WO2018137655A1 - Dérivé de pyrrolo-pyridine n-oxyde, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyrrolo-pyridine n-oxyde, son procédé de préparation et son utilisation Download PDF

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WO2018137655A1
WO2018137655A1 PCT/CN2018/073989 CN2018073989W WO2018137655A1 WO 2018137655 A1 WO2018137655 A1 WO 2018137655A1 CN 2018073989 W CN2018073989 W CN 2018073989W WO 2018137655 A1 WO2018137655 A1 WO 2018137655A1
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group
methyl
alkyl
pyrrolo
phenyl
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PCT/CN2018/073989
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Chinese (zh)
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野国中
李凯龙
黄志强
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 CN201880006296.4A priority Critical patent/CN110198941B/zh
Publication of WO2018137655A1 publication Critical patent/WO2018137655A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular 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

Definitions

  • the invention belongs to the field of medicine and relates to pyrrolopyridinium N-oxidized derivatives, a preparation method thereof and application of the pharmaceutical composition in medical research, and the invention discloses as a BRD4 inhibitor in treating cancer, inflammation, chronic liver disease and diabetes.
  • 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.
  • 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:
  • X, Y are each independently selected from the group consisting of a bond, N, O, -NR 5 -, -(CR 6 R 7 ) x -, and -(CR 6 R 7 ) x N(R 5 ) y -;
  • Z is selected from -NR 5 -, O and -O(CR 6 R 7 ) x -;
  • Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 1 is selected from the group consisting of alkyl, cycloalkyl and alkenyl; wherein said alkyl, alkenyl and cycloalkyl are optionally further selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 2 is selected from the group consisting of a hydrogen atom, an 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, an aryl group, a heteroaryl group, -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, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from alkyl, haloalkanes Base,
  • R 3 is selected from the group consisting of a non-existent hydrogen atom, an alkyl group, a halogenated alkyl group, an alkene group, an alkoxy group, a halogenated alkoxy group, a halogen group, 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 5 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 independently 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, Heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -(CH 2 ) t NR 9 R 10 , -(CH 2 ) t C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further optionally, it is selected
  • R 5 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 each independently selected from 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 cycloalkyl group, a heterocyclic group.
  • R 6 and R 7 may form a cycloalkyl or heterocyclic group, which 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
  • R 10 Replace
  • 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, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R Substituting one
  • 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 and a heteroaryl group, wherein the alkyl group, 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;
  • t is an integer of 0, 1, 2, 3, 4 or 5;
  • x is an integer of 0, 1, 2, 3 or 4;
  • y is an integer of 0 or 1.
  • the compound of the formula (I) is a compound of the formula (II):
  • B is selected from CH and N;
  • R 1 to R 4 , Z, X, Y and n are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (III):
  • B is selected from CH and N;
  • R 1 , R 2 , R 4 , Z, X and n are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (IV):
  • Z is selected from NH and O
  • B is selected from CH and N;
  • Ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, amino, Substituted by one or more substituents of a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • z is an integer of 0, 1, 2 or 3;
  • R 1 , R 2 , R 4 , X and n are as defined in the formula (I).
  • the compound represented by the formula (IV) is a compound represented by the formula (VA) or (VB):
  • Z is selected from NH and O
  • X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, -(CH 2 ) t NR 9 R 10 and -(CH 2 ) t C(O)NR 9 R 10 ;
  • R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl or 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • n, t is as defined in the general formula (I).
  • the compound of the formula (IV) is a compound of the formula (VIA) or (VIB):
  • Z is selected from NH and O
  • X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
  • R C is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, a ( CH 2 ) t NR 9 R 10 or -(CH 2 ) t C(O)NR 9 R 10 ;
  • R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • R 1 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 2-3 alkenyl or C 3-6 cycloalkyl; most preferably methyl .
  • the compound of the formula, wherein R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and a -6 membered heteroaryl group, wherein said C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are optionally further selected from C 1 Substituted by one or more substituents of -6 alkyl, halo C 1-6 alkyl, halogen, amino, cyano and hydroxy; preferably C 1-6 alkyl, halo C 1-6 alkyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, halo C 1-3 alkyl or C 3-6 cycloalkyl, most preferably methyl, ethyl, isopropyl, cyclopropyl, Cyclobutyl,
  • the compound of formula (I) is selected from the group consisting of:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 to R 4 , ring A, Z, X, Y and n are as defined in the formula (I).
  • a method for preparing a compound of the formula (I) comprises the following steps:
  • the compound of the formula (V) is oxidized by an oxidizing agent to give a compound of the formula (I);
  • the oxidizing agent is preferably m-chloroperoxybenzoic acid;
  • R 1 to R 4 , ring A, Z, X, Y and n are as defined in the formula (I);
  • a method for preparing a compound represented by the formula (VA) comprises the following steps:
  • the compound of the formula (VAA) is oxidized by an oxidizing agent to give a compound of the formula (VA);
  • the oxidizing agent is preferably m-chloroperoxybenzoic acid;
  • R 2 , R 4 , Z, X and n are as defined in the formula (VA);
  • a method for preparing a compound represented by the formula (VB) comprises the following steps:
  • the compound of the formula (VBB) is oxidized by an oxidizing agent to give a compound of the formula (VB);
  • the oxidizing agent is preferably m-chloroperoxybenzoic acid;
  • R 2 , R 4 , Z, X and n are as defined in the formula (VB);
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a process for the preparation of the above pharmaceutical composition which comprises the compounds of the formulas or their tautomers, meso, racemates, enantiomers, non-pairs
  • the conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof is admixed 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 preparation of a medicament for the prophylaxis and/or treatment of a medicament for the treatment of cancer, inflammation, 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 Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture 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, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and 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
  • 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 may be 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, glioblastoma, leukemia, lymph.
  • Tumor, myeloma and non-small cell lung cancer said chronic liver disease is selected from the group consisting of: primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced Cholestasis, 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, hemochromatos
  • 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.
  • the alkenyl 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 Alkylthio group.
  • 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 12 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
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • 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 8 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 tetrahydrofuranyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups 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 ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring
  • 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 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
  • 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 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.
  • Second step Preparation of (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone
  • the third step preparation of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine
  • the fourth step preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene
  • Step 7 N-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Preparation of phenyl) ethanesulfonamide
  • N-(3-Bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide 500 mg, 1.28 mmol
  • 4,4,4',4',5,5,5' , 5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (648 mg, 2.55 mmol)
  • 1,3,5,7-tetramethyl-6-phenyl -2,4,8-trioxa-6-phosphoryladamantane 37 mg, 0.128 mmol
  • tris(dibenzylideneacetone)dipalladium 35 mg, 0.038 mmol
  • potassium acetate 275 mg, 2.82 mmol
  • reaction solution was reacted at 80 ° C for 12 hours under nitrogen atmosphere, and then reacted at 105 ° C for 5 hours.
  • the reaction solution was evaporated to dryness and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
  • a mixture of ethanesulfonamide 500 mg was used directly in the next step.
  • Step 8 N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Preparation of sulfonamide
  • reaction solution was subjected to microwave reaction at 120 ° C for 0.5 hour under a nitrogen atmosphere.
  • Step 9 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
  • EtOAc EtOAc: EtOAc: EtOAc: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (12 mg, yield 19%).
  • 6-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (17.0 g, 74 mmol) was dissolved in N,N-dimethylformamide (50 mL).
  • Sodium hydride (5.9 g, 147 mmol) was added portionwise to the above solution, and after stirring for 10 minutes at 0 ° C, 4-methylsulfonyl chloride (18.3 g, 96 mmol) was dissolved in N,N-dimethyl
  • a solution of the amide (30 mL) was slowly added to the above reaction solution. After stirring at room temperature for 1 hour, the reaction was completed by LC/MS.
  • reaction solution was poured into ice water (500 mL) and stirred, a large white solid was precipitated, filtered, and the filter cake was washed with water (100 mL) and dried to give 6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrole And [2,3-b]pyridine (27.0 g, yield 94.7%).
  • the third step preparation of 4-chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
  • 6-Bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (15.5 g, 40 mmol) was dissolved in tetrahydrofuran (150 mL) and [1,1'-bis (two) Phenylphosphino)ferrocene]palladium dichloride (1.46 g, 2 mmol), replacing nitrogen, adding dimethyl zinc (20 mL, 1 M solution in toluene) under ice bath, heating to 70 ° C after completion of the addition. The reaction was carried out overnight, and the reaction was completed by LC/MS.
  • Step 6 N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Preparation of phenyl)phenylpropanesulfonamide
  • Step 8 4-(5-(Cyclopropanesulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
  • N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (40 mg, 0.087 mmol) was dissolved in THF (0.5 mL). m. m. m.
  • N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene Starting from -3,5-dimethylisoxazole-4-sulfonamide as a starting material, referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3- (6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide (70 mg, yield 83%) .
  • the third step 4-(2-(2,4-difluorophenoxy)-5-((3,5-dimethylisoxazole)-4-sulfonylamino)phenyl)-6-A Preparation of 7-oxidation of yl-1H-pyrrolo[2,3-b]pyridine
  • N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene The propane-2-sulfonamide was used as a starting material. Referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole was obtained. [2,3-b]pyridin-4-yl)phenyl)propane-2-sulfonamide (69 mg, yield 84%).
  • N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane-2- Sulfonamide was used as the starting material.
  • EtOAc 2,4-Difluorophenoxy-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2,2,2-trifluoroethane 1-sulfonamide (0.06 g) was used directly in the next reaction.
  • the third step 4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide
  • Step 6 4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide
  • N-(4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide 70 mg, 0.14 mmol was dissolved in tetrahydrofuran (2 mL), and m-chloroperoxybenzoic acid (42 mg, 0.21 mmol) was added and stirred at room temperature for 30 min. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL ⁇ 2) and then washed with brine (30 mL).
  • Second step 4-(2-(4-bromo-2-fluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl- Preparation of 1H-pyrrolo[2,3-b]pyridine-7-oxide
  • N-(3-Bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, 1.1 mmol), 6-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.5g , 1.3 mmol), potassium carbonate (350 mg, 2.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 0.1 mmol) dissolved in 1,4 dioxane Ring (10 mL) and water (2 mL) were stirred and stirred at 90 ° C for 2 hr under nitrogen.
  • Step 5 N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of oxo)phenyl)ethanesulfonamide
  • Step 6 4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide
  • Phenyl)ethanesulfonamide 100 mg, 0.23 mmol
  • m-chloroperoxybenzoic acid 95 mg, 0.46 mmol
  • Second step Preparation of 2-bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1,4-diamine
  • N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide 200mg, 0.5mmol
  • the compound N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-) Methylcyclohexyl)amino)phenyl)ethanesulfonamide 180 mg, yield: 58%).
  • Step 5 N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of amino)phenyl)ethanesulfonamide
  • N-(3-(6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methyl) Cyclohexyl)amino)phenyl)ethanesulfonamide 180 mg, 0.3 mmol was used as the starting material of the reaction, and the compound of N.sup. -b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (120 mg, yield: 91%).
  • Step 6 4-(5-(Ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine-7-oxide
  • the second step preparation of 2-bromo-1-fluoro-4-(methanesulfonyl)benzene
  • the third step preparation of 2-bromo-1-(cyclohexanetrienoxy)-4-(methanesulfonyl)benzene
  • the solution was reacted at 85 ° C for 16 hours under a nitrogen atmosphere.
  • the reaction mixture was evaporated to dryness, and then purified,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 5 Preparation of 4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
  • N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Aniline (200.0 mg, 0.57 mmol), dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), followed by tris(dibenzylideneacetone) dipalladium (16 mg, 0.0171 mmol) , tripotassium phosphate (302 mg, 1.43 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (18.3 mg, 0.0627 mmol) The mixture was stirred with nitrogen for 5 minutes and stirred at 120 ° C for one hour.
  • N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (21.0 mg, 0.056 Methyl acetate (2 mL) was added, and m-chloroperoxybenzoic acid (14 mg, 0.084 mmol) was added, and the mixture was stirred at room temperature for one hour and then quenched with sodium thiosulfate solution (5 mL). After the addition, dichloromethane (15 mL) was added, and then washed with water (20 mL ⁇ 2) and brine (20 mL) and dried over anhydrous sodium sulfate.
  • Second step Preparation of 2-(2-isobutoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan
  • Step 2 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
  • the third step 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
  • reaction mixture was diluted with ethyl acetate (20 mL) Wash (10 mL ⁇ 3), then wash with saturated brine (10 mL), EtOAc (EtOAc) /V), 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.23 g, light) Yellow solid, yield 68%).
  • Trans-4-tert-butylcyclohexanol (0.10 g, 0.66 mmol) was dissolved in N,N-dimethylformamide (3 mL), then sodium hydride (60%, EtOAc, The reaction solution was stirred at room temperature for half an hour.
  • trans-4-methylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-methylcyclohexyl)oxy).
  • -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide 0.035 g, white solid, yield 49%).
  • trans-4-ethylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-ethylcyclohexyl)oxy).
  • -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide 0.023 g, white solid, yield 58%).
  • trans-4-isopropylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans))-4-isopropylcyclohexyl.
  • Oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide 0.018 g, yield 44%).
  • 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
  • Step 7 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)-2-methylpropionitrile
  • Step 8 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl-2-methylpropionitrile
  • Step 9 4-(5-((2-Cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide
  • Second step 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl acetonitrile
  • Second step 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)cyclopropane-1-carbonitrile
  • Example 23 Taking 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile as the starting material, refer to the seventh step of Example 23 to obtain 1- ((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile (0.05 g, white solid, yield 42%).
  • the third step 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile
  • 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 64%).
  • the second step preparation of 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene
  • Step 5 Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
  • Step 6 4-(2-(Cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides
  • Example 26 Starting from cyclohexanol in place of cyclohexanol, the sixth step of Example 26 was carried out to obtain the compound 4-(2-(cyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6.
  • trans-4-tert-butylcyclohexanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)- 5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (0.040 g, white solid, yield 57%).
  • the trans-4-ethylcyclohexanol (0.077 g, 0.60 mmol) was dissolved in N,N-dimethylformamide (4 mL), then sodium hydride (60%, <RTIgt; After adding to the reaction solution, stirring at room temperature for half an hour, 4-(2-fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (0.04 g, 0.12 mmol) of N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture.
  • reaction mixture was diluted with methylene chloride (20 mL), washed with NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.008 g, white solid, yield 15%).
  • Second step 4-(2-(4-(aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide
  • Second step Preparation of (3-bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane
  • the third step preparation of 2-bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene
  • Step 5 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1-toluene
  • Step 6 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine
  • Step 7 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide
  • Step 8 4-(2-(2,4-Difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl) Preparation of -6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
  • reaction mixture was added ethyl acetate (50mL), then with saturated brine (50mL), dried over anhydrous sodium sulfate ,, and concentrated Purification by reverse phase preparative chromatography (C 18 column, mobile phase (acetonitrile / water To give 6-methyl-4-(2-((trans)-4-methylcyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropane-2) -yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.0 mg, yield 19%).

Abstract

L'invention concerne un dérivé de pyrrolo-pyridine N-oxyde représenté par la formule (I), son procédé de préparation, une composition pharmaceutique contenant le composé, et l'utilisation du composé en tant qu'inhibiteur de BRD4 pour traiter des maladies associées, par exemple, des cancers, des inflammations, des maladies hépatiques chroniques, le diabète, des maladies cardiovasculaires et le SIDA.
PCT/CN2018/073989 2017-01-25 2018-01-24 Dérivé de pyrrolo-pyridine n-oxyde, son procédé de préparation et son utilisation WO2018137655A1 (fr)

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CN115028646B (zh) * 2022-05-31 2023-06-30 山东第一医科大学(山东省医学科学院) 一种含氮杂环类化合物、制备方法及在抗肿瘤制剂中的应用

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