二氟苯氧基))(环丙基)(亚氨基)-λ6-硫烷酮与2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮反应，参考实施例55第七步，得到2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(环丙磺亚胺酰基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮，(产率56.8％)。(3-Bromo-4-(2,4-difluorophenoxy))(cyclopropyl)(imino)-λ6-sulfanone and 2,6-dimethyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone reaction, referring to the seventh step of Example 55, to obtain 2,6-dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(cyclopropanesulfonate) Aminoacyl)phenyl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 56.8%).
MS m/z(ESI):624.14[M+H] +. MS m/z (ESI): 624.14 [M+H] + .
第三步：4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Third step: 4-(5-(cyclopropionimido)-2-(2,4-difluorophenoxy)phenyl)-2,6-dimethyl-1,6-dihydro- Preparation of 7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000202
Figure PCTCN2018072204-appb-000202
以2,6-二甲基-4-(2-((反式-4-甲基环己基)氨基)-5-(环丙磺亚胺酰基)苯基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为起始原料，参考实施例1第八步得4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率76.2％)。2,6-Dimethyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(cyclopropylsulfinyl)phenyl)-1-toluenesulfonyl-1 , 6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one as the starting material, and the 4-step of the first step of Example 1 gave 4-(5-(cyclopropaneimidoyl)-2 -(2,4-difluorophenoxy)phenyl)-2,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 76.2%).
MS m/z(ESI):470.1[M+H] +. MS m/z (ESI): 470.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ11.87(br,1H),7.94(d,J＝2.4Hz,1H),7.80(dd,J＝8.4Hz,2.0Hz,1H),7.53-7.48(m,1H),7.40-7.37(m,2H),7.19-7.12(m,1H),6.93(d,J＝8.8Hz,1H),6.0(s,1H),4.22(s,1H),3.56(s,3H),2.73-2.69(m,1H),2.30(s,3H),1.15-1.07(m,1H),1.00-0.85(m,3H). 1 H NMR (400MHz, DMSO- d6): δ11.87 (br, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.53-7.48 (m, 1H), 7.40-7.37 (m, 2H), 7.19-7.12 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.0 (s, 1H), 4.22 (s, 1H), 3.56(s,3H), 2.73-2.69(m,1H), 2.30(s,3H),1.15-1.07(m,1H),1.00-0.85(m,3H).
实施例60Example 60
4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(cyclopropaneimidoyl)-2-(spiro[2.5]octane-6-ylamino)phenyl)-2,6-dimethyl-1,6-dihydro-7H- Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000203
Figure PCTCN2018072204-appb-000203
第一步：4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备First step: 4-(5-(cyclopropaneimido)-2-(spiro[2.5]octane-6-ylamino)phenyl)-2,6-dimethyl-1-toluenesulfonyl Of -1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000204
Figure PCTCN2018072204-appb-000204
以(3-溴-4-(螺[2.5]辛烷-6-基氨基)苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(50mg,0.13mmol)与2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮反应为反应原料，参考实施例45第七步，得到化合物4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(60mg,产率75％)。 (3-Bromo-4-(spiro[2.5]octane-6-ylamino)phenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (50 mg, 0.13 mmol) and 2,6 -Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one is reacted as a starting material for the reaction, and the compound of the fourth step of Example 45 is obtained to obtain the compound 4-(5-(cyclopropaneimidoyl)-2-(spiro[ 2.5]octane-6-ylamino)phenyl)-2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Ketone (60 mg, yield 75%).
MS m/z(ESI):619.3[M+H] + MS m/z (ESI): 619.3 [M+H] +
第二步：4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Second step: 4-(5-(cyclopropaneimido)-2-(spiro[2.5]octane-6-ylamino)phenyl)-2,6-dimethyl-1,6-di Preparation of hydrogen-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000205
Figure PCTCN2018072204-appb-000205
以4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例50第三步，得到化合物4-(5-(环丙磺亚胺酰基)-2-(螺[2.5]辛烷-6-基氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(白色固体，产率19％)4-(5-(cyclopropaneimido)-2-(spiro[2.5]octane-6-ylamino)phenyl)-2,6-dimethyl-1-toluenesulfonyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one is the starting material of the reaction, and the third step of Example 50 is obtained to obtain the compound 4-(5-(cyclopropaneimidoyl)-2. -(spiro[2.5]octane-6-ylamino)phenyl)-2,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ( White solid, yield 19%)
MS m/z(ESI):465.2[M+H] + MS m/z (ESI): 465.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.77(dd,J＝8.8Hz,2.4Hz,1H),7.62(d,J＝2.4Hz,1H),7.18(s,1H),6.88(d,J＝8.9Hz,1H),5.86(s,1H),3.69(s,3H),3.57–3.46(m,1H),2.69–2.63(m,1H),2.40(s,3H),1.96–1.89(m,2H),1.73–1.64(m,2H),1.34–1.21(m,4H),1.08–0.93(m,4H),0.33–0.24(m,2H),0.21–0.14(m,2H). 1 H NMR (400MHz, MeOD) δ7.77 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.18 (s, 1H), 6.88 (d, J = 8.9 Hz, 1H), 5.86 (s, 1H), 3.69 (s, 3H), 3.57–3.46 (m, 1H), 2.69–2.63 (m, 1H), 2.40 (s, 3H), 1.96–1.89 (m) , 2H), 1.73–1.64 (m, 2H), 1.34–1.21 (m, 4H), 1.08–0.93 (m, 4H), 0.33–0.24 (m, 2H), 0.21–0.14 (m, 2H).
实施例61Example 61
4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000206
Figure PCTCN2018072204-appb-000206
第一步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮First step: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl -1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000207
Figure PCTCN2018072204-appb-000207
以(3-溴-4-((反式--4-甲基环己基)氨基)苯基)(1-氯环丙基)(亚氨基)-λ 6-硫烷酮与2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮反应为原料，参考实施例4第四步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率32％)。 (3-Bromo-4-((trans--4-methylcyclohexyl)amino)phenyl)(1-chlorocyclopropyl)(imino)-λ 6 -sulfanone with 2,6- Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H - pyrrolo[2,3-c]pyridine-7-one is reacted as a starting material, and 4-(5-(1-chlorocyclopropane-1-sulfilimine)-2-(4-(4-chlorocyclopropane-1-sulfanilinoyl)-2-) is obtained according to the fourth step of Example 4. (trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone (yield 32%).
MS m/z(ESI):641.1[M+H] +. MS m/z (ESI): 641.1 [M+H] + .
第二步：4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6- 二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Second step: 4-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl -1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000208
Figure PCTCN2018072204-appb-000208
以-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得4-(5-(1-氯环丙烷-1-磺亚胺酰基)-2-((反式-4-甲基环己基)氨基)苯基)-2,6-二甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率25％)。-(5-(1-chlorocyclopropane-1-sulfoimidoyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1- Tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one was used as a starting material, and the eighth step of Example 1 was obtained to obtain 4-(5-(1-chlorocyclopropane)- 1-sulfoimidoyl-2-((trans-4-methylcyclohexyl)amino)phenyl)-2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H Pyrrolo[2,3-c]pyridine-7-one (yield 25%).
MS m/z(ESI):487.2[M+H] +。 MS m/z (ESI): 487.2 [M+H] + .
1H NMR(400MHz,MeOD):δ7.72(dd,J＝8.9Hz,2.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.06(s,1H),6.78(d,J＝9.0Hz,1H),5.76(s,1H),3.58(s,3H),3.33-3.26(m,1H),2.30(s,3H),1.97-1.89(m,2H),1.82-1.76(m,1H),1.66-1.58(m,2H),1.30-1.16(m,5H),1.08-0.95(m,3H),0.81(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) : δ7.72 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.56 (d, J = 2.4Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 9.0 Hz, 1H), 5.76 (s, 1H), 3.58 (s, 3H), 3.33 - 3.26 (m, 1H), 2.30 (s, 3H), 1.97-1.89 (m, 2H), 1.82-1.76 ( m, 1H), 1.66-1.58 (m, 2H), 1.30-1.16 (m, 5H), 1.08-0.95 (m, 3H), 0.81 (d, J = 6.5 Hz, 3H).
实施例62Example 62
4-(5-(2-氯丙烷-2-基磺亚胺酰基)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(5-(2-Chloropropan-2-ylsulfonimido)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1, Preparation of 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000209
Figure PCTCN2018072204-appb-000209
第一步：2-溴-4-((2-氯丙烷-2-基)亚硫酰基)-1-氟苯的制备First step: Preparation of 2-bromo-4-((2-chloropropan-2-yl)sulfinyl)-1-fluorobenzene
Figure PCTCN2018072204-appb-000210
Figure PCTCN2018072204-appb-000210
以2-溴-1-氟-4-(异丙基亚硫酰基)苯(50mg,0.19mmol)为反应原料，参考实施例41第一步，得到化合物2-溴-4-((2-氯丙烷-2-基)亚硫酰基)-1-氟苯(40mg,无色胶体，产率71％)2-Bromo-1-fluoro-4-(isopropylsulfinyl)benzene (50 mg, 0.19 mmol) was used as the starting material, and the first step of Example 41 was obtained to obtain the compound 2-bromo-4-((2- Chloropropan-2-yl)sulfinyl)-1-fluorobenzene (40 mg, colorless colloid, yield 71%)
1H NMR(400MHz,CDCl3)δ7.91(d,J＝4.8Hz,1H),7.66–7.57(m,1H),7.20(t,J＝8.2Hz,1H),1.82(s,3H),1.48(s,3H). 1 H NMR (400MHz, CDCl3) δ7.91 (d, J = 4.8Hz, 1H), 7.66-7.57 (m, 1H), 7.20 (t, J = 8.2Hz, 1H), 1.82 (s, 3H), 1.48(s,3H).
第二步：(3-溴-4-氟苯基)(2-氯丙烷-2-基)(亚氨基)-λ 6-硫烷酮的制备 Second step: Preparation of (3-bromo-4-fluorophenyl)(2-chloropropan-2-yl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000211
Figure PCTCN2018072204-appb-000211
以2-溴-4-((2-氯丙烷-2-基)亚硫酰基)-1-氟苯(200mg,0.67mmol)为反应原料，参考实施例5第三步，得到化合物(3-溴-4-氟苯基)(2-氯丙烷-2-基)(亚氨基)-λ 6-硫烷酮(150mg,黄色固体，产率71％) 2-Bromo-4-((2-chloropropan-2-yl)sulfinyl)-1-fluorobenzene (200 mg, 0.67 mmol) was used as the starting material, and the third step of Example 5 was used to obtain the compound (3- Bromo-4-fluorophenyl)(2-chloropropan-2-yl)(imino)-λ 6 -sulfanone (150 mg, yellow solid, yield 71%)
MS m/z(ESI):313.9/315.9(50/50)[M+H] +. MS m/z (ESI): 313.9 / 315.9 (50 / 50) [M+H] + .
第三步：4-(5-(2-氯丙烷-2-基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备The third step: 4-(5-(2-chloropropan-2-ylsulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H -Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000212
Figure PCTCN2018072204-appb-000212
以(3-溴-4-氟苯基)(2-氯丙烷-2-基)(亚氨基)-λ 6-硫烷酮(150mg,0.49mmol)为反应原料，参考实施例45第七步，得到化合物4-(5-(2-氯丙烷-2-基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(170mg,无色胶体，产率66％) (3-Bromo-4-fluorophenyl)(2-chloropropan-2-yl)(imino)-λ 6 -sulfanone (150 mg, 0.49 mmol) was used as the starting material of the reaction, and reference was made to the seventh step of Example 45. To give the compound 4-(5-(2-chloropropan-2-ylsulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H- Pyrrolo[2,3-c]pyridin-7-one (170 mg, colorless colloid, yield 66%)
MS m/z(ESI):536.0[M+H] + MS m/z (ESI): 536.0 [M+H] +
第四步：4-(5-(2-氯丙烷-2-基磺亚胺酰基)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 4: 4-(5-(2-Chloropropan-2-ylsulfonimido)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-A Preparation of keto-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000213
Figure PCTCN2018072204-appb-000213
以4-(5-(2-氯丙烷-2-基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(60mg,0.11mmol)为反应原料，参考实施例23第一步，得到化合物4-(5-(2-氯丙烷-2-基磺亚胺酰基)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(7.6mg,白色固体，产率13％)4-(5-(2-Chloropropan-2-ylsulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridin-7-one (60 mg, 0.11 mmol) was used as the starting material of the reaction, and the compound was obtained in the first step of Example 23 to give the compound 4-(5-(2-chloropropan-2-ylsulfinimido) )-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (7.6 mg, white solid, yield 13%)
MS m/z(ESI):475.2[M+H] + MS m/z (ESI): 475.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.87(dd,J＝8.9Hz,2.4Hz,1H),7.71(d,J＝2.4Hz,1H),7.36(d,J＝2.8Hz,1H),7.21(s,1H),6.92(d,J＝9.1Hz,1H),6.14(d,J＝2.8Hz,1H),3.71(s,3H),3.44–3.40(m,1H),2.05–1.99(m,2H),1.89(s,3H),1.86(s,3H),1.78–1.70(m,2H),1.37–1.32(m,1H),1.16–1.07(m,4H),0.92(d,J＝6.5Hz, 3H). 1 H NMR (400MHz, MeOD) δ7.87 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.71 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.21 (s, 1H), 6.92 (d, J = 9.1 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 3.71 (s, 3H), 3.44 - 3.40 (m, 1H), 2.05 - 1.99 ( m, 2H), 1.89 (s, 3H), 1.86 (s, 3H), 1.78 - 1.70 (m, 2H), 1.37 - 1.32 (m, 1H), 1.16 - 1.07 (m, 4H), 0.92 (d, J=6.5Hz, 3H).
实施例63Example 63
乙基4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯Ethyl 4-(5-(cyclopropanesulfonyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-7-carbonyl-6,7-dihydro -1H-pyrrolo[2,3-c]pyridine-2-carboxylate
Figure PCTCN2018072204-appb-000214
Figure PCTCN2018072204-appb-000214
第一步：乙基4-溴-6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯的制备First step: ethyl 4-bromo-6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate Preparation
Figure PCTCN2018072204-appb-000215
Figure PCTCN2018072204-appb-000215
将4-溴-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(3.8g,10mmol)溶于200毫升四氢呋喃中，干冰-丙酮浴冷却至-78度，1M浓度二异丙基氨基锂的四氢呋喃溶液(15ML，15mmol)缓慢滴入反应体系，反应内温保持在-70度以下。滴加完毕之后，反应升温至-50度搅拌1小时。氯甲酸乙酯(1.63g,15mmol)的四氢呋喃溶液(10毫升)缓慢滴入反应体系，滴加完毕后在同样温度继续反应2小时。饱和氯化铵溶液淬灭反应，升温至室温，乙酸乙酯萃取。合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥。滤去干燥剂，滤液旋干，剩余物使用硅胶柱层析纯化(石油醚：乙酸乙酯＝1：1)得到乙基4-溴-6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(2.6g,57％)。4-Bromo-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (3.8 g, 10 mmol) was dissolved in 200 mL of tetrahydrofuran The dry ice-acetone bath was cooled to -78 °C, and a 1 M solution of lithium diisopropylamide in tetrahydrofuran (15 ML, 15 mmol) was slowly dropped into the reaction system, and the internal temperature of the reaction was kept below -70 °C. After the completion of the dropwise addition, the reaction was heated to -50 °C and stirred for 1 hour. A solution of ethyl chloroformate (1.63 g, 15 mmol) in tetrahydrofuran (10 ml) was slowly dropped into the reaction system, and after the completion of the dropwise addition, the reaction was continued at the same temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was dried, and the residue was purified using silica gel column chromatography ( petroleum ether: ethyl acetate = 1:1) to give ethyl 4-bromo-6-methyl-7-carbonyl-1-toluenesulfonyl -6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2.6 g, 57%).
MS m/z(ESI):453.0/455.0(50/50)[M+H] +； MS m / z (ESI): 453.0 / 455.0 (50 / 50) [M+H] + ;
第二步：乙基6-甲基-7-羰基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯的制备The second step: ethyl 6-methyl-7-carbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluene Preparation of sulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
Figure PCTCN2018072204-appb-000216
Figure PCTCN2018072204-appb-000216
氩气气氛下，将乙基4-溴-6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(2.6g,5.7mmol)，4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(2.58g,11.4mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(228mg,0.29mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(138mg,0.29mmol)和乙酸钾(1.7g,17.1mmol)溶于100毫升预先脱气的无水1,4-二氧六环中，反应于80度条件下搅拌过夜。加水淬灭反应，乙酸乙酯萃取。合并有机 相，水洗，饱和食盐水洗，无水硫酸钠干燥。滤去干燥剂，滤液旋干，剩余物使用硅胶柱层析纯化(石油醚：乙酸乙酯＝1：2)得到乙基6-甲基-7-羰基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(1.6g,56％)。Ethyl 4-bromo-6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxyl under argon Acid ester (2.6g, 5.7mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxa boron Pentacyclo) (2.58g, 11.4mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2' -amino-1,1'-biphenyl)]palladium (228 mg, 0.29 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (138 mg, 0.29 mmol) and acetic acid Potassium (1.7 g, 17.1 mmol) was dissolved in 100 mL of pre-degassed anhydrous 1,4-dioxane and the reaction was stirred at 80 °C overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was dried, and the residue was purified using silica gel column chromatography ( petroleum ether: ethyl acetate = 1:2) to give ethyl 6-methyl-7-carbonyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2 - Carboxylic ester (1.6 g, 56%).
MS m/z(ESI):501.2[M+H] +； MS m/z (ESI): 501.2 [M+H] +
第三步：(3-溴-4-((反-4-甲基环己基)氨基)苯基)(环丙基)(亚氨基)-l6-硫烷酮的制备Third step: Preparation of (3-bromo-4-((trans-4-methylcyclohexyl)amino)phenyl)(cyclopropyl)(imino)-l6-sulfanone
Figure PCTCN2018072204-appb-000217
Figure PCTCN2018072204-appb-000217
25mL的微波管中加入实施例33中第五步的产物(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮(1.39g,5mmol)及反式-4-甲基环己烷-1-胺(10mL)。反应体系密封之后置于150摄氏度的油浴下反应12小时，然后冷却到室温。乙酸乙酯萃取，饱和食盐水洗涤。有机相干燥蒸干，粗品硅胶柱层析(石油醚：乙酸乙酯＝1:1)得到(3-溴-4-((反-4-甲基环己基)氨基)苯基)(环丙基)(亚氨基)-l6-硫烷酮(1.35g，产率72.8％)。 The product of the fifth step of Example 33 (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -sulfanone (1.39 g, 5 mmol) and the reverse were added to a 25 mL microwave tube. 4-Methylcyclohexane-1-amine (10 mL). The reaction system was sealed and placed in an oil bath at 150 ° C for 12 hours, and then cooled to room temperature. Extract with ethyl acetate and wash with saturated brine. The organic phase was dried and evaporated to dryness crystals eluted eluted eluted eluted eluted (imino)-l6-sulfanone (1.35 g, yield 72.8%).
MS m/z(ESI):371.1/373.1(50/50)[M+H] +第四步：(乙基4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯的制备 MS m/z (ESI): 371.1/373.1 (50/50) [M+H] + Step 4: (ethyl 4-(5-(cyclopropylsulfonimido)-2-((trans-4) -Methylcyclohexyl)amino)phenyl)-6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate Preparation of acid ester
Figure PCTCN2018072204-appb-000218
Figure PCTCN2018072204-appb-000218
氩气气氛下，将第二步得到的乙基6-甲基-7-羰基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(500mg,1mmol)，第三步得到的(3-溴-4-(((1r,4r)-4-甲基环己基)氨基)苯基)(环丙基)(亚氨基)-l6-硫烷酮(370mg,1mmol)，三(二亚苄基丙酮)二钯(45mg,0.05mmol)，1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(29mg,0.1mmol)和无水磷酸三钾(636mg,3mmol)溶于脱气的20毫升四氢呋喃和5毫升水的混合溶剂中，反应升温至60度搅拌3小时。加乙酸乙酯稀释，分液，水相使用乙酸乙酯萃取。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干。残余物使用硅胶柱层析纯化(石油醚：乙酸乙酯＝0:1)得到(乙基4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(360mg,54％)。Ethyl 6-methyl-7-carbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 obtained in the second step under argon atmosphere -yl-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (500 mg, 1 mmol), obtained in the third step (3-bromo) 4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)(cyclopropyl)(imino)-l6-sulfanone (370mg, 1mmol), tris(dibenzylidene) Acetone) dipalladium (45 mg, 0.05 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (29 mg, 0.1 mmol) Anhydrous tripotassium phosphate (636 mg, 3 mmol) was dissolved in a mixed solvent of degassed 20 ml of tetrahydrofuran and 5 ml of water, and the mixture was heated to 60 ° C and stirred for 3 hours. It was diluted with ethyl acetate, and the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc (EtOAc:EtOAc) Amino)phenyl)-6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (360 mg, 54%).
MS m/z(ESI):665.2[M+H] +； MS m/z (ESI): 665.2 [M+H] +
第五步：乙基4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-6-甲基-7-羰 基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯的制备The fifth step: ethyl 4-(5-(cyclopropylsulfinyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-7-carbonyl-6, Preparation of 7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
Figure PCTCN2018072204-appb-000219
Figure PCTCN2018072204-appb-000219
将(乙基4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(67mg,0.1mmol)溶于2毫升乙醇和2毫升60％硫酸混合溶液中，之后反应回流过夜。冰水淬灭反应，PH值调至中性，乙酸乙酯萃取三次。合并有机相，水洗，饱和食盐水洗，硫酸钠干燥，过滤，旋干。残余物使用反相制备柱纯化得到乙基4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(18.5mg,36％)。((Ethyl 4-(5-(cyclopropanesulfonyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-7-carbonyl-1-toluene) Acyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (67 mg, 0.1 mmol) was dissolved in 2 ml of ethanol and 2 ml of 60% sulfuric acid in a mixed solution. After refluxing overnight, the reaction was quenched with EtOAc (EtOAc)EtOAc. Ethyl 4-(5-(cyclopropanesulfonyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-7-carbonyl-6,7-dihydro -1H-pyrrolo[2,3-c]pyridine-2-carboxylate (18.5 mg, 36%).
MS m/z(ESI):511.2[M+H] +； MS m/z (ESI): 511.2 [M+H] +
1H NMR(400MHz,d4-MeOD):δ:7.68(dd,J＝8.8Hz,2.4Hz,,1H),7.51(d,J＝2.0Hz,1H),7.15(s,1H),6.79(d,J＝8.8Hz,1H),6.58(s,1H),4.27(q,J＝7.2Hz,2H),3.58(s,3H),3.28-3.27(m,1H),3.60-3.53(m,1H),1.92-1.88(m,2H),1.62-1.60(m,2H),1.28-1.19(m,5H),1.19-1.11(m,1H),1.02-0.97(m,5H),0.87-0.79(m,4H). 1 H NMR (400MHz, d4- MeOD): δ: 7.68 (dd, J = 8.8Hz, 2.4Hz ,, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.15 (s, 1H), 6.79 ( d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.58 (s, 3H), 3.28-3.27 (m, 1H), 3.60-3.53 (m , 1H), 1.92-1.88 (m, 2H), 1.62-1.60 (m, 2H), 1.28-1.19 (m, 5H), 1.19-1.11 (m, 1H), 1.02-0.97 (m, 5H), 0.87 -0.79 (m, 4H).
实施例64Example 64
4-(2-((1,4-二氧杂螺[4.5]癸烷-8-基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((1,4-Dioxaspiro[4.5]decane-8-yl)oxo)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1, 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000220
Figure PCTCN2018072204-appb-000220
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用1,4-二氧杂螺[4.5]癸烷-8-醇取代2,4-二氟苯酚，得到4-(2-((1,4-二氧杂螺[4.5]癸烷-8-基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率63％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting 1,4-dioxaspiro[4.5]decane-8-ol for 2,4-difluorophenol gives 4-(2) -((1,4-Dioxaspiro[4.5]decane-8-yl)oxo-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one (yield 63%).
MS m/z(ESI):472.2[M+H] +； MS m/z (ESI): 472.2 [M+H] +
1H NMR(400MHz,d4-MeOD):δ7.86-7.81(m,2H),7.26-7.23(m,2H),7.19(s,1H),6.16(d,J＝2.8Hz,1H),4.61-4.59(m,1H),3.80-3.74(m,4H),3.61(s,3H),3.16(q,J＝7.6Hz,2H),1.77-1.75(m,4H),1.50-1.39(m,4H),1.15(t,J＝7.6Hz,3H). 1 H NMR (400MHz, d4- MeOD): δ7.86-7.81 (m, 2H), 7.26-7.23 (m, 2H), 7.19 (s, 1H), 6.16 (d, J = 2.8Hz, 1H), 4.61-4.59 (m, 1H), 3.80-3.74 (m, 4H), 3.61 (s, 3H), 3.16 (q, J = 7.6 Hz, 2H), 1.77-1.75 (m, 4H), 1.50-1.39 ( m, 4H), 1.15 (t, J = 7.6 Hz, 3H).
实施例65Example 65
4-(2-((1H-吲哚-5-基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((1H-indol-5-yl)oxy)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000221
Figure PCTCN2018072204-appb-000221
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用1H-吲哚-5-酚取代2,4-二氟苯酚，得到4-(2-((1H-吲哚-5-基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率25％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, the 2,4-difluorophenol is substituted with 1H-indole-5-phenol to obtain 4-(2-((1H-吲哚-5). -yl)oxo-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ( Yield 25%).
MS m/z(ESI):447.1[M+H] +； MS m/z (ESI): 447.1 [M+H] +
1H NMR(400MHz,d4-MeOD):δ8.08(d,J＝2.4Hz,1H),7.85-7.82(dd,J＝8.8Hz,2.4Hz,1H),7.44-7.39(m,3H),7.31-7.26(m,2H),7.00(d,J＝8.8Hz,1H),6.87-6.84(m,1H),6.47-6.45(m,2H),3.72(s,3H),3.35(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, d4-MeOD): δ 8.08 (d, J = 2.4 Hz, 1H), 7.85 - 7.82 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.44 - 7.39 (m, 3H) , 7.31-7.26 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.87-6.84 (m, 1H), 6.47-6.45 (m, 2H), 3.72 (s, 3H), 3.35 (q) , J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).
实施例66Example 66
4-(5-(环丙磺亚胺酰基)-2-((4,4-二甲基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropanesulfonyl)-2-((4,4-dimethylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000222
Figure PCTCN2018072204-appb-000222
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用4,4-二甲基环己醇取代环丙基甲醇，参考实施例5第五步，得到4-(5-(环丙磺亚胺酰基)-2-((4,4-二甲基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(45％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material, and cyclopropylmethanol was replaced with 4,4-dimethylcyclohexanol. Referring to the fifth step of Example 5, 4-(5-(cyclopropaneimidoyl)-2 was obtained. -((4,4-Dimethylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (45 %).
MS m/z(ESI):454.2[M+H] + MS m/z (ESI): 454.2 [M+H] +
1H NMR(400MHz,CDCl 3):δ12.24(s,1H),8.20(d,J＝2.4Hz,1H),7.96-7.93(dd,J＝8.8,2.4Hz,1H),7.47(t,J＝2.4Hz,1H),7.43(s,1H),7.25(d,J＝8.8Hz,1H),6.38(t,J＝2.4Hz,1H),4.47(s,1H),3.82(s,3H),3.50-3.47(m,1H),2.09-2.04(m,1H),1.82-1.76(m,4H),1.68-1.50(m,4H),1.38-1.25(m,4H),0.90(s,3H),0.80(s,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 12.24 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.96-7.93 (dd, J = 8.8, 2.4 Hz, 1H), 7.47 (t , J=2.4Hz, 1H), 7.43(s,1H), 7.25(d,J=8.8Hz,1H), 6.38(t,J=2.4Hz,1H),4.47(s,1H),3.82(s , 3H), 3.50-3.47 (m, 1H), 2.09-2.04 (m, 1H), 1.82-1.76 (m, 4H), 1.68-1.50 (m, 4H), 1.38-1.25 (m, 4H), 0.90 (s, 3H), 0.80 (s, 3H).
实施例67Example 67
2-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈2-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000223
Figure PCTCN2018072204-appb-000223
第一步 2-溴-1-(环丙基甲氧基)-4-硝基苯的制备First step Preparation of 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene
Figure PCTCN2018072204-appb-000224
Figure PCTCN2018072204-appb-000224
将2-溴-1-氟-4-硝基苯(5g，22.7mmol)、环丙基甲醇(2g，27.3mmol)溶于N,N-二甲基甲酰胺(20mL)，在0℃下分批加入钠氢(1.2g，29.5mmol)，4小时后，加入冰水(30mL)，乙酸乙酯(50mL)萃取，分出乙酸乙酯，抽干得到2-溴-1-(环丙基甲氧基)-4-硝基苯(6.2g)，直接用作下一步。2-Bromo-1-fluoro-4-nitrobenzene (5g, 22.7mmol), cyclopropylmethanol (2g, 27.3mmol) was dissolved in N,N-dimethylformamide (20mL) at 0°C Add sodium hydrogen (1.2 g, 29.5 mmol) in portions, and after 4 hours, add ice water (30 mL), ethyl acetate (50 mL), extract ethyl acetate, and drain to give 2-bromo-1-(cyclopropyl) Methoxy)-4-nitrobenzene (6.2 g) was used directly as the next step.
第二步 3-溴-4-(环丙基甲氧基)苯胺的制备Second step Preparation of 3-bromo-4-(cyclopropylmethoxy)aniline
Figure PCTCN2018072204-appb-000225
Figure PCTCN2018072204-appb-000225
将2-溴-1-(环丙基甲氧基)-4-硝基苯(6.2g，22.7mmol)溶于乙醇(50mL)、四氢呋喃(50mL)与水(20mL)的混合溶剂中，加入铁粉(6.4g，113.7mmol)、氯化铵(6.1g，113.7mmol)，回流4小时，柱层析纯化得到3-溴-4-(环丙基甲氧基)苯胺(2.7g)。2-Bromo-1-(cyclopropylmethoxy)-4-nitrobenzene (6.2 g, 22.7 mmol) was dissolved in a mixed solvent of ethanol (50 mL), tetrahydrofuran (50 mL) and water (20 mL) Iron powder (6.4 g, 113.7 mmol), ammonium chloride (6.1 g, 113.7 mmol) was refluxed for 4 hours and purified by column chromatography to afford 3-bromo-4-(cyclopropylmethoxy)aniline (2.7 g).
第三步 2-溴-1-(环丙基甲氧基)-4-碘苯的制备Third step Preparation of 2-bromo-1-(cyclopropylmethoxy)-4-iodobenzene
Figure PCTCN2018072204-appb-000226
Figure PCTCN2018072204-appb-000226
将3-溴-4-(环丙基甲氧基)苯胺(2.1g，8.8mmol)悬浮于乙腈(50mL)与水(50mL)中，加入对甲苯磺酸(5.0g，26.4mmol)，在0℃下滴加亚硝酸钠(1.2g，17.6mmol)加入碘化钾(3.7g，22.0mmol)，柱层析得到2-溴-1-(环丙基甲氧基)-4-碘苯(1g)。3-Bromo-4-(cyclopropylmethoxy)aniline (2.1 g, 8.8 mmol) was suspended in acetonitrile (50 mL) and water (50 mL) and p-toluenesulfonic acid (5.0 g, 26.4 mmol) Sodium nitrite (1.2 g, 17.6 mmol) was added dropwise at 0 ° C. Potassium iodide (3.7 g, 22.0 mmol) was added, and column chromatography gave 2-bromo-1-(cyclopropylmethoxy)-4-iodobenzene (1 g) ).
第四步 S-(3-溴-4-(环丙基甲氧基)苯基)乙硫酸酯的制备Fourth step Preparation of S-(3-bromo-4-(cyclopropylmethoxy)phenyl)ethylsulfate
Figure PCTCN2018072204-appb-000227
Figure PCTCN2018072204-appb-000227
将2-溴-1-(环丙基甲氧基)-4-碘苯(1g,2.8mmol)、硫代乙酸钾(0.5g，4.2mmol)、碘化亚铜(54mg，0.28mmol)、1,10-菲啰啉(102mg，0.6mmol)至甲苯中(30mL)，氮气保护，在100℃下搅拌3小时，柱层析得到S-(3-溴-4-(环丙基甲氧基)苯基)乙 硫酸酯(0.87g)。2-Bromo-1-(cyclopropylmethoxy)-4-iodobenzene (1 g, 2.8 mmol), potassium thioacetate (0.5 g, 4.2 mmol), cuprous iodide (54 mg, 0.28 mmol), 1,10-phenanthroline (102 mg, 0.6 mmol) to toluene (30 mL), nitrogen-protected, stirred at 100 ° C for 3 hours, column chromatography gave S-(3-bromo-4-(cyclopropylmethoxy) Phenyl)ethyl sulphate (0.87 g).
第五步 2-((3-溴-4-(环丙基甲氧基)苯基)硫代)乙酰腈的制备Step 5 Preparation of 2-((3-bromo-4-(cyclopropylmethoxy)phenyl)thio)acetonitrile
Figure PCTCN2018072204-appb-000228
Figure PCTCN2018072204-appb-000228
将S-(3-溴-4-(环丙基甲氧基)苯基)乙硫酸酯(0.87g，2.9mmol)溶于乙醇(10mL)与水(2mL)，加入氢氧化钠(143mg，3.6mmol)、溴乙腈(429mg，3.6mmol)，在25℃下搅拌2小时，柱层析纯化得到2-((3-溴-4-(环丙基甲氧基)苯基)硫代)乙酰腈(1g)。S-(3-Bromo-4-(cyclopropylmethoxy)phenyl)ethylsulfate (0.87 g, 2.9 mmol) was dissolved in ethanol (10 mL) and water (2 mL). 3.6 mmol), bromoacetonitrile (429 mg, 3.6 mmol), stirred at 25 ° C for 2 hours, and purified by column chromatography to give 2-((3-bromo-4-(cyclopropylmethoxy)phenyl)thio) Acetonitrile (1 g).
第六步 2-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)乙酰腈的制备Step 6 Preparation of 2-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfene]) acetonitrile
Figure PCTCN2018072204-appb-000229
Figure PCTCN2018072204-appb-000229
反应操作同实施例4第二步，得到2-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)乙酰腈(收率86.8％)。The reaction was carried out in the same manner as in the second step of Example 4 to give 2-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfinyl)acetonitrile (yield: 86.8%).
1H NMR(400MHz,CDCl3):δ7.91(d,J＝2.4Hz,1H),7.68(dd,J＝8.4Hz,2.0Hz,1H),7.04(d,J＝8.4Hz,1H),3.92(d,J＝6.8Hz,2H),3.72(d,J＝15.6Hz,1H),3.64(d,J＝15.6Hz,1H),1.29-1.24(m,1H),0.65-0.60(m,2H),0.39-0.35(m,2H). 1 H NMR (400MHz, CDCl3) : δ7.91 (d, J = 2.4Hz, 1H), 7.68 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.04 (d, J = 8.4Hz, 1H), 3.92 (d, J = 6.8 Hz, 2H), 3.72 (d, J = 15.6 Hz, 1H), 3.64 (d, J = 15.6 Hz, 1H), 1.29-1.24 (m, 1H), 0.65-0.60 (m) , 2H), 0.39-0.35 (m, 2H).
第七步 2-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈的制备Step 7 Preparation of 2-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfene])-2-methylpropionitrile
Figure PCTCN2018072204-appb-000230
Figure PCTCN2018072204-appb-000230
将2-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)乙酰腈(535mg，1.7mmol)溶于四氢呋喃(20mL)中，加入碳酸铯(1.7g，5.2mmol)、碘甲烷(0.73g，5.2mmol)，在25℃搅拌3小时，柱层析纯化得到得到2-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈(387mg，收率66.8％)。2-((3-Bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfinyl>)acetonitrile (535 mg, 1.7 mmol) was dissolved in tetrahydrofuran (20 mL) and cesium carbonate was added. (1.7 g, 5.2 mmol), iodomethane (0.73 g, 5.2 mmol), stirred at 25 ° C for 3 hours, and purified by column chromatography to give 2-((3-bromo-4-(cyclopropylmethoxy)benzene) Base) sulfinyl <sulfinyl>)-2-methylpropionitrile (387 mg, yield 66.8%).
第八步 2-(3-溴-4-(环丙基甲氧基)苯基磺亚胺酰基)-2-甲基丙腈的制备Step 8 Preparation of 2-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000231
Figure PCTCN2018072204-appb-000231
以2-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈为起始原料，反应操作同实施例4第三步，得到2-(3-溴-4-(环丙基甲氧基)苯基磺亚胺酰基)-2-甲基丙腈(收率56.3％)。Starting from 2-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfinyl])-2-methylpropionitrile, the reaction operation is the same as in Example 4 Three steps gave 2-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonimido)-2-methylpropanenitrile (yield 56.3%).
MS m/z(ESI):357.0/359.0(50/50)[M+H] +. MS m/z (ESI): 357.0 / 359.0 (50 / 50) [M+H] + .
第九步 2-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并 [2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈的制备Step 9 2-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3 Of -c]pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000232
Figure PCTCN2018072204-appb-000232
以2-(3-溴-4-(环丙基甲氧基)苯基磺亚胺酰基)-2-甲基丙腈与中间体Im为反应原料，操作参考实施例4第四步，得到2-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(收率36.8％)。Taking 2-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonimido)-2-methylpropionitrile and the intermediate Im as the starting materials, the fourth step of the reference example 4 was obtained. 2-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile (yield 36.8%).
MS m/z(ESI):579.1[M+H] +. MS m/z (ESI): 579.1 [M+H] + .
第十步 2-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈的制备Step 10 2-(4-(Cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4 Of -phenyl)phenylsulfanimidoyl-2-methylpropionitrile
Figure PCTCN2018072204-appb-000233
Figure PCTCN2018072204-appb-000233
将2-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(100mg，0.173mmol)溶于乙醇(2mL)中，加入乙醇钠(38mg，0.52mmol)，在25℃搅拌2小时，柱层析纯化得到2-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(30mg，收率40.9％)。2-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c Pyridin-4-yl)phenylsulfanimidoyl-2-methylpropanenitrile (100 mg, 0.173 mmol) was dissolved in ethanol (2 mL), sodium ethoxide (38 mg, 0.52 mmol) was added and stirred at 25 ° C 2 After hours, purification by column chromatography gave 2-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c Pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile (30 mg, yield 40.9%).
MS m/z(ESI):425.1[M+H] +. MS m/z (ESI): 425.1 [M+H] + .
1H NMR(400MHz,CDCl3):δ10.71(br,1H),8.14(d,J＝2.4Hz,1H),8.06(dd,J＝2.4Hz,8.4Hz,1H),7.37(s,1H),7.25(s,1H),7.13(d,J＝8.8Hz,1H),6.40(d,J＝2Hz,1H),3.95(d,J＝6.8Hz,2H),3.80(s,3H),1.76(s,3H),1.69(s,3H),0.91-0.86(m,1H),0.60-0.55(m,2H),0.31-0.27(m,2H). 1 H NMR (400MHz, CDCl3) : δ10.71 (br, 1H), 8.14 (d, J = 2.4Hz, 1H), 8.06 (dd, J = 2.4Hz, 8.4Hz, 1H), 7.37 (s, 1H ), 7.25 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 2 Hz, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.80 (s, 3H) , 1.76 (s, 3H), 1.69 (s, 3H), 0.91 - 0.86 (m, 1H), 0.60 - 0.55 (m, 2H), 0.31 - 0.27 (m, 2H).
实施例68Example 68
2-(4-((环丙基甲基)氨基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈2-(4-((cyclopropylmethyl)amino)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4- Phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000234
Figure PCTCN2018072204-appb-000234
第一步：2-((3-溴-4-氟苯基)硫代)乙酰腈的制备First step: Preparation of 2-((3-bromo-4-fluorophenyl)thio)acetonitrile
Figure PCTCN2018072204-appb-000235
Figure PCTCN2018072204-appb-000235
将3-溴-4-氟苯硫醇(1g，4.8mmol)溶于N,N-二甲基甲酰胺(15mL)，加入碳酸钾(2g，14.5mmol)、碘化钠(72mg，0.48mmol)、溴乙腈(1.74g，14.5mmol)，在25℃搅拌3小时，加入水(40mL)，乙酸乙酯(50mL)萃取，分出有机层旋干，得到2-((3-溴-4-氟苯基)硫代)乙酰腈(0.82g，收率69.8％)。3-Bromo-4-fluorobenzenethiol (1 g, 4.8 mmol) was dissolved in N,N-dimethylformamide (15 mL), potassium carbonate (2 g, 14.5 mmol), sodium iodide (72 mg, 0.48 mmol) , bromoacetonitrile (1.74 g, 14.5 mmol), stirred at 25 ° C for 3 h, added water (40 mL), ethyl acetate (50 mL), and then evaporated. -Fluorophenyl)thio)acetonitrile (0.82 g, yield 69.8%).
第二步：2-((3-溴-4-氟苯基)硫代)乙酰腈的制备Second step: Preparation of 2-((3-bromo-4-fluorophenyl)thio)acetonitrile
Figure PCTCN2018072204-appb-000236
Figure PCTCN2018072204-appb-000236
2-((3-溴-4-氟苯基)硫代)乙酰腈(0.82g,3.35mmol溶于二氯甲烷(20mL)中，0℃下滴加间氯过氧苯甲酸(0.88mg，5.1mmol)的二氯甲烷溶液(10mL)，在0℃下搅拌0.5小时，加入亚硫酸钠搅拌5分钟，加入饱和碳酸氢钠水溶液(20mL)，分出有机层柱层析得柱层析得到2-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)乙酰腈(0.84g,收率96.1％)。2-((3-Bromo-4-fluorophenyl)thio)acetonitrile (0.82 g, 3.35 mmol, dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (0.88 mg, 5.1 mmol) dichloromethane solution (10 mL), stirred at 0 ° C for 0.5 h, added sodium sulfite and stirred for 5 min, then added saturated aqueous sodium bicarbonate (20 mL). ((3-Bromo-4-fluorophenyl)sulfinyl <sulfinyl>)acetonitrile (0.84 g, yield 96.1%).
1H NMR(400MHz,CDCl3):δ7.99(dd,J＝2Hz,6Hz,1H),7.69-7.73(m,1H),7.38(t,J＝8.0Hz,1H),3.68-3.82(m,2H)； 1 H NMR (400 MHz, CDCl 3 ): δ 7.99 (dd, J = 2 Hz, 6 Hz, 1H), 7.69 - 7.73 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 3.68-3.82 (m) , 2H);
第三步：2-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈的制备(A373-131)Third step: Preparation of 2-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl>)-2-methylpropionitrile (A373-131)
Figure PCTCN2018072204-appb-000237
Figure PCTCN2018072204-appb-000237
以2-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)乙酰腈为起始原料,实施例68第七步，得到2-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈(收率76.2％)。Starting from 2-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl>)acetonitrile, the seventh step of Example 68 gave 2-((3-bromo-4-fluoro) Phenyl)sulfinyl <sulfinyl>)-2-methylpropionitrile (yield 76.2%).
第四步：2-(3-溴-4-氟苯基磺亚胺酰基)-2-甲基丙腈的制备Fourth step: Preparation of 2-(3-bromo-4-fluorophenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000238
Figure PCTCN2018072204-appb-000238
以2-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈为起始原料，参考实施例1第六步，得到2-(3-溴-4-氟苯基磺亚胺酰基)-2-甲基丙腈(收率：67.3％)。Starting from 2-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl)-2-methylpropionitrile, referring to the sixth step of Example 1, 2-(3- Bromo-4-fluorophenylsulfonimido)-2-methylpropionitrile (yield: 67.3%).
MS m/z(ESI):304.9/306.9(50/50)[M+H] +. MS m/z (ESI): 304.9 / 306.9 (50 / 50) [M+H] + .
第五步：2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈的制备Step 5: 2-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4 Of -phenyl)phenylsulfanimidoyl-2-methylpropionitrile
Figure PCTCN2018072204-appb-000239
Figure PCTCN2018072204-appb-000239
以2-(3-溴-4-氟苯基磺亚胺酰基)-2-甲基丙腈与中间体Im为反应原料，参考实施例10第四步，得到2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(收率：37.4％)。2-(3-Bromo-4-fluorophenylsulfonimido)-2-methylpropionitrile and Intermediate Im as the starting materials of the reaction, referring to the fourth step of Example 10, to obtain 2-(4-fluoro-3) -(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfinimidoyl-2 - Methylpropionitrile (yield: 37.4%).
MS m/z(ESI):527.1[M+H] +。 MS m/z (ESI): 527.1 [M+H] + .
第六步：2-(4-((环丙基甲基)氨基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈的制备(A373-147)Step 6: 2-(4-((cyclopropylmethyl)amino)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c] Preparation of pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile (A373-147)
Figure PCTCN2018072204-appb-000240
Figure PCTCN2018072204-appb-000240
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈为起始原料，用环丙基甲胺代替反-4-甲基环己烷胺，参考实施例23第一步，得到2-(4-((环丙基甲基)氨基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(收率：27.6％)。2-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Phenylsulfanimidoyl-2-methylpropionitrile was used as a starting material, and cyclopropylmethylamine was used instead of trans-4-methylcyclohexaneamine. The first step of Example 23 was carried out to obtain 2-(4). -((cyclopropylmethyl)amino)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl Sulfimido)-2-methylpropionitrile (yield: 27.6%).
MS m/z(ESI):424.1[M+H] +. MS m/z (ESI): 424.1 [M+H] + .
1H NMR(400MHz,CDCl3):δ10.51(br,1H),7.92-7.89(m,1H),7.81(d,J＝2.4Hz,1H),7.30(s,1H),7.04(s,1H),6.75(d,J＝9.2Hz,1H),6.22(s,1H),4.64(s,1H),3.72(s,3H),3.04(d,J＝7.2Hz,2H),1.74(s,3H),1.66(s,3H),1.00-0.94(m,1H),0.49-0.46(m,2H),0.17-0.14(m,2H)； 1 H NMR (400MHz, CDCl3) : δ10.51 (br, 1H), 7.92-7.89 (m, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.30 (s, 1H), 7.04 (s, 1H), 6.75 (d, J = 9.2 Hz, 1H), 6.22 (s, 1H), 4.64 (s, 1H), 3.72 (s, 3H), 3.04 (d, J = 7.2 Hz, 2H), 1.74 ( s, 3H), 1.66 (s, 3H), 1.00-0.94 (m, 1H), 0.49-0.46 (m, 2H), 0.17-0.14 (m, 2H);
实施例69Example 69
2-甲基-2-(3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-((反式-4-甲基环己基)氨基)苯基磺亚胺酰基)丙腈392-0532-methyl-2-(3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(inverse 4-methylcyclohexyl)amino)phenylsulfonimido)propanenitrile 392-053
Figure PCTCN2018072204-appb-000241
Figure PCTCN2018072204-appb-000241
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈与反式-4-甲基环己烷氨为原料，参考实施例23第一步，得到标题化合物2-甲基-2-(3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-((反式-4-甲基环己基)氨基)苯基磺亚胺酰基)丙腈(产率18％)。2-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Phenylsulfanimidoyl-2-methylpropanenitrile and trans-4-methylcyclohexane ammonia were used as starting materials, and the title compound 2-methyl-2-(3- (6-Methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((trans-4-methylcyclohexyl)amino Phenylsulfonimido)propionitrile (yield 18%).
MS m/z(ESI):466.2[M+H] +. MS m/z (ESI): 466.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.88(dd,J＝8.9Hz,2.4Hz,1H),7.74(d,J＝2.4Hz,1H),7.37(d,J＝2.8Hz,1H),7.21(s,1H),6.94(d,J＝9.0Hz,1H),6.18(d,J＝2.8Hz,1H),3.71(s,3H),3.67–3.59(m,1H),1.95–1.85(m,2H),1.65–1.58(m,2H),1.69(s,3H),1.67(s,3H),1.26–1.24(m,1H),1.08–0.87(m,4H),0.92(d,J＝6.4Hz, 3H). 1 H NMR (400MHz, MeOD) δ7.88 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.74 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.21 (s, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 3.71 (s, 3H), 3.67 - 3.59 (m, 1H), 1.95 - 1.85 ( m, 2H), 1.65–1.58 (m, 2H), 1.69 (s, 3H), 1.67 (s, 3H), 1.26–1.24 (m, 1H), 1.08–0.87 (m, 4H), 0.92 (d, J=6.4Hz, 3H).
实施例70Example 70
1-(4-((环丙基甲基)氨基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈1-(4-((cyclopropylmethyl)amino)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4- Phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000242
Figure PCTCN2018072204-appb-000242
第一步：1-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈First step: 1-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000243
Figure PCTCN2018072204-appb-000243
将2-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)乙酰腈(1.0g，3.8mmol)溶于四氢呋喃(30mL)中，加入碳酸铯、1,2-二溴乙烷，在70℃搅拌5小时，柱层析纯化得到1-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈(930mg，产率84％)。2-((3-Bromo-4-fluorophenyl)sulfinyl <sulfinyl>)acetonitrile (1.0 g, 3.8 mmol) was dissolved in tetrahydrofuran (30 mL), and cesium carbonate, 1,2-di Ethyl bromide was stirred at 70 ° C for 5 hours and purified by column chromatography to give 1-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl)cyclopropane-1-carbonitrile (930 mg, yield Rate 84%).
第二步：1-(3-溴-4-氟苯基磺亚胺酰基)环丙烷-1-甲腈Second step: 1-(3-bromo-4-fluorophenylsulfonylimoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000244
Figure PCTCN2018072204-appb-000244
以1-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈为原料，参考参考实施例1第六步，得1-(3-溴-4-氟苯基磺亚胺酰基)环丙烷-1-甲腈(产率92％)。Starting from 1-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile, referring to the sixth step of Reference Example 1, 1-(3-bromo) was obtained. 4-fluorophenylsulfonylimidyl)cyclopropane-1-carbonitrile (yield 92%).
MS m/z(ESI):302.9/304.9(50/50)[M+H] +. MS m/z (ESI): 302.9 / 304.9 (50 / 50) [M+H] + .
第三步：1-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈The third step: 1-(4-fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4 -yl)phenylsulfinimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000245
Figure PCTCN2018072204-appb-000245
以1-(3-溴-4-氟苯基磺亚胺酰基)环丙烷-1-甲腈与中间体Im为原料，参考实施例10第四步，得1-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(产率65％)。Using 1-(3-bromo-4-fluorophenylsulfonylimidyl)cyclopropane-1-carbonitrile and Intermediate Im as starting materials, referring to the fourth step of Example 10, 1-(4-fluoro-3- (6-Methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfonimido)cyclopropane- 1-carbonitrile (yield 65%).
MS m/z(ESI):525.1[M+H] +。 MS m/z (ESI): 525.1 [M+H] + .
第四步：1-(4-((环丙基甲基)氨基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈Fourth step: 1-(4-((cyclopropylmethyl)amino)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000246
Figure PCTCN2018072204-appb-000246
以1-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈为原料，用环丙基甲胺代替反-4-甲基环己烷胺，参考实施例23第一步，得1-(4-((环丙基甲基)氨基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(产率12％)。1-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Phenyl sulfanimidoyl)cyclopropane-1-carbonitrile is used as a starting material, and cyclopropylmethylamine is used in place of trans-4-methylcyclohexaneamine. Referring to the first step of Example 23, 1-(4-( (cyclopropylmethyl)amino)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfonate Aminoacyl) cyclopropane-1-carbonitrile (yield 12%).
MS m/z(ESI):422.1[M+H] +. MS m/z (ESI): 4221. [M+H] + .
1H NMR(400MHz,MeOD)δ7.67(dd,J＝8.9Hz,2.4Hz,1H),7.55(d,J＝2.4Hz,1H),7.16(d,J＝2.8Hz,1H),7.04(s,1H),6.73(d,J＝8.9Hz,1H),6.02(d,J＝2.8Hz,1H),3.51(s,3H),2.91(d,J＝6.8Hz,2H),1.57(m,3H),1.46–1.38(m,1H),0.85(s,1H),0.32–0.22(m,2H),0.00(dd,J＝7.6,2.7Hz,2H). 1 H NMR (400MHz, MeOD) δ7.67 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.16 (d, J = 2.8Hz, 1H), 7.04 (s, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 3.51 (s, 3H), 2.91 (d, J = 6.8 Hz, 2H), 1.57 (m, 3H), 1.46–1.38 (m, 1H), 0.85 (s, 1H), 0.32–0.22 (m, 2H), 0.00 (dd, J=7.6, 2.7 Hz, 2H).
实施例71Example 71
1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4 -yl)phenylsulfinimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000247
Figure PCTCN2018072204-appb-000247
第一步：2-溴-1-(2,4-二氟苯氧基)-4-硝基苯的制备First step: Preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene
Figure PCTCN2018072204-appb-000248
Figure PCTCN2018072204-appb-000248
将2-溴-1-氟-4-硝基苯(5g，22.7mmol),2,4-二硝基苯酚(5.9g，45.4mmol)溶于乙腈(80mL)中，加入碳酸铯(14.8g,45.4mmol)，在60℃搅拌5小时，点板反应完成后，过滤，浓缩，柱层析纯化(石油醚/乙酸乙酯＝30/1)得到2-溴-1-(2,4-二氟苯氧基)-4-硝基苯(7.5g,100％)。2-Bromo-1-fluoro-4-nitrobenzene (5 g, 22.7 mmol), 2,4-dinitrophenol (5.9 g, 45.4 mmol) was dissolved in acetonitrile (80 mL) and cesium carbonate (14.8 g) , 45.4 mmol), stirred at 60 ° C for 5 hours, after completion of the reaction of the plate, filtered, concentrated, purified by column chromatography ( petroleum ether / ethyl acetate = 30/1) to give 2-bromo-1-(2,4- Difluorophenoxy)-4-nitrobenzene (7.5 g, 100%).
第二步：3-溴-4-(2,4-二氟苯氧基)苯胺的制备Second step: Preparation of 3-bromo-4-(2,4-difluorophenoxy)aniline
Figure PCTCN2018072204-appb-000249
Figure PCTCN2018072204-appb-000249
将2-溴-1-(2,4-二氟苯氧基)-4-硝基苯(7.5g，22.7mmol)溶于乙醇(100mL)中，加入铁粉(6.3g,114mmol)，氯化铵(12.3g，227mmol)，在80℃搅拌12小时，反应完成后，过滤，浓缩，柱层析纯化(石油醚/乙酸乙酯＝5/1)得到3-溴 -4-(2,4-二氟苯氧基)苯胺(5.6g,82％)。2-Bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (7.5 g, 22.7 mmol) was dissolved in ethanol (100 mL) and iron powder (6.3 g, 114 mmol) was added. Ammonium (12.3 g, 227 mmol) was stirred at 80 ° C for 12 hours. After the reaction was completed, filtered, concentrated and purified by column chromatography ( petroleum ether / ethyl acetate = 5 / 1) 4-Difluorophenoxy)aniline (5.6 g, 82%).
MS m/z(ESI):300.0/302.0(50/50)[M+H] +.第三步：2-((3-溴-4-(2,4-二氟苯氧基)苯基)硫代)乙酰腈的制备 MS m/z (ESI): 300.0 / 302.0 (50 / 50) [M+H] + . Step 3: 2-((3-bromo-4-(2,4-difluorophenoxy)phenyl Preparation of thio)acetonitrile
Figure PCTCN2018072204-appb-000250
Figure PCTCN2018072204-appb-000250
将溴乙腈(8.4g,70mmol)，五水合硫代硫酸钠(17.5g,70mmol)，五水合硫酸铜(750mg,3mmol)，2,2’-联吡啶(468mg,3mmol)溶于甲醇(30毫升)和水(30毫升)的混合溶剂中，反应升温至70度搅拌两小时。之后，将3-溴-4-(2,4-二氟苯氧基)苯胺(3g,10mmol)加入，反应体系降至0度，亚硝酸叔丁酯(1.8g,15mmol)缓慢滴入反应体系，滴毕搅拌十分钟，接着在室温下搅拌半个小时后升温至70度搅拌3小时。反应完成后，过滤，旋去有机相，水相用乙酸乙酯萃取。合并有机相，干燥，过滤，浓缩，柱层析纯化(石油醚/乙酸乙酯＝1/1)得到2-((3-溴-4-(2,4-二氟苯氧基)苯基)硫代)乙酰腈(1.5g,45％)。Bromoacetonitrile (8.4 g, 70 mmol), sodium thiosulfate pentahydrate (17.5 g, 70 mmol), copper sulfate pentahydrate (750 mg, 3 mmol), 2,2'-bipyridine (468 mg, 3 mmol) dissolved in methanol (30) In a mixed solvent of ML) and water (30 ml), the reaction was heated to 70 °C and stirred for two hours. Thereafter, 3-bromo-4-(2,4-difluorophenoxy)aniline (3 g, 10 mmol) was added, the reaction system was lowered to 0 °, and t-butyl nitrite (1.8 g, 15 mmol) was slowly added dropwise. The system was stirred for ten minutes, then stirred at room temperature for half an hour and then warmed to 70 degrees for 3 hours. After completion of the reaction, the mixture was filtered, the organic layer was evaporated, The combined organics were dried, filtered, concentrated and purified with EtOAc EtOAc ) thio)acetonitrile (1.5 g, 45%).
MS m/z(ESI):355.9/357.9(50/50)[M+H] +. MS m/z (ESI): 355.9 / 357.9 (50 / 50) [M+H] + .
第四步：2-((3-溴-4-(2,4-二氟苯氧基)苯基)亚硫酰基<亚磺酰>)乙酰腈的制备Fourth step: Preparation of 2-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfinyl <sulfinyl>) acetonitrile
Figure PCTCN2018072204-appb-000251
Figure PCTCN2018072204-appb-000251
以2-((3-溴-4-(2,4-二氟苯氧基)苯基)硫代)乙酰腈为原料，参考实施例1第五步得2-((3-溴-4-(2,4-二氟苯氧基)苯基)亚硫酰基<亚磺酰>)乙酰腈(产率92％)。2-((3-bromo-4-(2,4-difluorophenoxy)phenyl)thio)acetonitrile was used as the starting material, and the second step of Example 1 was followed to obtain 2-((3-bromo-4). -(2,4-Difluorophenoxy)phenyl)sulfinyl <sulfinyl>)acetonitrile (yield 92%).
MS m/z(ESI):371.9/373.9(50/50)[M+H] +. MS m/z (ESI): 371.9 / 373.9 (50 / 50) [M+H] + .
第五步：1-((3-溴-4-(2,4-二氟苯氧基)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈的制备Step 5: Preparation of 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000252
Figure PCTCN2018072204-appb-000252
以2-((3-溴-4-(2,4-二氟苯氧基)苯基)亚硫酰基<亚磺酰>)乙酰腈为原料，参考实施例70第一步得1-((3-溴-4-(2,4-二氟苯氧基)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈(产率85％)。Taking 2-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfinyl <sulfinyl]) acetonitrile as a starting material, the first step of Example 70 is obtained 1-( (3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile (yield 85%).
MS m/z(ESI):397.9/399.9(50/50)[M+H] +. MS m/z (ESI): 397.9 / 399.9 (50 / 50) [M+H] + .
第六步：1-(3-溴-4-(2,4-二氟苯氧基)苯基磺亚胺酰基)环丙烷-1-甲腈的制备Step 6: Preparation of 1-(3-bromo-4-(2,4-difluorophenoxy)phenylsulfinyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000253
Figure PCTCN2018072204-appb-000253
以1-((3-溴-4-(2,4-二氟苯氧基)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈为原料， 参考实施例1第六步得1-(3-溴-4-(2,4-二氟苯氧基)苯基磺亚胺酰基)环丙烷-1-甲腈(产率81％)。Starting from 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile, refer to Example 6 1-(3-Bromo-4-(2,4-difluorophenoxy)phenylsulfinamido)cyclopropane-1-carbonitrile (yield 81%) was obtained.
MS m/z(ESI):413.0/415.0(50/50)[M+H] +. MS m/z (ESI): 413.0 / 415.0 (50 / 50) [M+H] + .
第七步：1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈制备Step 7: 1-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrole Preparation of [2,3-c]pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000254
Figure PCTCN2018072204-appb-000254
以1-(3-溴-4-(2,4-二氟苯氧基)苯基磺亚胺酰基)环丙烷-1-甲腈为原料，参考实施例1第七步得1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(产率88％)。Starting from 1-(3-bromo-4-(2,4-difluorophenoxy)phenylsulfinyl)cyclopropane-1-carbonitrile, refer to the seventh step of Example 1 to obtain 1-(4) -(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine 4-yl)phenylsulfinimidoyl)cyclopropane-1-carbonitrile (yield 88%).
MS m/z(ESI):635.1[M+H] +. MS m/z (ESI): 635.1 [M+H] + .
第八步：1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈的制备Step 8: 1-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c Preparation of pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000255
Figure PCTCN2018072204-appb-000255
以1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈为原料，参考实施例1第八步得1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(产率73％)。1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2, 3-c]pyridin-4-yl)phenylsulfinimidoyl)cyclopropane-1-carbonitrile is used as a starting material, and the first step of the first step of Example 1 is given 1-(4-(2,4-difluorophenoxy). --3-(6-Methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfonimido)cyclopropane-1- Formonitrile (yield 73%).
MS m/z(ESI):481.1[M+H] +。 MS m/z (ESI): 481.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.11(d,J＝2.4Hz,1H),7.89(dd,J＝8.8Hz,2.4Hz,1H),7.26-7.17(m,2H),7.17-7.04(m,2H),6.97-6.87(m,2H),6.36(d,J＝2.8Hz,1H),3.61(s,3H),1.82-1.58(m,4H). 1 H NMR (400MHz, MeOD) δ8.11 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.26-7.17 (m, 2H), 7.17-7.04 ( m, 2H), 6.97-6.87 (m, 2H), 6.36 (d, J = 2.8 Hz, 1H), 3.61 (s, 3H), 1.82-1.58 (m, 4H).
..
实施例72Example 72
4-(5-(乙基磺亚胺酰基)-2-((4-氟苯基)硫代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-((4-fluorophenyl)thio)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000256
Figure PCTCN2018072204-appb-000256
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，用4-氟苯硫酚取代2,4-二氟苯酚，参考实施例4第五步，得到标题化合物4-(5-(乙基磺亚胺酰基)-2-((4-氟苯基)硫代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率15％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material, and 2,4-difluorophenol was replaced with 4-fluorothiophenol. The title compound 4-(5-(ethylsulfimidoyl)- 2-((4-Fluorophenyl)thio)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 15%) ).
MS m/z(ESI):442.1[M+H] +. MS m/z (ESI): 4421. [M+H] + .
1H NMR(400MHz,d4-MeOD):δ7.97(d,J＝2.4Hz,1H),7.81(dd,J＝8.8Hz,2.4Hz,1H),7.27-7.247(m,2H),7.12-7.10(m,3H),6.93-6.84(m,2H),6.27(d,J＝2.8Hz,1H),3.60(s,3H),3.19(q,J＝8.0Hz,2H),1.16(t,J＝8.0Hz,3H)。 1 H NMR (400MHz, d4- MeOD): δ7.97 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.27-7.247 (m, 2H), 7.12 -7.10 (m, 3H), 6.93-6.84 (m, 2H), 6.27 (d, J = 2.8 Hz, 1H), 3.60 (s, 3H), 3.19 (q, J = 8.0 Hz, 2H), 1.16 ( t, J = 8.0 Hz, 3H).
实施例73Example 73
1-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈1-(4-((4,4-difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000257
Figure PCTCN2018072204-appb-000257
第一步：2-溴-1-((4,4-二氟环己基)氧代)-4-硝基苯First step: 2-bromo-1-((4,4-difluorocyclohexyl)oxo)-4-nitrobenzene
Figure PCTCN2018072204-appb-000258
Figure PCTCN2018072204-appb-000258
将2-溴-1-氟-4-硝基苯(3.33g，15mmol),4,4-二氟环己烷-1-醇(2.0g，15mmol)溶于乙腈(30mL)中，加入碳酸铯(9.75g,30mmol)，在60℃搅拌5小时，点板反应完成后，过滤，浓缩，柱层析纯化(石油醚/乙酸乙酯＝5/1)得到2-溴-1-((4,4-二氟环己基)氧代)-4-硝基苯(4.5g，黄色固体，产率89％)。2-Bromo-1-fluoro-4-nitrobenzene (3.33 g, 15 mmol), 4,4-difluorocyclohexane-1-ol (2.0 g, 15 mmol) was dissolved in acetonitrile (30 mL).铯(9.75g, 30mmol), stirred at 60 ° C for 5 hours, after the completion of the reaction of the plate, filtered, concentrated, purified by column chromatography ( petroleum ether / ethyl acetate = 5 / 1) to give 2-bromo-1-(( 4,4-Difluorocyclohexyl)oxo)-4-nitrobenzene (4.5 g, yellow solid, yield 89%).
第二步：3-溴-4-((4,4-二氟环己基)氧代)苯胺Second step: 3-bromo-4-((4,4-difluorocyclohexyl)oxo)aniline
Figure PCTCN2018072204-appb-000259
Figure PCTCN2018072204-appb-000259
将2-溴-1-((4,4-二氟环己基)氧代)-4-硝基苯为起始原料，参考实施例71第二步，得到3-溴-4-((4,4-二氟环己基)氧代)苯胺(产率95％)。Using 2-bromo-1-((4,4-difluorocyclohexyl)oxo)-4-nitrobenzene as a starting material, referring to the second step of Example 71, 3-bromo-4-((4) , 4-difluorocyclohexyl)oxoaniline (yield 95%).
MS m/z(ESI):306.1/308.1(50/50)[M+H] + MS m/z (ESI): 306.1/308.1 (50/50) [M+H] +
第三步：2-溴-1-((4,4-二氟环己基)氧代)-4-碘苯The third step: 2-bromo-1-((4,4-difluorocyclohexyl)oxo)-4-iodobenzene
Figure PCTCN2018072204-appb-000260
Figure PCTCN2018072204-appb-000260
以3-溴-4-((4,4-二氟环己基)氧代)苯胺为反应原料，参考实施例67第三步得到2-溴-1-((4,4-二氟环己基)氧代)-4-碘苯(黄色油状物，产率41％)。Using 3-bromo-4-((4,4-difluorocyclohexyl)oxo)aniline as the starting material, the second step of Example 67 was followed to obtain 2-bromo-1-((4,4-difluorocyclohexyl). Oxo)-4-iodobenzene (yellow oil, yield 41%).
第四步：S-(3-溴-4-((4,4-二氟环己基)氧代)苯基)乙硫酸酯Fourth step: S-(3-bromo-4-((4,4-difluorocyclohexyl)oxo)phenyl)ethylsulfate
Figure PCTCN2018072204-appb-000261
Figure PCTCN2018072204-appb-000261
以2-溴-1-((4,4-二氟环己基)氧代)-4-碘苯为起始原料，参考实施例67第四步，得到S-(3-溴-4-((4,4-二氟环己基)氧代)苯基)乙硫酸酯(黄色油状物，产率75％)。Starting from 2-bromo-1-((4,4-difluorocyclohexyl)oxo)-4-iodobenzene, refer to the fourth step of Example 67 to obtain S-(3-bromo-4-( (4,4-Difluorocyclohexyl)oxo)phenyl)ethylsulfate (yellow oil, yield 75%).
第五步：2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)硫代)乙酰腈Step 5: 2-((3-Bromo-4-((4,4-difluorocyclohexyl))oxy)phenyl)thio)acetonitrile
Figure PCTCN2018072204-appb-000262
Figure PCTCN2018072204-appb-000262
将S-(3-溴-4-((4,4-二氟环己基)氧代)苯基)乙硫酸酯为起始原料，参考实施例67第五步，得到2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)硫代)乙酰腈(黄色油状物，产率88％)。Starting from S-(3-bromo-4-((4,4-difluorocyclohexyl)oxo)phenyl)ethylsulfate, refer to the fifth step of Example 67 to obtain 2-((3- Bromo-4-((4,4-difluorocyclohexyl)oxo)phenyl)thio)acetonitrile (yellow oil, yield 88%).
MS m/z(ESI):362.0/364.0(50/50)[M+H] +. MS m/z (ESI): 362.0 / 364.0 (50 / 50) [M+H] + .
第六步：2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)乙酰腈Step 6: 2-((3-Bromo-4-((4,4-difluorocyclohexyl))oxy)phenyl)sulfinyl <sulfinyl>)acetonitrile
Figure PCTCN2018072204-appb-000263
Figure PCTCN2018072204-appb-000263
以2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)硫代)乙酰腈为原料，参考实施例1第五步得2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)乙酰腈(产率83％)。Taking 2-((3-bromo-4-((4,4-difluorocyclohexyl))oxy)phenyl)thio)acetonitrile as a raw material, refer to the fifth step of Example 1 to obtain 2-((3- Bromo-4-((4,4-difluorocyclohexyl)oxo)phenyl)sulfinyl <sulfinyl>)acetonitrile (yield 83%).
MS m/z(ESI):378.0/380.0(50/50)[M+H] +. MS m/z (ESI): 378.0 / 380.0 (50 / 50) [M+H] + .
第七步：1-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈Step 7: 1-((3-Bromo-4-((4,4-difluorocyclohexyl))oxy)phenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000264
Figure PCTCN2018072204-appb-000264
以2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)乙酰腈为原料，参考实施例70第一步得1-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈(产率60％)。Taking 2-((3-bromo-4-((4,4-difluorocyclohexyl))oxy)phenyl)sulfinyl <sulfinyl)acetonitrile as a starting material, the first step of Example 70 was obtained. 1-((3-Bromo-4-((4,4-difluorocyclohexyl))oxy)phenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile (yield 60%).
第八步：1-(3-溴-4-((4,4-二氟环己基)氧代)苯基磺亚胺酰基)环丙烷-1-甲腈Step 8: 1-(3-Bromo-4-((4,4-difluorocyclohexyl)oxo)phenylsulfonimido)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000265
Figure PCTCN2018072204-appb-000265
以1-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈为原料，参考实施例1第六步得1-(3-溴-4-((4,4-二氟环己基)氧代)苯基磺亚胺酰基)环丙烷-1-甲腈(产率68％)。Starting from 1-((3-bromo-4-((4,4-difluorocyclohexyl)oxy)phenyl)sulfinyl <sulfinyl))cyclopropane-1-carbonitrile, reference example The sixth step gave 1-(3-bromo-4-((4,4-difluorocyclohexyl)oxo)phenylsulfanimidoyl)cyclopropane-1-carbonitrile (yield 68%).
MS m/z(ESI):419.0/421.0(50/50)[M+H] +. MS m/z (ESI): 419.0 / 421.0 (50 / 50) [M+H] + .
第九步：1-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈Step 9: 1-(4-((4,4-Difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H -pyrrolo[2,3-c]pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000266
Figure PCTCN2018072204-appb-000266
以1-(3-溴-4-((4,4-二氟环己基)氧代)苯基磺亚胺酰基)环丙烷-1-甲腈为原料，参考实施例1第七步得1-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(产率87％)。Taking 1-(3-bromo-4-((4,4-difluorocyclohexyl)oxo)phenylsulfonimido)cyclopropane-1-carbonitrile as a raw material, reference is made to the seventh step of the first embodiment. -(4-((4,4-difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2 , 3-c]pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile (yield 87%).
MS m/z(ESI):641.1[M+H] +. MS m/z (ESI): 641.1 [M+H] + .
第十步：1-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈Step 10: 1-(4-((4,4-Difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2, 3-c]pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000267
Figure PCTCN2018072204-appb-000267
以1-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈为原料，参考实施例1第八步得1-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(产率25％)。1-(4-((4,4-Difluorocyclohexyl)oxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrole [2,3-c]pyridin-4-yl)phenylsulfinimidoyl)cyclopropane-1-carbonitrile is used as a starting material, and the first step of the first embodiment is obtained by 1-(4-((4,4-) Fluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfinamido ) cyclopropane-1-carbonitrile (yield 25%).
MS m/z(ESI):487.1[M+H] +. MS m/z (ESI): 487.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.01–7.93(m,2H),7.35(d,J＝8.8Hz,1H),7.25(d,J＝2.8Hz,1H),7.20(s,1H),6.24(d,J＝2.9Hz,1H),4.74–4.71(m,1H),3.61(s,3H),1.91–1.74(m,6H),1.72–1.48(m,6H). 1 H NMR (400MHz, MeOD) δ8.01-7.93 (m, 2H), 7.35 (d, J = 8.8Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.20 (s, 1H), 6.24 (d, J = 2.9 Hz, 1H), 4.74 - 4.71 (m, 1H), 3.61 (s, 3H), 1.91 - 1.74 (m, 6H), 1.72 - 1.48 (m, 6H).
实施例74Example 74
4-(5-(环丁磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclobutanesulfinyl)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000268
Figure PCTCN2018072204-appb-000268
第一步：(3-溴-4-氟苯基)(环丁基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(cyclobutyl)sulfane
Figure PCTCN2018072204-appb-000269
Figure PCTCN2018072204-appb-000269
以实施例33中的3-溴-4-氟苯硫酚(1g,5mmol)为原料，在氮气气氛保护下，将其与环丁基溴(810mg,6mmol)和碳酸钾(1.36g，10mmol)在10毫升二甲亚砜中60度下反应过夜。体系用水稀释，乙酸乙酯萃取，有机相水洗，饱和食盐水洗涤，干燥，浓缩，残余物使用硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1)得到化合物(3-溴-4-氟苯基)(环丁基)硫烷(1.2g,92％)。3-bromo-4-fluorothiophenol (1 g, 5 mmol) in Example 33 was used as a starting material, and it was combined with cyclobutyl bromide (810 mg, 6 mmol) and potassium carbonate (1.36 g, 10 mmol) under a nitrogen atmosphere. ) Reaction in 60 ml of dimethyl sulfoxide overnight at 10 °C. The system was diluted with water, extracted with ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjj -Fluorophenyl)(cyclobutyl)sulfane (1.2 g, 92%).
1H NMR(400MHz,d-CDCl 3):δ7.47(dd,J＝2.4,6.4Hz,1H),7.22-7.18(m,1H),7.07(t,J＝8.4Hz,1H),3.35-3.47(m,1H),2.01-1.65(m,6H). 1 H NMR (400MHz, d- CDCl 3): δ7.47 (dd, J = 2.4,6.4Hz, 1H), 7.22-7.18 (m, 1H), 7.07 (t, J = 8.4Hz, 1H), 3.35 -3.47 (m, 1H), 2.01-1.65 (m, 6H).
第二步：2-溴-4-(环丁基亚硫酰基<亚磺酰>)-1-氟苯的制备Second step: Preparation of 2-bromo-4-(cyclobutylsulfinyl <sulfinyl)-1-fluorobenzene
Figure PCTCN2018072204-appb-000270
Figure PCTCN2018072204-appb-000270
以(3-溴-4-氟苯基)(环丁基)硫烷为反应原料，参考实施例1第五步，得到2-溴-4-(环丙基亚硫酰基<亚磺酰>)-1-氟苯(产率77％)。Using (3-bromo-4-fluorophenyl)(cyclobutyl)sulfane as the starting material, referring to the fifth step of Example 1, 2-bromo-4-(cyclopropylsulfinyl <sulfinyl> was obtained. )-1-fluorobenzene (yield 77%).
MS m/z(ESI):277.0/279.0(50/50)[M+H] + MS m/z (ESI): 277.0/279.0 (50/50) [M+H] +
第三步：(3-溴-4-氟苯基)(环丁基)(亚氨基)-λ 6-硫烷酮的制备 Third step: Preparation of (3-bromo-4-fluorophenyl)(cyclobutyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000271
Figure PCTCN2018072204-appb-000271
以2-溴-4-(环丁基亚硫酰基<亚磺酰>)-1-氟苯为原料，参考实施例1第六步，得到(3-溴-4-氟苯基)(环丁基)(亚氨基)-λ 6-硫烷酮(产率88％)。 Using 2-bromo-4-(cyclobutylsulfinyl <sulfinyl)-1-fluorobenzene as the starting material, referring to the sixth step of Example 1, to obtain (3-bromo-4-fluorophenyl) (cyclo) Butyl) (imino)-λ 6 -sulfanone (yield 88%).
MS m/z(ESI):292.0/294.0(50/50)[M+H] +. MS m/z (ESI): 292.0/294.0 (50 / 50) [M+H] + .
第四步：4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Fourth step: 4-(5-(cyclobutylsulfinyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, Preparation of 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000272
Figure PCTCN2018072204-appb-000272
以(3-溴-4-氟苯基)(环丙基)(亚氨基)-λ 6-硫烷酮与中间体Im为原料，参考实施例4第四步得到4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率47％) Using (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-λ 6 -thiol ketone and Intermediate Im as starting materials, the fourth step of Example 4 is obtained to obtain 4-(5-(ring). Butasulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Rate 47%)
MS m/z(ESI):514.1[M+H] + MS m/z (ESI): 514.1 [M+H] +
第五步：4-(5-(环丁磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备The fifth step: 4-(5-(cyclobutylsulfinyl)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro- Preparation of 7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000273
Figure PCTCN2018072204-appb-000273
以4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，4,4-二氟环己醇替代2,4-二氟苯酚，参考实施例10第五步反应条件，得到4-(5-(环丁磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率：46.7％)。4-(5-(Cyclobutylidene)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one as a starting material, 4,4-difluorocyclohexanol in place of 2,4-difluorophenol, referring to the reaction conditions of the fifth step of Example 10, to give 4-(5-(cyclobutanesulfinyl) )-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Yield: 46.7%).
MS m/z(ESI):476.2[M+H] +. MS m/z (ESI): 476.2 [M+H] + .
1H NMR(400MHz,d4-MeOD)δ7.98-7.92(m,2H),7.42(d,J＝9.2Hz,1H),7.25(d,J＝2.4Hz,1H),7.19(s,1H),6.12(d,J＝2.8Hz,1H),4.51-4.49(m,1H),3.60(s,3H),2.66-2.57(m,1H),2.45-2.35(m,2H),2.16-1.87(m,4H),1.84-1.53(m,8H).实施例75 1 H NMR (400MHz, d4- MeOD) δ7.98-7.92 (m, 2H), 7.42 (d, J = 9.2Hz, 1H), 7.25 (d, J = 2.4Hz, 1H), 7.19 (s, 1H ), 6.12 (d, J = 2.8 Hz, 1H), 4.51-4.49 (m, 1H), 3.60 (s, 3H), 2.66-2.57 (m, 1H), 2.45-2.35 (m, 2H), 2.16- 1.87 (m, 4H), 1.84-1.53 (m, 8H). Example 75
4-(5-(环戊磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopentamethyleneimido)-2-(cyclopropylmethoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one
Figure PCTCN2018072204-appb-000274
Figure PCTCN2018072204-appb-000274
第一步：(3-溴-4-氟苯基)(环戊基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(cyclopentyl)sulfane
Figure PCTCN2018072204-appb-000275
Figure PCTCN2018072204-appb-000275
将2-溴-1-氟-4-碘苯(18.0g，0.06mol)、Cu2O(36.0mg，0.25mmol)和KOH(5.6g，0.10mol)混合于1,4-二氧六环(20ml)中，氮气保护下经注射器向体系内加入环戊硫醇(5.1g，0.05mol)，升温至110℃反应过夜。反应液冷至室温后，加入乙酸乙酯(30ml)，过滤，滤饼以乙酸乙酯(20ml)洗涤。合并滤液，减压浓缩至干。剩余物经柱层析分离得标题化合物(12.0g，产率72％)。2-Bromo-1-fluoro-4-iodobenzene (18.0 g, 0.06 mol), Cu2O (36.0 mg, 0.25 mmol) and KOH (5.6 g, 0.10 mol) were mixed in 1,4-dioxane (20 ml) In the above, cyclopentyl mercaptan (5.1 g, 0.05 mol) was added to the system via a syringe under nitrogen atmosphere, and the mixture was heated to 110 ° C to react overnight. After the reaction mixture was cooled to room temperature, ethyl acetate (30 ml) was evaporated. The filtrate was combined and concentrated to dryness under reduced pressure. The residue was subjected to EtOAcjjjjjjjjj
1H NMR(400MHz,CDCl 3)δ7.62–7.49(m,1H),7.34–7.20(m,1H),7.09–6.95(m,1H),3.52(td,J＝7.2,3.6Hz,1H),2.08–1.92(m,2H),1.85–1.56(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 - 7.49 (m, 1H), 7.34 - 7.20 (m, 1H), 7.09 - 6.95 (m, 1H), 3.52 (td, J = 7.2, 3.6 Hz, 1H ), 2.08–1.92 (m, 2H), 1.85–1.56 (m, 6H).
第二步：2-溴-4-(环戊基亚硫酰基<亚磺酰>)-1-氟苯得制备The second step: preparation of 2-bromo-4-(cyclopentylsulfinyl <sulfinyl)-1-fluorobenzene
Figure PCTCN2018072204-appb-000276
Figure PCTCN2018072204-appb-000276
以(3-溴-4-氟苯基)(环戊基)硫烷为原料，参考实施例4第二步，得标题化合物2-溴-4-(环戊基亚硫酰基<亚磺酰>)-1-氟苯(产率80％)。Starting from (3-bromo-4-fluorophenyl)(cyclopentyl)sulfane as the starting material, the title compound 2-bromo-4-(cyclopentylsulfinyl <sulfinyl) was obtained according to the second step of Example 4. >)-1-fluorobenzene (yield 80%).
MS m/z(ESI):291.0/293.0(50/50)[M+H] +。 MS m/z (ESI): 291.0 / 293.0 (50 / 50) [M+H] + .
第三步：(3-溴-4-氟苯基)(环戊基)(亚氨基)-λ 6-硫烷酮的制备 Third step: Preparation of (3-bromo-4-fluorophenyl)(cyclopentyl)(imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000277
Figure PCTCN2018072204-appb-000277
以2-溴-4-(环戊基亚硫酰基<亚磺酰>)-1-氟苯为原料，参考实施例4第三步，得到标题化合物(3-溴-4-氟苯基)(环戊基)(亚氨基)-λ6-硫烷酮(产率78％)。Using 2-bromo-4-(cyclopentylsulfinyl <sulfinyl)-1-fluorobenzene as the starting material, the title compound (3-bromo-4-fluorophenyl) (Cyclopentyl) (imino)-λ6-sulfanone (yield 78%).
MS m/z(ESI):306.0/308.0(50/50)[M+H] +.第四步：4-(5-(环戊磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备 MS m/z (ESI): 306.0 / 308.0 (50 / 50) [M+H] + . Step 4: 4-(5-(cyclopentanilide)-2-fluorophenyl)-6- Preparation of methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000278
Figure PCTCN2018072204-appb-000278
以(3-溴-4-氟苯基)(环戊基)(亚氨基)-λ6-硫烷酮为原料。参考实施例4第四步，得到标题化合物4-(5-(环戊磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率31％)。(3-Bromo-4-fluorophenyl)(cyclopentyl)(imino)-λ6-sulfanone is used as a raw material. Referring to the fourth step of Example 4, the title compound 4-(5-(cyclopentanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one (yield 31%).
MS m/z(ESI):528.1[M+H] +. MS m/z (ESI): 528.1 [M+H] + .
第五步：4-(5-(环戊磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5: 4-(5-(cyclopentamethyleneimino)-2-(cyclopropylmethoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 , 3-c]pyridine-7-one preparation
Figure PCTCN2018072204-appb-000279
Figure PCTCN2018072204-appb-000279
以4-(5-(环戊磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例5第五步，得到标题化合物4-(5-(环戊磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率44％)。4-(5-(cyclopentamethyleneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as the starting material. The title compound 4-(5-(cyclopentylsulfinyl)-2-(cyclopropylmethoxy)phenyl)-6- Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 44%).
MS m/z(ESI):426.2[M+H] +. MS m/z (ESI): 426.2 [M+H] + .
1H NMR(400MHz,MeOD)δ8.02(dd,J＝8.9,2.6Hz,1H),7.97(d,J＝2.6Hz,1H),7.39(d,J＝9.0Hz,1H),7.33–7.18(m,2H),6.13(d,J＝2.9Hz,1H),4.47–4.24(m,1H),3.98(d,J＝6.9Hz,2H),3.62(s,3H),2.27–2.10(m,2H),1.94–1.81(m,2H),1.77–1.56(m,4H),1.12–1.06(m,1H),0.52–0.34(m,2H),0.30–0.12(m,2H). 1 H NMR (400 MHz, MeOD) δ 8.02 (dd, J = 8.9, 2.6 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.33 - 7.18 (m, 2H), 6.13 (d, J = 2.9 Hz, 1H), 4.47 - 4.24 (m, 1H), 3.98 (d, J = 6.9 Hz, 2H), 3.62 (s, 3H), 2.27 - 2.10 (m, 2H), 1.94–1.81 (m, 2H), 1.77–1.56 (m, 4H), 1.12–1.06 (m, 1H), 0.52–0.34 (m, 2H), 0.30–0.12 (m, 2H) .
实施例76Example 76
4-(2-((4,4-二甲基环己基)氧代)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((4,4-Dimethylcyclohexyl)oxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000280
Figure PCTCN2018072204-appb-000280
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用4,4,-二甲基环己醇取代2,4-二氟苯酚，得到4-(2-((4,4-二甲基环己基)氧代)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率22％)。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, replacing 2,4-difluorophenol with 4,4,-dimethylcyclohexanol gives 4-(2-((4) ,4-Dimethylcyclohexyl)oxo)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3- c] Pyridine-7-one (yield 22%).
MS m/z(ESI):428.2[M+H] +. MS m/z (ESI): 428.2 [M+H] + .
1H NMR(400MHz,DMSO)δ8.03(d,J＝2.5Hz,1H),8.00(d,J＝2.6Hz,1H),7.52(d,J＝8.8Hz,1H),7.34(s,1H),7.32(t,J＝2.8Hz,1H),6.26–6.08(m,1H),4.66-4.64(m,1H),3.80(s,3H),3.58(s,3H),2.05–1.94(m,2H),1.80-1.78(m,2H),1.66–1.38(m,4H),0.88(s,3H),0.77(s,3H). 1 H NMR (400MHz, DMSO) δ8.03 (d, J = 2.5Hz, 1H), 8.00 (d, J = 2.6Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.34 (s, 1H), 7.32 (t, J = 2.8 Hz, 1H), 6.26 - 6.08 (m, 1H), 4.66 - 4.64 (m, 1H), 3.80 (s, 3H), 3.58 (s, 3H), 2.05 - 1.94 (m, 2H), 1.80 - 1.78 (m, 2H), 1.66 - 1.38 (m, 4H), 0.88 (s, 3H), 0.77 (s, 3H).
实施例77Example 77
4-(5-(乙基磺亚胺酰基)-2-((4-羰基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-((4-carbonylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000281
Figure PCTCN2018072204-appb-000281
将化合物4-(2-((1,4-二氧杂螺[4.5]癸烷-8-基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(400mg,0.85mmol)溶于30毫升甲醇中，在搅拌条件下加入5毫升1M浓度的稀盐酸。反应在室温条件下搅拌过夜。减压条件下除去溶剂，残余物用乙酸乙酯/水分液萃取，有机相经过干燥，浓缩，柱层析纯化得到化合物4-(5-(乙基磺亚胺酰基)-2-((4-羰基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(320mg,88％)The compound 4-(2-((1,4-dioxaspiro[4.5]decane-8-yl)oxy)-5-(ethylsulfimido)phenyl)-6-methyl- 1,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (400 mg, 0.85 mmol) was dissolved in 30 ml of methanol, and 5 ml of 1 M diluted hydrochloric acid was added under stirring. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified ethyljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -carbonylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (320 mg, 88%)
MS m/z(ESI):428.1[M+H] +. MS m/z (ESI): 428.1 [M+H] + .
1H NMR(400MHz,d4-MeOD):δ7.90-7.81(m,2H),7.36-7.19(m,3H),6.17-6.16(m,1H),4.89-4.87(m,1H),3.60(s,3H),3.21(q,J＝7.3Hz,2H),2.14-1.94(m,5H),1.73-1.48(m,3H),1.16(t,J＝7.3Hz,3H). 1 H NMR (400MHz, d4- MeOD): δ7.90-7.81 (m, 2H), 7.36-7.19 (m, 3H), 6.17-6.16 (m, 1H), 4.89-4.87 (m, 1H), 3.60 (s, 3H), 3.21 (q, J = 7.3 Hz, 2H), 2.14-1.94 (m, 5H), 1.73-1.48 (m, 3H), 1.16 (t, J = 7.3 Hz, 3H).
实施例78Example 78
4-(2-((2,2-二氟环丙基)甲氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((2,2-Difluorocyclopropyl)methoxy)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H- Pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000282
Figure PCTCN2018072204-appb-000282
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用(2,2-二氟环丙基)甲醇取代2,4-二氟苯酚，得到4-(2-((2,2-二氟环丙基)甲氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率32％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as the starting material for the reaction. Referring to the fifth step of Example 10, 2,4-difluorophenol was replaced with (2,2-difluorocyclopropyl)methanol to give 4-(2-((2, 2-Difluorocyclopropyl)methoxy)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one (yield 32%).
MS m/z(ESI):422.1[M+H] +； MS m/z (ESI): 4221. [M+H] +
1H NMR(400MHz,d4-MeOD):δ8.03-7.99(m,2H),7.41(d,J＝8.4Hz,1H),7.26-7.24(m,2H),6.15(t,J＝2.8Hz,1H),4.30-4.25(m,1H),4.15-4.11(m,1H),3.84(q,J＝7.2Hz,2H),3.60(s,3H),1.52-1.41(m,1H),1.30-1.19(m,5H). 1 H NMR (400MHz, d4- MeOD): δ8.03-7.99 (m, 2H), 7.41 (d, J = 8.4Hz, 1H), 7.26-7.24 (m, 2H), 6.15 (t, J = 2.8 Hz, 1H), 4.30-4.25 (m, 1H), 4.15-4.11 (m, 1H), 3.84 (q, J = 7.2 Hz, 2H), 3.60 (s, 3H), 1.52-1.41 (m, 1H) , 1.30-1.19 (m, 5H).
实施例79Example 79
4-(2-((4,4-二甲基环己基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((4,4-Dimethylcyclohexyl)oxo)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000283
Figure PCTCN2018072204-appb-000283
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用4,4-二甲基环己醇取代2,4-二氟苯酚，得到4-(2-((4,4-二甲基环己基)氧代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率：35.5％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting 4,4-dimethylcyclohexanol for 2,4-difluorophenol gives 4-(2-((4,4-) Dimethylcyclohexyl)oxo-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7 - Ketone (yield: 35.5%).
MS m/z(ESI):442.1[M+H] +. MS m/z (ESI): 4421. [M+H] + .
1H NMR(400MHz,d4-MeOD):δ7.84-7.79(m,2H),7.23-7.17(m,3H),6.15(d,J＝2.8Hz,1H),4.48-4.45(m,1H),3.60(s,3H),3.15(q,J＝7.6Hz,2H),1.67-1.65(m,2H),1.52-1.51(m,2H),1.18-1.12(m,5H),1.07-1.01(m,2H),0.79(s,3H),0.65(s,3H). 1 H NMR (400MHz, d4- MeOD): δ7.84-7.79 (m, 2H), 7.23-7.17 (m, 3H), 6.15 (d, J = 2.8Hz, 1H), 4.48-4.45 (m, 1H ), 3.60 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 1.67-1.65 (m, 2H), 1.52-1.51 (m, 2H), 1.18-1.12 (m, 5H), 1.07- 1.01 (m, 2H), 0.79 (s, 3H), 0.65 (s, 3H).
实施例80Example 80
4-(5-(乙基磺亚胺酰基)-2-(4-氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-(4-fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one
Figure PCTCN2018072204-appb-000284
Figure PCTCN2018072204-appb-000284
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步,用对氟苯酚取代2,4-二氟苯酚，得到4-(5-(乙基磺亚胺酰基)-2-(4-氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率60％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one as a starting material, referring to the fifth step of Example 10, substituting p-fluorophenol for 2,4-difluorophenol to give 4-(5-(ethylsulfanimidoyl)-2-(4- Fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 60%).
MS m/z(ESI):426.1[M+H] +. MS m/z (ESI): 426.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.24(d,J＝2.6Hz,1H),8.11(dd,J＝8.9Hz,2.6Hz,1H),7.49(s,1H),7.42(d,J＝2.9Hz,1H),7.28–7.11(m,5H),6.40(d,J＝2.9Hz,1H),4.09(q,J＝7.3Hz,2H),3.74(s,3H),1.45(t,J＝7.3Hz,3H). 1 H NMR (400MHz, MeOD) δ8.24 (d, J = 2.6Hz, 1H), 8.11 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.49 (s, 1H), 7.42 (d, J = 2.9 Hz, 1H), 7.28 - 7.11 (m, 5H), 6.40 (d, J = 2.9 Hz, 1H), 4.09 (q, J = 7.3 Hz, 2H), 3.74 (s, 3H), 1.45 (t, J=7.3Hz, 3H).
实施例81Example 81
N-(乙基(4-(4-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(羰基)-l6-硫烷亚基)氰基酰胺N-(ethyl(4-(4-fluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4 -yl)phenyl)(carbonyl)-l6-sulfane subunit)cyanoamide
Figure PCTCN2018072204-appb-000285
Figure PCTCN2018072204-appb-000285
将4-(5-(乙基磺亚胺酰基)-2-(4-氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(56.2mg,0.13mmol)溶于5毫升无水乙腈，在室温条件下加入溴乙腈(16mg,0.15mmol)，接着在相同条件下搅拌过夜。加水淬灭反应，二氯甲烷萃取。有机相经过干燥，浓缩，制备TLC板分离(二氯甲烷/甲醇＝20:1)得到化合物N-(乙基(4-(4-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(羰基)-l6-硫烷亚基)氰基酰胺(6.0mg,收率10％)。4-(5-(ethylsulfimidoyl)-2-(4-fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3- c] Pyridin-7-one (56.2 mg, 0.13 mmol) was dissolved in 5 ml of dry acetonitrile, and bromoacetonitrile (16 mg, 0.15 mmol) was added at room temperature, followed by stirring under the same conditions overnight. The reaction was quenched with water and extracted with dichloromethane. The organic phase is dried, concentrated, and purified by preparative TLC (dichloromethane/methanol = 20:1) to give compound N-(ethyl(4-(4-fluorophenoxy)-3-(6-methyl-7) -carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)(carbonyl)-l6-sulfaninyl)cyanoamide (6.0 mg, yield 10%).
MS m/z(ESI):451.1[M+H] +； MS m/z (ESI): 451.1 [M+H] + ;
1H NMR(400MHz,d4-MeOD):δ8.01(d,J＝2.4Hz,1H),7.86(dd,J＝8.8Hz,2.4Hz,1H),7.31(s,1H),7.26(d,J＝2.8Hz,1H),7.00-7.08(m,5H),6.30(d,J＝2.8Hz,1H),3.61-3.55(m,5H),1.26(t,J＝7.2Hz,3H). 1 H NMR (400MHz, d4- MeOD): δ8.01 (d, J = 2.4Hz, 1H), 7.86 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.31 (s, 1H), 7.26 (d , J = 2.8 Hz, 1H), 7.00-7.08 (m, 5H), 6.30 (d, J = 2.8 Hz, 1H), 3.61-3.55 (m, 5H), 1.26 (t, J = 7.2 Hz, 3H) .
实施例82Example 82
4-(5-(环丁磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclobutanesulfinyl)-2-(cyclopropylmethoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one
Figure PCTCN2018072204-appb-000286
Figure PCTCN2018072204-appb-000286
以4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用环丙基甲醇取代用2,4-二氟苯酚，得到4-(5-(环丁磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率：11％)。4-(5-(Cyclobutylidene)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction, and the second step of Example 10 is followed by substituting cyclopropylmethanol for 2,4-difluorophenol to give 4-(5-(cyclobutaneimido)-2- (Cyclopropylmethoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield: 11%).
MS m/z(ESI):412.1[M+H] +； MS m/z (ESI): 4121. [M+H] + ;
1H NMR(400MHz,d4-MeOD)δ8.00(dd,J＝9.2Hz,2.8,1H),7.95(d,J＝2.8Hz,1H),7.39(d,J＝9.2Hz,1H),7.28(s,1H),7.27(d,J＝2.8Hz,1H),6.14(d,J＝3.2Hz,1H),3.97(d,J＝6.8Hz,2H),3.62(s,3H),2.71-1.91(m,7H),1.12-1.05(m,1H),0.47-0.42(m,2H),0.23-0.19(m,2H). 1 H NMR (400MHz, d4- MeOD) δ8.00 (dd, J = 9.2Hz, 2.8,1H), 7.95 (d, J = 2.8Hz, 1H), 7.39 (d, J = 9.2Hz, 1H), 7.28 (s, 1H), 7.27 (d, J = 2.8 Hz, 1H), 6.14 (d, J = 3.2 Hz, 1H), 3.97 (d, J = 6.8 Hz, 2H), 3.62 (s, 3H), 2.71-1.91 (m, 7H), 1.12-1.05 (m, 1H), 0.47-0.42 (m, 2H), 0.23-0.19 (m, 2H).
实施例83Example 83
4-(5-(环丁磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclobutylideneamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000287
Figure PCTCN2018072204-appb-000287
以4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与2,4-二氟苯酚为反应原料，参考实施例10第五步，得到4-(5-(环 丁磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率：26.6％)。4-(5-(Cyclobutylidene)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridine-7-one and 2,4-difluorophenol are the starting materials for the reaction. Referring to the fifth step of Example 10, 4-(5-(cyclobutanesulfinyl)-2-(2,4-difluoro) is obtained. Phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield: 26.6%).
MS m/z(ESI):470.1[M+H] +； MS m/z (ESI): 470.1 [M+H] +
1H NMR(400MHz,d4-MeOD)δ8.11(s,1H),8.00(d,J＝8.4Hz,1H),7.41-6.94(m,6H),6.28(s,1H),3.65(s,3H),2.69-1.94(m,7H). 1 H NMR (400MHz, d4- MeOD) δ8.11 (s, 1H), 8.00 (d, J = 8.4Hz, 1H), 7.41-6.94 (m, 6H), 6.28 (s, 1H), 3.65 (s , 3H), 2.69-1.94 (m, 7H).
实施例84Example 84
4-(2-(2,4-二氟苯氧基)-5-(噁丁环-3-磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-difluorophenoxy)-5-(oxabutyl-3-sulfanilino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000288
Figure PCTCN2018072204-appb-000288
第一步：噁丁环-3-基4-甲基苯磺酸酯的制备First step: Preparation of acetophen-3-yl 4-methylbenzenesulfonate
Figure PCTCN2018072204-appb-000289
Figure PCTCN2018072204-appb-000289
将噁丁环-3-醇(740mg,10mmol)和碳酸钾(2.7g,20mmol)加入反应瓶中，再加入40毫升无水乙腈作用溶剂。在搅拌的状况下分批加入对甲苯磺酰氯(2.3g,12mmol)固体，加完后反应升温至70度搅拌过夜。用水淬灭反应，乙酸乙酯萃取，有机相经过干燥，浓缩，剩余物通过硅胶柱层析(石油醚：乙酸乙酯＝20：1)得到化合物噁丁环-3-基4-甲基苯磺酸酯(1.8g,收率80％)。Isobutyl-3-ol (740 mg, 10 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to a reaction flask, and then 40 ml of anhydrous acetonitrile solvent was added. P-toluenesulfonyl chloride (2.3 g, 12 mmol) solid was added portionwise with stirring. After the addition, the reaction was warmed to 70 ° and stirred overnight. The reaction was quenched with EtOAc (EtOAc)EtOAc. Sulfonate (1.8 g, yield 80%).
1H NMR(400MHz,d-CDCl 3)δ7.78(d,J＝8.4Hz,2H),7.37(d,J＝8.0Hz,2H),5.33-5.27(m,1H),4.74-4.65(m,4H),2.46(s,3H). 1 H NMR (400 MHz, d-CDCl 3 ) δ 7.78 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 5.33-5.27 (m, 1H), 4.74 - 4.65 ( m, 4H), 2.46 (s, 3H).
第二步：3-((3-溴-4-氟苯基)硫代)噁丁环的制备Second step: Preparation of 3-((3-bromo-4-fluorophenyl)thio) oxetane
Figure PCTCN2018072204-appb-000290
Figure PCTCN2018072204-appb-000290
以3-溴-4-氟苯硫酚为原料，参考实施例74第一步，将环丁基溴更换为噁丁环-3-基4-甲基苯磺酸酯,得到化合物3-((3-溴-4-氟苯基)硫代)噁丁环(90％)。Taking 3-bromo-4-fluorothiophenol as a raw material, referring to the first step of Example 74, replacing cyclobutyl bromide with m-butyl-3-yl 4-methylbenzenesulfonate to obtain compound 3-( (3-Bromo-4-fluorophenyl)thio)oxabutyl ring (90%).
1H NMR(400MHz,d-CDCl 3):δ7.47(dd,J＝2.4,6.4Hz,1H),7.22-7.18(m,1H),7.07(t,J＝8.4Hz,1H),5.07(t,J＝7.6Hz,1H),4.62(t,J＝6.4Hz,2H),4.44-4.37(m,1H). 1 H NMR (400MHz, d- CDCl 3): δ7.47 (dd, J = 2.4,6.4Hz, 1H), 7.22-7.18 (m, 1H), 7.07 (t, J = 8.4Hz, 1H), 5.07 (t, J = 7.6 Hz, 1H), 4.62 (t, J = 6.4 Hz, 2H), 4.44 - 4.37 (m, 1H).
第三步：3-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)噁丁环的制备The third step: preparation of 3-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl]) butyl butyl ring
Figure PCTCN2018072204-appb-000291
Figure PCTCN2018072204-appb-000291
以(3-((3-溴-4-氟苯基)硫代)噁丁环为反应原料，参考实施例1第五步，得到2-溴-4-(环丙基亚硫酰基<亚磺酰>)-1-氟苯(产率73％)。Using (3-((3-bromo-4-fluorophenyl)thio)oxetane as the starting material for the reaction, referring to the fifth step of Example 1, 2-bromo-4-(cyclopropylsulfinyl) Sulfonyl])-1-fluorobenzene (yield 73%).
MS m/z(ESI):279.0/281.0(50/50)[M+H] + MS m/z (ESI): 279.0/281.0 (50/50) [M+H] +
第四步：(3-溴-4-氟苯基)(亚氨基)(噁丁环-3-基)-l6-硫烷酮的制备Fourth step: Preparation of (3-bromo-4-fluorophenyl)(imino)(oxabutan-3-yl)-l6-sulfanone
Figure PCTCN2018072204-appb-000292
Figure PCTCN2018072204-appb-000292
以2-溴-4-(环丙基亚硫酰基<亚磺酰>)-1-氟苯为原料，参考实施例1第六步，得到(3-溴-4-氟苯基)(亚氨基)(噁丁环-3-基)-I6-硫烷酮(产率75％)。Using 2-bromo-4-(cyclopropylsulfinyl <sulfinyl)-1-fluorobenzene as the starting material, referring to the sixth step of Example 1, the compound (3-bromo-4-fluorophenyl) was obtained. Amino) (oxabutan-3-yl)-I6-sulfanone (yield 75%).
MS m/z(ESI):294.0/296.0(50/50)[M+H] +. MS m/z (ESI): 294.0 / 296.0 (50 / 50) [M+H] + .
第四步：4-(2-氟-5-(噁丁环-3-磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Fourth step: 4-(2-Fluoro-5-(insecting)-3-methylimidoylphenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000293
Figure PCTCN2018072204-appb-000293
以(3-溴-4-氟苯基)(亚氨基)(噁丁环-3-基)-I6-硫烷酮为原料，参考实施例10第四步得到4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率39％)Using (3-bromo-4-fluorophenyl)(imino)(oxabutyl-3-yl)-I6-sulfanone as the starting material, the fourth step of Example 10 was obtained to obtain 4-(5-(cyclobutane). Sulfimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 39%)
MS m/z(ESI):516.1[M+H] +. MS m/z (ESI): 516.1 [M+H] + .
第五步：4-(2-(2,4-二氟苯氧基)-5-(噁丁环-3-磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5: 4-(2-(2,4-Difluorophenoxy)-5-(inhibitor-3-ylimidoyl)phenyl)-6-methyl-1,6-dihydro Preparation of -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000294
Figure PCTCN2018072204-appb-000294
以4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与4,4-二氟苯酚为原料，参考实施例10第五步得到4-(2-(2,4-二氟苯氧基)-5-(噁丁环-3-磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率：21.2％)。4-(5-(Cyclobutylidene)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one and 4,4-difluorophenol as starting materials, referring to the fifth step of Example 10 to obtain 4-(2-(2,4-difluorophenoxy)-5-(oxabutane-3) - sulfimidinyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield: 21.2%).
MS m/z(ESI):472.1[M+H] + MS m/z (ESI): 472.1 [M+H] +
1H NMR(400MHz,d4-MeOD)δ7.99(d,J＝4.2Hz,1H),7.85-7.82(m,1H),7.26-7.24(m,2H),7.11-7.01(m,2H),6.93-6.92(m,2H),6.26-6.25(m,1H),4.86-4.78(m,3H),4.70-4.65(m,2H),3.60(s,3H). 1 H NMR (400MHz, d4- MeOD) δ7.99 (d, J = 4.2Hz, 1H), 7.85-7.82 (m, 1H), 7.26-7.24 (m, 2H), 7.11-7.01 (m, 2H) , 6.93-6.92 (m, 2H), 6.26-6.25 (m, 1H), 4.86-4.78 (m, 3H), 4.70-4.65 (m, 2H), 3.60 (s, 3H).
实施例85Example 85
4-(2-(环丙基甲氧基)-5-(噁丁环-3-磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cyclopropylmethoxy)-5-(oxabutane-3-sulfolimidyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 ,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000295
Figure PCTCN2018072204-appb-000295
以4-(5-(环丁磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(52mg,0.1mmol)为反应原料，参考实施例10第五步，用环丙甲醇(46mg,0.6mmol)取代2,4-二氟苯酚，得到4-(2-(环丙基甲氧基)-5-(噁丁环-3-磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(4.5mg,10.9％)。4-(5-(Cyclobutylidene)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one (52 mg, 0.1 mmol) was used as the starting material of the reaction, and in the fifth step of Example 10, 2,4-difluorophenol was replaced with cyclopropanol (46 mg, 0.6 mmol) to give 4-(2-( Cyclopropylmethoxy)-5-(inhibitor-3-ylimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone (4.5 mg, 10.9%).
MS m/z(ESI):414.1[M+H] +； MS m/z (ESI): 414.1 [M+H] +
1H NMR(400MHz,d4-MeOD):δ7.87-7.85(m,2H),7.24-7.18(m,3H),6.15(d,J＝2.8Hz,1H),4.82-4.77(m,3H),4.71-4.67(m,2H),3.89(d,J＝6.8Hz,2H),3.61(s,3H),0.82-0.78(m,1H),0.43-0.40(m,2H),0.19-0.17(m,2H)。 1 H NMR (400 MHz, d4-MeOD): δ 7.87-7.85 (m, 2H), 7.24 - 7.18 (m, 3H), 6.15 (d, J = 2.8 Hz, 1H), 4.82-4.77 (m, 3H) ), 4.71-4.67 (m, 2H), 3.89 (d, J = 6.8 Hz, 2H), 3.61 (s, 3H), 0.82-0.78 (m, 1H), 0.43-0.40 (m, 2H), 0.19- 0.17 (m, 2H).
实施例86Example 86
4-(5-(环丙磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropaneimidoyl)-2-(cyclopropylmethoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one
Figure PCTCN2018072204-appb-000296
Figure PCTCN2018072204-appb-000296
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与环丙基甲醇为原料，参考实施例5第五步，得到4-(5-(环丙磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率32.6％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one and cyclopropylmethanol were used as starting materials. Referring to the fifth step of Example 5, 4-(5-(cyclopropylsulfinyl)-2-(cyclopropylmethoxy)phenyl) was obtained. -6-Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 32.6%).
MS m/z(ESI):398.1[M+H] +. MS m/z (ESI): 398.1 [M+H] + .
1H NMR(400MHz,MeOD):δ7.86(dd,J＝11.2Hz,2.4,1H),7.81(d,J＝2.4Hz,1H),7.24(t,J＝6.8Hz,2H),7.16(d,J＝8.8Hz,1H),6.17(d,J＝2.8Hz,1H),3.88(d,J＝6.8Hz,2H),3.61(s,3H),2.63-2.59(m,1H),1.08-0.85(m,5H),0.45-0.39(m,2H),0.20-0.16(m,2H). 1 H NMR (400MHz, MeOD) : δ7.86 (dd, J = 11.2Hz, 2.4,1H), 7.81 (d, J = 2.4Hz, 1H), 7.24 (t, J = 6.8Hz, 2H), 7.16 (d, J = 8.8 Hz, 1H), 6.17 (d, J = 2.8 Hz, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.61 (s, 3H), 2.63 - 2.59 (m, 1H) , 1.08-0.85 (m, 5H), 0.45-0.39 (m, 2H), 0.20-0.16 (m, 2H).
实施例87Example 87
4-(5-(环丙磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropanesulfonyl)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000297
Figure PCTCN2018072204-appb-000297
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与4,4-二氟环己醇为原料，参考实施例5第五步，得到4-(5-(环丙磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率28.0％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one and 4,4-difluorocyclohexanol were used as starting materials. Referring to the fifth step of Example 5, 4-(5-(cyclopropaneimidoyl)-2-((4,4-) was obtained. Difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 28.0%).
MS m/z(ESI):462.1[M+H] +. MS m/z (ESI): 4621. [M+H] + .
1H NMR(400MHz,d-DMSO):δ12.05(s,1H),7.87(d,J＝2.0Hz,1H),7.82(dd,J＝8.8Hz,2.4,1H),7.39(d,J＝8.8Hz,1H),7.31(s,1H),7.29(t,J＝2.4Hz,1H),6.16(t,J＝2.4Hz,1H),4.77(s,1H),4.10(s,1H),3.56(s,3H),2.70-2.51(m,2H),1.89-1.70(m,7H),1.12-1.07(m,1H),0.98-0.87(m,3H). 1 H NMR (400 MHz, d-DMSO): δ 12.05 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.8 Hz, 2.4, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 7.29 (t, J = 2.4 Hz, 1H), 6.16 (t, J = 2.4 Hz, 1H), 4.77 (s, 1H), 4.10 (s, 1H), 3.56 (s, 3H), 2.70-2.51 (m, 2H), 1.89-1.70 (m, 7H), 1.12-1.07 (m, 1H), 0.98-0.87 (m, 3H).
实施例88Example 88
4-(2-((环丙基甲基)氨基)-5-(2-羟基-2-甲基丙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((cyclopropylmethyl)amino)-5-(2-hydroxy-2-methylpropylsulfonimido)phenyl)-6-methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000298
Figure PCTCN2018072204-appb-000298
第一步：1-((3-溴-4-氟苯基)硫代)-2-甲基丙烷-2-醇的制备First step: Preparation of 1-((3-bromo-4-fluorophenyl)thio)-2-methylpropan-2-ol
Figure PCTCN2018072204-appb-000299
Figure PCTCN2018072204-appb-000299
以3-溴-4-氟苯硫酚(1g,5mmol)为原料，参考实施例74第一步，将环丁基溴更换为2,2-二甲基噁丙环(0.72g,10mmol)得到化合物1-((3-溴-4-氟苯基)硫代)-2-甲基丙烷-2-醇(1.18g,90％)。3-Bromo-4-fluorothiophenol (1 g, 5 mmol) was used as the starting material, and the first step of Example 74 was used to replace cyclobutyl bromide with 2,2-dimethyloxapropane (0.72 g, 10 mmol). The compound 1-((3-bromo-4-fluorophenyl)thio)-2-methylpropan-2-ol (1.18 g, 90%) was obtained.
MS m/z(ESI):279.0/281.0(50/50)[M+H] + MS m/z (ESI): 279.0/281.0 (50/50) [M+H] +
第二步：1-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)-2-甲基丙烷-2-醇的制备Second step: Preparation of 1-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl>)-2-methylpropan-2-ol
Figure PCTCN2018072204-appb-000300
Figure PCTCN2018072204-appb-000300
以1-((3-溴-4-氟苯基)硫代)-2-甲基丙烷-2-醇为反应原料，参考实施例1第五步，得到1-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)-2-甲基丙烷-2-醇(产率85％)。Using 1-((3-bromo-4-fluorophenyl)thio)-2-methylpropan-2-ol as the starting material, referring to the fifth step of Example 1, 1-((3-bromo-4) was obtained. -Fluorophenyl)sulfinyl <sulfinyl>)-2-methylpropan-2-ol (yield 85%).
MS m/z(ESI):295.0/297.0(50/50)[M+H] + MS m/z (ESI): 295.0/297.0 (50/50) [M+H] +
第三步：(3-溴-4-氟苯基)(2-羟基-2-甲基丙基)(亚氨基)-I6-硫烷酮的制备Third step: Preparation of (3-bromo-4-fluorophenyl)(2-hydroxy-2-methylpropyl)(imino)-I6-sulfanone
Figure PCTCN2018072204-appb-000301
Figure PCTCN2018072204-appb-000301
以1-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)-2-甲基丙烷-2-醇为原料，参考实施例1第六步，得到(3-溴-4-氟苯基)(2-羟基-2-甲基丙基)(亚氨基)-I6-硫烷酮(产率91％)。Using 1-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl>)-2-methylpropan-2-ol as the starting material, refer to the sixth step of Example 1, to obtain (3-bromo) 4-fluorophenyl)(2-hydroxy-2-methylpropyl)(imino)-I6-sulfanone (yield 91%).
MS m/z(ESI):310.0/312.0(50/50)[M+H] +. MS m/z (ESI): 310.0 / 312.0 (50 / 50) [M+H] + .
第四步：4-(2-氟-5-(2-羟基-2-甲基丙基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Fourth step: 4-(2-Fluoro-5-(2-hydroxy-2-methylpropylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydrogen Preparation of -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000302
Figure PCTCN2018072204-appb-000302
以(3-溴-4-氟苯基)(2-羟基-2-甲基丙基)(亚氨基)-I6-硫烷酮为原料，参考实施例10第四步得到4-(2-氟-5-(2-羟基-2-甲基丙基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率49％)Using (3-bromo-4-fluorophenyl)(2-hydroxy-2-methylpropyl)(imino)-I6-sulfanone as the starting material, refer to the fourth step of Example 10 to obtain 4-(2- Fluoro-5-(2-hydroxy-2-methylpropylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one (yield 49%)
MS m/z(ESI):532.1[M+H] + MS m/z (ESI): 532.1 [M+H] +
第五步：4-(2-((环丙基甲基)氨基)-5-(2-羟基-2-甲基丙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5: 4-(2-((cyclopropylmethyl)amino)-5-(2-hydroxy-2-methylpropylsulfaminynoyl)phenyl)-6-methyl-1,6 -Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000303
Figure PCTCN2018072204-appb-000303
反应管中加入环丙甲胺(76mg,1mmol)，4-(2-氟-5-(2-羟基-2-甲基丙基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(53mg,0.1mmol)和2毫升N-甲基吡咯烷酮。反应管密封之后加热到100度反应10小时。之后体系冷却到室温，乙酸乙酯萃取，合并有机相饱和食盐水洗涤，干燥，蒸干。粗品液相制备分离得到4-(2-((环丙基甲基)氨基)-5-(2-羟基-2-甲基丙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(7.9mg，18.5％)。To the reaction tube was added cyclopropylamine (76 mg, 1 mmol), 4-(2-fluoro-5-(2-hydroxy-2-methylpropylsulfonimido)phenyl)-6-methyl-1- Tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (53 mg, 0.1 mmol) and 2 ml of N-methylpyrrolidone. The reaction tube was sealed and heated to 100 degrees for 10 hours. After that, the system was cooled to room temperature, extracted with ethyl acetate, and washed with organic brine, dried and evaporated. The crude liquid phase was isolated to give 4-(2-((cyclopropylmethyl)amino)-5-(2-hydroxy-2-methylpropylsulfonimido)phenyl)-6-methyl-1 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (7.9 mg, 18.5%).
MS m/z(ESI):429.1[M+H] + MS m/z (ESI): 429.1 [M+H] +
1H NMR(400MHz,d4-MeOD)δ7.65(dd,J＝8.8Hz,2.4Hz,1H),7.50(d,J＝2.8Hz,1H),7.18(d,J＝2.8Hz,1H),7.06(s,1H),6.71(d,J＝8.8Hz,1H),5.98(d,J＝2.8Hz,1H),3.53(s,3H),3.26-3.21(m,2H),2.90(d,J＝6.8Hz,2H),2.02(t,J＝7.2Hz,1H),1.29(s,3H),1.09(s,3H),0.29-0.24(m,2H),0.16-0.11(m,2H). 1 H NMR (400MHz, d4- MeOD) δ7.65 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.50 (d, J = 2.8Hz, 1H), 7.18 (d, J = 2.8Hz, 1H) , 7.06 (s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.98 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H), 3.26 - 3.21 (m, 2H), 2.90 ( d, J = 6.8 Hz, 2H), 2.02 (t, J = 7.2 Hz, 1H), 1.29 (s, 3H), 1.09 (s, 3H), 0.29 - 0.24 (m, 2H), 0.16 - 0.11 (m) , 2H).
实施例89Example 89
4-(2-((环丙基甲基)氨基)-5-(2-羟基-2-甲基丙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((cyclopropylmethyl)amino)-5-(2-hydroxy-2-methylpropylsulfonimido)phenyl)-6-methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000304
Figure PCTCN2018072204-appb-000304
第一步：2-(((3-溴-4-氟苯基)硫代)甲基)-1,3-二噁戊环的制备First step: Preparation of 2-(((3-bromo-4-fluorophenyl))thio)methyl)-1,3-dioxolane
Figure PCTCN2018072204-appb-000305
Figure PCTCN2018072204-appb-000305
以3-溴-4-氟苯硫酚(1g,5mmol)为原料，参考实施例74第一步，将环丁基溴更换为2-(溴甲基)-1,3-二噁戊环(1.67g,10mmol)得到化合物2-(((3-溴-4-氟苯基)硫代)甲基)-1,3-二噁戊环(1.4g,95.6％)。Using 3-bromo-4-fluorothiophenol (1 g, 5 mmol) as a starting material, referring to the first step of Example 74, replacing cyclobutyl bromide with 2-(bromomethyl)-1,3-dioxolane (1.67 g, 10 mmol) gave the compound 2-(((3-bromo-4-fluorophenyl)thio)methyl)-1,3-dioxapentane (1.4 g, 95.6%).
MS m/z(ESI):293.0/295.0(50/50)[M+H] +. MS m/z (ESI): 293.0/295.0 (50 / 50) [M+H] + .
第二步：((1,3-二噁戊环-2-基)甲基)(3-溴-4-氟苯基)(亚氨基)-I6-硫烷酮的制备Second step: Preparation of ((1,3-dioxalan-2-yl)methyl)(3-bromo-4-fluorophenyl)(imino)-I6-sulfanone
Figure PCTCN2018072204-appb-000306
Figure PCTCN2018072204-appb-000306
将2-(((3-溴-4-氟苯基)硫代)甲基)-1,3-二噁戊环(1.4g,4.8mmol)溶于30毫升甲苯，依次加入氨基甲酸铵(1.46g,19.2mmol)和二乙酸碘苯(4.63g,14.4mmol)。反应于室温调价下搅拌过夜。旋干溶剂，残余物用水稀释，乙酸乙酯萃取。合并有机相水洗，饱和食盐水洗，无水硫酸钠干燥。滤去干燥剂，滤液旋干，残余物使用硅胶柱层析纯化(石油醚：乙酸乙酯＝1:1)得到(3-溴-4-氟苯基)(2-羟基-2-甲基丙基)(亚氨基)-I6-硫烷酮(1.16g,75％)。2-(((3-Bromo-4-fluorophenyl)thio)methyl)-1,3-dioxolane (1.4 g, 4.8 mmol) was dissolved in 30 ml of toluene, followed by ammonium carbamate ( 1.46 g, 19.2 mmol) and iodobenzene diacetate (4.63 g, 14.4 mmol). The reaction was stirred overnight at room temperature. The solvent was dried <RTI ID=0.0></RTI> and theEtOAc The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was evaporated to dryness, and the residue was purified to silica gel column chromatography (ethyl ether: ethyl acetate = 1:1) to give (3-bromo-4-fluorophenyl) (2-hydroxy-2-methyl) Propyl)(imino)-I6-sulfanone (1.16 g, 75%).
MS m/z(ESI):324.0/326(50:50)[M+H] +. MS m/z (ESI): 324.0 / 326 (50: 50) [M+H] + .
第三步：4-(5-(S-((1,3-二噁戊环-2-基)甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备The third step: 4-(5-(S-((1,3-dioxalan-2-yl)methyl)sulfonimido)-2-fluorophenyl)-6-methyl-1- Preparation of tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000307
Figure PCTCN2018072204-appb-000307
以(3-溴-4-氟苯基)(2-羟基-2-甲基丙基)(亚氨基)-I6-硫烷酮与中间体Im为原料，参考实施例10第四步得到4-(5-(S-((1,3-二噁戊环-2-基)甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率49％)。Taking (3-bromo-4-fluorophenyl)(2-hydroxy-2-methylpropyl)(imino)-I6-sulfanone and the intermediate Im as raw materials, the fourth step of the example 10 is obtained. -(5-(S-((1,3-dioxalan-2-yl)methyl)sulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 49%).
MS m/z(ESI):546.1[M+H] + MS m/z (ESI): 546.1 [M+H] +
第五步：4-(5-(S-((1,3-二噁戊环-2-基)甲基)磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5: 4-(5-(S-((1,3-Dioxapentan-2-yl)methyl)sulfonimido)-2-(2,4-difluorophenoxy)benzene Of 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000308
Figure PCTCN2018072204-appb-000308
以4-(5-(S-((1,3-二噁戊环-2-基)甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与4,4-二氟苯酚为起始原料，参考实施例10第五步反应，得到4-(5-(S-((1,3-二噁戊环-2-基)甲基)磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(26.9％)。4-(5-(S-((1,3-Dioxalan-2-yl)methyl)sulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl -1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and 4,4-difluorophenol as starting materials, refer to the fifth step of the reaction of Example 10 to obtain 4-( 5-(S-((1,3-Dioxalan-2-yl)methyl)sulfonimido)-2-(2,4-difluorophenoxy)phenyl)-6-methyl -1,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (26.9%).
MS m/z(ESI):502.1[M+H] + MS m/z (ESI): 502.1 [M+H] +
1H NMR(400MHz,d-DMSO)δ12.1(br,1H),7.99(d,J＝2.0Hz,1H),7.83(dd,J＝8.8Hz,2.4Hz,1H),7.54-7.48(m,1H),7.42-7.36(m,2H),7.31(t,J＝2.8Hz,1H),7.18-7.14(m,1H),6.93(d,J＝8.4Hz,1H),6.30(t,J＝2.4Hz,1H),5.22(t,J＝4.8Hz,1H),4.45(s,1H),3.81-3.72(m,4H),3.58(s,3H),3.54-3.52(m,2H). 1 H NMR (400MHz, d- DMSO) δ12.1 (br, 1H), 7.99 (d, J = 2.0Hz, 1H), 7.83 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.54-7.48 ( m,1H), 7.42-7.36 (m, 2H), 7.31 (t, J = 2.8 Hz, 1H), 7.18-7.14 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.30 (t , J = 2.4 Hz, 1H), 5.22 (t, J = 4.8 Hz, 1H), 4.45 (s, 1H), 3.81-3.72 (m, 4H), 3.58 (s, 3H), 3.54-3.52 (m, 2H).
实施例90Example 90
N-(环丙基(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(羰基)-l6-硫烷亚基)丙烯酰基酰胺的制备N-(cyclopropyl(4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c Preparation of pyridin-4-yl)phenyl)(carbonyl)-l6-sulfaninyl)acrylamide
Figure PCTCN2018072204-appb-000309
Figure PCTCN2018072204-appb-000309
以4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例2第一步，用烯丙酰氯代替环丙基磺酰氯，得到N-(环丙基(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(羰基)-l6-硫烷亚基)丙烯酰基酰胺(产率47％)。4-(5-(cyclopropanesulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 , 3-c]pyridine-7-one as the starting material, referring to the first step of Example 2, replacing the cyclopropylsulfonyl chloride with acryloyl chloride to obtain N-(cyclopropyl(4-(2,4-difluorobenzene) Oxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)(carbonyl)-l6-sulfur Alkylene) acrylamide (yield 47%).
MS m/z(ESI):510.1[M+H] + MS m/z (ESI): 510.1 [M+H] +
1H NMR(400MHz,d6-DMSO)δ12.14(br,1H),8.47(s,1H),7.94(d,J＝2.4Hz,1H),7.81(dd,J＝8.8Hz,2.4Hz,1H),7.45-7.56(m,3H),7.31(t,J＝2.4Hz,1H),7.21-7.16(m,1H),6.99(d,J＝8.8Hz,1H),6.28(t,J＝2.0Hz,1H),6.18(t,J＝2.4Hz,1H),5.73(dd,J＝8.8,2.4Hz,1H),3.58(s,3H),3.21-3.14(m,1H),1.40-1.03(m,4H). 1 H NMR (400MHz, d6- DMSO) δ12.14 (br, 1H), 8.47 (s, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.45-7.56 (m, 3H), 7.31 (t, J = 2.4 Hz, 1H), 7.21-7.16 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.28 (t, J =2.0 Hz, 1H), 6.18 (t, J = 2.4 Hz, 1H), 5.73 (dd, J = 8.8, 2.4 Hz, 1H), 3.58 (s, 3H), 3.21-3.14 (m, 1H), 1.40 -1.03 (m, 4H).
实施例91Example 91
4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-N-乙基-6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺4-(5-(cyclopropanesulfonyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-N-ethyl-6-methyl-7-carbonyl-6,7 -dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
Figure PCTCN2018072204-appb-000310
Figure PCTCN2018072204-appb-000310
将实施例63第五步得到的(乙基4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(67mg,1mmol)溶于2毫升35％乙胺的水溶液和2毫升乙醇中，体系加热至30度搅拌过夜。旋去溶液，剩余物使用反相制备得到产物4-(5-(环丙磺亚胺酰基)-2-((反-4-甲基环己基)氨基)苯基)-N-乙基-6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(4.5mg,9％)。(Ethyl 4-(5-(cyclopropylsulfinyl)-2-((trans-4-methylcyclohexyl)amino)phenyl)-6-methyl-) obtained in the fifth step of Example 63 7-Carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (67 mg, 1 mmol) dissolved in 2 mL of 35% ethylamine in water And 2 ml of ethanol, the system was heated to 30 degrees and stirred overnight. The solution was spun off, and the residue was prepared by reversed phase to give the product 4-(5-(cyclopropylsulfonimido)-2-((trans-4-methyl) Cyclohexyl)amino)phenyl)-N-ethyl-6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (4.5 mg ,9%).
MS m/z(ESI):510.3[M-H] +. MS m/z (ESI): 510.3 [MH] + .
1H NMR(400MHz,d4-MeOD):δ7.67(dd,J＝8.8Hz,2.4Hz,1H),7.53(d,J＝2.0Hz,1H),7.14(s,1H),6.78(d,J＝8.8Hz,1H),6.62(s,1H),3.59(s,3H),3.25-3.31(m,3H),2.56-2.55(m,1H),1.92-1.88(m,2H),1.62-1.60(m,2H),1.23-1.19(m,3H),1.15-1.09(m,4H),1.01-0.97(m,4H),0.87-0.79(m,4H). 1 H NMR (400MHz, d4- MeOD): δ7.67 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.14 (s, 1H), 6.78 (d , J=8.8 Hz, 1H), 6.62 (s, 1H), 3.59 (s, 3H), 3.25-3.31 (m, 3H), 2.56-2.55 (m, 1H), 1.92-1.88 (m, 2H), 1.62-1.60 (m, 2H), 1.23-1.19 (m, 3H), 1.15 - 1.09 (m, 4H), 1.01 - 0.97 (m, 4H), 0.87 - 0.79 (m, 4H).
实施例92Example 92
N-((4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(甲基)(羰基)-l6-硫烷亚基)丙烯酰基酰胺N-((4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Phenyl)(methyl)(carbonyl)-l6-sulfane subunit)acrylamide
Figure PCTCN2018072204-appb-000311
Figure PCTCN2018072204-appb-000311
将4-(2-(环丙基甲氧基)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(25mg)与三乙胺(8.8mg)溶于二氯甲烷(1.5ml)，冷却至0-5℃加入丙烯酰氯(6.1mg)，室温搅拌过夜。减压浓缩至干，经制备薄层层析分离得到N-((4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(甲基)(羰基)-l6-硫烷亚基)丙烯酰基酰胺(6.5mg，产率24％)。4-(2-(cyclopropylmethoxy)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one (25 mg) and triethylamine (8.8 mg) were dissolved in dichloromethane (1.5 ml), EtOAc (EtOAc) Concentrated to dryness under reduced pressure, and then purified by preparative thin layer chromatography to give N-((4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H- Pyrrolo[2,3-c]pyridin-4-yl)phenyl)(methyl)(carbonyl)-l6-sulfaninylene)acrylamide (6.5 mg, yield 24%).
MS m/z(ESI):426.2[M+H] +. MS m/z (ESI): 426.2 [M+H] + .
1H NMR(400MHz,CDCl 3)δ11.06(brs,1H),8.04(d,J＝2.5Hz,1H),7.95(dd,J＝8.8Hz,2.5Hz,1H),7.31(t,J＝2.7Hz,1H),7.20(s,1H),7.11(d,J＝8.8Hz,1H),6.40(dd,J＝17.2Hz,1.9Hz,1H),6.32–6.22(m,2H),5.73(dd,J＝10.0Hz,1.9Hz,1H),3.94(d,J＝6.8Hz,2H),3.75(s,3H),3.42(s,3H),1.20-1.15(m,1H),0.65–0.48(m,2H),0.29-0.25(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ11.06 (brs, 1H), 8.04 (d, J = 2.5Hz, 1H), 7.95 (dd, J = 8.8Hz, 2.5Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 7.20 (s, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.40 (dd, J = 17.2 Hz, 1.9 Hz, 1H), 6.32 - 6.22 (m, 2H), 5.73 (dd, J = 10.0 Hz, 1.9 Hz, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.42 (s, 3H), 1.20-1.15 (m, 1H), 0.65–0.48 (m, 2H), 0.29-0.25 (m, 2H).
实施例93Example 93
4-(2-((2,4-二氟苯基)硫代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((2,4-difluorophenyl)thio)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000312
Figure PCTCN2018072204-appb-000312
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步，用2,4-二氟苯硫酚取代2,4-二氟苯酚，得到标题化合物4-(2-((2,4-二氟苯基)硫代)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率18％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as the starting material. The title compound 4-(2-((2,4-) was obtained by substituting 2,4-difluorothiophenol for 2,4-difluorophenol according to the fifth step of Example 10. Difluorophenyl)thio)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Ketone (yield 18%).
MS m/z(ESI):460.1[M+H] +. MS m/z (ESI): 460.1 [M+H] + .
1H NMR(400MHz,DMSO)δ7.90(d,J＝2.1Hz,1H),7.86(dd,J＝8.5Hz,2.2Hz,1H),7.70–7.64(m,1H),7.55–7.50(m,1H),7.41(s,1H),7.35(s,1H),7.26(dd,J＝9.3Hz,7.1Hz,1H),7.09(d,J＝8.5Hz,1H),6.11(s,1H),3.78(q,J＝6.8Hz,2H),3.60(s,3H),1.19(t,J＝7.3Hz,3H). 1 H NMR (400MHz, DMSO) δ7.90 (d, J = 2.1Hz, 1H), 7.86 (dd, J = 8.5Hz, 2.2Hz, 1H), 7.70-7.64 (m, 1H), 7.55-7.50 ( m, 1H), 7.41 (s, 1H), 7.35 (s, 1H), 7.26 (dd, J = 9.3 Hz, 7.1 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.11 (s, 1H), 3.78 (q, J = 6.8 Hz, 2H), 3.60 (s, 3H), 1.19 (t, J = 7.3 Hz, 3H).
实施例94Example 94
6-甲基-4-(2-((顺式-4-甲基环己基)氧代)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮和6-甲基-4-(2-((反式-4-甲基环己基)氧代)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮6-Methyl-4-(2-((cis-4-methylcyclohexyl)oxo)-5-(S-methylsulfimidoyl)phenyl)-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one and 6-methyl-4-(2-((trans-4-methylcyclohexyl)oxo)-5-(S-methylsulfonate) Imidyl)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000313
Figure PCTCN2018072204-appb-000313
以4-(2-氟-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用4-甲基环己醇(顺反混合物)取代2,4-二氟苯酚，得到6-甲基-4-(2-((顺式/反式-4-甲基环己基)氧代)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率22％)和6-甲基-4-(2-((反式/顺式-4-甲基环己基)氧代)-5-(S-甲基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c] 吡啶-7-酮(30％)。4-(2-Fluoro-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, the 2,4-difluorophenol is replaced with 4-methylcyclohexanol (cis-mixture) to obtain 6-methyl-4- (2-((cis/trans-4-methylcyclohexyl)oxo)-5-(S-methylsulfimidoyl)phenyl)-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one (yield 22%) and 6-methyl-4-(2-((trans/cis-4-methylcyclohexyl)oxo)-5-( S-Methylsulfonimido)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (30%).
94-顺式/反式Cis：MS m/z(ESI):414.2[M+H] +. 94-cis/trans Cis: MS m/z (ESI): 414.2 [M+H] + .
1H NMR(400MHz,DMSO)δ7.95(dd,J＝4.6Hz,2.2Hz,2H),7.52–7.45(m,1H),7.27(s,1H),7.24(t,J＝2.7Hz,1H),6.12–6.07(m,1H).4.55–4.40(m,1H),3.79(s,3H),3.51(s,3H),2.00–1.90(m,2H),1.62–1.60(m,2H),1.28–1.22(m,1H),1.22–1.17(m,2H),1.07–1.01(m,2H),0.80(d,J＝6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ7.95 (dd, J = 4.6Hz, 2.2Hz, 2H), 7.52-7.45 (m, 1H), 7.27 (s, 1H), 7.24 (t, J = 2.7Hz, 1H), 6.12–6.07 (m, 1H). 4.55–4.40 (m, 1H), 3.79 (s, 3H), 3.51 (s, 3H), 2.00–1.90 (m, 2H), 1.62–1.60 (m, 2H), 1.28–1.22 (m, 1H), 1.22–1.17 (m, 2H), 1.07–1.01 (m, 2H), 0.80 (d, J=6.5 Hz, 3H).
94-反式/顺式:MS m/z(ESI):414.2[M+H] +. 94-trans/cis: MS m/z (ESI): 414.2 [M+H] + .
1H NMR(400MHz,DMSO)δ8.08(d,J＝2.6Hz,1H),8.04(dd,J＝8.9Hz,2.7Hz,1H),7.53(d,J＝9.1Hz,1H),7.37(s,1H),7.33(t,J＝2.8Hz,1H),6.31–6.15(m,1H),4.87–4.83(m,1H),3.91(s,3H),3.59(s,3H),1.92–1.73(m,2H),1.55(t,J＝12.1Hz,2H),1.41–1.26(m,2H),1.26–1.22(m,1H),1.01–0.81(m,2H),0.70(d,J＝6.3Hz,3H). 1 H NMR (400MHz, DMSO) δ8.08 (d, J = 2.6Hz, 1H), 8.04 (dd, J = 8.9Hz, 2.7Hz, 1H), 7.53 (d, J = 9.1Hz, 1H), 7.37 (s, 1H), 7.33 (t, J = 2.8 Hz, 1H), 6.31 - 6.15 (m, 1H), 4.87 - 4.83 (m, 1H), 3.91 (s, 3H), 3.59 (s, 3H), 1.92–1.73 (m, 2H), 1.55 (t, J = 12.1 Hz, 2H), 1.41–1.26 (m, 2H), 1.26–1.22 (m, 1H), 1.01–0.81 (m, 2H), 0.70 ( d, J = 6.3 Hz, 3H).
实施例95Example 95
4-(5-(环戊磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopentamethyleneimino)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000314
Figure PCTCN2018072204-appb-000314
以4-(5-(环戊磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步，用4,4-二氟环己醇取代2,4-二氟苯酚，得到标题化合物4-(5-(环戊磺亚胺酰基)-2-(环丙基甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率38％)。4-(5-(cyclopentamethyleneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material, and the title compound 4-(5-(cyclopentaneimine) was obtained by substituting 4,4-difluorocyclohexanol for 2,4-difluorophenol according to the fifth step of Example 10. Acyl)-2-(cyclopropylmethoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 38%) ).
MS m/z(ESI):490.2[M+H] +. MS m/z (ESI): 490.2 [M+H] + .
1H NMR(400MHz,MeOD)δ8.06(dd,J＝8.9Hz,2.6Hz,1H),8.00(d,J＝2.6Hz,1H),7.51(d,J＝9.1Hz,1H),7.28(d,J＝2.8Hz,1H),7.25(s,1H),6.13(d,J＝2.8Hz,1H),4.50–4.29(m,1H),3.63(s,3H),2.34–2.14(m,2H),1.99–1.51(m,15H). 1 H NMR (400MHz, MeOD) δ8.06 (dd, J = 8.9Hz, 2.6Hz, 1H), 8.00 (d, J = 2.6Hz, 1H), 7.51 (d, J = 9.1Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.25 (s, 1H), 6.13 (d, J = 2.8 Hz, 1H), 4.50 - 4.29 (m, 1H), 3.63 (s, 3H), 2.34 - 2.14 ( m, 2H), 1.99–1.51 (m, 15H).
实施例96Example 96
4-(5-(环戊磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopentamethyleneimido)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000315
Figure PCTCN2018072204-appb-000315
以4-(5-(环戊磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与2,4-二氟苯酚为原料，参考实施例10第五步，得到标题化合物 4-(5-(环戊磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率33％)。4-(5-(cyclopentamethyleneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one and 2,4-difluorophenol were used as starting materials, and the title compound 4-(5-(cyclopentanesulfinyl)-2-(2,4-di) Fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 33%).
MS m/z(ESI):484.1[M+H] +. MS m/z (ESI): 484.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.12(d,J＝2.6Hz,1H),8.00(dd,J＝8.9Hz,2.6Hz,1H),7.33(s,1H),7.28(d,J＝2.9Hz,1H),7.21(td,J＝9.1,5.4Hz,1H),7.16–7.10(m,1H),7.09(d,J＝7.9Hz,1H),7.00–6.92(m,1H),6.25(d,J＝2.9Hz,1H),4.50–4.29(m,1H),3.62(s,3H),2.35–2.13(m,2H),1.99–1.80(m,2H),1.80–1.55(m,4H). 1 H NMR (400MHz, MeOD) δ8.12 (d, J = 2.6Hz, 1H), 8.00 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.33 (s, 1H), 7.28 (d, J = 2.9 Hz, 1H), 7.21 (td, J = 9.1, 5.4 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.25 (d, J = 2.9 Hz, 1H), 4.50 - 4.29 (m, 1H), 3.62 (s, 3H), 2.35 - 2.13 (m, 2H), 1.99 - 1.80 (m, 2H), 1.80 - 1.55 ( m, 4H).
实施例97Example 97
2-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈2-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4 -yl)phenylsulfinimidoyl-2-methylpropionitrile
Figure PCTCN2018072204-appb-000316
Figure PCTCN2018072204-appb-000316
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈与2,4-二氟苯酚为原料，参考实施例10第五步，得到2-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(产率67％)。2-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Starting from phenylsulfanimidoyl-2-methylpropionitrile and 2,4-difluorophenol, the fifth step of Example 10 is carried out to obtain 2-(4-(2,4-difluorophenoxy). -3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfonimido)-2-methylpropane Nitrile (yield 67%).
MS m/z(ESI):483.1[M+H] +. MS m/z (ESI): 483.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.11(d,J＝2.4Hz,1H),7.92(dd,J＝8.8Hz,2.4Hz,1H),7.28(s,1H),7.25(d,J＝2.9Hz,1H),7.19–7.12(m,1H),7.11–7.03(m,1H),6.97(d,J＝8.7Hz,1H),6.90(t,J＝7.5Hz,1H),6.34(d,J＝2.9Hz,1H),3.60(s,3H),1.61(s,3H),1.59(s,3H). 1 H NMR (400MHz, MeOD) δ8.11 (d, J = 2.4Hz, 1H), 7.92 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.28 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.19–7.12 (m, 1H), 7.11–7.03 (m, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 6.34 ( d, J = 2.9 Hz, 1H), 3.60 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H).
实施例98Example 98
2-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈2-(4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 4-yl)phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000317
Figure PCTCN2018072204-appb-000317
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈与2-氟-4-溴苯酚为原料，参考实施例10第五步，得到标题化合物2-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(产率55％)。2-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Starting from the fifth step of Example 10, the title compound 2-(4-(4-bromo-2-fluoro) was obtained as the starting material from phenylsulfanilidyl)-2-methylpropanenitrile and 2-fluoro-4-bromophenol. Phenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfinimidoyl-2 - Methylpropionitrile (yield 55%).
MS m/z(ESI):543.0/545.0(50/50)[M+H] +. MS m/z (ESI): 543. / 504. (50 / 50) [M+H] + .
1H NMR(400MHz,MeOD)δ8.23(d,J＝2.5Hz,1H),8.06(dd,J＝8.8,2.5Hz, 1H),7.54-7.49(m,2H),7.38(s,1H),7.36(d,J＝2.9Hz,2H),7.19–7.11(m,1H),6.44(d,J＝2.9Hz,1H),3.71(s,3H),1.73(s,3H),1.71(s,3H).. 1 H NMR (400MHz, MeOD) δ8.23 (d, J = 2.5Hz, 1H), 8.06 (dd, J = 8.8,2.5Hz, 1H), 7.54-7.49 (m, 2H), 7.38 (s, 1H ), 7.36 (d, J = 2.9 Hz, 2H), 7.19 - 7.11 (m, 1H), 6.44 (d, J = 2.9 Hz, 1H), 3.71 (s, 3H), 1.73 (s, 3H), 1.71 (s, 3H)..
实施例99Example 99
2-(4-(4-氯-2-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈2-(4-(4-Chloro-2-fluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 4-yl)phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000318
Figure PCTCN2018072204-appb-000318
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈为原料，参考实施例10第五步，用2-氟-4-氯苯酚取代2,4-二氟苯酚，得到标题化合物2-(4-(4-氯-2-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(产率58％)。2-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Starting from phenylsulfanimidoyl-2-methylpropionitrile, the title compound 2-(4) was obtained by substituting 2-fluoro-4-chlorophenol for 2,4-difluorophenol according to the fifth step of Example 10. -(4-chloro-2-fluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Phenylsulfonimido)-2-methylpropionitrile (yield 58%).
MS m/z(ESI):499.1[M+H] +. MS m/z (ESI): 499.1 [M+H] + .
1H NMR(400MHz,MeOD)δ8.12(d,J＝2.4Hz,1H),7.94(dd,J＝8.8Hz,2.5Hz,1H),7.31–7.26(m,2H),7.25(d,J＝2.9Hz,1H),7.14–7.06(m,2H),7.04(d,J＝8.1Hz,1H),6.33(d,J＝2.9Hz,1H),3.60(s,3H),1.62(s,3H)1.60(s,3H). 1 H NMR (400MHz, MeOD) δ8.12 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.5Hz, 1H), 7.31-7.26 (m, 2H), 7.25 (d, J=2.9 Hz, 1H), 7.14–7.06 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.33 (d, J=2.9 Hz, 1H), 3.60 (s, 3H), 1.62 ( s, 3H) 1.60 (s, 3H).
实施例100Example 100
2-甲基-2-(3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(6-氮杂螺[2.5]辛烷-6-基)苯基磺亚胺酰基)丙腈2-methyl-2-(3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(6- Azaspiro[2.5]octane-6-yl)phenylsulfinylamino)propanenitrile
Figure PCTCN2018072204-appb-000319
Figure PCTCN2018072204-appb-000319
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈为原料，参考实施例23第一步，用6-氮杂螺[2.5]辛烷取代反-4-甲基环己烷胺，得到标题化合物2-甲基-2-(3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(6-氮杂螺[2.5]辛烷-6-基)苯基磺亚胺酰基)丙腈(产率40％)。2-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Starting from the first step of Example 23, substituting 6-azaspiro[2.5]octane for trans-4-methylcyclohexaneamine, the title was obtained from phenylsulfonimido)-2-methylpropionitrile. Compound 2-methyl-2-(3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(6 - azaspiro[2.5]octane-6-yl)phenylsulfonimido)propanenitrile (yield 40%).
MS m/z(ESI):464.2[M+H] +. MS m/z (ESI): 464.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.96(dd,J＝3.4Hz,2.3Hz,2H),7.43(s,1H),7.37(d,J＝2.8Hz,1H),7.33(d,J＝8.5Hz,1H),6.36(d,J＝2.8Hz,1H),3.73(s,3H),3.20–3.05(m,4H),1.71(s,3H),1.69(s,3H),1.28–1.14(m,4H),0.29-0.25(m,4H). 1 H NMR (400MHz, MeOD) δ7.96 (dd, J = 3.4Hz, 2.3Hz, 2H), 7.43 (s, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.36 (d, J = 2.8 Hz, 1H), 3.73 (s, 3H), 3.20 - 3.05 (m, 4H), 1.71 (s, 3H), 1.69 (s, 3H), 1.28 - 1.14 (m, 4H), 0.29-0.25 (m, 4H).
实施例101Example 101
4-(5-(环戊磺亚胺酰基)-2-((环丙基甲基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并 [2,3-c]吡啶-7-酮4-(5-(cyclopentamethyleneimido)-2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one
Figure PCTCN2018072204-appb-000320
Figure PCTCN2018072204-appb-000320
以4-(5-(环戊磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例23第一步，用环丙甲胺替代反-4-甲基环己烷胺，得到标题化合物4-(5-(环戊磺亚胺酰基)-2-((环丙基甲基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率29.6％)。4-(5-(cyclopentamethyleneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as the starting material, and the title compound 4-(5-(cyclopentaneimidoyl) was obtained by substituting cyclopropylmethylamine for the trans--4-methylcyclohexaneamine. -2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 29.6%) ).
MS m/z(ESI):425.2[M+H] +. MS m/z (ESI): 425.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.69(dd,J＝9.1Hz,2.6Hz,1H),7.50(d,J＝2.5Hz,1H),7.17(d,J＝2.8Hz,1H),7.06(s,1H),6.86(d,J＝9.1Hz,1H),5.92(d,J＝2.8Hz,1H),4.21–4.02(m,1H),3.50(s,3H),2.94(d,J＝6.7Hz,2H),2.09–1.96(m,2H),1.88–1.71(m,2H),1.60–1.44(m,4H),0.88–0.81(m,1H),0.35–0.17(m,2H),0.07-0.09(m,2H). 1 H NMR (400MHz, MeOD) δ7.69 (dd, J = 9.1Hz, 2.6Hz, 1H), 7.50 (d, J = 2.5Hz, 1H), 7.17 (d, J = 2.8Hz, 1H), 7.06 (s, 1H), 6.86 (d, J = 9.1 Hz, 1H), 5.92 (d, J = 2.8 Hz, 1H), 4.21 - 4.02 (m, 1H), 3.50 (s, 3H), 2.94 (d, J=6.7 Hz, 2H), 2.09–1.96 (m, 2H), 1.88–1.71 (m, 2H), 1.60–1.44 (m, 4H), 0.88–0.81 (m, 1H), 0.35–0.17 (m, 2H), 0.07-0.09 (m, 2H).
实施例102Example 102
4-(5-(乙基磺亚胺酰基)-2-(2-氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-(2-fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one
Figure PCTCN2018072204-appb-000321
Figure PCTCN2018072204-appb-000321
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步，用邻氟苯酚替代2，4-二氟苯酚，得4-(5-(乙基磺亚胺酰基)-2-(2-氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率14％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one as a starting material, referring to the fifth step of Example 10, replacing 2,4-difluorophenol with o-fluorophenol to obtain 4-(5-(ethylsulfanimidoyl)-2-(2- Fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 14%).
MS m/z(ESI):426.1[M+H] +. MS m/z (ESI): 426.1 [M+H] + .
1H NMR(400MHz,MeOD)δ7.98(d,J＝2.4Hz,1H),7.80(dd,J＝8.7Hz,2.4Hz,1H),7.28(s,1H),7.25(d,J＝2.9Hz,1H),7.16–7.00(m,4H),6.92(d,J＝8.7Hz,1H),6.29(d,J＝2.9Hz,1H),3.60(s,3H),3.17(d,J＝8.0Hz,1H),1.15(d,J＝7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ7.98 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.28 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.16 - 7.00 (m, 4H), 6.92 (d, J = 8.7 Hz, 1H), 6.29 (d, J = 2.9 Hz, 1H), 3.60 (s, 3H), 3.17 (d, J=8.0Hz, 1H), 1.15 (d, J=7.4Hz, 3H).
实施例103Example 103
4-(2-(4-(叔-丁基)苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(4-(tert-butyl)phenoxy)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000322
Figure PCTCN2018072204-appb-000322
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步，用叔丁基苯酚替代2，4-二氟苯酚，得4-(2-(4-(叔-丁基)苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率25％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one as a starting material, referring to the fifth step of Example 10, replacing 2,4-difluorophenol with tert-butylphenol to obtain 4-(2-(4-(tert-butyl)phenoxy) 5-(-Ethylsulfinyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 25%).
MS m/z(ESI):464.2[M+H] +. MS m/z (ESI): 464.2 [M+H] + .
1H NMR(400MHz,MeOD)δ8.08(d,J＝2.6Hz,1H),7.93(dd,J＝8.9Hz,2.6Hz,1H),7.41–7.34(m,2H),7.31(s,1H),7.27(d,J＝2.9Hz,1H),7.10(d,J＝8.9Hz,1H),6.95–6.88(m,2H),6.27(d,J＝2.9Hz,1H),3.84(q,J＝7.3Hz,2H),3.60(s,3H),1.31(t,J＝7.3Hz,3H),1.22(s,9H). 1 H NMR (400MHz, MeOD) δ8.08 (d, J = 2.6Hz, 1H), 7.93 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.41-7.34 (m, 2H), 7.31 (s, 1H), 7.27 (d, J = 2.9 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.95 - 6.88 (m, 2H), 6.27 (d, J = 2.9 Hz, 1H), 3.84 ( q, J = 7.3 Hz, 2H), 3.60 (s, 3H), 1.31 (t, J = 7.3 Hz, 3H), 1.22 (s, 9H).
实施例104Example 104
4-(2-(2,4-二氟苯氧基)-5-((甲基磺亚胺酰基甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-difluorophenoxy)-5-((methylsulfonimidomethyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000323
Figure PCTCN2018072204-appb-000323
以2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯与甲硫醇钠为起始原料，参考实施例1第四到第七步反应条件，得到4-(2-(2,4-二氟苯氧基)-5-((甲基磺亚胺酰基甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(4步总收率：10.5％)。Taking 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene and sodium methanethiolate as starting materials, referring to the reaction conditions of the fourth to seventh steps of Example 1, 4-(2-(2,4-Difluorophenoxy)-5-((methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one (4 steps total yield: 10.5%).
MS m/z(ESI):444.0[M+H] +. MS m/z (ESI): 444.0 [M+H] + .
1H NMR(400MHz,MeOD)δ7.61(d,J＝2.3Hz,1H),7.43(dd,J＝8.5Hz,2.3Hz,1H),7.25(d,J＝3.2Hz,2H),7.05–6.96(m,2H),6.91(d,J＝8.5Hz,1H),6.82(dd,J＝2.8Hz,1.6Hz,1H),6.30(d,J＝2.9Hz,1H),5.11-5.08(m,2H),3.59(s,3H),3.51(s,3H). 1 H NMR (400 MHz, MeOD) δ 7.61 (d, J = 2.3 Hz, 1H), 7.43 (dd, J = 8.5 Hz, 2.3 Hz, 1H), 7.25 (d, J = 3.2 Hz, 2H), 7.05 – 6.96 (m, 2H), 6.91 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 2.8 Hz, 1.6 Hz, 1H), 6.30 (d, J = 2.9 Hz, 1H), 5.11-5.08 (m, 2H), 3.59 (s, 3H), 3.51 (s, 3H).
实施例105Example 105
N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲基)(甲基)(羰基)-λ 6-硫烷亚基)氰基酰胺 N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 4-yl)benzyl)(methyl)(carbonyl)-λ 6 -sulfane subunit)cyanoamide
Figure PCTCN2018072204-appb-000324
Figure PCTCN2018072204-appb-000324
4-(2-(2,4-二氟苯氧基)-5-((甲基磺亚胺酰基甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(50mg,0.13mmol)溶于二氯甲烷(3mL)中，加入溴乙腈(43 mg,0.4mmol)和4-二甲氨基吡啶(50mg,0.4mmol)。反应在20℃下搅拌12小时，浓缩，HPLC分离得到N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲基)(甲基)(羰基)-λ 6-硫烷亚基)氰基酰胺(20mg,白色固体，收率38％)。 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonimidomethyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one (50 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), bromoacetonitrile (43 mg, 0.4 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol) The reaction was stirred at 20 ° C for 12 hours, concentrated, and separated by HPLC to give N-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7- Dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)(methyl)(carbonyl)-λ 6 -sulfaninyl)cyanoamide (20 mg, white solid, The rate is 38%).
MS m/z(ESI):469.0[M+H] +. MS m/z (ESI): 469.0 [M+H] + .
1H NMR(400MHz,MeOD)δ7.72(d,J＝2.2Hz,1H),7.52(dd,J＝8.5Hz,2.3Hz,1H),7.35(d,J＝3.3Hz,2H),7.12–6.99(m,3H),6.87(s,1H),6.45(d,J＝2.9Hz,1H),5.00-4.97(m,2H),3.70(s,3H),3.37(s,3H). 1 H NMR (400MHz, MeOD) δ7.72 (d, J = 2.2Hz, 1H), 7.52 (dd, J = 8.5Hz, 2.3Hz, 1H), 7.35 (d, J = 3.3Hz, 2H), 7.12 – 6.99 (m, 3H), 6.87 (s, 1H), 6.45 (d, J = 2.9 Hz, 1H), 5.00 - 4.97 (m, 2H), 3.70 (s, 3H), 3.37 (s, 3H).
实施例106Example 106
4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ 6-硫烷亚基)氨基)甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮 4-(2-(2,4-difluorophenoxy)-5-(((ethyl(methyl)(carbonyl)-λ 6 -sulfaninyl)amino)methyl)phenyl)-6 -methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000325
Figure PCTCN2018072204-appb-000325
第一步：((3-溴-4-(2,4-二氟苯氧基)苯甲基)亚氨基)(乙基)(甲基)-λ 6-硫烷酮 First step: ((3-bromo-4-(2,4-difluorophenoxy)benzyl)imino)(ethyl)(methyl)-λ 6 -thiol ketone
Figure PCTCN2018072204-appb-000326
Figure PCTCN2018072204-appb-000326
2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(100mg,0.26mmol)溶于1-甲基-2吡咯烷酮(2mL)中，加入氢化钠(28mg,0.6mmol)反应在20℃下搅拌30分钟，然后乙基(亚氨基)(甲基)-λ 6-硫烷酮(70mg,0.6mmol)加入到上述反应液中，室温下搅拌12小时。反应液用水淬灭，用乙酸乙酯萃取，干燥、浓缩，柱分离得到((3-溴-4-(2,4-二氟苯氧基)苯甲基)亚氨基)(乙基)(甲基)-λ 6-硫烷酮(80mg,白色固体，收率75％)。 2-Bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (100 mg, 0.26 mmol) was dissolved in 1-methyl-2-pyrrolidone (2 mL). The reaction was stirred at 20 ° C for 30 minutes, then ethyl (imino)(methyl)-λ 6 -sulfanone (70 mg, 0.6 mmol) was added to the above reaction mixture, and stirred at room temperature for 12 hours. . The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. Methyl)-λ 6 -sulfanone (80 mg, white solid, yield 75%).
MS m/z(ESI):404.0/406.0(50/50)M+H] +. MS m/z (ESI): 404.0 / 406.0 (50 / 50) M+H] + .
第二步：4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ 6-硫烷亚基)氨基)甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮 Second step: 4-(2-(2,4-difluorophenoxy)-5-(((ethyl(methyl)(carbonyl)-λ 6 -sulfaninyl)amino)methyl)benzene 6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000327
Figure PCTCN2018072204-appb-000327
以((3-溴-4-(2,4-二氟苯氧基)苯甲基)亚氨基)(乙基)(甲基)-λ 6-硫烷酮与中间体Im为原料，参考实施例4第四步得4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ 6-硫烷亚基)氨基)甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率40％)。 Taking ((3-bromo-4-(2,4-difluorophenoxy)benzyl)imino)(ethyl)(methyl)-λ 6 -thiol ketone and intermediate Im as raw materials, reference The fourth step of Example 4 gave 4-(2-(2,4-difluorophenoxy)-5-(((ethyl(methyl)(carbonyl)-λ 6 -sulfaninyl)amino)) Phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 40%).
MS m/z(ESI):626.2[M+H] +. MS m/z (ESI): 626.2 [M+H] + .
第三步：4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ 6-硫烷亚基)氨基)甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮 Third step: 4-(2-(2,4-difluorophenoxy)-5-(((ethyl(methyl)(carbonyl)-λ 6 -sulfaninyl)amino)methyl)benzene -6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000328
Figure PCTCN2018072204-appb-000328
以4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ 6-硫烷亚基)氨基)甲基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例1第八步得4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ 6-硫烷亚基)氨基)甲基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率40％)。 4-(2-(2,4-difluorophenoxy)-5-(((ethyl(methyl)(carbonyl)-λ 6 -sulfaninyl)amino)methyl)phenyl)- 6-Methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one was used as the starting material, and the fourth step of Example 1 was obtained 4-(2- (2,4-difluorophenoxy)-5-(((ethyl(methyl)(carbonyl)-λ 6 -sulfaninyl)amino)methyl)phenyl)-6-methyl-1 , 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 40%).
MS m/z(ESI):472.1[M+H] +. MS m/z (ESI): 4721. [M+H] + .
1H NMR(400MHz,MeOD)δ7.50(d,J＝2.2Hz,1H),7.34(dd,J＝8.4Hz,2.2Hz,1H),7.25(d,J＝2.8Hz,1H),7.20(s,1H),7.00–6.81(m,3H),6.79–6.72(m,1H),6.27(d,J＝2.8Hz,1H),4.49(s,2H),3.92(q,J＝7.5Hz,2H),3.68(s,3H),3.59(s,3H),1.44(t,J＝7.3Hz,3H). 1 H NMR (400MHz, MeOD) δ7.50 (d, J = 2.2Hz, 1H), 7.34 (dd, J = 8.4Hz, 2.2Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.20 (s, 1H), 7.00–6.81 (m, 3H), 6.79–6.72 (m, 1H), 6.27 (d, J=2.8 Hz, 1H), 4.49 (s, 2H), 3.92 (q, J=7.5) Hz, 2H), 3.68 (s, 3H), 3.59 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H).
实施例107Example 107
4-(2-(4-溴-2-氟苯氧基)-5-(环丙磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(4-Bromo-2-fluorophenoxy)-5-(cyclopropanesulfonyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 ,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000329
Figure PCTCN2018072204-appb-000329
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步得4-(2-(4-溴-2-氟苯氧基)-5-(环丙磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率20％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one was used as a starting material, and the fifth step of Example 10 was carried out to obtain 4-(2-(4-bromo-2-fluorophenoxy)-5-(cyclopropylsulfinyl)phenyl)-6. -Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 20%).
MS m/z(ESI):516.0/518.0(50/50)[M+H] +. MS m/z (ESI): 51.6.518.0 (50/50) [M+H] + .
1H NMR(400MHz,MeOD)δ8.00(d,J＝2.4Hz,1H),7.84(dd,J＝8.7Hz,2.4Hz,1H),7.38(dd,J＝10.3Hz,2.3Hz,1H),7.28–7.19(m,3H),7.02–6.92(m,2H),6.27(d,J＝2.9Hz,1H),3.60(s,3H),2.69-2.60(m,1H),1.25-1.17(m,1H),1.08-1.03(m,2H),0.94–0.88(m,1H). 1 H NMR (400MHz, MeOD) δ8.00 (d, J = 2.4Hz, 1H), 7.84 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.38 (dd, J = 10.3Hz, 2.3Hz, 1H ), 7.28–7.19 (m, 3H), 7.02–6.92 (m, 2H), 6.27 (d, J=2.9 Hz, 1H), 3.60 (s, 3H), 2.69-2.60 (m, 1H), 1.25- 1.17 (m, 1H), 1.08-1.03 (m, 2H), 0.94–0.88 (m, 1H).
实施例108Example 108
4-(2-(4-溴-2-氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 ,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000330
Figure PCTCN2018072204-appb-000330
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步得4-(2-(4-溴-2-氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率26％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one was used as a starting material, and the fifth step of Example 10 was carried out to obtain 4-(2-(4-bromo-2-fluorophenoxy)-5-(ethylsulfonimido)phenyl)-6. -Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 26%).
MS m/z(ESI):504.0/506.0(50/50)[M+H] +. MS m/z (ESI): 504.0 / 506.0 (50 / 50) [M+H] + .
1H NMR(400MHz,MeOD)δ7.99(d,J＝2.4Hz,1H),7.84(dd,J＝8.7Hz,2.4Hz,1H),7.37(dd,J＝10.3Hz,2.3Hz,1H),7.27–7.19(m,3H),7.03–6.93(m,2H),6.25(d,J＝2.9Hz,1H),3.59(s,3H),3.19(q,J＝7.2Hz,2H),1.17(t,J＝7.4Hz,3H).. 1 H NMR (400 MHz, MeOD) δ 7.99 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.37 (dd, J = 10.3 Hz, 2.3 Hz, 1H) ), 7.27–7.19 (m, 3H), 7.03–6.93 (m, 2H), 6.25 (d, J=2.9 Hz, 1H), 3.59 (s, 3H), 3.19 (q, J=7.2 Hz, 2H) , 1.17 (t, J = 7.4 Hz, 3H)..
实施例109Example 109
4-(2-(4-氯-2-氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(4-Chloro-2-fluorophenoxy)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 ,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000331
Figure PCTCN2018072204-appb-000331
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步得到4-(2-(4-氯-2-氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率38％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one was used as a starting material, and the fifth step of Example 10 was followed to obtain 4-(2-(4-chloro-2-fluorophenoxy)-5-(ethylsulfonimido)phenyl)-6. -Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 38%).
MS m/z(ESI):460.0[M+H] +. MS m/z (ESI): 460.0 [M+H] + .
1H NMR(400MHz,CD3Cl):δ10.92(br,1H),8.13(d,J＝2H，1H),7.88(dd,J＝8.8Hz,2.4Hz,1H),7.29(s,1H),7.23-7.18(m,2H),7.12-7.05(m,1H),6.99(t,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),6.37(s,1H),3.72(s,3H),3.28(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD3Cl) : δ10.92 (br, 1H), 8.13 (d, J = 2H, 1H), 7.88 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.29 (s, 1H) , 7.23-7.18 (m, 2H), 7.12-7.05 (m, 1H), 6.99 (t, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.37 (s, 1H), 3.72 (s, 3H), 3.28 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).
实施例110Example 110
4-(5-(环丙磺亚胺酰基)-2-(((1s,4s)-4-羟基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropaneimidoyl)-2-(((1s,4s)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000332
Figure PCTCN2018072204-appb-000332
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步，得到4-(5-(环丙磺亚胺酰基)-2-(((1s,4s)-4-羟基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7- 酮(白色固体，产率15％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one was used as a starting material. Referring to the fifth step of Example 10, 4-(5-(cyclopropaneimidoyl)-2-(((1s,4s)-4-hydroxycyclohexyl)oxo was obtained. Phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (white solid, yield 15%).
MS m/z(ESI):442.2[M+H] +. MS m / z (ESI): 442.2 [M + H] +.
1H NMR(400MHz,MeOD)δ8.04–7.94(m,2H),7.39(d,J＝8.9Hz,1H),7.29–7.22(m,2H),6.16(d,J＝2.9Hz,1H),3.62(s,3H),3.58-3.51(m,1H),3.32-3.29(m,1H),2.68-2.60(m,1H),1.90-1.82(m,2H),1.66-1.45(m,5H),1.42–1.37(m,1H),1.35-1.25(m,2H),1.21-1.12(m,2H). 1 H NMR (400 MHz, MeOD) δ 8.04 - 7.94 (m, 2H), 7.39 (d, J = 8.9 Hz, 1H), 7.29 - 7.22 (m, 2H), 6.16 (d, J = 2.9 Hz, 1H) ), 3.62 (s, 3H), 3.58-3.51 (m, 1H), 3.32-3.29 (m, 1H), 2.68-2.60 (m, 1H), 1.90 - 1.82 (m, 2H), 1.66-1.45 (m , 5H), 1.42–1.37 (m, 1H), 1.35-1.25 (m, 2H), 1.21-1.12 (m, 2H).
实施例111Example 111
4-(5-((二乙基(羰基)-λ 6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮 4-(5-((Diethyl(carbonyl)-λ 6 -sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000333
Figure PCTCN2018072204-appb-000333
第一步 (乙基亚硫酰基<亚磺酰>)乙烷First step (ethylsulfinyl <sulfinyl) ethane
Figure PCTCN2018072204-appb-000334
Figure PCTCN2018072204-appb-000334
将二乙基硫烷(2g，22.2mmol)溶于二氯甲烷(20mL)中，在0℃下滴加间氯过氧苯甲酸(3.5g，15.5mmol)的二氯甲烷，0.5小时后，蒸除二氯甲烷，加入氢氧化钠(1g)的水溶液(30mL)，蒸除水，加入二氯甲烷(30mL)，打浆过滤，母液蒸除二氯甲烷得(乙基亚硫酰基<亚磺酰>)乙烷(1.2g，产率51％)。Diethyl sulfane (2 g, 22.2 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (3.5 g, 15.5 mmol) of dichloromethane was added dropwise at 0 ° C. Evaporate the dichloromethane, add aqueous solution of sodium hydroxide (1 g) (30 mL), dilute water, add dichloromethane (30 mL), filter with a slurry, and distill off methylene chloride to give (ethyl sulfinyl < sulfin Acyl>) ethane (1.2 g, yield 51%).
1H NMR(400MHz,CD3Cl):δ2.66-2.77(m,4H),1.34(t,J＝7.2Hz，6H). 1 H NMR (400 MHz, CD 3 Cl): δ 2.66-2.77 (m, 4H), 1.34 (t, J = 7.2 Hz, 6H).
第二步 二乙基(亚氨基)-λ 6-硫烷酮 Second step diethyl (imino)-λ 6 -sulfanone
Figure PCTCN2018072204-appb-000335
Figure PCTCN2018072204-appb-000335
将(乙基亚硫酰基<亚磺酰>)乙烷(1.1g，10.4mmol)溶于甲醇(30mL)中，在25℃下加氨基甲酰胺(3.2g，41.4mmol)、二乙酰氧基碘苯(10g，31.0mmol)，2小时后，蒸除甲醇，柱层析得到二乙基(亚氨基)-λ6-硫烷酮(0.5g，产率40％)。(Ethylsulfinyl <sulfinyl) ethane (1.1 g, 10.4 mmol) was dissolved in methanol (30 mL) and carbamide (3.2 g, 41.4 mmol) was added at 25 ° C, diacetoxy Iodobenzene (10 g, 31.0 mmol), after 2 hours, methanol was evaporated, and then purified to give diethyl(imino)-[lambda]6-sulfanone (0.5 g, yield 40%).
1H NMR(400MHz,CD3Cl):δ3.12-3.06(m,4H),2.06(s,1H),1.42(t,J＝7.6Hz，6H) 1 H NMR (400MHz, CD3Cl) : δ3.12-3.06 (m, 4H), 2.06 (s, 1H), 1.42 (t, J = 7.6Hz, 6H)
第三步至第五步：4-(5-((二乙基(羰基)-λ 6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮 Steps 3 to 5: 4-(5-((diethyl(carbonyl)-λ 6 -sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1-toluene Sulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000336
Figure PCTCN2018072204-appb-000336
以二乙基(亚氨基)-λ6-硫烷酮与2-溴-4-碘-1-苯氧基苯为起始原料，反应操作参考实施例19第五至七步，得4-(5-((二乙基(羰基)-λ 6-硫烷亚基)氨基)-2-苯氧基苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(38mg)。 Taking diethyl(imino)-λ6-sulfanone and 2-bromo-4-iodo-1-phenoxybenzene as starting materials, the reaction operation is carried out in the fifth to seventh steps of Reference Example 19 to obtain 4-( 5-((Diethyl(carbonyl)-λ 6 -sulfaninyl)amino)-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one (38 mg).
MS m/z(ESI):436.1[M+H]+.MS m/z (ESI): 436.1 [M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.97(br,1H),7.26-7.19(m,4H),7.09(d,J＝2.8Hz,1H),6.97-6.90(m,3H),6.78-6.76(m,2H),6.23(t,J＝2.0Hz,1H),3.47(s,3H),3.32-3.27(m,4H),1.28(t,J＝7.6Hz,6H).实施例112 1 H NMR (400MHz, DMSO- d6): δ11.97 (br, 1H), 7.26-7.19 (m, 4H), 7.09 (d, J = 2.8Hz, 1H), 6.97-6.90 (m, 3H), 6.78-6.76 (m, 2H), 6.23 (t, J = 2.0 Hz, 1H), 3.47 (s, 3H), 3.32-3.27 (m, 4H), 1.28 (t, J = 7.6 Hz, 6H). Example 112
2-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈2-(4-((4,4-difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000337
Figure PCTCN2018072204-appb-000337
第一步：2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈First step: 2-((3-bromo-4-((4,4-difluorocyclohexyl)oxy)phenyl)sulfinyl <sulfinyl>)-2-methylpropanenitrile
Figure PCTCN2018072204-appb-000338
Figure PCTCN2018072204-appb-000338
以2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)乙酰腈为原料，参考实施例67第七步得2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈(产率70％)。Taking 2-((3-bromo-4-((4,4-difluorocyclohexyl)oxy)phenyl)sulfinyl <sulfinyl)) acetonitrile as a raw material, refer to the seventh step of Example 67 2-((3-Bromo-4-((4,4-difluorocyclohexyl))oxy)phenyl)sulfinyl <sulfinyl>)-2-methylpropanenitrile (yield 70%).
第二步：2-(3-溴-4-((4,4-二氟环己基)氧代)苯基磺亚胺酰基)-2-甲基丙腈Second step: 2-(3-bromo-4-((4,4-difluorocyclohexyl)oxo)phenylsulfonimido)-2-methylpropanenitrile
Figure PCTCN2018072204-appb-000339
Figure PCTCN2018072204-appb-000339
以2-((3-溴-4-((4,4-二氟环己基)氧代)苯基)亚硫酰基<亚磺酰>)-2-甲基丙腈为原料，参考实施例1第六步得2-(3-溴-4-((4,4-二氟环己基)氧代)苯基磺亚胺酰基)-2-甲基丙腈(产率68％)。Taking 2-((3-bromo-4-((4,4-difluorocyclohexyl)oxy)phenyl)sulfinyl <sulfinyl))-2-methylpropionitrile as a raw material, reference example The sixth step gave 2-(3-bromo-4-((4,4-difluorocyclohexyl)oxo)phenylsulfonimido)-2-methylpropanenitrile (yield 68%).
MS m/z(ESI):421.0/423.0(50/50)[M+H] +. MS m/z (ESI): 421.0 / 423.0 (50 / 50) [M+H] + .
第三步：2-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈The third step: 2-(4-((4,4-difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H -pyrrolo[2,3-c]pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000340
Figure PCTCN2018072204-appb-000340
以2-(3-溴-4-((4,4-二氟环己基)氧代)苯基磺亚胺酰基)-2-甲基丙腈为原料，参考实施 例1第七步得2-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(产率87％)。Taking 2-(3-bromo-4-((4,4-difluorocyclohexyl)oxo)phenylsulfonimido)-2-methylpropionitrile as the starting material, refer to the seventh step of Example 1 -(4-((4,4-difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2 , 3-c]pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile (yield 87%).
MS m/z(ESI):643.1[M+H] +. MS m/z (ESI): 643.1 [M+H] + .
第四步：2-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈Fourth step: 2-(4-((4,4-difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2, 3-c]pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile
Figure PCTCN2018072204-appb-000341
Figure PCTCN2018072204-appb-000341
以2-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈为原料，参考实施例1第八步得2-(4-((4,4-二氟环己基)氧代)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)-2-甲基丙腈(产率29％)。2-(4-((4,4-Difluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrole [2,3-c]pyridin-4-yl)phenylsulfonimido)-2-methylpropionitrile was used as the starting material, and the second step of Example 1 was obtained to obtain 2-(4-((4,4-) Fluorocyclohexyl)oxo)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfinamido )-2-methylpropionitrile (yield 29%).
MS m/z(ESI):489.1[M+H] +. MS m/z (ESI): 489.1 [M+H] + .
1H NMR(400MHz,MeOD)δ7.98(dd,J＝10.9Hz,2.4Hz,2H),7.35(d,J＝8.4Hz,1H),7.25(d,J＝2.9Hz,1H),7.18(s,1H),6.22(d,J＝2.9Hz,1H),4.75–4.70(m,1H),3.61(s,3H),1.92–1.78(m,4H),1.78–1.64(m,4H),1.61(s,3H),1.59(s,3H). 1 H NMR (400MHz, MeOD) δ7.98 (dd, J = 10.9Hz, 2.4Hz, 2H), 7.35 (d, J = 8.4Hz, 1H), 7.25 (d, J = 2.9Hz, 1H), 7.18 (s, 1H), 6.22 (d, J = 2.9 Hz, 1H), 4.75 - 4.70 (m, 1H), 3.61 (s, 3H), 1.92 - 1.78 (m, 4H), 1.78 - 1.64 (m, 4H) ), 1.61 (s, 3H), 1.59 (s, 3H).
实施例113Example 113
1-(3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-((反式-4-甲基环己基)氨基)苯基磺亚胺酰基)环丙烷-1-甲腈1-(3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((trans-4-) Cyclohexyl)amino)phenylsulfinimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000342
Figure PCTCN2018072204-appb-000342
以1-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈为原料，参考实施例23第一步，得到1-(3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-((反式-4-甲基环己基)氨基)苯基磺亚胺酰基)环丙烷-1-甲腈(白色固体，产率11％)。1-(4-Fluoro-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Starting from the first step of Example 23, phenylsulfonimidoyl)cyclopropane-1-carbonitrile was used as the starting material to give 1-(3-(6-methyl-7-carbonyl-6,7-dihydro-1H- Pyrrolo[2,3-c]pyridin-4-yl)-4-((trans-4-methylcyclohexyl)amino)phenylsulfonimidoyl)cyclopropane-1-carbonitrile (white solid, Yield 11%).
MS m/z(ESI):464.2[M+H] +. MS m/z (ESI): 464.2 [M+H] + .
1H NMR(400MHz,MeOD)δ7.75(dd,J＝8.9Hz,2.4Hz,1H),7.62(d,J＝2.4Hz,1H),7.25(d,J＝2.8Hz,1H),7.11(s,1H),6.82(d,J＝9.1Hz,1H),6.08(d,J＝2.8Hz,1H),3.59(s,3H),3.35-3.27(m,1H),1.99-1.85(m,2H),1.74–1.61(m,4H),1.54–1.50(m,1H),1.25-1.16(m,2H),1.07-0.95(m,4H),0.81(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ7.75 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.11 (s, 1H), 6.82 (d, J = 9.1 Hz, 1H), 6.08 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.35-3.27 (m, 1H), 1.99-1.85 ( m, 2H), 1.74–1.61 (m, 4H), 1.54–1.50 (m, 1H), 1.25-1.16 (m, 2H), 1.07-0.95 (m, 4H), 0.81 (d, J = 6.5 Hz, 3H).
实施例114Example 114
4-(5-((二乙基(羰基)-λ 6-硫烷亚基)氨基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮 4-(5-((Diethyl(carbonyl)-λ 6 -sulfaninyl)amino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6 -dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000343
Figure PCTCN2018072204-appb-000343
第一步至第三步：4-(5-((二乙基(羰基)-λ 6-硫烷亚基)氨基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备 First to third steps: 4-(5-((diethyl(carbonyl)-λ 6 -sulfaninyl)amino)-2-(2,4-difluorophenoxy)phenyl)- Preparation of 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000344
Figure PCTCN2018072204-appb-000344
以2-溴-1-(2,4-二氟苯氧基)-4-碘苯与二乙基(亚氨基)-λ6-硫烷酮为原料，反应操作参考实施例19第五至七步，得到4-(5-((二乙基(羰基)-λ 6-硫烷亚基)氨基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(三步总收率8.5％)。 2-bromo-1-(2,4-difluorophenoxy)-4-iodobenzene and diethyl(imino)-λ6-sulfanone were used as starting materials, and the reaction operation was carried out in the fifth to seventh of Reference Example 19. Step to give 4-(5-((diethyl(carbonyl)-λ 6 -sulfaninyl)amino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl- 1,6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (total yield of 8.5% in three steps).
MS m/z(ESI):472.1[M+H]+.MS m/z (ESI): 472.1 [M+H]+.
1H NMR(400MHz,DMSO-d6):δ12.00(br,1H),7.34-7.25(m,3H),7.07(d,J＝2.8Hz,1H),6.97-6.91(m,3H),6.81-6.78(m,1H),6.21(t,J＝2.0Hz,1H),3.51(s,3H),3.32-3.27(m,4H),1.26(t,J＝7.6Hz,6H)实施例115 1 H NMR (400MHz, DMSO- d6): δ12.00 (br, 1H), 7.34-7.25 (m, 3H), 7.07 (d, J = 2.8Hz, 1H), 6.97-6.91 (m, 3H), 6.81-6.78 (m, 1H), 6.21 (t, J = 2.0 Hz, 1H), 3.51 (s, 3H), 3.32-3.27 (m, 4H), 1.26 (t, J = 7.6 Hz, 6H) Examples 115
4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(S-(cyclopropylmethyl)sulfonimido)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000345
Figure PCTCN2018072204-appb-000345
第一步：(3-溴-4-氟苯基)(环丙基甲基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(cyclopropylmethyl)sulfane
Figure PCTCN2018072204-appb-000346
Figure PCTCN2018072204-appb-000346
将3-溴-4-氟苯硫醇(1g，4.8mmol)、(溴甲基)环丙烷(1.9g，14.5mmol)、碳酸铯(4.7g，14.5mmol)、碘化钠(72mg，0.5mmol)悬浮于二甲亚砜(20mL)中，在25℃下搅拌3小时，加入水(40mL)，乙酸乙酯(20mL)萃取，硫酸钠干燥，过滤旋干得到(3-溴-4-氟苯基)(环丙基甲基)硫烷(1.5g)，直接用做下一步。3-Bromo-4-fluorobenzenethiol (1 g, 4.8 mmol), (bromomethyl)cyclopropane (1.9 g, 14.5 mmol), cesium carbonate (4.7 g, 14.5 mmol), sodium iodide (72 mg, 0.5) Methanol) was suspended in dimethyl sulfoxide (20 mL), and stirred at 25 ° C for 3 hr, then water (40 mL), ethyl acetate (20 mL) Fluorophenyl)(cyclopropylmethyl)sulfane (1.5 g) was used directly as the next step.
第二步：2-溴-4-((环丙基甲基)亚硫酰基<亚磺酰>)-1-氟苯的制备Second step: Preparation of 2-bromo-4-((cyclopropylmethyl)sulfinyl <sulfinyl>)-1-fluorobenzene
Figure PCTCN2018072204-appb-000347
Figure PCTCN2018072204-appb-000347
以(3-溴-4-氟苯基)(环丙基甲基)硫烷为原料，参考实施例1第五步，得到2-溴-4-((环丙基甲基)亚硫酰基<亚磺酰>)-1-氟苯(收率86.3％)。Using (3-bromo-4-fluorophenyl)(cyclopropylmethyl)sulfane as a starting material, referring to the fifth step of Example 1, 2-bromo-4-((cyclopropylmethyl)sulfinyl group was obtained. <sulfinyl>)-1-fluorobenzene (yield 86.3%).
1H NMR(400MHz,CDCl 3):δ7.89(dd,J＝2.4,6.4Hz,1H),7.59-7.55(m,1H),7.27(t,J＝8.0Hz,1H),2.86-2.82(m,1H),2.70-2.65(m,1H),1.00-0.96(m,1H),0.68-0.65(m,2H),0.30-0.27(m,1H). 1 H NMR (400MHz, CDCl 3 ): δ7.89 (dd, J = 2.4,6.4Hz, 1H), 7.59-7.55 (m, 1H), 7.27 (t, J = 8.0Hz, 1H), 2.86-2.82 (m, 1H), 2.70-2.65 (m, 1H), 1.00-0.96 (m, 1H), 0.68-0.65 (m, 2H), 0.30-0.27 (m, 1H).
第三步：(3-溴-4-氟苯基)(环丙基甲基)(亚氨基)-λ6-硫烷酮的制备Third step: Preparation of (3-bromo-4-fluorophenyl)(cyclopropylmethyl)(imino)-λ6-sulfanone
Figure PCTCN2018072204-appb-000348
Figure PCTCN2018072204-appb-000348
以2-溴-4-((环丙基甲基)亚硫酰基<亚磺酰>)-1-氟苯为原料，参考实施例1第六步得到(3-溴-4-氟苯基)(环丙基甲基)(亚氨基)-λ6-硫烷酮(收率84.6％)。Using 2-bromo-4-((cyclopropylmethyl)sulfinyl <sulfinyl>)-1-fluorobenzene as the starting material, refer to the sixth step of Example 1 to obtain (3-bromo-4-fluorophenyl). (cyclopropylmethyl)(imino)-λ6-sulfanone (yield 84.6%).
MS m/z(ESI):292.0/294.0(50/50)[M+H] +。 MS m/z (ESI): 292.0 / 294.0 (50 / 50) [M+H] + .
第四步：4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮Fourth step: 4-(5-(S-(cyclopropylmethyl)sulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000349
Figure PCTCN2018072204-appb-000349
以(3-溴-4-氟苯基)(环丙基甲基)(亚氨基)-λ6-硫烷酮与6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考参考实施例10第四步，得到4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率36.3％)。(3-Bromo-4-fluorophenyl)(cyclopropylmethyl)(imino)-λ6-sulfanone and 6-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one as a raw material, reference Referring to the fourth step of Example 10, 4-(5-(S-(cyclopropylmethyl)sulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1 was obtained. 6-Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 36.3%).
MS m/z(ESI):514.1[M+H] +。 MS m/z (ESI): 514.1 [M+H] + .
第五步 4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 5 4-(5-(S-(Cyclopropylmethyl)sulfonimido)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6- Preparation of dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000350
Figure PCTCN2018072204-appb-000350
以4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与2,4-二氟苯酚为原料，反应操作同实施例5第五步，得到4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率29.6％)。4-(5-(S-(Cyclopropylmethyl)sulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one and 2,4-difluorophenol as raw materials, the reaction operation is the same as the fifth step of the embodiment 5, to obtain 4-(5-(S-(cyclopropylmethyl)). Sulfimido)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Ketone (yield 29.6%).
MS m/z(ESI):470.1[M+H] +. MS m/z (ESI): 470.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ12.16(br,1H),8.12(d,J＝2.8H，1H),7.99(dd, J＝9.2Hz,2.8Hz,1H),7.59-7.45(m,3H),7.33(t,J＝2.8Hz,1H),7.22-7.19(m,1H),7.12(d,J＝8.4Hz,1H),6.30(t,J＝2.0Hz,1H),4.01-3.93(m,2H),3.57(s,3H),1.03-0.98(m,1H),0.56-0.50(m,2H),0.26-0.21(m,1H),0.19-0.15(m,1H). 1 H NMR (400MHz, DMSO- d6): δ12.16 (br, 1H), 8.12 (d, J = 2.8H, 1H), 7.99 (dd, J = 9.2Hz, 2.8Hz, 1H), 7.59-7.45 (m, 3H), 7.33 (t, J = 2.8 Hz, 1H), 7.22-7.19 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.30 (t, J = 2.0 Hz, 1H) , 4.01-3.93 (m, 2H), 3.57 (s, 3H), 1.03-0.98 (m, 1H), 0.56-0.50 (m, 2H), 0.26-0.21 (m, 1H), 0.19-0.15 (m, 1H).
实施例116Example 116
4-(2-(环丙基甲氧基)-5-(S-(环丙基甲基)磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cyclopropylmethoxy)-5-(S-(cyclopropylmethyl)sulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000351
Figure PCTCN2018072204-appb-000351
以4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，反应操作同实施例5第五步，用环丙基甲醇替代2,4-二氟苯酚，得到4-(2-(环丙基甲氧基)-5-(S-(环丙基甲基)磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率39.8％)。4-(5-(S-(Cyclopropylmethyl)sulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one as the starting material, the reaction operation is the same as the fifth step of the embodiment 5, replacing the 2,4-difluorophenol with cyclopropylmethanol to obtain 4-(2-(cyclopropyl) Methoxy)-5-(S-(cyclopropylmethyl)sulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone (yield 39.8%).
MS m/z(ESI):412.1[M+H] +. MS m/z (ESI): 4121. [M+H] + .
1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),7.85-7.81(m,2H),7.32(s,1H),7.29-7.25(m,2H),6.14(t,J＝2.0Hz,1H),4.02(s,1H),3.96(d,J＝6.8Hz,2H),3.58(s,3H),3.08(dd,J＝7.2Hz,2.8Hz,2H),1.15-1.08(m,1H),0.93-0.86(m,1H),0.49-0.43(m,2H),0.40-0.37(m,2H),0.29-0.25(m,2H),0.06-0.03(m,2H). 1 H NMR (400MHz, DMSO- d6): δ12.02 (s, 1H), 7.85-7.81 (m, 2H), 7.32 (s, 1H), 7.29-7.25 (m, 2H), 6.14 (t, J =2.0 Hz, 1H), 4.02 (s, 1H), 3.96 (d, J = 6.8 Hz, 2H), 3.58 (s, 3H), 3.08 (dd, J = 7.2 Hz, 2.8 Hz, 2H), 1.15- 1.08 (m, 1H), 0.93-0.86 (m, 1H), 0.49-0.43 (m, 2H), 0.40-0.37 (m, 2H), 0.29-0.25 (m, 2H), 0.06-0.03 (m, 2H) ).
实施例117Example 117
4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(S-(cyclopropylmethyl)sulfonimido)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6- Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000352
Figure PCTCN2018072204-appb-000352
以4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，反应操作同实施例5第五步，用4,4-二氟环己醇替代2,4-二氟苯酚，得到4-(5-(S-(环丙基甲基)磺亚胺酰基)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率43.5％)。4-(5-(S-(Cyclopropylmethyl)sulfonimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one as a raw material, the reaction operation is the same as the fifth step of the embodiment 5, and 4,4-difluorocyclohexanol is used instead of 2,4-difluorophenol to obtain 4-(5). -(S-(cyclopropylmethyl)sulfonimido)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H Pyrrolo[2,3-c]pyridine-7-one (yield 43.5%).
MS m/z(ESI):476.2[M+H]+.MS m/z (ESI): 476.2 [M+H]+.
1H NMR(400MHz,DMSO-d6):δ12.04(s,1H),7.88-7.83(m,2H),7.39(d,J＝8.4Hz,1H),7.29-7.26(m,2H),6.13(t,J＝2.0Hz,1H),4.77(s,1H),4.08-4.01(m,1H),3.56(s,3H),3.11-3.08(m,2H),1.86-1.66(m,8H),0.95-0.86(m,1H),0.42-0.38(m,2H),0.09-0.04(m,2H).1H NMR (400MHz, DMSO-d6): δ 12.04 (s, 1H), 7.88-7.83 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.29-7.26 (m, 2H), 6.13 (t, J = 2.0 Hz, 1H), 4.77 (s, 1H), 4.08-4.01 (m, 1H), 3.56 (s, 3H), 3.11-3.08 (m, 2H), 1.86-1.66 (m, 8H) ), 0.95-0.86 (m, 1H), 0.42-0.38 (m, 2H), 0.09-0.04 (m, 2H).
实施例118Example 118
1-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈1-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl) Phenylsulfonimido)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000353
Figure PCTCN2018072204-appb-000353
第一步 1-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈First Step 1-((3-Bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000354
Figure PCTCN2018072204-appb-000354
以2-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)乙酰腈为原料，参考实施例70第一步反应条件，得到1-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈(收率：65.8％)。Using 2-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfinyl)acetonitrile as the starting material, referring to the first step reaction conditions of Example 70, 1-( (3-Bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfinyl>)cyclopropane-1-carbonitrile (yield: 65.8%).
第二步 1-(3-溴-4-(环丙基甲氧基)苯基磺亚胺酰基)环丙烷-1-甲腈Second step 1-(3-Bromo-4-(cyclopropylmethoxy)phenylsulfinyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000355
Figure PCTCN2018072204-appb-000355
以1-((3-溴-4-(环丙基甲氧基)苯基)亚硫酰基<亚磺酰>)环丙烷-1-甲腈为原料，参考参考实施例1第六步，得到1-(3-溴-4-(环丙基甲氧基)苯基磺亚胺酰基)环丙烷-1-甲腈(收率：78.8％)。Starting from 1-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfinyl <sulfinyl])cyclopropane-1-carbonitrile, refer to the sixth step of Reference Example 1, 1-(3-Bromo-4-(cyclopropylmethoxy)phenylsulfinimidoyl)cyclopropane-1-carbonitrile was obtained (yield: 78.8%).
MS m/z(ESI):355.0/357.0(50/50)[M+H] +. MS m/z (ESI): 355.0 / 357.0 (50 / 50) [M+H] + .
第三步 1-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈The third step 1-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000356
Figure PCTCN2018072204-appb-000356
以1-(3-溴-4-(环丙基甲氧基)苯基磺亚胺酰基)环丙烷-1-甲腈与中间体Im为原料，反应操作同实施例1第七步，得到1-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(收率：28.4％)。Taking 1-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonimido)cyclopropane-1-carbonitrile and Intermediate Im as raw materials, the reaction operation is the same as the seventh step of Example 1, 1-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridin-4-yl)phenylsulfolinimido)cyclopropane-1-carbonitrile (yield: 28.4%).
MS m/z(ESI):577.1[M+H] +. MS m/z (ESI): 577.1 [M+H] + .
第四步 1-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈Fourth step 1-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4 -yl)phenylsulfinimidoyl)cyclopropane-1-carbonitrile
Figure PCTCN2018072204-appb-000357
Figure PCTCN2018072204-appb-000357
以1-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺酰-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈为原料，参考实施例1第八步，得到1-(4-(环丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基磺亚胺酰基)环丙烷-1-甲腈(收率：55.6％)。1-(4-(cyclopropylmethoxy)-3-(6-methyl-7-carbonyl-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c ] pyridin-4-yl)phenylsulfinimidoyl)cyclopropane-1-carbonitrile as a starting material, referring to the eighth step of Example 1, to give 1-(4-(cyclopropylmethoxy)-3-( 6-Methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylsulfonimidoyl)cyclopropane-1-carbonitrile (yield : 55.6%).
MS m/z(ESI):423.1[M+H] +. MS m/z (ESI): 423.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ12.08(br,1H),7.93(d,J＝2.0Hz,1H),7.89(dd,J＝8.8Hz,2.4Hz,1H),7.35(d,J＝8.8Hz,1H),7.31-7.30(m,2H),6.25(s,1H),5.21(s,1H),4.01(d,J＝6.8Hz,2H),3.58(s,3H),1.85-1.60(m,4H),1.19-1.12(m,1H),0.52-0.48(m,2H),0.33-0.29(m,2H). 1 H NMR (400MHz, DMSO- d6): δ12.08 (br, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.35 (d , J = 8.8 Hz, 1H), 7.31-7.30 (m, 2H), 6.25 (s, 1H), 5.21 (s, 1H), 4.01 (d, J = 6.8 Hz, 2H), 3.58 (s, 3H) , 1.85-1.60 (m, 4H), 1.19-1.12 (m, 1H), 0.52-0.48 (m, 2H), 0.33-0.29 (m, 2H).
实施例119Example 119
4-(5-(环丙磺亚胺酰基)-2-(2-氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropaneimidoyl)-2-(2-fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one
Figure PCTCN2018072204-appb-000358
Figure PCTCN2018072204-appb-000358
以实施例33第七步产物4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与2,4-二氟苯酚为原料，参考实施例4第四步，用2-氟苯酚替代2,4-二氟苯酚，得到4-(5-(环丙磺亚胺酰基)-2-(2-氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率：32.6％)。The product of the seventh step of Example 33, 4-(5-(cyclopropanesulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridin-7-one and 2,4-difluorophenol as raw materials, referring to the fourth step of Example 4, replacing 2,4-difluorophenol with 2-fluorophenol to obtain 4-( 5-(cyclopropanesulfonyl)-2-(2-fluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (yield: 32.6%).
MS m/z(ESI):438.1[M+H] +. MS m/z (ESI): 438.1 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ12.10(br,1H),7.97(d,J＝2.4Hz,1H),7.82(dd,J＝8.8Hz,2.4Hz,1H),7.44-7.38(m,2H),7.22(s,1H),7.33-7.24(m,3H),6.93(d,J＝8.4Hz,1H),6.30(t,J＝2.0Hz,1H),4.23(s,1H),3.58(s,3H),2.76-2.70(m,1H),0.98-0.94(m,1H),0.94-0.92(m,3H). 1 H NMR (400MHz, DMSO- d6): δ12.10 (br, 1H), 7.97 (d, J = 2.4Hz, 1H), 7.82 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.44-7.38 (m, 2H), 7.22 (s, 1H), 7.33 - 7.24 (m, 3H), 6.93 (d, J = 8.4 Hz, 1H), 6.30 (t, J = 2.0 Hz, 1H), 4.23 (s, 1H), 3.58 (s, 3H), 2.76-2.70 (m, 1H), 0.98-0.94 (m, 1H), 0.94-0.92 (m, 3H).
实施例120Example 120
N-(环丙基(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(羰基)-λ6-硫烷亚基)乙酰胺N-(cyclopropyl(4-(2,4-difluorophenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c Pyridin-4-yl)phenyl)(carbonyl)-λ6-sulfaninyl)acetamide
Figure PCTCN2018072204-appb-000359
Figure PCTCN2018072204-appb-000359
以4-(5-(环丙磺亚胺酰基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例2第一步，用乙基磺酰氯替代环丙基磺酰氯，得到N-(环丙基(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)(羰基)-λ6-硫烷亚基)乙酰胺(收率64.6％)4-(5-(cyclopropanesulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 , 3-c]pyridine-7-one as a starting material, referring to the first step of Example 2, replacing cyclopropylsulfonyl chloride with ethylsulfonyl chloride to obtain N-(cyclopropyl(4-(2,4-difluoro) Phenoxy)-3-(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)(carbonyl)-λ6- Sulfox subunit) acetamide (yield 64.6%)
MS m/z(ESI):498.0[M+H] +. MS m/z (ESI): 498.0 [M+H] + .
1H NMR(400MHz,DMSO)δ12.14(br,1H),8.48(s,1H),7.93(d,J＝2.4Hz,1H),7.80(dd,J＝8.8Hz,2.4Hz,1H),7.59-7.43(m,2H),7.40-7.29(m,1H),7.28-7.14(m,1H),6.97(d,J＝8.7Hz,1H),6.28(s,1H),3.59(s,3H),3.15-3.05(m,1H),1.98(s,3H),1.38-0.90(m,4H). 1 H NMR (400MHz, DMSO) δ12.14 (br, 1H), 8.48 (s, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.8Hz, 2.4Hz, 1H) , 7.59-7.43 (m, 2H), 7.40-7.29 (m, 1H), 7.28-7.14 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.28 (s, 1H), 3.59 (s) , 3H), 3.15-3.05 (m, 1H), 1.98 (s, 3H), 1.38-0.90 (m, 4H).
实施例121Example 121
4-(2-(环辛基氨基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cyclooctylamino)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine -7-ketone
Figure PCTCN2018072204-appb-000360
Figure PCTCN2018072204-appb-000360
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例23第一步，用环辛氨替代反式-4甲基环己烷胺，得到4-(2-(环辛基氨基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(24mg)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one was used as a starting material. Referring to the first step of Example 23, replacing trans-4-methylcyclohexaneamine with cyclooctylamine gave 4-(2-(cyclooctylamino)-5-(B Sulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (24 mg).
MS m/z(ESI):441.2[M+H] +. MS m/z (ESI): 441.2 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ12.14(br,1H),7.67(dd,J＝8.8Hz,2.0Hz,1H),7.57(d,J＝2.4Hz，1H),7.30(t,J＝2.4Hz,1H),7.23(s,1H),6.74(d,J＝8.8Hz,1H),6.0(t,J＝2.0Hz,1H),3.64-3.57(m,1H),3.56(s,3H),3.04(q,J＝7.2Hz,2H),1.78-1.66(m,2H),1.60-1.40(m,12H),1.08(t,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO- d6): δ12.14 (br, 1H), 7.67 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.57 (d, J = 2.4Hz, 1H), 7.30 (t , J = 2.4 Hz, 1H), 7.23 (s, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.0 (t, J = 2.0 Hz, 1H), 3.64 - 3.57 (m, 1H), 3.56 (s, 3H), 3.04 (q, J = 7.2 Hz, 2H), 1.78-1.66 (m, 2H), 1.60-1.40 (m, 12H), 1.08 (t, J = 7.2 Hz, 3H).
实施例122Example 122
6-甲基-4-(2-((反-4-甲基环己基)氨基)-5-(丙烷-2-基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备6-Methyl-4-(2-((trans-4-methylcyclohexyl)amino)-5-(propan-2-ylsulfonimido)phenyl)-1,6-dihydro-7H- Preparation of pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000361
Figure PCTCN2018072204-appb-000361
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(35mg,0.07mmol)为反应原料，参考实施例23第一步，得到化合物6-甲基-4-(2-((反-4-甲基环己基)氨基)-5-(丙烷-2-基磺亚胺酰基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(7.0mg,白色固体，产率23％)4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one (35 mg, 0.07 mmol) was used as the starting material of the reaction, and the compound was obtained in the first step of Example 23 to give the compound 6-methyl-4-(2-((trans-4-methylcyclohexyl)) Amino)-5-(propan-2-ylsulfonimido)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (7.0 mg, white solid, Yield 23%)
MS m/z(ESI):441.1[M+H] + MS m/z (ESI): 441.1 [M+H] +
1H NMR(400MHz,MeOD)δ7.74(dd,J＝8.8Hz,2.4Hz,1H),7.58(d,J＝2.3Hz,1H),7.35(d,J＝2.8Hz,1H),7.19(s,1H),6.89(d,J＝9.0Hz,1H),6.11(d,J＝2.8Hz,1H),3.69(s,3H),3.42–3.35(m,1H),3.29–3.22(m,1H),2.02–1.95(m,2H),1.76–1.67(m,2H),1.37–1.25(m,7H),1.15–1.00(m,4H),0.91(d,J＝6.8Hz,3H). 1 H NMR (400MHz, MeOD) δ7.74 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.58 (d, J = 2.3Hz, 1H), 7.35 (d, J = 2.8Hz, 1H), 7.19 (s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.11 (d, J = 2.8 Hz, 1H), 3.69 (s, 3H), 3.42 - 3.35 (m, 1H), 3.29 - 3.22 ( m,1H), 2.02–1.95 (m, 2H), 1.76–1.67 (m, 2H), 1.37–1.25 (m, 7H), 1.15–1.00 (m, 4H), 0.91 (d, J=6.8 Hz, 3H).
实施例123Example 123
4-(2-(环庚基氨基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备4-(2-(cycloheptylamino)-5-(propan-2-ylsulfinylimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3- c] Preparation of pyridin-7-one
Figure PCTCN2018072204-appb-000362
Figure PCTCN2018072204-appb-000362
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(35mg,0.07mmol)为反应原料，参考实施例23第一步，得到化合物4-(2-(环庚基氨基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(7.7mg，白色固体，产率25％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one (35 mg, 0.07 mmol) was used as the starting material of the reaction. The compound was obtained in the first step of Example 23 to give the compound 4-(2-(cycloheptylamino)-5-(propan-2-ylsulfonate) Imidyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (7.7 mg, white solid, yield 25%).
MS m/z(ESI):441.2[M+H] + MS m/z (ESI): 441.2 [M+H] +
1H NMR(400MHz,MeOD)δ7.75(dd,J＝8.8Hz,2.4Hz,1H),7.59(d,J＝2.3Hz,1H),7.35(d,J＝2.8Hz,1H),7.20(s,1H),6.80(d,J＝9.0Hz,1H),6.11(d,J＝2.8Hz,1H),3.70(s,3H),3.68–3.60(m,1H),3.30–3.25(m,1H),1.96–1.85(m,2H),1.64–1.36(m,10H),1.28(t,J＝7.1Hz,6H). 1 H NMR (400MHz, MeOD) δ7.75 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.59 (d, J = 2.3Hz, 1H), 7.35 (d, J = 2.8Hz, 1H), 7.20 (s, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.11 (d, J = 2.8 Hz, 1H), 3.70 (s, 3H), 3.68 - 3.60 (m, 1H), 3.30 - 3.25 ( m, 1H), 1.96–1.85 (m, 2H), 1.64–1.36 (m, 10H), 1.28 (t, J = 7.1 Hz, 6H).
实施例124Example 124
4-(2-(环丙基甲氧基)-5-((二乙基(羰基)-λ 6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮 4-(2-(cyclopropylmethoxy)-5-((diethyl(carbonyl)-λ 6 -sulfaninyl)amino)phenyl)-6-methyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000363
Figure PCTCN2018072204-appb-000363
以2-溴-1-(环丙基甲氧基)-4-碘苯与二乙基(亚氨基)-λ6-硫烷酮为起始原料，参考实施例19第五步至第七步反应条件，得到4-(2-(环丙基甲氧基)-5-((二乙基(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(75mg)。Taking 2-bromo-1-(cyclopropylmethoxy)-4-iodobenzene and diethyl(imino)-λ6-sulfanone as starting materials, refer to Example 19, Steps 5 to 7 The reaction conditions give 4-(2-(cyclopropylmethoxy)-5-((diethyl(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1,6 -Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (75 mg).
MS m/z(ESI):414.2[M+H]+.MS m/z (ESI): 414.2 [M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.95(br,1H),7.26(t,J＝2.8Hz,1H),7.24(s,1H),6.97(d,J＝2.4Hz,1H),6.92-6.85(m,2H),6.14(t,J＝2.8Hz,1H),3.73(d,J＝6.8Hz,2H),3.55(s,3H),3.23(q,J＝7.6Hz,4H),1.24(t,J＝7.6Hz,6H),1.08-0.85(m,1H),0.45-0.36(m,2H),0.24-0.15(m,2H). 1 H NMR (400MHz, DMSO- d6): δ11.95 (br, 1H), 7.26 (t, J = 2.8Hz, 1H), 7.24 (s, 1H), 6.97 (d, J = 2.4Hz, 1H) , 6.92-6.85 (m, 2H), 6.14 (t, J = 2.8 Hz, 1H), 3.73 (d, J = 6.8 Hz, 2H), 3.55 (s, 3H), 3.23 (q, J = 7.6 Hz, 4H), 1.24 (t, J = 7.6 Hz, 6H), 1.08-0.85 (m, 1H), 0.45-0.36 (m, 2H), 0.24-0.15 (m, 2H).
实施例125Example 125
4-(2-((2,2-二氟环丙基)甲氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((2,2-difluorocyclopropyl)methoxy)-5-(propan-2-ylsulfanilidinoyl)phenyl)-6-methyl-1,6-dihydro -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000364
Figure PCTCN2018072204-appb-000364
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例5第五步，用(2,2-二氟环丙基)甲醇替代环丙基甲醇，得到4-(2-((2,2-二氟环丙基)甲氧基)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(23.2mg,产率41％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 5, replacing the cyclopropylmethanol with (2,2-difluorocyclopropyl)methanol to give 4-(2-((2, 2-Difluorocyclopropyl)methoxy)-5-(propan-2-ylsulfinylimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3 -c]pyridine-7-one (23.2 mg, yield 41%).
MS m/z(ESI):436.1[M+H] +. MS m/z (ESI): 436.1 [M+H] + .
1H NMR(400MHz,CDCl3)δ11.17(br,1H),8.11–7.99(m,1H),7.99–7.87(m,1H),7.35–7.29(m,1H),7.15(s,1H),7.11–7.01(m,1H),6.32–6.17(m,1H),4.24–4.06(m,2H),3.74(s,3H),3.37–3.22(m,1H),2.05–1.88(m,1H),1.58–1.44(m,1H),1.44–1.27(m,6H),1.29–1.13(m,1H). 1 H NMR (400MHz, CDCl3) δ11.17 (br, 1H), 8.11-7.99 (m, 1H), 7.99-7.87 (m, 1H), 7.35-7.29 (m, 1H), 7.15 (s, 1H) , 7.11–7.01 (m, 1H), 6.32–6.17 (m, 1H), 4.24–4.06 (m, 2H), 3.74 (s, 3H), 3.37–3.22 (m, 1H), 2.05–1.88 (m, 1H), 1.58–1.44 (m, 1H), 1.44–1.27 (m, 6H), 1.29–1.13 (m, 1H).
实施例126Example 126
4-(2-((顺-4-羟基环己基)氧代)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-((cis-4-hydroxycyclohexyl)oxo)-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H- Pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000365
Figure PCTCN2018072204-appb-000365
以4-(2-氟-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡 咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例5第五步，用顺-1，4-环己二醇替代环丙基甲醇，得到4-(2-((顺-4-羟基环己基)氧代)-5-(丙烷-2-基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(2.0mg,产率5％)。4-(2-Fluoro-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one is the starting material of the reaction. Referring to the fifth step of Example 5, replacing cyclopropylmethanol with cis-1,4-cyclohexanediol to obtain 4-(2-((cis-4-) Hydroxycyclohexyl)oxo-5-(propan-2-ylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine- 7-ketone (2.0 mg, yield 5%).
MS m/z(ESI):444.1[M+H] +. MS m/z (ESI): 444.1 [M+H] + .
1H NMR(400MHz,CDCl3)δ10.36(br,1H),8.04-7.92(m,1H),7.92-7.81(m,1H),7.25-7.17(m,2H),7.16-7.11(m,1H),7.11-7.00(m,1H),6.29(br,1H),4.51(br,1H),3.79-3.71(m,1H),3.70(s,3H),3.43-3.32(m,1H),3.33-3.18(m,1H),2.08-1.98(m,2H),1.80-1.68(m,4H),1.55-1.41(m,2H),1.41-1.27(m,6H). 1 H NMR (400MHz, CDCl3) δ10.36 (br, 1H), 8.04-7.92 (m, 1H), 7.92-7.81 (m, 1H), 7.25-7.17 (m, 2H), 7.16-7.11 (m, 1H), 7.11-7.00 (m, 1H), 6.29 (br, 1H), 4.51 (br, 1H), 3.79-3.71 (m, 1H), 3.70 (s, 3H), 3.43-3.32 (m, 1H) , 3.33-3.18 (m, 1H), 2.08-1.98 (m, 2H), 1.80-1.68 (m, 4H), 1.55-1.41 (m, 2H), 1.41-1.27 (m, 6H).
实施例127Example 127
4-(5-(乙基磺亚胺酰基)-2-((四氢呋喃-3-基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfanimidoyl)-2-((tetrahydrofuran-3-yl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000366
Figure PCTCN2018072204-appb-000366
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用四氢呋喃-3-醇取代2,4-二氟苯酚，得到4-(5-(乙基磺亚胺酰基)-2-((四氢呋喃-3-基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率37％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, the 2,4-difluorophenol is substituted with tetrahydrofuran-3-ol to give 4-(5-(ethylsulfanimidoyl)-2- ((Tetrahydrofuran-3-yl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield 37%).
MS m/z(ESI):402.1[M+H] +； MS m/z (ESI): 4021. [M+H] +
1H NMR(400MHz,CDCl 3):δ10.80(s,1H),8.02(d,J＝2.4Hz,1H),7.96-7.93(dd,J＝8.8Hz,2.4Hz,1H),7.29-7.26(dd,J＝7.2,2.4Hz,1H),7.08(s,1H),7.02-7.00(d,J＝8.8Hz,1H),6.21(s,1H),5.03-5.00(m,1H),4.03-3.99(m,1H),3.90-3.83(m,3H),3.80(s,3H),3.25(q,J＝7.2Hz,2H),2.23-2.18(m,1H),2.05-2.03(m,1H),1.32(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ10.80 (s, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.96-7.93 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.29- 7.26 (dd, J = 7.2, 2.4 Hz, 1H), 7.08 (s, 1H), 7.02-7.00 (d, J = 8.8 Hz, 1H), 6.21 (s, 1H), 5.03-5.00 (m, 1H) , 4.03-3.99 (m, 1H), 3.90-3.83 (m, 3H), 3.80 (s, 3H), 3.25 (q, J = 7.2 Hz, 2H), 2.23-2.18 (m, 1H), 2.05-2.03 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H).
实施例128Example 128
4-(2-(4-溴-3-氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(4-Bromo-3-fluorophenoxy)-5-(ethylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 ,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000367
Figure PCTCN2018072204-appb-000367
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用4-溴-2-氟苯酚取代2,4-二氟苯酚，得到4-(2-(4-溴-3-氟苯氧基)-5-(乙基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H- 吡咯并[2,3-c]吡啶-7-酮(产率18％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting 4-bromo-2-fluorophenol for 2,4-difluorophenol gives 4-(2-(4-bromo-3-fluoro) Phenoxy)-5-(ethylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (yield 18%).
MS m/z(ESI):504.1/506.1(50/50)[M+H] +. MS m/z (ESI): 504.1 / 506.1 (50 / 50) [M+H] + .
1H NMR(400MHz,d4-MeOD):δ8.14(d,J＝2.8Hz,1H),8.04-8.01(dd,J＝8.8Hz,2.4Hz,1H),7.53-7.48(m,1H),7.32-7.27(m,3H),6.90-6.87(dd,J＝9.6,2.8Hz,1H),6.74-6.71(m,1H),6.25(d,J＝3.2Hz,1H),3.87(q,J＝7.2Hz,2H),3.58(s,3H),1.32(t,J＝7.2Hz,3H) 1 H NMR (400MHz, d4- MeOD): δ8.14 (d, J = 2.8Hz, 1H), 8.04-8.01 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53-7.48 (m, 1H) , 7.32 - 7.27 (m, 3H), 6.90-6.87 (dd, J = 9.6, 2.8 Hz, 1H), 6.74 - 6.71 (m, 1H), 6.25 (d, J = 3.2 Hz, 1H), 3.87 (q , J=7.2Hz, 2H), 3.58(s, 3H), 1.32 (t, J=7.2Hz, 3H)
实施例129Example 129
4-(5-(环丙磺亚胺酰基)-2-((2,2-二氟环丁基)甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropanesulfonyl)-2-((2,2-difluorocyclobutyl)methoxy)phenyl)-6-methyl-1,6-dihydro-7H- Pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000368
Figure PCTCN2018072204-appb-000368
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用(2,2-二氟环丙基)甲醇取代2,4-二氟苯酚，得到4-(5-(环丙磺亚胺酰基)-2-((2,2-二氟环丁基)甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率52％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, the 2,4-difluorophenol is replaced with (2,2-difluorocyclopropyl)methanol to give 4-(5-(cyclopropanesulfonate). Imidyl)-2-((2,2-difluorocyclobutyl)methoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c] Pyridine-7-one (yield 52%).
MS m/z(ESI):436.1[M+H] +. MS m/z (ESI): 436.1 [M+H] + .
1H NMR(400MHz,CDCl 3):δ10.51(s,1H),8.01(d,J＝2.4Hz,1H),7.98-7.95(dd,J＝8.8Hz,2.4Hz,1H),7.27(d,J＝2.8Hz,1H),7.11-7.09(m,2H),6.17(t,J＝2.4Hz,1H),4.09(d,J＝4.2Hz,2H),3.70(s,3H),3.27(q,J＝7.2Hz,2H),2.57-2.48(m,3H),2.37-2.27(m,2H),1.30(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 10.51 (s, 1H), 8.1 (d, J = 2.4 Hz, 1H), 7.98 - 7.95 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.27 ( d, J = 2.8 Hz, 1H), 7.11 - 7.09 (m, 2H), 6.17 (t, J = 2.4 Hz, 1H), 4.09 (d, J = 4.2 Hz, 2H), 3.70 (s, 3H), 3.27 (q, J = 7.2 Hz, 2H), 2.57-2.48 (m, 3H), 2.37-2.27 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H).
实施例130Example 130
4-(5-(乙基磺亚胺酰基)-2-(2-氟-4-甲氧基苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfanimido)-2-(2-fluoro-4-methoxyphenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000369
Figure PCTCN2018072204-appb-000369
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用4-甲氧基-2-氟苯酚取代2,4-二氟苯酚，得到4-(5-(乙基磺亚胺酰基)-2-(2-氟-4-甲氧基苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率21％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c Pyridine-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting 4-methoxy-2-fluorophenol for 2,4-difluorophenol gives 4-(5-(ethylsulfonimide). Acyl)-2-(2-fluoro-4-methoxyphenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Ketone (yield 21%).
MS m/z(ESI):456.1[M+H] +； MS m/z (ESI): 456.1 [M+H] +
1H NMR(400MHz,d4-MeOD):δ8.11(d,J＝2.4Hz,1H),8.00-7.97(dd,J＝8.8Hz, 2.4Hz,1H),7.36(s,1H),7.28(d,J＝2.8Hz,1H),7.08-7.02(m,2H),6.85-6.81(dd,J＝12.4Hz,2.8Hz,1H),6.74-6.71(m,1H),6.29(d,J＝3.2Hz,1H),3.97(q,J＝7.2Hz,2H),3.72(s,3H),3.64(s,3H),1.32(t,J＝7.2Hz,3H)。 1 H NMR (400MHz, d4- MeOD): δ8.11 (d, J = 2.4Hz, 1H), 8.00-7.97 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36 (s, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.08-7.02 (m, 2H), 6.85-6.81 (dd, J = 12.4 Hz, 2.8 Hz, 1H), 6.74-6.71 (m, 1H), 6.29 (d, J = 3.2 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.64 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).
实施例131Example 131
4-(2-(2,4-二氟苯氧基)-5-((乙基(甲基)(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-difluorophenoxy)-5-((ethyl(methyl)(carbonyl)-λ6-sulfaninyl)amino)phenyl)-6-methyl-1 ,6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000370
Figure PCTCN2018072204-appb-000370
第一步:(甲基亚硫酰基<亚磺酰>)乙烷的制备First step: Preparation of (methylsulfinyl <sulfinyl) ethane
Figure PCTCN2018072204-appb-000371
Figure PCTCN2018072204-appb-000371
反应操作同实施例五第一步，得到(甲基亚硫酰基<亚磺酰>)乙烷(2.25g)。The reaction was carried out in the same manner as in the first step of Example 5 to give (methylsulfinyl <sulfinyl) ethane (2.25 g).
第二步:乙基(亚氨基)(甲基)-λ6-硫烷酮的制备Step 2: Preparation of ethyl (imino)(methyl)-λ6-sulfanone
Figure PCTCN2018072204-appb-000372
Figure PCTCN2018072204-appb-000372
反应操作同实施例五第二步，得到乙基(亚氨基)(甲基)-λ6-硫烷酮(1.5g)。The reaction was carried out in the same manner as in the second step of Example 5 to give ethyl (imino)(methyl)- </RTI> <RTIgt;
第三步至第五步:4-(2-(2,4-二氟苯氧基)-5-((乙基(甲基)(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Steps 3 to 5: 4-(2-(2,4-difluorophenoxy)-5-((ethyl(methyl)(carbonyl)-λ6-sulfaninyl)amino)phenyl Preparation of 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Figure PCTCN2018072204-appb-000373
Figure PCTCN2018072204-appb-000373
以2-溴-1-(2,4-二氟苯氧基)-4-碘苯与乙基(亚氨基)(甲基)-λ6-硫烷酮为原料，反应操作参考实施例19第五至七步，得到4-(2-(2,4-二氟苯氧基)-5-((乙基(甲基)(羰基)-λ6-硫烷亚基)氨基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(三步总收率11.8％)。2-bromo-1-(2,4-difluorophenoxy)-4-iodobenzene and ethyl(imino)(methyl)-λ6-sulfanone were used as starting materials, and the reaction operation was carried out in Reference Example 19 Five to seven steps to give 4-(2-(2,4-difluorophenoxy)-5-((ethyl(methyl)(carbonyl)-λ6-sulfaninyl)amino)phenyl)- 6-Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (three-step total yield 11.8%).
MS m/z(ESI):458.1[M+H]+.MS m/z (ESI): 458.1 [M+H]+.
1H NMR(400MHz,DMSO-d6):δ12.0(br,1H),7.35-7.25(m,3H)，7.06(s,1H),6.98-6.91(m,3H),6.81(d,J＝8.4Hz,1H),6.22(t,J＝2.0Hz,1H),3.52(s,3H),3.36(q,J＝7.2Hz,2H),3.12(s,3H),1.30(t,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO- d6): δ12.0 (br, 1H), 7.35-7.25 (m, 3H), 7.06 (s, 1H), 6.98-6.91 (m, 3H), 6.81 (d, J = 8.4 Hz, 1H), 6.22 (t, J = 2.0 Hz, 1H), 3.52 (s, 3H), 3.36 (q, J = 7.2 Hz, 2H), 3.12 (s, 3H), 1.30 (t, J) =7.2Hz, 3H).
实施例132Example 132
4-(5-(环丙磺亚胺酰基)-2-((2,2-二氟环丙基)甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(cyclopropaneimidoyl)-2-((2,2-difluorocyclopropyl)methoxy)phenyl)-6-methyl-1,6-dihydro-7H- Pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000374
Figure PCTCN2018072204-appb-000374
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例5第五步，用(2,2-二氟环丙基)甲醇替代环丙基甲醇,得到4-(5-(环丙磺亚胺酰基)-2-((2,2-二氟环丙基)甲氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(43％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one as a starting material, referring to the fifth step of Example 5, replacing cyclopropylmethanol with (2,2-difluorocyclopropyl)methanol to give 4-(5-(cyclopropaneimidoyl) -2-((2,2-Difluorocyclopropyl)methoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Ketone (43%).
MS m/z(ESI):434.2[M+H] +； MS m/z (ESI): 434.2 [M+H] +
1H NMR(400MHz,CDCl 3):δ7.89-7.87(m,2H),7.17-7.12(m,2H),7.05(s,1H),6.17(d,J＝2.8Hz,1H),5.09-5.04(m,1H),4.28-4.23(m,1H),3.60(s,3H),2.58-2.52(m,1H),2.31-2.22(m,1H),1.52-0.98(m,6H). 1 H NMR (400MHz, CDCl 3 ): δ7.89-7.87 (m, 2H), 7.17-7.12 (m, 2H), 7.05 (s, 1H), 6.17 (d, J = 2.8Hz, 1H), 5.09 -5.04 (m, 1H), 4.28-4.23 (m, 1H), 3.60 (s, 3H), 2.58-2.52 (m, 1H), 2.31-2.22 (m, 1H), 1.52-0.98 (m, 6H) .
实施例133Example 133
4-(5-(环丙磺亚胺酰基)-2-((四氢-2H-吡喃-4-基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(Cyclopropioni)-2-((tetrahydro-2H-pyran-4-yl)oxo)phenyl)-6-methyl-1,6-dihydro-7H -pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000375
Figure PCTCN2018072204-appb-000375
以4-(5-(环丙磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例5第五步，得到4-(5-(环丙磺亚胺酰基)-2-((四氢-2H-吡喃-4-基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(48％)。4-(5-(cyclopropaneimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one as a starting material, referring to the fifth step of Example 5, to give 4-(5-(cyclopropylsulfinyl)-2-((tetrahydro-2H-pyran-4-yl)oxo Phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (48%).
MS m/z(ESI):428.2[M+H]+MS m/z (ESI): 428.2 [M+H]+
1H NMR(400MHz,CDCl 3):δ10.81(s,1H),8.03(d,J＝2.4Hz,1H),7.95-7.92(dd,J＝8.8Hz,2.4Hz,1H),7.29-7.26(t,J＝2.4Hz,1H),7.10(s,1H),7.10-7.08(d,J＝8.8Hz,1H),6.26(t,J＝2.4Hz,1H),4.62(t,J＝3.6Hz,1H),3.80-3.73(m,5H),3.54-3.45(m,2H),2.65-2.62(m,2H),1.99-1.95(m,2H),1.72-1.68(m,2H),1.42-0.98(m,4H)。 1 H NMR (400MHz, CDCl 3 ): δ10.81 (s, 1H), 8.03 (d, J = 2.4Hz, 1H), 7.95-7.92 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.29- 7.26 (t, J = 2.4 Hz, 1H), 7.10 (s, 1H), 7.10-7.08 (d, J = 8.8 Hz, 1H), 6.26 (t, J = 2.4 Hz, 1H), 4.62 (t, J = 3.6 Hz, 1H), 3.80-3.73 (m, 5H), 3.54-3.45 (m, 2H), 2.65-2.62 (m, 2H), 1.99-1.95 (m, 2H), 1.72-1.68 (m, 2H) ), 1.42 - 0.98 (m, 4H).
实施例134Example 134
4-(2-(顺-4-羟基环己基)氧代)-5-(S-甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(cis-4-hydroxycyclohexyl)oxo)-5-(S-methylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000376
Figure PCTCN2018072204-appb-000376
4-(5-(S-甲基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为反应原料，参考实施例10第五步，用顺-1,4-二羟基环己烷替代2,4-二氟苯酚，得到4-(2-(顺-4-羟基环己基)氧代)-5-(甲基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率10％.)4-(5-(S-methylsulfamidyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3- c] Pyridin-7-one is the starting material for the reaction. Referring to the fifth step of Example 10, substituting cis-1,4-dihydroxycyclohexane for 2,4-difluorophenol gives 4-(2-(cis-4) -hydroxycyclohexyl)oxo-5-(methylsulfanimidoyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Ketone (yield 10%.)
MS m/z(ESI):416[M+H] +. MS m/z (ESI): 416 [M+H] + .
1H NMR(400MHz,DMSO):δ12.04(br,1H),7.85(d,J＝2.4Hz,1H),7.75(d,J＝8.4Hz,2.4Hz,1H),7.28(s,1H),7.25-7.22(m,2H),6.13(d,J＝2.4Hz,1H),4.57-4.52(br,1H),4.42-4.32(br,1H),4.0(s,1H),3.51(s,3H),3.48-3.45(m,1H),3.0(s,3H),1.77-1.69(m,2H),1.55-1.39(m,4H),1.33-1.21(m,2H). 1 H NMR (400MHz, DMSO) : δ12.04 (br, 1H), 7.85 (d, J = 2.4Hz, 1H), 7.75 (d, J = 8.4Hz, 2.4Hz, 1H), 7.28 (s, 1H ), 7.25-7.22 (m, 2H), 6.13 (d, J = 2.4 Hz, 1H), 4.57-4.52 (br, 1H), 4.42-4.32 (br, 1H), 4.0 (s, 1H), 3.51 ( s, 3H), 3.48-3.45 (m, 1H), 3.0 (s, 3H), 1.77-1.69 (m, 2H), 1.55-1.39 (m, 4H), 1.33-1.21 (m, 2H).
实施例135Example 135
4-(5-(乙基磺亚胺酰基)-2-((4-羟基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-((4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, 3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000377
Figure PCTCN2018072204-appb-000377
将化合物4-(5-(乙基磺亚胺酰基)-2-((4-羰基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(42.8mg,0.1mmol)溶于10毫升二氯甲烷中，冰水浴下加入硼氢化钠(12mg,0.3mmol)。反应在室温条件下搅拌2小时。减压条件下除去溶剂，残余物用乙酸乙酯/水分液萃取，有机相经过干燥，浓缩，制备TLC板分离(二氯甲烷/甲醇＝20:1)得到化合物4-(5-(乙基磺亚胺酰基)-2-((4-羟基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(21mg,49％)。The compound 4-(5-(ethylsulfimidoyl)-2-((4-carbonylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one (42.8 mg, 0.1 mmol) was dissolved in dichloromethane (10 mL). The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified ethyl acetate /jjjjjjjjjjjjjjjjjjjjjjjjjjjj Sulfimido)-2-((4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7- Ketone (21 mg, 49%).
MS m/z(ESI):430.1[M+H] +； MS m/z (ESI): 430.1 [M+H] +
1H NMR(400MHz,d4-MeOD):δ7.88-7.80(m,2H),7.25-7.16(m,3H),6.19-6.13(m,1H),4.56-4.44(m,1H),3.61-3.59(m,3H),3.55-3.49(m,1H),3.19-3.13(m,2H),1.98-1.29(m,8H),1.19-1.12(m,3H). 1 H NMR (400MHz, d4- MeOD): δ7.88-7.80 (m, 2H), 7.25-7.16 (m, 3H), 6.19-6.13 (m, 1H), 4.56-4.44 (m, 1H), 3.61 -3.59 (m, 3H), 3.55-3.49 (m, 1H), 3.19-3.13 (m, 2H), 1.98-1.29 (m, 8H), 1.19-1.12 (m, 3H).
实施例136Example 136
4-(5-(乙基磺亚胺酰基)-2-((4-羟基-4-甲基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-((4-hydroxy-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H- Pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000378
Figure PCTCN2018072204-appb-000378
将化合物4-(5-(乙基磺亚胺酰基)-2-((4-羰基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(42.8mg,0.1mmol)溶于10毫升无水四氢呋喃中，-78℃条件下滴入1M浓度的甲基格式试剂四氢呋喃溶液(0.15mL,0.15mmol)。 反应自然升温至室温并搅拌过夜。饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，有机相经过干燥，浓缩，制备TLC板分离(二氯甲烷/甲醇＝20:1)得到化合物4-(5-(乙基磺亚胺酰基)-2-((4-羟基-4-甲基环己基)氧代)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(10.5mg,49％)The compound 4-(5-(ethylsulfimidoyl)-2-((4-carbonylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[ 2,3-c]pyridine-7-one (42.8 mg, 0.1 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran, and a solution of 1 M concentration of methyl reagent in tetrahydrofuran (0.15 mL, 0.15 mmol) was added dropwise at -78 °C. . The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate. The organic phase was dried and concentrated to give a TLC plate (dichloromethane/methanol = 20:1) to give the compound 4-(5-(ethylsulfanilide) )-2-((4-hydroxy-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7 -ketone (10.5 mg, 49%)
MS m/z(ESI):444.2[M+H] +； MS m/z (ESI): 444.2 [M+H] +
1H NMR(400MHz,d4-MeOD):δ7.85-7.80(m,2H),7.24-7.16(m,3H),6.16-6.14(m,1H),4.63-4.38(m,1H),3.60(s,3H),3.55-3.49(m,1H),3.18-3.14(m,2H),1.82-1.35(m,7H),1.17-1.13(m,3H),1.01-0.83(m,3H). 1 H NMR (400MHz, d4- MeOD): δ7.85-7.80 (m, 2H), 7.24-7.16 (m, 3H), 6.16-6.14 (m, 1H), 4.63-4.38 (m, 1H), 3.60 (s, 3H), 3.55-3.49 (m, 1H), 3.18-3.14 (m, 2H), 1.82-1.35 (m, 7H), 1.7-1.13 (m, 3H), 1.01-0.83 (m, 3H) .
实施例137Example 137
4-(2-(2,4-二氟苯氧基)-5-(4-甲基苯基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(2-(2,4-Difluorophenoxy)-5-(4-methylphenylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000379
Figure PCTCN2018072204-appb-000379
第一步：(3-溴-4-氟苯基)(p-苯甲基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(p-benzyl)sulfane
Figure PCTCN2018072204-appb-000380
Figure PCTCN2018072204-appb-000380
在氩气气氛下，4-甲基苯硫酚(651mg,5.25mmol)，2-溴-1-氟-4-碘苯(1.5g,5mmol)，氧化亚铜(36mg,0.25mmol)，氢氧化钾(560mg,10mmol)和30毫升1,4-二氧六环加入圆底瓶中，反应加热至回流搅拌过夜。反应用水稀释，硅藻土过滤出去参与的铜催化剂，滤液用乙酸乙酯萃取三遍。合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥。滤去干燥剂，滤液旋干。残余物硅胶柱层析分离(石油醚：乙酸乙酯＝2:1)得到(3-溴-4-氟苯基)(p-苯甲基)硫烷(1.1g,74％)。4-methylthiophenol (651 mg, 5.25 mmol), 2-bromo-1-fluoro-4-iodobenzene (1.5 g, 5 mmol), cuprous oxide (36 mg, 0.25 mmol), hydrogen under argon atmosphere Potassium oxide (560 mg, 10 mmol) and 30 ml of 1,4-dioxane were added to a round bottom flask and the reaction was heated to reflux and stirred overnight. The reaction was diluted with water, the celite was filtered to remove the copper catalyst, and the filtrate was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was dried. The residue was subjected to EtOAcjjjjjjjjjjj
第二步：2-溴-1-氟-4-(p-苯甲基亚硫酰基<亚磺酰>)苯的制备Second step: Preparation of 2-bromo-1-fluoro-4-(p-benzylsulfinyl <sulfinyl) benzene
Figure PCTCN2018072204-appb-000381
Figure PCTCN2018072204-appb-000381
以(3-溴-4-氟苯基)(p-苯甲基)硫烷为反应原料，参考实施例74第二步，得到2-溴-1-氟-4-(p-苯甲基亚硫酰基<亚磺酰>)苯(产率95％)。Using (3-bromo-4-fluorophenyl)(p-benzyl)sulfane as the starting material, referring to the second step of Example 74, 2-bromo-1-fluoro-4-(p-benzyl) was obtained. Thionyl <sulfinyl>)benzene (yield 95%).
MS m/z(ESI):313.0/315.0(50/50)[M+H] + MS m/z (ESI): 313.0/315.0 (50/50) [M+H] +
第三步：(3-溴-4-氟苯基)(亚氨基)(p-苯甲基)-l6-硫烷酮的制备Third step: Preparation of (3-bromo-4-fluorophenyl)(imino)(p-benzyl)-l6-sulfanone
Figure PCTCN2018072204-appb-000382
Figure PCTCN2018072204-appb-000382
以1-((3-溴-4-氟苯基)亚硫酰基<亚磺酰>)-2-甲基丙烷-2-醇为原料，参考实施例74第三步，得到(3-溴-4-氟苯基)(亚氨基)(p-苯甲基)-l6-硫烷酮(产率63％)。Using 1-((3-bromo-4-fluorophenyl)sulfinyl <sulfinyl])-2-methylpropan-2-ol as the starting material, refer to the third step of Example 74 to obtain (3-bromo) 4-fluorophenyl)(imino)(p-benzyl)-l6-sulfanone (yield 63%).
MS m/z(ESI):328.0/330.0(50/50)[M+H] +. MS m/z (ESI): 328.0 / 330.0 (50 / 50) [M+H] + .
第四步：4-(2-氟-5-(4-甲基苯基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Fourth step: 4-(2-Fluoro-5-(4-methylphenylsulfinamido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrole Preparation of [2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000383
Figure PCTCN2018072204-appb-000383
以(3-溴-4-氟苯基)(亚氨基)(p-苯甲基)-l6-硫烷酮为原料，参考实施例74第四步得到4-(2-氟-5-(4-甲基苯基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(产率67％)Using (3-bromo-4-fluorophenyl)(imino)(p-benzyl)-l6-sulfanone as the starting material, the fourth step of Example 74 was obtained to obtain 4-(2-fluoro-5-( 4-methylphenylsulfonimido)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one ( Yield 67%)
MS m/z(ESI):550.1[M+H] + MS m/z (ESI): 550.1 [M+H] +
第六步：4-(2-(2,4-二氟苯氧基)-5-(4-甲基苯基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮的制备Step 6: 4-(2-(2,4-Difluorophenoxy)-5-(4-methylphenylsulfimidoyl)phenyl)-6-methyl-1,6-dihydro Preparation of -7H-pyrrolo[2,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000384
Figure PCTCN2018072204-appb-000384
以4-(2-氟-5-(4-甲基苯基磺亚胺酰基)苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮与2,4-二氟苯酚为反应原料，参考实施例10第五步，得到4-(2-(2,4-二氟苯氧基)-5-(4-甲基苯基磺亚胺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(52％)。4-(2-Fluoro-5-(4-methylphenylsulfimidoyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2 , 3-c]pyridine-7-one and 2,4-difluorophenol as the starting materials for the reaction, referring to the fifth step of Example 10, to obtain 4-(2-(2,4-difluorophenoxy)-5- (4-Methylphenylsulfonimido)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (52%).
MS m/z(ESI):506.1[M+H] +； MS m/z (ESI): 506.1 [M+H] + ;
1H NMR(400MHz,d6-DMSO)δ12.10(brs,1H),8.01(d,J＝2.8Hz,1H),7.85(d,J＝8.4Hz,3H),7.51-7.45(m,1H),7.37-7.34(m,5H),7.15-7.10(m,1H)6.88(d,J＝8.8Hz,1H),6.19(t,J＝2.4Hz,1H),4.90(s,1H),3.57(s,3H),2.34(s,3H). 1 H NMR (400MHz, d6- DMSO) δ12.10 (brs, 1H), 8.01 (d, J = 2.8Hz, 1H), 7.85 (d, J = 8.4Hz, 3H), 7.51-7.45 (m, 1H ), 7.37-7.34 (m, 5H), 7.15-7.10 (m, 1H) 6.88 (d, J = 8.8 Hz, 1H), 6.19 (t, J = 2.4 Hz, 1H), 4.90 (s, 1H), 3.57 (s, 3H), 2.34 (s, 3H).
实施例138Example 138
4-(5-(乙基磺亚胺酰基)-2-(3-(羟甲基)苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮4-(5-(ethylsulfimidoyl)-2-(3-(hydroxymethyl)phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 ,3-c]pyridine-7-one
Figure PCTCN2018072204-appb-000385
Figure PCTCN2018072204-appb-000385
以4-(5-(乙基磺亚胺酰基)-2-氟苯基)-6-甲基-1-甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮为原料，参考实施例10第五步，以3-羟甲基苯酚替代2,4-二氟苯酚，得到4-(5-(乙基磺亚胺酰基)-2-(3-(羟甲基)苯氧基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(收率：8％)。4-(5-(ethylsulfanimido)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c ] Pyridin-7-one as a starting material, referring to the fifth step of Example 10, replacing 2,4-difluorophenol with 3-hydroxymethylphenol to give 4-(5-(ethylsulfanimidoyl)-2- (3-(Hydroxymethyl)phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (yield: 8%) ).
MS m/z(ESI):438.1[M+H] +； MS m/z (ESI): 438.1 [M+H] +
1H NMR(400MHz,d4-MeOD)δ7.98(d,J＝2.0Hz,1H),7.81(dd,J＝8.8Hz,2.4Hz,1H),7.25-7.19(m,3H),7.06-7.00(m,2H),6.90(s,1H),6.78(d,J＝9.6Hz,1H),6.28(d,J＝3.2Hz,1H),4.45(s,2H),3.56(s,3H),3.18(q,J＝7.6Hz,2H),1.17(t,J＝7.6Hz,3H). 1 H NMR (400MHz, d4- MeOD) δ7.98 (d, J = 2.0Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.25-7.19 (m, 3H), 7.06- 7.00 (m, 2H), 6.90 (s, 1H), 6.78 (d, J = 9.6 Hz, 1H), 6.28 (d, J = 3.2 Hz, 1H), 4.45 (s, 2H), 3.56 (s, 3H) ), 3.18 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).
生物学评价Biological evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The invention is further described below in conjunction with the test examples, but these examples are not intended to limit the scope of the invention.
测试例1、本发明化合物对BRD4结合活性的测定Test Example 1. Determination of binding activity of BRD4 by the compound of the present invention
BRD4结合活性测试通过以下的方法进行测试。The BRD4 binding activity test was tested by the following method.
该方法用来测定本发明中的化合物对BRD4结合活性的抑制作用。This method was used to determine the inhibitory effect of the compounds of the present invention on BRD4 binding activity.
实验步骤Experimental procedure
为了测试化合物对BRD4于乙酰化蛋白结合的的影响，本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对BRD4与乙酰化底物结合活性的抑制作用，并得出化合物对BRD4结合活性的半数抑制浓度IC 50。 In order to test the effect of compounds on the binding of BRD4 to acetylated proteins, this experiment used fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effect of compounds on the binding activity of BRD4 to acetylated substrates, and to obtain the binding of compounds to BRD4. The half-inhibitory concentration of activity is IC 50 .
具体实验操作如下：The specific experimental operation is as follows:
1、在384孔板中加入1～5ul BRD4酶溶液，酶终浓度为1～20nM；1. Add 1 to 5 ul of BRD4 enzyme solution to the 384-well plate, and the final concentration of the enzyme is 1 to 20 nM;
2、加入1～5ul梯度稀释好的化合物溶液；2. Add 1 to 5 ul of the gradient diluted compound solution;
3、加入1～5ul底物混合液包含乙酰化底物多肽终浓度2～50nM；3, adding 1 ~ 5ul substrate mixture containing acetylated substrate polypeptide final concentration of 2 ~ 50nM;
4、室温孵育0.5～3小时；4. Incubate for 0.5 to 3 hours at room temperature;
5、加入10ul EDTA和含标记抗体的检测液，室温孵育1小时；5. Add 10 ul of EDTA and the labeled antibody-containing test solution, incubate for 1 hour at room temperature;
6、酶标仪测定各板孔的665nm荧光信号值；6. The 665 nm fluorescence signal value of each plate hole was measured by a microplate reader;
7、通过荧光信号值计算抑制率；7. Calculate the inhibition rate by the fluorescence signal value;
8、根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 8. A compound according to obtain IC 50 inhibition rate of different concentration by curve fitting.
本发明中化合物对BRD4结合活性通过以上的试验进行测定，测得的IC 50值见表1。 The BRD4 binding activity of the compounds of the present invention was determined by the above test, and the measured IC 50 values are shown in Table 1.
表1本发明中化合物对BRD4结合活性抑制IC 50 Table 1 Inhibition of BRD4 Binding Activity by Compounds of the Invention IC 50
实施例编号Example number IC 50(nM) IC 50 (nM) 实施例编号Example number IC 50(nM) IC 50 (nM)
11 17.717.7 6767 16.316.3
22 13.813.8 6868 5.35.3
33 27.427.4 6969 13.213.2
44 30.430.4 7070 12.412.4
55 8.98.9 7171 7.47.4
66 8.08.0 7272 12.812.8
77 11.511.5 7373 9.79.7
88 31.231.2 7474 1010
99 20.920.9 7575 9.09.0
1010 5.95.9 7676 2.42.4
1111 20.420.4 7777 14.614.6
1212 18.418.4 7878 22.522.5
1414 24twenty four 7979 1.71.7
1515 6.26.2 8080 10.310.3
1616 20.420.4 8181 15.415.4
1717 33.233.2 8282 18.718.7
1818 37.237.2 8383 4.74.7
1919 3.03.0 8484 11.211.2
2020 11.111.1 8585 16.816.8
22twenty two 12.612.6 8686 7.77.7
23twenty three 14.614.6 8787 6.46.4
24twenty four 17.217.2 8888 29.129.1
2525 8.78.7 9191 16.216.2
2626 8.58.5 9292 29.529.5
2727 11.911.9 9393 5.55.5
2828 12.112.1 94-顺式/反式94-cis/trans 5.15.1
2929 22.922.9 94-反式/顺式94-trans/cis 9.39.3
3030 16.416.4 9595 10.210.2
3131 27.427.4 9696 12.012.0
3232 8.98.9 9797 14.014.0
3333 12.712.7 9898 11.711.7
34S34S 5.15.1 9999 19.319.3
34R34R 7.37.3 100100 13.613.6
3535 13.713.7 103103 14.814.8
3838 21.521.5 104104 20.920.9
3939 11.011.0 107107 17.717.7
40R40R 16.716.7 108108 12.512.5
4141 14.914.9 109109 26.226.2
4242 11.511.5 110110 10.910.9
4343 6.16.1 111111 6.36.3
4444 10.210.2 112112 16.116.1
4545 8.38.3 113113 13.913.9
4646 22.422.4 114114 8.88.8
4747 14.314.3 115115 20.720.7
4848 6.56.5 116116 15.015.0
4949 2020 117117 17.417.4
5050 21.921.9 118118 12.412.4
5151 11.911.9 119119 16.016.0
5252 11.211.2 121121 6.96.9
5353 22.022.0 122122 5.25.2
5454 18.118.1 123123 5.85.8
5555 15.515.5 124124 13.513.5
56S56S 3.83.8 125125 25.525.5
56R56R 5.05.0 126126 15.715.7
5757 11.311.3 127127 27.127.1
58S58S 5.85.8 128128 33.833.8
58R58R 8.28.2 129129 24.224.2
5959 24.324.3 130130 10.710.7
6060 9.79.7 131131 4.24.2
6161 10.310.3 132132 36.936.9
6262 13.513.5 133133 15.215.2
6363 11.811.8 134134 25.525.5
6464 18.818.8 135135 1.71.7
6565 16.116.1 136136 2.22.2
6666 8.88.8    
结论：本发明化合物对BRD4结合活性具有明显的抑制作用。Conclusion: The compounds of the present invention have a significant inhibitory effect on BRD4 binding activity.
测试例2、本发明化合物对结肠癌肿瘤细胞colo205增殖活性的测定Test Example 2: Determination of Proliferative Activity of Colon Cancer Cell Colo205 by Compounds of the Invention
化合物对结肠癌肿瘤细胞colo205增殖活性通过以下的方法进行测试。The compound's proliferative activity against colon cancer tumor cell colo205 was tested by the following method.
该方法用来测定本发明中的化合物对结肠癌肿瘤细胞colo205增殖活性的抑制作用。This method was used to determine the inhibitory effect of the compound of the present invention on the proliferative activity of colon cancer tumor cell colo205.
实验步骤Experimental procedure
本实验采用CellTiter-Glo的方法测试化合物对colo205细胞增殖的抑制作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50。 The method of the present study, the inhibition of a test compound on the colo205 CellTiter-Glo cell proliferation, and to obtain the compound inhibited cell proliferation half maximal inhibitory concentration IC 50 activity.
1、在96孔细胞培养板中接种50～100μL的colo205细胞悬液，密度为1～5*104细胞/ml，将培养板于培养箱培养16～24小时(37℃，5％CO 2)。 1. Inoculate 50-100 μL of colo205 cell suspension in a 96-well cell culture plate at a density of 1 to 5*104 cells/ml. Incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5% CO 2 ). .
2、向培养板细胞中加入梯度稀释的不同浓度的待测化合物溶液，将培养板在培养箱孵育6天(37℃，5％CO 2)。 2. Add gradient dilutions of different concentrations of the test compound solution to the culture plate cells, and incubate the culture plates in the incubator for 6 days (37 ° C, 5% CO 2 ).
3、每孔加入50～100μL CellTiter-Glo试剂，并振荡10分钟，室温静置10分钟。3. Add 50-100 μL of CellTiter-Glo reagent to each well, shake for 10 minutes, and let stand for 10 minutes at room temperature.
4、酶标仪测定各板的化学发光信号值。4. The plate reader measures the chemiluminescence signal value of each plate.
5、通过化学发光信号值计算抑制率。5. Calculate the inhibition rate by the value of the chemiluminescence signal.
6、根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 6, obtained according to compound IC 50 inhibition rate of different concentration by curve fitting.
本发明中化合物对结肠癌肿瘤细胞colo205增殖活性的试验进行测定，测得的IC 50值见表2。 The compound of the present invention was assayed for the proliferative activity of colon cancer tumor cell colo205, and the measured IC 50 values are shown in Table 2.
表2本发明中化合物对结肠癌肿瘤细胞colo205增殖活性抑制IC 50 Table Compound colo205 proliferation of colon cancer cells were inhibition IC 50 in the present invention
实施例编号Example number IC 50(nM) IC 50 (nM)
55 11.711.7
66 39.439.4
77 5.35.3
1515 33.833.8
1919 10.010.0
2020 29.129.1
22twenty two 9.79.7
2525 10.810.8
2626 16.516.5
2727 16.816.8
56S56S 7.67.6
58S58S 25.425.4
6464 22.022.0
7474 15.015.0
7676 2.12.1
8686 19.619.6
9292 4.64.6
94-顺式/反式94-cis/trans 1.41.4
94-反式/顺式94-trans/cis 26.826.8
9595 18.318.3
103103 18.918.9
131131 5.15.1
135135 29.629.6
136136 22.022.0
结论：本发明化合物对结肠癌肿瘤细胞colo205增殖活性具有明显的抑制作用。Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation activity of colon cancer tumor cell colo205.
测试例3、本发明化合物对白血病细胞MV4-11增殖活性的影响Test Example 3, Effect of the Compound of the Invention on Proliferative Activity of Leukemia Cell Line MV4-11
化合物对白血病细胞MV4-11增殖活性的影响通过以下的方法进行测试。The effect of the compound on the proliferative activity of leukemia cell MV4-11 was tested by the following method.
该方法用来测定本发明中的化合物对白血病细胞MV4-11增殖活性的影响。This method was used to determine the effect of the compounds of the present invention on the proliferative activity of leukemia cells MV4-11.
本实验采用CellTiter-Glo的方法测试化合物对MV4-11细胞增殖的抑制作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50。 This experiment uses the CellTiter-Glo method for testing compounds for inhibition of the proliferation of MV4-11 cells, the compounds inhibit cell proliferation and draw half maximal inhibitory concentration IC 50 activity.
实验步骤：Experimental steps:
1、在96孔细胞培养板中接种50～100μL的MV4-11细胞悬液，密度为1～5*10 4细胞/ml，将培养板于培养箱培养16～24小时(37℃，5％CO 2)。 1. Inoculate 50-100 μL of MV4-11 cell suspension in a 96-well cell culture plate at a density of 1 to 5*10 4 cells/ml. Incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5%). CO 2 ).
2、向培养板细胞中加入梯度稀释的不同浓度的待测化合物溶液，将培养板 在培养箱孵育72小时(37℃，5％CO 2)。 2. Add gradient dilutions of different concentrations of the test compound solution to the culture plate cells, and incubate the plate for 72 hours (37 ° C, 5% CO 2 ) in the incubator.
3、每孔加入50～100μL CellTiter-Glo试剂，并振荡10分钟，室温静置10分钟。3. Add 50-100 μL of CellTiter-Glo reagent to each well, shake for 10 minutes, and let stand for 10 minutes at room temperature.
4、酶标仪测定各板的化学发光信号值。4. The plate reader measures the chemiluminescence signal value of each plate.
5、通过化学发光信号值计算抑制率。5. Calculate the inhibition rate by the value of the chemiluminescence signal.
6、根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 6, obtained according to compound IC 50 inhibition rate of different concentration by curve fitting.
本发明中化合物对白血病细胞MV4-11增殖活性的试验进行测定，测得的IC 50值见表3。 The compound of the present invention was assayed for the proliferative activity of leukemia cell MV4-11, and the measured IC 50 values are shown in Table 3.
表3本发明中化合物对白血病细胞MV4-11增殖活性抑制IC 50 Table 3 Inhibition of proliferation of leukemia cell MV4-11 by the compound of the present invention IC 50
Figure PCTCN2018072204-appb-000386
Figure PCTCN2018072204-appb-000386
Figure PCTCN2018072204-appb-000387
Figure PCTCN2018072204-appb-000387
结论：本发明化合物对白血病细胞MV4-11增殖活性具有明显的抑制作用。Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferative activity of leukemia cell MV4-11.
测试例4、本发明化合物对小鼠的PK分析测试Test Example 4, PK analysis test of the compound of the present invention on mice
本发明优选实施例的小鼠药物代谢动力学试验采用Balb/c小鼠(上海杰思捷实验动物有限公司)进行。The mouse pharmacokinetic test of the preferred embodiment of the present invention was carried out using Balb/c mice (Shanghai Jiesijie Experimental Animal Co., Ltd.).
给药方式：单次灌胃给药Mode of administration: single intragastric administration
给药剂量：5毫克/10毫升/千克Dosage: 5 mg / 10 ml / kg
制剂处方：0.5％CMC-Na和1％Tween 80，超声溶解Formulation formulation: 0.5% CMC-Na and 1% Tween 80, sonicated
取样点：给药后0.5、1、2、4、6、8和24小时Sampling point: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration
样品处理：Sample processing:
静脉采血0.1mL，置于K2EDTA试管中，室温1000～3000×g离心5～20min分离血浆，于-80℃保存。0.1 mL of venous blood was collected and placed in a K2EDTA test tube, and the plasma was separated by centrifugation at 1000 to 3000 × g for 5 to 20 minutes at room temperature, and stored at -80 °C.
血浆样品40uL加入160uL乙腈沉淀，混合后500～2000×g离心5～20分钟。The plasma sample was added to 160 uL of acetonitrile precipitate, and after mixing, it was centrifuged at 500 to 2000 × g for 5 to 20 minutes.
取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度，LC/MS/MS分析仪器：AB Sciex API 4000。The supernatant of the supernatant solution was subjected to LC/MS/MS analysis for concentration of the test compound, LC/MS/MS analytical instrument: AB Sciex API 4000.
液相条件：Shimadzu LC-20AD泵Liquid phase conditions: Shimadzu LC-20AD pump
色谱柱：phenomenex Gemiu 5μm C18 50×4.6mmColumn: phenomenex Gemiu 5μm C18 50×4.6mm
移动相：A液为0.1％甲酸水溶液，B液为乙腈Mobile phase: solution A is 0.1% aqueous formic acid, and solution B is acetonitrile.
流速：0.8mL/minFlow rate: 0.8mL/min
药代动力学：Pharmacokinetics:
主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表4The main parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in Table 4 below.
Figure PCTCN2018072204-appb-000388
Figure PCTCN2018072204-appb-000388
Figure PCTCN2018072204-appb-000389
Figure PCTCN2018072204-appb-000389
从表中小鼠药代实验结果可以看出：本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度Cmax都表现良好。It can be seen from the results of the mouse pharmacokinetic experiments in the table that the compounds of the examples of the present invention exhibited good metabolic properties, and both the exposure AUC and the maximum blood concentration Cmax performed well.
测试例5、本发明化合物对体内药效试验测试Test Example 5: Test of the efficacy of the compound of the present invention in vivo
实验目的：通过体内药效实验筛选出药效较为明显且毒副作用较小的化合物。实验主要仪器和试剂Objective: To screen out compounds with more obvious effects and less toxic side effects by in vivo pharmacodynamic experiments. Experimental main instruments and reagents
仪器：instrument:
1、超净工作台(BSC-1300II A2，上海博讯实业有限公司医疗设备厂)1. Ultra-clean workbench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)
2、CO2培养箱(Thermo)2. CO2 incubator (Thermo)
3、离心机(Centrifuge 5720R，Eppendorf)3. Centrifuge (Centrifuge 5720R, Eppendorf)
4、全自动细胞计数仪(Countess II，Life)4, automatic cell counter (Countess II, Life)
5、移液器(10-20uL，Eppendorf)5, pipette (10-20uL, Eppendorf)
6、显微镜(TS100，尼康)6, microscope (TS100, Nikon)
6、游标卡尺(500-196，日本三丰)6, vernier caliper (500-196, Mitutoyo, Japan)
7、细胞培养瓶(T25/T75/T225，Corning)7. Cell culture flask (T25/T75/T225, Corning)
试剂：Reagents:
1、MEM培养基(11095-080，gibico)1, MEM medium (11095-080, gibico)
2、胎牛血清(FBS)(10099-141，gibico)2, fetal bovine serum (FBS) (10099-141, gibico)
3、0.25％胰蛋白酶(25200-056，gibico)3, 0.25% trypsin (25200-056, gibico)
4、青链霉素双抗(SV30010，GE)4. Streptomycin double antibody (SV30010, GE)
5、磷酸盐缓冲液(PBS)(10010-023，gibico)5, phosphate buffer (PBS) (10010-023, gibico)
实验步骤Experimental procedure
1、细胞培养及细胞悬液制备1. Cell culture and cell suspension preparation
a,从细胞库中取出一株Hep3B细胞，用MEM培养基(MEM+10％FBS+1％Glu+1％SP)复苏细胞，复苏后的细胞置细胞培养瓶中(在瓶壁标记好细胞种类、日期、培养人名字等)置于CO 2培养箱中培养(培养箱温度为37℃，CO 2浓度为5％)。 a, remove a Hep3B cell from the cell bank, resuscitate the cells with MEM medium (MEM + 10% FBS + 1% Glu + 1% SP), and resuscitate the cells in a cell culture flask (marked cells in the bottle wall) The type, date, culture name, etc.) were cultured in a CO 2 incubator (incubator temperature 37 ° C, CO 2 concentration 5%).
b,待细胞铺满培养瓶底部80-90％后传代，传代后细胞继续置于CO 2培养箱中培养，重复该过程直到细胞数满足体内药效需求。 b. After the cells are covered with 80-90% of the bottom of the culture flask, the cells are passaged. After passage, the cells are continuously cultured in a CO 2 incubator, and the process is repeated until the number of cells satisfies the therapeutic effect in vivo.
c,收集培养好的细胞，用全自动细胞计数仪计数，根据计数结果用PBS重悬 细胞，制成细胞悬液(密度7×107/mL)，置于冰盒中待用。c. The cultured cells were collected, counted by a fully automatic cell counter, and the cells were resuspended in PBS according to the counting results to prepare a cell suspension (density: 7 × 10 7 /mL), which was placed in an ice box for use.
2、细胞接种、量瘤：2, cell inoculation, tumor:
a,接种前用一次性大小鼠通用耳标标记裸鼠，并用75％医用酒精消毒接种部位皮肤。a. Nude mice were labeled with a one-time large mouse universal ear tag before inoculation, and the skin of the inoculated site was disinfected with 75% medical alcohol.
b,接种时混匀细胞悬液，用1mL注射器抽取0.1～1mL细胞悬液、排除气泡，然后将注射器置于冰袋上待用。b. Mix the cell suspension at the time of inoculation, extract 0.1 to 1 mL of the cell suspension with a 1 mL syringe, remove air bubbles, and place the syringe on an ice pack for use.
c,依次给试验裸鼠接种(接种部位位于裸鼠右侧背部靠右肩位置皮下接种0.1mL细胞悬液)。c. The test nude mice were inoculated in turn (the inoculation site was placed subcutaneously inoculated with 0.1 mL of cell suspension on the right side of the right side of the nude mouse).
3、荷瘤鼠量瘤、分组、给药3, tumor-bearing mice, tumor, grouping, drug delivery
a,根据肿瘤生长情况，在接种后第14-16天量瘤、并计算肿瘤大小。a, according to tumor growth, tumors were counted on days 14-16 after inoculation, and tumor size was calculated.
肿瘤体积计算：肿瘤体积(mm 3)＝长(mm)×宽(mm)×宽(mm)/2 Tumor volume calculation: tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2
b,根据肿瘤大小，采用随机分组的方法进行分组。b, according to the size of the tumor, grouped by random grouping method.
c,根据分组结果，开始给予测试药物(给药方式：口服给药，给药剂量：30mg/kg，给药体积：10mL/kg，给药频率：2次/天，给药周期：14天，溶媒：0.5％CMC/1％吐温80)。c, according to the results of the grouping, the administration of the test drug (administration method: oral administration, administration dose: 30 mg/kg, administration volume: 10 mL/kg, administration frequency: 2 times/day, administration period: 14 days) , solvent: 0.5% CMC / 1% Tween 80).
d,开始给予测试药物后每周二次量瘤、称重。d, the tumor was dosed twice a week after the test drug was administered, and weighed.
e,实验结束后安乐死动物。e. Animals are euthanized after the end of the experiment.
4、试验数据：4. Test data:
Figure PCTCN2018072204-appb-000390
Figure PCTCN2018072204-appb-000390
5、实验结果5, the experimental results
从上述结果中可以看出，本专利的上述实施例有较好的抑瘤率。As can be seen from the above results, the above embodiment of the present patent has a better tumor inhibition rate.

Claims (21)

  1. 一种通式(I)所示的化合物：A compound of the formula (I):
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    M为CH或N；M is CH or N;
    L选自O、NR v、C(O)、-(CH 2) n-、S(O) m、-O(CR 6R 7) n-或-NR v(CR 6R 7) n-； L is selected from O, NR v , C(O), -(CH 2 ) n -, S(O) m , -O(CR 6 R 7 ) n - or -NR v (CR 6 R 7 ) n -;
    X、Y各自独立的选自N、NR v、-(CR 6R 7) n-或-(CR 6R 7) nN(R v) x-，且X、Y至少有一个与S原子形成S＝N； X and Y are each independently selected from N, NR v , -(CR 6 R 7 ) n - or -(CR 6 R 7 ) n N(R v ) x -, and at least one of X and Y forms with S atom S=N;
    R 1选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Base, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are described. Optionally further selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C Substituting one or more substituents of (O) R 12 and -NR 11 S(O) m R 12 ;
    Ra选自氢原子、烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氧代基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-NR 9(CH 2) nR 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； Ra is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, an oxo group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group. , heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -NR 9 (CH 2 ) n R 10 And -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, The cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , Substituting one or more substituents of -C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
    R 2选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯烃、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10； 其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 2 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally selected Further selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C(O Substituting one or more substituents of R 12 and -NR 11 S(O) m R 12 ;
    R 3选自氢原子、氘原子、烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烯烃、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, an alkene, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group. Aryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, olefin, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C(O)R 12 And one or more substituents of -NR 11 S(O) m R 12 are substituted;
    或者，R 2和R 3连接形成一个杂环基或杂芳基；其中所述的杂环基和杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代； Alternatively, R 2 and R 3 are bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substitutions in R 10 Substituted by
    再或者，R 2、R 3各自独立的与X基团上的R 6、R 7或R v连接形成一个杂环基或杂芳基；其中所述的杂环基和杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代； Further, R 2 and R 3 are each independently bonded to R 6 , R 7 or R v on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
    R 4选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、烯基、硝基、羟基、羟基甲基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10；其中所述的烷基、卤代烷基、烯烃、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkene, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, an alkenyl group, a nitro group, a hydroxyl group, a hydroxymethyl group, a cyano group, Cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, haloalkyl group, olefin, cycloalkyl group, heterocyclic group The aryl and heteroaryl groups are optionally further selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 Substituting one or more substituents of R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
    R 5选自氢原子、烷基、卤代烷基、羟烷基、氘代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基； R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
    R v选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基； R v is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
    R 6和R 7相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、 烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10； R 6 and R 7 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkane. Base, heterocyclic group, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C (O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
    或者，R 6和R 7可以形成环烷基或杂环基，其中所述环烷基或杂环基任选进一步被选自烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代； Alternatively, R 6 and R 7 may form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy. , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substitutions in R 10 Substituted by
    R 8选自氢原子、烷基、卤代烷基、烯基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、烯基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cyclo Alkyl, heterocyclic, aryl, heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 ,- Substituting one or more substituents of C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
    R 9和R 10相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基、杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 11 , -C(O)R. 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S( O) m R 12 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy Substituted by one or more substituents of a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
    R 11和R 12相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 11 and R 12 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;
    m为0、1或2的整数；m is an integer of 0, 1, or 2;
    n为0、1、2、3、4或5的整数；且n is an integer of 0, 1, 2, 3, 4 or 5;
    x为0或1的整数。x is an integer of 0 or 1.
  2. 根据权利要求1所述的化合物，其为通式(II)所示的化合物：A compound according to claim 1 which is a compound of the formula (II):
    Figure PCTCN2018072204-appb-100002
    Figure PCTCN2018072204-appb-100002
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    L选自S、-(CH 2) n-、-O(CR 6R 7) n-或-NR v(CR 6R 7) n-； L is selected from S, -(CH 2 ) n -, -O(CR 6 R 7 ) n - or -NR v (CR 6 R 7 ) n -;
    R v为氢原子或C 1-8烷基； R v is a hydrogen atom or a C 1-8 alkyl group;
    R 2选自C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、氰基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基；其中所述的C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基任选进一步被选自C 1-8烷基、C 1-8卤代烷基、卤素、氰基、羟基、C 1-8烷氧基、C 1-8卤代烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OR 11、-C(O)R 11、-C(O)OR 11、-S(O) mR 11、-NR 11R 12、-C(O)NR 11R 12、-NR 11C(O)R 12和-NR 11S(O) mR 12中的一个或多个取代基所取代； R 2 is selected from C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, cyano, C 3-8 cycloalkyl, 3-10 membered hetero a cyclic group, a 6-10 membered aryl group and a 5-10 membered heteroaryl group; wherein said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 alkoxy group, C 1-8 haloalkoxy group The base, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally further selected from C 1-8 alkyl, C 1-8 haloalkane. Base, halogen, cyano, hydroxy, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, 6 -10-membered aryl, 5-10 membered heteroaryl, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) m R 11 , -NR 11 R 12 ,- Substituting one or more substituents of C(O)NR 11 R 12 , -NR 11 C(O)R 12 and -NR 11 S(O) m R 12 ;
    R 3选自氢原子、氘原子、C 1-8烷基、C 1-8卤代烷基、氰基、-S(O) mR 8和-C(O)R 8； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, -S(O) m R 8 and -C(O)R 8 ;
    R 4选自氢原子、C 1-8烷基、-C(O)OR 8和-C(O)NR 9R 10； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ;
    R 5为氢原子或C 1-8烷基； R 5 is a hydrogen atom or a C 1-8 alkyl group;
    R 6和R 7相同或不同，且各自独立地选自氢原子或C 1-8烷基； R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom or a C 1-8 alkyl group;
    环A选自C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基，其中所述的C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基任选进一步被选自氢原子、C 1-8烷基、C 1-8卤代烷基、卤素、氨基、硝基、羟基、氰基、氧代基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基中的一个或多个取代基所取代； Ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein said C 3-8 cycloalkyl, 3-10 The heterocyclic group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally further selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a halogen, an amino group, a nitro group, and a hydroxyl group. , cyano, oxo, C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl and 5-10 Substituted by one or more substituents in the heteroaryl group;
    Ra相同或不同，其各自独立的选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8羟烷基、C 1-8卤代烷氧基、卤素、羟基、氰基-和-OR 8； Ra is the same or different and is independently selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkoxy group. Base, halogen, hydroxyl, cyano- and -OR 8 ;
    y为0、1、2、3或4的整数；Y is an integer of 0, 1, 2, 3 or 4;
    z为0、1、2或3的整数；z is an integer of 0, 1, 2 or 3;
    n为0、1、2、3、4或5的整数；且n is an integer of 0, 1, 2, 3, 4 or 5;
    R 8～R 12如权利要求1中所定义。 R 8 to R 12 are as defined in claim 1.
  3. 根据权利要求1所述的化合物，其为通式(III)所示的化合物：A compound according to claim 1 which is a compound of the formula (III):
    Figure PCTCN2018072204-appb-100003
    Figure PCTCN2018072204-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    L为-O(CH 2) n-或-NR v(CH 2) n-； L is -O(CH 2 ) n - or -NR v (CH 2 ) n -;
    R v为氢原子或C 1-8烷基； R v is a hydrogen atom or a C 1-8 alkyl group;
    R 2为C 1-8烷基或C 1-8卤代烷基； R 2 is C 1-8 alkyl or C 1-8 haloalkyl;
    R 3为C 1-8烷基或C 1-8卤代烷基； R 3 is C 1-8 alkyl or C 1-8 haloalkyl;
    R 4选自氢原子、C 1-8烷基、-C(O)OR 8和-C(O)NR 9R 10；优选氢原子； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ; preferably a hydrogen atom;
    R 5为氢原子或C 1-8烷基；优选甲基； R 5 is a hydrogen atom or a C 1-8 alkyl group; preferably a methyl group;
    环A选自C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基，其中所述的C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基任选进一步被选自氢原子、C 1-8烷基、卤素、氨基、硝基、羟基、氰基、氧代基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基中的一个或多个取代基所取代； Ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein said C 3-8 cycloalkyl, 3-10 The heterocyclic group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally further selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and an oxo group. One of a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 3-8 cycloalkyl group, a 3-10 membered heterocyclic group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group. Substituted by a plurality of substituents;
    Ra相同或不同，其各自独立的选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8羟烷基、C 1-8卤代烷氧基、卤素、羟基、氰基和-OR 8； Ra is the same or different and is independently selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkoxy group. Base, halogen, hydroxyl, cyano and -OR 8 ;
    y为0、1、2、3或4的整数；Y is an integer of 0, 1, 2, 3 or 4;
    z为0、1、2或3的整数；且z is an integer of 0, 1, 2 or 3;
    n为0、1、2或3的整数。n is an integer of 0, 1, 2 or 3.
  4. 根据权利要求2所述的化合物，其为通式(IV)和(IVA)所示的化合物：A compound according to claim 2 which is a compound of the formulae (IV) and (IVA):
    Figure PCTCN2018072204-appb-100004
    Figure PCTCN2018072204-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    n为0、1或2的整数；且n is an integer of 0, 1, or 2;
    环A、R 2、R 3、R 4、R a、R v和y如权利要求2中所定义。 Rings A, R 2 , R 3 , R 4 , R a , R v and y are as defined in claim 2.
  5. 根据权利要求4所述的化合物，其为通式(V)和(VA)、(VB)所示的化合物：The compound according to claim 4 which is a compound represented by the general formulae (V) and (VA), (VB):
    Figure PCTCN2018072204-appb-100005
    Figure PCTCN2018072204-appb-100005
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    u、p、q各自相同或不同，各自独立的选自0、1、2或3的整数；u, p, q are each the same or different, and each is independently selected from an integer of 0, 1, 2 or 3;
    环A、R 2、R 3、R 4、R a、R v和n如权利要求2中所定义。 Rings A, R 2 , R 3 , R 4 , R a , R v and n are as defined in claim 2.
  6. 根据权利要求1所述的化合物，其为通式(VI)所示的化合物：A compound according to claim 1 which is a compound of the formula (VI):
    Figure PCTCN2018072204-appb-100006
    Figure PCTCN2018072204-appb-100006
    其中：among them:
    L选自O和NR v；优选O或NH； L is selected from O and NR v ; preferably O or NH;
    R a选自氢原子、卤素、羟基、氧代基、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基和C 1-8卤代烷氧基；优选氢原子、卤素、氧代基、羟基、C 1-6烷基和C 1-6卤代烷基；更优选氢原子、卤素、羟基、C 1-3烷基或C 1-3卤代烷基； R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an oxo group, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, and a C 1-8 haloalkoxy group; preferably a hydrogen atom or a halogen , oxo, hydroxy, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen, halogen, hydroxy, C 1-3 alkyl or C 1-3 haloalkyl;
    或者任意两个R a形成一个C 3-8环烷基或3-10元的杂环基，其中所述的C 3-8环烷基或3-10元的杂环基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基或C 1-8羟烷基中的一个或多个取代基所取代； Or any two R a form a C 3-8 cycloalkyl or a 3-10 membered heterocyclic group, wherein the C 3-8 cycloalkyl or 3-10 membered heterocyclic group is optionally further selected Substituted from one or more substituents of C 1-8 alkyl, halo, hydroxy, amino, nitro, cyano, C 1-8 alkoxy or C 1-8 hydroxyalkyl;
    R 2选自C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基和6-10元芳基，其中所述的C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基和6-10元芳基任选进一步被选自C 1-8烷基、卤素、羟基、氨 基、硝基、氰基、C 1-8烷氧基、C 3-8环烷基和C 1-8羟烷基中的一个或多个取代基所取代；优选C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、卤代C 3-8环烷基或氰基取代的C 3-8环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基、氰基取代的环丙基及其氘代物； R 2 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aryl Wherein C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl and 6-10 membered aromatic The group is optionally further selected from the group consisting of C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1-8 alkoxy, C 3-8 cycloalkyl and C 1-8 hydroxyalkyl Substituted by one or more substituents; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano substituted C 3 8 -cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl Most preferred are methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl, cyano substituted cyclopropyl and their progeny;
    R 3选自氢原子、氘原子、C 1-8烷基、C 1-8卤代烷基、氰基、C 3-8环烷基、卤代C 3-8环烷基、氰基取代的C 3-8环烷基、-S(O) mR 8和-C(O)R 8；优选C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基或氰基取代的环丙基； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, a cyano substituted C 3-8 cycloalkyl, -S(O) m R 8 and -C(O)R 8 ; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 ring An alkyl or cyano substituted C 3-6 cycloalkyl; most preferably a methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl or cyano substituted cyclopropyl;
    R 4选自氢原子、C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、-C(O)OR 8和-C(O)NR 9R 10；其中所述的C 1-8烷基、C 3-8环烷基和C 1-8卤代烷基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基或C 1-8羟烷基中的一个或多个取代基所取代；优选C 1-6烷基或C 1-6卤代烷基；更优选C 1-3烷基或C 1-3卤代烷基； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 1-8 haloalkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ; C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are optionally further selected from C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1- Substituted by one or more substituents in the 8 -alkoxy group or the C 1-8 hydroxyalkyl group; preferably a C 1-6 alkyl group or a C 1-6 haloalkyl group; more preferably a C 1-3 alkyl group or a C 1- 3- haloalkyl;
    z为0或1的整数；且z is an integer of 0 or 1;
    p为0、1、2、3、4或5的整数。p is an integer of 0, 1, 2, 3, 4 or 5.
  7. 根据权利要求1所述的化合物，其为通式(VII)所示的化合物：A compound according to claim 1 which is a compound of the formula (VII):
    Figure PCTCN2018072204-appb-100007
    Figure PCTCN2018072204-appb-100007
    其中：among them:
    L选自O和NR v；优选O或NH； L is selected from O and NR v ; preferably O or NH;
    R a选自氢原子、卤素、羟基、氨基、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基和C 1-8羟烷基；优选氢原子、卤素、C 1-6烷基或C 1-6羟烷基；更优选氢原子、卤素、或C 1-3羟烷基； R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an amino group, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, and a C 1-8 hydroxyalkyl group; preferably a hydrogen atom, a halogen, C a 1-6 alkyl group or a C 1-6 hydroxyalkyl group; more preferably a hydrogen atom, a halogen, or a C 1-3 hydroxyalkyl group;
    R 2选自C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基和6-10元芳基，其中所述的C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 3-8卤代环烷基、3-10元杂环基和6-10元芳基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基、C 3-8环烷基和C 1-8羟烷基中的一个或多个取代基所取代；优选C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、卤代C 3-8环烷基或氰基取代的C 3-8环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基、氰基 取代的环丙基及其氘代物； R 2 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aryl Wherein C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl and 6-10 membered aromatic The group is optionally further selected from the group consisting of C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1-8 alkoxy, C 3-8 cycloalkyl and C 1-8 hydroxyalkyl Substituted by one or more substituents; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano substituted C 3 8 -cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl Most preferred are methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl, cyano substituted cyclopropyl and their progeny;
    R 3选自氢原子、氘原子、C 1-8烷基、C 1-8卤代烷基、氰基、C 3-8环烷基、卤代C 3-8环烷基、氰基取代的C 3-8环烷基、-S(O) mR 8和-C(O)R 8；优选C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；更优选C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、卤代C 3-6环烷基或氰基取代的C 3-6环烷基；最优选甲基、乙基、异丙基、环丙基、卤代环丙基或氰基取代的环丙基； R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, a cyano substituted C 3-8 cycloalkyl, -S(O) m R 8 and -C(O)R 8 ; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogenated C 3-6 ring An alkyl or cyano substituted C 3-6 cycloalkyl; most preferably a methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl or cyano substituted cyclopropyl;
    R 4选自氢原子、C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、-C(O)OR 8和-C(O)NR 9R 10；其中所述的C 1-8烷基、C 3-8环烷基和C 1-8卤代烷基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、硝基、氰基、C 1-8烷氧基或C 1-8羟烷基中的一个或多个取代基所取代；优选C 1-6烷基或C 1-6卤代烷基；更优选C 1-3烷基或C 1-3卤代烷基； R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 1-8 haloalkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ; C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are optionally further selected from C 1-8 alkyl, halogen, hydroxy, amino, nitro, cyano, C 1- Substituted by one or more substituents in the 8 -alkoxy group or the C 1-8 hydroxyalkyl group; preferably a C 1-6 alkyl group or a C 1-6 haloalkyl group; more preferably a C 1-3 alkyl group or a C 1- 3- haloalkyl;
    z为0或1的整数；且z is an integer of 0 or 1;
    p为0、1、2、3、4或5的整数。p is an integer of 0, 1, 2, 3, 4 or 5.
  8. 根据权利要求6所述的化合物，其为通式(VIII)所示的化合物：A compound according to claim 6 which is a compound of the formula (VIII):
    Figure PCTCN2018072204-appb-100008
    Figure PCTCN2018072204-appb-100008
    其中：among them:
    R 2～R 4、L、R a和p如权利要求6中所定义。 R 2 to R 4 , L, R a and p are as defined in claim 6.
  9. 根据权利要求7所述的化合物，其为通式(IX)所示的化合物：The compound according to claim 7, which is a compound of the formula (IX):
    Figure PCTCN2018072204-appb-100009
    Figure PCTCN2018072204-appb-100009
    其中：among them:
    R 2～R 4、L、R a和p如权利要求7中所定义。 R 2 to R 4 , L, R a and p are as defined in claim 7.
  10. 根据权利要求1～9中任一项所述的化合物，其中L选自O、S、NRv、-O(CH 2) n-和-NH(CH 2) n-；优选O、-OCH 2-、NH或-NHCH 2-。 The compound according to any one of claims 1 to 9, wherein L is selected from the group consisting of O, S, NRv, -O(CH 2 ) n - and -NH(CH 2 ) n -; preferably O, -OCH 2 - , NH or -NHCH 2 -.
  11. 根据权利要求1～10中任一项所述的化合物，其中环A选自C 3-8环烷基、3-10元杂环基和6-10元芳基；优选苯基、环丙基、环已基或吡喃基。 The compound according to any one of claims 1 to 10, wherein ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-10 membered heterocyclic group and 6-10 membered aryl; preferably phenyl, cyclopropyl , cyclohexyl or pyranyl.
  12. 根据权利要求1～11中任一项所述的化合物，其中R 2选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基和6-10元芳基，其中所述的C 1-8烷基、C 1-8卤代烷基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基和6-10元芳基任选进一步被选自C 1-8烷基、卤素、羟基、氨基、氰基、C 3-8环烷基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基和3-10元杂环基中的一个或多个取代基所取代；优选氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-8羟烷基、氰基取代的C 1-6烷基、C 3-6环烷基、卤代C 3-6环烷基、氰基取代的C 3-6环烷基、C 3-6羟基基取代的环烷基、4-6元杂环基和苯基。 The compound according to any one of claims 1 to 11, wherein R 2 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 hydroxyalkyl group, a C 3-8 ring An alkyl group, a 3-10 membered heterocyclic group and a 6-10 membered aryl group, wherein said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 3-8 cycloalkane The 3-, 10-membered heterocyclic group and the 6-10 membered aryl group are optionally further selected from the group consisting of C 1-8 alkyl, halogen, hydroxy, amino, cyano, C 3-8 cycloalkyl, C 1-8 Substituted with one or more substituents of alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl and 3-10 membered heterocyclic; preferably hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-8 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, cyano substituted C 3 6 cycloalkyl, C 3-6 hydroxy substituted cycloalkyl, 4-6 membered heterocyclyl and phenyl.
  13. 根据权利要求1～12中任一项所述的化合物，其中R 3选自氢原子、C 1-8烷基、C 1-8卤代烷基、氰基、-S(O) mR 8和-C(O)R 8；R 8选自C 1-8烷基、C 2-8烯基和C 3-8环烷基；R 3优选氢原子、C 1-6烷基、氰基、-S(O) mR 8或C(O)R 8，R 8优选C 1-6烷基、C 2-4烯基或C 3-6环烷基。 The compound according to any one of claims 1 to 12, wherein R 3 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a cyano group, -S(O) m R 8 and - C(O)R 8 ; R 8 is selected from C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; R 3 is preferably a hydrogen atom, a C 1-6 alkyl group, a cyano group, or S(O) m R 8 or C(O)R 8 , R 8 is preferably C 1-6 alkyl, C 2-4 alkenyl or C 3-6 cycloalkyl.
  14. 根据权利要求1～13中任一项所述的化合物，其中R 4选自氢原子、C 1-8烷基、-C(O)OR 8和-C(O)NR 9R 10；优选氢原子、C 1-6烷基、-C(O)OR 8或-C(O)NR 9R 10，更优选氢原子或甲基。 The compound according to any one of claims 1 to 13, wherein R 4 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, -C(O)OR 8 and -C(O)NR 9 R 10 ; preferably hydrogen Atom, C 1-6 alkyl, -C(O)OR 8 or -C(O)NR 9 R 10 , more preferably a hydrogen atom or a methyl group.
  15. 根据权利要求1～14任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：The compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds:
    Figure PCTCN2018072204-appb-100010
    Figure PCTCN2018072204-appb-100010
    Figure PCTCN2018072204-appb-100011
    Figure PCTCN2018072204-appb-100011
    Figure PCTCN2018072204-appb-100012
    Figure PCTCN2018072204-appb-100012
    Figure PCTCN2018072204-appb-100013
    Figure PCTCN2018072204-appb-100013
    Figure PCTCN2018072204-appb-100014
    Figure PCTCN2018072204-appb-100014
    Figure PCTCN2018072204-appb-100015
    Figure PCTCN2018072204-appb-100015
    Figure PCTCN2018072204-appb-100016
    Figure PCTCN2018072204-appb-100016
  16. 权利要求1～15任一项所述的化合物、其立体异构体或其药学上可接受的盐的中间体，其为通式(X)、通式(X-A)和通式(X)所示的化合物：An intermediate of the compound according to any one of claims 1 to 15, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is represented by the formula (X), the formula (XA) and the formula (X) Compound shown:
    Figure PCTCN2018072204-appb-100017
    Figure PCTCN2018072204-appb-100017
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof,
    其中：among them:
    G和G’为卤素；G and G' are halogen;
    Pg为氨基保护基，选自苄氧羰基、叔丁氧羰基、烯丙基羰基、笏甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻(对)硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4-二甲氧基苄基、对甲氧基苄基或苄基，优选对甲苯磺酰基；Pg is an amino protecting group selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilyloxycarbonyl, phthaloyl, Tosyl, trifluoroacetyl, o-(p)nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or a benzyl group, preferably a p-toluenesulfonyl group;
    环A、R 2～R 4、y、z、R a和L如权利要求2中所定义。 Rings A, R 2 to R 4 , y, z, R a and L are as defined in claim 2.
  17. 权利要求2所述的化合物、其立体异构体或其药学上可接受的盐的制备方法，包括如下步骤：A method of producing a compound according to claim 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
    Figure PCTCN2018072204-appb-100018
    Figure PCTCN2018072204-appb-100018
    通式(XI)化合物脱去氨基保护基，得到通式(II)化合物；Deprotecting a compound of formula (XI) to give a compound of formula (II);
    其中：among them:
    Pg为氨基保护基，选自苄氧羰基、叔丁氧羰基、烯丙基羰基、笏甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻(对)硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4-二甲氧基苄基、对甲氧基苄基或苄基，优选对甲苯磺酰基；Pg is an amino protecting group selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilyloxycarbonyl, phthaloyl, Tosyl, trifluoroacetyl, o-(p)nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or a benzyl group, preferably a p-toluenesulfonyl group;
    环A、R 1～R 4、R a、L、z和y如权利要求2中所定义。 Ring A, R 1 to R 4 , R a , L, z and y are as defined in claim 2.
  18. 一种药用组合物，其包括治疗有效剂量的如权利要求1～15任一项所述的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable Carrier, diluent or excipient.
  19. 根据权利要求1～15任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求19所述的药用组合物在制备BRD4抑制剂药物中的应用。The use of the compound according to any one of claims 1 to 15, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 for the preparation of a medicament for BRD4 inhibitor.
  20. 根据权利要求1～15任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求19所述的药用组合物在制备治疗癌症、炎症、慢性肝病、糖尿病、心血管疾病和AIDS的药物中的应用。The compound according to any one of claims 1 to 15, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a cancer, inflammation, chronic liver disease, diabetes , the application of drugs for cardiovascular disease and AIDS.
  21. 根据权利要求21所述的应用，其中所述的癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌；所述的慢性肝病选自原 发性硬化、脑脏性黄瘤症、原发性硬化性胆囊炎、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病、非酒精性脂肪性肝炎、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病或α 1一抗膜蛋白酶缺乏症。 The use according to claim 21, wherein said cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, and nerve glue. Maternal tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer; the chronic liver disease is selected from the group consisting of primary sclerosis, cerebral xanthoma, primary sclerosing cholecystitis, drug-induced cholestasis, Intrahepatic cholestasis of pregnancy, parenteral absorption-related cholestasis, bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, Liver transplantation-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease , hemochromatosis or α 1 -antimembrane protease deficiency.
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