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WO2018130174A1 - Dérivé de pyrrolo[2,3-c]pyridine, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé de pyrrolo[2,3-c]pyridine, son procédé de préparation et son utilisation en médecine 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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Prior art keywords
group
cycloalkyl
alkyl
haloalkyl
methyl
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Chinese (zh)
Inventor
苏熠东
古鹏
陈晓坡
刘磊
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Priority to CN201880006265.9A priority Critical patent/CN110167939B/zh
Publication of WO2018130174A1 publication Critical patent/WO2018130174A1/fr
Anticipated expiration legal-status Critical
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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

La présente invention concerne un dérivé de pyrrolo[2,3-c]pyridine, son procédé de préparation et son utilisation en médecine. L'invention concerne particulièrement, un dérivé de pyrrolo[2,3-c]pyridine représenté par la formule générale (1), son procédé de préparation, une composition pharmaceutique comprenant le dérivé, ainsi que leur utilisation en tant qu'inhibiteur de BRD4 dans le traitement de maladies associées telles que les cancers, les inflammations, les maladies hépatiques chroniques, le diabète, les maladies cardiovasculaires et le SIDA, chaque substituant dans la formule générale (I) étant tel que défini dans la description.
PCT/CN2018/072204 2017-01-11 2018-01-11 Dérivé de pyrrolo[2,3-c]pyridine, son procédé de préparation et son utilisation en médecine Ceased WO2018130174A1 (fr)

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