WO2022121844A1 - Dihydropyrimidine compound, preparation method therefor, and application thereof - Google Patents

Dihydropyrimidine compound, preparation method therefor, and application thereof Download PDF

Info

Publication number
WO2022121844A1
WO2022121844A1 PCT/CN2021/135751 CN2021135751W WO2022121844A1 WO 2022121844 A1 WO2022121844 A1 WO 2022121844A1 CN 2021135751 W CN2021135751 W CN 2021135751W WO 2022121844 A1 WO2022121844 A1 WO 2022121844A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
alkylene
independently
pyridin
Prior art date
Application number
PCT/CN2021/135751
Other languages
French (fr)
Chinese (zh)
Inventor
唐国志
马大为
陈军利
黄孟炜
张金良
Original Assignee
上海维申医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海维申医药有限公司 filed Critical 上海维申医药有限公司
Priority to CN202180010983.5A priority Critical patent/CN115003673B/en
Publication of WO2022121844A1 publication Critical patent/WO2022121844A1/en

Links

Images

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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 invention relates to a dihydropyrimidine compound, a preparation method and application thereof.
  • Hepatitis B virus belongs to the small, enveloped, mainly hepadnaviridae family of hepatitis viruses, with a partially double-stranded DNA genome of about 3.2 kb in size. HBV infection has been a major public health problem. Despite the availability of safe and effective preventive HBV vaccines, an estimated 240 million people worldwide are chronically infected with HBV. Chronic HBV infection puts patients at high risk for cirrhosis and liver cancer, and it is estimated that more than 686,000 people die each year from HBV complications. (WHO.Global hepatitis report 2017)
  • nucleoside (nucleotide) analogs often require prolonged or potentially lifelong treatment, and some suffer from drug resistance, low efficacy and tolerability issues. Therefore, there is still a huge medical need to discover and develop effective and safe anti-HBV drugs with novel mechanisms of action to improve disease cure rates.
  • HBV capsid is assembled from the HBV core protein, which protects the closed viral genome and creates an environment for reverse transcription of pregenomic RNA (pgRNA) into DNA.
  • Capsid proteins play a crucial role in the life cycle of viruses.
  • Modulators of HBV capsid assembly have been shown to interfere with capsid assembly and function and block multiple steps in the HBV life cycle. These agents interfere with both the production of new viruses and the trafficking of the nucleocapsid to the nucleus, preventing the establishment of new cccDNAs. These functions can provide potent clinical antiviral activity with synergistic effects if used in combination with approved anti-HBV nucleotide analogs and other anti-HBV drugs. (Diab, Ahmed, et al. Antiviral research 149(2018): 211-220.)
  • the technical problem to be solved by the present invention is the single problem of drugs for treating and preventing HBV infection in the prior art, and provides a dihydropyrimidine compound, a preparation method and application thereof, and the dihydropyrimidine compound has better properties.
  • the anti-HBV (hepatitis B virus) activity and low cytotoxicity can be used to prepare medicines for treating and/or preventing HBV infection.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a dihydropyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof,
  • R 1 is 2-thiazolyl, 2-thiazolyl substituted by one or more R 1a , R 1a is independently halogen or methyl; when there are multiple substituents, they are the same or different;
  • R 2 , R 3 , R 4 are independently H, halogen, methyl, -CN, methyl-O- or -CF 3 ;
  • R 5 is C 1-3 alkyl
  • R 6 is H, halogen, hydroxyl, C 1-3 alkyl, cyclopropyl
  • R 6 and R 7 together with the connected carbon atoms can form: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; in the 3-6 membered heterocycloalkyl, the heteroatom is selected from N, O, S, the number of heteroatoms is 1 or 2;
  • R 9 is H, methyl
  • W N- (forms a double bond with the adjacent C), -C(R 11 R 12 )-;
  • R 11 , R 12 are independently H, C 1-3 alkyl
  • R 13 is H, phenyl-L 1 -, pyridyl-L 2 -, 3-7-membered monocyclic cycloalkyl-L 3 -, C 1-6 alkyl-L 4 -, or, by one or Multiple R 1b substituted: C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 -, 3-7 membered monocyclic cycloalkyl-L 3 -; when substituent When there are multiple, the same or different;
  • -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently connecting bonds, C 1-3 alkylene, and R 8 substituted C 1-3 alkylene;
  • R 8 is independently C 1-3 alkyl, 3-7 membered cycloalkyl;
  • R 1b is independently -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 - C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, OH, C 1-3 alkane Base-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, halogen, C 1-6 alkyl, CN, C 1-3 alkylsulfonyl, 3-7 membered ring Alkyl; or substituted by one or more R 1c : -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene) -CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • certain groups in the dihydropyrimidine compounds represented by formula I or their pharmaceutically acceptable salts are defined as follows, and the unmentioned groups are the same as those in this application Described in any scheme (referred to as "in a certain scheme of the present invention"),
  • R 1 is 2-thiazolyl (for example ).
  • R 2 , R 3 , R 4 are independently H, halogen, methyl; eg, H, F, Cl, Br, methyl.
  • R 5 is methyl or ethyl, eg ethyl.
  • R 6 is H, halogen, hydroxy, C 1-3 alkyl; such as H, F, OH, methyl; another example is H, F, methyl.
  • R 6 and R 7 are taken together with the attached carbon to form a 3-6 membered heterocycloalkyl; for example, oxacyclopropyl; i.e. for
  • R9 is H.
  • R 11 and R 12 are independently H.
  • R 13 is H, C 1-6 alkyl-L 4 -, or, substituted with one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2- , 3-7 membered monocyclic cycloalkyl-L 3 -;
  • H methyl, isopropyl, (E.g ), (E.g ), (E.g ).
  • -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linking bond, a methylene group, or -CH( CH3 )-.
  • R 1b is independently -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 - C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl- O-, halogen, C 1-6 alkyl, 3-7 membered cycloalkyl; or substituted by one or more substituents R 1c : C 1-3 alkyl-O-, C 1-6 alkyl;
  • Another example is -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, C 1-3 alkyl-O-, C 1- 6 alkyl, halogen, 3-7 membered cycloalkyl, or C 1-3 alkyl-O- substituted by one or more substituents R 1c ;
  • At least one R 1b is CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl.
  • R 13 is H, C 1-6 alkyl-L 4 -.
  • R 13 is H or phenyl-L 1 - substituted with one or more R 1b ; eg, H.
  • R 1 is 2-thiazolyl
  • R 2 , R 3 , R 4 are independently H, halogen, methyl
  • R 5 is C 1-3 alkyl (eg, ethyl);
  • R 6 is H, halogen, (eg F), OH, C 1-3 alkyl (eg methyl);
  • R6 and R7 together with the attached carbon form a 3-6 membered heterocycloalkyl
  • R 9 is H
  • R 11 , R 12 are independently H;
  • R 13 is H, C 1-6 alkyl-L 4 -, or, substituted with one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2- , 3-7 membered monocyclic cycloalkyl-L 3 -;
  • -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linkage, C 1-3 alkylene (eg methylene, ethylene);
  • R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, CO 2 H, -(C 2-6 alkenylene)-CO 2 H , -(C 1-6 alkylene)-CO 2 H, -CO 2 -C 1-3 alkyl, substituted by one or more substituents R 1c : C 1-3 alkyl-O- or C 1-6 alkyl; R 1c is independently halogen; and at least one R 1b is CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, - (C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl;
  • R 1 is 2-thiazolyl
  • R 2 , R 3 , R 4 are independently H, halogen, methyl
  • R 5 is C 1-3 alkyl (eg, ethyl or methyl);
  • R 6 is H, F, OH, methyl
  • R and R together with the attached carbon form a 3 - membered heterocycloalkyl
  • R 9 is H
  • W is C (R 11 R 12 ) or N (forms a double bond with the adjacent C);
  • R 11 , R 12 are independently H;
  • R 13 is H, C 1-6 alkyl-L 4 -, or, substituted with one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl, 3 -7-membered monocyclic cycloalkyl-L 3 -;
  • -L 1 -, -L 3 -, -L 4 - are independently a linkage, a methylene group, -CH(CH 3 )-;
  • R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, -CO 2 -C 1-3 alkyl, 3-7 membered cycloalkyl, or C 1-6 substituted with one or more R 1c Alkyl or C 1-3 alkyl-O-; R 1c is independently halogen; at least one R 1b is -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2- 6 alkenylene) -CO 2 H, -CO 2 -C 1-3 alkyl;
  • R 13 is C 1-6 alkyl-L 4 -, or, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 - , pyridyl, 3 -7-membered monocyclic cycloalkyl-L 3 -;
  • R 13 is H or C 1-6 alkyl.
  • R 1 is 2-thiazolyl
  • R 2 , R 3 , R 4 are independently H, halogen, methyl
  • R 5 is C 1-3 alkyl (eg, ethyl or methyl);
  • R 6 is H, F, methyl
  • R 9 is H
  • R 1 is 2-thiazolyl
  • R 2 , R 3 , R 4 are independently H, halogen, methyl
  • R 5 is C 1-3 alkyl
  • R 9 is H
  • R 13 is H, phenyl-L 1 - substituted by one or more R 1b ;
  • -L 1 - is independently a linkage, C 1-3 alkylene
  • R 1b is independently C 1-6 alkyl, C 1-3 alkyl-O-, -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkene and at least one R 1b is -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H ;
  • R 13 is phenyl substituted by one or more R 1b ;
  • At least one R 1b is -CO 2 H.
  • R 1 is 2-thiazolyl
  • R 2 , R 3 , R 4 are independently H, halogen, methyl
  • R 5 is C 1-3 alkyl
  • R 6 is H, F, methyl
  • R 9 is H
  • R 13 is H, C 1-6 alkyl-L 4 -, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 - , 3-7 membered monocyclic cycloalkyl-L 3 -;
  • -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linkage, a methylene group, -CH(CH 3 )-;
  • R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, CO 2 H, -(C 2-6 alkenylene)-CO 2 H , -(C 1-6 alkylene)-CO 2 H, -CO 2 -C 1-3 alkyl, substituted by one or more substituents R 1c : C 1-3 alkyl-O- or C 1-6 alkyl; R 1c is independently halogen; and at least one R 1b is -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 - C 1-3 alkyl;
  • R 1a is independently halogen
  • said halogen is F, Cl, Br.
  • R 2 , R 3 , and R 4 are independently halogen, the halogen is F, Cl, or Br.
  • R 5 is a C 1-3 alkyl group
  • the C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl; for example, ethyl.
  • R 6 is a C 1-3 alkyl group
  • the C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl; for example, methyl.
  • R 6 is halogen
  • the halogen is F, Cl, Br; for example, F.
  • the C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl; for example, methyl.
  • R7 is halogen
  • the halogen is F, Cl, Br; for example, F.
  • the 3-6 membered heterocycloalkyl group is oxanepropyl.
  • R 13 is C 1-6 alkyl-L 4 -, C 1-6 alkyl-L 4 - substituted by one or more R 1b
  • said C 1-6 alkyl - L 4 -, C 1-6 alkyl (eg methyl, ethyl, propyl, butyl, pentyl or hexyl) in C 1-6 alkyl substituted by one or more R 1b -L 4 - is independently C 1 - C4 alkyl; for example methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or tert-butyl.
  • R 13 is a 3-7-membered monocyclic cycloalkyl-L 3 -, a 3-7-membered monocyclic cycloalkyl substituted by one or more R 1b
  • the 3-7-membered monocyclic cycloalkyl in the 3-7-membered monocyclic cycloalkyl substituted by one or more R 1b is independently cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl.
  • R 8 substituted C 1-3 alkylene, the C 1- C 1-3 alkylene in C 1-3 alkylene substituted by 3 alkylene and R 8 is methylene (-CH 2 -), ethylene (for example -CH 2 CH 2 -, -CH (CH 3 )-, ), isopropylidene (eg -CH(CH 3 )CH 2 - or -C(CH 3 ) 2 -); preferably -(CH 2 )-, or -CH( CH3 )-.
  • R 8 is independently C 1-4 alkyl
  • said C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or tert-butyl.
  • R8 is independently a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; for example, cyclopropyl.
  • R 1b is independently C 1-6 alkyl; or C 1-6 alkyl substituted by one or more R 1c , said C 1-6 alkyl, and substituted by one or more R 1c
  • the C 1-6 alkyl group (such as methyl, ethyl, propyl, butyl, pentyl or hexyl) in the C 1-6 alkyl group is independently a C 1 -C 4 alkyl group (such as methyl, ethyl group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); for example methyl.
  • R 1b is independently -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-3 alkylene)-, C 1-3 alkylsulfonyl; or by One or more R 1c substituted: -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene )-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-3 alkylene)-, C 1-3 alkylsulfonyl When, the -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl,
  • R 1b is independently -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O -(C 1-6 alkylene)-, or substituted with one or more R 1c : -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 alkylene)-, said -(C 1-6 alkylene)-CO 2 H, -( C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 alkylene)-, and substituted by one or more R 1c : -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 alkylene)-
  • R 1b is independently -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, or by one or more R 1c Substituted: -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, the -(C 2-6 alkene alkenyl)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, and substituted by one or more R 1c : -(C 2-6 alkenylene) -CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 2-6 alkenylene in C 1-3 alkyl is independently C 2 -C 3 alkenylene, for example or its isomers (such as cis-trans isomers); preferably
  • R 1b is independently a 3-7 membered cycloalkyl, a 3-7 membered cycloalkyl substituted by one or more R 1c , the 3-7 membered cycloalkyl, and a 3-7 membered cycloalkyl group substituted by one or more R
  • the 3-7 membered cycloalkyl in the 1c -substituted 3-7 membered cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; for example, cyclopropyl.
  • R 1c is independently halogen
  • the halogen is F, Cl; eg, F.
  • R 1c is independently C 1-4 alkyl
  • said C 1-4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl base or tert-butyl.
  • R 1c is independently a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; for example, cyclopropyl base.
  • R 1b is independently F, Cl, methyl, isopropyl, cyclopropyl, methyl-O-, -O- CF3 , -CF3 , -CO2H ,
  • R 13 is H, C 1-6 alkyl-L 4 -, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 - , 3-7 membered monocyclic cycloalkyl-L 3 -; such as H, Isopropyl, methyl,
  • dihydropyrimidine compounds shown in formula I are selected from the following compounds:
  • dihydropyrimidine compounds shown in formula I are selected from the following compounds:
  • dihydropyrimidine compounds shown in the present invention as shown in formula I or their pharmaceutically acceptable salts can be synthesized by methods similar to those known in the chemical field, and the steps and conditions can refer to the steps and conditions, in particular the synthesis was carried out according to the description herein.
  • Starting materials are typically from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online database).
  • the dihydropyrimidine compound shown in formula I can also be modified by peripheral modification of the prepared dihydropyrimidine compound shown in formula I using conventional methods in the art Further, other described heterocyclic compounds represented by formula I are obtained.
  • the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified.
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • the preparation method of the heterocyclic compound shown in formula I comprises the following steps: in a solvent, in the presence of a condensing agent, compound the compound shown in formula VI with the compound shown in formula X
  • the compound or its salt is subjected to the amination reaction shown below to obtain the dihydropyrimidine compound shown in formula I;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 13 , W, Z 1 , Z 2 , Z 3 , and * are as defined in either scheme above.
  • the conditions and operations of the amination reaction can be conventional conditions and operations in this type of reaction in the art.
  • the condensing agent is 2,2,6,6-tetramethylpiperidine (TEMP).
  • the solvent can be a nitrile solvent and/or a halogenated hydrocarbon solvent, such as acetonitrile and dichloromethane, and the volume ratio thereof is 1:3.
  • the temperature of the amination reaction may be room temperature (eg, 10°C to 30°C).
  • the molar ratio of the condensing agent to the compound represented by the following formula X or its salt can be 1.2:1; the compound represented by the formula VI and the compound represented by the formula X or The molar ratio of the salt to the salt can be 1.1:1; the volume molar ratio of the solvent to the compound represented by the formula X can be 8L/moL.
  • the present invention also provides a compound represented by formula X or a salt thereof,
  • R 6 , R 7 , R 9 , R 13 , W and is defined as in any of the above scenarios.
  • the compound represented by the following formula X or its salt can be any of the following compounds:
  • compositions such as those of formula I are either commercially available or prepared by synthetic methods known in the art.
  • Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound.
  • Pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
  • salt formation examples include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid , mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
  • Dihydropyrimidines as shown in formula I may have one or more chiral carbon atoms, so optically pure isomers can be isolated, such as pure enantiomers, or racemates, or mixed isomeric isomers Construct. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
  • the chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and protecting groups including tert-butoxycarbonyl (Boc).
  • the above methods may additionally include steps before or after the steps specifically described herein, where appropriate protecting groups may be added or removed to obtain the target compound. Additionally, various synthetic steps can be performed alternately or sequentially to obtain the final target product.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof, and, (one or more) pharmaceutical excipients (such as excipients) excipient or carrier).
  • a pharmaceutical composition may comprise one or more additional dihydropyrimidine compounds of formula I, or a pharmaceutically acceptable salt thereof.
  • the amount of the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.
  • the present invention also provides the use of the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of an HBV inhibitor.
  • the HBV inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or preparing according to conventional methods in the art into a kit to provide rapid detection of the inhibitory effect of HBV.
  • the present invention also provides a use of the dihydropyrimidine compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicine; the medicine can be used for prevention and/or treatment and Drugs for HBV infection.
  • Another aspect of the present invention relates to a method for preventing and/or treating HBV infection, comprising administering to a patient a therapeutically effective dose of the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • Another aspect of the present invention relates to a medicament for treating and/or preventing HBV infection, comprising the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof or a medicament comprising the same combination.
  • the compounds, pharmaceutical compositions of the present invention may be administered topically or systemically, eg, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals, especially humans.
  • enteral administration such as rectal or oral administration
  • parenteral administration to mammals, especially humans.
  • rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures, but in the rectal cavity Melt and/or dissolve to release drug.
  • the compounds of the invention may also be administered parenterally, eg, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
  • the compounds, pharmaceutical compositions of the present invention can be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and A therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof is included as an active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier.
  • the therapeutically effective amount of the active ingredient is as defined above and below, and depends on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated and the mode of administration.
  • enteral administration such as oral administration
  • the compounds of the present invention can be formulated into a wide variety of dosage forms.
  • An effective amount of a compound, pharmaceutical composition or medicament of the present invention can be readily determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation.
  • the pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed.
  • the pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.
  • adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeten
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants
  • compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical dosage forms of the compounds of the present invention may be provided in immediate release, controlled release, sustained release or targeted drug release systems.
  • common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and lyophilized preparations.
  • special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • a pharmaceutical dosage form often consists of a drug, an excipient, and a container/closure system.
  • excipients also known as inactive ingredients
  • excipients may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration and safety of the drug and may provide for the desired drug release Curve method.
  • the type of excipients added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the steps of preparation.
  • Pharmaceutically acceptable excipients exist in the art and include those listed in various pharmacopeias. (See U.S. Pharmacopoeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); the U.S. Food and Drug Administration (the U.S. Food and Drug Administration).
  • compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into formulations for pharmaceutical use.
  • compositions and dosage forms may contain, as an active ingredient, one or more compounds of the present invention or one or more pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is usually a finely divided solid which is in admixture with the finely divided active component.
  • the active component is usually mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like .
  • the formulation of the active compound can include as carrier an encapsulating material providing a capsule in which the active component, with or without carriers, is surrounded by a carrier in association with it.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions can be prepared in solutions, such as aqueous propylene glycol, or can contain emulsifying agents, such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, fragrances, stabilizers and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with binders such as natural or synthetic gums, resins, methyl cellulose, carboxymethyl cellulose, and other conventional suspending agents.
  • Solid form preparations include solutions, suspensions and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers Wait.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable or infusible injectable preparations, eg, as sterile aqueous or oily suspensions.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents.
  • the sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a nontoxic parenterally acceptable diluent or solvent.
  • the pharmaceutical composition can be a solution in 1,3-butanediol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite, or ascorbic acid, citric acid, and salts thereof and sodium EDTA, alone or in combination.
  • Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite, or ascorbic acid, citric acid, and salts thereof and sodium EDTA, alone or in combination.
  • Parenteral solutions may also contain preservatives such as benzalkonium chloride, paraben or propyl paraben, and chlorobutanol.
  • a therapeutically effective dose can first be estimated using various methods well known in the art. Initial doses for animal studies can be based on effective concentrations established in cell culture assays. Dosage ranges suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as medicaments for oral administration.
  • an effective or therapeutically effective amount or dose of an agent refers to the amount of the agent or compound that results in an improvement in symptoms or prolonged survival in an individual.
  • Toxicity and therapeutic efficacy of the molecule can be determined in cell cultures or experimental animals by standard medical procedures, for example by measuring the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). dose).
  • the dose ratio of toxic to therapeutic effects is the therapeutic index and can be expressed as LD50 / ED50 . Agents that exhibit high therapeutic indices are preferred.
  • An effective or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician.
  • the dosage lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and/or the route of administration employed.
  • the correct formulation, route of administration, dosage and dosing interval should be selected according to methods known in the art, taking into account the particularities of the individual situation.
  • MEC minimal effective concentration
  • the amount of the agent or composition administered may depend on various factors, including the sex, age and weight of the individual being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.
  • compositions of the present invention can be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient, as required.
  • the package or device may comprise metal or plastic foil (eg, blister packs) or glass and rubber stoppers, as in vials.
  • the pack or dispenser device may be accompanied by instructions for use.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • C1 - C6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
  • the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of.
  • a substituent group may be substituted at various substitutable positions of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position.
  • the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges.
  • the term " C1 - C6 alkyl” or " C1-6 alkyl” specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkanes
  • C 1-4 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl ), C 4 alkyl (ie butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).
  • halogen is selected from F, Cl, Br or I, especially F or Cl.
  • alkyl as a group or part of another group refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 12 carbon atoms, preferably containing 1 Alkyl groups of up to 6 carbon atoms are straight or branched.
  • General formula C n H 2n+1 .
  • the ""Alkyl” refers to a C1 - C6 alkyl group.
  • the "alkyl” refers to a C1 - C4 alkyl group.
  • Lower alkyl containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl base, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, 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, etc.
  • Non-limiting examples containing 1 to 12 carbon atoms include the above-mentioned examples of lower alkyl groups containing 1 to 6 carbon atoms, as well as 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3 , 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-di Methylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2 -Methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond, and no carbon-carbon triple bond, having, for example, 2 - A straight or branched hydrocarbon chain group of 10 (preferably 2-6, more preferably 2-4) carbon atoms connected to the rest of the molecule by a single bond.
  • the one or more carbon-carbon double bonds may be internal (eg, in 2-butenyl) or terminal (eg, in 1-butenyl).
  • an alkenyl group has 2 to 4 carbon atoms ("C2 - C4 alkenyl").
  • one carbon-carbon double bond is present.
  • C 2 -C 4 alkenyl groups examples include vinyl (C 2 ; ), 1-propenyl (C 3 ; ), 2-propenyl or isopropenyl (C 3 ; ), allyl (C 3 ; ), 1-butenyl (C 4 ; ), 2-butenyl (crotyl), 2-methallyl (C 4 ; ), 2-methylprop-1-en-1-yl (C 4 ; ), but-3-en-1-yl (C 4 ; ), butadienyl ⁇ C 4 ; for example (E)-but-1,3-dien-1-ylbenzene ⁇ , and isomers (eg, cis-trans isomers or stereoisomers).
  • cycloalkyl as part of a group or other group, unless otherwise specified, means a saturated monocyclic, polycyclic or bridged carbocyclic substituted consisting solely of carbon and hydrogen atoms is attached to the rest of the molecule by a single bond via any suitable carbon atom; when polycyclic, it may be a copular or spiro (i.e., two geminal hydrogens on a carbon atom are linked by an alkylene substituted) bridged ring system or spiro ring system. Cycloalkyl substituents can be attached to the central molecule through any suitable carbon atom. In some embodiments, rings having 3-10 carbon atoms may be represented as C3 - C10 cycloalkyl.
  • the C 3 -C 6 cycloalkyl group includes cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ).
  • examples of C 3 -C 10 cycloalkyl groups include the above-mentioned C 3 -C 6 cycloalkyl groups together with cycloheptyl (C 7 ), cyclooctyl (C 8 ), cyclononyl ( C 9 ) and cyclodecyl (C 10 ).
  • heterocycloalkyl as a group or part of another group means a stable compound consisting of 2-6 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen and sulfur 3- to 7-membered saturated cyclic group.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane groups, or stereoisomers thereof; exemplary 4-membered heterocyclyl groups Including, but not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include, but are not Limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxygen Heterothiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof.
  • Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, cyclopentyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl , piperazinyl, triazinyl, or isomers and stereoisomers thereof;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepane radicals, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof.
  • heterocycloalkyl is a C 2 -C 5 heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 indivual.
  • aryl as part of a group or other group refers to a monocyclic or polycyclic group having 6-14 ring atoms and zero heteroatoms provided in the aromatic ring system (eg, bicyclic or tricyclic) groups of 4n+2 aromatic ring systems (eg, with 6, 10, or 14 shared p electrons in a cyclic array) (“ C6 - C14aryl ) ”).
  • aromatic ring system eg, bicyclic or tricyclic
  • 4n+2 aromatic ring systems eg, with 6, 10, or 14 shared p electrons in a cyclic array
  • Examples of the above-mentioned aryl unit include phenyl, naphthyl, phenanthryl, or anthracenyl.
  • heteroaryl as part of a group or other group means having carbon atoms and 1-3 heteroatoms (wherein each heteroatom is independently provided in the aromatic ring system) Groups (" 4-16 membered heteroaryl”).
  • heteroaryl groups containing one or more nitrogen atoms the point of attachment can be a carbon or nitrogen atom, as valence allows.
  • the heteroaryl group is one or more heteroatoms selected from N, O and S, and a 4-6 membered heteroaryl group with 1 to 3 heteroatoms, preferably It is a 5-6-membered heteroaryl group.
  • Exemplary 5-membered heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazole oxadiazolyl, thiadiazolyl, furazanyl, oxtriazolyl or tetrazolyl.
  • Exemplary 6-membered heteroaryl groups include, but are not limited to: pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, or tetrazinyl.
  • moiety refers to a specific fragment or functional group in a molecule.
  • a chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • alkyl group when an alkyl group is clearly represented as a linking group, the alkyl group represents the alkylene group to which it is attached, eg, the group "halo-C 1 -C 6 alkane
  • a C 1 -C 6 alkyl group in "radical” should be understood as a C 1 -C 6 alkylene group.
  • alkylene refers to a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group.
  • alkylene groups include methylene ( -CH2- ), ethylene ⁇ including -CH2CH2- or -CH( CH3 )- ⁇ , isopropylidene ⁇ including -CH( CH3 ) )CH 2 -or -C(CH 3 ) 2 - ⁇ and so on.
  • each step and condition may refer to the conventional operation steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the description mode "...independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups.
  • the description mode "...independently” can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same symbols are The specific options expressed between them do not affect each other.
  • “Pharmaceutically acceptable” means that which can be used in the preparation of pharmaceutical combinations, is generally safe and non-toxic, and is not biologically and otherwise undesirable, and includes both for veterinary and human pharmaceutical use acceptable situation.
  • excipient refers to a pharmaceutically acceptable chemical substance, such as an agent known to those of ordinary skill in the art of pharmacy to aid in the administration of pharmaceuticals. It is a compound that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically or otherwise undesirable, including excipients that are pharmaceutically acceptable for veterinary and human use. Common excipients include binders, surfactants, diluents, disintegrants and lubricants.
  • treatment effective amount refers to an amount of a compound used that, when administered to a subject to treat a disease state, is sufficient to effect such treatment of the disease state.
  • the “administratively effective amount” will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and mode of administration, the judgment of the attending medical or veterinarian, and the like.
  • in treatment means obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical outcomes include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in disease severity, stabilization of disease state (if not worsening), prevention of disease spread, delay or slowing of disease progression, disease state improvement or remission, and partial or complete improvement, whether detectable or undetectable.
  • the term can also refer to prolonging survival as compared to expected survival corresponding to no treatment.
  • mammal refers to a human or any mammal such as a primate, farm animal, pet animal or laboratory animal. Examples of such animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice and rats and the like. Mammals are preferred to humans.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that: the present invention provides a dihydropyrimidine compound, the dihydropyrimidine compound has better anti-HBV (hepatitis B virus) activity and lower cytotoxicity, and can be used for preparing therapeutic and Drugs to prevent HBV infection.
  • HBV hepatitis B virus
  • Figure 1 shows the X-Ray single crystal structure of intermediate 7-3b.
  • the target compound I can be prepared by general synthetic route 1.
  • Compound II, compound III and compound IV are prepared by one-pot reaction under basic conditions to obtain compound V, compound V can be prepared and separated by chromatography to obtain compound Va or prepared by chemical separation method to obtain compound Va, and compound Va is brominated
  • the compound VI is obtained by the reaction, and the target compound I is obtained by reacting the compound VI with the compound X or its salt.
  • the target compound I can be prepared by general synthetic route 2.
  • Compound Vb is subjected to bromination reaction to obtain compound VII, and compound VII is reacted with compound X or its salt to obtain target compound I.
  • the target compound I can be prepared by general synthetic route 3.
  • Compound V is subjected to bromination reaction to obtain compound VIII, and compound VIII is reacted with compound X or its salt to obtain target compound I.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • SHIMADZU LC system column: CSH TM Prep-C18, 19*150mm, liquid handler LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% trifluoroacetic acid in water).
  • LC/MS spectra of compounds were obtained using LC/MS (Agilent Technologies 1200 Series). LC/MS conditions were as follows (run time was 10 min):
  • Acidic conditions A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoroacetic acid in acetonitrile;
  • the intermediates and final compounds were purified by silica gel column chromatography, or used Purification by preparative HPLC on a CSH TM Prep-C18 (5 ⁇ m, OBD TM 19*150 mm) column or on a reverse phase column using XBridgeTM Prep Phenyl (5 ⁇ m, OBD TM 30*100 mm).
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Thin-layer chromatography (TLC) silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of the silica gel plates used for TLC detection products are 0.15mm to 0.2mm, and the specifications for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • reaction mixture was stirred at 20°C for 4 hours, and then thiazole-2-carboxamide hydrochloride (104.9 g, 0.49 mol) and triethylamine (72.8 g, 0.72 mol) were added to the above reaction solution in sequence After the addition, the reaction mixture was further stirred at 20°C-30°C for 12 hours, and then the reaction mixture was further stirred at 70°C-75°C for 8 hours.
  • reaction mixture was stirred at 75°C for 4 hours, the reaction mixture was cooled to 30°C, then filtered, the filter cake was washed with ethanol (180 mL), the filter cake was suspended in dichloromethane (180 L) and the Heat to reflux, add ethanol (0.9 L) to the suspension and continue stirring at 40°C for 30 minutes until the solution is clear, add ethanol (0.9 L) to the above reaction solution at 40°C, and evaporate at 40°C to 60°C Dichloromethane, the obtained reaction solution was stirred at 60°C for 1 hour, the reaction mixture was cooled to 30°C, filtered, and the filter cake was washed with ethanol (180 mL) and dried to obtain a yellow solid (S)-4-(3 -Fluoro-2-methylphenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester mono(R)-(-)-1
  • the intermediate A2-1 was chiral resolved by SFC (column type: CHIRALPAK-AD-H, 5cm x 25cm, 5 ⁇ m column, mobile phase: 20% ethanol in carbon dioxide) to obtain intermediate A2- as a yellow solid 1a (faster eluting, retention time 1.08 minutes) and the second component peak intermediate A2-1b (slower eluting, retention time 1.28 minutes). MS: 380.2 (M+H) + .
  • intermediate 2-2 was done with reference to intermediate 1-4/step 2 by using 3-hydroxy-2-methyl-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c ]pyridine-6-carboxylate tert-butyl ester (intermediate 2-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate 2-Methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazoline[3,4-c]pyridine-3 was prepared from tert-butyl acid (Intermediate 1-4-1) - Keto trifluoroacetate (Intermediate 2-2). MS: 154.3 (M+H) + .
  • intermediate 5-2 was done with reference to intermediate 1-4/step 2 by using 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c] tert-Butyl pyridine-5-carboxylate (Intermediate 5-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylic acid tert-Butyl ester (Intermediate 1-4-1) was prepared to give 2,3,4,5,6,7-hexahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate ( Intermediate 5-2). MS: 139.3 (M+H) + .
  • intermediate 6-3 was done with reference to intermediate 1-4/step 2 by using 4-(5-(tert-butoxycarbonyl)-1-oxo-1,3,4,5,6,7-hexahydro -2H-pyrrole[3,4-c]pyridin-2-yl)benzoic acid (intermediate 6-2) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3, 4-c]Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) prepared to give 4-(1-oxo-1,3,4,5,6,7-hexahydro-2H-pyrrole [3,4-c]pyridin-2-yl)benzoic acid trifluoroacetate (Intermediate 6-3). MS: 259.1 (M+H) + .
  • intermediate 7-1 cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1) was chiral resolved by SFC (column model: CHIRALPAK IH , 5cm x 25cm, 5 ⁇ m column, mobile phase: 35% isopropanol in carbon dioxide) to obtain intermediate 7-1a (faster eluting, retention time 2.978 minutes) as white solids and the middle of the second component peak Body 7-1b (slower eluting, retention time 3.123 minutes). MS: 241.2 (M+H) + .
  • Intermediate 7-2a was synthesized with reference to Intermediate 1-4/Step 2 by using tertiary (3aR,7aS)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylic acid Butyl ester (Intermediate 7-1a) in place of tert-butyl 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazolino[3,4-c]pyridine-6-carboxylate (Intermediate 1 -4-1) Preparation of (3aS,7aS)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (intermediate 7-2a). MS: 141.2 (M+H) + .
  • Intermediate 7-2b was synthesized with reference to Intermediate 1-4/Step 2 by using tertiary (3aS,7aR)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylic acid Butyl ester (Intermediate 7-1b) in place of tert-butyl 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate (Intermediate 1 -4-1) Preparation of (3aR,7aR)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (intermediate 7-2b). MS: 141.2 (M+H) + .
  • Intermediate 7-3b was identified by X-Ray crystal structure analysis as (3aS,7aR)-5-(4-chlorobenzoyl)octahydro-1H-pyrro[3,4-c]pyridin-1-one (see figure 1).
  • the structure of intermediate 7-2b was thus determined (3aR,7aR)-octahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate; correspondingly, the structure of intermediate 7-2a was (3aS,7aS)-Octahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate.
  • intermediate 9-3 The synthesis of intermediate 9-3 was carried out with reference to intermediate 6-3 by using cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7 -1) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1 ) and methyl 3-iodobenzoate instead of methyl 4-iodobenzoate to prepare cis-3-(1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid Trifluoroacetate salt (Intermediate 9-3). MS: 261.2 (M+H) + .
  • intermediate 10-3 The synthesis of intermediate 10-3 was carried out with reference to intermediate 6-3 by using cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7 -1) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1 ) and methyl 2-(4-bromophenyl)-2-methylpropanoate instead of methyl 4-iodobenzoate to prepare cis-2-methyl-2-(4-((3aS,7aS)- 1-Oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)phenyl)propanoic acid trifluoroacetate (Intermediate 10-3).
  • cuprous bromide dimethyl sulfide complex (853 mg, 4.15 mmol) was suspended in tetrahydrofuran (10 mL), and 1 M methylmagnesium bromide (3.1 M methylmagnesium bromide) was added to the reaction mixture with stirring at -40°C. mL) and continued stirring for 0.5 hours, then to the reaction mixture was added trimethylchlorosilane (901 mg, 8.30 mmol) with stirring at -78°C and stirring was continued for 10 minutes.
  • Step 1 Preparation of intermediate cis-23-1
  • intermediate cis-23-1 The synthesis of intermediate cis-23-1 was carried out with reference to intermediate 6-1 by using (cis)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester ( Intermediate 7-1) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1) Preparation of intermediate cis-23-1. MS: 375.2 (M+H) + .
  • Intermediate cis-23-4 was synthesized with reference to intermediate 6-3 by using (3aR,7aS)-2-(4-(methoxycarbonyl)phenyl)-7a-methyl-1-oxooctahydro- 5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis-23-2) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1, 2,3,4,6,7-Hexahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 6-1) was prepared to give intermediate cis-23-4. MS: 275.2 (M+H) + .
  • Intermediate 24-1 was synthesized with reference to Intermediate 6-1 by using (3aR,7aS)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate Compound 7-1a) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (Intermediate 5 -1) Preparation of intermediate 24-1. MS: 375.2 (M+H) + .
  • Step 1 Preparation of intermediate cis 26-1
  • Intermediate 26-3a was synthesized with reference to intermediate 22-7 by using (3aS,7aS)-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 26-2a) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aR,7aS)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 26-3a) .
  • Intermediate 26-3b was synthesized with reference to intermediate 22-7 by using (3aR,7aR)-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 26-2b) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aS,7aR)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 26-3b) .
  • Step 1 Preparation of the intermediate trans 27-1
  • Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (18.0 g, 68.9 mmol) and DBU (2.10 g, 13.8 mmol) were dissolved in DMSO (250 mL) and stirred at 20°C Nitromethane (8.41 g, 137.8 mmol) was added to the reaction mixture and stirring was continued for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate.
  • Ethyl trans-1-benzyl-3-hydroxy-3-(nitromethyl)piperidine-4-carboxylate (intermediate trans 27-1, 2.50 g, 7.76 mmol) was dissolved in ethanol ( 50 mL), Raney Ni (2.5 g) was added to the reaction mixture with stirring. The reaction mixture was stirred at 40°C for 12 hours under the influence of hydrogen, and then the mixture solution was filtered.
  • Ethyl trans-3-(aminomethyl)-1-benzyl-3-hydroxypiperidine-4-carboxylate (intermediate trans 27-2, 2.0 g, 6.84 mmol) was dissolved in toluene (40 mL), the reaction mixture was stirred at 130 °C for 16 hours, the reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate.
  • Intermediate trans 27-4 was synthesized with reference to intermediate 22-7 by using trans-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate trans 27-3) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl) Ethyl) tert-butyl carbamate (intermediate 22-7) was prepared to give trans-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate trans 27-4) .
  • Step 1 Preparation of intermediate cis 28-1
  • Intermediate cis 28-1 was synthesized with reference to intermediate 7-1 by using cis-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate cis-26-2) instead of 5-benzyl-2,3,4,5,6,7-hexahydro-1H-pyrro[3,4-c]pyridin-1-one was prepared to give cis-(3aS, 7aS)-3a-Hydroxy-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate cis 28-1).
  • Step 2 Preparation of intermediate cis 28-2
  • intermediate cis 29-2 Referring to intermediate cis 28-3, cis 3-((3aR, cis 3-((3aR, 7aS)-3a-Hydroxy-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,2-dimethylpropionic acid ethyl ester (Intermediate cis 29-2 ). MS: 285.2 (M+H) + .
  • Step 3 Intermediate cis 30-2a and Intermediate cis 30-2b
  • Step 4 Preparation of intermediate cis 30-3a and intermediate cis 30-3b
  • Intermediate 31-2a was synthesized with reference to intermediate 22-7 by using (3aS,7aR)-5-benzyl-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 31-1a) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aR,7aR)-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 31-2a) .
  • Intermediate 31-2b was synthesized with reference to intermediate 22-7 by using (3aR,7aS)-5-benzyl-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 31-1b) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aS,7aS)-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 31-2b) .
  • Step 4 Preparation of intermediate cis 32-4
  • Intermediate cis 32-4 was synthesized with reference to intermediate 22-7 by using (cis-(3aS,7aS)-5-benzyl-1-oxooctahydro-3aH-pyrrole[3,4-c] Pyridine-3a-carboxylic acid (Intermediate 32-3) in place of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl) tert-Butyl pyrrolidin-3-yl)ethyl)carbamate (Intermediate 22-7) was prepared to give cis(3aR,7aS)-1-oxooctahydro-3aH-pyrro[3,4-c]pyridine Methyl 3a-carboxylate (Intermediate cis 32-4). MS: 199.1 (M+H) + .
  • Step 1 Preparation of intermediate cis 33-1
  • intermediate cis 33-2 refers to intermediate 1-4/step 2 by using intermediate cis 33-1 in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[ 3,4-c]Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give cis (3aR,7aS)-3a-methoxy-2-methyloctahydro-1H-pyrrole [3,4-c]pyridin-1-one (Intermediate cis 33-2). MS: 185.1 (M+H) + .
  • Intermediate 34-2 was chiral resolved by SFC (column model: DAICEL CHIRALPAK AD 250mm*50mm, 10um chromatographic column, mobile phase: 35% 0.1% NH 3 H 2 O-ETOH) to obtain intermediate 34 as white solids -2a (357 mg, RT 3.039 min) and the second component peak Intermediate 34-2b (365 mg, RT 3.718 min).
  • intermediate 34-3a was referred to intermediate 1-4/step 2 by using intermediate 34-2a in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4- c] tert-butyl pyridine-6-carboxylate (Intermediate 1-4-1) was prepared to give (3aR,7aS)-3a-hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridine -1-one (Intermediate 34-3a). MS: 171.1 (M+H) + .
  • intermediate 34-3b was referred to intermediate 1-4/step 2 by using intermediate 34-2b in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4- c] tert-butyl pyridine-6-carboxylate (Intermediate 1-4-1) was prepared to give (3aS,7aR)-3a-hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridine -1-one (Intermediate 34-3b). MS: 171.1 (M+H) + .
  • Intermediate 35-1 was synthesized with reference to Intermediate 6-3 by using Intermediate 34-2a in place of 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4 -c] Pyridine-5-carboxylate tert-butyl ester (Intermediate 5-1) was prepared to give 4-((3aR,7aS)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrrole[ 3,4-c]pyridin-2-yl)benzoic acid (Intermediate 35-1).
  • Intermediate 36-1 was synthesized with reference to Intermediate 6-3 by using Intermediate 34-2b in place of 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4 -c] Pyridine-5-carboxylate tert-butyl ester (Intermediate 5-1) was prepared to give 4-((3aS,7aR)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrrole[ 3,4-c]pyridin-2-yl)benzoic acid (Intermediate 36-1).
  • Step 1 Preparation of intermediate cis 37-1
  • Step 2 Preparation of intermediate cis 37-2
  • intermediate cis 38-1 was referenced to intermediate 1-4/step 2 by using (3aR,7aR)-2-(3-chloro-4-(methoxycarbonyl)phenyl)-7a-fluoro-1 -Oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis 37-2) in place of 3-hydroxy-2,4,5,7-tetrahydro- 6H-Pyrazoline[3,4-c]pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give cis-2-chloro-4-((3aS,7aR)-7a- Methyl fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoate (Intermediate cis 38-1). MS: 327.8 (M+H) +
  • Intermediate 40-3 was synthesized with reference to intermediate 39-3 by using (3aS,7aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate (3aR,7aS)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1a) was prepared to give (3aR, 7aS)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 40-3). MS: 159.1 (M+H) + .
  • Intermediate 46-1 was synthesized with reference to intermediate 37-2 by using (3aS,7aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate body 7-1b) in place of cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1) and methyl 4-iodobenzoate Ester instead of methyl 2-chloro-4-iodobenzoate was prepared to give (3aS,7aS)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole[ 3,4-c]Pyridine-5-carboxylate tert-butyl ester (Intermediate 46-1).
  • Intermediate 48-1 was synthesized with reference to intermediate 46-1 by using (3aR,7aS)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate Compound 7-1a) instead of (3aS,7aR)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1b) was prepared to give (3aR, 7aR)-7a-Fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 48-1).
  • Intermediate 49-1 was synthesized with reference to Intermediate 6-1 by using (3aR,7aR)-7a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylic acid ( Intermediate 41-2) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1) and methyl 3-iodobenzoate instead of methyl 4-iodobenzoate to prepare (3aR, 7aR)-7a-fluoro-2-(3-(methoxycarbonyl)phenyl)-1-oxo Octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 49-1).
  • intermediate 51-1 Referring to intermediate 49-2, prepared by using methyl 3-fluoro-4-iodobenzoate instead of methyl 3-iodobenzoate to give 3-fluoro-4-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 51-1). MS: 297.2 (M+H) + .
  • intermediate 53-1 Referring to intermediate 49-2, prepared by using methyl 3-iodo-5-fluorobenzoate instead of methyl 3-iodobenzoate to give 3-fluoro-5-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 53-1). MS: 297.1 (M+H) + .
  • Intermediate 57-1 was synthesized with reference to intermediate 41-4 by using methyl 3-(bromomethyl)benzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41-1 ) to obtain 3-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid (intermediate 57- 1). MS: 293.1 (M+H) + .
  • intermediate 60-1 was referenced to intermediate 41-4 by using methyl 4-(bromomethyl)benzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41-1 ) to obtain 4-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid (intermediate 60- 1). MS: 293.1 (M+H) + .
  • Intermediate 64-2 was synthesized with reference to Intermediate 1-4/Step 2 by using 6-((3aR,7aR)-5-(tert-butoxycarbonyl)-7a-fluoro-1-oxooctahydro-2H- Pyrro[3,4-c]pyridin-2-yl)nicotinic acid (Intermediate 64-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c ] Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give 6-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrole[3,4-c ]pyridin-2-yl)nicotinic acid (Intermediate 64-2). MS: 280.2 (M+H) + .
  • intermediate 69-1 was referenced to intermediate 41-2 by using (3aR,7aS)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 40-3) Prepared in place of (3aS,7aR)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 39-3) to give (3aS,7aS)-7a-fluoro-1-oxo Substituted octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 69-1).
  • Butyl ester (intermediate 69-1) in place of (3aR,7aR)-7a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 41 -2) and methyl 3-methyl-4-iodobenzoate instead of methyl 3-iodobenzoate to prepare 4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrrole[ 3,4-c]pyridin-2-yl)-3-methylbenzoic acid (Intermediate 69-2). MS: 293.1 (M+H) + .
  • intermediate 70-1 was referred to intermediate 69-2, prepared by using methyl 3-fluoro-4-bromobenzoate instead of methyl 3-methyl-4-iodobenzoate to give 3-fluoro-4-(( 3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 70-1).
  • intermediate 88-1 was referred to intermediate 69-2, prepared by using methyl 3-chloro-4-bromobenzoate in place of methyl 3-methyl-4-iodobenzoate to give 3-chloro-4-(( 3aR,7aS)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 88-1). MS: 313.1 (M+H) + .
  • intermediate 90-1 was referenced to intermediate 41-4 by using methyl 6-(chloromethyl)nicotinate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41-1 ) to prepare 6-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)nicotinic acid (intermediate 90- 1). MS: 294.1 (M+H) + .
  • intermediate 96-1 was referred to intermediate 64-2, which was prepared by using 3-(5-iodo-2-methylphenyl)-2,2-dimethylpropionic acid in place of 6-bromonicotinic acid to give 3- (5-((3As,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methylphenyl)-2,2- Dimethylpropionic acid (Intermediate 96-1). MS: 349.2 (M+H) + .
  • intermediate 100-1 was referenced to intermediate 41-4 by using methyl 4-(1-chloroethyl)benzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41 -1)
  • Intermediate 41 -1 Preparation of 4-(1-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)ethyl)benzoic acid ( Intermediate 100-1).
  • MS 307.1 (M+H) + .
  • Intermediate 103-1 was synthesized with reference to Intermediate 6-3 by using Intermediate 7-1a in place of 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4 -c] tert-butyl pyridine-5-carboxylate (intermediate 5-1) and methyl 4-iodo-2-methylbenzoate instead of methyl 4-iodobenzoate were prepared to give intermediate 103-1.
  • intermediate 104-1 refers to intermediate 49-2, which was prepared by using methyl 6-iodo-4-methylnicotinate instead of methyl 3-iodobenzoate to obtain intermediate 104-1.
  • intermediate 105-1 refers to intermediate 49-2, which was prepared by using methyl 6-iodo-5-methylnicotinate instead of methyl 3-iodobenzoate to obtain intermediate 105-1.
  • intermediate 106-1 refers to intermediate 49-2, which was prepared by using methyl 6-iodo-2-methylnicotinate instead of methyl 3-iodobenzoate to obtain intermediate 106-1.
  • intermediate 107-1 was prepared by using methyl 4-iodo-2-fluorobenzoate instead of methyl 3-iodobenzoate. MS: 297.2 (M+H) + .
  • intermediate 108-1 was prepared by using methyl 5-iodo-3-methylpicolinate instead of methyl 3-iodobenzoate. MS: 294.2 (M+H) + .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are a dihydropyrimidine compound, a preparation method therefor, and an application thereof. Provided are a dihydropyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof. The dihydropyrimidine compound has good anti-HBV activity and lower cytotoxicity, and can be used to prepare drugs for treating and/or preventing HBV infection.

Description

一种二氢嘧啶类化合物、其制备方法及应用A kind of dihydropyrimidine compound, its preparation method and application
本申请要求申请日为2020/12/9的中国专利申请2020114499862的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2020114499862 with an application date of 2020/12/9. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明涉及一种二氢嘧啶类化合物、其制备方法及应用。The invention relates to a dihydropyrimidine compound, a preparation method and application thereof.
背景技术Background technique
乙型肝炎病毒(HBV)属于小型，有包膜，主要是嗜肝病毒的肝炎病毒科，具有约3.2kb大小的部分双链DNA基因组。HBV感染一直是主要的公共卫生问题。尽管可获得安全有效的预防性HBV疫苗，但据估计，全世界约有2.4亿人被乙肝病毒慢性感染。慢性HBV感染使患者处于肝硬化和肝癌的高风险中，据估计每年有686,000多人死于乙肝并发症。(WHO.Global hepatitis report 2017)Hepatitis B virus (HBV) belongs to the small, enveloped, mainly hepadnaviridae family of hepatitis viruses, with a partially double-stranded DNA genome of about 3.2 kb in size. HBV infection has been a major public health problem. Despite the availability of safe and effective preventive HBV vaccines, an estimated 240 million people worldwide are chronically infected with HBV. Chronic HBV infection puts patients at high risk for cirrhosis and liver cancer, and it is estimated that more than 686,000 people die each year from HBV complications. (WHO.Global hepatitis report 2017)
当前的治疗仅限于两类药物，它们是核苷(核苷酸)类似物(拉米夫定，阿德福韦，替诺福韦，替比夫定和恩替卡韦)和干扰素α(INF-α，包括非聚乙二醇化和聚乙二醇化)。尽管两种疗法均可降低HBV DNA并使肝酶正常化，但两种疗法均无法提供高水平的临床治愈率，这是由HBV表面抗原(HBsAg)丧失(有或没有血清转化)定义的。基于干扰素的疗法耐受性差，仅对某些病毒基因型有效。尽管核苷(核苷酸)类似物经常需要延长或可能终生治疗，并且一些具有耐药性，功效低下和耐受性问题。因此，发现和开发具有新颖的作用机制以提高疾病治愈率的有效和安全的抗HBV药物仍然存在巨大的医疗需求。(Marcellin,Patrick,et al.The Lancet 381.9865(2013):468-475；Tang,Lydia SY,et al.Jama 319.17(2018):1802-1813.)Current treatments are limited to two classes of drugs, which are nucleoside (nucleotide) analogs (lamivudine, adefovir, tenofovir, telbivudine and entecavir) and interferon alpha (INF- alpha, including non-pegylated and pegylated). Although both therapies reduced HBV DNA and normalized liver enzymes, neither therapy provided high levels of clinical cure rates, as defined by HBV surface antigen (HBsAg) loss (with or without seroconversion). Interferon-based therapy is poorly tolerated and is only effective against certain viral genotypes. Although nucleoside (nucleotide) analogs often require prolonged or potentially lifelong treatment, and some suffer from drug resistance, low efficacy and tolerability issues. Therefore, there is still a huge medical need to discover and develop effective and safe anti-HBV drugs with novel mechanisms of action to improve disease cure rates. (Marcellin, Patrick, et al. The Lancet 381.9865(2013): 468-475; Tang, Lydia SY, et al. Jama 319.17(2018): 1802-1813.)
HBV衣壳由HBV核心蛋白组装而成，可保护封闭的病毒基因组，并为前基因组RNA(pgRNA)逆转录为DNA创造了环境。衣壳蛋白在病毒的生命周期中起着至关重要的作用。业已证明，HBV衣壳装配调节剂会干扰衣壳的装配和功能，并阻断HBV生命周期中的多个步骤。这些试剂既干扰新病毒的产生，又干扰核衣壳向细胞核的运输，从而阻止了新cccDNA的建立。如果与经批准的抗-HBV核苷酸类似物和其他抗-HBV药物联合使用，这些功能可以提供有效的临床抗病毒活性，并具有协同增效作用。(Diab,Ahmed,et al.Antiviral research 149(2018):211-220.)The HBV capsid is assembled from the HBV core protein, which protects the closed viral genome and creates an environment for reverse transcription of pregenomic RNA (pgRNA) into DNA. Capsid proteins play a crucial role in the life cycle of viruses. Modulators of HBV capsid assembly have been shown to interfere with capsid assembly and function and block multiple steps in the HBV life cycle. These agents interfere with both the production of new viruses and the trafficking of the nucleocapsid to the nucleus, preventing the establishment of new cccDNAs. These functions can provide potent clinical antiviral activity with synergistic effects if used in combination with approved anti-HBV nucleotide analogs and other anti-HBV drugs. (Diab, Ahmed, et al. Antiviral research 149(2018): 211-220.)
已经开发了不同化学系列的HBV衣壳装配调节剂。但仍然需要继续开发高活性、更安全和治疗高度有效的衣壳装配调节剂。Different chemical series of modulators of HBV capsid assembly have been developed. However, there is still a need to continue to develop highly active, safer and therapeutically highly effective modulators of capsid assembly.
发明内容SUMMARY OF THE INVENTION
本发明所要解决的技术问题是现有技术中治疗与预防HBV感染的药物单一的问题，而提供了一种二氢嘧啶类化合物、其制备方法及应用，该二氢嘧啶类化合物具有较好的抗HBV(乙肝病毒)活性、以及较低的细胞毒性，可用于制备治疗和/或预防HBV感染的药物。The technical problem to be solved by the present invention is the single problem of drugs for treating and preventing HBV infection in the prior art, and provides a dihydropyrimidine compound, a preparation method and application thereof, and the dihydropyrimidine compound has better properties. The anti-HBV (hepatitis B virus) activity and low cytotoxicity can be used to prepare medicines for treating and/or preventing HBV infection.
本发明是通过下述技术方案来解决上述技术问题的。The present invention solves the above-mentioned technical problems through the following technical solutions.
本发明提供了一种如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，The present invention provides a dihydropyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021135751-appb-000001
Figure PCTCN2021135751-appb-000001
其中，
Figure PCTCN2021135751-appb-000002
为
Figure PCTCN2021135751-appb-000003
in,
Figure PCTCN2021135751-appb-000002
for
Figure PCTCN2021135751-appb-000003
R 1为2-噻唑基，被一个或多个R 1a取代的2-噻唑基，R 1a独立地为卤素或甲基；当取代基为多个时，相同或不同； R 1 is 2-thiazolyl, 2-thiazolyl substituted by one or more R 1a , R 1a is independently halogen or methyl; when there are multiple substituents, they are the same or different;
R 2，R 3，R 4独立地为H，卤素，甲基，-CN，甲基-O-或-CF 3； R 2 , R 3 , R 4 are independently H, halogen, methyl, -CN, methyl-O- or -CF 3 ;
R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
R 6为H，卤素，羟基、C 1-3烷基，环丙基； R 6 is H, halogen, hydroxyl, C 1-3 alkyl, cyclopropyl;
R 7为H，卤素，C 1-3烷基，羟基，甲氧基，C 1-3烷基-O-C(＝O)-； R 7 is H, halogen, C 1-3 alkyl, hydroxy, methoxy, C 1-3 alkyl-OC(=O)-;
或者，R 6和R 7与相连的碳原子一起可以形成：3-6元环烷基或3-6元杂环烷基；所述的3-6元杂环烷基中，杂原子选自N、O、S，杂原子个数为1或2； Alternatively, R 6 and R 7 together with the connected carbon atoms can form: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; in the 3-6 membered heterocycloalkyl, the heteroatom is selected from N, O, S, the number of heteroatoms is 1 or 2;
R 9为H，甲基； R 9 is H, methyl;
W为＝N-(与相邻的C形成双键)，-C(R 11R 12)-； W is =N- (forms a double bond with the adjacent C), -C(R 11 R 12 )-;
R 11，R 12独立地为H，C 1-3烷基； R 11 , R 12 are independently H, C 1-3 alkyl;
R 13为H、苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-；当取代基为多个时，相同或不同； R 13 is H, phenyl-L 1 -, pyridyl-L 2 -, 3-7-membered monocyclic cycloalkyl-L 3 -, C 1-6 alkyl-L 4 -, or, by one or Multiple R 1b substituted: C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 -, 3-7 membered monocyclic cycloalkyl-L 3 -; when substituent When there are multiple, the same or different;
-L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、C 1-3亚烷基、R 8取代的C 1-3亚烷基；R 8独立地为C 1-3烷基、3-7元环烷基； -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently connecting bonds, C 1-3 alkylene, and R 8 substituted C 1-3 alkylene; R 8 is independently C 1-3 alkyl, 3-7 membered cycloalkyl;
R 1b独立地为-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，OH，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-，卤素，C 1-6烷基，CN，C 1-3烷基磺酰基，3-7元环烷基；或者被一个或多个R 1c取代的：-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-，C 1-6烷基，C 1-3烷基磺酰基，3-7元环烷基；R 1c独立地为卤素、C 1- 4烷基、3-7元环烷基； R 1b is independently -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 - C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, OH, C 1-3 alkane Base-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, halogen, C 1-6 alkyl, CN, C 1-3 alkylsulfonyl, 3-7 membered ring Alkyl; or substituted by one or more R 1c : -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene) -CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1- 3 alkyl-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, C 1-6 alkyl, C 1-3 alkylsulfonyl, 3-7 membered cycloalkyl ; R 1c is independently halogen, C 1-4 alkyl, 3-7 membered cycloalkyl;
Figure PCTCN2021135751-appb-000004
表示单键或双键；
Figure PCTCN2021135751-appb-000004
Indicates a single bond or a double bond;
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
在本发明某些优选实施方案中，所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐中的某些基团如下定义，未提及的基团同本申请任一方案所述(简称“在本发明某一方案中”)，In some preferred embodiments of the present invention, certain groups in the dihydropyrimidine compounds represented by formula I or their pharmaceutically acceptable salts are defined as follows, and the unmentioned groups are the same as those in this application Described in any scheme (referred to as "in a certain scheme of the present invention"),
R 1为2-噻唑基(例如
Figure PCTCN2021135751-appb-000005
)。 R 1 is 2-thiazolyl (for example
Figure PCTCN2021135751-appb-000005
).
在本发明某一方案中，In a certain aspect of the present invention,
R 2，R 3，R 4独立地为H，卤素，甲基；例如H，F，Cl，Br，甲基。 R 2 , R 3 , R 4 are independently H, halogen, methyl; eg, H, F, Cl, Br, methyl.
在本发明某一方案中，In a certain aspect of the present invention,
R 5为甲基或乙基，例如乙基。 R 5 is methyl or ethyl, eg ethyl.
在本发明某一方案中，In a certain aspect of the present invention,
R 6为H，卤素，羟基、C 1-3烷基；例如H，F，OH，甲基；又例如H，F，甲基。 R 6 is H, halogen, hydroxy, C 1-3 alkyl; such as H, F, OH, methyl; another example is H, F, methyl.
在本发明某一方案中，In a certain aspect of the present invention,
R 7为H，卤素，羟基，甲氧基，C 1-3烷基-O-C(＝O)-；例如H，F，OH，甲氧基、甲氧基羰基；又例如H，OH，F，还例如H，OH。 R 7 is H, halogen, hydroxy, methoxy, C 1-3 alkyl-OC(=O)-; such as H, F, OH, methoxy, methoxycarbonyl; another example is H, OH, F , also for example H, OH.
在本发明某一方案中，In a certain aspect of the present invention,
R 6和R 7与连接的碳一起形成3-6元杂环烷基；例如氧杂环丙基；即
Figure PCTCN2021135751-appb-000006
为
Figure PCTCN2021135751-appb-000007
Figure PCTCN2021135751-appb-000008
R 6 and R 7 are taken together with the attached carbon to form a 3-6 membered heterocycloalkyl; for example, oxacyclopropyl; i.e.
Figure PCTCN2021135751-appb-000006
for
Figure PCTCN2021135751-appb-000007
Figure PCTCN2021135751-appb-000008
在本发明某一方案中，In a certain aspect of the present invention,
Figure PCTCN2021135751-appb-000009
为
Figure PCTCN2021135751-appb-000010
例如
Figure PCTCN2021135751-appb-000011
Figure PCTCN2021135751-appb-000009
for
Figure PCTCN2021135751-appb-000010
E.g
Figure PCTCN2021135751-appb-000011
在本发明某一方案中，In a certain aspect of the present invention,
R 9为H。 R9 is H.
在本发明某一方案中，In a certain aspect of the present invention,
R 11，R 12独立地为H。 R 11 and R 12 are independently H.
在本发明某一方案中，In a certain aspect of the present invention,
当W为N时，
Figure PCTCN2021135751-appb-000012
为
Figure PCTCN2021135751-appb-000013
例如。
Figure PCTCN2021135751-appb-000014
When W is N,
Figure PCTCN2021135751-appb-000012
for
Figure PCTCN2021135751-appb-000013
E.g.
Figure PCTCN2021135751-appb-000014
在本发明某一方案中，In a certain aspect of the present invention,
当W为C(R 11R 12)时，
Figure PCTCN2021135751-appb-000015
为
Figure PCTCN2021135751-appb-000016
例如
Figure PCTCN2021135751-appb-000017
When W is C(R 11 R 12 ),
Figure PCTCN2021135751-appb-000015
for
Figure PCTCN2021135751-appb-000016
E.g
Figure PCTCN2021135751-appb-000017
在本发明某一方案中，In a certain aspect of the present invention,
R 13为H，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-； R 13 is H, C 1-6 alkyl-L 4 -, or, substituted with one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2- , 3-7 membered monocyclic cycloalkyl-L 3 -;
例如H，甲基，异丙基，
Figure PCTCN2021135751-appb-000018
Figure PCTCN2021135751-appb-000019
(例如
Figure PCTCN2021135751-appb-000020
)、
Figure PCTCN2021135751-appb-000021
(例如
Figure PCTCN2021135751-appb-000022
)、
Figure PCTCN2021135751-appb-000023
(例如
Figure PCTCN2021135751-appb-000024
)。 For example H, methyl, isopropyl,
Figure PCTCN2021135751-appb-000018
Figure PCTCN2021135751-appb-000019
(E.g
Figure PCTCN2021135751-appb-000020
),
Figure PCTCN2021135751-appb-000021
(E.g
Figure PCTCN2021135751-appb-000022
),
Figure PCTCN2021135751-appb-000023
(E.g
Figure PCTCN2021135751-appb-000024
).
在本发明某一方案中，In a certain aspect of the present invention,
-L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、亚甲基、
Figure PCTCN2021135751-appb-000025
或-CH(CH 3)-。 -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linking bond, a methylene group,
Figure PCTCN2021135751-appb-000025
or -CH( CH3 )-.
在本发明某一方案中，In a certain aspect of the present invention,
R 1b独立地为-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，卤素，C 1-6烷基，3-7元环烷基；或者被一个或多个取代基R 1c取代的：C 1-3烷基-O-，C 1-6烷基； R 1b is independently -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 - C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl- O-, halogen, C 1-6 alkyl, 3-7 membered cycloalkyl; or substituted by one or more substituents R 1c : C 1-3 alkyl-O-, C 1-6 alkyl;
又例如，-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，C 1-3烷基-O-，卤素，C 1-6烷基，3-7元环烷基，被一个或多个取代基R 1c取代的：C 1-3烷基-O-，C 1-6烷基； Another example, -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, C 1-3 alkyl-O-, halogen, C 1-6 alkyl, 3-7 membered cycloalkyl, substituted by one or more substituents R 1c : C 1-3 alkyl-O-, C 1 -6 alkyl;
再例如-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，C 1-3烷基-O-，C 1-6烷基，卤素，3-7元环烷基，或被一个或多个取代基R 1c取代的C 1-3烷基-O-； Another example is -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, C 1-3 alkyl-O-, C 1- 6 alkyl, halogen, 3-7 membered cycloalkyl, or C 1-3 alkyl-O- substituted by one or more substituents R 1c ;
还例如-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，C 1-3烷基-O-，C 1-6烷基。 Also for example -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, C 1-3 alkyl-O-, C 1- 6 alkyl.
在本发明某一方案中，In a certain aspect of the present invention,
至少一个R 1b为CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2- 6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基。 At least one R 1b is CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl.
在本发明某一方案中，In a certain aspect of the present invention,
当W为N(与相邻的C形成双键)(即
Figure PCTCN2021135751-appb-000026
为
Figure PCTCN2021135751-appb-000027
)时，R 13为H，C 1-6烷基-L 4-。 When W is N (forms a double bond with the adjacent C) (ie
Figure PCTCN2021135751-appb-000026
for
Figure PCTCN2021135751-appb-000027
), R 13 is H, C 1-6 alkyl-L 4 -.
在本发明某一方案中，当W为C(R 11R 12)、
Figure PCTCN2021135751-appb-000028
为
Figure PCTCN2021135751-appb-000029
时，R 13为H或被一个或多个R 1b取代的苯基-L 1-；例如H。 In a certain scheme of the present invention, when W is C(R 11 R 12 ),
Figure PCTCN2021135751-appb-000028
for
Figure PCTCN2021135751-appb-000029
, R 13 is H or phenyl-L 1 - substituted with one or more R 1b ; eg, H.
在本发明某一方案中，In a certain aspect of the present invention,
其中，in,
R 1为2-噻唑基， R 1 is 2-thiazolyl,
R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
R 5为C 1-3烷基(例如乙基)； R 5 is C 1-3 alkyl (eg, ethyl);
R 6为H，卤素，(例如F)，OH，C 1-3烷基(例如甲基)； R 6 is H, halogen, (eg F), OH, C 1-3 alkyl (eg methyl);
R 7为H，F，OH，甲氧基、C 1-3烷基-O-C(＝O)-(例如甲氧基羰基)； R 7 is H, F, OH, methoxy, C 1-3 alkyl-OC(=O)- (eg methoxycarbonyl);
或者，R 6和R 7与连接的碳一起形成3-6元杂环烷基； Alternatively, R6 and R7 together with the attached carbon form a 3-6 membered heterocycloalkyl;
R 9为H； R 9 is H;
W为C(R 11R 12)或＝N-(与相邻的C形成双键)； W is C(R 11 R 12 ) or =N- (forms a double bond with the adjacent C);
R 11，R 12独立地为H； R 11 , R 12 are independently H;
R 13为H，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-； R 13 is H, C 1-6 alkyl-L 4 -, or, substituted with one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2- , 3-7 membered monocyclic cycloalkyl-L 3 -;
-L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、C 1-3亚烷基(例如亚甲基、亚乙基)； -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linkage, C 1-3 alkylene (eg methylene, ethylene);
R 1b独立地为卤素，C 1-6烷基，C 1-3烷基-O-，3-7元环烷基，CO 2H，-(C 2-6亚烯基)-CO 2H，-(C 1-6亚烷基)-CO 2H，-CO 2-C 1-3烷基，被一个或多个取代基R 1c取代的：C 1-3烷基-O-或C 1-6烷基；R 1c独立地为卤素；且至少一个R 1b为CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基； R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, CO 2 H, -(C 2-6 alkenylene)-CO 2 H , -(C 1-6 alkylene)-CO 2 H, -CO 2 -C 1-3 alkyl, substituted by one or more substituents R 1c : C 1-3 alkyl-O- or C 1-6 alkyl; R 1c is independently halogen; and at least one R 1b is CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, - (C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl;
Figure PCTCN2021135751-appb-000030
为
Figure PCTCN2021135751-appb-000031
Figure PCTCN2021135751-appb-000030
for
Figure PCTCN2021135751-appb-000031
例如
Figure PCTCN2021135751-appb-000032
为
Figure PCTCN2021135751-appb-000033
E.g
Figure PCTCN2021135751-appb-000032
for
Figure PCTCN2021135751-appb-000033
在本发明某一方案中，In a certain aspect of the present invention,
其中，in,
R 1为2-噻唑基， R 1 is 2-thiazolyl,
R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
R 5为C 1-3烷基(例如乙基或甲基)； R 5 is C 1-3 alkyl (eg, ethyl or methyl);
R 6为H，F，OH，甲基； R 6 is H, F, OH, methyl;
R 7为H，F，OH，甲氧基、C 1-3烷基-O-C(＝O)-(例如甲氧基羰基)； R 7 is H, F, OH, methoxy, C 1-3 alkyl-OC(=O)- (eg methoxycarbonyl);
或者，R 6和R 7与连接的碳一起形成3元杂环烷基； Alternatively, R and R together with the attached carbon form a 3 - membered heterocycloalkyl;
R 9为H； R 9 is H;
W为C(R 11R 12)或N(与相邻的C形成双键)； W is C (R 11 R 12 ) or N (forms a double bond with the adjacent C);
R 11，R 12独立地为H； R 11 , R 12 are independently H;
R 13为H，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基，3-7元单环的环烷基-L 3-； R 13 is H, C 1-6 alkyl-L 4 -, or, substituted with one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl, 3 -7-membered monocyclic cycloalkyl-L 3 -;
-L 1-，-L 3-，-L 4-独立地为连接键、亚甲基、-CH(CH 3)-； -L 1 -, -L 3 -, -L 4 - are independently a linkage, a methylene group, -CH(CH 3 )-;
R 1b独立地为卤素，C 1-6烷基，C 1-3烷基-O-，3-7元环烷基，-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，-CO 2-C 1-3烷基，3-7元环烷基，或被一个或多个R 1c取代的C 1-6烷基或C 1-3烷基-O-；R 1c独立地为卤素；至少一个R 1b为-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，-CO 2-C 1-3烷基； R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, -CO 2 -C 1-3 alkyl, 3-7 membered cycloalkyl, or C 1-6 substituted with one or more R 1c Alkyl or C 1-3 alkyl-O-; R 1c is independently halogen; at least one R 1b is -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2- 6 alkenylene) -CO 2 H, -CO 2 -C 1-3 alkyl;
Figure PCTCN2021135751-appb-000034
为
Figure PCTCN2021135751-appb-000035
Figure PCTCN2021135751-appb-000034
for
Figure PCTCN2021135751-appb-000035
例如，当
Figure PCTCN2021135751-appb-000036
为
Figure PCTCN2021135751-appb-000037
时，R 13为C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1- 6烷基-L 4-，苯基-L 1-，吡啶基，3-7元单环的环烷基-L 3-； For example, when
Figure PCTCN2021135751-appb-000036
for
Figure PCTCN2021135751-appb-000037
, R 13 is C 1-6 alkyl-L 4 -, or, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 - , pyridyl, 3 -7-membered monocyclic cycloalkyl-L 3 -;
当
Figure PCTCN2021135751-appb-000038
为
Figure PCTCN2021135751-appb-000039
时，R 13为H或C 1-6烷基。 when
Figure PCTCN2021135751-appb-000038
for
Figure PCTCN2021135751-appb-000039
, R 13 is H or C 1-6 alkyl.
在本发明某一方案中，In a certain aspect of the present invention,
其中，in,
R 1为2-噻唑基， R 1 is 2-thiazolyl,
R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
R 5为C 1-3烷基(例如乙基或甲基)； R 5 is C 1-3 alkyl (eg, ethyl or methyl);
Figure PCTCN2021135751-appb-000040
为
Figure PCTCN2021135751-appb-000041
Figure PCTCN2021135751-appb-000040
for
Figure PCTCN2021135751-appb-000041
R 6为H，F，甲基； R 6 is H, F, methyl;
R 9为H； R 9 is H;
Figure PCTCN2021135751-appb-000042
为
Figure PCTCN2021135751-appb-000043
Figure PCTCN2021135751-appb-000042
for
Figure PCTCN2021135751-appb-000043
在本发明某一方案中，In a certain aspect of the present invention,
其中，in,
Figure PCTCN2021135751-appb-000044
为
Figure PCTCN2021135751-appb-000045
Figure PCTCN2021135751-appb-000044
for
Figure PCTCN2021135751-appb-000045
例如，E.g,
R 1为2-噻唑基， R 1 is 2-thiazolyl,
R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
R 9为H； R 9 is H;
R 13为H，被一个或多个R 1b取代的苯基-L 1-； R 13 is H, phenyl-L 1 - substituted by one or more R 1b ;
-L 1-独立地为连接键、C 1-3亚烷基； -L 1 - is independently a linkage, C 1-3 alkylene;
R 1b独立地为C 1-6烷基，C 1-3烷基-O-，-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H；且至少一个R 1b为-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H； R 1b is independently C 1-6 alkyl, C 1-3 alkyl-O-, -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkene and at least one R 1b is -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H ;
Figure PCTCN2021135751-appb-000046
为
Figure PCTCN2021135751-appb-000047
Figure PCTCN2021135751-appb-000046
for
Figure PCTCN2021135751-appb-000047
又例如R 13为被一个或多个R 1b取代的苯基； Another example R 13 is phenyl substituted by one or more R 1b ;
且至少一个R 1b为-CO 2H。 And at least one R 1b is -CO 2 H.
在本发明某一方案中，In a certain aspect of the present invention,
其中，in,
Figure PCTCN2021135751-appb-000048
为
Figure PCTCN2021135751-appb-000049
Figure PCTCN2021135751-appb-000048
for
Figure PCTCN2021135751-appb-000049
R 1为2-噻唑基， R 1 is 2-thiazolyl,
R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
R 6为H，F，甲基； R 6 is H, F, methyl;
R 7为H，F，OH，甲氧基、C 1-3烷基-O-C(＝O)-； R 7 is H, F, OH, methoxy, C 1-3 alkyl-OC(=O)-;
R 6和R 7与连接的碳一起形成氧杂环丙基； R 6 and R 7 together with the attached carbon form oxanyl;
R 9为H； R 9 is H;
R 13为H，C 1-6烷基-L 4-，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-； R 13 is H, C 1-6 alkyl-L 4 -, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 - , 3-7 membered monocyclic cycloalkyl-L 3 -;
-L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、亚甲基、-CH(CH 3)-； -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linkage, a methylene group, -CH(CH 3 )-;
R 1b独立地为卤素，C 1-6烷基，C 1-3烷基-O-，3-7元环烷基，CO 2H，-(C 2-6亚烯基)-CO 2H，-(C 1-6亚烷基)-CO 2H，-CO 2-C 1-3烷基，被一个或多个取代基R 1c取代的：C 1-3烷基-O-或C 1-6烷基；R 1c独立地为卤素；且至少一个R 1b为-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基； R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, CO 2 H, -(C 2-6 alkenylene)-CO 2 H , -(C 1-6 alkylene)-CO 2 H, -CO 2 -C 1-3 alkyl, substituted by one or more substituents R 1c : C 1-3 alkyl-O- or C 1-6 alkyl; R 1c is independently halogen; and at least one R 1b is -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 - C 1-3 alkyl;
Figure PCTCN2021135751-appb-000050
为
Figure PCTCN2021135751-appb-000051
Figure PCTCN2021135751-appb-000050
for
Figure PCTCN2021135751-appb-000051
在本发明某一方案中，In a certain aspect of the present invention,
当R 1a独立地为卤素时，所述的卤素为F、Cl、Br。 When R 1a is independently halogen, said halogen is F, Cl, Br.
在本发明某一方案中，In a certain aspect of the present invention,
当R 2，R 3，R 4独立地为卤素时，所述的卤素为F、Cl、Br。 When R 2 , R 3 , and R 4 are independently halogen, the halogen is F, Cl, or Br.
在本发明某一方案中，In a certain aspect of the present invention,
当R 5为C 1-3烷基时，所述的C 1-3烷基为甲基、乙基、正丙基、异丙基；例如乙基。 When R 5 is a C 1-3 alkyl group, the C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl; for example, ethyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 6为C 1-3烷基时，所述的C 1-3烷基为甲基、乙基、正丙基、异丙基；例如甲基。 When R 6 is a C 1-3 alkyl group, the C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl; for example, methyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 6为卤素时，所述的卤素为F、Cl、Br；例如F。 When R 6 is halogen, the halogen is F, Cl, Br; for example, F.
在本发明某一方案中，In a certain aspect of the present invention,
当R 7为C 1-3烷基、C 1-3烷基-O-C(＝O)-时，所述的C 1-3烷基、C 1-3烷基-O-C(＝O)-里的C 1-3烷基为甲基、乙基、正丙基、异丙基；例如甲基。 When R 7 is C 1-3 alkyl, C 1-3 alkyl-OC(=O)-, said C 1-3 alkyl, C 1-3 alkyl-OC(=O)- The C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl; for example, methyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 7为卤素时，所述的卤素为F、Cl、Br；例如F。 When R7 is halogen, the halogen is F, Cl, Br; for example, F.
在本发明某一方案中，In a certain aspect of the present invention,
当R 6和R 7与相连的碳原子一起可以形成3-6元杂环烷基时，所述的3-6元杂环烷基为氧杂环丙基。 When R 6 and R 7 together with the attached carbon atoms can form a 3-6 membered heterocycloalkyl group, the 3-6 membered heterocycloalkyl group is oxanepropyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 13为C 1-6烷基-L 4-，被一个或多个R 1b取代的C 1-6烷基-L 4-时，所述的C 1-6烷基-L 4-，被一个或多个R 1b取代的C 1-6烷基-L 4-里的C 1-6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基；例如甲基、乙基、正丙基、异丙基、异丁基、仲丁基或叔丁基。 When R 13 is C 1-6 alkyl-L 4 -, C 1-6 alkyl-L 4 - substituted by one or more R 1b, said C 1-6 alkyl - L 4 -, C 1-6 alkyl (eg methyl, ethyl, propyl, butyl, pentyl or hexyl) in C 1-6 alkyl substituted by one or more R 1b -L 4 - is independently C 1 - C4 alkyl; for example methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or tert-butyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 13为3-7元单环的环烷基-L 3-，被一个或多个R 1b取代的3-7元单环的环烷基时，所述的3-7元单环的环烷基-L 3-，被一个或多个R 1b取代的3-7元单环的环烷基里的3-7元单环的环烷基独立地为环丙基、环丁基、环戊基、环己基。 When R 13 is a 3-7-membered monocyclic cycloalkyl-L 3 -, a 3-7-membered monocyclic cycloalkyl substituted by one or more R 1b , the 3-7-membered monocyclic cycloalkyl Cycloalkyl-L 3 -, the 3-7-membered monocyclic cycloalkyl in the 3-7-membered monocyclic cycloalkyl substituted by one or more R 1b is independently cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl.
在本发明某一方案中，In a certain aspect of the present invention,
当-L 1-，-L 2-，-L 3-，-L 4-独立地为C 1-3亚烷基、R 8取代的C 1-3亚烷基时，所述的C 1-3亚烷基和R 8取代的C 1-3亚烷基里的C 1-3亚烷基为亚甲基(-CH 2-)，亚乙基(例如-CH 2CH 2-、-CH(CH 3)-、
Figure PCTCN2021135751-appb-000052
Figure PCTCN2021135751-appb-000053
)，亚异丙基(例如-CH(CH 3)CH 2-或-C(CH 3) 2-)；较佳地为-(CH 2)-、
Figure PCTCN2021135751-appb-000054
或-CH(CH 3)-。 When -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently C 1-3 alkylene, R 8 substituted C 1-3 alkylene, the C 1- C 1-3 alkylene in C 1-3 alkylene substituted by 3 alkylene and R 8 is methylene (-CH 2 -), ethylene (for example -CH 2 CH 2 -, -CH (CH 3 )-,
Figure PCTCN2021135751-appb-000052
Figure PCTCN2021135751-appb-000053
), isopropylidene (eg -CH(CH 3 )CH 2 - or -C(CH 3 ) 2 -); preferably -(CH 2 )-,
Figure PCTCN2021135751-appb-000054
or -CH( CH3 )-.
在本发明某一方案中，In a certain aspect of the present invention,
当R 8独立地为C 1-4烷基时，所述的C 1-4烷基为甲基、乙基、正丙基、异丙基、异丁基、仲丁基或叔丁基。 When R 8 is independently C 1-4 alkyl, said C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or tert-butyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 8独立地为3-7元环烷基时，所述的3-7元环烷基为环丙基、环丁基、环戊基、环己基、环庚基；例如环丙基。 When R8 is independently a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; for example, cyclopropyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 1b独立地为C 1-6烷基；或者被一个或多个R 1c取代的C 1-6烷基时，所述的C 1-6烷基，和被一个或多个R 1c取代的C 1-6烷基里的C 1-6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；例如甲基。 When R 1b is independently C 1-6 alkyl; or C 1-6 alkyl substituted by one or more R 1c , said C 1-6 alkyl, and substituted by one or more R 1c The C 1-6 alkyl group (such as methyl, ethyl, propyl, butyl, pentyl or hexyl) in the C 1-6 alkyl group is independently a C 1 -C 4 alkyl group (such as methyl, ethyl group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); for example methyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 1b独立地为-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-3亚烷基)-，C 1-3烷基磺酰基；或者被一个或多个R 1c取代的：-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-3亚烷基)-，C 1-3烷基磺酰基时，所述的-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-，C 1-3烷基磺酰基，和被一个或多个R 1c取代的：-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-， C 1-3烷基磺酰基里的C 1-3烷基独立地为甲基、乙基、正丙基、异丙基；例如甲基。 When R 1b is independently -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-3 alkylene)-, C 1-3 alkylsulfonyl; or by One or more R 1c substituted: -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene )-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-3 alkylene)-, C 1-3 alkylsulfonyl When, the -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, C 1-3 alkylsulfonyl, and by a Or more R 1c substituted: -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene) -CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, C 1-3 alkyl sulfonyl The C 1-3 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl; for example, methyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 1b独立地为-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-，或者被一个或多个R 1c取代的：-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-时，所述的-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-，和被一个或多个R 1c取代的：-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-里的C 1-6亚烷基独立地为亚甲基(-CH 2-)，亚乙基(例如-CH 2CH 2-、-CH(CH 3)-、
Figure PCTCN2021135751-appb-000055
)，亚异丙基(例如-CH(CH 3)CH 2-或-C(CH 3) 2-)，
Figure PCTCN2021135751-appb-000056
When R 1b is independently -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O -(C 1-6 alkylene)-, or substituted with one or more R 1c : -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 alkylene)-, said -(C 1-6 alkylene)-CO 2 H, -( C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 alkylene)-, and substituted by one or more R 1c : -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 C 1-6 alkylene in alkylene)- is independently methylene (-CH 2 -), ethylene (eg -CH 2 CH 2 -, -CH(CH 3 )-,
Figure PCTCN2021135751-appb-000055
), isopropylidene (eg -CH(CH 3 )CH 2 - or -C(CH 3 ) 2 -),
Figure PCTCN2021135751-appb-000056
在本发明某一方案中，In a certain aspect of the present invention,
当R 1b独立地为-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，或者被一个或多个R 1c取代的：-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基时，所述的-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，和被一个或多个R 1c取代的：-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基里的C 2-6亚烯基独立地为C 2～C 3亚烯基，例如
Figure PCTCN2021135751-appb-000057
或其异构体(例如顺反异构体)；较佳地为
Figure PCTCN2021135751-appb-000058
When R 1b is independently -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, or by one or more R 1c Substituted: -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, the -(C 2-6 alkene alkenyl)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, and substituted by one or more R 1c : -(C 2-6 alkenylene) -CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 2-6 alkenylene in C 1-3 alkyl is independently C 2 -C 3 alkenylene, for example
Figure PCTCN2021135751-appb-000057
or its isomers (such as cis-trans isomers); preferably
Figure PCTCN2021135751-appb-000058
在本发明某一方案中，In a certain aspect of the present invention,
当R 1b独立地为3-7元环烷基，被一个或多个R 1c取代的3-7元环烷基时，所述的3-7元环烷基，和被一个或多个R 1c取代的3-7元环烷基里的3-7元环烷基独立地为环丙基、环丁基、环戊基、环己基、环庚基；例如环丙基。 When R 1b is independently a 3-7 membered cycloalkyl, a 3-7 membered cycloalkyl substituted by one or more R 1c , the 3-7 membered cycloalkyl, and a 3-7 membered cycloalkyl group substituted by one or more R The 3-7 membered cycloalkyl in the 1c -substituted 3-7 membered cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; for example, cyclopropyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 1c独立地为卤素时，所述的卤素为F，Cl；例如F。 When R 1c is independently halogen, the halogen is F, Cl; eg, F.
在本发明某一方案中，In a certain aspect of the present invention,
当R 1c独立地为C 1-4烷基时，所述的C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 When R 1c is independently C 1-4 alkyl, said C 1-4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl base or tert-butyl.
在本发明某一方案中，In a certain aspect of the present invention,
当R 1c独立地为3-7元环烷基时，所述的3-7元环烷基独立地为环丙基、环丁基、环戊基、环己基、环庚基；例如环丙基。 When R 1c is independently a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; for example, cyclopropyl base.
在本发明某一方案中，In a certain aspect of the present invention,
Figure PCTCN2021135751-appb-000059
为
Figure PCTCN2021135751-appb-000060
Figure PCTCN2021135751-appb-000059
for
Figure PCTCN2021135751-appb-000060
在本发明某一方案中，In a certain aspect of the present invention,
Figure PCTCN2021135751-appb-000061
为
Figure PCTCN2021135751-appb-000062
Figure PCTCN2021135751-appb-000061
for
Figure PCTCN2021135751-appb-000062
R 1b独立地为F、Cl、甲基、异丙基、环丙基、甲基-O-、-O-CF 3、-CF 3、-CO 2H、
Figure PCTCN2021135751-appb-000063
Figure PCTCN2021135751-appb-000064
R 1b is independently F, Cl, methyl, isopropyl, cyclopropyl, methyl-O-, -O- CF3 , -CF3 , -CO2H ,
Figure PCTCN2021135751-appb-000063
Figure PCTCN2021135751-appb-000064
在本发明某一方案中，In a certain aspect of the present invention,
R 13为H，C 1-6烷基-L 4-，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-；例如H、
Figure PCTCN2021135751-appb-000065
Figure PCTCN2021135751-appb-000066
Figure PCTCN2021135751-appb-000067
异丙基、
Figure PCTCN2021135751-appb-000068
Figure PCTCN2021135751-appb-000069
Figure PCTCN2021135751-appb-000070
甲基、
Figure PCTCN2021135751-appb-000071
Figure PCTCN2021135751-appb-000072
R 13 is H, C 1-6 alkyl-L 4 -, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 - , 3-7 membered monocyclic cycloalkyl-L 3 -; such as H,
Figure PCTCN2021135751-appb-000065
Figure PCTCN2021135751-appb-000066
Figure PCTCN2021135751-appb-000067
Isopropyl,
Figure PCTCN2021135751-appb-000068
Figure PCTCN2021135751-appb-000069
Figure PCTCN2021135751-appb-000070
methyl,
Figure PCTCN2021135751-appb-000071
Figure PCTCN2021135751-appb-000072
在本发明某一方案中，In a certain aspect of the present invention,
Figure PCTCN2021135751-appb-000073
为
Figure PCTCN2021135751-appb-000074
(例如
Figure PCTCN2021135751-appb-000075
Figure PCTCN2021135751-appb-000076
)；
Figure PCTCN2021135751-appb-000073
for
Figure PCTCN2021135751-appb-000074
(E.g
Figure PCTCN2021135751-appb-000075
Figure PCTCN2021135751-appb-000076
);
例如
Figure PCTCN2021135751-appb-000077
Figure PCTCN2021135751-appb-000078
E.g
Figure PCTCN2021135751-appb-000077
Figure PCTCN2021135751-appb-000078
又例如
Figure PCTCN2021135751-appb-000079
为
Figure PCTCN2021135751-appb-000080
Figure PCTCN2021135751-appb-000081
Figure PCTCN2021135751-appb-000082
(例如
Figure PCTCN2021135751-appb-000083
)； Another example
Figure PCTCN2021135751-appb-000079
for
Figure PCTCN2021135751-appb-000080
Figure PCTCN2021135751-appb-000081
Figure PCTCN2021135751-appb-000082
(E.g
Figure PCTCN2021135751-appb-000083
);
再例如，
Figure PCTCN2021135751-appb-000084
Figure PCTCN2021135751-appb-000085
For another example,
Figure PCTCN2021135751-appb-000084
Figure PCTCN2021135751-appb-000085
Figure PCTCN2021135751-appb-000086
Figure PCTCN2021135751-appb-000086
Figure PCTCN2021135751-appb-000087
Figure PCTCN2021135751-appb-000087
在本发明某一方案中，所述的如式I所示的二氢嘧啶类化合物选自如下化合物：In a certain scheme of the present invention, the described dihydropyrimidine compounds shown in formula I are selected from the following compounds:
Figure PCTCN2021135751-appb-000088
Figure PCTCN2021135751-appb-000088
Figure PCTCN2021135751-appb-000089
Figure PCTCN2021135751-appb-000089
Figure PCTCN2021135751-appb-000090
Figure PCTCN2021135751-appb-000090
Figure PCTCN2021135751-appb-000091
Figure PCTCN2021135751-appb-000091
Figure PCTCN2021135751-appb-000092
Figure PCTCN2021135751-appb-000092
Figure PCTCN2021135751-appb-000093
Figure PCTCN2021135751-appb-000093
在本发明某一方案中，所述的如式I所示的二氢嘧啶类化合物选自如下化合物：In a certain scheme of the present invention, the described dihydropyrimidine compounds shown in formula I are selected from the following compounds:
在下述条件下保留时间为4.341min的化合物
Figure PCTCN2021135751-appb-000094
制备分离(色谱柱：
Figure PCTCN2021135751-appb-000095
CSH TM Prep-C18(5μm，OBD TM 19*150mm)；柱温：室温；流速:40mL/min；波长:254nm；溶剂系统：乙腈和0.05％三氟乙酸水溶液，乙腈梯度为20％～60％)。 Compounds with a retention time of 4.341 min under the following conditions
Figure PCTCN2021135751-appb-000094
Preparative separation (column:
Figure PCTCN2021135751-appb-000095
CSH TM Prep-C18 (5μm, OBD TM 19*150mm); column temperature: room temperature; flow rate: 40mL/min; wavelength: 254nm; solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution, acetonitrile gradient is 20%～60% ).
在下述条件下保留时间为4.522min的化合物
Figure PCTCN2021135751-appb-000096
制备分离(色谱柱：
Figure PCTCN2021135751-appb-000097
CSH TM Prep-C18(5μm，OBD TM 19*150mm)；柱温：室温；流速:40mL/min；波长:254nm；溶剂系统：乙腈和0.05％三氟乙酸水溶液，乙腈梯度为20％～60％)。 Compounds with a retention time of 4.522 min under the following conditions
Figure PCTCN2021135751-appb-000096
Preparative separation (column:
Figure PCTCN2021135751-appb-000097
CSH TM Prep-C18 (5μm, OBD TM 19*150mm); column temperature: room temperature; flow rate: 40mL/min; wavelength: 254nm; solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution, acetonitrile gradient is 20%～60% ).
由此，在本说明书通篇中，本领域技术人员可对所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐中所述基团及其取代基进行选择，以提供稳定的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，包括但不限于本发明的实施例中所述的化合物。Thus, throughout this specification, those skilled in the art can select the group and its substituent in the dihydropyrimidine compound shown in formula I or a pharmaceutically acceptable salt thereof, In order to provide stable dihydropyrimidine compounds represented by formula I or pharmaceutically acceptable salts thereof, including but not limited to the compounds described in the embodiments of the present invention.
本发明所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐可通过包括与化学领域公知方法相似的方法合成，其步骤和条件可参考本领域类似反应的步骤和条件，特别是根据本文说明进行合成。起始原料通常是来自商业来源，例如Aldrich或可使用本领域技术人员公知的方法(通过SciFinder、Reaxys联机数据库得到)容易地制备。The dihydropyrimidine compounds shown in the present invention as shown in formula I or their pharmaceutically acceptable salts can be synthesized by methods similar to those known in the chemical field, and the steps and conditions can refer to the steps and conditions, in particular the synthesis was carried out according to the description herein. Starting materials are typically from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online database).
本发明中，所述的如式I所示的二氢嘧啶类化合物，也可以通过已制备得到的所述的如式I所示的二氢嘧啶类化合物，采用本领域常规方法，经外周修饰进而得到其他所述的如式I所示的杂环类化合物。In the present invention, the dihydropyrimidine compound shown in formula I can also be modified by peripheral modification of the prepared dihydropyrimidine compound shown in formula I using conventional methods in the art Further, other described heterocyclic compounds represented by formula I are obtained.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式I所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified. The following reaction schemes and examples serve to further illustrate the content of the present invention.
本发明中，所述的如式I所示的杂环类化合物的制备方法，其包括如下步骤：在溶剂中，在缩合剂存在下，将如式VI所示的化合物与式X所示的化合物或其盐进行如下所示的胺化反应，得到所述的如式I所示的二氢嘧啶类化合物即可；In the present invention, the preparation method of the heterocyclic compound shown in formula I comprises the following steps: in a solvent, in the presence of a condensing agent, compound the compound shown in formula VI with the compound shown in formula X The compound or its salt is subjected to the amination reaction shown below to obtain the dihydropyrimidine compound shown in formula I;
Figure PCTCN2021135751-appb-000098
Figure PCTCN2021135751-appb-000098
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 9、R 13、W、Z 1、Z 2、Z 3、
Figure PCTCN2021135751-appb-000099
和*的定义如上任一方案所述。 Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 13 , W, Z 1 , Z 2 , Z 3 ,
Figure PCTCN2021135751-appb-000099
and * are as defined in either scheme above.
所述的胺化反应的条件和操作可为本领域该类反应中常规的条件和操作。本发明中，所述的缩合剂为2,2,6,6-四甲基哌啶(TEMP)。所述的溶剂可为腈类溶剂和/或卤代烃类溶剂，例如乙腈和二氯甲烷，又例如其体积比为1:3。所述胺化反应的温度可为室温(例如10℃～30℃)。所述的缩合剂与所述的如下式X所示的化合物或其盐地摩尔比可为1.2:1；所述的如式VI所示的化合物与所述的如式X所示的化合物或其盐地摩尔比可为1.1:1；所述的溶剂与所述的如式X所示的化合物的体积摩尔比可为8L/moL。The conditions and operations of the amination reaction can be conventional conditions and operations in this type of reaction in the art. In the present invention, the condensing agent is 2,2,6,6-tetramethylpiperidine (TEMP). The solvent can be a nitrile solvent and/or a halogenated hydrocarbon solvent, such as acetonitrile and dichloromethane, and the volume ratio thereof is 1:3. The temperature of the amination reaction may be room temperature (eg, 10°C to 30°C). The molar ratio of the condensing agent to the compound represented by the following formula X or its salt can be 1.2:1; the compound represented by the formula VI and the compound represented by the formula X or The molar ratio of the salt to the salt can be 1.1:1; the volume molar ratio of the solvent to the compound represented by the formula X can be 8L/moL.
本发明还提供了一种如式X所示的化合物或其盐，The present invention also provides a compound represented by formula X or a salt thereof,
Figure PCTCN2021135751-appb-000100
Figure PCTCN2021135751-appb-000100
其中，R 6、R 7、R 9、R 13、W和
Figure PCTCN2021135751-appb-000101
的定义如上任一方案所述。 wherein R 6 , R 7 , R 9 , R 13 , W and
Figure PCTCN2021135751-appb-000101
is defined as in any of the above scenarios.
在本发明的某一方案中，所述的如下式X所示的化合物或其盐可为如下任一化合物：In a certain aspect of the present invention, the compound represented by the following formula X or its salt can be any of the following compounds:
Figure PCTCN2021135751-appb-000102
Figure PCTCN2021135751-appb-000102
Figure PCTCN2021135751-appb-000103
Figure PCTCN2021135751-appb-000103
Figure PCTCN2021135751-appb-000104
Figure PCTCN2021135751-appb-000104
用于制备如式I中化合物的必要原料或试剂可以商购获得，或者通过本领域已知的合成方法制备。如下实验部分所描述的方法，可以制备游离碱或者其加酸所成盐的本发明的化合物。术语药学上可接受的盐指的是本文所定义的药学上可接受的盐，并且具有母体化合物所有的药学活性。药学上可接受的盐可以通过在有机碱的合适的有机溶剂中加入相应的酸，根据常规方法处理来制备药学上可接受的 盐。The necessary starting materials or reagents for the preparation of compounds such as those of formula I are either commercially available or prepared by synthetic methods known in the art. Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound. Pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
成盐实例包括：与无机酸成盐，如盐酸、氢溴酸、硫酸、硝酸、磷酸；和有机酸所形成的盐，如醋酸、苯磺酸、苯甲酸、樟脑磺酸、柃檬酸、乙磺酸、富马酸、葡庚糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、黏糠酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、酒石酸、对甲苯磺酸或三甲基乙酸。Examples of salt formation include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid , mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
如式I所示的二氢嘧啶类化合物可能具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。Dihydropyrimidines as shown in formula I may have one or more chiral carbon atoms, so optically pure isomers can be isolated, such as pure enantiomers, or racemates, or mixed isomeric isomers Construct. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
本专利所述的合成路线中所用的化学品，包括溶剂，试剂，催化剂以及保护基团，脱保护基团，保护基团包括叔丁氧基羰基(Boc)。上述方法还可以另外包括在本文具体描述的步骤之前或之后的步骤，可以添加或除去合适的保护基团，以得到目标化合物。另外，各种合成步骤可以交替或顺次的进行以得到最终的目标产物。The chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and protecting groups including tert-butoxycarbonyl (Boc). The above methods may additionally include steps before or after the steps specifically described herein, where appropriate protecting groups may be added or removed to obtain the target compound. Additionally, various synthetic steps can be performed alternately or sequentially to obtain the final target product.
本发明提供了一种药物组合物，其包含如上所述的式I所示的二氢嘧啶类化合物或其药学上可接受的盐，和，(一种或多种)药用辅料(例如赋形剂或载体)。举例来说，这种药物组合物可以包含一种或多种另外的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐。在所述的药物组合物中，所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐的用量可为治疗有效量。The present invention provides a pharmaceutical composition comprising the above-mentioned dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof, and, (one or more) pharmaceutical excipients (such as excipients) excipient or carrier). For example, such a pharmaceutical composition may comprise one or more additional dihydropyrimidine compounds of formula I, or a pharmaceutically acceptable salt thereof. In the pharmaceutical composition, the amount of the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.
本发明还提供了一种所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐在制备HBV抑制剂中的应用。在所述的应用中，所述的HBV抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为HBV的抑制效果提供快速检测。The present invention also provides the use of the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of an HBV inhibitor. In the application, the HBV inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or preparing according to conventional methods in the art into a kit to provide rapid detection of the inhibitory effect of HBV.
本发明还提供了一种所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐在制备药物中的应用；所述的药物可为用于预防和/或治疗与HBV感染的药物。The present invention also provides a use of the dihydropyrimidine compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicine; the medicine can be used for prevention and/or treatment and Drugs for HBV infection.
本发明的另一方面涉及一种预防和/或治疗HBV感染的方法，其包括向患者施用治疗有效剂量的所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐或包含其的药物组合物。Another aspect of the present invention relates to a method for preventing and/or treating HBV infection, comprising administering to a patient a therapeutically effective dose of the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
本发明的另一方面涉及一种用于治疗和/或预防HBV感染的药物，其包括所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐或包含其的药物组合物。Another aspect of the present invention relates to a medicament for treating and/or preventing HBV infection, comprising the dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof or a medicament comprising the same combination.
本发明的化合物、药物组合物可以用局部或全身给药，例如，用于肠内给药，比如直肠或口服用药，或用于肠胃外给药至哺乳动物(尤其指人)。用于直肠给药的示例性组合包括栓剂，其可以包含例如适合的非刺激性赋形剂，例如可可脂、合成甘油酯或聚乙二醇，其在常温下是固体，但是在直肠腔中融化和/或溶解以释放药物。本发明的化合物也可在肠胃外给药，例如，通过吸入式、注射或输液、如通过静脉内、动脉内、骨内、肌内、大脑内、脑室外、滑膜内、胸骨内、鞘内、病灶内、颅内、肿瘤内、皮内和皮下注射或输入。The compounds, pharmaceutical compositions of the present invention may be administered topically or systemically, eg, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals, especially humans. Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures, but in the rectal cavity Melt and/or dissolve to release drug. The compounds of the invention may also be administered parenterally, eg, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
本发明所述的化合物、药物组合物可以用局部或全身给药，例如，用于肠内给药，比如直肠或口服用药，或用于肠胃外给药至哺乳动物(尤其指人)，并且包括根据本发明的化合物或其药学上可接 受的盐作为活性成分的治疗有效量，连同药学上可接受的赋形剂，如药学上可接受的载体。活性成份的治疗有效量如上下文所定义，并且取决于哺乳动物的种类、体重、年龄、个体状况、个体药代动力学参数、待治疗的疾病和给药方式对于肠内给药，如口服药，本发明化合物可以配制成广泛的多种剂型。The compounds, pharmaceutical compositions of the present invention can be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and A therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof is included as an active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined above and below, and depends on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated and the mode of administration. For enteral administration, such as oral administration, , the compounds of the present invention can be formulated into a wide variety of dosage forms.
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定，最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。An effective amount of a compound, pharmaceutical composition or medicament of the present invention can be readily determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation.
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。The pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed. The pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, Sweeteners, Flavours and Fragrances, Preservatives and Antioxidants.
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。The pharmaceutical compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放系统形式提供。例如，常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定，可能需要特殊装置来施用或给予药物，例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Specialflask)。药物剂型常常由药物、赋形剂和容器/密封系统组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性，并且可提供获得所需药物释放曲线的方法。因此，添加到药物中的赋形剂类型可视各种因素而定，例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(European Pharmacopoeia, EP)和英国药典(British pharmacopoeia,BP)；美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物，例如《非活性组分指南》(Inactive Ingredient Guide,1996)；Ash和Ash编写的《药物添加剂手册》(Hand book of Pharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY；etc.)。Pharmaceutical dosage forms of the compounds of the present invention may be provided in immediate release, controlled release, sustained release or targeted drug release systems. For example, common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and lyophilized preparations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. A pharmaceutical dosage form often consists of a drug, an excipient, and a container/closure system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration and safety of the drug and may provide for the desired drug release Curve method. Thus, the type of excipients added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the steps of preparation. Pharmaceutically acceptable excipients exist in the art and include those listed in various pharmacopeias. (See U.S. Pharmacopoeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); the U.S. Food and Drug Administration (the U.S. Food and Drug Administration). Administration, www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, such as the Inactive Ingredient Guide (1996); Ash and Ash's Handbook of Drug Additives (Hand book of Pharmaceutical Additives, 2002, Synapse Information Resources, Inc., Endicott NY; etc.).
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造，例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。如上文所述，本发明的组合物可包括一种或一种以上生理学上可接受的非活性成分，这些非活性成分会促进活性分子被加工成用于医药用途的制剂。Pharmaceutical dosage forms of the compounds of this invention can be manufactured by any of the methods well known in the art, such as by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extrusion, spray drying, Milling, emulsification, (nano/micro) encapsulation, encapsulation or lyophilization processes. As noted above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into formulations for pharmaceutical use.
所述药物组合物和剂型可以包含一种或多种本发明的化合物或其一种或多种药学上可接受的盐作为活性组分。药学上可接受的载体可以是固体或液体。固体的形式的制剂包括粉剂、片剂、丸剂、锭剂、胶囊剂、扁嚢剂、栓剂和可分散的颗粒剂。固体载体可以还是作为稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或者包封材料的一种或多种物质。在粉剂中，载体通常是细碎的固体，其是与细碎的活性组分的混合物。在片剂中，活性组分通常与具有必要粘合能力的载体以合适的比例混合并按照所需的形状和尺寸压实。合适的载体包括但不限于碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精，淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡，可可脂等。活性化合物的制剂可以包括作为载体的包封材料，提供胶囊，其中有或没有载体的活性组分被与其结合的载体包围。The pharmaceutical compositions and dosage forms may contain, as an active ingredient, one or more compounds of the present invention or one or more pharmaceutically acceptable salts thereof. Pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories and dispersible granules. A solid carrier can also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active component. In tablets, the active component is usually mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like . The formulation of the active compound can include as carrier an encapsulating material providing a capsule in which the active component, with or without carriers, is surrounded by a carrier in association with it.
适于口服给药的其它形式包括液体形式制剂，包括乳液、糖浆剂、酏剂、水溶液、水性悬浊液、或意图在使用前不久转化成液体形式制剂的固体形式制剂。乳液可以在溶液中制备，例如丙二醇水溶液中，或者可以含有乳化剂，如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶。水溶液可以通过将活性组分溶解在水中并加入合适的着色剂、香料、稳定剂和增稠剂来制备。水性混悬液可以通过将细小颗粒的活性成分用粘合剂如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素和其它常用的悬浮剂分散在水中制备。固体形式的制剂包括溶液剂、混悬剂和乳液，除了活性组分外，还可以含有着色剂、香料、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions can be prepared in solutions, such as aqueous propylene glycol, or can contain emulsifying agents, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, fragrances, stabilizers and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with binders such as natural or synthetic gums, resins, methyl cellulose, carboxymethyl cellulose, and other conventional suspending agents. Solid form preparations include solutions, suspensions and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers Wait.
对于肠胃外给药，本发明的药物组合物可以是无菌可注射或可输注射剂制剂的形式，例如，作为无菌水性或油性混悬液。该混悬液可以根据本领域已知的技术使用合适的分散剂或润湿剂(例如吐温80)和悬浮剂来配制。无菌可注射或可输注制剂也可以是无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射或可输注溶液或混悬液。例如，药物组合物可以是1,3-丁二醇中的溶液。可以用于本发明药物组合物中的可接受的媒介和溶剂的其它实例包括但不限于甘露醇、水、林格溶液和等渗氯化钠溶液。此外，无菌非挥发性油通常用作溶剂或悬浮介质。为此目的可以使用任何温和的非挥发性油，包括合成的甘油单酯或甘油二酯。脂肪酸如油酸及其甘油脂衍生物可用于制备注射剂，同样还有天然的药学上可接受的油，例如橄榄油或蓖麻油，特别是其聚氧乙基化形式。这些油溶液或混悬液也可含有长链醇稀释剂或分散剂。用于肠胃外使用的溶液也可以包括合适的稳定剂，如果需要，可以包含缓冲物质。 合适的稳定剂包括抗氧化剂，例如单独或组合的硫酸氢钠，亚硫酸钠或抗坏血酸、柃檬酸以及其盐和EDTA钠盐。肠胃外溶液也可以包含防腐剂，如苯扎氯铵、对羟基苯甲酸或对羟基苯甲酸丙酯和氯丁醇。For parenteral administration, the pharmaceutical compositions of the present invention may be in the form of sterile injectable or infusible injectable preparations, eg, as sterile aqueous or oily suspensions. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents. The sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a nontoxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition can be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant. Solutions for parenteral use may also contain suitable stabilizers and, if desired, buffer substances. Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite, or ascorbic acid, citric acid, and salts thereof and sodium EDTA, alone or in combination. Parenteral solutions may also contain preservatives such as benzalkonium chloride, paraben or propyl paraben, and chlorobutanol.
治疗有效剂量可首先使用本领域中熟知的各种方法来估算。用于动物研究的初始剂量可基于细胞培养测定中所确立的有效浓度。适合于人个体的剂量范围例如可使用从动物研究和细胞培养测定所获得的数据来确定。在某些实施方案中，可以将本发明的化合物制备为用于口服的药剂。A therapeutically effective dose can first be estimated using various methods well known in the art. Initial doses for animal studies can be based on effective concentrations established in cell culture assays. Dosage ranges suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as medicaments for oral administration.
药剂(例如本发明的化合物)的有效量或治疗有效量或剂量指的是引起个体症状改善或存活延长的药剂或化合物的量。所述分子的毒性和治疗功效可在细胞培养物或实验动物中通过标准医药程序来测定，例如通过测LD 50(使群体50％致死的剂量)和ED 50(对群体的50％治疗有效的剂量)。毒性作用与治疗作用的剂量比是治疗指数，可表示为LD 50/ED 50。优选显示高治疗指数的药剂。 An effective or therapeutically effective amount or dose of an agent (eg, a compound of the present invention) refers to the amount of the agent or compound that results in an improvement in symptoms or prolonged survival in an individual. Toxicity and therapeutic efficacy of the molecule can be determined in cell cultures or experimental animals by standard medical procedures, for example by measuring the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). dose). The dose ratio of toxic to therapeutic effects is the therapeutic index and can be expressed as LD50 / ED50 . Agents that exhibit high therapeutic indices are preferred.
有效量或治疗有效量是将会引发研究人员、兽医、医生或其它临床医生所探求的组织、系统、动物或人类的生物或医学反应的化合物或医药组合物的量。剂量优选在包括极小毒性或无毒性的ED 50的循环浓度的范围内。剂量可在这个范围内变化，视所用的剂型和/或所用的给药途径而定。应根据本领域中已知的方法，考虑个体状况的特殊性来选择正确的制剂、给药途径、剂量和给药间隔时间。 An effective or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician. The dosage lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and/or the route of administration employed. The correct formulation, route of administration, dosage and dosing interval should be selected according to methods known in the art, taking into account the particularities of the individual situation.
剂量和间隔时间可个别地加以调整以提供足以获得所需效果的活性部分的血浆水平；即最小有效浓度(minimal effective concentration，MEC)。各化合物的MEC将有所不同，但可以例如从体外(invitro)数据和动物实验估算。获得MEC所必需的剂量将视个体特征和给药途径而定。在局部给药或选择性摄取的情况下，药物的有效局部浓度可能与血浆浓度无关。Doses and intervals can be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect; ie, the minimal effective concentration (MEC). The MEC will vary from compound to compound, but can be estimated, for example, from invitro data and animal experiments. The dose necessary to obtain MEC will depend on individual characteristics and route of administration. In the case of topical administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.
所施予的药剂或组合物的量可视各种因素而定，包括所治疗个体的性别、年龄和体重、病痛的严重性、给药方式和处方医师的判断。The amount of the agent or composition administered may depend on various factors, including the sex, age and weight of the individual being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.
在需要时，本发明的组合物可以用含有一个或一个以上单位剂型(含有活性成分)的包装或分配装置提供。举例来说，所述包装或装置可包含金属或塑料箔(如发泡包装)或玻璃和橡皮塞，如在小瓶中。所述包装或分配装置可附有用药说明书。也可以制备包含在相容性医药载体中配制的本发明化合物的组合物，将其置于适当容器中，并且加上用于治疗指定病状的标签。The compositions of the present invention can be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient, as required. For example, the package or device may comprise metal or plastic foil (eg, blister packs) or glass and rubber stoppers, as in vials. The pack or dispenser device may be accompanied by instructions for use. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。Unless otherwise defined, all technical and scientific terms used herein have the standard meaning in the art to which the claimed subject matter belongs. If more than one definition exists for a term, the definitions herein prevail.
基团定义group definition
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions as used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , the entire contents of which are incorporated herein by reference.
在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在 化学上等同的取代基。In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds. When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left.
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C 1-C 6烷基是指具有总共1、2、3、4、5或6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。 Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1 - C6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
在本文中，取代基中定义的数值范围如0至4、1-4、1至3等表明该范围内的整数，如1-6为1、2、3、4、5、6。As used herein, numerical ranges defined in substituents such as 0 to 4, 1-4, 1 to 3, etc. indicate integers within the range, such as 1-6 being 1, 2, 3, 4, 5, 6.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings shown below unless specifically indicated otherwise.
术语“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的。除非其他方面表明，一个取代基团可以在被取代基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Further, when the group is substituted by one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of. Unless otherwise indicated, a substituent group may be substituted at various substitutable positions of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1～C 6烷基”或“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基；“C 1- 4烷基”特指独立公开的甲基、乙基、C 3烷基(即丙基，包括正丙基和异丙基)、C 4烷基(即丁基，包括正丁基、异丁基、仲丁基和叔丁基)。 In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " C1 - C6 alkyl" or " C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkanes "C 1-4 alkyl" specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl ), C 4 alkyl (ie butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).
术语“卤素”选自于F，Cl，Br或I，尤其指F或Cl。The term "halogen" is selected from F, Cl, Br or I, especially F or Cl.
在本申请中，作为基团或是其它基团的一部分，术语“烷基”是指饱和脂肪族烃基团，其为包含1至12个碳原子的直链或支链基团，优选含有1至6个碳原子的烷基直链或支链的。通式C nH 2n+1。术语“C 1-C 6烷基”、“C 1- 6烷基是指烷基部分包含1，2，3，4，5或6个碳原子。在某一实施方案中，所述的“烷基”是指C 1-C 6烷基。在某一实施方案中，所述的“烷基”是指C 1-C 4烷基。 In this application, the term "alkyl" as a group or part of another group refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 12 carbon atoms, preferably containing 1 Alkyl groups of up to 6 carbon atoms are straight or branched. General formula C n H 2n+1 . The terms "C 1 -C 6 alkyl", "C 1 -6 alkyl" mean that the alkyl moiety contains 1, 2, 3, 4, 5 or 6 carbon atoms. In a certain embodiment, the ""Alkyl" refers to a C1 - C6 alkyl group. In a certain embodiment, the "alkyl" refers to a C1 - C4 alkyl group.
含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。含有1至12个碳原子的非限制性实例包括上述含有1至6个碳原子的低级烷基的实例，以及2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基 -3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正奎基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。Lower alkyl containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl base, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, 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, etc. Non-limiting examples containing 1 to 12 carbon atoms include the above-mentioned examples of lower alkyl groups containing 1 to 6 carbon atoms, as well as 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3 , 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-di Methylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2 -Methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2 , 2-diethylpentyl, n-quinyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个碳碳双键、并且没有碳碳三键的具有例如2-10个(优选为2-6个，更优选为2-4个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。该一个或多个碳碳双键可以是内部的(例如在2-丁烯基中)或末端的(例如在1-丁烯基中)。在一些实施例中，烯基基团具有2至4个碳原子(“C 2-C 4的烯基”)。优选存在一个碳碳双键。C 2-C 4的烯基的实例包括乙烯基(C 2；
Figure PCTCN2021135751-appb-000105
)、1-丙烯基(C 3；
Figure PCTCN2021135751-appb-000106
)、2-丙烯基或异丙烯基(C 3；
Figure PCTCN2021135751-appb-000107
)、烯丙基(C 3；
Figure PCTCN2021135751-appb-000108
)、1-丁烯基(C 4；
Figure PCTCN2021135751-appb-000109
)、2-丁烯基
Figure PCTCN2021135751-appb-000110
(巴豆基)、2-甲基烯丙基(C 4；
Figure PCTCN2021135751-appb-000111
)、2-甲基丙-1-烯-1-基(C 4；
Figure PCTCN2021135751-appb-000112
)、丁-3-烯-1-基(C 4；
Figure PCTCN2021135751-appb-000113
)、丁二烯基{C 4；例如(E)-丁-1,3-二烯-1-基苯
Figure PCTCN2021135751-appb-000114
}，以及异构体(例如顺反异构体或立体异构体)。 In this application, the term "alkenyl" as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond, and no carbon-carbon triple bond, having, for example, 2 - A straight or branched hydrocarbon chain group of 10 (preferably 2-6, more preferably 2-4) carbon atoms connected to the rest of the molecule by a single bond. The one or more carbon-carbon double bonds may be internal (eg, in 2-butenyl) or terminal (eg, in 1-butenyl). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2 - C4 alkenyl"). Preferably one carbon-carbon double bond is present. Examples of C 2 -C 4 alkenyl groups include vinyl (C 2 ;
Figure PCTCN2021135751-appb-000105
), 1-propenyl (C 3 ;
Figure PCTCN2021135751-appb-000106
), 2-propenyl or isopropenyl (C 3 ;
Figure PCTCN2021135751-appb-000107
), allyl (C 3 ;
Figure PCTCN2021135751-appb-000108
), 1-butenyl (C 4 ;
Figure PCTCN2021135751-appb-000109
), 2-butenyl
Figure PCTCN2021135751-appb-000110
(crotyl), 2-methallyl (C 4 ;
Figure PCTCN2021135751-appb-000111
), 2-methylprop-1-en-1-yl (C 4 ;
Figure PCTCN2021135751-appb-000112
), but-3-en-1-yl (C 4 ;
Figure PCTCN2021135751-appb-000113
), butadienyl {C 4 ; for example (E)-but-1,3-dien-1-ylbenzene
Figure PCTCN2021135751-appb-000114
}, and isomers (eg, cis-trans isomers or stereoisomers).
在本申请中，作为基团或是其它基团的一部分，除非另有规定，术语“环烷基”意指仅由碳原子和氢原子组成的饱和的单环、多环或者桥接碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；当为多环时，可为并环连接或螺环连接(即，碳原子上的两个偕氢被亚烷基取代)的桥环体系或螺环体系。环烷基取代基可以经任何适宜的碳原子连接在中心分子上。在一些实施例中，具有3-10个碳原子的环可以表示为C 3-C 10环烷基。在一些实施例中，C 3～C 6的环烷基包括环丙基(C 3)、环丁基(C 4)、环戊基(C 5)及环己基(C 6)。在一些实施例中，C 3～C 10的环烷基的实例包括上述C 3～C 6环烷基基团连同环庚基(C 7)、环辛基(C 8)、环壬基(C 9)及环癸基(C 10)。 In this application, the term "cycloalkyl" as part of a group or other group, unless otherwise specified, means a saturated monocyclic, polycyclic or bridged carbocyclic substituted consisting solely of carbon and hydrogen atoms is attached to the rest of the molecule by a single bond via any suitable carbon atom; when polycyclic, it may be a copular or spiro (i.e., two geminal hydrogens on a carbon atom are linked by an alkylene substituted) bridged ring system or spiro ring system. Cycloalkyl substituents can be attached to the central molecule through any suitable carbon atom. In some embodiments, rings having 3-10 carbon atoms may be represented as C3 - C10 cycloalkyl. In some embodiments, the C 3 -C 6 cycloalkyl group includes cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ). In some embodiments, examples of C 3 -C 10 cycloalkyl groups include the above-mentioned C 3 -C 6 cycloalkyl groups together with cycloheptyl (C 7 ), cyclooctyl (C 8 ), cyclononyl ( C 9 ) and cyclodecyl (C 10 ).
在本申请中，作为基团或是其它基团的一部分，术语“杂环烷基”意指由2-6个碳原子以及1-4个选自氮、氧和硫的杂原子组成的稳定的3元至7元饱和环状基团。示例性3-元杂环基基团包括但不限于，氮杂环丙基、环氧乙烷基以及硫杂环丙烷基，或者其立体异构体；示例性4-元杂环基基团包括但不限于，氮杂环丁烷基，环氧丙烷基，硫杂环丁烷基，或者其同分异构体和立体异构体；示例性5-元杂环基基团包括但不限于，四氢呋喃基，四氢噻吩基，吡咯烷基，噻唑烷基，异噻唑烷基，噁唑烷基，异噁唑烷基，咪唑烷基，吡唑烷基，二氧戊环基，氧杂硫呋喃基，二硫呋喃基，或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于，哌啶基，四氢吡喃基，硫化环戊烷基，吗啉基，硫代吗啉基，二噻烷基，二噁烷基，哌嗪基，三嗪烷基，或者其同分异构体和立体异构体；示例性7-元杂环基基团包括但不限于，氮杂环庚烷基，氧杂环庚烷基，硫杂环庚烷基，以及二氮杂环庚基，或者其同分异构体和立体异构体。在某一方案中，“杂环烷基”为C 2～C 5杂环烷基，其中杂原子选自N、 O和S中的一种或多种，杂原子数为1、2或3个。 In this application, the term "heterocycloalkyl" as a group or part of another group means a stable compound consisting of 2-6 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen and sulfur 3- to 7-membered saturated cyclic group. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane groups, or stereoisomers thereof; exemplary 4-membered heterocyclyl groups Including, but not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include, but are not Limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxygen Heterothiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, cyclopentyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl , piperazinyl, triazinyl, or isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepane radicals, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof. In a certain scheme, "heterocycloalkyl" is a C 2 -C 5 heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 indivual.
在本申请中，作为基团或是其它基团的一部分，术语“芳基”是指具有6-14个环原子以及提供在芳香族环系统中的零个杂原子单环的或多环的(例如，二环的或三环的)4n+2芳香族环系统(例如，在循环阵列中具有6，10，或14个共享的p电子)的基团(“C 6-C 14芳基”)。上述芳基单元的实例包括苯基、萘基、菲基、或者蒽基。 In this application, the term "aryl" as part of a group or other group refers to a monocyclic or polycyclic group having 6-14 ring atoms and zero heteroatoms provided in the aromatic ring system (eg, bicyclic or tricyclic) groups of 4n+2 aromatic ring systems (eg, with 6, 10, or 14 shared p electrons in a cyclic array) (" C6 - C14aryl ) ”). Examples of the above-mentioned aryl unit include phenyl, naphthyl, phenanthryl, or anthracenyl.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”是指具有碳原子以及提供在该芳香族环系统中的1-3个杂原子(其中每个杂原子独立地选自氮、氧以及硫)的4-16元单环的或二环的4n+2芳香族环系统(例如，在循环阵列中具有6或10个共享的p电子)的基团(“4-16元杂芳基”)。在包含一个或多个氮原子的杂芳基基团中，连接点可以是碳或氮原子，只要化合价允许。In this application, the term "heteroaryl" as part of a group or other group means having carbon atoms and 1-3 heteroatoms (wherein each heteroatom is independently provided in the aromatic ring system) Groups (" 4-16 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence allows.
在一些实施例中，所述的杂芳基为杂原子选自N、O和S中的一种或多种，杂原子数为1～3个的4-6元杂芳基，较佳地为5-6元杂芳基。In some embodiments, the heteroaryl group is one or more heteroatoms selected from N, O and S, and a 4-6 membered heteroaryl group with 1 to 3 heteroatoms, preferably It is a 5-6-membered heteroaryl group.
示例性5-元杂芳基基团包括但不限于：吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、噁二唑基、噻二唑基、呋咱基、噁三唑基或四唑基。示例性6-元杂芳基基团包括但不限于：吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基或四嗪基。Exemplary 5-membered heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazole oxadiazolyl, thiadiazolyl, furazanyl, oxtriazolyl or tetrazolyl. Exemplary 6-membered heteroaryl groups include, but are not limited to: pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, or tetrazinyl.
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When a listed substituent does not indicate through which atom it is attached to a compound included in the general formula but not specifically mentioned, such substituent may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.
在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“卤代-C 1～C 6烷基”中的C 1-C 6烷基应当理解为C 1～C 6亚烷基。 In some specific structures, when an alkyl group is clearly represented as a linking group, the alkyl group represents the alkylene group to which it is attached, eg, the group "halo-C 1 -C 6 alkane A C 1 -C 6 alkyl group in "radical" should be understood as a C 1 -C 6 alkylene group.
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH 2-)，亚乙基{包括-CH 2CH 2-或-CH(CH 3)-}，亚异丙基{包括-CH(CH 3)CH 2-或-C(CH 3) 2-}等等。 The term "alkylene" refers to a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group. Examples of alkylene groups include methylene ( -CH2- ), ethylene {including -CH2CH2- or -CH( CH3 )-}, isopropylidene {including -CH( CH3 ) )CH 2 -or -C(CH 3 ) 2 -} and so on.
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。Unless otherwise defined, all technical and scientific terms used herein have the standard meaning in the art to which the claimed subject matter belongs. If more than one definition exists for a term, the definitions herein prevail.
应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。此外，术语“包括”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排除其他方面的内容。It should be understood that singular forms such as "a" used in the present invention include plural referents unless stated otherwise. In addition, the term "comprising" is an open definition rather than a closed one, that is, it includes the contents specified in the present invention, but does not exclude other aspects.
除非另有说明，本发明采用质谱、元素分析的传统方法，各步骤和条件可参照本领域常规的操作步骤和条件。Unless otherwise specified, the present invention adopts traditional methods of mass spectrometry and elemental analysis, and each step and condition may refer to the conventional operation steps and conditions in the art.
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。 在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地为”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地为”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless clearly stated otherwise, the description mode "...independently" used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups. In more detail, the description mode "...independently" can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same symbols are The specific options expressed between them do not affect each other.
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2021135751-appb-000115
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。 It can be understood by those skilled in the art that, according to the conventions used in the art, the formula used in the structural formula of the group described in this application
Figure PCTCN2021135751-appb-000115
It means that the corresponding group is connected with other fragments and groups in the compound through this site.
“药学上可接受的”是指可用于制备药物组合的情形，通常是安全的和无毒的，且非生物学以及其它方面所不期望，并且包括对于兽用和用于人的药物用途的可接受的情形。"Pharmaceutically acceptable" means that which can be used in the preparation of pharmaceutical combinations, is generally safe and non-toxic, and is not biologically and otherwise undesirable, and includes both for veterinary and human pharmaceutical use acceptable situation.
术语“赋形剂”是指药学上可接受的化学物质，例如药学领域的普通技术人员已知的用于帮助给予药用的试剂。它是可以用于制备药物组分的化合物，通常是安全的、无毒的，且是生物学或者其它方面所不可期望的，其包括对于兽用和人用药物可接受的赋形剂。通常的赋形剂包括粘合剂、表面活性剂、稀释剂、崩解剂和润滑剂。The term "excipient" refers to a pharmaceutically acceptable chemical substance, such as an agent known to those of ordinary skill in the art of pharmacy to aid in the administration of pharmaceuticals. It is a compound that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically or otherwise undesirable, including excipients that are pharmaceutically acceptable for veterinary and human use. Common excipients include binders, surfactants, diluents, disintegrants and lubricants.
术语“有效治理量”是指当给予受试者来治疗疾病状态时足以实现疾病状态的这种治理的所用化合物的量。“有效治理量”将根据化合物、所治疗的疾病状态、所治疗疾病的严重程度、受试者的年龄和相对健康、给药途径和方式、主治医疗或兽医的判断等而变化。The term "treatment effective amount" refers to an amount of a compound used that, when administered to a subject to treat a disease state, is sufficient to effect such treatment of the disease state. The "administratively effective amount" will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and mode of administration, the judgment of the attending medical or veterinarian, and the like.
本专利所用“治理”或“治理中”是获得有益或期望结果，包括临床结果。有益或期望的临床结果包括但不限于一个或多个症状或病症的减轻或改善、疾病程度的减少、疾病状态的稳定化(如不恶化)，预防疾病传播、延迟或减缓疾病进展、疾病状态的改善或缓解，以及部分或全部好转，无论是可检测或不可检测的情形。相比对应没有治疗的预期生存期，该术语也可指延长生存期。As used in this patent, "in treatment" or "in treatment" means obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical outcomes include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in disease severity, stabilization of disease state (if not worsening), prevention of disease spread, delay or slowing of disease progression, disease state improvement or remission, and partial or complete improvement, whether detectable or undetectable. The term can also refer to prolonging survival as compared to expected survival corresponding to no treatment.
术语哺乳动物是指人或任何哺乳动物，如灵长类动物、农场动物、宠物动物或者实验动物。这些动物的实例有猴、母牛、羊、马、猪、狗、猫、兔、小鼠和大鼠等。哺乳动物优选于人。The term mammal refers to a human or any mammal such as a primate, farm animal, pet animal or laboratory animal. Examples of such animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice and rats and the like. Mammals are preferred to humans.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明提供了一种二氢嘧啶类化合物，该二氢嘧啶类化合物具有较好的抗HBV(乙肝病毒)活性、以及较低的细胞毒性，可用于制备治疗与预防HBV感染的药物。The positive improvement effect of the present invention is that: the present invention provides a dihydropyrimidine compound, the dihydropyrimidine compound has better anti-HBV (hepatitis B virus) activity and lower cytotoxicity, and can be used for preparing therapeutic and Drugs to prevent HBV infection.
附图说明Description of drawings
图1为中间体7-3b的X-Ray单晶结构。Figure 1 shows the X-Ray single crystal structure of intermediate 7-3b.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
本发明中，当式中存在“cis”、“trans”或
Figure PCTCN2021135751-appb-000116
表示的构型时，其以“cis”、“trans”为准。以
Figure PCTCN2021135751-appb-000117
为例，表示顺式的
Figure PCTCN2021135751-appb-000118
In the present invention, when there is "cis", "trans" or
Figure PCTCN2021135751-appb-000116
When indicating the configuration, it is subject to "cis" and "trans". by
Figure PCTCN2021135751-appb-000117
For example, expressing cis
Figure PCTCN2021135751-appb-000118
通用合成路线1：General synthetic route 1:
Figure PCTCN2021135751-appb-000119
Figure PCTCN2021135751-appb-000119
目标化合物I可以通过通用合成路线1制备得到。化合物II，化合物III和化合物IV在碱性条件下，进行一锅反应制备得到化合物V，化合物V可以经色谱制备分离得到化合物Va或者通过化学拆分的方法制备得到化合物Va，化合物Va进行溴化反应得到化合物VI，化合物VI与化合物X或 者其盐反应得到目标化合物I。The target compound I can be prepared by general synthetic route 1. Compound II, compound III and compound IV are prepared by one-pot reaction under basic conditions to obtain compound V, compound V can be prepared and separated by chromatography to obtain compound Va or prepared by chemical separation method to obtain compound Va, and compound Va is brominated The compound VI is obtained by the reaction, and the target compound I is obtained by reacting the compound VI with the compound X or its salt.
通用合成路线2：General synthetic route 2:
Figure PCTCN2021135751-appb-000120
Figure PCTCN2021135751-appb-000120
目标化合物I可以通过通用合成路线2制备得到。化合物Vb进行溴化反应得到化合物VII，化合物VII与化合物X或者其盐反应得到目标化合物I。The target compound I can be prepared by general synthetic route 2. Compound Vb is subjected to bromination reaction to obtain compound VII, and compound VII is reacted with compound X or its salt to obtain target compound I.
通用合成路线3：General synthetic route 3:
Figure PCTCN2021135751-appb-000121
Figure PCTCN2021135751-appb-000121
目标化合物I可以通过通用合成路线3制备得到。化合物V进行溴化反应得到化合物VIII，化合物VIII与化合物X或者其盐反应得到目标化合物I。The target compound I can be prepared by general synthetic route 3. Compound V is subjected to bromination reaction to obtain compound VIII, and compound VIII is reacted with compound X or its salt to obtain target compound I.
以下实施例中，化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 In the following examples, the structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
SHIMADZU LC系统(色谱柱：
Figure PCTCN2021135751-appb-000122
CSH TM Prep-C18，19*150mm，液体处理机LH-40，泵LC-20AP，检测器SPD-20A，系统控制器CBM-20A，溶剂系统：乙腈和0.05％三氟乙酸水溶液)。 SHIMADZU LC system (column:
Figure PCTCN2021135751-appb-000122
CSH ™ Prep-C18, 19*150mm, liquid handler LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% trifluoroacetic acid in water).
使用LC/MS(Agilent Technologies 1200 Series)获得化合物的LC/MS光谱。LC/MS条件如下(运行时间为10分钟)：LC/MS spectra of compounds were obtained using LC/MS (Agilent Technologies 1200 Series). LC/MS conditions were as follows (run time was 10 min):
酸性条件：A：0.05％三氟乙酸的水溶液；B：0.05％三氟乙酸的乙腈溶液；Acidic conditions: A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoroacetic acid in acetonitrile;
碱性条件：A：0.05％NH 3·H 2O的水溶液；B：乙腈 Basic conditions: A: 0.05% NH 3 ·H 2 O in water; B: acetonitrile
中性条件：A：10mM NH 4OAC的水溶液；B：乙腈 Neutral conditions: A: 10 mM NH4OAC in water; B: acetonitrile
如无特别说明，以下实施例中，中间体和最终化合物使用硅胶柱色谱法纯化、或使用
Figure PCTCN2021135751-appb-000123
CSH TM Prep-C18(5μm，OBD TM 19*150mm)色谱柱或使用XBridgeTM Prep Phenyl(5μm，OBD TM 30*100mm)在反相色谱柱上通过制备性HPLC纯化。 Unless otherwise specified, in the following examples, the intermediates and final compounds were purified by silica gel column chromatography, or used
Figure PCTCN2021135751-appb-000123
Purification by preparative HPLC on a CSH ™ Prep-C18 (5 μm, OBD ™ 19*150 mm) column or on a reverse phase column using XBridge™ Prep Phenyl (5 μm, OBD ™ 30*100 mm).
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层色谱法(TLC)硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析检测产品使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。Thin-layer chromatography (TLC) silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for TLC detection products are 0.15mm to 0.2mm, and the specifications for TLC separation and purification products are 0.4mm～0.5mm.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
缩略词：AcOH：乙酸；ACN：乙腈；AcCl：乙酰氯；Ag 2O：氧化银；BH 3：硼烷；Boc 2O：碳酸叔丁氧基羰基叔丁酯；Boc：叔丁氧羰基；BnBr:溴苄；Conc.HCl：浓盐酸；Cbz：苄氧羰基；CH 3I：碘甲烷；Cs 2CO 3：碳酸铯；CuI：碘化亚铜；CuBr：溴化亚铜；CH 3NO 2:硝基甲烷；CBr 4:四溴化碳；DAST：二乙胺基三氟化硫；DBU:1,8-二氮杂环十一烯DIEA：N,N-二异丙基乙胺；DMAP：4-二甲氨基吡啶；DCM：二氯甲烷；Dioxane：1,4-二氧六环；DMF：二甲基甲酰胺；DMA：二甲基乙酰胺；DMSO：二甲亚砜；Dppf：双二苯基膦二茂铁；EEtOH：乙醇；Et 3N：三乙胺；H 2：氢气；IPA：异丙醇；K 2CO 3：碳酸钾；LiHMDS：双(三甲基硅基)氨基锂；LDA：二异丙基氨基锂；LiOH：氢氧化锂；MeOH：甲醇；MsCl：甲磺酰氯；MW：微波反应；MeI：碘甲烷；Me 2S:二甲硫醚；MeMgBr:甲基溴化镁；NaOH：氢氧化钠；NaH：氢化钠；NaHMDS：双(三甲基硅基)氨基钠；NFSI:N-氟代双苯磺酰胺；NBS：N-溴代丁二酰亚胺；NaCN:氰化钠；Ph 3P：三苯基磷；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯；Pd(OH) 2:氢氧化钯；Pd(OAc) 2:醋酸钯；Pd/C：钯碳；SelectFluor：1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐；t-BuOK：叔丁醇钾；Toluene：甲苯；TsOH：对甲苯磺酸；THF：四氢呋喃；TFA：三氟乙酸；TEA：三乙胺；TiCl 4：四氯化钛；TMSCl:三甲基氯硅烷；TFAA:三氟乙酸酐；Xphos：2-二环己基磷-2,4,6-三异丙基联苯；Xantphos：4,5-双(二苯基膦)-9,9-二甲基氧杂蒽 Abbreviations: AcOH: acetic acid; ACN: acetonitrile; AcCl: acetyl chloride; Ag 2 O: silver oxide; BH 3 : borane ; ; BnBr: benzyl bromide; Conc.HCl: concentrated hydrochloric acid; Cbz: benzyloxycarbonyl; CH 3 I: methyl iodide; Cs 2 CO 3 : cesium carbonate; CuI: cuprous iodide; CuBr: cuprous bromide; CH 3 NO 2 : nitromethane; CBr 4 : carbon tetrabromide; DAST: diethylaminosulfur trifluoride; DBU: 1,8-diazacycloundecene DIEA: N,N-diisopropylethyl acetate Amine; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; Dioxane: 1,4-dioxane; DMF: dimethylformamide; DMA: dimethylacetamide; DMSO: dimethylsulfoxide ; Dppf: bisdiphenylphosphinoferrocene; EEtOH: ethanol; Et3N : triethylamine; H2 : hydrogen ; IPA: isopropanol ; K2CO3: potassium carbonate; LiHMDS: bis(trimethyl) silyl) lithium amide; LDA: lithium diisopropylamide; LiOH: lithium hydroxide; MeOH: methanol; MsCl: methanesulfonyl chloride; MW: microwave reaction; MeI: methyl iodide; Me 2 S: dimethyl sulfide; MeMgBr: methylmagnesium bromide; NaOH: sodium hydroxide; NaH: sodium hydride; NaHMDS: sodium bis(trimethylsilyl)amide; NFSI: N-fluorobisbenzenesulfonamide; NBS: N-bromobutane Diimide; NaCN: sodium cyanide; Ph 3 P: triphenylphosphorus; Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl 2 : [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(OH) 2 : palladium hydroxide; Pd(OAc) 2 : palladium acetate; Pd/C: palladium on carbon; SelectFluor: 1-chloromethane yl-4-fluoro-1,4-diazobicyclo 2.2.2 octane bis(tetrafluoroborate) salt; t-BuOK: potassium tert-butoxide; Toluene: toluene; TsOH: p-toluenesulfonic acid; THF: TFA: trifluoroacetic acid; TEA: triethylamine; TiCl 4 : titanium tetrachloride; TMSCl: trimethylchlorosilane; TFAA: trifluoroacetic anhydride; Xphos: 2-dicyclohexylphosphorus-2,4, 6-Triisopropylbiphenyl; Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
制备例1中间体A1:Preparation Example 1 Intermediate A1:
(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯Ethyl (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ester
Figure PCTCN2021135751-appb-000124
Figure PCTCN2021135751-appb-000124
Figure PCTCN2021135751-appb-000125
Figure PCTCN2021135751-appb-000125
步骤1：中间体A1-1的制备Step 1: Preparation of Intermediate A1-1
将3-氟-2-甲基苯甲醛(77.0克，0.56摩尔)和3-氧代丁酸乙酯(113.2克，0.87摩尔)溶于IPA(770毫升)中，在20℃-30℃时搅拌缓慢加入哌啶(4.75克，0.056摩尔)和乙酸(3.7克，0.06摩尔)。滴完后，将反应混合物在20℃搅拌4小时，然后将噻唑-2-甲酰胺盐酸盐(104.9克，0.49摩尔)和三乙胺(72.8克，0.72摩尔)依次加入到上述反应液中，加完后，将反应混合物在20℃-30℃继续搅拌12小时，然后将反应混合物在70℃-75℃继续搅拌8小时。将反应混合物冷却到30℃，向反应液中缓慢加入(770毫升)水，将反应悬浮液在20℃-30℃继续搅拌10小时，然后过滤，滤饼用异丙醇/水(v/v＝1:1，80毫升)和水(v/v＝1:1，80毫升)洗涤，干燥得到黄色固体4-(3-氟-2-甲基-苯基)-6-甲基-2-噻唑-2-基-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1-1，160克，80％收率)。3-Fluoro-2-methylbenzaldehyde (77.0 g, 0.56 mol) and ethyl 3-oxobutanoate (113.2 g, 0.87 mol) were dissolved in IPA (770 mL) at 20-30 °C Piperidine (4.75 g, 0.056 mol) and acetic acid (3.7 g, 0.06 mol) were added slowly with stirring. After dropping, the reaction mixture was stirred at 20°C for 4 hours, and then thiazole-2-carboxamide hydrochloride (104.9 g, 0.49 mol) and triethylamine (72.8 g, 0.72 mol) were added to the above reaction solution in sequence After the addition, the reaction mixture was further stirred at 20°C-30°C for 12 hours, and then the reaction mixture was further stirred at 70°C-75°C for 8 hours. The reaction mixture was cooled to 30°C, water (770 mL) was slowly added to the reaction solution, the reaction suspension was stirred at 20°C-30°C for 10 hours, and then filtered, and the filter cake was washed with isopropanol/water (v/v = 1:1, 80 mL) and water (v/v=1:1, 80 mL), and dried to give a yellow solid 4-(3-fluoro-2-methyl-phenyl)-6-methyl-2 - Ethyl thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Intermediate A1-1, 160 g, 80% yield).
步骤2：中间体A1-2的制备Step 2: Preparation of Intermediate A1-2
将4-(3-氟-2-甲基-苯基)-6-甲基-2-噻唑-2-基-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1-1，180克，0.5摩尔)溶于乙醇(1.8升)中，在75℃时搅拌缓慢加入(R)-(-)-1,1'-联萘-2,2'-磷酸二氢酯(174.5克，0.5摩尔)。加完后，将反应混合物在75℃并搅拌4小时，将反应混合物冷却到30℃，然后过滤，滤饼用乙醇(180毫升)洗涤，将滤饼悬浮在二氯甲烷(180升)中并加热回流，将乙醇(0.9升)加入到悬浮液中并在40度继续搅拌30分钟直至溶液澄清，将乙醇(0.9升)在40度加入到上述反应液中，在40度到60度蒸除二氯甲烷，将得到的反应液在60度继续搅拌1小时，将反应混合物冷却到30℃，然后过滤，滤饼用乙醇(180毫升)洗涤，干燥得到黄色固体(S)-4-(3-氟-2-甲基苯基)-6-甲基-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯单(R)-(-)-1,1'-联萘-2,2'-磷酸二氢盐(中间体A1-2，160克，45％收率)。 1H NMR(DMSO-d 6,400MHz)δ8.02-8.11(m,6H),7.42-7.52(m,4H),7.32-7.36(m,2H),7.16-7.22(m,3H),7.02-7.10(m,2H),5.83(s,1H),3.95(q,J＝7.2Hz,2H),2.45(s,3H),2.41(s,2H),1.02 (t,J＝7.2Hz,3H)。 Ethyl 4-(3-fluoro-2-methyl-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Intermediate A1-1 , 180 g, 0.5 mol) was dissolved in ethanol (1.8 L), and (R)-(-)-1,1'-binaphthyl-2,2'-dihydrogen phosphate (174.5 g, 0.5 mol). After the addition was complete, the reaction mixture was stirred at 75°C for 4 hours, the reaction mixture was cooled to 30°C, then filtered, the filter cake was washed with ethanol (180 mL), the filter cake was suspended in dichloromethane (180 L) and the Heat to reflux, add ethanol (0.9 L) to the suspension and continue stirring at 40°C for 30 minutes until the solution is clear, add ethanol (0.9 L) to the above reaction solution at 40°C, and evaporate at 40°C to 60°C Dichloromethane, the obtained reaction solution was stirred at 60°C for 1 hour, the reaction mixture was cooled to 30°C, filtered, and the filter cake was washed with ethanol (180 mL) and dried to obtain a yellow solid (S)-4-(3 -Fluoro-2-methylphenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester mono(R)-(-)-1 ,1'-Binaphthalene-2,2'-dihydrogen phosphate (Intermediate A1-2, 160 g, 45% yield). 1 H NMR(DMSO-d 6 , 400MHz)δ8.02-8.11(m,6H),7.42-7.52(m,4H),7.32-7.36(m,2H),7.16-7.22(m,3H),7.02 -7.10(m, 2H), 5.83(s, 1H), 3.95(q, J=7.2Hz, 2H), 2.45(s, 3H), 2.41(s, 2H), 1.02 (t, J=7.2Hz, 3H).
步骤3：中间体A1-1a的制备Step 3: Preparation of Intermediate A1-1a
将(S)-4-(3-氟-2-甲基苯基)-6-甲基-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯单(R)-(-)-1,1'-联萘-2,2'-磷酸二氢盐(中间体A1-2，22.5克，31.8毫摩尔)悬浮在二氯甲烷(225毫升)中，在25℃时搅拌缓慢加入20％的氢氧化钠溶液(6.36克，31.8毫摩尔)。滴完后，将反应混合物在25℃并搅拌1小时，反应完毕后，将反应混合物过滤，滤饼用二氯甲烷(60毫升)洗涤，有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体(中间体A1-1a)直接用于下一步反应。Monoethyl (S)-4-(3-fluoro-2-methylphenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (R)-(-)-1,1'-Binaphthalene-2,2'-dihydrogen phosphate (Intermediate A1-2, 22.5 g, 31.8 mmol) was suspended in dichloromethane (225 mL), A 20% solution of sodium hydroxide (6.36 g, 31.8 mmol) was added slowly with stirring at 25°C. After dropping, the reaction mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with dichloromethane (60 mL), the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. It was then filtered and concentrated to give a yellow solid (Intermediate A1-1a) which was used directly in the next reaction.
步骤4：中间体A1的制备Step 4: Preparation of Intermediate A1
将(S)-4-(3-氟-2-甲基苯基)-6-甲基-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1-1a，11.39克，31.7毫摩尔)悬浮在二氯甲烷(115毫升)中，在42℃时搅拌缓慢加入NBS(5.92克，33.3毫摩尔)。加完后，将反应混合物在42℃并搅拌0.5小时，然后将反应混合物溶液冷却到室温，浓缩蒸干得到中间体A1。(S)-ethyl 4-(3-fluoro-2-methylphenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ( Intermediate A1-1a, 11.39 g, 31.7 mmol) was suspended in dichloromethane (115 mL) and NBS (5.92 g, 33.3 mmol) was added slowly with stirring at 42°C. After the addition, the reaction mixture was stirred at 42° C. for 0.5 hours, then the reaction mixture solution was cooled to room temperature, concentrated and evaporated to dryness to obtain Intermediate A1.
制备例2中间体A2和A2-bPreparation Example 2 Intermediates A2 and A2-b
(R)-6-(溴甲基)-4-(2-氯-3-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(R)-6-(Bromomethyl)-4-(2-chloro-3-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
(S)-6-(溴甲基)-4-(2-氯-3-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(Bromomethyl)-4-(2-chloro-3-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000126
Figure PCTCN2021135751-appb-000126
Figure PCTCN2021135751-appb-000127
Figure PCTCN2021135751-appb-000127
中间体A2-1的合成参考中间体A1-1，通过使用2-氯-3-氟苯甲醛代替3-氟-2-甲基苯甲醛制备得到黄色中间体A2-1。Synthesis of intermediate A2-1 Referring to intermediate A1-1, yellow intermediate A2-1 was prepared by using 2-chloro-3-fluorobenzaldehyde instead of 3-fluoro-2-methylbenzaldehyde.
将中间体A2-1经SFC手性拆分(柱型号：CHIRALPAK-AD-H，5cm x 25cm，5μm色谱柱，流动相：20％乙醇在二氧化碳中)得到均为黄色固体的中间体A2-1a(faster eluting，保留时间为1.08分钟)和第二个组分峰中间体A2-1b(slower eluting，保留时间为1.28分钟)。MS:380.2(M+H) +。 The intermediate A2-1 was chiral resolved by SFC (column type: CHIRALPAK-AD-H, 5cm x 25cm, 5μm column, mobile phase: 20% ethanol in carbon dioxide) to obtain intermediate A2- as a yellow solid 1a (faster eluting, retention time 1.08 minutes) and the second component peak intermediate A2-1b (slower eluting, retention time 1.28 minutes). MS: 380.2 (M+H) + .
中间体A2的合成参考中间体A1，通过使用中间体A2-1a代替中间体A1-1a制备得到(R)-6-(溴甲基)-4-(2-氯-3-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A2)。Synthesis of Intermediate A2 Referring to Intermediate A1, (R)-6-(bromomethyl)-4-(2-chloro-3-fluorophenyl) was prepared by using Intermediate A2-1a in place of Intermediate A1-1a -2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester (Intermediate A2).
中间体A2-b的合成参考中间体A1，通过使用中间体A2-1b代替中间体A1-1a制备得到(S)-6-(溴甲基)-4-(2-氯-3-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A2-b)。Synthesis of Intermediate A2-b Referring to Intermediate A1, (S)-6-(bromomethyl)-4-(2-chloro-3-fluorobenzene was prepared by using Intermediate A2-1b in place of Intermediate A1-1a yl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Intermediate A2-b).
制备例3中间体A3Preparation Example 3 Intermediate A3
(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(R)-6-(Bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000128
Figure PCTCN2021135751-appb-000128
中间体A3的合成参考中间体A1，通过使用2-氯-4-氟苯甲醛代替3-氟-2-甲基苯甲醛制备得到黄色中间体A3。Synthesis of intermediate A3 Referring to intermediate A1, yellow intermediate A3 was prepared by using 2-chloro-4-fluorobenzaldehyde instead of 3-fluoro-2-methylbenzaldehyde.
制备例4中间体A4Preparation Example 4 Intermediate A4
(S)-6-(溴甲基)-4-(4-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯Ethyl (S)-6-(bromomethyl)-4-(4-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ester
Figure PCTCN2021135751-appb-000129
Figure PCTCN2021135751-appb-000129
中间体A4的合成参考中间体A1，通过使用4-氟-2-甲基苯甲醛代替3-氟-2-甲基苯甲醛制备得到黄色中间体A4。Synthesis of intermediate A4 Referring to intermediate A1, yellow intermediate A4 was prepared by using 4-fluoro-2-methylbenzaldehyde instead of 3-fluoro-2-methylbenzaldehyde.
制备例5中间体A5Preparation Example 5 Intermediate A5
(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸甲酯(R)-6-(Bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate methyl ester
Figure PCTCN2021135751-appb-000130
Figure PCTCN2021135751-appb-000130
中间体A5的合成参考中间体A1，通过使用3-氧代丁酸甲酯代替3-氧代丁酸乙酯和2-氯-4-氟苯甲醛代替3-氟-2-甲基苯甲醛制备得到黄色中间体A5。Synthesis of Intermediate A5 Refers to Intermediate A1 by using methyl 3-oxobutyrate in place of ethyl 3-oxobutyrate and 2-chloro-4-fluorobenzaldehyde in place of 3-fluoro-2-methylbenzaldehyde The yellow intermediate A5 was prepared.
制备例6中间体A6Preparation Example 6 Intermediate A6
(R)-4-(2-溴-4-氟苯基)-6-(溴甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸甲酯(R)-4-(2-Bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate methyl ester
Figure PCTCN2021135751-appb-000131
Figure PCTCN2021135751-appb-000131
中间体A6的合成参考中间体A1，通过使用3-氧代丁酸甲酯代替3-氧代丁酸乙酯和2-溴-4-氟苯甲醛代替3-氟-2-甲基苯甲醛制备得到黄色中间体A6。Synthesis of Intermediate A6 Refers to Intermediate A1 by using methyl 3-oxobutyrate in place of ethyl 3-oxobutyrate and 2-bromo-4-fluorobenzaldehyde in place of 3-fluoro-2-methylbenzaldehyde The yellow intermediate A6 was prepared.
制备例7中间体A7Preparation Example 7 Intermediate A7
(R)-4-(2-溴-4-氟苯基)-6-(溴甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(R)-4-(2-Bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000132
Figure PCTCN2021135751-appb-000132
中间体A7的合成参考中间体A1，通过使用2-溴-4-氟苯甲醛代替3-氟-2-甲基苯甲醛制备得到黄色中间体A7。Synthesis of intermediate A7 Referring to intermediate A1, yellow intermediate A7 was prepared by using 2-bromo-4-fluorobenzaldehyde instead of 3-fluoro-2-methylbenzaldehyde.
制备例8中间体A8Preparation Example 8 Intermediate A8
(S)-6-(溴甲基)-4-(3,4-二氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(Bromomethyl)-4-(3,4-difluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Ethyl carboxylate
Figure PCTCN2021135751-appb-000133
Figure PCTCN2021135751-appb-000133
中间体A8的合成参考中间体A1，通过使用3,4-二氟-2-甲基苯甲醛代替3-氟-2-甲基苯甲醛制备得到黄色中间体A8。Synthesis of intermediate A8 Referring to intermediate A1, yellow intermediate A8 was prepared by using 3,4-difluoro-2-methylbenzaldehyde instead of 3-fluoro-2-methylbenzaldehyde.
制备例9中间体1-4Preparation Example 9 Intermediates 1-4
4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐4,5,6,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate
Figure PCTCN2021135751-appb-000134
Figure PCTCN2021135751-appb-000134
步骤1：中间体1-4-1的制备Step 1: Preparation of Intermediate 1-4-1
将1-(叔丁基)4-乙基3-氧哌啶-1,4-二羧酸酯(2克，7.37毫摩尔)溶于乙醇(20毫升)中，在25℃时搅拌缓慢加入水合肼(0.554克，11.06毫摩尔)。滴完后，将反应混合物在80℃搅拌反应3小时，反应完毕后，将反应混合物冷却到室温，过滤，滤饼乙醇(10毫升)洗涤，干燥，得到白色固体3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1，1.42克)。MS:240.1(M+H) +。 1-(tert-Butyl)4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2 g, 7.37 mmol) was dissolved in ethanol (20 mL) and added slowly with stirring at 25°C Hydrazine hydrate (0.554 g, 11.06 mmol). After dropping, the reaction mixture was stirred at 80°C for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (10 mL) and dried to obtain a white solid 3-hydroxy-2,4, 5,7-Tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1, 1.42 g). MS: 240.1 (M+H) + .
步骤2：中间体1-4的制备Step 2: Preparation of Intermediates 1-4
将3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(239毫克，1.0毫摩尔)溶于二氯甲烷(3 毫升)和三氟乙酸(1毫升)中，反应混合物在室温搅1小时，然后将反应混合物溶液浓缩得到黄色油状物4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4，139毫克)直接用于下一步反应。MS:140.1(M+H) +。 3-Hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate tert-butyl ester (239 mg, 1.0 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL), the reaction mixture was stirred at room temperature for 1 hour, then the reaction mixture solution was concentrated to give 4,5,6,7-tetrahydro-2H-pyrazoline[3 ,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4, 139 mg) was used directly in the next reaction. MS: 140.1 (M+H) + .
制备例10中间体2-2Preparation Example 10 Intermediate 2-2
2-甲基-2,3a,4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐2-Methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolin[3,4-c]pyridin-3-one trifluoroacetate
Figure PCTCN2021135751-appb-000135
Figure PCTCN2021135751-appb-000135
步骤1：中间体2-1的制备Step 1: Preparation of Intermediate 2-1
将1-(叔丁基)4-乙基3-氧哌啶-1,4-二羧酸酯(2.2克，8.11毫摩尔)溶于甲醇(30毫升)中，在25℃时搅拌缓慢加入甲基肼(0.747克，16.22毫摩尔)。滴完后，将反应混合物在55℃搅拌反应2小时，反应完毕后，将反应混合物冷却到室温，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体3-羟基-2-甲基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体2-1，580毫克，28％收率)。MS:254.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.47(s,1H),4.34(s,2H),3.44(d,J＝6.2Hz,5H),2.26(t,J＝5.7Hz,2H),1.40(s,9H)。 1-(tert-Butyl)4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.2 g, 8.11 mmol) was dissolved in methanol (30 mL) and added slowly with stirring at 25°C Methylhydrazine (0.747 g, 16.22 mmol). After dropping, the reaction mixture was stirred at 55°C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 3-hydroxy-2-methyl as a white solid. - 2,4,5,7-Tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylic acid tert-butyl ester (Intermediate 2-1, 580 mg, 28% yield). MS: 254.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.47(s,1H),4.34(s,2H),3.44(d,J=6.2Hz,5H),2.26(t,J=5.7Hz,2H) , 1.40 (s, 9H).
步骤2：中间体2-2的制备Step 2: Preparation of Intermediate 2-2
中间体2-2的合成参考中间体1-4/步骤2，通过使用3-羟基-2-甲基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体2-1)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到2-甲基-2,3a,4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐(中间体2-2)。MS:154.3(M+H) +。 Synthesis of intermediate 2-2 was done with reference to intermediate 1-4/step 2 by using 3-hydroxy-2-methyl-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c ]pyridine-6-carboxylate tert-butyl ester (intermediate 2-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate 2-Methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazoline[3,4-c]pyridine-3 was prepared from tert-butyl acid (Intermediate 1-4-1) - Keto trifluoroacetate (Intermediate 2-2). MS: 154.3 (M+H) + .
制备例11中间体3-3Preparation Example 11 Intermediate 3-3
3a-甲基-2,3a,4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐3a-Methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolin[3,4-c]pyridin-3-one trifluoroacetate
Figure PCTCN2021135751-appb-000136
Figure PCTCN2021135751-appb-000136
步骤1：中间体3-1的制备Step 1: Preparation of Intermediate 3-1
将1-(叔丁基)4-乙基3-恶哌啶-1,4-二羧酸酯(2.0克，7.38毫摩尔)溶于丙酮(20毫升)中，在室温 搅拌下加入K 2CO 3(2.04克，14.76毫摩尔)和碘甲烷(2.10克，14.76毫摩尔)，反应混合物在室温搅拌15小时，然后用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物1-(叔丁基)4-乙基4-甲基-3-恶哌啶-1,4-二羧酸酯(中间体3-1，1.40克，66.7％收率)。MS:230.2(M+H-56) +。 1-(tert-Butyl)4-ethyl 3-oxapiperidine-1,4-dicarboxylate (2.0 g, 7.38 mmol) was dissolved in acetone ( 20 mL) and K was added with stirring at room temperature CO3 (2.04 g, 14.76 mmol) and iodomethane (2.10 g, 14.76 mmol), the reaction mixture was stirred at room temperature for 15 hours, then diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 1-(tert-butyl)4-ethyl4-methyl as a yellow oil -3-oxapiperidine-1,4-dicarboxylate (Intermediate 3-1, 1.40 g, 66.7% yield). MS: 230.2 (M+H-56) + .
步骤2：中间体3-2的制备Step 2: Preparation of Intermediate 3-2
将1-(叔丁基)4-乙基4-甲基-3-恶哌啶-1,4-二羧酸酯(中间体3-1，1.40克，4.91毫摩尔)溶于乙醇(15毫升)中，在室温搅拌下加入水合肼(0.46克，7.37毫摩尔)，将反应混合物缓慢升至60℃并搅拌0.5小时，然后将反应混合物冷却至室温，并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体3a-甲基-3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体3-2，870毫克，70.0％收率)。MS:254.1(M+H) +。 1-(tert-Butyl)4-ethyl 4-methyl-3-oxapiperidine-1,4-dicarboxylate (Intermediate 3-1, 1.40 g, 4.91 mmol) was dissolved in ethanol (15 mL), hydrazine hydrate (0.46 g, 7.37 mmol) was added with stirring at room temperature, the reaction mixture was slowly warmed to 60 °C and stirred for 0.5 h, then the reaction mixture was cooled to room temperature and diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid 3a-methyl-3-oxo-2,3,3a, 4,5,7-Hexahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate tert-butyl ester (Intermediate 3-2, 870 mg, 70.0% yield). MS: 254.1 (M+H) + .
步骤3：中间体3-3的制备Step 3: Preparation of Intermediates 3-3
中间体3-3的合成参考中间体1-4/步骤2，通过使用3a-甲基-3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体3-2)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到3a-甲基-2,3a,4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐(中间体3-3)。MS:154.1(M+H) +。 Synthesis of intermediate 3-3 was done with reference to intermediate 1-4/step 2 by using 3a-methyl-3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazoline[ 3,4-c]Pyridine-6-carboxylate tert-butyl ester (Intermediate 3-2) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c] 3a-methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazoline[3,4- c] Pyridin-3-one trifluoroacetate (Intermediate 3-3). MS: 154.1 (M+H) + .
制备例12中间体4-3Preparation Example 12 Intermediate 4-3
3a-氟-2,3a,4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐3a-Fluoro-2,3a,4,5,6,7-hexahydro-3H-pyrazolin[3,4-c]pyridin-3-one trifluoroacetate
Figure PCTCN2021135751-appb-000137
Figure PCTCN2021135751-appb-000137
步骤1：中间体4-1的制备Step 1: Preparation of Intermediate 4-1
将1-(叔丁基)4-乙基3-恶哌啶-1,4-二羧酸酯(2.0克，7.38毫摩尔)溶于乙腈(100毫升)中，在室温搅拌下加入TiCl 4(1摩尔/L in DCM，0.67毫升)并继续搅拌反应10分钟，然后在0℃搅拌条件下向反应混合物中加入SelectFluor(3.14克，8.86毫摩尔)，将反应混合物缓慢升至室温并继续搅拌2小时。将反应混合物用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物1-(叔丁基)4-乙基-4-氟-3-氧杂哌啶-1,4-二羧酸酯(中间体4-1，1.3克，62％收率)。MS:234.2(M+H-56) +。 1-(tert-Butyl)4-ethyl 3-oxapiperidine-1,4-dicarboxylate (2.0 g, 7.38 mmol) was dissolved in acetonitrile (100 mL) and TiCl was added with stirring at room temperature (1 mol/L in DCM, 0.67 mL) and continued to stir the reaction for 10 min, then SelectFluor (3.14 g, 8.86 mmol) was added to the reaction mixture at 0°C with stirring, the reaction mixture was slowly warmed to room temperature and stirring continued 2 hours. The reaction mixture was diluted with ethyl acetate and extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 1-(tert-butyl)4-ethyl-4-fluoro as a yellow oil -3-oxapiperidine-1,4-dicarboxylate (Intermediate 4-1, 1.3 g, 62% yield). MS: 234.2 (M+H-56) + .
步骤2：中间体4-2的制备Step 2: Preparation of Intermediate 4-2
将1-(叔丁基)4-乙基-4-氟-3-氧杂哌啶-1,4-二羧酸酯(中间体4-1，0.2克，0.7毫摩尔)溶于乙醇(15毫升)中，在室温搅拌下加入水合肼(86.5毫克，1.4毫摩尔)，将反应混合物缓慢升至60℃并搅拌 0.5小时，然后将反应混合物冷却至室温，并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体3a-氟-3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体4-2，126毫克，71％收率)。MS:258.1(M+H) +。 1-(tert-Butyl) 4-ethyl-4-fluoro-3-oxapiperidine-1,4-dicarboxylate (Intermediate 4-1, 0.2 g, 0.7 mmol) was dissolved in ethanol ( 15 mL), hydrazine hydrate (86.5 mg, 1.4 mmol) was added with stirring at room temperature, the reaction mixture was slowly warmed to 60 °C and stirred for 0.5 h, then the reaction mixture was cooled to room temperature and diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 3a-fluoro-3-oxo-2,3,3a,4 as a white solid , 5,7-Hexahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylic acid tert-butyl ester (Intermediate 4-2, 126 mg, 71% yield). MS: 258.1 (M+H) + .
步骤3：中间体4-3的制备Step 3: Preparation of Intermediates 4-3
中间体4-3的合成参考中间体1-4/步骤2，通过使用3a-氟-3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体4-2)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到3a-氟-2,3a,4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐(中间体4-3)。MS:158.1(M+H) +。 Synthesis of intermediate 4-3 was done with reference to intermediate 1-4/step 2 by using 3a-fluoro-3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazoline[3 ,4-c]pyridine-6-carboxylate tert-butyl ester (intermediate 4-2) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine -6-Carboxylic acid tert-butyl ester (Intermediate 1-4-1) prepared to give 3a-fluoro-2,3a,4,5,6,7-hexahydro-3H-pyrazoline[3,4-c] Pyridin-3-one trifluoroacetate (Intermediate 4-3). MS: 158.1 (M+H) + .
制备例13中间体5-2Preparation Example 13 Intermediate 5-2
2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐2,3,4,5,6,7-Hexahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate
Figure PCTCN2021135751-appb-000138
Figure PCTCN2021135751-appb-000138
步骤1：中间体5-1的制备Step 1: Preparation of Intermediate 5-1
将5-苄基-2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮(2.0克，8.76毫摩尔)溶于二氯甲烷(20毫升)中，然后在0℃搅拌条件下向反应混合物中加入1-氯乙基碳酰氯(1.25克，8.76毫摩尔)，将反应混合物缓慢升至室温并继续搅拌1小时，然后回流搅拌3小时。将反应混合物浓缩得到黄色油状物，将黄色油状物溶于甲醇(20毫升)和6N的盐酸HCl(10毫升)溶液中，并在70℃搅拌反应3小时，浓缩并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮(1.2克)。MS:139.2(M+H) +。 5-Benzyl-2,3,4,5,6,7-hexahydro-1H-pyrro[3,4-c]pyridin-1-one (2.0 g, 8.76 mmol) was dissolved in dichloromethane ( 20 mL), then 1-chloroethylcarbonyl chloride (1.25 g, 8.76 mmol) was added to the reaction mixture with stirring at 0°C, the reaction mixture was slowly warmed to room temperature and stirred for 1 hour, then refluxed for 3 Hour. The reaction mixture was concentrated to give a yellow oil, which was dissolved in methanol (20 mL) and 6N hydrochloric acid HCl (10 mL) solution, and the reaction was stirred at 70°C for 3 hours, concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product 2,3,4,5,6,7-hexahydro-1H-pyrrole[3,4-c]pyridine-1 - Ketone (1.2 g). MS: 139.2 (M+H) + .
将2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮(1.2克，8.68毫摩尔)溶于四氢呋喃(20毫升)和水(20毫升)中，在室温搅拌下加入氢氧化钠(1.04克，26.1毫摩尔)和Boc 2O(2.84克，13.0毫摩尔)，将反应混合物在室温搅拌1小时，然后用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1，1.4克，67％收率)。MS:239.3(M+H) +。 2,3,4,5,6,7-Hexahydro-1H-pyrro[3,4-c]pyridin-1-one (1.2 g, 8.68 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL), sodium hydroxide (1.04 g, 26.1 mmol) and Boc2O (2.84 g , 13.0 mmol) were added with stirring at room temperature, and the reaction mixture was stirred at room temperature for 1 hour, then diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-oxo-1,2,3,4,6,7 as a yellow solid - Hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 5-1, 1.4 g, 67% yield). MS: 239.3 (M+H) + .
步骤2：中间体5-2的制备Step 2: Preparation of Intermediate 5-2
中间体5-2的合成参考中间体1-4/步骤2，通过使用1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体5-2)。MS:139.3(M+H) +。 Synthesis of intermediate 5-2 was done with reference to intermediate 1-4/step 2 by using 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c] tert-Butyl pyridine-5-carboxylate (Intermediate 5-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylic acid tert-Butyl ester (Intermediate 1-4-1) was prepared to give 2,3,4,5,6,7-hexahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate ( Intermediate 5-2). MS: 139.3 (M+H) + .
制备例14中间体6-3Preparation Example 14 Intermediate 6-3
4-(1-氧代-1,3,4,5,6,7-六氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐4-(1-oxo-1,3,4,5,6,7-hexahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid trifluoroacetate
Figure PCTCN2021135751-appb-000139
Figure PCTCN2021135751-appb-000139
步骤1：中间体6-1的制备Step 1: Preparation of Intermediate 6-1
将1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1，100毫克，0.42毫摩尔)溶于甲苯(5毫升)中，在20度搅拌条件下向反应混合物中加入4-碘苯甲酸甲酯(165毫克，0.63毫摩尔)，碘化亚铜(40毫克，0.21毫摩尔),(1R，2R)-N，N'-二甲基-1,2-环己二胺(60毫克，0.42毫摩尔)和碳酸钾(116毫克，0.84毫摩尔)，将反应混合物在120℃搅拌反应15小时，反应混合物冷却到室温并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1，65毫克，42％收率)。MS:373.1(M+H) +。 1-Oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 5-1, 100 mg , 0.42 mmol) was dissolved in toluene (5 mL), and to the reaction mixture was added methyl 4-iodobenzoate (165 mg, 0.63 mmol), cuprous iodide (40 mg, 0.21 mmol) with stirring at 20°C mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (60 mg, 0.42 mmol) and potassium carbonate (116 mg, 0.84 mmol), the reaction mixture was mixed The reaction was stirred at 120°C for 15 hours, the reaction mixture was cooled to room temperature and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 2-(4-(methoxycarbonyl)phenyl)-1 as a yellow oil -oxo-1,2,3,4,6,7-hexahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 6-1, 65 mg, 42% yield). MS: 373.1 (M+H) + .
步骤2：中间体6-2的制备Step 2: Preparation of Intermediate 6-2
将2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1，65毫克，0.17毫摩尔)溶于甲醇(2毫升)和水(1毫升)中，在室温搅拌下加入氢氧化钠(14毫克，0.34毫摩尔)，将反应混合物在室温50℃搅拌反应2小时，然后用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物4-(5-(叔丁氧羰基)-1-氧代-1,3,4,5,6,7-六氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体6-2，40毫克，64％收率)。MS:359.1(M+H) +。 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-Butyl acid (Intermediate 6-1, 65 mg, 0.17 mmol) was dissolved in methanol (2 mL) and water (1 mL), and sodium hydroxide (14 mg, 0.34 mmol) was added with stirring at room temperature, The reaction mixture was stirred at room temperature 50°C for 2 hours, then diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4-(5-(tert-butoxycarbonyl)-1-oxygen as a yellow oil Sub-1,3,4,5,6,7-hexahydro-2H-pyrrole[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 6-2, 40 mg, 64% yield) . MS: 359.1 (M+H) + .
步骤3:中间体6-3的制备Step 3: Preparation of Intermediate 6-3
中间体6-3的合成参考中间体1-4/步骤2，通过使用4-(5-(叔丁氧羰基)-1-氧代-1,3,4,5,6,7-六氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体6-2)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到4-(1-氧代-1,3,4,5,6,7-六氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐(中间体6-3)。MS:259.1(M+H) +。 Synthesis of intermediate 6-3 was done with reference to intermediate 1-4/step 2 by using 4-(5-(tert-butoxycarbonyl)-1-oxo-1,3,4,5,6,7-hexahydro -2H-pyrrole[3,4-c]pyridin-2-yl)benzoic acid (intermediate 6-2) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3, 4-c]Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) prepared to give 4-(1-oxo-1,3,4,5,6,7-hexahydro-2H-pyrrole [3,4-c]pyridin-2-yl)benzoic acid trifluoroacetate (Intermediate 6-3). MS: 259.1 (M+H) + .
制备例15中间体7-2a和中间体7-2b和中间体7-3bPreparation Example 15 Intermediate 7-2a and Intermediate 7-2b and Intermediate 7-3b
(3aS,7aS)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体7-2a)和(3aR,7aR)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体7-2b)(3aS,7aS)-Octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (Intermediate 7-2a) and (3aR,7aR)-octahydro-1H-pyrrole[ 3,4-c]pyridin-1-one trifluoroacetate (Intermediate 7-2b)
Figure PCTCN2021135751-appb-000140
Figure PCTCN2021135751-appb-000140
步骤1：中间体7-1的制备Step 1: Preparation of Intermediate 7-1
将5-苄基-2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮(500毫克，2.190毫摩尔)，二碳酸二叔丁酯(2.39克，10.95毫摩尔)溶于甲醇(10毫升)中，在搅拌条件下向反应混合物中加入钯碳(50毫克)。反应混合物在氢气作用下室温搅拌2小时，然后将混合物溶液过滤。将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体顺式-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1，450毫克，86％收率)。MS:241.2(M+H) +。 5-benzyl-2,3,4,5,6,7-hexahydro-1H-pyrro[3,4-c]pyridin-1-one (500 mg, 2.190 mmol), di-tert-butyl dicarbonate The ester (2.39 g, 10.95 mmol) was dissolved in methanol (10 mL) and palladium on carbon (50 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 2 hours, and then the mixture solution was filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (intermediate) as a white solid. body 7-1, 450 mg, 86% yield). MS: 241.2 (M+H) + .
步骤2：中间体7-1a和中间体7-1b的制备Step 2: Preparation of Intermediate 7-1a and Intermediate 7-1b
将顺式-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1)经SFC手性拆分(柱型号：CHIRALPAK IH，5cm x 25cm，5μm色谱柱，流动相：35％异丙醇在二氧化碳中)得到均为白色固体的中间体7-1a(faster eluting，保留时间为2.978分钟)和第二个组分峰中间体7-1b(slower eluting，保留时间为3.123分钟)。MS:241.2(M+H) +。 cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1) was chiral resolved by SFC (column model: CHIRALPAK IH , 5cm x 25cm, 5μm column, mobile phase: 35% isopropanol in carbon dioxide) to obtain intermediate 7-1a (faster eluting, retention time 2.978 minutes) as white solids and the middle of the second component peak Body 7-1b (slower eluting, retention time 3.123 minutes). MS: 241.2 (M+H) + .
步骤3：中间体7-2a和中间体7-2b的制备Step 3: Preparation of Intermediate 7-2a and Intermediate 7-2b
中间体7-2a的合成参考中间体1-4/步骤2，通过使用(3aR，7aS)-1-氧代八氢-5H-吡咯并[3，4-c]吡啶-5-羧酸叔丁酯(中间体7-1a)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到(3aS,7aS)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体7-2a)。MS:141.2(M+H) +。 Intermediate 7-2a was synthesized with reference to Intermediate 1-4/Step 2 by using tertiary (3aR,7aS)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylic acid Butyl ester (Intermediate 7-1a) in place of tert-butyl 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazolino[3,4-c]pyridine-6-carboxylate (Intermediate 1 -4-1) Preparation of (3aS,7aS)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (intermediate 7-2a). MS: 141.2 (M+H) + .
中间体7-2b的合成参考中间体1-4/步骤2，通过使用(3aS，7aR)-1-氧代八氢-5H-吡咯并[3，4-c]吡啶-5-羧酸叔丁酯(中间体7-1b)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到(3aR,7aR)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体7-2b)。MS:141.2(M+H) +。 Intermediate 7-2b was synthesized with reference to Intermediate 1-4/Step 2 by using tertiary (3aS,7aR)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylic acid Butyl ester (Intermediate 7-1b) in place of tert-butyl 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate (Intermediate 1 -4-1) Preparation of (3aR,7aR)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (intermediate 7-2b). MS: 141.2 (M+H) + .
步骤4：中间体7-3b的制备Step 4: Preparation of Intermediate 7-3b
将4-氯苯甲酸(470毫克，3.0毫摩尔)溶于二氯甲烷(5毫升)中，在0℃搅拌下加入草酰氯(1毫升)，将反应混合物回流反应2小时，然后将反应混合物浓缩蒸干得到黄色油状物。将黄色油状物的二氯甲烷(2毫升)溶液在0℃下加入到(3aR,7aR)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(580毫克，2.3毫摩尔)和TEA(630毫克，6.3毫摩尔)的二氯甲烷(10毫升)溶液中，将反应混合物在室温搅 拌反应1小时，反应混合物用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体中间体7-3b(530毫克，83％收率)。MS:279.1(M+H) +。 4-Chlorobenzoic acid (470 mg, 3.0 mmol) was dissolved in dichloromethane (5 mL), oxalyl chloride (1 mL) was added with stirring at 0°C, and the reaction mixture was refluxed for 2 hours, then the reaction mixture was Concentrate and evaporate to dryness to obtain a yellow oil. A solution of the yellow oil in dichloromethane (2 mL) was added at 0°C to (3aR,7aR)-octahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate (580 mg, 2.3 mmol) and TEA (630 mg, 6.3 mmol) in dichloromethane (10 mL), the reaction mixture was stirred at room temperature for 1 hour, and the reaction mixture was diluted with ethyl acetate and extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate 7-3b (530 mg, 83% yield) as a white solid. MS: 279.1 (M+H) + .
中间体7-3b通过X-Ray晶体结构分析确定为(3aS，7aR)-5-(4-氯苯甲酰基)八氢-1H-吡咯[3,4-c]吡啶-1-酮(见图1)。因此确定中间体7-2b的结构(3aR,7aR)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐；相应地，中间体7-2a的结构为(3aS,7aS)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐。Intermediate 7-3b was identified by X-Ray crystal structure analysis as (3aS,7aR)-5-(4-chlorobenzoyl)octahydro-1H-pyrro[3,4-c]pyridin-1-one (see figure 1). The structure of intermediate 7-2b was thus determined (3aR,7aR)-octahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate; correspondingly, the structure of intermediate 7-2a was (3aS,7aS)-Octahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate.
制备例16中间体9-3Preparation Example 16 Intermediate 9-3
顺式-3-(1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐cis-3-(1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid trifluoroacetate
Figure PCTCN2021135751-appb-000141
Figure PCTCN2021135751-appb-000141
中间体9-3的合成参考中间体6-3，通过使用顺式-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1)代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)和3-碘苯甲酸甲酯代替4-碘苯甲酸甲酯制备得到顺式-3-(1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐(中间体9-3)。MS:261.2(M+H) +。 The synthesis of intermediate 9-3 was carried out with reference to intermediate 6-3 by using cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7 -1) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1 ) and methyl 3-iodobenzoate instead of methyl 4-iodobenzoate to prepare cis-3-(1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid Trifluoroacetate salt (Intermediate 9-3). MS: 261.2 (M+H) + .
制备例17中间体10-3Preparation Example 17 Intermediate 10-3
顺式-2-甲基-2-(4-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙酸三氟乙酸盐cis-2-methyl-2-(4-((3aS,7aS)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)propanoic acid trifluoro acetate
Figure PCTCN2021135751-appb-000142
Figure PCTCN2021135751-appb-000142
中间体10-3的合成参考中间体6-3，通过使用顺式-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1)代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)和2-(4-溴苯基)-2-甲基丙酸甲酯代替4-碘苯甲酸甲酯制备得到顺式-2-甲基-2-(4-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙酸三氟乙酸盐(中间体10-3)。The synthesis of intermediate 10-3 was carried out with reference to intermediate 6-3 by using cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7 -1) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1 ) and methyl 2-(4-bromophenyl)-2-methylpropanoate instead of methyl 4-iodobenzoate to prepare cis-2-methyl-2-(4-((3aS,7aS)- 1-Oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)phenyl)propanoic acid trifluoroacetate (Intermediate 10-3).
制备例18中间体18和中间体19Preparation Example 18 Intermediate 18 and Intermediate 19
3-(4-溴苯基)丁酸甲酯和(E)-3-(4-溴苯基)丙烯酸甲酯Methyl 3-(4-bromophenyl)butyrate and (E)-methyl 3-(4-bromophenyl)acrylate
Figure PCTCN2021135751-appb-000143
Figure PCTCN2021135751-appb-000143
将溴化亚铜的二甲硫醚复合物(853毫克，4.15毫摩尔)悬浮于四氢呋喃(10毫升)中，在-40度搅拌条件下向反应混合物中加入1M的甲基溴化镁(3.1毫升)并继续搅拌0.5小时，然后在-78度搅拌条件下向反应混合物中加入三甲基氯硅烷(901毫克，8.30毫摩尔)并继续搅拌10分钟。在-78度搅拌条件下向反应混合物中加入(E)-3-(4-溴苯基)丙烯酸甲酯(500毫克，2.07毫摩尔)的四氢呋喃(10毫升)溶液，将反应混合物在-78度继续搅拌反应1.5小时。反应混合物用冰水淬灭反应并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到均为无色油状物3-(4-溴苯基)丁酸甲酯(中间体18，150毫克)和(E)-3-(4-溴苯基)丙烯酸甲酯(中间体19，120毫克)。The cuprous bromide dimethyl sulfide complex (853 mg, 4.15 mmol) was suspended in tetrahydrofuran (10 mL), and 1 M methylmagnesium bromide (3.1 M methylmagnesium bromide) was added to the reaction mixture with stirring at -40°C. mL) and continued stirring for 0.5 hours, then to the reaction mixture was added trimethylchlorosilane (901 mg, 8.30 mmol) with stirring at -78°C and stirring was continued for 10 minutes. A solution of (E)-methyl 3-(4-bromophenyl)acrylate (500 mg, 2.07 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture with stirring at -78°C, and the reaction mixture was heated at -78°C. The reaction was continued to stir for 1.5 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain methyl 3-(4-bromophenyl)butyrate as colorless oil. ester (Intermediate 18, 150 mg) and (E)-methyl 3-(4-bromophenyl)acrylate (Intermediate 19, 120 mg).
制备例19中间体20-5Preparation Example 19 Intermediate 20-5
2-甲基-3-(4-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙酸三氟乙酸盐2-Methyl-3-(4-((3aS,7aS)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)propanoic acid trifluoroacetate
Figure PCTCN2021135751-appb-000144
Figure PCTCN2021135751-appb-000144
步骤1：中间体20-1的制备Step 1: Preparation of Intermediate 20-1
将2-(二乙氧基磷酰)丙酸乙酯((280毫克，1.18毫摩尔)溶于无水四氢呋喃(4毫升)中，在0度搅拌下加入60％的钠氢(94毫克，2.35毫摩尔)并继续搅拌反应60分钟，然后在0度搅拌条件下向反应混合物中加入4-碘苯甲醛(327毫克，1.41毫摩尔)，将反应混合物缓慢升至室温并继续搅拌15小时。将反应混合物用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(E)-3-(4-碘苯基)-2-甲基丙烯酸乙酯(中间体20-1，250毫克，73％收率)。MS:310.2(M+H) +。 Ethyl 2-(diethoxyphosphoryl)propionate ((280 mg, 1.18 mmol) was dissolved in dry tetrahydrofuran (4 mL), and 60% sodium hydrogen (94 mg, 60%) was added with stirring at 0°C. 2.35 mmol) and continued stirring the reaction for 60 minutes, then 4-iodobenzaldehyde (327 mg, 1.41 mmol) was added to the reaction mixture with stirring at 0 degrees, the reaction mixture was slowly warmed to room temperature and stirring was continued for 15 hours. The reaction mixture was diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless oil (E)- Ethyl 3-(4-iodophenyl)-2-methacrylate (Intermediate 20-1, 250 mg, 73% yield). MS: 310.2 (M+H) + .
步骤2：中间体20-2的制备Step 2: Preparation of Intermediate 20-2
将(3aR,7aS)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸(中间体7-1a，50毫克，0.21毫摩尔),(E)-3-(4-碘苯基)-2-甲基丙烯酸乙酯(中间体20-1，78毫克，0.27毫摩尔)，CuI(19.8毫克，0.1毫摩尔)，碳酸钾(57.5毫克，0.42毫摩尔)和(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(29.6毫克，0.21毫摩尔)溶于甲苯(5毫升)中，将反应混合物在115度搅拌12小时，然后用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体(3aR，7aS)-2-(4-((E)-3-甲氧基-2-甲基-3-氧代丙烷-1-烯-1-基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体20-2，30毫克，36％收率)。MS:415.2(M+H) +。 (3aR,7aS)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylic acid (Intermediate 7-1a, 50 mg, 0.21 mmol), (E)-3 -(4-Iodophenyl)-2-methacrylate ethyl ester (intermediate 20-1, 78 mg, 0.27 mmol), CuI (19.8 mg, 0.1 mmol), potassium carbonate (57.5 mg, 0.42 mmol) ) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (29.6 mg, 0.21 mmol) were dissolved in toluene (5 mL) and the reaction mixture was stirred at 115°C for 12 hours, then diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid (3aR, 7aS)-2-(4-((E)- 3-Methoxy-2-methyl-3-oxopropan-1-en-1-yl)phenyl)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5- tert-Butyl carboxylate (Intermediate 20-2, 30 mg, 36% yield). MS: 415.2 (M+H) + .
步骤3：中间体20-3的制备Step 3: Preparation of Intermediate 20-3
将(3aR，7aS)-2-(4-((E)-3-甲氧基-2-甲基-3-氧代丙烷-1-烯-1-基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体20-2，50毫克，0.21毫摩尔)和氢氧化钠(6毫克，0.15毫摩尔)溶于甲醇(2毫升)和水(0.5毫升)中，将反应混合物在50度搅拌2小时，然后用1N的稀盐酸中和并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物(E)-3-(4-((3aR，7aS)-5-(叔丁氧羰基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙烯酸(中间体20-3，26毫克，90％收率)。MS:401.2(M+H) +。 (3aR,7aS)-2-(4-((E)-3-methoxy-2-methyl-3-oxopropan-1-en-1-yl)phenyl)-1-oxo Octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 20-2, 50 mg, 0.21 mmol) and sodium hydroxide (6 mg, 0.15 mmol) were dissolved in The reaction mixture was stirred at 50°C for 2 hours in methanol (2 mL) and water (0.5 mL), then neutralized with 1N dilute hydrochloric acid and diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow oil (E)-3-(4-((3aR,7aS)-5-(tert-butoxycarbonyl)-1- Oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)-2-methacrylic acid (Intermediate 20-3, 26 mg, 90% yield). MS: 401.2 (M+H) + .
步骤4：中间体20-4的制备Step 4: Preparation of Intermediate 20-4
将(E)-3-(4-((3aR，7aS)-5-(叔丁氧羰基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙烯酸(中间体20-3，26毫克，0.064毫摩尔)溶于乙酸乙酯(2毫升)和甲醇(0.5毫升)中，在搅拌条件下向反应混合物中加入钯碳(10毫克)。反应混合物在氢气作用下室温搅拌12小时，然后将混合物溶液过滤。将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物3-(4-((3aR，7aS)-5-(叔丁氧羰基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸(中间体20-4，26毫克，100％收率)。MS:403.2(M+H) +。 (E)-3-(4-((3aR,7aS)-5-(tert-butoxycarbonyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene yl)-2-methacrylic acid (intermediate 20-3, 26 mg, 0.064 mmol) was dissolved in ethyl acetate (2 mL) and methanol (0.5 mL), and palladium on carbon was added to the reaction mixture with stirring (10 mg). The reaction mixture was stirred at room temperature under the influence of hydrogen for 12 hours, and then the mixture solution was filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 3-(4-((3aR,7aS)-5-(tert-butoxycarbonyl)-1-oxooctahydro-2H-pyrrole as a yellow oil [3,4-c]pyridin-2-yl)phenyl)-2-methylpropionic acid (Intermediate 20-4, 26 mg, 100% yield). MS: 403.2 (M+H) + .
步骤5：中间体20-5的制备Step 5: Preparation of Intermediate 20-5
中间体20-5的合成参考中间体1-4/步骤2，通过使用3-(4-((3aR，7aS)-5-(叔丁氧羰基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸(中间体20-4)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到2-甲基-3-(4-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙酸三氟乙酸盐(中间体20-5)。MS:303.2(M+H) +。 Intermediate 20-5 was synthesized with reference to Intermediate 1-4/Step 2 by using 3-(4-((3aR,7aS)-5-(tert-butoxycarbonyl)-1-oxooctahydro-2H-pyrrole [3,4-c]pyridin-2-yl)phenyl)-2-methylpropionic acid (Intermediate 20-4) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazole 2-Methyl-3-(4-((3aS,7aS)-1-oxoocta Hydrogen-2H-pyrrole[3,4-c]pyridin-2-yl)phenyl)propionic acid trifluoroacetate (Intermediate 20-5). MS: 303.2 (M+H) + .
制备例20中间体21-2Preparation Example 20 Intermediate 21-2
6-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸三氟乙酸盐6-((3aS,7aS)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)nicotinic acid trifluoroacetate
Figure PCTCN2021135751-appb-000145
Figure PCTCN2021135751-appb-000145
步骤1：中间体21-1的制备Step 1: Preparation of Intermediate 21-1
将(3aR,7aS)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(50毫克，0.21毫摩尔),6-溴烟酸(46毫克，0.23毫摩尔),(9,9-二甲基-9H-杂蒽-4,5-二基)双(二苯基膦)(24.0毫克，0.042毫摩尔)，醋酸钯(4.67毫克，0.021毫摩尔)和2-甲基丙-2-油酸钾(51毫克，0.46毫摩尔)溶于DMF(1毫升)中。反应混合物在120度搅拌2小时，然后用1N的稀盐酸中和并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物6-((3aR,7aS)-5-(叔丁氧羰基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸(中间体21-1，39毫克)。MS:362.3(M+H) +。 (3aR,7aS)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (50 mg, 0.21 mmol), 6-bromonicotinic acid (46 mg , 0.23 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24.0 mg, 0.042 mmol), palladium acetate (4.67 mg, 0.021 mmol) and potassium 2-methylprop-2-oleate (51 mg, 0.46 mmol) were dissolved in DMF (1 mL). The reaction mixture was stirred at 120 degrees for 2 hours, then neutralized with 1N dilute hydrochloric acid and diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow oily substance 6-((3aR,7aS)-5-(tert-butoxycarbonyl)-1-oxooctahydro-2H- Pyrrolo[3,4-c]pyridin-2-yl)nicotinic acid (Intermediate 21-1, 39 mg). MS: 362.3 (M+H) + .
步骤2：中间体21-2的制备Step 2: Preparation of Intermediate 21-2
中间体21-2的合成参考中间体1-4/步骤2，通过使用6-((3aR,7aS)-5-(叔丁氧羰基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸(中间体21-1)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到6-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸三氟乙酸盐(中间体21-2)。MS:262.2(M+H) +。 Intermediate 21-2 was synthesized with reference to Intermediate 1-4/Step 2 by using 6-((3aR,7aS)-5-(tert-butoxycarbonyl)-1-oxooctahydro-2H-pyrrole[3, 4-c]pyridin-2-yl)nicotinic acid (intermediate 21-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazolin[3,4-c]pyridine-6 - tert-butyl carboxylate (Intermediate 1-4-1) was prepared to give 6-((3aS,7aS)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) nicotine acid trifluoroacetate (Intermediate 21-2). MS: 262.2 (M+H) + .
制备例21中间体22-10Preparation Example 21 Intermediate 22-10
(3aS)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(3aS)-Octahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate
Figure PCTCN2021135751-appb-000146
Figure PCTCN2021135751-appb-000146
步骤1：中间体22-1的制备Step 1: Preparation of Intermediate 22-1
将2-亚甲基琥珀酸(89克，0.68摩尔)和(R)-1-苯基乙烷-1-胺(83克，0.68摩尔)的混合物溶液在160度搅拌4小时，然后用乙醇(400毫升)和H 2O(400毫升)进行重结晶，然后过滤，干燥得到(R)-5-氧代-1-((R)-1-苯乙基)吡咯烷-3-羧酸(中间体22-1，61克，38％收率)。MS:234.1(M+H) +。 A mixture solution of 2-methylenesuccinic acid (89 g, 0.68 mol) and (R)-1-phenylethan-1-amine (83 g, 0.68 mol) was stirred at 160°C for 4 hours, then washed with ethanol (400 mL) and H2O (400 mL) were recrystallized, then filtered and dried to give (R)-5-oxo-1-((R)-1-phenethyl)pyrrolidine-3-carboxylic acid (Intermediate 22-1, 61 g, 38% yield). MS: 234.1 (M+H) + .
步骤2：中间体22-2的制备Step 2: Preparation of Intermediate 22-2
将(R)-5-氧代-1-((R)-1-苯乙基)吡咯烷-3-羧酸(中间体22-1，20.0克，85.8毫摩尔)溶于THF(200毫升)中，在0度搅拌下向反应混合物中滴加1M硼烷四氢呋喃溶液(103毫升，103毫摩尔)并在0度继续搅拌3小时，然后用甲醇在0度淬灭反应并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(R)-4-(羟甲基)-1-((R)-1-苯乙基)吡咯烷-2-酮(中间体22-2，17.3克，92％收率)。MS:220.2(M+H) +。 (R)-5-oxo-1-((R)-1-phenethyl)pyrrolidine-3-carboxylic acid (Intermediate 22-1, 20.0 g, 85.8 mmol) was dissolved in THF (200 mL) ), 1M solution of borane in tetrahydrofuran (103 mL, 103 mmol) was added dropwise to the reaction mixture with stirring at 0°C and stirring was continued at 0°C for 3 hours, then the reaction was quenched with methanol at 0°C and diluted with ethyl acetate extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain (R)-4-(hydroxymethyl)- 1-((R)-1-phenethyl)pyrrolidin-2-one (Intermediate 22-2, 17.3 g, 92% yield). MS: 220.2 (M+H) + .
步骤3：中间体22-3的制备Step 3: Preparation of Intermediate 22-3
将(R)-4-(羟甲基)-1-((R)-1-苯乙基)吡咯烷-2-酮(中间体22-2，13.3克，60.7毫摩尔)溶于THF(150毫升)中，在0度搅拌下向反应混合物中缓慢加入钠氢(3.64克，91.9毫摩尔)并在20度继 续搅拌1小时，然后将苄溴(13.4克，78.9毫摩尔)加入到上述反应混合物中并在室温搅拌12小时。反应混合物用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(R)-4-((苄氧基)甲基)-1-((R)-1-苯乙基)吡咯烷-2-酮(中间体22-3，16.2克，86％收率)。MS:310.2(M+H) +。 (R)-4-(Hydroxymethyl)-1-((R)-1-phenethyl)pyrrolidin-2-one (Intermediate 22-2, 13.3 g, 60.7 mmol) was dissolved in THF ( 150 mL), sodium hydrogen (3.64 g, 91.9 mmol) was slowly added to the reaction mixture with stirring at 0 °C and stirring was continued at 20 °C for 1 h, then benzyl bromide (13.4 g, 78.9 mmol) was added to the above. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain (R)-4-((benzyloxy) as a colorless oil. Methyl)-1-((R)-1-phenethyl)pyrrolidin-2-one (Intermediate 22-3, 16.2 g, 86% yield). MS: 310.2 (M+H) + .
步骤4：中间体22-4的制备Step 4: Preparation of Intermediate 22-4
将(R)-4-((苄氧基)甲基)-1-((R)-1-苯乙基)吡咯烷-2-酮(中间体22-3，10.0克,32.4毫摩尔)溶于THF(100毫升)中，在-78度搅拌下向反应混合物中缓慢加入2M的LDA四氢呋喃溶液(21毫升，42毫摩尔)并在-78度继续搅拌1小时，然后将2-溴乙腈(5.0克，42.1毫摩尔)的四氢呋喃(10毫升)溶液在-78度下加入到上述反应混合物中并升温至室温继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物2-((3R，4R)-4-((苄氧基)甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙腈(中间体22-4，3.27克，29％收率)。MS:349.2(M+H) +。 (R)-4-((benzyloxy)methyl)-1-((R)-1-phenethyl)pyrrolidin-2-one (Intermediate 22-3, 10.0 g, 32.4 mmol) Dissolved in THF (100 mL), a 2M solution of LDA in tetrahydrofuran (21 mL, 42 mmol) was slowly added to the reaction mixture with stirring at -78 °C and stirring was continued at -78 °C for 1 h, then 2-bromoacetonitrile was added (5.0 g, 42.1 mmol) in tetrahydrofuran (10 mL) was added to the above reaction mixture at -78°C and allowed to warm to room temperature and continue stirring for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 2-((3R,4R)-4-( as a colorless oil. (benzyloxy)methyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)acetonitrile (Intermediate 22-4, 3.27 g, 29% yield) . MS: 349.2 (M+H) + .
步骤5：中间体22-5的制备Step 5: Preparation of Intermediate 22-5
将2-((3R，4R)-4-((苄氧基)甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙腈(中间体22-4，3.0克，8.6毫摩尔)溶于甲醇(30毫升)中，在搅拌条件下向反应混合物中加入Raney Ni(500毫克)。反应混合物在氢气作用下室温搅拌12小时，然后将混合物溶液过滤。将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(3R，4R)-3-(2-氨基乙基)-4-((苄氧基)甲基)-1-((R)-1-苯乙基)吡咯烷-2-酮(中间体22-5,2.67克,88％收率)。MS:353.2(M+H) +。 2-((3R,4R)-4-((benzyloxy)methyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)acetonitrile (intermediate Compound 22-4, 3.0 g, 8.6 mmol) was dissolved in methanol (30 mL) and Raney Ni (500 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 12 hours, and then the mixture solution was filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography to give (3R,4R)-3-(2-aminoethyl)-4-((benzyloxy)methyl)-1- as a colorless oil ((R)-1-phenethyl)pyrrolidin-2-one (Intermediate 22-5, 2.67 g, 88% yield). MS: 353.2 (M+H) + .
步骤6：中间体22-6的制备Step 6: Preparation of Intermediate 22-6
将(3R，4R)-3-(2-氨基乙基)-4-((苄氧基)甲基)-1-((R)-1-苯乙基)吡咯烷-2-酮(中间体22-5，2.5克，7.1毫摩尔)溶于二氯甲烷(30毫升)中，在室温搅拌下向反应混合物中缓慢加入TEA(1.1克，10.7毫摩尔)和Boc 2O(1.7克，7.8毫摩尔)并在室温继续搅拌5小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(2-((3R，4R)-4-((苄氧基)甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-6，2.86克，89％收率)。MS:453.2(M+H) +。 (3R,4R)-3-(2-aminoethyl)-4-((benzyloxy)methyl)-1-((R)-1-phenethyl)pyrrolidin-2-one (intermediate Compound 22-5, 2.5 g, 7.1 mmol) was dissolved in dichloromethane (30 mL), and to the reaction mixture were slowly added TEA (1.1 g, 10.7 mmol) and Boc 2 O (1.7 g, 7.8 mmol) and continued stirring at room temperature for 5 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless oil (2-((3R,4R)-4- tert-Butyl ((benzyloxy)methyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl)carbamate (Intermediate 22-6, 2.86 g, 89% yield). MS: 453.2 (M+H) + .
步骤7：中间体22-7的制备Step 7: Preparation of Intermediate 22-7
将(2-((3R，4R)-4-((苄氧基)甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-6，2.0克，4.4毫摩尔)溶于甲醇(20毫升)中，在搅拌条件下向反应混合物中加入钯碳(200毫克)。反应混合物在氢气作用下室温搅拌2小时，然后将混合物溶液过滤。将滤液浓缩得到无色油状物(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7，1.44克，90％收率)。MS:363.2(M+H) +。 (2-((3R,4R)-4-((benzyloxy)methyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl ) tert-butyl carbamate (Intermediate 22-6, 2.0 g, 4.4 mmol) was dissolved in methanol (20 mL) and palladium on carbon (200 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 2 hours, and then the mixture solution was filtered. The filtrate was concentrated to give (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl) as a colorless oil ) ethyl) tert-butyl carbamate (Intermediate 22-7, 1.44 g, 90% yield). MS: 363.2 (M+H) + .
步骤8：中间体22-8的制备Step 8: Preparation of Intermediate 22-8
将(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7，1.44克，4.0毫摩尔)和TEA(0.6克，6.0毫摩尔)溶于二氯甲烷(30毫升)中，在0 度搅拌下向反应混合物中缓慢加入MsCl(0.55克，4.8毫摩尔)并在室温继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物((3R，4R)-4-(2-((叔丁氧羰基)氨基)乙基)-5-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)甲基磺酸甲酯(中间体22-8，1.45克，83％收率)。MS:441.2(M+H) +。 (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl)carbamic acid tertiary Butyl ester (intermediate 22-7, 1.44 g, 4.0 mmol) and TEA (0.6 g, 6.0 mmol) were dissolved in dichloromethane (30 mL) and to the reaction mixture was slowly added MsCl ( 0.55 g, 4.8 mmol) and stirring was continued at room temperature for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless oil ((3R, 4R)-4-(2- Methyl ((tert-butoxycarbonyl)amino)ethyl)-5-oxo-1-(((R)-1-phenethyl)pyrrolidin-3-yl)methanesulfonate (Intermediate 22-8 , 1.45 g, 83% yield). MS: 441.2 (M+H) + .
步骤9：中间体22-9的制备Step 9: Preparation of Intermediate 22-9
将((3R,4R)-4-(2-((叔丁氧羰基)氨基)乙基)-5-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)甲基磺酸甲酯(中间体22-8，0.5克，1.15毫摩尔)溶于DMF(5毫升)中，在100度搅拌下向反应混合物中缓慢加入叔丁醇钾(0.13克，1.15毫摩尔)并在100度继续搅拌0.5小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(3aR，7aR)-1-氧代-2-((R)-1-苯乙基)八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体22-9，70毫克，18％收率)。MS:345.2(M+H) +。 ((3R,4R)-4-(2-((tert-butoxycarbonyl)amino)ethyl)-5-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl ) methyl methanesulfonate (intermediate 22-8, 0.5 g, 1.15 mmol) was dissolved in DMF (5 mL), and potassium tert-butoxide (0.13 g, 1.15 g) was slowly added to the reaction mixture with stirring at 100°C. mmol) and continued stirring at 100 degrees for 0.5 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain (3aR, 7aR)-1-oxo-2 as a colorless oil. -((R)-1-phenethyl)octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 22-9, 70 mg, 18% yield). MS: 345.2 (M+H) + .
步骤10：中间体22-10的制备Step 10: Preparation of Intermediate 22-10
将(3aR，7aR)-1-氧代-2-((R)-1-苯乙基)八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体22-9，70毫克，0.20毫摩尔)溶于TFA(10毫升)中，将反应混合物在150度微波反应1小时。反应混合物液浓缩得到黄色油状物(3aS)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体22-10，60毫克)。MS:141.1(M+H) +。 (3aR,7aR)-1-oxo-2-((R)-1-phenethyl)octahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 22-9, 70 mg, 0.20 mmol) was dissolved in TFA (10 mL) and the reaction mixture was microwaved at 150 degrees for 1 hour. The reaction mixture was concentrated to give (3aS)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (Intermediate 22-10, 60 mg) as a yellow oil. MS: 141.1 (M+H) + .
制备例22中间体cis-23-4Preparation Example 22 Intermediate cis-23-4
顺式-4-(7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐cis-4-(7a-Methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid trifluoroacetate
Figure PCTCN2021135751-appb-000147
Figure PCTCN2021135751-appb-000147
步骤1：中间体cis-23-1的制备Step 1: Preparation of intermediate cis-23-1
中间体cis-23-1的合成参考中间体6-1，通过使用(cis)-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1)代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)制备得到中间体cis-23-1。MS:375.2(M+H) +。 The synthesis of intermediate cis-23-1 was carried out with reference to intermediate 6-1 by using (cis)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester ( Intermediate 7-1) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1) Preparation of intermediate cis-23-1. MS: 375.2 (M+H) + .
步骤2：中间体cis-23-2的制备Step 2: Preparation of intermediate cis-23-2
将(3aR,7aS)-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体cis-23-1，100毫克，0.27毫摩尔)溶于无水四氢呋喃(5毫升)中，在-78度搅拌条件下向反应混合物中加入LiHMDS(0.54毫摩尔)并继续搅拌0.5小时，然后将碘甲烷(75毫克，0.54毫摩尔)加入到上述反应混合液中，并继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体(3aR，7aS)-2-(4-(甲氧羰基)苯基)-7a-甲基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体cis-23-2，78毫克，75％收率)。MS:389.2(M+H) +。 (3aR,7aS)-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis-23-1, 100 mg, 0.27 mmol) was dissolved in dry tetrahydrofuran (5 mL), LiHMDS (0.54 mmol) was added to the reaction mixture with stirring at -78°C and stirring was continued for 0.5 h, then the Iodomethane (75 mg, 0.54 mmol) was added to the above reaction mixture and stirring was continued for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid (3aR, 7aS)-2-(4-(methoxycarbonyl)) Phenyl)-7a-methyl-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate cis-23-2, 78 mg, 75% yield Rate). MS: 389.2 (M+H) + .
步骤3：中间体cis-23-4的制备Step 3: Preparation of intermediate cis-23-4
中间体cis-23-4的合成参考中间体6-3，通过使用(3aR，7aS)-2-(4-(甲氧羰基)苯基)-7a-甲基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体cis-23-2)代替2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到中间体cis-23-4。MS:275.2(M+H) +。 Intermediate cis-23-4 was synthesized with reference to intermediate 6-3 by using (3aR,7aS)-2-(4-(methoxycarbonyl)phenyl)-7a-methyl-1-oxooctahydro- 5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis-23-2) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1, 2,3,4,6,7-Hexahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 6-1) was prepared to give intermediate cis-23-4. MS: 275.2 (M+H) + .
制备例23中间体24-3Preparation Example 23 Intermediate 24-3
4-((3aS,7aR)-7a-羟基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-7a-hydroxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000148
Figure PCTCN2021135751-appb-000148
步骤1：中间体24-1的制备Step 1: Preparation of Intermediate 24-1
中间体24-1的合成参考中间体6-1，通过使用(3aR，7aS)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1a)代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)制备得到中间体24-1。MS:375.2(M+H) +。 Intermediate 24-1 was synthesized with reference to Intermediate 6-1 by using (3aR,7aS)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate Compound 7-1a) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (Intermediate 5 -1) Preparation of intermediate 24-1. MS: 375.2 (M+H) + .
步骤2：中间体24-2的制备Step 2: Preparation of Intermediate 24-2
将(3aR，7aS)-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体24-1，100毫克，0.27毫摩尔)溶于无水四氢呋喃(5毫升)中，在-78度搅拌条件下向反应混合物中加入LiHMDS(0.4毫摩尔)并继续搅拌0.5小时，然后将3-苯基-2-(苯磺酰基)-1,2-恶嗪啶(105毫克，0.4毫摩尔)加入到上述反应混合液中，并继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱 层析纯化得到白色固体(3aR，7aR)-7a-羟基-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体24-2，100毫克，60％收率)。MS:391.3(M+H) +。 (3aR,7aS)-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 24-1, 100 mg, 0.27 mmol) was dissolved in dry tetrahydrofuran (5 mL), LiHMDS (0.4 mmol) was added to the reaction mixture with stirring at -78°C and stirring was continued for 0.5 h, then 3- Phenyl-2-(benzenesulfonyl)-1,2-oxazinidine (105 mg, 0.4 mmol) was added to the above reaction mixture and stirring was continued for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid (3aR, 7aR)-7a-hydroxy-2-(4-( Methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 24-2, 100 mg, 60% yield). MS: 391.3 (M+H) + .
步骤3：中间体24-3的制备Step 3: Preparation of Intermediate 24-3
中间体24-3的合成参考中间体6-3，通过使用(3aR,7aR)-7a-羟基-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体24-2)代替2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到中间体24-3。MS:277.2(M+H) +。 Intermediate 24-3 was synthesized with reference to Intermediate 6-3 by using (3aR,7aR)-7a-hydroxy-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole [3,4-c]Pyridine-5-carboxylate tert-butyl ester (Intermediate 24-2) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1,2,3,4 , 6,7-Hexahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 6-1) was prepared to give Intermediate 24-3. MS: 277.2 (M+H) + .
制备例24中间体25-2Preparation Example 24 Intermediate 25-2
4-((3aS,7aR)-7a-甲氧基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-7a-methoxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000149
Figure PCTCN2021135751-appb-000149
步骤1：中间体25-1的制备Step 1: Preparation of Intermediate 25-1
将(3aR,7aR)-7a-羟基-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体24-2，100毫克，0.26毫摩尔)溶于无水四氢呋喃(5毫升)中，在0度搅拌条件下向反应混合物中加入钠氢(12毫克，0.5毫摩尔)并继续搅拌0.5小时，然后将碘甲烷(72毫克，0.5毫摩尔)加入到上述反应混合液中，并继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(3aR,7aR)-7a-甲氧基-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体25-1，50毫克，48％收率)。MS:405.6(M+H) +。 (3aR,7aR)-7a-hydroxy-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl The ester (intermediate 24-2, 100 mg, 0.26 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and sodium hydrogen (12 mg, 0.5 mmol) was added to the reaction mixture with stirring at 0°C and stirring was continued After 0.5 h, iodomethane (72 mg, 0.5 mmol) was added to the above reaction mixture and stirring was continued for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (3aR,7aR)-7a-methoxy-2-( 4-(Methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 25-1, 50 mg, 48% yield Rate). MS: 405.6 (M+H) + .
步骤2：中间体25-2的制备Step 2: Preparation of Intermediate 25-2
中间体25-2的合成参考中间体6-3，通过使用(3aR,7aR)-7a-甲氧基-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体25-1)代替2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到中间体25-2。MS:291.2(M+H) +。 Intermediate 25-2 was synthesized with reference to Intermediate 6-3 by using (3aR,7aR)-7a-methoxy-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H -pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 25-1) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1,2,3 , 4,6,7-Hexahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 6-1) was prepared to give Intermediate 25-2. MS: 291.2 (M+H) + .
制备例25中间体26-3a和中间体26-3bPreparation Example 25 Intermediate 26-3a and Intermediate 26-3b
(3aR,7aS)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-3a)(3aR,7aS)-3a-Hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 26-3a)
(3aS,7aR)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-3b)(3aS,7aR)-3a-Hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 26-3b)
Figure PCTCN2021135751-appb-000150
Figure PCTCN2021135751-appb-000150
步骤1：中间体顺式26-1的制备Step 1: Preparation of intermediate cis 26-1
将1-苄基-3-氧哌啶-4-羧酸乙酯(2.0克，7.65毫摩尔)和DBU(233.0毫克，1.53毫摩尔)溶于DMSO(30毫升)中，在20度搅拌条件下向反应混合物中加入硝基甲烷(934.4毫克，15.3毫摩尔)并继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物1-苄基-3-羟基-3-(硝基甲基)哌啶-4-羧酸乙酯(中间体顺式26-1，600.0毫克，22.5％收率)。 1H NMR(400MHz,Chloroform-d)δ7.39-7.25(m,5H),4.98-4.77(m,2H),4.25-4.17(m,2H),3.62-3.52(m,2H),2.99(br d,J＝11.6Hz,1H),2.81-2.65(m,2H),2.36-2.18(m,2H),2.13-1.99(m,1H),1.83-1.73(m,1H),1.66(br s,1H),1.31(t,J＝7.1Hz,3H)。 Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (2.0 g, 7.65 mmol) and DBU (233.0 mg, 1.53 mmol) were dissolved in DMSO (30 mL) and stirred at 20°C Nitromethane (934.4 mg, 15.3 mmol) was added to the reaction mixture and stirring was continued for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-benzyl-3-hydroxy-3-(nitromethyl) as a yellow oil. yl)piperidine-4-carboxylate (Intermediate cis 26-1, 600.0 mg, 22.5% yield). 1 H NMR(400MHz, Chloroform-d)δ7.39-7.25(m,5H),4.98-4.77(m,2H),4.25-4.17(m,2H),3.62-3.52(m,2H),2.99( br d, J＝11.6Hz, 1H), 2.81-2.65(m, 2H), 2.36-2.18(m, 2H), 2.13-1.99(m, 1H), 1.83-1.73(m, 1H), 1.66(br s, 1H), 1.31 (t, J=7.1 Hz, 3H).
步骤2：中间体顺式26-2的制备Step 2: Preparation of intermediate cis 26-2
将1-苄基-3-羟基-3-(硝基甲基)哌啶-4-羧酸乙酯(中间体顺式26-1，500.0毫克，1.55毫摩尔)溶于乙醇(5毫升)中，在搅拌条件下向反应混合物中加入Raney Ni(500毫克)。反应混合物在氢气作用下40度搅拌12小时，然后将混合物溶液过滤。将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体顺式-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式26-2，180毫克)。Ethyl 1-benzyl-3-hydroxy-3-(nitromethyl)piperidine-4-carboxylate (Intermediate cis 26-1, 500.0 mg, 1.55 mmol) was dissolved in ethanol (5 mL) To the reaction mixture was added Raney Ni (500 mg) with stirring. The reaction mixture was stirred at 40°C for 12 hours under the influence of hydrogen, and then the mixture solution was filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain cis-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate) as a white solid. cis 26-2, 180 mg).
步骤3：中间体26-2a和中间体26-2bStep 3: Intermediate 26-2a and Intermediate 26-2b
将顺式-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-2，180毫克)经SFC手性拆分(柱型号：DAICEL CHIRALPAK AD，25cm x 30cm，10μm色谱柱，流动相：30％0.1％NH 3H 2O-ETOH)得到均为白色固体的中间体26-2a(保留时间为0.801分钟)和第二个组分峰中间体26-2b(保留时间为0.814分钟)。 cis-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 26-2, 180 mg) was chiral resolved by SFC (column model: DAICEL CHIRALPAK AD, 25cm x 30cm, 10μm column, mobile phase: 30% 0.1% NH3H2O - ETOH) gave intermediates 26-2a (retention time 0.801 min) and the second group both as white solids Fractionated intermediate 26-2b (retention time 0.814 min).
中间体26-2a(保留时间为0.801分钟，71.6毫克)。1H NMR(400MHz,Chloroform-d)δ7.50(s,1H),7.35-7.28(m,4H),7.28-7.21(m,1H),5.06(s,1H),3.53-3.42(m,2H),3.21(d,J＝9.7Hz,1H),2.93(d,J＝9.7Hz,1H),2.39-2.32(m,1H),2.29-2.22(m,2H),2.20-2.12(m,1H),2.03-1.96(m,1H),1.87(dtd,J＝3.4,6.8,13.5Hz,1H),1.55-1.43(m,1H)。Intermediate 26-2a (RT 0.801 min, 71.6 mg). 1H NMR(400MHz, Chloroform-d)δ7.50(s,1H),7.35-7.28(m,4H),7.28-7.21(m,1H),5.06(s,1H),3.53-3.42(m,2H) ), 3.21(d, J=9.7Hz, 1H), 2.93(d, J=9.7Hz, 1H), 2.39-2.32(m, 1H), 2.29-2.22(m, 2H), 2.20-2.12(m, 1H), 2.03-1.96 (m, 1H), 1.87 (dtd, J=3.4, 6.8, 13.5Hz, 1H), 1.55-1.43 (m, 1H).
中间体26-2b(保留时间为0.814分钟，65.6毫克)。1H NMR(400MHz,Chloroform-d)δ7.50(s, 1H),7.35-7.28(m,4H),7.28-7.21(m,1H),5.06(s,1H),3.53-3.41(m,2H),3.21(d,J＝9.7Hz,1H),2.93(d,J＝9.7Hz,1H),2.39-2.33(m,1H),2.30-2.22(m,2H),2.20-2.10(m,1H),2.03-1.95(m,1H),1.87(dtd,J＝3.5,6.8,13.4Hz,1H),1.57-1.42(m,1H)。Intermediate 26-2b (RT 0.814 min, 65.6 mg). 1H NMR(400MHz, Chloroform-d) δ7.50(s, 1H), 7.35-7.28(m, 4H), 7.28-7.21(m, 1H), 5.06(s, 1H), 3.53-3.41(m, 2H) ),3.21(d,J=9.7Hz,1H),2.93(d,J=9.7Hz,1H),2.39-2.33(m,1H),2.30-2.22(m,2H),2.20-2.10(m, 1H), 2.03-1.95 (m, 1H), 1.87 (dtd, J=3.5, 6.8, 13.4Hz, 1H), 1.57-1.42 (m, 1H).
步骤4：中间体26-3a和中间体26-3b的制备Step 4: Preparation of Intermediate 26-3a and Intermediate 26-3b
中间体26-3a的合成参考中间体22-7，通过使用(3aS,7aS)-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-2a)代替(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7)制备得到(3aR,7aS)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-3a)。Intermediate 26-3a was synthesized with reference to intermediate 22-7 by using (3aS,7aS)-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 26-2a) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aR,7aS)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 26-3a) .
中间体26-3b的合成参考中间体22-7，通过使用(3aR，7aR)-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-2b)代替(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7)制备得到(3aS,7aR)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-3b)。Intermediate 26-3b was synthesized with reference to intermediate 22-7 by using (3aR,7aR)-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 26-2b) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aS,7aR)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 26-3b) .
制备例26中间体反式27-4Preparation Example 26 Intermediate Trans 27-4
反式-(3aS,7aS)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮trans-(3aS,7aS)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one
Figure PCTCN2021135751-appb-000151
Figure PCTCN2021135751-appb-000151
步骤1：中间体反式27-1的制备Step 1: Preparation of the intermediate trans 27-1
将1-苄基-3-氧哌啶-4-羧酸乙酯(18.0克，68.9毫摩尔)和DBU(2.10克，13.8毫摩尔)溶于DMSO(250毫升)中，在20度搅拌条件下向反应混合物中加入硝基甲烷(8.41克，137.8毫摩尔)并继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物反式-1-苄基-3-羟基-3-(硝基甲基)哌啶-4-羧酸乙酯(中间体反式27-1，3.1克，13.1％收率)。 1H NMR(400MHz,Chloroform-d)δ7.41-7.26(m,5H),4.81-4.62(m,2H),4.31-4.15(m,3H),3.67-3.53(m,2H),2.87(d,J＝11.5Hz,1H),2.80(br d,J＝7.0Hz,1H),2.68-2.59(m,1H),2.41(d,J＝11.8Hz,1H),2.24-2.12(m,2H),1.97-1.88(m,1H),1.75(br s,1H),1.31(t,J＝7.0Hz,3H)。 Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (18.0 g, 68.9 mmol) and DBU (2.10 g, 13.8 mmol) were dissolved in DMSO (250 mL) and stirred at 20°C Nitromethane (8.41 g, 137.8 mmol) was added to the reaction mixture and stirring was continued for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain trans-1-benzyl-3-hydroxy-3-( Ethyl nitromethyl)piperidine-4-carboxylate (Intermediate trans 27-1, 3.1 g, 13.1% yield). 1 H NMR (400MHz, Chloroform-d) δ7.41-7.26(m, 5H), 4.81-4.62(m, 2H), 4.31-4.15(m, 3H), 3.67-3.53(m, 2H), 2.87( d, J=11.5Hz, 1H), 2.80 (br d, J=7.0Hz, 1H), 2.68-2.59 (m, 1H), 2.41 (d, J=11.8Hz, 1H), 2.24-2.12 (m, 2H), 1.97-1.88 (m, 1H), 1.75 (br s, 1H), 1.31 (t, J=7.0Hz, 3H).
步骤2：中间体反式27-2的制备Step 2: Preparation of the intermediate trans 27-2
将反式-1-苄基-3-羟基-3-(硝基甲基)哌啶-4-羧酸乙酯(中间体反式27-1，2.50克，7.76毫摩尔)溶于乙醇(50毫升)中，在搅拌条件下向反应混合物中加入Raney Ni(2.5克)。反应混合物在氢气作用下40度搅拌12小时，然后将混合物溶液过滤。将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体反式-3-(氨基甲基)-1-苄基-3-羟基哌啶-4-羧酸乙酯(中间体反式27-2，2.0克)。Ethyl trans-1-benzyl-3-hydroxy-3-(nitromethyl)piperidine-4-carboxylate (intermediate trans 27-1, 2.50 g, 7.76 mmol) was dissolved in ethanol ( 50 mL), Raney Ni (2.5 g) was added to the reaction mixture with stirring. The reaction mixture was stirred at 40°C for 12 hours under the influence of hydrogen, and then the mixture solution was filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain ethyl trans-3-(aminomethyl)-1-benzyl-3-hydroxypiperidine-4-carboxylate as a white solid (intermediate trans-3-(aminomethyl)-1-benzyl-3-hydroxypiperidine-4-carboxylate). Formula 27-2, 2.0 g).
步骤3：中间体反式27-3的制备Step 3: Preparation of Intermediate Trans 27-3
将反式-3-(氨基甲基)-1-苄基-3-羟基哌啶-4-羧酸乙酯(中间体反式27-2，2.0克，6.84毫摩尔)溶于甲苯(40毫升)中，反应混合物在130度搅拌16小时，反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体反式5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮混合物(中间体反式27-3，250毫克)。 1H NMR(400MHz,DMSO-d 6)δ7.42-7.29(m,5H),7.28-7.21(m,1H),4.17(d,J＝1.3Hz,1H),3.67-3.59(m,1H),3.58-3.50(m,1H),3.15(dd,J＝1.3,9.9Hz,1H),3.03(dd,J＝2.1,9.9Hz,1H),2.88(br d,J＝11.1Hz,1H),2.77(d,J＝10.4Hz,1H),2.14(d,J＝10.3Hz,1H),2.06-1.94(m,2H),1.75-1.53(m,2H)。 Ethyl trans-3-(aminomethyl)-1-benzyl-3-hydroxypiperidine-4-carboxylate (intermediate trans 27-2, 2.0 g, 6.84 mmol) was dissolved in toluene (40 mL), the reaction mixture was stirred at 130 °C for 16 hours, the reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain trans-5-benzyl-3a-hydroxyoctahydro-1H-pyrrole as a white solid [3,4-c]pyridin-1-one mixture (Intermediate trans 27-3, 250 mg). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.42-7.29 (m, 5H), 7.28-7.21 (m, 1H), 4.17 (d, J=1.3Hz, 1H), 3.67-3.59 (m, 1H) ),3.58-3.50(m,1H),3.15(dd,J＝1.3,9.9Hz,1H),3.03(dd,J＝2.1,9.9Hz,1H),2.88(br d,J＝11.1Hz,1H ), 2.77 (d, J=10.4Hz, 1H), 2.14 (d, J=10.3Hz, 1H), 2.06-1.94 (m, 2H), 1.75-1.53 (m, 2H).
步骤4：中间体反式27-4的制备Step 4: Preparation of intermediate trans 27-4
中间体反式27-4的合成参考中间体22-7，通过使用反式-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体反式27-3)代替(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7)制备得到反式-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体反式27-4)。Intermediate trans 27-4 was synthesized with reference to intermediate 22-7 by using trans-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate trans 27-3) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl) Ethyl) tert-butyl carbamate (intermediate 22-7) was prepared to give trans-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate trans 27-4) .
制备例27中间体顺式28-3Preparation Example 27 Intermediate cis 28-3
顺式-(3aR,7aS)-3a-羟基-2-异丙基八氢-1H-吡咯[3,4-c]吡啶-1-酮cis-(3aR,7aS)-3a-hydroxy-2-isopropyloctahydro-1H-pyrro[3,4-c]pyridin-1-one
Figure PCTCN2021135751-appb-000152
Figure PCTCN2021135751-appb-000152
步骤1：中间体顺式28-1的制备Step 1: Preparation of intermediate cis 28-1
中间体顺式28-1的合成参考中间体7-1，通过使用顺式-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式26-2)代替5-苄基-2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮制备得到顺式-(3aS,7aS)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式28-1)。Intermediate cis 28-1 was synthesized with reference to intermediate 7-1 by using cis-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate cis-26-2) instead of 5-benzyl-2,3,4,5,6,7-hexahydro-1H-pyrro[3,4-c]pyridin-1-one was prepared to give cis-(3aS, 7aS)-3a-Hydroxy-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate cis 28-1).
步骤2：中间体顺式28-2的制备Step 2: Preparation of intermediate cis 28-2
将顺式-(3aS,7aS)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式28-1，120毫克，0.47毫摩尔)，叔丁醇钾(158毫克，1.41毫摩尔)和2-溴丙烷(288毫克，2.34毫摩尔)的DMF(4毫升)混合物在室温搅拌2小时，反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到淡黄 色油状物顺式-(7aS)-3a-羟基-2-异丙基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式28-2，30毫克，21.4％收率)。MS:299.2(M+H) +。 cis-(3aS,7aS)-3a-hydroxy-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis 28-1,120 mg, 0.47 mmol), potassium tert-butoxide (158 mg, 1.41 mmol) and 2-bromopropane (288 mg, 2.34 mmol) in DMF (4 mL) was stirred at room temperature for 2 h, the reaction mixture was washed with ice water Quenched and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain cis-(7aS)-3a-hydroxy-2-iso as a pale yellow oil. Propyl-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate cis 28-2, 30 mg, 21.4% yield). MS: 299.2 (M+H) + .
步骤3：中间体顺式28-3的制备Step 3: Preparation of intermediate cis 28-3
中间体顺式28-3的合成参考中间体1-4/步骤2，通过使用顺式-(7aS)-3a-羟基-2-异丙基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式28-2)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到顺式-(3aR,7aS)-3a-羟基-2-异丙基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式28-3)。MS:199.1(M+H) +。 Synthesis of intermediate cis 28-3 with reference to intermediate 1-4/step 2 by using cis-(7aS)-3a-hydroxy-2-isopropyl-1-oxooctahydro-5H-pyrrole[3 ,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis 28-2) instead of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c ] Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give cis-(3aR,7aS)-3a-hydroxy-2-isopropyloctahydro-1H-pyrrole[3,4- c] Pyridin-1-one (Intermediate cis 28-3). MS: 199.1 (M+H) + .
制备例28中间体顺式29-2Preparation Example 28 Intermediate cis 29-2
顺式3-((3aR,7aS)-3a-羟基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸乙酯cis-3-((3aR,7aS)-3a-hydroxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2-dimethylpropionic acid ethyl ester
Figure PCTCN2021135751-appb-000153
Figure PCTCN2021135751-appb-000153
中间体顺式29-2的合成参考中间体顺式28-3，通过使用3-溴-2,2-二甲基丙酸乙酯代替2-溴丙烷制备得到顺式3-((3aR,7aS)-3a-羟基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸乙酯(中间体顺式29-2)。MS:285.2(M+H) +。 Synthesis of intermediate cis 29-2 Referring to intermediate cis 28-3, cis 3-((3aR, cis 3-((3aR, 7aS)-3a-Hydroxy-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,2-dimethylpropionic acid ethyl ester (Intermediate cis 29-2 ). MS: 285.2 (M+H) + .
制备例29中间体顺式30-3a和中间体顺式30-3bPreparation Example 29 Intermediate cis 30-3a and intermediate cis 30-3b
顺式-7a-氟-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式30-3a)cis-7a-Fluoro-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate cis 30-3a)
顺式-六氢-1H-3a,7a环氧吡咯[3,4-c]吡啶-1-酮(中间体顺式30-3b)cis-hexahydro-1H-3a,7a epoxypyrro[3,4-c]pyridin-1-one (Intermediate cis 30-3b)
Figure PCTCN2021135751-appb-000154
Figure PCTCN2021135751-appb-000154
步骤1：中间体30-1的制备Step 1: Preparation of Intermediate 30-1
将1-(叔丁基)4-乙基4-氟-3-氧哌啶-1,4-二羧酸酯(1.0克，3.5毫摩尔)和DBU(790毫克，5.2毫 摩尔)溶于DMSO(10毫升)中，在20度搅拌条件下向反应混合物中加入硝基甲烷(250毫克，4.2毫摩尔)并继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到1-(叔丁基)4-乙基4-氟-3-羟基-3-(硝基甲基)哌啶-1,4-二羧酸酯(中间体30-1，980毫克，81％收率)。MS:351.3(M+H) +。 1-(tert-Butyl)4-ethyl 4-fluoro-3-oxopiperidine-1,4-dicarboxylate (1.0 g, 3.5 mmol) and DBU (790 mg, 5.2 mmol) were dissolved in Nitromethane (250 mg, 4.2 mmol) was added to the reaction mixture in DMSO (10 mL) with stirring at 20°C and stirring was continued for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-(tert-butyl)4-ethyl 4-fluoro-3-hydroxyl -3-(Nitromethyl)piperidine-1,4-dicarboxylate (Intermediate 30-1, 980 mg, 81% yield). MS: 351.3 (M+H) + .
步骤2：中间体30-2的制备Step 2: Preparation of Intermediate 30-2
将1-(叔丁基)4-乙基4-氟-3-羟基-3-(硝基甲基)哌啶-1,4-二羧酸酯(中间体30-1，200毫克，0.57毫摩尔)溶于甲醇(5毫升)中，在搅拌条件下向反应混合物中加入Raney Ni(100毫克)。反应混合物在氢气作用下室温搅拌12小时，然后将混合物溶液过滤。将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到1-(叔丁基)4-乙基3-(氨甲基)-4-氟-3-羟基哌啶-1,4-二羧酸酯(中间体30-2，170毫克，92％收率)。MS:321.1(M+H) +。 1-(tert-Butyl)4-ethyl 4-fluoro-3-hydroxy-3-(nitromethyl)piperidine-1,4-dicarboxylate (Intermediate 30-1, 200 mg, 0.57 mmol) was dissolved in methanol (5 mL) and Raney Ni (100 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 12 hours, and then the mixture solution was filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-(tert-butyl)4-ethyl3-(aminomethyl)-4-fluoro-3-hydroxypiperidine-1,4-di Carboxylic acid ester (Intermediate 30-2, 170 mg, 92% yield). MS: 321.1 (M+H) + .
步骤3：中间体顺式30-2a和中间体顺式30-2bStep 3: Intermediate cis 30-2a and Intermediate cis 30-2b
将1-(叔丁基)4-乙基3-(氨甲基)-4-氟-3-羟基哌啶-1,4-二羧酸酯(中间体30-2，170毫克，0.53毫摩尔)和DBU(16毫克，0.11毫摩尔)溶于甲醇(5毫升)中，反应混合物在50度续搅拌0.5小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用1N的盐酸和饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到顺式-7a-氟-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式30-2a，100毫克)。MS:275.1(M+H) +。顺式-1-氧代四氢-1H-3a，7a环氧吡咯[3,4-c]吡啶-5(4H)-羧酸叔丁酯(中间体顺式30-2b，70毫克)。MS:255.1(M+H) +。 1-(tert-Butyl)4-ethyl 3-(aminomethyl)-4-fluoro-3-hydroxypiperidine-1,4-dicarboxylate (Intermediate 30-2, 170 mg, 0.53 mM mol) and DBU (16 mg, 0.11 mmol) were dissolved in methanol (5 mL) and the reaction mixture was stirred at 50°C for 0.5 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain cis-7a-fluoro-3a-hydroxy-1-oxo Substituted octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate cis 30-2a, 100 mg). MS: 275.1 (M+H) + . cis-1-oxotetrahydro-1H-3a,7a epoxypyrrole[3,4-c]pyridine-5(4H)-carboxylate tert-butyl ester (intermediate cis 30-2b, 70 mg). MS: 255.1 (M+H) + .
步骤4：中间体顺式30-3a和中间体顺式30-3b的制备Step 4: Preparation of intermediate cis 30-3a and intermediate cis 30-3b
中间体顺式30-3a的合成参考中间体1-4/步骤2，通过使用顺式-7a-氟-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式30-2a)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到顺式-7a-氟-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式30-3a)。MS:175.1(M+H) +。 Synthesis of intermediate cis 30-3a with reference to intermediate 1-4/step 2 by using cis-7a-fluoro-3a-hydroxy-1-oxooctahydro-5H-pyrro[3,4-c]pyridine - tert-butyl 5-carboxylate (intermediate cis 30-2a) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate tert-butyl acid (Intermediate 1-4-1) was prepared to give cis-7a-fluoro-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate cis 30- 3a). MS: 175.1 (M+H) + .
中间体顺式30-3b的合成参考中间体1-4/步骤2，通过使用顺式-1-氧代四氢-1H-3a，7a环氧吡咯[3,4-c]吡啶-5(4H)-羧酸叔丁酯(中间体顺式30-2b)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到顺式-六氢-1H-3a,7a环氧吡咯[3,4-c]吡啶-1-酮(中间体顺式30-3b)。MS:155.1(M+H) +。 Synthesis of intermediate cis 30-3b with reference to intermediate 1-4/step 2 by using cis-1-oxotetrahydro-1H-3a,7a epoxypyrro[3,4-c]pyridine-5( 4H)-carboxylate tert-butyl ester (intermediate cis 30-2b) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine-6-carboxylate tert-Butyl acid (Intermediate 1-4-1) was prepared to give cis-hexahydro-1H-3a,7a epoxypyrrole[3,4-c]pyridin-1-one (Intermediate cis 30-3b) . MS: 155.1 (M+H) + .
制备例30中间体31-2a和中间体31-2bPreparation Example 30 Intermediate 31-2a and Intermediate 31-2b
(3aR,7aR)-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-2a)(3aR,7aR)-3a-Fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 31-2a)
(3aS,7aS)-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-2b)(3aS,7aS)-3a-Fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 31-2b)
Figure PCTCN2021135751-appb-000155
Figure PCTCN2021135751-appb-000155
步骤1：中间体31-1a和中间体31-1b的制备Step 1: Preparation of Intermediate 31-1a and Intermediate 31-1b
将顺式-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式26-2，500.0毫克，2.03毫摩尔)和DAST(490.8毫克，3.05毫摩尔)溶于二氯甲烷(5毫升)中，反应混合物在0度搅拌1小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经SFC手性制备(柱型号：AICEL CHIRALPAK AS250mm*30mm,10um色谱柱，流动相：[0.1％NH 3H 2O ETOH]；B％:35％-35％)得到均为白色固体的中间体31-1a(57毫克，保留时间为3.099分钟)和第二个组分峰中间体31-1b(77毫克，保留时间为3.146分钟)。 cis-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate cis 26-2, 500.0 mg, 2.03 mmol) and DAST (490.8 mg, 3.05 mmol) was dissolved in dichloromethane (5 mL) and the reaction mixture was stirred at 0 degrees for 1 hour. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was prepared by SFC chirality (column type: AICEL CHIRALPAK AS250mm*30mm, 10um chromatographic column, Mobile phase: [0.1% NH 3 H 2 O ETOH]; B%: 35%-35%) to give intermediate 31-1a (57 mg, retention time 3.099 min) and the second component both as white solids Peak Intermediate 31-1b (77 mg, RT 3.146 min).
中间体31-1a(57毫克，保留时间为3.099分钟)。 1H NMR(400MHz,DMSO-d 6)δ7.83(s,1H),7.38-7.25(m,5H),3.57(s,2H),3.52-3.42(m,1H),2.71-2.62(m,1H),2.43-2.30(m,2H),2.26-2.18(m,1H),1.97(qd,J＝6.6,9.9Hz,1H),1.58-1.42(m,1H)。 Intermediate 31-1a (57 mg, RT 3.099 min). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.83(s, 1H), 7.38-7.25(m, 5H), 3.57(s, 2H), 3.52-3.42(m, 1H), 2.71-2.62(m , 1H), 2.43-2.30 (m, 2H), 2.26-2.18 (m, 1H), 1.97 (qd, J=6.6, 9.9Hz, 1H), 1.58-1.42 (m, 1H).
中间体31-1b(77毫克，保留时间为3.146分钟)。 1H NMR(400MHz,DMSO-d 6)δ7.83(s,1H),7.40-7.24(m,5H),3.59-3.54(m,2H),2.66(t,J＝12.9Hz,1H),2.41-2.30(m,2H),2.21(ddd,J＝3.4,8.8,11.7Hz,1H),2.03-1.92(m,1H),1.56-1.44(m,1H)。 Intermediate 31-1b (77 mg, RT 3.146 min). 1 H NMR (400MHz, DMSO-d 6 )δ7.83(s,1H),7.40-7.24(m,5H),3.59-3.54(m,2H),2.66(t,J=12.9Hz,1H), 2.41-2.30 (m, 2H), 2.21 (ddd, J=3.4, 8.8, 11.7 Hz, 1H), 2.03-1.92 (m, 1H), 1.56-1.44 (m, 1H).
步骤2：中间体31-2a和中间体31-2b的制备Step 2: Preparation of Intermediate 31-2a and Intermediate 31-2b
中间体31-2a的合成参考中间体22-7，通过使用(3aS,7aR)-5-苄基-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-1a)代替(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7)制备得到(3aR,7aR)-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-2a)。Intermediate 31-2a was synthesized with reference to intermediate 22-7 by using (3aS,7aR)-5-benzyl-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 31-1a) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aR,7aR)-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 31-2a) .
中间体31-2b的合成参考中间体22-7，通过使用(3aR,7aS)-5-苄基-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-1b)代替(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7)制备得到(3aS,7aS)-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-2b)。Intermediate 31-2b was synthesized with reference to intermediate 22-7 by using (3aR,7aS)-5-benzyl-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate body 31-1b) instead of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl)pyrrolidin-3-yl)ethyl (3aS,7aS)-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 31-2b) .
制备例31中间体顺式32-4Preparation Example 31 Intermediate cis 32-4
顺式(3aR,7aS)-1-氧代八氢-3aH-吡咯[3,4-c]吡啶-3a-羧酸甲酯cis(3aR,7aS)-1-oxooctahydro-3aH-pyrrole[3,4-c]pyridine-3a-carboxylate methyl ester
Figure PCTCN2021135751-appb-000156
Figure PCTCN2021135751-appb-000156
步骤1：中间体32-1的制备Step 1: Preparation of Intermediate 32-1
将顺式-5-苄基-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式26-2，3.00克，12.2毫摩尔)和Et 3N(14.8克，146.2毫摩尔))溶于二氯乙烷(50毫升)中，在0度搅拌下将MsCl(9.68克，84.5毫摩尔)加入到上述反应混合物中。反应混合物在75度继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用碳酸氢钠溶液和饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到棕色油状物(中间体32-1，3.95克，粗品)未经纯化直接用于下一步反应。 cis-5-benzyl-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate cis 26-2, 3.00 g, 12.2 mmol) and Et3N (14.8 g, 146.2 mmol)) was dissolved in dichloroethane (50 mL) and MsCl (9.68 g, 84.5 mmol) was added to the above reaction mixture with stirring at 0 degrees. The reaction mixture was stirred at 75 degrees for a further 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a brown oil (intermediate 32-1, 3.95 g, crude product) which was used in the next reaction without purification.
步骤2：中间体32-2的制备Step 2: Preparation of Intermediate 32-2
将中间体32-1(3.95克，12.2毫摩尔)和氰化钠(2.32克，47.4毫摩尔)溶于DMF(80毫升)中。反应混合物在55度继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用碳酸氢钠溶液和饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(中间体32-2，182.8毫克，5.8％收率)。 1H NMR:(400MHz,DMSO-d 6)δ7.74(s,1H),7.38-7.20(m,5H),3.85-3.73(m,1H),3.68-3.60(m,1H),3.46(d,J＝10.8Hz,1H),3.14-2.96(m,3H),2.77(dd,J＝2.0,9.7Hz,1H),2.67(dt,J＝3.4,8.4Hz,1H),2.47-2.35(m,1H),2.07-1.93(m,1H),1.89-1.76(m,1H)。 Intermediate 32-1 (3.95 g, 12.2 mmol) and sodium cyanide (2.32 g, 47.4 mmol) were dissolved in DMF (80 mL). The reaction mixture was stirred at 55 degrees for a further 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (Intermediate 32-2, 182.8 mg, 5.8 mg. % yield). 1 H NMR: (400MHz, DMSO-d 6 )δ7.74(s, 1H), 7.38-7.20(m, 5H), 3.85-3.73(m, 1H), 3.68-3.60(m, 1H), 3.46( d, J=10.8Hz, 1H), 3.14-2.96 (m, 3H), 2.77 (dd, J=2.0, 9.7Hz, 1H), 2.67 (dt, J=3.4, 8.4Hz, 1H), 2.47-2.35 (m, 1H), 2.07-1.93 (m, 1H), 1.89-1.76 (m, 1H).
步骤3：中间体32-3的制备Step 3: Preparation of Intermediate 32-3
将中间体32-2(30毫克，0.12毫摩尔)溶于甲醇(3毫升)中，在0度搅拌下将乙酰氯(1毫升)加入到上述反应混合物中。反应混合物在60度继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用碳酸氢钠溶液和饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体顺式-(3aS,7aS)-5-苄基-1-氧代八氢-3aH-吡咯[3,4-c]吡啶-3a-羧酸(中间体32-3，40毫克)。MS:289.1(M+H) +。 Intermediate 32-2 (30 mg, 0.12 mmol) was dissolved in methanol (3 mL) and acetyl chloride (1 mL) was added to the above reaction mixture with stirring at 0 degrees. The reaction mixture was stirred at 60 degrees for a further 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow solid cis-(3aS,7aS)-5-benzyl-1-oxooctahydro-3aH- Pyrro[3,4-c]pyridine-3a-carboxylic acid (Intermediate 32-3, 40 mg). MS: 289.1 (M+H) + .
步骤4:中间体顺式32-4的制备Step 4: Preparation of intermediate cis 32-4
中间体顺式32-4的合成参考中间体22-7，通过使用(顺式-(3aS,7aS)-5-苄基-1-氧代八氢-3aH-吡咯[3,4-c]吡啶-3a-羧酸(中间体32-3)代替(2-((3R，4R)-4-(羟甲基)-2-氧代-1-((R)-1-苯乙基)吡咯烷-3-基)乙基)氨基甲酸叔丁酯(中间体22-7)制备得到顺式(3aR,7aS)-1-氧代八氢-3aH-吡咯 [3,4-c]吡啶-3a-羧酸甲酯(中间体顺式32-4)。MS:199.1(M+H) +。 Intermediate cis 32-4 was synthesized with reference to intermediate 22-7 by using (cis-(3aS,7aS)-5-benzyl-1-oxooctahydro-3aH-pyrrole[3,4-c] Pyridine-3a-carboxylic acid (Intermediate 32-3) in place of (2-((3R,4R)-4-(hydroxymethyl)-2-oxo-1-((R)-1-phenethyl) tert-Butyl pyrrolidin-3-yl)ethyl)carbamate (Intermediate 22-7) was prepared to give cis(3aR,7aS)-1-oxooctahydro-3aH-pyrro[3,4-c]pyridine Methyl 3a-carboxylate (Intermediate cis 32-4). MS: 199.1 (M+H) + .
制备例32中间体顺式33-2Preparation Example 32 Intermediate cis 33-2
顺式(3aR,7aS)-3a-甲氧基-2-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮cis(3aR,7aS)-3a-methoxy-2-methyloctahydro-1H-pyrro[3,4-c]pyridin-1-one
Figure PCTCN2021135751-appb-000157
Figure PCTCN2021135751-appb-000157
步骤1：中间体顺式33-1的制备Step 1: Preparation of intermediate cis 33-1
将顺式-(3aS,7aS)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式28-1，150.0毫克，585.3微摩尔)和CH 3I(249.2毫克，1.76毫摩尔)，Ag 2O(678.1毫克,2.93毫摩尔))溶于乙腈(3毫升)中，反应混合物在80度继续搅拌16小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用碳酸氢钠溶液和饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(中间体顺式33-1，31.5毫克，18.9％收率)。MS:285.1(M+H) +。 1H NMR(400MHz,DMSO-d6)δ3.89-4.10(m,1H),3.41-3.62(m,1H),3.36-3.40(m,1H),3.31(s,1H),3.20(br s,3H),3.10(br d,J＝9.79Hz,1H),2.89(br d,J＝10.79Hz,1H),2.74(s,3H),1.69(br d,J＝5.27Hz,2H),1.40(s,9H)。 cis-(3aS,7aS)-3a-hydroxy-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis 28-1, 150.0 mg, 585.3 μmol) and CH3I (249.2 mg, 1.76 mmol), Ag2O (678.1 mg, 2.93 mmol)) were dissolved in acetonitrile (3 mL) and the reaction mixture was stirred at 80° for a further 16 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless oil (intermediate cis 33-1, 31.5 mg, 18.9% yield). MS: 285.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ3.89-4.10(m,1H),3.41-3.62(m,1H),3.36-3.40(m,1H),3.31(s,1H),3.20(br s ,3H),3.10(br d,J＝9.79Hz,1H),2.89(br d,J＝10.79Hz,1H),2.74(s,3H),1.69(br d,J＝5.27Hz,2H), 1.40(s, 9H).
步骤2：中间体顺式33-2的制备Step 2: Preparation of intermediate cis 33-2
中间体顺式33-2的合成参考中间体1-4/步骤2，通过使用中间体顺式33-1代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到顺式(3aR,7aS)-3a-甲氧基-2-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式33-2)。MS:185.1(M+H) +。 Synthesis of intermediate cis 33-2 refer to intermediate 1-4/step 2 by using intermediate cis 33-1 in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[ 3,4-c]Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give cis (3aR,7aS)-3a-methoxy-2-methyloctahydro-1H-pyrrole [3,4-c]pyridin-1-one (Intermediate cis 33-2). MS: 185.1 (M+H) + .
制备例33中间体34-3a和中间体34-3bPreparation Example 33 Intermediate 34-3a and Intermediate 34-3b
(3aR,7aS)-3a-羟基-7a-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体34-3a)(3aR,7aS)-3a-Hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 34-3a)
(3aS,7aR)-3a-羟基-7a-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体34-3b)(3aS,7aR)-3a-Hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 34-3b)
Figure PCTCN2021135751-appb-000158
Figure PCTCN2021135751-appb-000158
步骤1：中间体34-1的制备Step 1: Preparation of Intermediate 34-1
将1-(叔丁基)4-乙基3-恶哌啶-1,4-二羧酸酯(50.0克，184.3毫摩尔)和碳酸钾(68.8克，497.6毫摩尔)溶于乙腈(400毫升)中，在室温搅拌下将碘甲烷(31.4克，221.2毫摩尔)滴加到上述反应液中。将反应混合物在30度继续搅拌16小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用碳酸氢钠溶液和饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(中间体34-1，40.0克，72.3％收率)。MS:285.1(M+H) +。 1H NMR(400MHz,Chloroform-d)δ4.54-3.36(m,6H),2.58(td,J＝5.0,14.1Hz,1H),1.77-1.64(m,1H),1.51-1.40(m,9H),1.35(s,3H),1.26(t,J＝7.2Hz,3H)。 1-(tert-Butyl)4-ethyl 3-oxapiperidine-1,4-dicarboxylate (50.0 g, 184.3 mmol) and potassium carbonate (68.8 g, 497.6 mmol) were dissolved in acetonitrile (400 g mL), iodomethane (31.4 g, 221.2 mmol) was added dropwise to the above reaction solution with stirring at room temperature. The reaction mixture was stirred at 30 degrees for a further 16 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oil (Intermediate 34-1, 40.0 g, 72.3% yield). MS: 285.1 (M+H) + . 1 H NMR (400MHz, Chloroform-d) δ4.54-3.36(m, 6H), 2.58(td, J=5.0, 14.1Hz, 1H), 1.77-1.64(m, 1H), 1.51-1.40(m, 9H), 1.35(s, 3H), 1.26(t, J=7.2Hz, 3H).
步骤2：中间体34-2a和中间体34-2b的制备Step 2: Preparation of Intermediate 34-2a and Intermediate 34-2b
中间体34-2的合成参考中间体28-1，通过使用中间体34-1代替1-(叔丁基)4-乙基3-恶哌啶-1,4-二羧酸酯制备得到中间体34-2。Synthesis of Intermediate 34-2 Referring to Intermediate 28-1, intermediate was prepared by using Intermediate 34-1 in place of 1-(tert-butyl)4-ethyl 3-oxapiperidine-1,4-dicarboxylate Body 34-2.
中间体34-2经SFC手性拆分(柱型号：DAICEL CHIRALPAK AD 250mm*50mm,10um色谱柱，流动相：35％0.1％NH 3H 2O-ETOH)得到均为白色固体的中间体34-2a(357毫克，保留时间为3.039分钟)和第二个组分峰中间体34-2b(365毫克，保留时间为3.718分钟)。 Intermediate 34-2 was chiral resolved by SFC (column model: DAICEL CHIRALPAK AD 250mm*50mm, 10um chromatographic column, mobile phase: 35% 0.1% NH 3 H 2 O-ETOH) to obtain intermediate 34 as white solids -2a (357 mg, RT 3.039 min) and the second component peak Intermediate 34-2b (365 mg, RT 3.718 min).
中间体34-2a(357毫克，保留时间为3.039分钟)。 1H NMR(400MHz,DMSO-d 6)δ7.54(s,1H),5.17(s,1H),3.47(br d,J＝13.4Hz,1H),3.34-3.26(m,1H),3.15-3.01(m,4H),1.44(t,J＝5.7Hz,2H),1.39(s,9H),0.96(s,3H)。 Intermediate 34-2a (357 mg, rt 3.039 min). 1 H NMR (400MHz, DMSO-d 6 )δ7.54(s,1H),5.17(s,1H),3.47(br d,J=13.4Hz,1H),3.34-3.26(m,1H),3.15 -3.01(m, 4H), 1.44(t, J=5.7Hz, 2H), 1.39(s, 9H), 0.96(s, 3H).
中间体34-2b(365毫克，保留时间为3.718分钟)。 1H NMR(400MHz,DMSO-d 6)δ7.54(s,1H),5.18(br s,1H),3.47(br d,J＝13.2Hz,1H),3.33-3.27(m,1H),3.19-2.96(m,4H),1.44(br t,J＝5.7Hz,2H),1.40(s,9H),0.96(s,3H)。 Intermediate 34-2b (365 mg, retention time 3.718 min). 1 H NMR (400MHz, DMSO-d 6 )δ7.54(s,1H),5.18(br s,1H),3.47(br d,J＝13.2Hz,1H),3.33-3.27(m,1H), 3.19-2.96(m, 4H), 1.44(br t, J=5.7Hz, 2H), 1.40(s, 9H), 0.96(s, 3H).
步骤3：中间体34-3a和中间体34-3b的制备Step 3: Preparation of Intermediate 34-3a and Intermediate 34-3b
中间体34-3a的合成参考中间体1-4/步骤2，通过使用中间体34-2a代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到(3aR,7aS)-3a-羟基-7a-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体34-3a)。MS:171.1(M+H) +。 The synthesis of intermediate 34-3a was referred to intermediate 1-4/step 2 by using intermediate 34-2a in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4- c] tert-butyl pyridine-6-carboxylate (Intermediate 1-4-1) was prepared to give (3aR,7aS)-3a-hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridine -1-one (Intermediate 34-3a). MS: 171.1 (M+H) + .
中间体34-3b的合成参考中间体1-4/步骤2，通过使用中间体34-2b代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到(3aS,7aR)-3a-羟基-7a-甲基八氢-1H-吡咯 [3,4-c]吡啶-1-酮(中间体34-3b)。MS:171.1(M+H) +。 The synthesis of intermediate 34-3b was referred to intermediate 1-4/step 2 by using intermediate 34-2b in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4- c] tert-butyl pyridine-6-carboxylate (Intermediate 1-4-1) was prepared to give (3aS,7aR)-3a-hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridine -1-one (Intermediate 34-3b). MS: 171.1 (M+H) + .
制备例34中间体35-1Preparation Example 34 Intermediate 35-1
4-((3aR,7aS)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aR,7aS)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000159
Figure PCTCN2021135751-appb-000159
中间体35-1的合成参考中间体6-3，通过使用中间体34-2a代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)制备得到4-((3aR,7aS)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体35-1)。Intermediate 35-1 was synthesized with reference to Intermediate 6-3 by using Intermediate 34-2a in place of 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4 -c] Pyridine-5-carboxylate tert-butyl ester (Intermediate 5-1) was prepared to give 4-((3aR,7aS)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrrole[ 3,4-c]pyridin-2-yl)benzoic acid (Intermediate 35-1).
制备例35中间体36-1Preparation Example 35 Intermediate 36-1
4-((3aS,7aR)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000160
Figure PCTCN2021135751-appb-000160
中间体36-1的合成参考中间体6-3，通过使用中间体34-2b代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)制备得到4-((3aS,7aR)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体36-1)。Intermediate 36-1 was synthesized with reference to Intermediate 6-3 by using Intermediate 34-2b in place of 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4 -c] Pyridine-5-carboxylate tert-butyl ester (Intermediate 5-1) was prepared to give 4-((3aS,7aR)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrrole[ 3,4-c]pyridin-2-yl)benzoic acid (Intermediate 36-1).
制备例36中间体顺式37-3Preparation Example 36 Intermediate cis 37-3
顺式-2-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸cis-2-Chloro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000161
Figure PCTCN2021135751-appb-000161
步骤1:中间体顺式37-1的制备Step 1: Preparation of intermediate cis 37-1
中间体顺式37-1的合成参考中间体6-1，通过使用顺式-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧 酸叔丁酯(中间体7-1)代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)和2-氯-4-碘苯甲酸甲酯代替-碘苯甲酸甲酯制备得到(3aR,7aS)-2-(3-氯-4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式37-1)。Synthesis of intermediate cis 37-1 with reference to intermediate 6-1 by using cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate body 7-1) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5 (3aR,7aS)-2-(3-chloro-4-(methoxycarbonyl)phenyl)-1- Oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate cis 37-1).
步骤2:中间体顺式37-2的制备Step 2: Preparation of intermediate cis 37-2
将(3aR,7aS)-2-(3-氯-4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式37-1,260毫克,0.64毫摩尔)溶于无水四氢呋喃(5毫升)中，在-78度搅拌条件下向反应混合物中加入LiHMDS(0.83毫摩尔)并继续搅拌0.5小时，然后将NFSI(261毫克,0.83毫摩尔)加入到上述反应混合液中，并继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体(3aR，7aR)-2-(3-氯-4-(甲氧羰基)苯基)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式37-2,150毫克,52％收率)。MS:427.8(M+H) +。 (3aR,7aS)-2-(3-Chloro-4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl The ester (intermediate cis 37-1, 260 mg, 0.64 mmol) was dissolved in dry tetrahydrofuran (5 mL), LiHMDS (0.83 mmol) was added to the reaction mixture with stirring at -78°C and stirring was continued for 0.5 h, NFSI (261 mg, 0.83 mmol) was then added to the above reaction mixture and stirring was continued for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid (3aR, 7aR)-2-(3-chloro-4-( Methoxycarbonyl)phenyl)-7a-fluoro-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate cis 37-2, 150 mg, 52% yield). MS: 427.8 (M+H) + .
步骤3:中间体顺式37-3的制备Step 3: Preparation of intermediate cis 37-3
中间体顺式37-3的合成参考中间体6-3，通过使用(3aR，7aR)-2-(3-氯-4-(甲氧羰基)苯基)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式37-2)代替2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到顺式-2-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体顺式37-3)。MS:313.2(M+H) +。 Synthesis of intermediate cis 37-3 with reference to intermediate 6-3 by using (3aR,7aR)-2-(3-chloro-4-(methoxycarbonyl)phenyl)-7a-fluoro-1-oxo Octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis 37-2) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo -1,2,3,4,6,7-Hexahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 6-1) prepared to give cis-2-chloro -4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid (intermediate cis 37-3). MS: 313.2 (M+H) + .
制备例37中间体顺式38-1Preparation Example 37 Intermediate cis 38-1
顺式-2-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸甲酯Methyl cis-2-chloro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoate
Figure PCTCN2021135751-appb-000162
Figure PCTCN2021135751-appb-000162
中间体顺式38-1的合成参考中间体1-4/步骤2，通过使用(3aR，7aR)-2-(3-氯-4-(甲氧羰基)苯基)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体顺式37-2)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到顺式-2-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸甲酯(中间体顺式38-1)。MS:327.8(M+H) +。 Synthesis of intermediate cis 38-1 was referenced to intermediate 1-4/step 2 by using (3aR,7aR)-2-(3-chloro-4-(methoxycarbonyl)phenyl)-7a-fluoro-1 -Oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate cis 37-2) in place of 3-hydroxy-2,4,5,7-tetrahydro- 6H-Pyrazoline[3,4-c]pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give cis-2-chloro-4-((3aS,7aR)-7a- Methyl fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoate (Intermediate cis 38-1). MS: 327.8 (M+H) + .
制备例38中间体39-3Preparation Example 38 Intermediate 39-3
(3aS,7aR)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(3aS,7aR)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one
Figure PCTCN2021135751-appb-000163
Figure PCTCN2021135751-appb-000163
步骤1:中间体39-1的制备Step 1: Preparation of Intermediate 39-1
将(3aR,7aS)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1a,4.8克,20毫摩尔)溶于二氯甲烷(100毫升)中，在室温搅拌条件下向反应混合物中加入DMAP(2.44克,20毫摩尔)和Boc 2O(6.54克,30毫摩尔)并在室温继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体二叔丁基(3aS,7aS)-1-氧代六氢-2H-吡咯[3,4-c]吡啶-2,5(3H)-二羧酸酯(中间体39-1,6.3克,92％收率)。MS:341.2(M+H) +。 (3aR,7aS)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 7-1a, 4.8 g, 20 mmol) was dissolved in bismuth In methyl chloride (100 mL), DMAP (2.44 g, 20 mmol) and Boc2O (6.54 g , 30 mmol) were added to the reaction mixture with stirring at room temperature and stirring was continued at room temperature for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid di-tert-butyl(3aS,7aS)-1-oxohexahydro -2H-pyrrole[3,4-c]pyridine-2,5(3H)-dicarboxylate (Intermediate 39-1, 6.3 g, 92% yield). MS: 341.2 (M+H) + .
步骤2:中间体39-2的制备Step 2: Preparation of Intermediate 39-2
将二叔丁基(3aS,7aS)-1-氧代六氢-2H-吡咯[3,4-c]吡啶-2,5(3H)-二羧酸酯(中间体39-1,6.3克,18毫摩尔)溶于无水四氢呋喃(100毫升)中，在-78度搅拌条件下向反应混合物中加入LiHMDS(27.6毫升,27毫摩尔)并继续搅拌1小时，然后将NFSI(8.8克,27毫摩尔)加入到上述反应混合液中，并缓慢升至室温继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体二叔丁基(3aS,7aR)-7a-氟-1-氧代六氢-2H-吡咯[3,4-c]吡啶-2,5(3H)-二羧酸酯(中间体39-2,5.6克,86.9％收率)。MS:359.2(M+H) +。 Di-tert-butyl(3aS,7aS)-1-oxohexahydro-2H-pyrrole[3,4-c]pyridine-2,5(3H)-dicarboxylate (Intermediate 39-1, 6.3 g , 18 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), LiHMDS (27.6 mL, 27 mmol) was added to the reaction mixture with stirring at -78°C and stirring was continued for 1 hour, then NFSI (8.8 g, 27 mmol) was added to the above reaction mixture, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid di-tert-butyl(3aS,7aR)-7a-fluoro-1- Oxohexahydro-2H-pyrrole[3,4-c]pyridine-2,5(3H)-dicarboxylate (Intermediate 39-2, 5.6 g, 86.9% yield). MS: 359.2 (M+H) + .
步骤3:中间体39-3的制备Step 3: Preparation of Intermediate 39-3
中间体39-3的合成参考中间体1-4/步骤2，通过使用二叔丁基(3aS,7aR)-7a-氟-1-氧代六氢-2H-吡咯[3,4-c]吡啶-2,5(3H)-二羧酸酯(中间体39-2)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到(3aS,7aR)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体39-3)。MS:159.1(M+H) +。 Synthesis of Intermediate 39-3 was done with reference to Intermediate 1-4/Step 2 by using di-tert-butyl(3aS,7aR)-7a-fluoro-1-oxohexahydro-2H-pyrrole[3,4-c] Pyridine-2,5(3H)-dicarboxylate (Intermediate 39-2) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c]pyridine- tert-Butyl 6-carboxylate (Intermediate 1-4-1) was prepared to give (3aS,7aR)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 39- 3). MS: 159.1 (M+H) + .
制备例39中间体40-3Preparation Example 39 Intermediate 40-3
(3aR,7aS)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(3aR,7aS)-7a-Fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one
Figure PCTCN2021135751-appb-000164
Figure PCTCN2021135751-appb-000164
中间体40-3的合成参考中间体39-3，通过使用(3aS，7aR)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1b)代替(3aR,7aS)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体7- 1a)制备得到(3aR,7aS)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体40-3)。MS:159.1(M+H) +。 Intermediate 40-3 was synthesized with reference to intermediate 39-3 by using (3aS,7aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate (3aR,7aS)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1a) was prepared to give (3aR, 7aS)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 40-3). MS: 159.1 (M+H) + .
制备例40中间体41-4Preparation Example 40 Intermediate 41-4
2-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丙烷-1-羧酸2-(((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclopropane-1-carboxylic acid
Figure PCTCN2021135751-appb-000165
Figure PCTCN2021135751-appb-000165
步骤1:中间体41-1的制备Step 1: Preparation of Intermediate 41-1
将2-(羟甲基)环丙烷-1-羧酸乙酯(300毫克,2.08毫摩尔)溶于二氯甲烷(10毫升)中，在0度搅拌条件下向反应混合物中加入四溴化碳(1.04克,3.12毫摩尔)和三苯基膦(823毫克,3.12毫摩尔)并在室温继续搅拌1小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物2-(溴甲基)环丙烷-1-羧酸乙酯(中间体41-1,310毫克,72％收率)。MS:207.1(M+H) +。 Ethyl 2-(hydroxymethyl)cyclopropane-1-carboxylate (300 mg, 2.08 mmol) was dissolved in dichloromethane (10 mL) and tetrabromide was added to the reaction mixture with stirring at 0 degrees carbon (1.04 g, 3.12 mmol) and triphenylphosphine (823 mg, 3.12 mmol) and stirring was continued at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain ethyl 2-(bromomethyl)cyclopropane-1-carboxylate as a yellow oil. Ester (Intermediate 41-1, 310 mg, 72% yield). MS: 207.1 (M+H) + .
步骤2:中间体41-2的制备Step 2: Preparation of Intermediate 41-2
将(3aS,7aR)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体39-3,2.37克,15毫摩尔)溶于二氯甲烷(100毫升)中，在0度搅拌条件下向反应混合物中加入TEA(2.7克,27毫摩尔)和Boc 2O(4.7克,22毫摩尔)并在室温继续搅拌15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体(3aR,7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-2,2.78克,72％收率)。MS:259.1(M+H) +。 (3aS,7aR)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 39-3, 2.37 g, 15 mmol) was dissolved in dichloromethane (100 mL) ), TEA (2.7 g, 27 mmol) and Boc 2 O (4.7 g, 22 mmol) were added to the reaction mixture with stirring at 0 degrees and stirring was continued at room temperature for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid (3aR,7aR)-7a-fluoro-1-oxooctahydro -5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 41-2, 2.78 g, 72% yield). MS: 259.1 (M+H) + .
步骤3:中间体41-3的制备Step 3: Preparation of Intermediate 41-3
将2-(溴甲基)环丙烷-1-羧酸乙酯(中间体41-1,310毫克,1.5毫摩尔),(3aR,7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-2,387毫克,1.5毫摩尔)和Cs 2CO 3(977毫克,3毫摩尔)溶于DMF(6毫升)中，反应混合物中在室温继续搅拌3小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体(3aR,7aR)-7a-氟-2-((2-(甲氧羰基)环丙基)甲基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-3,100毫克,18％收率)。MS:371.2(M+H) +。 Ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (Intermediate 41-1, 310 mg, 1.5 mmol), (3aR,7aR)-7a-fluoro-1-oxooctahydro-5H-pyrrole tert-Butyl [3,4-c]pyridine-5-carboxylate (Intermediate 41-2,387 mg, 1.5 mmol) and Cs2CO3 (977 mg, 3 mmol) were dissolved in DMF (6 mL), Stirring of the reaction mixture was continued at room temperature for 3 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid (3aR,7aR)-7a-fluoro-2-((2- (Methoxycarbonyl)cyclopropyl)methyl)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 41-3, 100 mg, 18% yield Rate). MS: 371.2 (M+H) + .
步骤4:中间体41-4的制备Step 4: Preparation of Intermediate 41-4
中间体41-4的合成参考中间体6-3，通过使用(3aR,7aR)-7a-氟-2-((2-(甲氧羰基)环丙基)甲基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-3)代替2-(4-(甲氧羰基)苯基)-1- 氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到2-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丙烷-1-羧酸(中间体41-4)。MS:257.1(M+H) +。 Intermediate 41-4 was synthesized with reference to intermediate 6-3 by using (3aR,7aR)-7a-fluoro-2-((2-(methoxycarbonyl)cyclopropyl)methyl)-1-oxoocta Hydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 41-3) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1, 2,3,4,6,7-Hexahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 6-1) was prepared to give 2-(((3aS,7aR) -7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)methyl)cyclopropane-1-carboxylic acid (Intermediate 41-4). MS: 257.1 (M+H) + .
制备例41中间体42-3Preparation Example 41 Intermediate 42-3
3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸3-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2-dimethylpropionic acid
Figure PCTCN2021135751-appb-000166
Figure PCTCN2021135751-appb-000166
步骤1:中间体42-1的制备Step 1: Preparation of Intermediate 42-1
将3-羟基-2,2-二甲基丙酸乙酯(1.0克,6.84毫摩尔)溶于二氯甲烷(20毫升)中，在0度搅拌条件下向反应混合物中加入吡啶(812毫克,10.26毫摩尔)和TFAA(2.89克,10.26毫摩尔)。反应混合物中在0度继续搅拌2小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产品(中间体42-1,1.6克)未经纯化直接用于下一步反应。Ethyl 3-hydroxy-2,2-dimethylpropionate (1.0 g, 6.84 mmol) was dissolved in dichloromethane (20 mL), and pyridine (812 mg) was added to the reaction mixture with stirring at 0 degrees. , 10.26 mmol) and TFAA (2.89 g, 10.26 mmol). Stirring was continued in the reaction mixture at 0 degrees for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (intermediate 42-1, 1.6 g), which was directly used in the next reaction without purification.
步骤2:中间体42-2的制备Step 2: Preparation of Intermediate 42-2
将(3aR,7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-2,60毫克,0.23毫摩尔)溶于DMF(2毫升)中，在0度搅拌条件下向反应混合物中加入叔丁醇钾(39.1毫克,0.35毫摩尔)和中间体42-1(97毫克,0.35毫摩尔)。反应混合物中在室温继续搅拌12小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产品(中间体42-2,90毫克)未经纯化直接用于下一步反应。MS:387.6(M+H) +。 (3aR,7aR)-7a-fluoro-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 41-2,60 mg, 0.23 mmol ) was dissolved in DMF (2 mL) and potassium tert-butoxide (39.1 mg, 0.35 mmol) and Intermediate 42-1 (97 mg, 0.35 mmol) were added to the reaction mixture with stirring at 0°C. Stirring of the reaction mixture was continued at room temperature for 12 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product (intermediate 42-2, 90 mg) which was directly used in the next reaction without purification. MS: 387.6 (M+H) + .
步骤3:中间体42-3的制备Step 3: Preparation of Intermediate 42-3
中间体42-3的合成参考中间体6-3，通过使用(3aR,7aR)-2-(3-乙氧基-2,2-二甲基-3-氧丙基)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体42-2)代替2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸(中间体42-3)。MS:259.2(M+H) +。 Intermediate 42-3 was synthesized with reference to Intermediate 6-3 by using (3aR,7aR)-2-(3-ethoxy-2,2-dimethyl-3-oxopropyl)-7a-fluoro- 1-Oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 42-2) in place of 2-(4-(methoxycarbonyl)phenyl)-1- 3-(( 3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,2-dimethylpropionic acid (Intermediate 42-3). MS: 259.2 (M+H) + .
制备例42中间体43-1Preparation Example 42 Intermediate 43-1
3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸3-(((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclobutane-1-carboxylic acid
Figure PCTCN2021135751-appb-000167
Figure PCTCN2021135751-appb-000167
中间体43-1的合成参考中间体42-3，通过使用3-(羟甲基)环丁烷-1-羧酸甲酯代替3-羟基-2,2- 二甲基丙酸乙酯制备得到3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸(中间体43-1)。MS:253.1(M+H) +。 Synthesis of Intermediate 43-1 Reference Intermediate 42-3, prepared by using methyl 3-(hydroxymethyl)cyclobutane-1-carboxylate in place of ethyl 3-hydroxy-2,2-dimethylpropionate 3-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclobutane-1-carboxylic acid ( Intermediate 43-1). MS: 253.1 (M+H) + .
制备例43中间体44-3Preparation Example 43 Intermediate 44-3
3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸3-(((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)cyclopentane-1-carboxylic acid
Figure PCTCN2021135751-appb-000168
Figure PCTCN2021135751-appb-000168
步骤1:中间体44-1的制备Step 1: Preparation of Intermediate 44-1
将3-羟基环戊烷-1-羧酸甲酯(200毫克,1.4毫摩尔)和TEA(210毫克,2.1毫摩尔)溶于二氯甲烷(10毫升)中，在0度搅拌条件下向反应混合物中加入MsCl(175毫克,1.5毫摩尔)并在室温继续搅拌1小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物3-((甲磺酰基)氧基)环戊烷-1-羧酸甲酯(中间体44-1,197毫克,64％收率)。MS:223.1(M+H) +。 Methyl 3-hydroxycyclopentane-1-carboxylate (200 mg, 1.4 mmol) and TEA (210 mg, 2.1 mmol) were dissolved in dichloromethane (10 mL) under stirring at 0°C. To the reaction mixture was added MsCl (175 mg, 1.5 mmol) and stirring was continued at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 3-((methylsulfonyl)oxy)cyclopentane as a colorless oil -Methyl 1-carboxylate (Intermediate 44-1, 197 mg, 64% yield). MS: 223.1 (M+H) + .
步骤2:中间体44-2的制备Step 2: Preparation of Intermediate 44-2
将3-((甲磺酰基)氧基)环戊烷-1-羧酸甲酯(中间体44-1，197毫克,0.89毫摩尔),(3aR,7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-2,100毫克,0.39毫摩尔)和Cs 2CO 3(265毫克，0.77毫摩尔)溶于DMF(6毫升)中，反应混合物中在100度继续搅拌13小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体(3aR，7aR)-7a-氟-2-(3-(甲氧羰基)环戊基)-1-氧代八氢十六烷基-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体44-2,54毫克,36％收率)。MS:385.2(M+H) +。 Methyl 3-((methylsulfonyl)oxy)cyclopentane-1-carboxylate (Intermediate 44-1, 197 mg, 0.89 mmol), (3aR,7aR)-7a-fluoro-1-oxo Substituted octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 41-2, 100 mg, 0.39 mmol) and Cs2CO3 ( 265 mg, 0.77 mmol) were dissolved in The reaction mixture was stirred in DMF (6 mL) at 100°C for a further 13 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid (3aR, 7aR)-7a-fluoro-2-(3-( Methoxycarbonyl)cyclopentyl)-1-oxooctahydrohexadecyl-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 44-2,54 mg, 36 % yield). MS: 385.2 (M+H) + .
步骤2:中间体44-3的制备Step 2: Preparation of Intermediate 44-3
中间体44-3的合成参考中间体6-3，通过使用(3aR，7aR)-7a-氟-2-(3-(甲氧羰基)环戊基)-1-氧代八氢十六烷基-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体44-2)代替2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸(中间体44-3)。MS:271.1(M+H) +。 Intermediate 44-3 was synthesized with reference to Intermediate 6-3 by using (3aR,7aR)-7a-fluoro-2-(3-(methoxycarbonyl)cyclopentyl)-1-oxooctahydrohexadecane tert-butyl-5H-pyrro[3,4-c]pyridine-5-carboxylate (Intermediate 44-2) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1, 2,3,4,6,7-Hexahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 6-1) was prepared to give 3-(((3aS,7aR) -7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)cyclopentane-1-carboxylic acid (Intermediate 44-3). MS: 271.1 (M+ H) + .
制备例44中间体45-1Preparation Example 44 Intermediate 45-1
2-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸2-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)cyclopentane-1-carboxylic acid
Figure PCTCN2021135751-appb-000169
Figure PCTCN2021135751-appb-000169
中间体45-1的合成参考中间体44-3，通过使用环戊-1-烯-1-羧酸甲酯代替3-((甲磺酰基)氧基)环戊烷-1-羧酸甲酯(中间体44-1)制备得到2-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸(中间体45-1)。MS:271.1(M+H) +。 Synthesis of Intermediate 45-1 Refers to Intermediate 44-3 by using methyl cyclopent-1-ene-1-carboxylate in place of methyl 3-((methylsulfonyl)oxy)cyclopentane-1-carboxylate Esters (Intermediate 44-1) were prepared to give 2-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)cyclopentane- 1-Carboxylic acid (Intermediate 45-1). MS: 271.1 (M+H) + .
制备例45中间体46-2Preparation Example 45 Intermediate 46-2
4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸甲酯Methyl 4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoate
Figure PCTCN2021135751-appb-000170
Figure PCTCN2021135751-appb-000170
步骤1:中间体46-1的制备Step 1: Preparation of Intermediate 46-1
中间体46-1的合成参考中间体37-2，通过使用(3aS,7aR)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1b)代替顺式-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1)和4-碘苯甲酸甲酯代替2-氯-4-碘苯甲酸甲酯制备得到(3aS,7aS)-7a-氟-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体46-1)。Intermediate 46-1 was synthesized with reference to intermediate 37-2 by using (3aS,7aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate body 7-1b) in place of cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1) and methyl 4-iodobenzoate Ester instead of methyl 2-chloro-4-iodobenzoate was prepared to give (3aS,7aS)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole[ 3,4-c]Pyridine-5-carboxylate tert-butyl ester (Intermediate 46-1).
步骤2:中间体46-2的制备Step 2: Preparation of Intermediate 46-2
中间体46-2的合成参考中间体1-4/步骤2，通过使用(3aS,7aS)-7a-氟-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体46-1)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸甲酯(中间体46-2)。MS:293.2(M+H) +。 Intermediate 46-2 was synthesized with reference to Intermediate 1-4/Step 2 by using (3aS,7aS)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro- 5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 46-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3, 4-c]Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give 4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrrole[3, Methyl 4-c]pyridin-2-yl)benzoate (Intermediate 46-2). MS: 293.2 (M+H) + .
制备例46中间体47-1Preparation Example 46 Intermediate 47-1
4-(((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸4-(((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000171
Figure PCTCN2021135751-appb-000171
中间体47-1的合成参考中间体6-3，通过使用(3aS,7aS)-7a-氟-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体46-1)代替2-(4-(甲氧羰基)苯基)-1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体6-1)制备得到4-(((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体47-1)。MS:279.1(M+H) +。 Intermediate 47-1 was synthesized with reference to Intermediate 6-3 by using (3aS,7aS)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole [3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 46-1) in place of 2-(4-(methoxycarbonyl)phenyl)-1-oxo-1,2,3,4 ,6,7-Hexahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 6-1) was prepared to give 4-(((3aR,7aS)-7a-fluoro- 1-Oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 47-1). MS: 279.1 (M+H) + .
制备例47中间体48-2Preparation Example 47 Intermediate 48-2
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000172
Figure PCTCN2021135751-appb-000172
步骤1:中间体48-1的制备Step 1: Preparation of Intermediate 48-1
中间体48-1的合成参考中间体46-1，通过使用(3aR,7aS)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1a)代替(3aS,7aR)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1b)制备得到(3aR,7aR)-7a-氟-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体48-1)。Intermediate 48-1 was synthesized with reference to intermediate 46-1 by using (3aR,7aS)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate Compound 7-1a) instead of (3aS,7aR)-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1b) was prepared to give (3aR, 7aR)-7a-Fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 48-1).
步骤2:中间体48-2的制备Step 2: Preparation of Intermediate 48-2
中间体48-2的合成参考中间体47-1，通过使用(3aR,7aR)-7a-氟-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体48-1)代替(3aS,7aS)-7a-氟-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体46-1)制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体48-2)。MS:279.1(M+H) +。 Intermediate 48-2 was synthesized with reference to Intermediate 47-1 by using (3aR,7aR)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole tert-Butyl [3,4-c]pyridine-5-carboxylate (Intermediate 48-1) in place of (3aS,7aS)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1- Oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 46-1) prepared to give 4-((3aS,7aR)-7a-fluoro-1-oxo Octahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 48-2). MS: 279.1 (M+H) + .
制备例48中间体49-2Preparation Example 48 Intermediate 49-2
3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000173
Figure PCTCN2021135751-appb-000173
步骤1:中间体49-1的制备Step 1: Preparation of Intermediate 49-1
中间体49-1的合成参考中间体6-1，通过使用(3aR，7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸(中间体41-2)代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1) 和3-碘苯甲酸甲酯代替4-碘苯甲酸甲酯制备得到(3aR，7aR)-7a-氟-2-(3-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体49-1)。Intermediate 49-1 was synthesized with reference to Intermediate 6-1 by using (3aR,7aR)-7a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylic acid ( Intermediate 41-2) in place of tert-butyl 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (intermediate 5-1) and methyl 3-iodobenzoate instead of methyl 4-iodobenzoate to prepare (3aR, 7aR)-7a-fluoro-2-(3-(methoxycarbonyl)phenyl)-1-oxo Octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 49-1).
步骤1:中间体49-2的制备Step 1: Preparation of Intermediate 49-2
中间体49-2的合成参考中间体47-1，通过使用((3aR，7aR)-7a-氟-2-(3-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体49-1)代替(3aS,7aS)-7a-氟-2-(4-(甲氧羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体46-1)制备得到3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)。MS:279.1(M+H) +。 Intermediate 49-2 was synthesized with reference to Intermediate 47-1 by using ((3aR,7aR)-7a-fluoro-2-(3-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H- Pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 49-1) in place of (3aS,7aS)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1 -Oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 46-1) prepared to give 3-((3aS,7aR)-7a-fluoro-1-oxo Substituted octahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 49-2). MS: 279.1 (M+H) + .
制备例49中间体50-1Preparation Example 49 Intermediate 50-1
3-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Chloro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000174
Figure PCTCN2021135751-appb-000174
中间体50-1的合成参考中间体49-2，通过使用3-氯-4-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到3-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体50-1)。MS:313.2(M+H) +。 Synthesis of Intermediate 50-1 Referring to Intermediate 49-2, prepared by using methyl 3-chloro-4-iodobenzoate instead of methyl 3-iodobenzoate to give 3-chloro-4-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 50-1). MS: 313.2 (M+H) + .
制备例50中间体51-1Preparation Example 50 Intermediate 51-1
3-氟-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Fluoro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000175
Figure PCTCN2021135751-appb-000175
中间体51-1的合成参考中间体49-2，通过使用3-氟-4-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到3-氟-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体51-1)。MS:297.2(M+H) +。 Synthesis of intermediate 51-1 Referring to intermediate 49-2, prepared by using methyl 3-fluoro-4-iodobenzoate instead of methyl 3-iodobenzoate to give 3-fluoro-4-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 51-1). MS: 297.2 (M+H) + .
制备例51中间体52-1Preparation Example 51 Intermediate 52-1
4-氟-3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸4-Fluoro-3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000176
Figure PCTCN2021135751-appb-000176
中间体52-1的合成参考中间体49-2，通过使用3-碘-4-氟苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到4-氟-3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体52-1)。MS:297.1(M+H) +。 Synthesis of Intermediate 52-1 Referring to Intermediate 49-2, prepared by using methyl 3-iodo-4-fluorobenzoate instead of methyl 3-iodobenzoate to give 4-fluoro-3-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 52-1). MS: 297.1 (M+H) + .
制备例52中间体53-1Preparation Example 52 Intermediate 53-1
3-氟-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Fluoro-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000177
Figure PCTCN2021135751-appb-000177
中间体53-1的合成参考中间体49-2，通过使用3-碘-5-氟苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到3-氟-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体53-1)。MS:297.1(M+H) +。 Synthesis of intermediate 53-1 Referring to intermediate 49-2, prepared by using methyl 3-iodo-5-fluorobenzoate instead of methyl 3-iodobenzoate to give 3-fluoro-5-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 53-1). MS: 297.1 (M+H) + .
制备例53中间体54-1Preparation Example 53 Intermediate 54-1
3-氯-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Chloro-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000178
Figure PCTCN2021135751-appb-000178
中间体54-1的合成参考中间体49-2，通过使用3-碘-5-氯苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到3-氯-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体54-1)。MS:313.1(M+H) +。 Synthesis of Intermediate 54-1 Referring to Intermediate 49-2, prepared by using methyl 3-iodo-5-chlorobenzoate instead of methyl 3-iodobenzoate to give 3-chloro-5-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 54-1). MS: 313.1 (M+H) + .
制备例54中间体55-1Preparation Example 54 Intermediate 55-1
3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丁酸3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)butanoic acid
Figure PCTCN2021135751-appb-000179
Figure PCTCN2021135751-appb-000179
中间体55-1的合成参考中间体49-2，通过使用3-(3-溴苯基)丁酸叔丁酯代替3-碘苯甲酸甲酯制备得到3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丁酸(中间体55-1)。MS:321.1(M+H) +。 Synthesis of Intermediate 55-1 Referring to Intermediate 49-2, 3-(3-((3aS,7aR was prepared by using tert-butyl 3-(3-bromophenyl)butyrate in place of methyl 3-iodobenzoate )-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)butanoic acid (Intermediate 55-1). MS: 321.1 (M+H) + .
制备例55中间体56-1Preparation Example 55 Intermediate 56-1
2-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸2-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)-2-methylpropionic acid
Figure PCTCN2021135751-appb-000180
Figure PCTCN2021135751-appb-000180
中间体56-1的合成参考中间体49-2，通过使用2-(3-溴苯基)-2-甲基丙酸甲酯代替3-碘苯甲酸甲酯制备得到2-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸(中间体56-1)。MS:335.1(M+H) +。 Synthesis of Intermediate 56-1 Refers to Intermediate 49-2, prepared by using methyl 2-(3-bromophenyl)-2-methylpropanoate instead of methyl 3-iodobenzoate to give 2-(3-( (3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)-2-methylpropionic acid (Intermediate 56-1) . MS: 335.1 (M+H) + .
制备例56中间体57-1Preparation Example 56 Intermediate 57-1
3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸3-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid
Figure PCTCN2021135751-appb-000181
Figure PCTCN2021135751-appb-000181
中间体57-1的合成参考中间体41-4，通过使用3-(溴甲基)苯甲酸甲酯代替2-(溴甲基)环丙烷-1-羧酸乙酯(中间体41-1)制备得到3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸(中间体57-1)。MS:293.1(M+H) +。 Intermediate 57-1 was synthesized with reference to intermediate 41-4 by using methyl 3-(bromomethyl)benzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41-1 ) to obtain 3-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid (intermediate 57- 1). MS: 293.1 (M+H) + .
制备例57中间体58-2Preparation Example 57 Intermediate 58-2
(E)-3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙烯酸(E)-3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)acrylic acid
Figure PCTCN2021135751-appb-000182
Figure PCTCN2021135751-appb-000182
步骤1:中间体58-1的制备Step 1: Preparation of Intermediate 58-1
将3-溴苯甲醛(5克,27.0毫摩尔))溶于THF(50毫升)中，在0度搅拌下向反应混合物中加入钠氢(1.297克,54.0毫摩尔)并在0度继续搅拌0.5小时，然后将2-(二乙氧基磷酰)乙酸叔丁酯(8.18克,32.4毫摩尔)在0度下加入到上述反应混合物中，反应混合物在室温搅拌反应1小时。然后用冰水淬灭反应并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，将滤液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(E)-3-(3-溴苯基)丙烯酸叔丁酯(中间体58-1,3.4克,44.4％收率)。MS:220.2(M+H) +。 3-Bromobenzaldehyde (5 g, 27.0 mmol)) was dissolved in THF (50 mL) and sodium hydrogen (1.297 g, 54.0 mmol) was added to the reaction mixture with stirring at 0 degrees and stirring was continued at 0 degrees After 0.5 hours, tert-butyl 2-(diethoxyphosphoryl)acetate (8.18 g, 32.4 mmol) was added to the above reaction mixture at 0 degrees, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was then quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oil (E)-3-(3-bromophenyl) tert-Butyl acrylate (Intermediate 58-1, 3.4 g, 44.4% yield). MS: 220.2 (M+H) + .
步骤2:中间体58-2的制备Step 2: Preparation of Intermediate 58-2
中间体58-2的合成参考中间体49-2，通过使用(E)-3-(3-溴苯基)丙烯酸叔丁酯(中间体58-1)代替3-碘苯甲酸甲酯制备得到(E)-3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙烯酸(中间体58-2)。MS:305.1(M+H) +。 Synthesis of Intermediate 58-2 Reference Intermediate 49-2, prepared by using (E)-tert-butyl 3-(3-bromophenyl)acrylate (Intermediate 58-1) in place of methyl 3-iodobenzoate (E)-3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)acrylic acid (intermediate 58-2). MS: 305.1 (M+H) + .
制备例58中间体59-1Preparation Example 58 Intermediate 59-1
3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2,2-二甲基丙酸3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)-2,2-dimethyl propionic acid
Figure PCTCN2021135751-appb-000183
Figure PCTCN2021135751-appb-000183
中间体59-1的合成参考中间体49-2，通过使用3-(3-溴苯基)-2,2-二甲基丙酸甲酯代替3-碘苯甲酸甲酯制备得到3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2,2-二甲基丙酸(中间体59-1)。MS:335.1(M+H) +。 Synthesis of Intermediate 59-1 Refers to Intermediate 49-2, prepared by using methyl 3-(3-bromophenyl)-2,2-dimethylpropanoate instead of methyl 3-iodobenzoate to give 3-( 3-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)-2,2-dimethylpropionic acid ( Intermediate 59-1). MS: 335.1 (M+H) + .
制备例59中间体60-1Preparation Example 59 Intermediate 60-1
4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸4-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid
Figure PCTCN2021135751-appb-000184
Figure PCTCN2021135751-appb-000184
中间体60-1的合成参考中间体41-4，通过使用4-(溴甲基)苯甲酸甲酯代替2-(溴甲基)环丙 烷-1-羧酸乙酯(中间体41-1)制备得到4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸(中间体60-1)。MS:293.1(M+H) +。 The synthesis of intermediate 60-1 was referenced to intermediate 41-4 by using methyl 4-(bromomethyl)benzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41-1 ) to obtain 4-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid (intermediate 60- 1). MS: 293.1 (M+H) + .
制备例60中间体61-1Preparation Example 60 Intermediate 61-1
3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-4-甲基苯甲酸3-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-4-methylbenzoic acid
Figure PCTCN2021135751-appb-000185
Figure PCTCN2021135751-appb-000185
中间体61-1的合成参考中间体49-2，通过使用3-碘-4-甲基苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-4-甲基苯甲酸(中间体61-1)。MS:293.1(M+H) +。 Synthesis of intermediate 61-1 Referring to intermediate 49-2, 3-((3aS,7aR)-7a-fluoro was prepared by using methyl 3-iodo-4-methylbenzoate in place of methyl 3-iodobenzoate -1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-4-methylbenzoic acid (Intermediate 61-1). MS: 293.1 (M+H) + .
制备例61中间体62-1Preparation Example 61 Intermediate 62-1
5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲氧基苯甲酸5-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methoxybenzoic acid
Figure PCTCN2021135751-appb-000186
Figure PCTCN2021135751-appb-000186
中间体62-1的合成参考中间体49-2，通过使用2-甲氧基-5-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲氧基苯甲酸(中间体62-1)。MS:309.1(M+H) +。 Synthesis of Intermediate 62-1 Referring to Intermediate 49-2, 5-((3aS,7aR)-7a- was prepared by using methyl 2-methoxy-5-iodobenzoate in place of methyl 3-iodobenzoate Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methoxybenzoic acid (Intermediate 62-1). MS: 309.1 (M+H) + .
制备例62中间体63-1Preparation Example 62 Intermediate 63-1
5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸5-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000187
Figure PCTCN2021135751-appb-000187
中间体63-1的合成参考中间体49-2，通过使用2-甲基-5-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体63-1)。MS:293.1(M+H) +。 Synthesis of Intermediate 63-1 Referring to Intermediate 49-2, 5-((3aS,7aR)-7a-fluoro was prepared by using methyl 2-methyl-5-iodobenzoate in place of methyl 3-iodobenzoate -1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methylbenzoic acid (Intermediate 63-1). MS: 293.1 (M+H) + .
制备例63中间体64-2Preparation Example 63 Intermediate 64-2
6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸6-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)nicotinic acid
Figure PCTCN2021135751-appb-000188
Figure PCTCN2021135751-appb-000188
步骤1:中间体64-1的制备Step 1: Preparation of Intermediate 64-1
将(3aR,7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-2，100毫克,0.39毫摩尔),6-溴烟酸(86毫克,0.43毫摩尔),叔丁醇钾(96毫克,0.85毫摩尔),醋酸钯(17毫克,0.08毫摩尔)和(9,9-二甲基-9H-杂蒽-4,5-二基)双(二苯基膦)(22.4毫克,0.04毫摩尔)的DMF(2毫升)混合溶液在110度搅拌反应15小时。反应混合物用冰水淬灭并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体6-((3aR,7aR)-5-(叔丁氧羰基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸(中间体64-1,120毫克,82％收率)。MS:380.3(M+H) +。 (3aR,7aR)-7a-Fluoro-1-oxooctahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 41-2, 100 mg, 0.39 mmol ), 6-bromonicotinic acid (86 mg, 0.43 mmol), potassium tert-butoxide (96 mg, 0.85 mmol), palladium acetate (17 mg, 0.08 mmol) and (9,9-dimethyl-9H A mixed solution of -xanthene-4,5-diyl)bis(diphenylphosphine) (22.4 mg, 0.04 mmol) in DMF (2 mL) was stirred at 110 degrees for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid 6-((3aR,7aR)-5-(tert-butoxycarbonyl) )-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)nicotinic acid (Intermediate 64-1, 120 mg, 82% yield). MS: 380.3 (M+H) + .
步骤2:中间体64-2的制备Step 2: Preparation of Intermediate 64-2
中间体64-2的合成参考中间体1-4/步骤2，通过使用6-((3aR,7aR)-5-(叔丁氧羰基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸(中间体64-1)代替3-羟基-2,4,5,7-四氢-6H-吡唑啉[3,4-c]吡啶-6-羧酸叔丁酯(中间体1-4-1)制备得到6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸(中间体64-2)。MS:280.2(M+H) +。 Intermediate 64-2 was synthesized with reference to Intermediate 1-4/Step 2 by using 6-((3aR,7aR)-5-(tert-butoxycarbonyl)-7a-fluoro-1-oxooctahydro-2H- Pyrro[3,4-c]pyridin-2-yl)nicotinic acid (Intermediate 64-1) in place of 3-hydroxy-2,4,5,7-tetrahydro-6H-pyrazoline[3,4-c ] Pyridine-6-carboxylate tert-butyl ester (Intermediate 1-4-1) was prepared to give 6-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrole[3,4-c ]pyridin-2-yl)nicotinic acid (Intermediate 64-2). MS: 280.2 (M+H) + .
制备例64中间体65-1Preparation Example 64 Intermediate 65-1
3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲氧基苯甲酸3-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methoxybenzoic acid
Figure PCTCN2021135751-appb-000189
Figure PCTCN2021135751-appb-000189
中间体65-1的合成参考中间体64-2，通过使用3-溴-5-甲氧基苯甲酸代替6-溴烟酸制备得到3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲氧基苯甲酸(中间体65-1)。MS:309.2(M+H) +。 Synthesis of Intermediate 65-1 Referring to Intermediate 64-2, 3-((3aS,7aR)-7a-fluoro-1- was prepared by using 3-bromo-5-methoxybenzoic acid in place of 6-bromonicotinic acid Oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methoxybenzoic acid (Intermediate 65-1). MS: 309.2 (M+H) + .
制备例65中间体66-1Preparation Example 65 Intermediate 66-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000190
Figure PCTCN2021135751-appb-000190
中间体66-1的合成参考中间体49-2，通过使用2-甲基-4-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体66-1)。MS:293.1(M+H) +。 Synthesis of Intermediate 66-1 Referring to Intermediate 49-2, 4-((3aS,7aR)-7a-fluoro was prepared by using methyl 2-methyl-4-iodobenzoate in place of methyl 3-iodobenzoate -1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methylbenzoic acid (Intermediate 66-1). MS: 293.1 (M+H) + .
制备例66中间体67-1Preparation Example 66 Intermediate 67-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methylbenzoic acid
Figure PCTCN2021135751-appb-000191
Figure PCTCN2021135751-appb-000191
中间体67-1的合成参考中间体49-2，通过使用3-甲基-4-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸(中间体67-1)。MS:293.1(M+H) +。 Synthesis of Intermediate 67-1 Referring to Intermediate 49-2, 4-((3aS,7aR)-7a-fluoro was prepared by using methyl 3-methyl-4-iodobenzoate in place of methyl 3-iodobenzoate -1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-3-methylbenzoic acid (Intermediate 67-1). MS: 293.1 (M+H) + .
制备例67中间体68-1Preparation Example 67 Intermediate 68-1
3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲基苯甲酸3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methylbenzoic acid
Figure PCTCN2021135751-appb-000192
Figure PCTCN2021135751-appb-000192
中间体68-1的合成参考中间体49-2，通过使用3-甲基-5-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲基苯甲酸(中间体68-1)。MS:293.1(M+H) +。 Synthesis of Intermediate 68-1 Referring to Intermediate 49-2, 3-((3aS,7aR)-7a-fluoro was prepared by using methyl 3-methyl-5-iodobenzoate in place of methyl 3-iodobenzoate -1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-5-methylbenzoic acid (Intermediate 68-1). MS: 293.1 (M+H) + .
制备例68中间体69-2Preparation Example 68 Intermediate 69-2
4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸4-((3aR,7aS)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methylbenzoic acid
Figure PCTCN2021135751-appb-000193
Figure PCTCN2021135751-appb-000193
步骤1:中间体69-1的制备Step 1: Preparation of Intermediate 69-1
中间体69-1的合成参考中间体41-2，通过使用(3aR,7aS)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体40-3)代替(3aS,7aR)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体39-3)制备得到(3aS，7aS)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体69-1)。The synthesis of intermediate 69-1 was referenced to intermediate 41-2 by using (3aR,7aS)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 40-3) Prepared in place of (3aS,7aR)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (Intermediate 39-3) to give (3aS,7aS)-7a-fluoro-1-oxo Substituted octahydro-5H-pyrrole[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 69-1).
步骤2:中间体69-2的制备Step 2: Preparation of Intermediate 69-2
中间体69-2的合成参考中间体49-2，通过使用(3aS，7aS)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体69-1)代替(3aR,7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-羧酸叔丁酯(中间体41-2)和3-甲基-4-碘苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸(中间体69-2)。MS:293.1(M+H) +。 Intermediate 69-2 was synthesized with reference to intermediate 49-2 by using (3aS,7aS)-7a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylic acid tert. Butyl ester (intermediate 69-1) in place of (3aR,7aR)-7a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 41 -2) and methyl 3-methyl-4-iodobenzoate instead of methyl 3-iodobenzoate to prepare 4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrrole[ 3,4-c]pyridin-2-yl)-3-methylbenzoic acid (Intermediate 69-2). MS: 293.1 (M+H) + .
制备例69中间体70-1Preparation Example 69 Intermediate 70-1
3-氟-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Fluoro-4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000194
Figure PCTCN2021135751-appb-000194
中间体70-1的合成参考中间体69-2，通过使用3-氟-4-溴苯甲酸甲酯代替3-甲基-4-碘苯甲酸甲酯制备得到3-氟-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体70-1)。MS:297.1(M+H) +。 The synthesis of intermediate 70-1 was referred to intermediate 69-2, prepared by using methyl 3-fluoro-4-bromobenzoate instead of methyl 3-methyl-4-iodobenzoate to give 3-fluoro-4-(( 3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 70-1). MS: 297.1 (M+H) + .
制备例70中间体71-1Preparation Example 70 Intermediate 71-1
4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aR,7aS)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000195
Figure PCTCN2021135751-appb-000195
中间体71-1的合成参考中间体69-2，通过使用2-甲基-4-碘苯甲酸甲酯代替3-甲基-4-碘苯甲酸甲酯制备得到4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体71- 1)。MS:293.1(M+H) +。 Synthesis of Intermediate 71-1 Refers to Intermediate 69-2, prepared by using methyl 2-methyl-4-iodobenzoate in place of methyl 3-methyl-4-iodobenzoate to give 4-((3aR,7aS )-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid (Intermediate 71-1). MS: 293.1 (M+H) + .
制备例71中间体72-1Preparation Example 71 Intermediate 72-1
5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,3-二甲基苯甲酸5-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,3-dimethylbenzoic acid
Figure PCTCN2021135751-appb-000196
Figure PCTCN2021135751-appb-000196
中间体72-1的合成参考中间体64-2，通过使用5-溴-2,3-二甲基苯甲酸代替6-溴烟酸制备得到5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,3-二甲基苯甲酸(中间体72-1)。MS:307.2(M+H) +。 Synthesis of Intermediate 72-1 Referring to Intermediate 64-2, 5-((3aS,7aR)-7a-fluoro- 1-Oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,3-dimethylbenzoic acid (Intermediate 72-1). MS: 307.2 (M+H) + .
制备例72中间体73-1Preparation Example 72 Intermediate 73-1
3-氟-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸3-Fluoro-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000197
Figure PCTCN2021135751-appb-000197
中间体73-1的合成参考中间体64-2，通过使用5-溴-2-甲基-3-氟苯甲酸代替6-溴烟酸制备得到3-氟-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体73-1)。MS:311.2(M+H) +。 Synthesis of Intermediate 73-1 Referring to Intermediate 64-2, 3-fluoro-5-((3aS,7aR) was prepared by using 5-bromo-2-methyl-3-fluorobenzoic acid in place of 6-bromonicotinic acid -7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methylbenzoic acid (Intermediate 73-1). MS: 311.2 (M+H) + .
制备例73中间体74-1Preparation Example 73 Intermediate 74-1
5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,4-二甲基苯甲酸5-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,4-dimethylbenzoic acid
Figure PCTCN2021135751-appb-000198
Figure PCTCN2021135751-appb-000198
中间体74-1的合成参考中间体64-2，通过使用5-溴-2,4-二甲基苯甲酸代替6-溴烟酸制备得到5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,4-二甲基苯甲酸(中间体74-1)。MS:307.2(M+H) +。 Synthesis of Intermediate 74-1 Referring to Intermediate 64-2, 5-((3aS,7aR)-7a-fluoro- 1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,4-dimethylbenzoic acid (Intermediate 74-1). MS: 307.2 (M+H) + .
制备例74中间体75-1Preparation Example 74 Intermediate 75-1
3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,6-二甲基苯甲酸3-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,6-dimethylbenzoic acid
Figure PCTCN2021135751-appb-000199
Figure PCTCN2021135751-appb-000199
中间体75-1的合成参考中间体64-2，通过使用3-溴-2,6-二甲基苯甲酸代替6-溴烟酸制备得到3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,6-二甲基苯甲酸(中间体75-1)。MS:307.2(M+H) +。 Synthesis of Intermediate 75-1 Referring to Intermediate 64-2, 3-((3aS,7aR)-7a-fluoro- 1-Oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,6-dimethylbenzoic acid (Intermediate 75-1). MS: 307.2 (M+H) + .
制备例75中间体76-1Preparation Example 75 Intermediate 76-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,6-二甲基苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,6-dimethylbenzoic acid
Figure PCTCN2021135751-appb-000200
Figure PCTCN2021135751-appb-000200
中间体76-1的合成参考中间体64-2，通过使用4-溴-2,6-二甲基苯甲酸代替6-溴烟酸制备得到4-((3aS，7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,6-二甲基苯甲酸(中间体76-1)。MS:307.2(M+H) +。 Synthesis of Intermediate 76-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro- 1-Oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,6-dimethylbenzoic acid (Intermediate 76-1). MS: 307.2 (M+H) + .
制备例76中间体77-1Preparation Example 76 Intermediate 77-1
5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸5-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethoxy)benzoic acid
Figure PCTCN2021135751-appb-000201
Figure PCTCN2021135751-appb-000201
中间体77-1的合成参考中间体64-2，通过使用5-溴-2-三氟甲氧基苯甲酸代替6-溴烟酸制备得到5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸(中间体77-1)。MS:363.2(M+H) +。 Synthesis of Intermediate 77-1 Referring to Intermediate 64-2, 5-((3aS,7aR)-7a-fluoro- 1-Oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethoxy)benzoic acid (Intermediate 77-1). MS: 363.2 (M+H) + .
制备例77中间体78-1Preparation Example 77 Intermediate 78-1
4-((3as,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-异丙基苯甲酸4-((3as,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-isopropylbenzoic acid
Figure PCTCN2021135751-appb-000202
Figure PCTCN2021135751-appb-000202
中间体78-1的合成参考中间体64-2，通过使用5-溴-2-甲氧基苯甲酸代替6-溴烟酸制备得到4-((3as,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-异丙基苯甲酸(中间体78-1)。MS:321.2(M+H) +。 Synthesis of Intermediate 78-1 Referring to Intermediate 64-2, 4-((3as,7aR)-7a-fluoro-1- was prepared by using 5-bromo-2-methoxybenzoic acid in place of 6-bromonicotinic acid Oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-3-isopropylbenzoic acid (Intermediate 78-1). MS: 321.2 (M+H) + .
制备例78中间体79-1Preparation Example 78 Intermediate 79-1
5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸5-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethyl)benzoic acid
Figure PCTCN2021135751-appb-000203
Figure PCTCN2021135751-appb-000203
中间体79-1的合成参考中间体64-2，通过使用5-溴-2-三氟甲基苯甲酸代替6-溴烟酸制备得到5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸(中间体79-1)。MS:347.2(M+H) +。 Synthesis of Intermediate 79-1 Referring to Intermediate 64-2, 5-((3aS,7aR)-7a-fluoro-1 was prepared by using 5-bromo-2-trifluoromethylbenzoic acid in place of 6-bromonicotinic acid -oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethyl)benzoic acid (Intermediate 79-1). MS: 347.2 (M+H) + .
制备例79中间体80-1Preparation Example 79 Intermediate 80-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,5-二甲基苯甲酸4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,5-dimethylbenzoic acid
Figure PCTCN2021135751-appb-000204
Figure PCTCN2021135751-appb-000204
中间体80-1的合成参考中间体64-2，通过使用4-溴-2,5-二甲基苯甲酸代替6-溴烟酸制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,5-二甲基苯甲酸(中间体80-1)。MS:307.2(M+H) +。 Synthesis of Intermediate 80-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro- 1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2,5-dimethylbenzoic acid (Intermediate 80-1). MS: 307.2 (M+H) + .
制备例80中间体81-1Preparation Example 80 Intermediate 81-1
5-氟-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸5-Fluoro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000205
Figure PCTCN2021135751-appb-000205
中间体81-1的合成参考中间体64-2，通过使用4-溴-2-甲基-5-氟苯甲酸代替6-溴烟酸制备得到5-氟-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体81-1)。MS:311.2(M+H) +。 Synthesis of Intermediate 81-1 Referring to Intermediate 64-2, 5-fluoro-4-((3aS,7aR) was prepared by using 4-bromo-2-methyl-5-fluorobenzoic acid in place of 6-bromonicotinic acid -7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methylbenzoic acid (Intermediate 81-1). MS: 311.2 (M+H) + .
制备例81中间体82-1Preparation Example 81 Intermediate 82-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲氧基苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methoxybenzoic acid
Figure PCTCN2021135751-appb-000206
Figure PCTCN2021135751-appb-000206
中间体82-1的合成参考中间体64-2，通过使用4-溴-3-甲氧基苯甲酸代替6-溴烟酸制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲氧基苯甲酸(中间体82-1)。MS:309.2(M+H) +。 Synthesis of Intermediate 82-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro-1- was prepared by using 4-bromo-3-methoxybenzoic acid in place of 6-bromonicotinic acid Oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-3-methoxybenzoic acid (Intermediate 82-1). MS: 309.2 (M+H) + .
制备例82中间体83-1Preparation Example 82 Intermediate 83-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethoxy)benzoic acid
Figure PCTCN2021135751-appb-000207
Figure PCTCN2021135751-appb-000207
中间体83-1的合成参考中间体64-2，通过使用4-溴-2-三氟甲氧基苯甲酸代替6-溴烟酸制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸(中间体83-1)。MS:363.2(M+H) +。 Synthesis of Intermediate 83-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro- 1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethoxy)benzoic acid (Intermediate 83-1). MS: 363.2 (M+H) + .
制备例83中间体84-1Preparation Example 83 Intermediate 84-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲氧基苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methoxybenzoic acid
Figure PCTCN2021135751-appb-000208
Figure PCTCN2021135751-appb-000208
中间体84-1的合成参考中间体64-2，通过使用4-溴-2-甲氧基苯甲酸代替6-溴烟酸制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲氧基苯甲酸(中间体84-1)。MS:309.2(M+H) +。 Synthesis of Intermediate 84-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro-1- was prepared by using 4-bromo-2-methoxybenzoic acid in place of 6-bromonicotinic acid Oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methoxybenzoic acid (Intermediate 84-1). MS: 309.2 (M+H) + .
制备例84中间体85-1Preparation Example 84 Intermediate 85-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-isopropylbenzoic acid
Figure PCTCN2021135751-appb-000209
Figure PCTCN2021135751-appb-000209
中间体85-1的合成参考中间体64-2，通过使用4-溴-2-异丙基苯甲酸代替6-溴烟酸制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸(中间体85-1)。MS:321.2(M+H) +。 Synthesis of Intermediate 85-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro-1- was prepared by using 4-bromo-2-isopropylbenzoic acid in place of 6-bromonicotinic acid Oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-isopropylbenzoic acid (Intermediate 85-1). MS: 321.2 (M+H) + .
制备例85中间体86-1Preparation Example 85 Intermediate 86-1
2-环丙基-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸2-Cyclopropyl-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000210
Figure PCTCN2021135751-appb-000210
中间体86-1的合成参考中间体64-2，通过使用4-溴-2-环丙基苯甲酸代替6-溴烟酸制备得到2-环丙基-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体86-1)。MS:319.2(M+H) +。 Synthesis of Intermediate 86-1 Referring to Intermediate 64-2, 2-cyclopropyl-4-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 86-1). MS: 319.2 (M+H) + .
制备例86中间体87-1Preparation Example 86 Intermediate 87-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethyl)benzoic acid
Figure PCTCN2021135751-appb-000211
Figure PCTCN2021135751-appb-000211
中间体87-1的合成参考中间体64-2，通过使用4-溴-2-三氟甲基苯甲酸代替6-溴烟酸制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸(中间体87-1)。MS:347.2(M+H) +。 Synthesis of Intermediate 87-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro-1 was prepared by using 4-bromo-2-trifluoromethylbenzoic acid in place of 6-bromonicotinic acid -oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoromethyl)benzoic acid (Intermediate 87-1). MS: 347.2 (M+H) + .
制备例87中间体88-1Preparation Example 87 Intermediate 88-1
3-氯-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Chloro-4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000212
Figure PCTCN2021135751-appb-000212
中间体88-1的合成参考中间体69-2，通过使用3-氯-4-溴苯甲酸甲酯代替3-甲基-4-碘苯甲酸甲酯制备得到3-氯-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体88-1)。MS:313.1(M+H) +。 The synthesis of intermediate 88-1 was referred to intermediate 69-2, prepared by using methyl 3-chloro-4-bromobenzoate in place of methyl 3-methyl-4-iodobenzoate to give 3-chloro-4-(( 3aR,7aS)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 88-1). MS: 313.1 (M+H) + .
制备例88中间体89-1Preparation Example 88 Intermediate 89-1
2-氯-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸2-Chloro-4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000213
Figure PCTCN2021135751-appb-000213
中间体89-1的合成参考中间体69-2，通过使用2-氯-4-溴苯甲酸甲酯代替3-甲基-4-碘苯甲酸甲酯制备得到2-氯-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体89-1)。MS:313.1(M+H) +。 Synthesis of Intermediate 89-1 Refers to Intermediate 69-2, prepared by using methyl 2-chloro-4-bromobenzoate in place of methyl 3-methyl-4-iodobenzoate to give 2-chloro-4-(( 3aR,7aS)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 89-1). MS: 313.1 (M+H) + .
制备例89中间体90-1Preparation Example 89 Intermediate 90-1
6-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)烟酸6-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)nicotinic acid
Figure PCTCN2021135751-appb-000214
Figure PCTCN2021135751-appb-000214
中间体90-1的合成参考中间体41-4，通过使用6-(氯甲基)烟酸甲酯代替2-(溴甲基)环丙烷-1-羧酸乙酯(中间体41-1)制备得到6-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)烟酸(中间体90-1)。MS:294.1(M+H) +。 The synthesis of intermediate 90-1 was referenced to intermediate 41-4 by using methyl 6-(chloromethyl)nicotinate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41-1 ) to prepare 6-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)nicotinic acid (intermediate 90- 1). MS: 294.1 (M+H) + .
制备例90中间体91-1Preparation Example 90 Intermediate 91-1
3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯基)-3-甲基丁酸3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl)-3-methylbutanoic acid
Figure PCTCN2021135751-appb-000215
Figure PCTCN2021135751-appb-000215
中间体91-1的合成参考中间体64-2，通过使用3-(3-溴苯基)-3-甲基丁酸代替6-溴烟酸制备得到3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯基)-3-甲基丁酸(中间体91-1)。MS:335.2(M+H) +。 Synthesis of Intermediate 91-1 Referring to Intermediate 64-2, 3-(3-((3aS,7aR was prepared by using 3-(3-bromophenyl)-3-methylbutanoic acid in place of 6-bromonicotinic acid )-7a-Fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl)-3-methylbutanoic acid (Intermediate 91-1). MS: 335.2 (M+H) + .
制备例91中间体92-1Preparation Example 91 Intermediate 92-1
5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸5-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-isopropylbenzoic acid
Figure PCTCN2021135751-appb-000216
Figure PCTCN2021135751-appb-000216
中间体92-1的合成参考中间体64-2，通过使用2-异丙基-5-溴苯甲酸代替6-溴烟酸制备得到5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸(中间体92-1)。MS:321.2(M+H) +。 Synthesis of Intermediate 92-1 Referring to Intermediate 64-2, by using 2-isopropyl-5-bromobenzoic acid in place of 6-bromonicotinic acid, 5-((3aS,7aR)-7a-fluoro-1- Oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-isopropylbenzoic acid (Intermediate 92-1). MS: 321.2 (M+H) + .
制备例92中间体93-1Preparation Example 92 Intermediate 93-1
3-环丙基-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Cyclopropyl-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000217
Figure PCTCN2021135751-appb-000217
中间体93-1的合成参考中间体64-2，通过使用3-环丙基-4-溴苯甲酸代替6-溴烟酸制备得到3-环丙基-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体93-1)。MS:319.2(M+H) +。 Synthesis of Intermediate 93-1 Referring to Intermediate 64-2, by using 3-cyclopropyl-4-bromobenzoic acid in place of 6-bromonicotinic acid, 3-cyclopropyl-4-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 93-1). MS: 319.2 (M+H) + .
制备例93中间体94-1Preparation Example 93 Intermediate 94-1
4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-(三氟甲氧基)苯甲酸4-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-(trifluoromethoxy)benzoic acid
Figure PCTCN2021135751-appb-000218
Figure PCTCN2021135751-appb-000218
中间体94-1的合成参考中间体64-2，通过使用3-三氟甲氧基-4-溴苯甲酸代替6-溴烟酸制备得到4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-(三氟甲氧基)苯甲酸(中间体94-1)。MS:363.2(M+H) +。 Synthesis of Intermediate 94-1 Referring to Intermediate 64-2, 4-((3aS,7aR)-7a-fluoro- 1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-(trifluoromethoxy)benzoic acid (Intermediate 94-1). MS: 363.2 (M+H) + .
制备例94中间体95-1Preparation Example 94 Intermediate 95-1
2-环丙基-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸2-Cyclopropyl-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000219
Figure PCTCN2021135751-appb-000219
中间体95-1的合成参考中间体64-2，通过使用2-环丙基-5-溴苯甲酸代替6-溴烟酸制备得到2-环丙基-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体95-1)。MS:319.2(M+H) +。 Synthesis of Intermediate 95-1 Referring to Intermediate 64-2, 2-cyclopropyl-5-((3aS,7aR)- 7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 95-1). MS: 319.2 (M+H) + .
制备例95中间体96-1Preparation Example 95 Intermediate 96-1
3-(5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯基)-2,2-二甲基丙酸3-(5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylphenyl)-2, 2-Dimethylpropionic acid
Figure PCTCN2021135751-appb-000220
Figure PCTCN2021135751-appb-000220
中间体96-1的合成参考中间体64-2，通过使用3-(5-碘-2-甲基苯基)-2,2-二甲基丙酸代替6-溴烟酸制备得到3-(5-((3As,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯基)- 2,2-二甲基丙酸(中间体96-1)。MS:349.2(M+H) +。 The synthesis of intermediate 96-1 was referred to intermediate 64-2, which was prepared by using 3-(5-iodo-2-methylphenyl)-2,2-dimethylpropionic acid in place of 6-bromonicotinic acid to give 3- (5-((3As,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methylphenyl)-2,2- Dimethylpropionic acid (Intermediate 96-1). MS: 349.2 (M+H) + .
制备例96中间体97-1Preparation Example 96 Intermediate 97-1
1-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丙烷-1-羧酸1-(((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)methyl)cyclopropane-1-carboxylic acid
Figure PCTCN2021135751-appb-000221
Figure PCTCN2021135751-appb-000221
中间体97-1的合成参考中间体42-3，通过使用1-(溴甲基)环丙烷-1-羧酸代替中间体42-制备得到1-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丙烷-1-羧酸(中间体97-1)。MS:257.2(M+H) +。 Synthesis of intermediate 97-1 Referring to intermediate 42-3, 1-(((3aS,7aR)-7a-fluoro was prepared by using 1-(bromomethyl)cyclopropane-1-carboxylic acid in place of intermediate 42- -1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)methyl)cyclopropane-1-carboxylic acid (Intermediate 97-1). MS: 257.2 (M+H) + .
制备例97中间体98-1Preparation Example 97 Intermediate 98-1
4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-2-甲基苯甲酸4-(((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000222
Figure PCTCN2021135751-appb-000222
中间体98-1的合成参考中间体41-4，通过使用4-(氯甲基)-2-甲基苯甲酸甲酯代替2-(溴甲基)环丙烷-1-羧酸乙酯(中间体41-1)制备得到4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-2-甲基苯甲酸(中间体98-1)。MS:307.1(M+H) +。 Intermediate 98-1 was synthesized with reference to Intermediate 41-4 by using methyl 4-(chloromethyl)-2-methylbenzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate ( Intermediate 41-1) was prepared to give 4-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)-2 -Toluic acid (Intermediate 98-1). MS: 307.1 (M+H) + .
制备例98中间体99-1Preparation Example 98 Intermediate 99-1
4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-3-甲基苯甲酸4-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)-3-methylbenzoic acid
Figure PCTCN2021135751-appb-000223
Figure PCTCN2021135751-appb-000223
中间体99-1的合成参考中间体41-4，通过使用4-(氯甲基)-3-甲基苯甲酸甲酯代替2-(溴甲基)环丙烷-1-羧酸乙酯(中间体41-1)制备得到4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-3-甲基苯甲酸(中间体99-1)。MS:307.1(M+H) +。 Intermediate 99-1 was synthesized with reference to Intermediate 41-4 by using methyl 4-(chloromethyl)-3-methylbenzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate ( Intermediate 41-1) was prepared to give 4-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)-3 -Toluic acid (Intermediate 99-1). MS: 307.1 (M+H) + .
制备例99中间体100-1Preparation Example 99 Intermediate 100-1
4-(1-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)乙基)苯甲酸4-(1-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)ethyl)benzoic acid
Figure PCTCN2021135751-appb-000224
Figure PCTCN2021135751-appb-000224
中间体100-1的合成参考中间体41-4，通过使用4-(1-氯乙基)苯甲酸甲酯代替2-(溴甲基)环丙烷-1-羧酸乙酯(中间体41-1)制备得到4-(1-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)乙基)苯甲酸(中间体100-1)。MS:307.1(M+H) +。 The synthesis of intermediate 100-1 was referenced to intermediate 41-4 by using methyl 4-(1-chloroethyl)benzoate in place of ethyl 2-(bromomethyl)cyclopropane-1-carboxylate (intermediate 41 -1) Preparation of 4-(1-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)ethyl)benzoic acid ( Intermediate 100-1). MS: 307.1 (M+H) + .
制备例100中间体101-1Preparation Example 100 Intermediate 101-1
1-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸1-(((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclobutane-1-carboxylic acid
Figure PCTCN2021135751-appb-000225
Figure PCTCN2021135751-appb-000225
中间体101-1的合成参考中间体42-3，通过使用1-(溴甲基)环丁烷-1-羧酸甲酯代替3-羟基-2,2-二甲基丙酸乙酯制备得到1-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸(中间体101-1)。MS:271.1(M+H) +。 Synthesis of Intermediate 101-1 Reference to Intermediate 42-3, prepared by using methyl 1-(bromomethyl)cyclobutane-1-carboxylate in place of ethyl 3-hydroxy-2,2-dimethylpropionate 1-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclobutane-1-carboxylic acid ( Intermediate 101-1). MS: 271.1 (M+H) + .
制备例101中间体102-1Preparation Example 101 Intermediate 102-1
1-(((3As,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环戊烷-1-羧酸1-(((3As,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclopentane-1-carboxylic acid
Figure PCTCN2021135751-appb-000226
Figure PCTCN2021135751-appb-000226
中间体102-1的合成参考中间体42-3，通过使用1-(溴甲基)环戊烷-1-羧酸甲酯代替3-羟基-2,2-二甲基丙酸乙酯制备得到1-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环戊烷-1-羧酸(中间体102-1)。MS:285.1(M+H) +。 Synthesis of Intermediate 102-1 Reference to Intermediate 42-3, prepared by using methyl 1-(bromomethyl)cyclopentane-1-carboxylate in place of ethyl 3-hydroxy-2,2-dimethylpropionate 1-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclopentane-1-carboxylic acid ( Intermediate 102-1). MS: 285.1 (M+H) + .
制备例102中间体103-1Preparation Example 102 Intermediate 103-1
2-甲基-4-((3aS,7aS)-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸2-Methyl-4-((3aS,7aS)-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000227
Figure PCTCN2021135751-appb-000227
中间体103-1的合成参考中间体6-3，通过使用中间体7-1a代替1-氧代-1,2,3,4,6,7-六氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体5-1)和4-碘-2-甲基苯甲酸甲酯代替4-碘苯甲酸甲酯制备得到中间体103-1。MS:275.2(M+H) +。 Intermediate 103-1 was synthesized with reference to Intermediate 6-3 by using Intermediate 7-1a in place of 1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,4 -c] tert-butyl pyridine-5-carboxylate (intermediate 5-1) and methyl 4-iodo-2-methylbenzoate instead of methyl 4-iodobenzoate were prepared to give intermediate 103-1. MS: 275.2 (M+H) + .
制备例103中间体104-1Preparation Example 103 Intermediate 104-1
6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)-4-甲基烟酸6-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-4-methylnicotinic acid
Figure PCTCN2021135751-appb-000228
Figure PCTCN2021135751-appb-000228
中间体104-1的合成参考中间体49-2，通过使用6-碘-4-甲基烟酸甲酯代替3-碘苯甲酸甲酯制备得到制备得到中间体104-1。MS:294.2(M+H) +。 The synthesis of intermediate 104-1 refers to intermediate 49-2, which was prepared by using methyl 6-iodo-4-methylnicotinate instead of methyl 3-iodobenzoate to obtain intermediate 104-1. MS: 294.2 (M+H) + .
制备例104中间体105-1Preparation Example 104 Intermediate 105-1
6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)-5-甲基烟酸6-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-5-methylnicotinic acid
Figure PCTCN2021135751-appb-000229
Figure PCTCN2021135751-appb-000229
中间体105-1的合成参考中间体49-2，通过使用6-碘-5-甲基烟酸甲酯代替3-碘苯甲酸甲酯制备得到制备得到中间体105-1。MS:294.2(M+H) +。 The synthesis of intermediate 105-1 refers to intermediate 49-2, which was prepared by using methyl 6-iodo-5-methylnicotinate instead of methyl 3-iodobenzoate to obtain intermediate 105-1. MS: 294.2 (M+H) + .
制备例105中间体106-1Preparation Example 105 Intermediate 106-1
6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)-2-甲基烟酸6-((3aS,7aR)-7a-Fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-methylnicotinic acid
Figure PCTCN2021135751-appb-000230
Figure PCTCN2021135751-appb-000230
中间体106-1的合成参考中间体49-2，通过使用6-碘-2-甲基烟酸甲酯代替3-碘苯甲酸甲酯制备得到制备得到中间体106-1。MS:294.2(M+H) +。 The synthesis of intermediate 106-1 refers to intermediate 49-2, which was prepared by using methyl 6-iodo-2-methylnicotinate instead of methyl 3-iodobenzoate to obtain intermediate 106-1. MS: 294.2 (M+H) + .
制备例106中间体107-1Preparation Example 106 Intermediate 107-1
2-氟-4-((3As,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸2-Fluoro-4-((3As,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000231
Figure PCTCN2021135751-appb-000231
中间体107-1的合成参考中间体49-2，通过使用4-碘-2-氟苯甲酸甲酯代替3-碘苯甲酸甲酯制备得到制备得到中间体107-1。MS:297.2(M+H) +。 Synthesis of intermediate 107-1 Referring to intermediate 49-2, intermediate 107-1 was prepared by using methyl 4-iodo-2-fluorobenzoate instead of methyl 3-iodobenzoate. MS: 297.2 (M+H) + .
制备例107中间体108-1Preparation Example 107 Intermediate 108-1
5-((3aS,7aR)-7a-氟-1-氧辛烷氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基吡啶酸5-((3aS,7aR)-7a-Fluoro-1-oxooctanehydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-picoline acid
Figure PCTCN2021135751-appb-000232
Figure PCTCN2021135751-appb-000232
中间体108-1的合成参考中间体49-2，通过使用5-碘-3-甲基吡啶甲酸甲酯代替3-碘苯甲酸甲酯 制备得到制备得到中间体108-1。MS:294.2(M+H) +。 Synthesis of intermediate 108-1 Referring to intermediate 49-2, intermediate 108-1 was prepared by using methyl 5-iodo-3-methylpicolinate instead of methyl 3-iodobenzoate. MS: 294.2 (M+H) + .
实施例1Example 1
化合物1:Compound 1:
(4S)-4-(3-氟-2-甲基苯基)-6-((3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑并[3,4-c]吡啶-6-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(4S)-4-(3-Fluoro-2-methylphenyl)-6-((3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000233
Figure PCTCN2021135751-appb-000233
将4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4,139毫克,1.0毫摩尔)溶于二氯甲烷(6毫升)和乙腈(2毫升)中，在20℃时搅拌加入2,2,6,6-四甲基哌啶(169毫克,1.2毫摩尔)和(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物A1,482毫克,1.1毫摩尔)的二氯甲烷(6毫升)溶液。滴完后，将反应混合物在20℃搅拌12小时，然后加入1N的盐酸溶液，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到黄色固体(4S)-4-(3-氟-2-甲基苯基)-6-((3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑并[3,4-c]吡啶-6-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物1,54毫克,11％收率)。MS:497.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.1Hz,1H),7.86(d,J＝3.1Hz,1H),7.29(d,J＝7.7Hz,1H),7.24–7.18(m,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.77(d,J＝16.2Hz,1H),4.67(d,J＝16.2Hz,1H),4.54(br,2H),4.08(q,J＝7.2Hz,2H),3.75-3.65(m,2H),2.97-2.92(m,2H),2.46(s,3H),1.11(t,J＝7.2Hz,3H)。 4,5,6,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4, 139 mg, 1.0 mmol) was dissolved in dichloro Methane (6 mL) and acetonitrile (2 mL) were added with stirring at 20°C 2,2,6,6-tetramethylpiperidine (169 mg, 1.2 mmol) and (S)-6-(bromomethyl) yl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester (Compound A1, 482 mg, 1.1 mmol) in dichloromethane (6 mL). After completion of dropping, the reaction mixture was stirred at 20°C for 12 hours, and then a 1N hydrochloric acid solution was added, followed by extraction with dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a yellow solid (4S)-4-(3-fluoro-2-methylphenyl) )-6-((3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)-2- (Thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (compound 1,54 mg, 11% yield). MS: 497.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.1Hz,1H),7.86(d,J=3.1Hz,1H),7.29(d,J=7.7Hz,1H),7.24 –7.18(m,1H),7.00(t,J=8.9Hz,1H),6.00(s,1H),4.77(d,J=16.2Hz,1H),4.67(d,J=16.2Hz,1H) ,4.54(br,2H),4.08(q,J=7.2Hz,2H),3.75-3.65(m,2H),2.97-2.92(m,2H),2.46(s,3H),1.11(t,J =7.2Hz, 3H).
实施例2Example 2
化合物2:Compound 2:
(4S)-4-(3-氟-2-甲基苯基)-6-((2-甲基-3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑并[3,4-c]吡啶-6-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(4S)-4-(3-Fluoro-2-methylphenyl)-6-((2-methyl-3-oxo-2,3,3a,4,5,7-hexahydro-6H- Pyrazolo[3,4-c]pyridin-6-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000234
Figure PCTCN2021135751-appb-000234
化合物2的合成参考化合物1，通过使用(2-甲基-2,3a,4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐(中间体2-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到化合物2。Synthesis of compound 2 Reference compound 1 by using (2-methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolin[3,4-c]pyridin-3-one trifluoro Acetate (Intermediate 2-2) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 2.
化合物2(58.0毫克)。MS:510.7(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.1Hz,1H),7.86(d,J＝3.1Hz,1H),7.29(dd,J＝7.8,1.2Hz,1H),7.23-7.18(m,1H),7.02-6.98(m,1H),5.99(s,1H),4.78(d,J＝16.0,1H),4.66(d,J＝16.0,1H),4.47(br,2H),4.07(q,J＝7.1Hz,2H),3.72(br,2H),3.60(s,3H),2.95-2.91(m,2H),2.46(d,J＝2.0Hz,3H),1.10(t,J＝7.1Hz,3H)。 Compound 2 (58.0 mg). MS: 510.7 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.1Hz,1H),7.86(d,J=3.1Hz,1H),7.29(dd,J=7.8,1.2Hz,1H) ,7.23-7.18(m,1H),7.02-6.98(m,1H),5.99(s,1H),4.78(d,J=16.0,1H),4.66(d,J=16.0,1H),4.47( br, 2H), 4.07(q, J=7.1Hz, 2H), 3.72(br, 2H), 3.60(s, 3H), 2.95-2.91(m, 2H), 2.46(d, J=2.0Hz, 3H) ), 1.10 (t, J=7.1 Hz, 3H).
实施例3Example 3
化合物3:Compound 3:
(4S)-4-(3-氟-2-甲基苯基)-6-((3a-甲基-3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑并[3,4-c]吡啶-6-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(4S)-4-(3-Fluoro-2-methylphenyl)-6-((3a-methyl-3-oxo-2,3,3a,4,5,7-hexahydro-6H- Pyrazolo[3,4-c]pyridin-6-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000235
Figure PCTCN2021135751-appb-000235
化合物3的合成参考化合物1，通过使用3a-甲基-2,3a，4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐(中间体3-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到化合物3。Synthesis of compound 3 Reference compound 1 by using 3a-methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolin[3,4-c]pyridin-3-one trifluoroethyl acid salt (Intermediate 3-3) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 3 was prepared.
化合物3(91.0毫克)。MS:511.2(M+H) +。 1H NMR(400MHz,Chloroform-d)δ9.25(br,1H),8.63(br,1H),7.78(d,J＝3.1Hz,1H),7.39(d,J＝3.1Hz,1H),7.13–7.02(m,1H),7.01-6.96(m,1H),6.92–6.88(m,1H),6.01(s,1H),4.29(d,J＝17.0Hz,1H),4.15–4.0(m,3H),3.94(d,17.0Hz,1H),3.65–3.48(m,1H),3.37-3.30(m,1H),2.92–2.80(m,2H),2.75-2.65(m,1H),2.53(s,3H),2.00–1.85(m,2H),1.38(s,3H),1.11(t,J＝7.1Hz,3H)。 Compound 3 (91.0 mg). MS: 511.2 (M+H) + . 1 H NMR (400MHz, Chloroform-d)δ9.25(br,1H),8.63(br,1H),7.78(d,J=3.1Hz,1H),7.39(d,J=3.1Hz,1H), 7.13–7.02 (m, 1H), 7.01–6.96 (m, 1H), 6.92–6.88 (m, 1H), 6.01 (s, 1H), 4.29 (d, J=17.0Hz, 1H), 4.15–4.0 ( m,3H),3.94(d,17.0Hz,1H),3.65-3.48(m,1H),3.37-3.30(m,1H),2.92-2.80(m,2H),2.75-2.65(m,1H) , 2.53 (s, 3H), 2.00–1.85 (m, 2H), 1.38 (s, 3H), 1.11 (t, J=7.1 Hz, 3H).
实施例4Example 4
化合物4:Compound 4:
(4S)-4-(3-氟-2-甲基苯基)-6-(((3a-氟-3-氧代-2,3,3a,4,5,7-六氢-6H-吡唑并[3,4-c]吡啶-6-基) 甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(4S)-4-(3-Fluoro-2-methylphenyl)-6-((((3a-fluoro-3-oxo-2,3,3a,4,5,7-hexahydro-6H- Pyrazolo[3,4-c]pyridin-6-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000236
Figure PCTCN2021135751-appb-000236
化合物4的合成参考化合物1，通过使用3a-氟-2,3a，4,5,6,7-六氢-3H-吡唑啉[3,4-c]吡啶-3-酮三氟乙酸盐(中间体4-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物4。Synthesis of compound 4 Reference compound 1 by using 3a-fluoro-2,3a,4,5,6,7-hexahydro-3H-pyrazolin[3,4-c]pyridin-3-one trifluoroacetic acid Salt (Intermediate 4-3) was prepared in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 4 was obtained as a yellow solid.
化合物4(48.0毫克)。MS:515.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98(d,J＝2.9Hz,1H),7.86(d,J＝2.9Hz,1H),7.25–7.15(m,2H),6.99(dd,J＝7.9Hz,7.9Hz,1H),6.01(s,1H),4.61(d,J＝16.2,1H),4.44(d,J＝16.2Hz,1H),4.26(d,J＝13.3Hz,1H),4.17–4.03(m,3H),3.69–3.33(m,2H),2.63-2.52(m,1H),2.47(s,3H),2.31–2.17(m,1H),1.12(t,J＝7.1Hz,3H)。 Compound 4 (48.0 mg). MS: 515.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98(d,J=2.9Hz,1H),7.86(d,J=2.9Hz,1H),7.25-7.15(m,2H),6.99(dd, J=7.9Hz, 7.9Hz, 1H), 6.01(s, 1H), 4.61(d, J=16.2, 1H), 4.44(d, J=16.2Hz, 1H), 4.26(d, J=13.3Hz, 1H), 4.17–4.03 (m, 3H), 3.69–3.33 (m, 2H), 2.63–2.52 (m, 1H), 2.47 (s, 3H), 2.31–2.17 (m, 1H), 1.12 (t, J=7.1Hz, 3H).
实施例5Example 5
化合物5:Compound 5:
(S)-4-(3-氟-2-甲基苯基)-6-((1-氧代-1,2,3,4,6,7-六氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((1-oxo-1,2,3,4,6,7-hexahydro-5H-pyrrole[3,4 -c]pyridin-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000237
Figure PCTCN2021135751-appb-000237
化合物5的合成参考化合物1，通过使用2,3,4,5,6,7-六氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体5-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物5。Synthesis of compound 5 Reference compound 1, by using 2,3,4,5,6,7-hexahydro-1H-pyrro[3,4-c]pyridin-1-one trifluoroacetate (intermediate 5- 2) Substitute 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) to prepare compound 5 as a yellow solid.
化合物5(22.0毫克)。MS:496.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.1Hz,1H),7.87(d,J＝3.0Hz,1H),7.29(d,J＝7.9Hz,1H),7.20(d,J＝6.8Hz,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.79(d,J＝16.1Hz,1H),4.66(d,J＝16.0Hz,1H),4.38(s,2H),4.17–4.01(m,4H),3.70(d,J＝23.6Hz,2H),2.75(s,2H),2.45(s,3H),1.11(t,J＝7.2Hz,3H)。 Compound 5 (22.0 mg). MS: 496.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.1Hz,1H),7.87(d,J=3.0Hz,1H),7.29(d,J=7.9Hz,1H),7.20 (d, J=6.8Hz, 1H), 7.00 (t, J=8.9Hz, 1H), 6.00 (s, 1H), 4.79 (d, J=16.1Hz, 1H), 4.66 (d, J=16.0Hz) ,1H),4.38(s,2H),4.17–4.01(m,4H),3.70(d,J=23.6Hz,2H),2.75(s,2H),2.45(s,3H),1.11(t, J=7.2Hz, 3H).
实施例6Example 6
化合物6:Compound 6:
(S)-4-(5-((5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代-1,3,4,5,6,7-六氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(S)-4-(5-((5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-3,6-dihydro Pyrimidin-4-yl)methyl)-1-oxo-1,3,4,5,6,7-hexahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000238
Figure PCTCN2021135751-appb-000238
化合物6的合成参考化合物1，通过使用4-(1-氧代-1,3,4,5,6,7-六氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐(中间体6-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物6。Synthesis of compound 6 Reference compound 1 by using 4-(1-oxo-1,3,4,5,6,7-hexahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene Formic acid trifluoroacetate (intermediate 6-3) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) Preparation of compound 6 as a yellow solid.
化合物6(3.6毫克)。MS:616.6(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.1Hz,1H),7.87(d,J＝3.0Hz,1H),7.29(d,J＝7.9Hz,1H),7.20(d,J＝6.8Hz,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.79(d,J＝16.1Hz,1H),4.66(d,J＝16.0Hz,1H),4.38(s,2H),4.17–4.01(m,4H),3.70(d,J＝23.6Hz,2H),2.75(s,2H),2.45(s,3H),1.11(t,J＝7.2Hz,3H)。 Compound 6 (3.6 mg). MS: 616.6 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.1Hz,1H),7.87(d,J=3.0Hz,1H),7.29(d,J=7.9Hz,1H),7.20 (d, J=6.8Hz, 1H), 7.00 (t, J=8.9Hz, 1H), 6.00 (s, 1H), 4.79 (d, J=16.1Hz, 1H), 4.66 (d, J=16.0Hz) ,1H),4.38(s,2H),4.17–4.01(m,4H),3.70(d,J=23.6Hz,2H),2.75(s,2H),2.45(s,3H),1.11(t, J=7.2Hz, 3H).
实施例7Example 7
化合物7:Compound 7:
(S)-4-(3-氟-2-甲基苯基)-6-(((3aR,7aS)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-(((3aR,7aS)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5- yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000239
Figure PCTCN2021135751-appb-000239
化合物7的合成参考化合物1，通过使用(3aS，7aS)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体7-2a)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物7。Synthesis of compound 7 Reference compound 1 by using (3aS,7aS)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (intermediate 7-2a) in place of 4,5 ,6,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 7 as a yellow solid.
化合物7(48毫克)。MS:498.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝8.3Hz,1H),7.92–7.83(m,1H),7.57–7.46(m,1H),7.27(d,J＝7.8Hz,1H),7.19(d,J＝7.0Hz,1H),6.99(t,J＝8.9Hz,1H),5.97(d,J＝4.1Hz,1H),4.77–4.62(m,1H),4.61–4.45(m,1H),4.25–4.13(m,1H),4.06(q,J＝7.1Hz,2H),3.91–3.58(m,3H),3.27–3.12(m,4H),2.45(s,4H),1.10(t,J＝7.1Hz,3H)。 Compound 7 (48 mg). MS: 498.2 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.97(d,J=8.3Hz,1H),7.92-7.83(m,1H),7.57-7.46(m,1H),7.27(d,J=7.8 Hz, 1H), 7.19(d, J＝7.0Hz, 1H), 6.99(t, J＝8.9Hz, 1H), 5.97(d, J＝4.1Hz, 1H), 4.77–4.62(m, 1H), 4.61–4.45 (m, 1H), 4.25–4.13 (m, 1H), 4.06 (q, J=7.1Hz, 2H), 3.91–3.58 (m, 3H), 3.27–3.12 (m, 4H), 2.45 ( s, 4H), 1.10 (t, J=7.1 Hz, 3H).
实施例8Example 8
化合物8:Compound 8:
(S)-4-(3-氟-2-甲基苯基)-6-(((3aS,7aR)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-(((3aS,7aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5- yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000240
Figure PCTCN2021135751-appb-000240
化合物8的合成参考化合物1，通过使用(3aR，7aR)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体7-2b)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物8。Synthesis of compound 8 Reference compound 1 by using (3aR,7aR)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (intermediate 7-2b) in place of 4,5 ,6,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 8 as a yellow solid.
化合物8(42毫克)。MS:498.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98(dd,J＝3.1,1.2Hz,1H),7.87(dd,J＝5.9,3.1Hz,1H),7.85–7.80(m,1H),7.30–7.25(m,1H),7.23–7.15(m,1H),7.03–6.95(m,1H),5.97(d,J＝3.3Hz,1H),4.68(t,J＝16.4Hz,1H),4.60–4.43(m,1H),4.17(dt,J＝10.2,5.0Hz,1H),4.06(q,J＝7.1Hz,2H),3.89–3.61(m,3H),3.27–3.04(m,4H),2.51(s,1H),2.45(d,J＝1.9Hz,3H),1.09(t,J＝7.1Hz,3H)。 Compound 8 (42 mg). MS: 498.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98(dd,J=3.1,1.2Hz,1H),7.87(dd,J=5.9,3.1Hz,1H),7.85-7.80(m,1H), 7.30–7.25 (m, 1H), 7.23–7.15 (m, 1H), 7.03–6.95 (m, 1H), 5.97 (d, J=3.3Hz, 1H), 4.68 (t, J=16.4Hz, 1H) ,4.60–4.43(m,1H),4.17(dt,J=10.2,5.0Hz,1H),4.06(q,J=7.1Hz,2H),3.89–3.61(m,3H),3.27–3.04(m , 4H), 2.51 (s, 1H), 2.45 (d, J=1.9Hz, 3H), 1.09 (t, J=7.1Hz, 3H).
实施例9Example 9
化合物9：Compound 9:
3-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸和3-((3aR,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid and 3-((3aR,7aR )-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-3,6-dihydro Pyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000241
Figure PCTCN2021135751-appb-000241
化合物9的合成参考化合物1，通过使用顺式-3-(1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐(中间体9-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物9。Synthesis of Compound 9 Reference compound 1, by using cis-3-(1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid trifluoroacetate (Intermediate 9 -3) Substitute 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) to prepare yellow solid compound 9 .
化合物9(36毫克)。MS:618.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.31(s,1H),7.97(d,J＝8.3Hz,2H),7.92–7.83(m,2H),7.57–7.46(m,1H),7.27(d,J＝7.8Hz,1H),7.19(d,J＝7.0Hz,1H), 6.99(t,J＝8.9Hz,1H),5.97(d,J＝4.1Hz,1H),4.77–4.62(m,1H),4.61–4.45(m,1H),4.25–4.13(m,1H),4.06(q,J＝7.1Hz,2H),3.91–3.58(m,3H),3.27–3.12(m,4H),2.45(s,5H),1.10(t,J＝7.1Hz,3H)。 Compound 9 (36 mg). MS: 618.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.31(s,1H),7.97(d,J=8.3Hz,2H),7.92-7.83(m,2H),7.57-7.46(m,1H), 7.27(d,J＝7.8Hz,1H),7.19(d,J＝7.0Hz,1H), 6.99(t,J＝8.9Hz,1H),5.97(d,J＝4.1Hz,1H),4.77– 4.62 (m, 1H), 4.61–4.45 (m, 1H), 4.25–4.13 (m, 1H), 4.06 (q, J=7.1Hz, 2H), 3.91–3.58 (m, 3H), 3.27–3.12 ( m, 4H), 2.45 (s, 5H), 1.10 (t, J=7.1 Hz, 3H).
实施例10Example 10
化合物10:Compound 10:
2-(4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸和2-(4-((3aR,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸2-(4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)-2-methyl propionic acid and 2-(4-((3aR,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl) -2-Methylpropionic acid
Figure PCTCN2021135751-appb-000242
Figure PCTCN2021135751-appb-000242
化合物10的合成参考化合物1，通过使用顺式-2-甲基-2-(4-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙酸三氟乙酸盐(中间体10-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物10。Synthesis of compound 10 Reference compound 1 by using cis-2-methyl-2-(4-((3aS,7aS)-1-oxooctahydro-2H-pyrro[3,4-c]pyridine-2 -yl)phenyl)propionic acid trifluoroacetate (Intermediate 10-3) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol tri Fluoroacetate (Intermediate 1-4) was prepared to give compound 10 as a yellow solid.
化合物10(48毫克)。MS:660.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(t,J＝2.8Hz,1H),7.89–7.82(m,1H),7.61(dd,J＝8.8,3.1Hz,2H),7.47–7.38(m,2H),7.31–7.24(m,1H),7.19(td,J＝6.8,5.5,3.6Hz,1H),6.99(t,J＝8.9Hz,1H),5.98(d,J＝3.5Hz,1H),4.69(dd,J＝16.2,8.4Hz,1H),4.51(dd,J＝16.2,12.2Hz,1H),4.19–4.11(m,1H),4.06(q,J＝7.1Hz,2H),3.80(d,J＝10.5Hz,1H),3.77–3.63(m,1H),3.56(t,J＝9.8Hz,1H),3.15(s,4H),2.49(s,1H),2.46–2.42(m,3H),2.41–2.28(m,1H),1.55(d,J＝1.5Hz,6H),1.10(t,J＝7.1Hz,3H)。 Compound 10 (48 mg). MS: 660.2 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.97(t,J=2.8Hz,1H),7.89-7.82(m,1H),7.61(dd,J=8.8,3.1Hz,2H),7.47- 7.38(m,2H),7.31–7.24(m,1H),7.19(td,J=6.8,5.5,3.6Hz,1H),6.99(t,J=8.9Hz,1H),5.98(d,J= 3.5Hz, 1H), 4.69 (dd, J=16.2, 8.4Hz, 1H), 4.51 (dd, J=16.2, 12.2Hz, 1H), 4.19–4.11 (m, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.80(d, J=10.5Hz, 1H), 3.77–3.63(m, 1H), 3.56(t, J=9.8Hz, 1H), 3.15(s, 4H), 2.49(s, 1H) ), 2.46–2.42 (m, 3H), 2.41–2.28 (m, 1H), 1.55 (d, J=1.5Hz, 6H), 1.10 (t, J=7.1Hz, 3H).
实施例11Example 11
化合物11:Compound 11:
4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000243
Figure PCTCN2021135751-appb-000243
化合物11的合成参考化合物10，通过使用(3aR，7aS)-1-氧代八氢-5H-吡咯并[3，4-c]吡啶-5-羧酸叔丁酯(中间体7-1a)代替顺式-1-氧代八氢-5H-吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(中间体7-1)和4-碘苯甲酸甲酯代替2-(4-溴苯基)-2-甲基丙酸甲酯制备得到黄色固体化合物11。Synthesis of compound 11 Reference compound 10 by using (3aR,7aS)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 7-1a) In place of cis-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 7-1) and methyl 4-iodobenzoate in place of 2-( 4-Bromophenyl)-2-methylpropionic acid methyl ester was prepared to give compound 11 as a yellow solid.
化合物11(39.2毫克)。MS:618.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.05(d,J＝8.5Hz,2H),7.86(d,J＝3.1Hz,1H),7.82(d,J＝8.7Hz,2H),7.27(d,J＝7.9Hz,1H),7.24–7.15(m,1H),6.99(t,J＝8.9Hz,1H),5.97(s,1H),4.65(d,J＝16.2Hz,1H),4.53(d,J＝16.2Hz,1H),4.17(dd,J＝10.6,4.9Hz,1H),4.06(q,J＝7.1Hz,2H),3.89–3.69(m,2H),3.64(d,J＝10.6Hz,1H),3.16(d,J＝26.0Hz,4H),2.54(d,J＝15.4Hz,1H),2.44(d,J＝2.0Hz,3H),2.39(d,J＝13.3Hz,1H),1.09(t,J＝7.1Hz,3H)。 Compound 11 (39.2 mg). MS: 618.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.05(d,J=8.5Hz,2H),7.86(d,J=3.1Hz,1H),7.82(d,J=8.7Hz,2H),7.27 (d, J=7.9Hz, 1H), 7.24–7.15 (m, 1H), 6.99 (t, J=8.9Hz, 1H), 5.97 (s, 1H), 4.65 (d, J=16.2Hz, 1H) ,4.53(d,J＝16.2Hz,1H),4.17(dd,J＝10.6,4.9Hz,1H),4.06(q,J＝7.1Hz,2H),3.89–3.69(m,2H),3.64( d, J＝10.6Hz, 1H), 3.16(d, J＝26.0Hz, 4H), 2.54(d, J＝15.4Hz, 1H), 2.44(d, J＝2.0Hz, 3H), 2.39(d, J=13.3 Hz, 1H), 1.09 (t, J=7.1 Hz, 3H).
实施例12Example 12
化合物12:Compound 12:
4-((3aR,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aR,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000244
Figure PCTCN2021135751-appb-000244
化合物12的合成参考化合物11，通过使用(3aS，7aR)-1-氧代八氢-5H-吡咯并[3，4-c]吡啶-5-羧酸叔丁酯(中间体7-1b)代替(3aR，7aS)-1-氧代八氢-5H-吡咯并[3，4-c]吡啶-5-羧酸叔丁酯(中间体7-1a)制备得到黄色固体化合物12。Synthesis of compound 12 Reference compound 11 by using (3aS,7aR)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 7-1b) Substitute for (3aR,7aS)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1a), compound 12 was prepared as a yellow solid.
化合物12(43毫克)。MS:618.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.11–8.03(m,2H),7.98(d,J＝3.1Hz,1H),7.90–7.87(m,1H),7.87–7.80(m,2H),7.27(d,J＝7.8Hz,1H),7.25–7.13(m,1H),6.99(t,J＝8.9Hz,1H),5.98(s,1H),4.75–4.65(m,1H),4.53–4.43(m,1H),4.22–4.13(m,1H),4.06(q,J＝7.1Hz,2H),3.89–3.79(m,1H),3.72–3.63(m,2H),3.27–3.03(m,4H),2.58–2.48(m,1H),2.45(s,3H),2.40–2.27(m,1H),1.09(t,J＝7.1Hz,3H)。 Compound 12 (43 mg). MS: 618.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.11-8.03(m,2H),7.98(d,J=3.1Hz,1H),7.90-7.87(m,1H),7.87-7.80(m,2H) ),7.27(d,J=7.8Hz,1H),7.25-7.13(m,1H),6.99(t,J=8.9Hz,1H),5.98(s,1H),4.75-4.65(m,1H) , 4.53–4.43 (m, 1H), 4.22–4.13 (m, 1H), 4.06 (q, J=7.1Hz, 2H), 3.89–3.79 (m, 1H), 3.72–3.63 (m, 2H), 3.27 -3.03 (m, 4H), 2.58 - 2.48 (m, 1H), 2.45 (s, 3H), 2.40 - 2.27 (m, 1H), 1.09 (t, J = 7.1 Hz, 3H).
实施例13Example 13
化合物13:Compound 13:
4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-氟苯甲酸4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-fluorobenzoic acid
Figure PCTCN2021135751-appb-000245
Figure PCTCN2021135751-appb-000245
化合物13的合成参考化合物11，通过使用4-溴-3-氟苯甲酸甲酯代替4-碘苯甲酸甲酯制备得到黄色固体化合物13。Synthesis of compound 13 Referring to compound 11, compound 13 was prepared as a yellow solid by using methyl 4-bromo-3-fluorobenzoate instead of methyl 4-iodobenzoate.
化合物13(71毫克)。MS:636.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.1Hz,1H),7.92–7.80(m,3H),7.68(t,J＝7.9Hz,1H),7.27(d,J＝7.8Hz,1H),7.19(q,J＝7.6Hz,1H),6.99(t,J＝8.9Hz,1H),5.98(s,1H),4.69(d,J＝15.8Hz,1H),4.57(d,J＝16.1Hz,1H),4.18(dd,J＝10.4,4.2Hz,1H),4.08(q,J＝7.1Hz,2H),3.80(dd,J＝42.5,10.6Hz,2H),3.53(d,J＝10.7Hz,1H),3.16(dd,J＝24.0,11.6Hz,4H),2.59–2.33(m,5H),1.11(t,J＝7.1Hz,3H)。 Compound 13 (71 mg). MS: 636.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.1Hz,1H),7.92-7.80(m,3H),7.68(t,J=7.9Hz,1H),7.27(d, J=7.8Hz, 1H), 7.19(q, J=7.6Hz, 1H), 6.99(t, J=8.9Hz, 1H), 5.98(s, 1H), 4.69(d, J=15.8Hz, 1H) ,4.57(d,J＝16.1Hz,1H),4.18(dd,J＝10.4,4.2Hz,1H),4.08(q,J＝7.1Hz,2H),3.80(dd,J＝42.5,10.6Hz, 2H), 3.53 (d, J=10.7Hz, 1H), 3.16 (dd, J=24.0, 11.6Hz, 4H), 2.59–2.33 (m, 5H), 1.11 (t, J=7.1Hz, 3H).
实施例14Example 14
化合物14:Compound 14:
4-((3aR,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-氟苯甲酸4-((3aR,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-fluorobenzoic acid
Figure PCTCN2021135751-appb-000246
Figure PCTCN2021135751-appb-000246
化合物14的合成参考化合物12，通过使用4-溴-3-氟苯甲酸甲酯代替4-碘苯甲酸甲酯制备得到黄色固体化合物14。Synthesis of compound 14 Referring to compound 12, compound 14 was prepared as a yellow solid by using methyl 4-bromo-3-fluorobenzoate instead of methyl 4-iodobenzoate.
化合物14(54毫克)。MS:636.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98(d,J＝3.1Hz,1H),7.92–7.81(m,3H),7.69(t,J＝7.9Hz,1H),7.28(d,J＝7.8Hz,1H),7.19(q,J＝7.5Hz,1H),6.99(t,J＝8.9 Hz,1H),5.99(s,1H),4.78–4.70(m,1H),4.53(d,J＝16.1Hz,1H),4.22–4.16(m,1H),4.08(q,J＝7.2Hz,2H),3.88(s,1H),3.69(d,J＝12.1Hz,1H),3.61–3.54(m,1H),3.25(d,J＝6.5Hz,2H),3.18(s,1H),3.07(s,1H),2.56–2.30(m,5H),1.10(t,J＝7.1Hz,3H)。 Compound 14 (54 mg). MS: 636.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98(d,J=3.1Hz,1H),7.92-7.81(m,3H),7.69(t,J=7.9Hz,1H),7.28(d, J=7.8Hz, 1H), 7.19(q, J=7.5Hz, 1H), 6.99(t, J=8.9 Hz, 1H), 5.99(s, 1H), 4.78–4.70(m, 1H), 4.53( d, J=16.1Hz, 1H), 4.22–4.16 (m, 1H), 4.08 (q, J=7.2Hz, 2H), 3.88 (s, 1H), 3.69 (d, J=12.1Hz, 1H), 3.61-3.54(m, 1H), 3.25(d, J=6.5Hz, 2H), 3.18(s, 1H), 3.07(s, 1H), 2.56-2.30(m, 5H), 1.10(t, J= 7.1Hz, 3H).
实施例15Example 15
化合物15:Compound 15:
4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-氟苯甲酸4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-fluorobenzoic acid
Figure PCTCN2021135751-appb-000247
Figure PCTCN2021135751-appb-000247
化合物15的合成参考化合物11，通过使用4-溴-2-氟苯甲酸乙酯代替4-碘苯甲酸甲酯制备得到黄色固体化合物15。Synthesis of compound 15 Referring to compound 11, compound 15 was prepared as a yellow solid by using ethyl 4-bromo-2-fluorobenzoate instead of methyl 4-iodobenzoate.
化合物15(19.3毫克)。MS:636.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.99–7.93(m,2H),7.85(d,J＝3.0Hz,1H),7.83–7.77(m,1H),7.49(dd,J＝8.8,2.0Hz,1H),7.26(d,J＝7.8Hz,1H),7.19(q,J＝7.7Hz,1H),6.99(t,J＝8.9Hz,1H),5.97(s,1H),4.65(d,J＝16.1Hz,1H),4.52(d,J＝16.1Hz,1H),4.12(dd,J＝10.7,4.7Hz,1H),4.05(q,J＝7.1Hz,2H),3.80(dt,J＝7.7,4.1Hz,1H),3.74(d,J＝12.9Hz,1H),3.59(s,3H),3.19(s,1H),3.12(d,J＝15.4Hz,1H),2.53(d,J＝15.5Hz,1H),2.44(s,3H),2.38(q,J＝14.0,10.1Hz,1H),1.08(t,J＝7.1Hz,3H)。 Compound 15 (19.3 mg). MS: 636.3 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.99-7.93(m,2H),7.85(d,J=3.0Hz,1H),7.83-7.77(m,1H),7.49(dd,J=8.8 ,2.0Hz,1H),7.26(d,J＝7.8Hz,1H),7.19(q,J＝7.7Hz,1H),6.99(t,J＝8.9Hz,1H),5.97(s,1H), 4.65(d,J＝16.1Hz,1H),4.52(d,J＝16.1Hz,1H),4.12(dd,J＝10.7,4.7Hz,1H),4.05(q,J＝7.1Hz,2H), 3.80(dt,J=7.7,4.1Hz,1H),3.74(d,J=12.9Hz,1H),3.59(s,3H),3.19(s,1H),3.12(d,J=15.4Hz,1H) ), 2.53 (d, J=15.5 Hz, 1H), 2.44 (s, 3H), 2.38 (q, J=14.0, 10.1 Hz, 1H), 1.08 (t, J=7.1 Hz, 3H).
实施例16Example 16
化合物16:Compound 16:
2-(4-((3aS,7aS)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)乙酸2-(4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2- (yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)acetic acid
Figure PCTCN2021135751-appb-000248
Figure PCTCN2021135751-appb-000248
化合物16的合成参考化合物11，通过使用2-(4-碘苯)乙酸乙酯代替4-碘苯甲酸甲酯制备得到黄色固体化合物16。Synthesis of compound 16 Referring to compound 11, compound 16 was prepared as a yellow solid by using ethyl 2-(4-iodobenzene)acetate instead of methyl 4-iodobenzoate.
化合物16(48毫克)。MS:632.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(d,J＝3.1Hz,1H),7.84(d,J＝3.1Hz,1H),7.60(d,J＝8.3Hz,2H),7.32(d,J＝8.3Hz,2H),7.26(d,J＝7.8Hz,1H),7.23–7.15(m,1H),6.99(t,J＝8.9Hz,1H),5.97(s,1H),4.67(d,J＝16.1Hz,1H),4.52(d,J＝16.1Hz,1H),4.20–4.11(m,1H),4.11–4.02(m,2H),3.80(d,J＝8.6Hz,1H),3.72(d,J＝12.1Hz,1H),3.61(s,2H),3.55(d,J＝10.7Hz,1H),3.15(s,4H),2.51(d,J＝15.0Hz,1H),2.44(d,J＝2.0Hz,3H),2.37(d,J＝13.9Hz,1H),1.09(t,J＝7.1Hz,3H)。 Compound 16 (48 mg). MS: 632.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(d,J=3.1Hz,1H),7.84(d,J=3.1Hz,1H),7.60(d,J=8.3Hz,2H),7.32 (d, J=8.3Hz, 2H), 7.26 (d, J=7.8Hz, 1H), 7.23–7.15 (m, 1H), 6.99 (t, J=8.9Hz, 1H), 5.97 (s, 1H) ,4.67(d,J=16.1Hz,1H),4.52(d,J=16.1Hz,1H),4.20–4.11(m,1H),4.11–4.02(m,2H),3.80(d,J=8.6 Hz, 1H), 3.72(d, J=12.1Hz, 1H), 3.61(s, 2H), 3.55(d, J=10.7Hz, 1H), 3.15(s, 4H), 2.51(d, J=15.0 Hz, 1H), 2.44 (d, J=2.0 Hz, 3H), 2.37 (d, J=13.9 Hz, 1H), 1.09 (t, J=7.1 Hz, 3H).
实施例17Example 17
化合物17:Compound 17:
3-(4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙酸3-(4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)propionic acid
Figure PCTCN2021135751-appb-000249
Figure PCTCN2021135751-appb-000249
化合物17的合成参考化合物11，通过使用3-(4-碘苯基)丙酸甲酯代替4-碘苯甲酸甲酯制备得到黄色固体化合物17。Synthesis of compound 17 Referring to compound 11, compound 17 was prepared as a yellow solid by using methyl 3-(4-iodophenyl)propionate instead of methyl 4-iodobenzoate.
化合物17(32毫克)。MS:646.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.1Hz,1H),7.85(d,J＝3.0Hz,1H),7.55(d,J＝8.2Hz,2H),7.27(dd,J＝8.4,4.0Hz,3H),7.18(q,J＝7.6Hz,1H),6.99(t,J＝8.9Hz,1H),5.97(s,1H),4.70–4.47(m,2H),4.09(dq,J＝21.4,7.2,6.8Hz,3H),3.76(dd,J＝30.5,10.9Hz,2H),3.53(d,J＝10.6Hz,1H),3.14(s,4H),2.91(t,J＝7.6Hz,2H),2.59(t,J＝7.5Hz,2H),2.56–2.33(m,5H),1.09(t,J＝7.1Hz,3H)。 Compound 17 (32 mg). MS: 646.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.1Hz,1H),7.85(d,J=3.0Hz,1H),7.55(d,J=8.2Hz,2H),7.27 (dd, J=8.4, 4.0Hz, 3H), 7.18(q, J=7.6Hz, 1H), 6.99(t, J=8.9Hz, 1H), 5.97(s, 1H), 4.70–4.47(m, 2H),4.09(dq,J=21.4,7.2,6.8Hz,3H),3.76(dd,J=30.5,10.9Hz,2H),3.53(d,J=10.6Hz,1H),3.14(s,4H ), 2.91 (t, J=7.6Hz, 2H), 2.59 (t, J=7.5Hz, 2H), 2.56–2.33 (m, 5H), 1.09 (t, J=7.1Hz, 3H).
实施例18Example 18
化合物18:Compound 18:
3-(4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丁酸3-(4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)butanoic acid
Figure PCTCN2021135751-appb-000250
Figure PCTCN2021135751-appb-000250
化合物18的合成参考化合物11，通过使用3-(4-溴苯基)丁酸甲酯(中间体18)代替4-碘苯甲酸甲酯制备得到黄色固体化合物18。Synthesis of compound 18 Referring to compound 11, compound 18 was prepared as a yellow solid by using methyl 3-(4-bromophenyl)butyrate (intermediate 18) in place of methyl 4-iodobenzoate.
化合物18(23毫克)。MS:660.4(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(d,J＝3.1Hz,1H),7.85(d,J＝3.0Hz,1H),7.56(d,J＝8.2Hz,2H),7.28(dd,J＝14.7,8.0Hz,3H),7.18(q,J＝7.4Hz,1H),6.99(t,J＝9.0Hz,1H),5.97(s,1H),4.69–4.48(m,2H),4.16–4.02(m,3H),3.85–3.65(m,2H),3.53(d,J＝10.6Hz,1H),3.13(s,5H),2.53(dd,J＝26.8,11.1Hz,3H),2.44(s,3H),2.36(d,J＝15.4Hz,1H),1.28(d,J＝6.9Hz,3H),1.09(t,J＝7.1Hz,3H)。 Compound 18 (23 mg). MS: 660.4 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(d,J=3.1Hz,1H),7.85(d,J=3.0Hz,1H),7.56(d,J=8.2Hz,2H),7.28 (dd, J=14.7, 8.0Hz, 3H), 7.18 (q, J=7.4Hz, 1H), 6.99 (t, J=9.0Hz, 1H), 5.97 (s, 1H), 4.69–4.48 (m, 2H), 4.16–4.02 (m, 3H), 3.85–3.65 (m, 2H), 3.53 (d, J=10.6Hz, 1H), 3.13 (s, 5H), 2.53 (dd, J=26.8, 11.1Hz) , 3H), 2.44 (s, 3H), 2.36 (d, J=15.4Hz, 1H), 1.28 (d, J=6.9Hz, 3H), 1.09 (t, J=7.1Hz, 3H).
实施例19Example 19
化合物19:Compound 19:
(E)-3-(4-((3aR,7aR)-5-(((S)-5-(乙氧羰基)-6-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯基)丙烯酸(E)-3-(4-((3aR,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-6-(3-fluoro-2-methylphenyl)-2 -(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl )acrylic acid
Figure PCTCN2021135751-appb-000251
Figure PCTCN2021135751-appb-000251
化合物19的合成参考化合物11，通过使用(3aS，7aR)-1-氧代八氢-5H-吡咯并[3，4-c]吡啶-5-羧酸叔丁酯(中间体7-1b)代替(3aR，7aS)-1-氧代八氢-5H-吡咯并[3，4-c]吡啶-5-羧酸叔丁酯(中间体7-1a)和(E)-3-(4-溴苯基)丙烯酸甲酯(中间体19)代替4-碘苯甲酸甲酯制备得到黄色固体化合物19。Synthesis of compound 19 Reference compound 11 by using (3aS,7aR)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (intermediate 7-1b) Substitute for (3aR,7aS)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate tert-butyl ester (Intermediate 7-1a) and (E)-3-(4 -Bromophenyl) methyl acrylate (intermediate 19) was prepared in place of methyl 4-iodobenzoate to give compound 19 as a yellow solid.
化合物19(6.5毫克)。MS:644.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.0Hz,1H),7.87(d,J＝3.0Hz,1H),7.77(d,J＝8.4Hz,2H),7.68–7.63(m,3H),7.29–7.14(m,2H),6.99(t,J＝9.0Hz,1H),6.45(d,J＝16.0Hz,1H),5.98(s,1H),4.68(d,J＝16.3Hz,1H),4.48(d,J＝16.3Hz,1H),4.16(dd,J＝10.5,5.1Hz,1H),4.06(q,J＝7.1Hz,2H),3.81(s,1H),3.63(d,J＝10.2Hz,2H),3.17(d,J＝9.5Hz,4H),2.51(d,J＝15.4Hz,1H),2.44(s,3H),2.40–2.27(m,1H),1.09(t,J＝7.2Hz,3H)。 Compound 19 (6.5 mg). MS: 644.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.0Hz,1H),7.87(d,J=3.0Hz,1H),7.77(d,J=8.4Hz,2H),7.68 –7.63(m,3H),7.29–7.14(m,2H),6.99(t,J=9.0Hz,1H),6.45(d,J=16.0Hz,1H),5.98(s,1H),4.68( d, J＝16.3Hz, 1H), 4.48(d, J＝16.3Hz, 1H), 4.16(dd, J＝10.5, 5.1Hz, 1H), 4.06(q, J＝7.1Hz, 2H), 3.81( s, 1H), 3.63 (d, J=10.2Hz, 2H), 3.17 (d, J=9.5Hz, 4H), 2.51 (d, J=15.4Hz, 1H), 2.44 (s, 3H), 2.40– 2.27(m, 1H), 1.09(t, J=7.2Hz, 3H).
实施例20Example 20
化合物20:Compound 20:
3-(4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸3-(4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)-2-methyl propionic acid
Figure PCTCN2021135751-appb-000252
Figure PCTCN2021135751-appb-000252
化合物20的合成参考化合物1，通过使用2-甲基-3-(4-((3aS，7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙酸三氟乙酸盐(中间体20-5)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物20。Synthesis of compound 20 Reference compound 1 by using 2-methyl-3-(4-((3aS,7aS)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Phenyl)propionic acid trifluoroacetate (Intermediate 20-5) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetic acid The salt (intermediate 1-4) was prepared to give compound 20 as a yellow solid.
化合物20(48.0毫克)。MS:660.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.55(d,J＝8.1Hz,2H),7.29–7.14(m,4H),6.99(t,J＝9.0Hz,1H),5.97(s,1H),4.66(d,J＝16.2Hz,1H),4.53(d,J＝16.2Hz,1H),4.16–4.01(m,3H),3.84–3.67(m,2H),3.53(d,J＝10.7Hz,1H),3.15-3.09(m,4H),3.00-2.96(m,1H),2.73-2.65(m,2H),2.55–2.35(m,5H),1.16–1.06(m,6H)。 Compound 20 (48.0 mg). MS: 660.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=2.8Hz,1H),7.85(d,J=2.8Hz,1H),7.55(d,J=8.1Hz,2H),7.29 –7.14(m,4H),6.99(t,J＝9.0Hz,1H),5.97(s,1H),4.66(d,J＝16.2Hz,1H),4.53(d,J＝16.2Hz,1H) ,4.16-4.01(m,3H),3.84-3.67(m,2H),3.53(d,J=10.7Hz,1H),3.15-3.09(m,4H),3.00-2.96(m,1H),2.73 -2.65 (m, 2H), 2.55–2.35 (m, 5H), 1.16–1.06 (m, 6H).
实施例21Example 21
化合物21:Compound 21:
6-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸6-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)nicotinic acid
Figure PCTCN2021135751-appb-000253
Figure PCTCN2021135751-appb-000253
化合物21的合成参考化合物1，通过使用6-((3aS,7aS)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸三氟乙酸盐(中间体21-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物21。Synthesis of compound 21 Reference compound 1 by using 6-((3aS,7aS)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)nicotinic acid trifluoroacetate ( Intermediate 21-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) was prepared to give yellow Solid compound 21.
化合物21(23.0毫克)。MS:619.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.94(d,J＝2.1Hz,1H),8.51(d,J＝8.8Hz,1H),8.33(dd,J＝8.8,2.2Hz,1H),7.97(d,J＝3.1Hz,1H),7.86(d,J＝3.1Hz,1H), 7.26(d,J＝7.8Hz,1H),7.23–7.15(m,1H),6.99(t,J＝8.9Hz,1H),5.97(s,1H),4.63(d,J＝16.2Hz,1H),4.52(d,J＝16.2Hz,1H),4.19–4.00(m,4H),3.88–3.68(m,2H),3.28–3.04(m,4H),2.63–2.32(m,5H),1.08(t,J＝7.1Hz,3H)。 Compound 21 (23.0 mg). MS: 619.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.94(d,J=2.1Hz,1H),8.51(d,J=8.8Hz,1H),8.33(dd,J=8.8,2.2Hz,1H) ,7.97(d,J＝3.1Hz,1H),7.86(d,J＝3.1Hz,1H), 7.26(d,J＝7.8Hz,1H),7.23–7.15(m,1H),6.99(t, J＝8.9Hz,1H),5.97(s,1H),4.63(d,J＝16.2Hz,1H),4.52(d,J＝16.2Hz,1H),4.19–4.00(m,4H),3.88– 3.68 (m, 2H), 3.28–3.04 (m, 4H), 2.63–2.32 (m, 5H), 1.08 (t, J=7.1 Hz, 3H).
实施例22Example 22
化合物22Compound 22
(S)-4-(3-氟-2-甲基苯基)-6-(((3aR,7aR)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-(((3aR,7aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5- yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000254
Figure PCTCN2021135751-appb-000254
化合物22A的合成参考化合物1，通过使用(3aS)-八氢-1H-吡咯[3,4-c]吡啶-1-酮三氟乙酸盐(中间体22-10)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体(4S)-4-(3-氟-2-甲基苯基)-6-(((3aR)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物22A,60毫克)。MS:498.2(M+H) +。 Synthesis of compound 22A Reference compound 1 by using (3aS)-octahydro-1H-pyrrole[3,4-c]pyridin-1-one trifluoroacetate (intermediate 22-10) in place of 4,5,6 ,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared as a yellow solid (4S)-4-(3-fluoro- 2-Methylphenyl)-6-(((3aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl)methyl)-2-(thiazole-2- yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 22A, 60 mg). MS: 498.2 (M+H) + .
将(4S)-4-(3-氟-2-甲基苯基)-6-(((3aR)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物22A,60毫克)经SFC手性拆分(柱型号：CHIRAL Cellulose-SC column(5cm×25cm，5um)色谱柱，流动相：乙醇在正己烷中)得到均为黄色固体的化合物22(保留时间为1.74分钟,21毫克)和第二个组分峰化合物7(保留时间为2.49分钟,19毫克)。(4S)-4-(3-Fluoro-2-methylphenyl)-6-(((3aR)-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl )methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester (Compound 22A, 60 mg) was chiral resolved by SFC (column model: CHIRAL Cellulose-SC column (5cm×25cm, 5um) column, mobile phase: ethanol in n-hexane) to obtain compound 22 (retention time 1.74 minutes, 21 mg) and the second component peak compound 7 (retention time) as yellow solids for 2.49 minutes, 19 mg).
化合物22： 1H NMR(400MHz,Methanol-d 4)δ7.91(d,J＝3.2Hz,1H),7.70(d,J＝3.2Hz,1H),7.18–7.02(m,2H),6.92(t,J＝9.0Hz,1H),5.96(s,1H),4.10(d,J＝17.2Hz,1H),4.05(q,J＝7.1Hz,2H),3.97(d,J＝17.2Hz,1H),3.20–2.97(m,3H),2.51(d,J＝2.1Hz,3H),2.46(t,J＝10.8Hz,1H),2.33(d,J＝6.6Hz,2H),2.13–2.05(m,1H),2.00-1.96(m,1H),1.71–1.58(m,1H),1.12(t,J＝7.1Hz,3H。 Compound 22: 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.91 (d, J=3.2 Hz, 1H), 7.70 (d, J=3.2 Hz, 1H), 7.18-7.02 (m, 2H), 6.92 (t, J=9.0Hz, 1H), 5.96 (s, 1H), 4.10 (d, J=17.2Hz, 1H), 4.05 (q, J=7.1Hz, 2H), 3.97 (d, J=17.2Hz) ,1H),3.20–2.97(m,3H),2.51(d,J＝2.1Hz,3H),2.46(t,J＝10.8Hz,1H),2.33(d,J＝6.6Hz,2H),2.13 -2.05(m, 1H), 2.00-1.96(m, 1H), 1.71-1.58(m, 1H), 1.12(t, J=7.1Hz, 3H.
实施例23Example 23
化合物23Compound 23
4-((3aS,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸和4-((3aR,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid and 4- ((3aR,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-3 ,6-dihydropyrimidin-4-yl)methyl)-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000255
Figure PCTCN2021135751-appb-000255
化合物23的合成参考化合物6，通过使用顺式-4-(7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐(中间体cis-23-4)代替4-(1-氧代-1,3,4,5,6,7-六氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸三氟乙酸盐(中间体6-3)制备得到化合物23。Synthesis of compound 23 Reference compound 6 by using cis-4-(7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid trifluoroacetic acid Salt (intermediate cis-23-4) in place of 4-(1-oxo-1,3,4,5,6,7-hexahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid trifluoroacetate (Intermediate 6-3) was prepared to give compound 23.
化合物23(63.0毫克)。MS:632.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.05(d,J＝8.4Hz,2H),8.01–7.93(m,1H),7.85(dd,J＝18.5,8.0Hz,3H),7.26(d,J＝7.9Hz,1H),7.19(t,J＝7.1Hz,1H),6.99(t,J＝8.9Hz,1H),5.97(d,J＝3.5Hz,1H),4.77–4.43(m,2H),4.27(t,J＝8.2Hz,1H),4.06(q,J＝7.2Hz,2H),3.90–3.60(m,3H),3.20(s,2H),2.85(s,1H),2.44(s,4H),2.05(d,J＝13.5Hz,1H),1.38(s,3H),1.09(t,J＝7.2Hz,3H)。 Compound 23 (63.0 mg). MS: 632.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.05(d,J=8.4Hz,2H),8.01-7.93(m,1H),7.85(dd,J=18.5,8.0Hz,3H),7.26( d, J＝7.9Hz, 1H), 7.19(t, J＝7.1Hz, 1H), 6.99(t, J＝8.9Hz, 1H), 5.97(d, J＝3.5Hz, 1H), 4.77–4.43( m, 2H), 4.27(t, J=8.2Hz, 1H), 4.06(q, J=7.2Hz, 2H), 3.90–3.60(m, 3H), 3.20(s, 2H), 2.85(s, 1H ), 2.44(s, 4H), 2.05(d, J=13.5Hz, 1H), 1.38(s, 3H), 1.09(t, J=7.2Hz, 3H).
实施例24Example 24
化合物24:Compound 24:
4-((3aS,7aR)-5-((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-羟基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-5-((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-hydroxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000256
Figure PCTCN2021135751-appb-000256
化合物24的合成参考化合物1，通过使用4-((3aS,7aR)-7a-羟基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体24-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物24。Synthesis of compound 24 reference compound 1 by using 4-((3aS,7aR)-7a-hydroxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 24-3) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) was prepared to give a yellow solid Compound 24.
化合物24(16.4毫克)。MS:634.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.08(d,J＝8.6Hz,2H),7.95(d,J＝3.1Hz,1H),7.90–7.82(m,3H),7.27(d,J＝7.9Hz,1H),7.23–7.16(m,1H),6.99(t,J＝8.9Hz,1H),5.98(s,1H),4.61(s,2H),4.23(t,J＝8.9Hz,1H),4.07(q,J＝7.2Hz,2H),3.79-3.74(m,2H),3.68-3.63(m,1H),3.49-3.45(m,1H),3.35-3.31(m,1H),2.92-2.85(m,1H),2.47-2.43(m,4H),2.27-2.21(m,1H),1.10(t,J＝7.2Hz,3H)。 Compound 24 (16.4 mg). MS: 634.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.08(d,J=8.6Hz,2H),7.95(d,J=3.1Hz,1H),7.90-7.82(m,3H),7.27(d, J=7.9Hz, 1H), 7.23-7.16(m, 1H), 6.99(t, J=8.9Hz, 1H), 5.98(s, 1H), 4.61(s, 2H), 4.23(t, J=8.9 Hz, 1H), 4.07(q, J=7.2Hz, 2H), 3.79-3.74(m, 2H), 3.68-3.63(m, 1H), 3.49-3.45(m, 1H), 3.35-3.31(m, 1H), 2.92-2.85 (m, 1H), 2.47-2.43 (m, 4H), 2.27-2.21 (m, 1H), 1.10 (t, J=7.2Hz, 3H).
实施例25Example 25
化合物25:Compound 25:
4-((3aS,7aR)-5-((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-甲氧基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-5-((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-methoxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000257
Figure PCTCN2021135751-appb-000257
化合物25的合成参考化合物1，通过使用4-((3aS,7aR)-7a-甲氧基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体25-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物25。Synthesis of compound 25 Reference compound 1 by using 4-((3aS,7aR)-7a-methoxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 25-2) was prepared in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 25 as a yellow solid.
化合物25(24.4毫克)。MS:648.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.08(d,J＝8.6Hz,2H),7.96(d,J＝3.1Hz,1H),7.93–7.83(m,3H),7.27(d,J＝7.9Hz,1H),7.21-7.17(m,1H),6.99(t,J＝9.0Hz,1H),5.98(s,1H),4.69–4.56(m,2H),4.26(dd,J＝10.3,6.6Hz,1H),4.06(q,J＝7.2Hz,2H),3.83-3.68(s,3H),3.42(s,3H),3.35-3.25(m,2H),3.11-3.07(m,1H),2.65-2.60(m,1H),2.45(s,3H),2.25-2.21(m,1H),1.10(t,J＝7.2Hz,3H)。 Compound 25 (24.4 mg). MS: 648.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.08(d,J=8.6Hz,2H),7.96(d,J=3.1Hz,1H),7.93-7.83(m,3H),7.27(d, J=7.9Hz, 1H), 7.21-7.17(m, 1H), 6.99(t, J=9.0Hz, 1H), 5.98(s, 1H), 4.69-4.56(m, 2H), 4.26(dd, J =10.3,6.6Hz,1H),4.06(q,J=7.2Hz,2H),3.83-3.68(s,3H),3.42(s,3H),3.35-3.25(m,2H),3.11-3.07( m, 1H), 2.65-2.60 (m, 1H), 2.45 (s, 3H), 2.25-2.21 (m, 1H), 1.10 (t, J=7.2Hz, 3H).
实施例26Example 26
化合物26:Compound 26:
(S)-4-(3-氟-2-甲基苯基)-6-((3aR,7aR)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aR,7aR)-3a-hydroxy-1-oxooctahydro-5H-pyrro[3,4-c]pyridine -5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000258
Figure PCTCN2021135751-appb-000258
化合物26的合成参考化合物1，通过使用(3aS,7aR)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-3b)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物26。Synthesis of compound 26 Reference compound 1 by using (3aS,7aR)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 26-3b) in place of 4,5,6 ,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 26 as a yellow solid.
化合物26(28.8毫克)。MS:514.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(d,J＝3.1Hz,1H),7.87(d,J＝3.1Hz,1H),7.32–7.16(m,2H),6.99(t,J＝9.0Hz,1H),5.98(s,1H),4.61(s,2H),4.07(q,J＝7.2Hz,2H),3.68(d,J＝13.1Hz,1H),3.55(d,J＝13.6Hz,1H),3.42(d,J＝13.0Hz,1H),3.34-3.27(m,2H),3.15-3.08(m,1H),2.78(br,1H),2.45(s,3H),2.33(br,2H),1.10(t,J＝7.2Hz,3H)。 Compound 26 (28.8 mg). MS: 514.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(d,J=3.1Hz,1H),7.87(d,J=3.1Hz,1H),7.32-7.16(m,2H),6.99(t, J=9.0Hz, 1H), 5.98(s, 1H), 4.61(s, 2H), 4.07(q, J=7.2Hz, 2H), 3.68(d, J=13.1Hz, 1H), 3.55(d, J=13.6Hz, 1H), 3.42(d, J=13.0Hz, 1H), 3.34-3.27(m, 2H), 3.15-3.08(m, 1H), 2.78(br, 1H), 2.45(s, 3H) ), 2.33(br, 2H), 1.10(t, J=7.2Hz, 3H).
实施例27Example 27
化合物27:Compound 27:
(S)-4-(3-氟-2-甲基苯基)-6-((3aS,7aS)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aS,7aS)-3a-hydroxy-1-oxooctahydro-5H-pyrro[3,4-c]pyridine -5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000259
Figure PCTCN2021135751-appb-000259
化合物27的合成参考化合物1，通过使用(3aR,7aS)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体26-3a)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物27。Synthesis of compound 27 Reference compound 1 by using (3aR,7aS)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 26-3a) in place of 4,5,6 ,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 27 as a yellow solid.
化合物27(21.6毫克)。MS:514.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.95(d,J＝2.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.26(d,J＝7.9Hz,1H),7.23–7.16(m,1H),6.99(t,J＝9.0Hz,1H),5.98(s,1H),4.78(d,J＝15.8Hz,1H),4.42(d,J＝15.8Hz,1H),4.07(q,J＝7.2Hz,2H),3.58(dd,J＝18.5,12.6Hz,2H),3.35-3.30(m,2H),3.23(d,J＝10.4Hz,1H),3.14-3.08(m,1H),2.77(br,1H),2.44(s,3H),2.37-2.33(m,2H),1.10(t,J＝7.2Hz,3H)。 Compound 27 (21.6 mg). MS: 514.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.95(d,J=2.8Hz,1H),7.86(d,J=2.8Hz,1H),7.26(d,J=7.9Hz,1H),7.23 –7.16(m,1H),6.99(t,J＝9.0Hz,1H),5.98(s,1H),4.78(d,J＝15.8Hz,1H),4.42(d,J＝15.8Hz,1H) ,4.07(q,J＝7.2Hz,2H),3.58(dd,J＝18.5,12.6Hz,2H),3.35-3.30(m,2H),3.23(d,J＝10.4Hz,1H),3.14- 3.08 (m, 1H), 2.77 (br, 1H), 2.44 (s, 3H), 2.37-2.33 (m, 2H), 1.10 (t, J=7.2Hz, 3H).
实施例28Example 28
化合物28:Compound 28:
(S)-4-(3-氟-2-甲基苯基)-6-((3aR,7aS)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯和S)-4-(3-氟-2-甲基苯基)-6-((3aS,7aR)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aR,7aS)-3a-hydroxy-1-oxooctahydro-5H-pyrro[3,4-c]pyridine -5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester and S)-4-(3-fluoro-2-methylphenyl )-6-((3aS,7aR)-3a-hydroxy-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl)methyl)-2-(thiazol-2-yl )-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000260
Figure PCTCN2021135751-appb-000260
化合物28的合成参考化合物1，通过使用反式-(3aS,7aS)-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体反式27-4)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物28。Synthesis of compound 28 Reference compound 1, by using trans-(3aS,7aS)-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate trans 27-4) instead 4,5,6,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 28 as a yellow solid.
化合物28(23毫克)。MS:514.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96-7.94(m,1H),7.87-7.85(m,1H),7.23(dq,J＝21.4,7.2Hz,2H),7.00(t,J＝8.9Hz,1H),5.99-5.98(m,1H),4.76(d,J＝16.0Hz,0.5H),4.68-4.58(m,1H),4.47(d,J＝16.0Hz,0.5H),4.12-4.04(m,2H),3.79(d,J＝11.5Hz,1H),3.73–3.36(m,4H),3.29–3.18(m,1H),2.64(dd,J＝12.7,4.2Hz,1H),2.45(s,3H),2.32(dd,J＝14.8,11.1Hz, 1H),2.13(d,J＝11.5Hz,1H),1.10(td,J＝7.1,1.9Hz,3H)。 Compound 28 (23 mg). MS: 514.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96-7.94(m,1H),7.87-7.85(m,1H),7.23(dq,J=21.4,7.2Hz,2H),7.00(t,J =8.9Hz,1H),5.99-5.98(m,1H),4.76(d,J=16.0Hz,0.5H),4.68-4.58(m,1H),4.47(d,J=16.0Hz,0.5H) ,4.12-4.04(m,2H),3.79(d,J＝11.5Hz,1H),3.73-3.36(m,4H),3.29-3.18(m,1H),2.64(dd,J＝12.7,4.2Hz ,1H),2.45(s,3H),2.32(dd,J＝14.8,11.1Hz,1H),2.13(d,J＝11.5Hz,1H),1.10(td,J＝7.1,1.9Hz,3H) .
实施例29Example 29
化合物29:Compound 29:
(S)-6-(((3aR,7aS)-2-(3-乙氧基-2,2-二甲基-3-氧丙基)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯和(S)-6-((3aS,7aR)-2-(3-乙氧基-2,2-二甲基-3-氧丙烷基)-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(((3aR,7aS)-2-(3-ethoxy-2,2-dimethyl-3-oxopropyl)-3a-hydroxy-1-oxooctahydro-5H -pyrrole[3,4-c]pyridin-5-yl)methyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydro Pyrimidine-5-carboxylate ethyl ester and (S)-6-((3aS,7aR)-2-(3-ethoxy-2,2-dimethyl-3-oxopropanyl)-3a-hydroxy- 1-Oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl)methyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) )-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000261
Figure PCTCN2021135751-appb-000261
化合物29的合成参考化合物1，通过使用顺式3-((3aR,7aS)-3a-羟基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸乙酯(中间体顺式29-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物29。Synthesis of compound 29 Reference compound 1 by using cis 3-((3aR,7aS)-3a-hydroxy-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2 ,2-Dimethylpropionate ethyl ester (intermediate cis 29-2) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoro Acetate salt (Intermediate 1-4) was prepared to give compound 29 as a yellow solid.
化合物29(53.6毫克)。MS:642.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(t,J＝3.5Hz,1H),7.87(d,J＝3.1Hz,1H),7.26(t,J＝6.1Hz,1H),7.19(t,J＝6.7Hz,1H),6.99(t,J＝9.1Hz,1H),5.98(s,1H),4.93–4.85(m,1H),4.80–4.70(m,1H),4.67–4.58(m,1H),4.18–4.03(m,4H),3.69–3.49(m,3H),3.45–3.34(m,2H),3.28–3.20(m,1H),3.05(d,J＝10.6Hz,1H),2.79(s,1H),2.45(t,J＝2.1Hz,3H),2.31(s,2H),1.26(t,J＝7.1Hz,3H),1.20(dd,J＝8.8,3.0Hz,6H),1.10(td,J＝7.1,2.8Hz,3H)。 Compound 29 (53.6 mg). MS: 642.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(t,J=3.5Hz,1H),7.87(d,J=3.1Hz,1H),7.26(t,J=6.1Hz,1H),7.19 (t, J=6.7Hz, 1H), 6.99 (t, J=9.1Hz, 1H), 5.98 (s, 1H), 4.93–4.85 (m, 1H), 4.80–4.70 (m, 1H), 4.67– 4.58 (m, 1H), 4.18–4.03 (m, 4H), 3.69–3.49 (m, 3H), 3.45–3.34 (m, 2H), 3.28–3.20 (m, 1H), 3.05 (d, J=10.6 Hz, 1H), 2.79(s, 1H), 2.45(t, J＝2.1Hz, 3H), 2.31(s, 2H), 1.26(t, J＝7.1Hz, 3H), 1.20(dd, J＝8.8 , 3.0Hz, 6H), 1.10 (td, J=7.1, 2.8Hz, 3H).
实施例30Example 30
化合物30:Compound 30:
(S)-4-(3-氟-2-甲基苯基)-6-((3aR,7aS)-3a-羟基-2-异丙基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯和(S)-4-(3-氟-2-甲基苯基)-6-((3aS,7aR)-3a-羟基-2-异丙基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aR,7aS)-3a-hydroxy-2-isopropyl-1-oxooctahydro-5H-pyrrole[3 ,4-c]pyridin-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester and (S)-4-(3-fluoro -2-Methylphenyl)-6-((3aS,7aR)-3a-hydroxy-2-isopropyl-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl )methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000262
Figure PCTCN2021135751-appb-000262
化合物30的合成参考化合物1，通过使用顺式-(3aR,7aS)-3a-羟基-2-异丙基八氢-1H-吡咯[3,4- c]吡啶-1-酮(中间体顺式28-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物30。Synthesis of compound 30 Reference compound 1, by using cis-(3aR,7aS)-3a-hydroxy-2-isopropyloctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate cis- Formula 28-3) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give a yellow solid Compound 30.
化合物30(4.6毫克)。MS:556.4(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(s,1H),7.87(s,1H),7.29–7.17(m,2H),6.99(t,J＝9.2Hz,1H),5.98(s,1H),4.92–4.84(m,1H),4.75(t,J＝8.4Hz,1H),4.59(s,1H),4.45–4.28(m,1H),4.11–4.00(m,2H),3.68–3.44(m,2H),3.36(d,J＝8.9Hz,1H),3.25(d,J＝12.2Hz,1H),3.11(qd,J＝15.5,14.1,5.6Hz,1H),2.79(s,1H),2.45(s,3H),2.32(s,2H),1.17(d,J＝6.5Hz,6H),1.13–1.06(m,3H)。 Compound 30 (4.6 mg). MS: 556.4 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(s,1H),7.87(s,1H),7.29-7.17(m,2H),6.99(t,J=9.2Hz,1H),5.98( s, 1H), 4.92–4.84 (m, 1H), 4.75 (t, J=8.4Hz, 1H), 4.59 (s, 1H), 4.45–4.28 (m, 1H), 4.11–4.00 (m, 2H) ,3.68–3.44(m,2H),3.36(d,J=8.9Hz,1H),3.25(d,J=12.2Hz,1H),3.11(qd,J=15.5,14.1,5.6Hz,1H), 2.79(s, 1H), 2.45(s, 3H), 2.32(s, 2H), 1.17(d, J=6.5Hz, 6H), 1.13–1.06(m, 3H).
实施例31Example 31
化合物31和化合物32：Compound 31 and Compound 32:
(S)-4-(3-氟-2-甲基苯基)-6-((3aS,7aR)-7a-氟-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物31或者32)(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aS,7aR)-7a-fluoro-3a-hydroxy-1-oxooctahydro-5H-pyrrole[3,4 -c]pyridin-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester (compound 31 or 32)
(S)-4-(3-氟-2-甲基苯基)-6-((3aR,7aS)-7a-氟-3a-羟基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物32或者31)(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aR,7aS)-7a-fluoro-3a-hydroxy-1-oxooctahydro-5H-pyrrole[3,4 -c]pyridin-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (compound 32 or 31)
Figure PCTCN2021135751-appb-000263
Figure PCTCN2021135751-appb-000263
化合物31和化合物32的合成参考化合物1，通过使用顺式-7a-氟-3a-羟基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式30-3a)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)薄层层析制备得到黄色固体化合物31(第一个组分，5毫克)和化合物32(第二个组分，9毫克)。MS:532.2(M+H) +。 Synthesis of compound 31 and compound 32 Reference compound 1 by using cis-7a-fluoro-3a-hydroxyoctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate cis 30-3a) Substitution of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) by thin layer chromatography to obtain a yellow solid compound 31 (first component, 5 mg) and compound 32 (second component, 9 mg). MS: 532.2 (M+H) + .
实施例32Example 32
化合物33:Compound 33:
4-((3aR,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000264
Figure PCTCN2021135751-appb-000264
化合物33的合成参考化合物1，通过使用4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体71-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物33。Synthesis of compound 33 Reference compound 1 by using 4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methyl benzoic acid (Intermediate 71-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 33 as a yellow solid.
化合物33(42毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.02(d,J＝9.3Hz,1H),7.96(d,J＝3.1Hz,1H),7.90(d,J＝3.1Hz,1H),7.67(ddt,J＝4.2,2.0,1.3Hz,2H),7.26(dd,J＝7.9,1.3Hz,1H),7.19(td,J＝8.0,5.5Hz,1H),7.00(ddd,J＝9.5,8.0,1.3Hz,1H),6.00(s,1H),4.71(d,J＝16.4Hz,1H),4.48(d,J＝16.4Hz,1H),4.27(dd,J＝10.5,6.6Hz,1H),4.07(q,J＝7.1Hz,2H),3.81(dt,J＝11.9,5.8Hz,2H),3.70–3.60(m,1H),3.39–3.32(m,1H),3.29–3.16(m,2H),2.63(s,4H),2.46(d,J＝2.1Hz,4H),1.10(t,J＝7.1Hz,3H)。 Compound 33 (42 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.02(d,J=9.3Hz,1H),7.96(d,J=3.1Hz,1H),7.90(d,J=3.1Hz,1H),7.67 (ddt, J=4.2, 2.0, 1.3Hz, 2H), 7.26 (dd, J=7.9, 1.3Hz, 1H), 7.19 (td, J=8.0, 5.5Hz, 1H), 7.00 (ddd, J=9.5 ,8.0,1.3Hz,1H),6.00(s,1H),4.71(d,J＝16.4Hz,1H),4.48(d,J＝16.4Hz,1H),4.27(dd,J＝10.5,6.6Hz ,1H),4.07(q,J=7.1Hz,2H),3.81(dt,J=11.9,5.8Hz,2H),3.70–3.60(m,1H),3.39–3.32(m,1H),3.29– 3.16 (m, 2H), 2.63 (s, 4H), 2.46 (d, J=2.1 Hz, 4H), 1.10 (t, J=7.1 Hz, 3H).
实施例33Example 33
化合物34和化合物35：Compound 34 and Compound 35:
(S)-4-(3-氟-2-甲基苯基)-6-((3aS,7aR)-1-氧代四氢-1H-3a，7a环氧吡咯[3,4-c]吡啶-5(4H)-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物34或35)(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aS,7aR)-1-oxotetrahydro-1H-3a,7aepoxypyrrole[3,4-c] Pyridin-5(4H)-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester (compound 34 or 35)
(S)-4-(3-氟-2-甲基苯基)-6-((3aR,7aS)-1-氧代四氢-1H-3a，7a环氧吡咯[3,4-c]吡啶-5(4H)-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物35或34)(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aR,7aS)-1-oxotetrahydro-1H-3a,7aepoxypyrrole[3,4-c] Pyridin-5(4H)-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester (compound 35 or 34)
Figure PCTCN2021135751-appb-000265
Figure PCTCN2021135751-appb-000265
化合物34和化合物35的合成参考化合物1，通过使用顺式-六氢-1H-3a,7a环氧吡咯[3,4-c]吡啶-1-酮(中间体顺式30-3b)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)薄层层析制备得到黄色固体化合物34(第一个组分，8毫克)和化合物35(第二组分，6毫克)。MS:512.2(M+H) +。 Synthesis of compound 34 and compound 35 Reference compound 1 by using cis-hexahydro-1H-3a,7a epoxypyrrole[3,4-c]pyridin-1-one (intermediate cis 30-3b) in place of 4 ,5,6,7-Tetrahydro-2H-pyrazoline[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared by thin layer chromatography to give compound 34 as a yellow solid ( First component, 8 mg) and compound 35 (second component, 6 mg). MS: 512.2 (M+H) + .
实施例34Example 34
化合物36:Compound 36:
(S)-6-(((3aR,7aS)-3a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(((3aR,7aS)-3a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl)methyl)-4-(3- Fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000266
Figure PCTCN2021135751-appb-000266
化合物36的合成参考化合物1，通过使用(3aS,7aS)-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-2b)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物36。Synthesis of compound 36 Reference compound 1 by using (3aS,7aS)-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 31-2b) in place of 4,5,6 ,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 36 as a yellow solid.
化合物36(14.6毫克)。MS:516.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.99(d,J＝3.1Hz,1H),7.90(d,J＝3.1Hz,1H),7.29(d,J＝7.9Hz,1H),7.25–7.18(m,1H),7.01(t,J＝8.9Hz,1H),6.00(s,1H),4.64(d,J＝16.6Hz,1H),4.59(d,J＝16.6Hz,1H),4.12–4.03(m,3H),3.70–3.49(m,4H),3.21–3.07(m,2H),2.46(s,3H),2.41-2.28(m,2H),1.11(t,J＝7.1,3H)。 Compound 36 (14.6 mg). MS: 516.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.99(d,J=3.1Hz,1H),7.90(d,J=3.1Hz,1H),7.29(d,J=7.9Hz,1H),7.25 –7.18(m,1H),7.01(t,J=8.9Hz,1H),6.00(s,1H),4.64(d,J=16.6Hz,1H),4.59(d,J=16.6Hz,1H) ,4.12-4.03(m,3H),3.70-3.49(m,4H),3.21-3.07(m,2H),2.46(s,3H),2.41-2.28(m,2H),1.11(t,J= 7.1, 3H).
实施例35Example 35
化合物37:Compound 37:
(S)-6-(((3aS,7aR)-3a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(((3aS,7aR)-3a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl)methyl)-4-(3- Fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000267
Figure PCTCN2021135751-appb-000267
化合物37的合成参考化合物1，通过使用(3aR,7aR)-3a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体31-2a)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物37。Synthesis of compound 37 Reference compound 1 by using (3aR,7aR)-3a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 31-2a) in place of 4,5,6 ,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 37 as a yellow solid.
化合物37(18.6毫克)。MS:516.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98(d,J＝3.1Hz,1H),7.88(d,J＝3.1Hz,1H),7.27(d,J＝7.8Hz,1H),7.24–7.16(m,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.77(d,J＝16.3Hz,1H),4.46(d,J＝16.3Hz,1H),4.14–3.93(m,3H),3.65–3.45(m,4H),3.20–3.05(m,2H),2.46(s,3H),2.45–2.28(m,2H),1.11(t,J＝7.1Hz,3H)。 Compound 37 (18.6 mg). MS: 516.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98(d,J=3.1Hz,1H),7.88(d,J=3.1Hz,1H),7.27(d,J=7.8Hz,1H),7.24 –7.16(m,1H),7.00(t,J=8.9Hz,1H),6.00(s,1H),4.77(d,J=16.3Hz,1H),4.46(d,J=16.3Hz,1H) ,4.14-3.93(m,3H),3.65-3.45(m,4H),3.20-3.05(m,2H),2.46(s,3H),2.45-2.28(m,2H),1.11(t,J= 7.1Hz, 3H).
实施例36Example 36
化合物38:Compound 38:
顺式-(3aS,7aS)-5-((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-3aH-吡咯[3,4-c]吡啶-3a-羧酸甲酯cis-(3aS,7aS)-5-((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-3aH-pyrrole[3,4-c]pyridine-3a-carboxylate methyl ester
Figure PCTCN2021135751-appb-000268
Figure PCTCN2021135751-appb-000268
化合物38的合成参考化合物1，通过使用顺式(3aR,7aS)-1-氧代八氢-3aH-吡咯[3,4-c]吡啶-3a-羧酸甲酯(中间体顺式32-4)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物38。Synthesis of compound 38 Reference compound 1, by using methyl cis(3aR,7aS)-1-oxooctahydro-3aH-pyrro[3,4-c]pyridine-3a-carboxylate (intermediate cis 32- 4) Substituting 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) to prepare yellow solid compound 38.
化合物38(1.6毫克)。MS:566.2(M+H) +。 Compound 38 (1.6 mg). MS: 566.2 (M+H) + .
实施例37Example 37
化合物39:Compound 39:
(S)-4-(3-氟-2-甲基苯基)-6-((3aR,7aS)-3a-甲氧基-2-甲基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯和(S)-4-(3-氟-2-甲基苯基)-6-((3aS,7aR)-3a-甲氧基-2-甲基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aR,7aS)-3a-methoxy-2-methyl-1-oxooctahydro-5H-pyrrole[ 3,4-c]pyridin-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester and (S)-4-(3- Fluoro-2-methylphenyl)-6-((3aS,7aR)-3a-methoxy-2-methyl-1-oxooctahydro-5H-pyrro[3,4-c]pyridine-5 -yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000269
Figure PCTCN2021135751-appb-000269
化合物39的合成参考化合物1，通过使用顺式(3aR,7aS)-3a-甲氧基-2-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体顺式33-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物39。The synthesis of compound 39 referenced compound 1 by using cis (3aR,7aS)-3a-methoxy-2-methyloctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate cis Formula 33-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give a yellow solid Compound 39.
化合物39(36毫克)。MS:542.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98-7.96(m,1H),7.90-7.88(m,1H),7.26(d,J＝7.7Hz,1H),7.23–7.17(m,1H),7.02-6.97(m,1H),5.98(s,1H),4.78(d,J＝16.0Hz,0.5H),4.67(d,J＝16.0Hz,0.5H),4.56(d,J＝16.0Hz,0.5H),4.36(d,J＝16.0Hz,0.5H),4.07(q,J＝7.2Hz,2H),3.96(d,J＝12.5Hz,0.5H),3.83(d,J＝12.5Hz,0.5H),3.74-3.68(m,1H),3.65-3.53(m,1H),3.41(s,1.5H),3.34(s,1.5H),3.23–3.16(m,1H),3.11-3.07(m,3H),2.90(s,1.5H),2.89(s,1.5H),2.44(s,3H),2.38–2.18(m,2H),1.10(t,J＝7.2,3H)。 Compound 39 (36 mg). MS: 542.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98-7.96(m,1H),7.90-7.88(m,1H),7.26(d,J=7.7Hz,1H),7.23-7.17(m,1H) ), 7.02-6.97(m, 1H), 5.98(s, 1H), 4.78(d, J=16.0Hz, 0.5H), 4.67(d, J=16.0Hz, 0.5H), 4.56(d, J= 16.0Hz, 0.5H), 4.36 (d, J=16.0Hz, 0.5H), 4.07 (q, J=7.2Hz, 2H), 3.96 (d, J=12.5Hz, 0.5H), 3.83 (d, J =12.5Hz,0.5H),3.74-3.68(m,1H),3.65-3.53(m,1H),3.41(s,1.5H),3.34(s,1.5H),3.23-3.16(m,1H) ,3.11-3.07(m,3H),2.90(s,1.5H),2.89(s,1.5H),2.44(s,3H),2.38-2.18(m,2H),1.10(t,J=7.2, 3H).
实施例38Example 38
化合物40:Compound 40:
(S)-4-(3-氟-2-甲基苯基)-6-((3aS,7aS)-3a-羟基-7a-甲基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aS,7aS)-3a-hydroxy-7a-methyl-1-oxooctahydro-5H-pyrrole[3, 4-c]Pyridin-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000270
Figure PCTCN2021135751-appb-000270
化合物40的合成参考化合物1，通过使用(3aR,7aS)-3a-羟基-7a-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体34-3a)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物40。Synthesis of compound 40 Reference compound 1, by using (3aR,7aS)-3a-hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 34-3a) instead 4,5,6,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 40 as a yellow solid.
化合物40(68.7毫克)。MS:528.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.0Hz,1H),7.88(d,J＝3.0Hz,1H),7.27(d,J＝7.8Hz,1H),7.24–7.17(m,1H),7.00(t,J＝8.9Hz,1H),5.98(s,1H),4.62(s,2H),4.08(q,J＝7.2Hz,2H),3.68(d,J＝13.0Hz,1H),3.54(d,J＝13.0Hz,1H),3.49–3.37(m,2H),3.30-3.25(m,1H),3.18-3.11(m,1H),2.45(s,3H),2.25-2.21(m,1H),2.03-1.95(m,1H),1.23(s,3H),1.11(t,J＝7.2Hz,3H)。 Compound 40 (68.7 mg). MS: 528.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.0Hz,1H),7.88(d,J=3.0Hz,1H),7.27(d,J=7.8Hz,1H),7.24 –7.17(m, 1H), 7.00(t, J=8.9Hz, 1H), 5.98(s, 1H), 4.62(s, 2H), 4.08(q, J=7.2Hz, 2H), 3.68(d, J=13.0Hz, 1H), 3.54(d, J=13.0Hz, 1H), 3.49-3.37(m, 2H), 3.30-3.25(m, 1H), 3.18-3.11(m, 1H), 2.45(s) , 3H), 2.25-2.21 (m, 1H), 2.03-1.95 (m, 1H), 1.23 (s, 3H), 1.11 (t, J=7.2Hz, 3H).
实施例39Example 39
化合物41:Compound 41:
(S)-4-(3-氟-2-甲基苯基)-6-((3aR,7aR)-3a-羟基-7a-甲基-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-4-(3-Fluoro-2-methylphenyl)-6-((3aR,7aR)-3a-hydroxy-7a-methyl-1-oxooctahydro-5H-pyrrole[3, 4-c]Pyridin-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000271
Figure PCTCN2021135751-appb-000271
化合物41的合成参考化合物1，通过使用(3aS,7aR)-3a-羟基-7a-甲基八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体34-3b)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物41。Synthesis of compound 41 Reference compound 1, by using (3aS,7aR)-3a-hydroxy-7a-methyloctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 34-3b) in place of 4,5,6,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 41 as a yellow solid.
化合物41(67.1毫克)。MS:528.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(d,J＝3.1Hz,1H),7.87(d,J＝3.1Hz,1H),7.26(d,J＝7.9Hz,1H),7.24–7.17(m,1H),6.99(t,J＝8.9Hz,1H),5.99(s,1H),4.78(d,J＝16.0Hz,1H),4.42(d,J＝16.0Hz,1H),4.07(q,J＝7.1Hz,2H),3.60-3.55(m,2H),3.41-3.33(m,2H),3.26–3.07(m,2H),2.45(s,3H),2.25-2.21(m,1H),2.08–1.96(m,1H),1.22(s,3H),1.10(t,J＝7.1Hz,3H)。 Compound 41 (67.1 mg). MS: 528.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(d,J=3.1Hz,1H),7.87(d,J=3.1Hz,1H),7.26(d,J=7.9Hz,1H),7.24 –7.17(m,1H),6.99(t,J=8.9Hz,1H),5.99(s,1H),4.78(d,J=16.0Hz,1H),4.42(d,J=16.0Hz,1H) ,4.07(q,J＝7.1Hz,2H),3.60-3.55(m,2H),3.41-3.33(m,2H),3.26-3.07(m,2H),2.45(s,3H),2.25-2.21 (m, 1H), 2.08–1.96 (m, 1H), 1.22 (s, 3H), 1.10 (t, J=7.1 Hz, 3H).
实施例40Example 40
化合物42:Compound 42:
4-((3aR,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene Formic acid
Figure PCTCN2021135751-appb-000272
Figure PCTCN2021135751-appb-000272
化合物42的合成参考化合物1，通过使用4-((3aR,7aS)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体35-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物42。Synthesis of compound 42 Reference compound 1 by using 4-((3aR,7aS)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl ) benzoic acid (Intermediate 35-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 42 as a yellow solid.
化合物42(110毫克)。MS:648.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.08–8.01(m,2H),7.94(d,J＝3.1Hz,1H),7.85(d,J＝3.1Hz,1H),7.82–7.77(m,2H),7.26(d,J＝7.9Hz,1H),7.21-7.16(m,1H),7.01-6.96(m,1H),5.98(s,1H),4.80(d,J＝16.0Hz,1H),4.42(d,J＝16.0Hz,1H),4.05(q,J＝7.1Hz,2H),3.97(d,J＝10.4Hz,1H),3.88-3.80(m,1H),3.63-3.57(m,2H),3.43(d,J＝13.2Hz,1H),3.23(td,J＝12.4,3.5Hz,1H),2.44(s,3H),2.36-2.32(m,1H),2.16-2.08(m,1H),1.32(s,3H),1.08(t,J＝7.1Hz,3H)。 Compound 42 (110 mg). MS: 648.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.08-8.01(m,2H),7.94(d,J=3.1Hz,1H),7.85(d,J=3.1Hz,1H),7.82-7.77( m, 2H), 7.26(d, J=7.9Hz, 1H), 7.21-7.16(m, 1H), 7.01-6.96(m, 1H), 5.98(s, 1H), 4.80(d, J=16.0Hz ,1H),4.42(d,J＝16.0Hz,1H),4.05(q,J＝7.1Hz,2H),3.97(d,J＝10.4Hz,1H),3.88-3.80(m,1H),3.63 -3.57(m, 2H), 3.43(d, J=13.2Hz, 1H), 3.23(td, J=12.4, 3.5Hz, 1H), 2.44(s, 3H), 2.36-2.32(m, 1H), 2.16-2.08 (m, 1H), 1.32 (s, 3H), 1.08 (t, J=7.1 Hz, 3H).
实施例41Example 41
化合物43:Compound 43:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene Formic acid
Figure PCTCN2021135751-appb-000273
Figure PCTCN2021135751-appb-000273
化合物43的合成参考化合物1，通过使用4-((3aS,7aR)-3a-羟基-7a-甲基-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体36-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物43。Synthesis of compound 43 Reference compound 1 by using 4-((3aS,7aR)-3a-hydroxy-7a-methyl-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl ) benzoic acid (Intermediate 36-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 43 as a yellow solid.
化合物43(122毫克)。MS:648.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.09–8.02(m,2H),7.96(d,J＝3.1Hz,1H),7.88(d,J＝3.1Hz,1H),7.84–7.78(m,2H),7.27(dd,J＝7.8,1.2Hz,1H),7.22-7.18(m,1H),7.01-6.97(m,1H),5.98(s,1H),4.62(s,2H),4.06(q,J＝7.1Hz,2H),3.99(d,J＝10.4Hz,1H),3.93-3.87(m,1H),3.74-3.68(m,1H),3.58-3.48(m,2H),3.30–3.23(m,1H),2.45(s,3H),2.37-2.33(m,1H),2.13-2.06(m,1H),1.33(s,3H),1.10(t,J＝7.1Hz,3H)。 Compound 43 (122 mg). MS: 648.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.09-8.02(m,2H),7.96(d,J=3.1Hz,1H),7.88(d,J=3.1Hz,1H),7.84-7.78( m, 2H), 7.27(dd, J=7.8, 1.2Hz, 1H), 7.22-7.18(m, 1H), 7.01-6.97(m, 1H), 5.98(s, 1H), 4.62(s, 2H) ,4.06(q,J=7.1Hz,2H),3.99(d,J=10.4Hz,1H),3.93-3.87(m,1H),3.74-3.68(m,1H),3.58-3.48(m,2H ), 3.30-3.23(m, 1H), 2.45(s, 3H), 2.37-2.33(m, 1H), 2.13-2.06(m, 1H), 1.33(s, 3H), 1.10(t, J=7.1 Hz, 3H).
实施例42Example 42
化合物44:Compound 44:
(S)-6-(((3aR,7aR)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(((3aR,7aR)-7a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl)methyl)-4-(3- Fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000274
Figure PCTCN2021135751-appb-000274
化合物44的合成参考化合物1，通过使用(3aS,7aR)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体39-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物44。Synthesis of compound 44 Reference compound 1 by using (3aS,7aR)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 39-3) in place of 4,5,6 ,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 44 as a yellow solid.
化合物44(44毫克)。MS:516.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98(d,J＝3.2Hz,1H),7.88(d,J＝3.2Hz,1H),7.27(d,J＝7.7Hz,1H),7.23-7.17(m,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.69–4.55(m,2H),4.08(q,J＝7.1Hz,2H),3.84(dd,J＝13.2,6.2Hz,1H),3.72(dd,J＝10.8,6.2Hz,2H),3.33–3.23(m,2H),3.15-3.05(m,1H),2.60-2.50(m,1H),2.49-2.42(m,4H),1.11(t,J＝7.1Hz,3H)。 Compound 44 (44 mg). MS: 516.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98(d,J=3.2Hz,1H),7.88(d,J=3.2Hz,1H),7.27(d,J=7.7Hz,1H),7.23 -7.17(m, 1H), 7.00(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.69–4.55(m, 2H), 4.08(q, J=7.1Hz, 2H), 3.84( dd,J＝13.2,6.2Hz,1H),3.72(dd,J＝10.8,6.2Hz,2H),3.33-3.23(m,2H),3.15-3.05(m,1H),2.60-2.50(m, 1H), 2.49-2.42 (m, 4H), 1.11 (t, J=7.1 Hz, 3H).
实施例43Example 43
化合物45:Compound 45:
(S)-6-(((3aS,7aS)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(((3aS,7aS)-7a-fluoro-1-oxooctahydro-5H-pyrro[3,4-c]pyridin-5-yl)methyl)-4-(3- Fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000275
Figure PCTCN2021135751-appb-000275
化合物45的合成参考化合物1，通过使用(3aR,7aS)-7a-氟八氢-1H-吡咯[3,4-c]吡啶-1-酮(中间体40-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物45。Synthesis of compound 45 Reference compound 1 by using (3aR,7aS)-7a-fluorooctahydro-1H-pyrro[3,4-c]pyridin-1-one (intermediate 40-3) in place of 4,5,6 ,7-Tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 45 as a yellow solid.
化合物45(30毫克)。MS:516.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98(d,J＝2.9Hz,1H),7.88(d,J＝2.9Hz,1H),7.26(d,J＝7.9Hz,1H),7.22-7.18(m,1H),6.99(t,J＝9.1Hz,1H),5.98(s,1H),4.73(d,J＝16.7Hz,1H),4.50(d,J＝16.7Hz,1H),4.07(q,J＝7.2Hz,2H),3.86–3.76(m,1H),3.72-3.66(m,2H),3.35-3.28(m,1H),3.25–3.04(m,3H),2.45(s,5H),1.10(t,J＝7.2Hz,3H)。 Compound 45 (30 mg). MS: 516.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98(d,J=2.9Hz,1H),7.88(d,J=2.9Hz,1H),7.26(d,J=7.9Hz,1H),7.22 -7.18(m,1H),6.99(t,J=9.1Hz,1H),5.98(s,1H),4.73(d,J=16.7Hz,1H),4.50(d,J=16.7Hz,1H) ,4.07(q,J＝7.2Hz,2H),3.86-3.76(m,1H),3.72-3.66(m,2H),3.35-3.28(m,1H),3.25-3.04(m,3H),2.45 (s, 5H), 1.10 (t, J=7.2 Hz, 3H).
实施例44Example 44
化合物46:Compound 46:
2-氯-4-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸和2-氯-4-((3aR,7aS)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸2-Chloro-4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid and 2-Chloro-4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000276
Figure PCTCN2021135751-appb-000276
化合物46的合成参考化合物1，通过使用顺式-2-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体顺式37-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物46。Synthesis of compound 46 Reference compound 1 by using cis-2-chloro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridine- 2-yl)benzoic acid (intermediate cis 37-3) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate ( Intermediate 1-4) was prepared to obtain compound 46 as a yellow solid.
化合物46(58毫克)。MS:671.6(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.03-7.86(m,4H),7.74(dd,J＝8.7,2.5Hz,1H),7.26(d,J＝7.9Hz,1H),7.23-7.18(m,1H),6.99(t,J＝8.9Hz,1H),5.99(s,1H),4.69(d,J＝16.4Hz,0.5H),4.61(d,J＝16.4Hz,0.5H),4.52(d,J＝16.4Hz,0.5H),4.45(d,J＝16.4Hz,0.5H),4.30-4.22(m,1H),4.07(q,J＝7.2Hz,2H),3.88–3.71(m,2H),3.65-3.60(m,1H),3.37-3.33(m,1H),3.27-3.20(m,2H),2.63-2.59(m,1H),2.49-2.45(m,4H),1.10(t,J＝7.2Hz,3H)。 Compound 46 (58 mg). MS: 671.6 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ8.03-7.86(m, 4H), 7.74(dd, J=8.7, 2.5Hz, 1H), 7.26(d, J=7.9Hz, 1H), 7.23- 7.18(m, 1H), 6.99(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.69(d, J=16.4Hz, 0.5H), 4.61(d, J=16.4Hz, 0.5H) ),4.52(d,J＝16.4Hz,0.5H),4.45(d,J＝16.4Hz,0.5H),4.30-4.22(m,1H),4.07(q,J＝7.2Hz,2H),3.88 –3.71(m, 2H), 3.65-3.60(m, 1H), 3.37-3.33(m, 1H), 3.27-3.20(m, 2H), 2.63-2.59(m, 1H), 2.49-2.45(m, 4H), 1.10 (t, J=7.2Hz, 3H).
实施例45Example 45
化合物47:Compound 47:
(S)-6-((3aS,7aR)-2-(3-氯-4-(甲氧羰基)苯基)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯和(S)-6-((3aR,7aS)-2-(3-氯-4-(甲氧羰基)苯基)-7a-氟-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-((3aS,7aR)-2-(3-chloro-4-(methoxycarbonyl)phenyl)-7a-fluoro-1-oxooctahydro-5H-pyrrole[3,4- c]Pyridin-5-yl)methyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl Esters and (S)-6-((3aR,7aS)-2-(3-chloro-4-(methoxycarbonyl)phenyl)-7a-fluoro-1-oxooctahydro-5H-pyrrole[3, 4-c]pyridin-5-yl)methyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Ethyl acetate
Figure PCTCN2021135751-appb-000277
Figure PCTCN2021135751-appb-000277
化合物47的合成参考化合物1，通过使用顺式-2-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯 [3,4-c]吡啶-2-基)苯甲酸甲酯(中间体顺式38-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物47。Synthesis of compound 47 Reference compound 1 by using cis-2-chloro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridine-2 -yl) methyl benzoate (intermediate cis 38-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) was prepared to give compound 47 as a yellow solid.
化合物47(5.8毫克)。MS:685.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.04(s,1H),7.99–7.92(m,2H),7.92–7.86(m,1H),7.76(d,J＝8.8Hz,1H),7.30–7.13(m,2H),6.99(t,J＝9.0Hz,1H),5.99(s,1H),4.59(d,J＝16.4Hz,1H),4.50(d,J＝16.4Hz,1H),4.32-4.25(m,1H),4.08(q,J＝7.2Hz,2H),3.91(s,3H),3.88–3.72(m,2H),3.64-3.58(m,1H),3.36-3.30(m,1H),3.24-3.17(m,2H),2.70–2.56(m,1H),2.50-2.45(m,4H),1.10(t,J＝7.2Hz,3H)。 Compound 47 (5.8 mg). MS: 685.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.04(s,1H),7.99-7.92(m,2H),7.92-7.86(m,1H),7.76(d,J=8.8Hz,1H), 7.30–7.13(m, 2H), 6.99(t, J=9.0Hz, 1H), 5.99(s, 1H), 4.59(d, J=16.4Hz, 1H), 4.50(d, J=16.4Hz, 1H) ), 4.32-4.25(m, 1H), 4.08(q, J=7.2Hz, 2H), 3.91(s, 3H), 3.88-3.72(m, 2H), 3.64-3.58(m, 1H), 3.36- 3.30 (m, 1H), 3.24-3.17 (m, 2H), 2.70-2.56 (m, 1H), 2.50-2.45 (m, 4H), 1.10 (t, J=7.2Hz, 3H).
实施例46Example 46
化合物48:Compound 48:
2-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丙烷-1-羧酸2-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclopropane -1-Carboxylic acid
Figure PCTCN2021135751-appb-000278
Figure PCTCN2021135751-appb-000278
化合物48的合成参考化合物1，通过使用2-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丙烷-1-羧酸(中间体41-4)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物48。Synthesis of compound 48 Reference compound 1 by using 2-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Cyclopropane-1-carboxylic acid (intermediate 41-4) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate Body 1-4) was prepared to obtain compound 48 as a yellow solid.
化合物48(9.8毫克)。MS:614.1(M+H) +。 Compound 48 (9.8 mg). MS: 614.1 (M+H) + .
实施例47Example 47
化合物49:Compound 49:
3-((3aS，7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2-di Methylpropionic acid
Figure PCTCN2021135751-appb-000279
Figure PCTCN2021135751-appb-000279
化合物49的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸(中间体42-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体 1-4)制备得到黄色固体化合物49。Synthesis of compound 49 Reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2 - Dimethylpropionic acid (Intermediate 42-3) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 49 was prepared as a yellow solid.
化合物49(19.8毫克)。MS:616.5(M+H) +。 Compound 49 (19.8 mg). MS: 616.5 (M+H) + .
实施例48Example 48
化合物50:Compound 50:
3-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸3-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclobutane Alkane-1-carboxylic acid
Figure PCTCN2021135751-appb-000280
Figure PCTCN2021135751-appb-000280
化合物50的合成参考化合物1，通过使用3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸(中间体43-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物50。Synthesis of compound 50 Reference compound 1 by using 3-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Cyclobutane-1-carboxylic acid (Intermediate 43-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate ( Intermediate 1-4) was prepared to obtain compound 50 as a yellow solid.
化合物50(17毫克)。MS:628.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(dd,J＝5.9,3.1Hz,1H),7.83(d,J＝3.1Hz,1H),7.22–7.12(m,2H),7.00–6.94(m,1H),5.98(s,1H),4.48–4.28(m,2H),4.06(q,J＝7.1Hz,2H),3.72-3.65(m,1H),3.58–3.37(m,3H),3.19-3.13(m,1H),3.06-3.28(m,4H),2.61-2.57(m,1H),2.52–2.22(m,8H),2.14–1.95(m,2H),1.11(t,J＝7.1Hz,3H)。 Compound 50 (17 mg). MS: 628.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(dd,J=5.9,3.1Hz,1H),7.83(d,J=3.1Hz,1H),7.22-7.12(m,2H),7.00- 6.94(m, 1H), 5.98(s, 1H), 4.48-4.28(m, 2H), 4.06(q, J=7.1Hz, 2H), 3.72-3.65(m, 1H), 3.58-3.37(m, 3H), 3.19-3.13(m, 1H), 3.06-3.28(m, 4H), 2.61-2.57(m, 1H), 2.52-2.22(m, 8H), 2.14-1.95(m, 2H), 1.11( t, J=7.1 Hz, 3H).
实施例49Example 49
化合物51:Compound 51:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)cyclopentane-1- carboxylic acid
Figure PCTCN2021135751-appb-000281
Figure PCTCN2021135751-appb-000281
化合物51的合成参考化合物1，通过使用3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸(中间体44-3)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物51。Synthesis of compound 51 Reference compound 1 by using 3-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)cyclopentane -1-Carboxylic acid (Intermediate 44-3) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1 -4) Preparation of yellow solid compound 51.
化合物51(17毫克)。MS:628.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.99–7.94(m,1H), 7.91–7.85(m,1H),7.26–7.15(m,2H),7.01-6.96(m,1H),5.98(s,1H),4.62-4.45(m,3H),4.07(q,J＝7.1Hz,2H),3.79-3.74(m,1H),3.66-3.62(m,1H),3.54-3.50(m,1H),3.16-3.10(m,2H),3.05–2.86(m,2H),2.46(d,J＝2.1Hz,5H),2.27–2.18(m,1H),2.13-2.09(m,1H),2.08–1.68(m,5H),1.11(t,J＝7.1Hz,3H)。 Compound 51 (17 mg). MS: 628.2 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.99-7.94(m,1H), 7.91-7.85(m,1H), 7.26-7.15(m,2H), 7.01-6.96(m,1H), 5.98 (s,1H),4.62-4.45(m,3H),4.07(q,J=7.1Hz,2H),3.79-3.74(m,1H),3.66-3.62(m,1H),3.54-3.50(m ,1H),3.16-3.10(m,2H),3.05-2.86(m,2H),2.46(d,J=2.1Hz,5H),2.27-2.18(m,1H),2.13-2.09(m,1H ), 2.08–1.68 (m, 5H), 1.11 (t, J=7.1Hz, 3H).
实施例50Example 50
化合物52:Compound 52:
2-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸2-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)cyclopentane-1- carboxylic acid
Figure PCTCN2021135751-appb-000282
Figure PCTCN2021135751-appb-000282
化合物52的合成参考化合物1，通过使用2-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)环戊烷-1-羧酸(中间体45-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物52。Synthesis of compound 52 Reference compound 1 by using 2-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)cyclopentane- 1-Carboxylic acid (Intermediate 45-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) Preparation of yellow solid compound 52.
化合物52(55毫克)。MS:628.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.92-7.86(m,1H),7.72-7.69(m,1H),7.16–7.04(m,2H),6.94-6.89(m,1H),5.96(d,J＝1.5Hz,1H),4.63-4.57(m,1H),4.14–3.87(m,4H),3.63-3.59(m,1H),3.47-3.43(m,1H),3.02–2.80(m,2H),2.75–2.47(m,7H),2.21–1.89(m,5H),1.81-1.77(m,3H),1.11(t,J＝7.1Hz,3H)。 Compound 52 (55 mg). MS: 628.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.92-7.86(m,1H),7.72-7.69(m,1H),7.16-7.04(m,2H),6.94-6.89(m,1H),5.96 (d, J＝1.5Hz, 1H), 4.63-4.57(m, 1H), 4.14-3.87(m, 4H), 3.63-3.59(m, 1H), 3.47-3.43(m, 1H), 3.02-2.80 (m, 2H), 2.75-2.47 (m, 7H), 2.21-1.89 (m, 5H), 1.81-1.77 (m, 3H), 1.11 (t, J=7.1 Hz, 3H).
实施例51Example 51
化合物53:Compound 53:
(S)-6-(((3aR,7aS)-7a-氟-2-(4-(甲氧基羰基)苯基)-1-氧代八氢-5H-吡咯[3,4-c]吡啶-5-基)甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(S)-6-(((3aR,7aS)-7a-fluoro-2-(4-(methoxycarbonyl)phenyl)-1-oxooctahydro-5H-pyrrole[3,4-c] Pyridin-5-yl)methyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate ethyl ester
Figure PCTCN2021135751-appb-000283
Figure PCTCN2021135751-appb-000283
化合物53的合成参考化合物1，通过使用4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸甲酯(中间体46-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物53。Synthesis of compound 53 Reference compound 1 by using methyl 4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoate (Intermediate 46-2) prepared in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 53 as a yellow solid.
化合物53(26.7毫克)。MS:650.7(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.14–8.05(m,2H),7.92(d,J＝3.2Hz,1H),7.90–7.84(m,3H),7.25–7.14(m,2H),6.98(t,J＝8.8Hz,1H),5.99(s,1H),4.61(d,J＝16.5Hz,1H),4.38(d,J＝16.5Hz,1H),4.23(dd,J＝10.5,6.7Hz,1H),4.06(q,J＝7.2Hz,2H),3.90(s,3H),3.87(dd,J＝10.5,4.5Hz,1H),3.63(br,1H),3.47(br,1H),3.25-3.15(m,3H),2.62-2.52(m,1H),2.48-2.36(m,4H),1.10(t,J＝7.2,3H)。 Compound 53 (26.7 mg). MS: 650.7 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.14-8.05(m,2H),7.92(d,J=3.2Hz,1H),7.90-7.84(m,3H),7.25-7.14(m,2H) ),6.98(t,J＝8.8Hz,1H),5.99(s,1H),4.61(d,J＝16.5Hz,1H),4.38(d,J＝16.5Hz,1H),4.23(dd,J =10.5,6.7Hz,1H),4.06(q,J=7.2Hz,2H),3.90(s,3H),3.87(dd,J=10.5,4.5Hz,1H),3.63(br,1H),3.47 (br, 1H), 3.25-3.15 (m, 3H), 2.62-2.52 (m, 1H), 2.48-2.36 (m, 4H), 1.10 (t, J=7.2, 3H).
实施例52Example 52
化合物54:Compound 54:
4-((3aR,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000284
Figure PCTCN2021135751-appb-000284
化合物54的合成参考化合物1，通过使用4-(((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体47-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物54。Synthesis of compound 54 Reference compound 1 by using 4-(((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 47-1) was prepared in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 54 as a yellow solid.
化合物54(30毫克)。MS:636.6(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.10(d,J＝8.5Hz,2H),7.95(d,J＝3.2Hz,1H),7.90(d,J＝3.2Hz,1H),7.86(d,J＝8.5Hz,2H),7.25(d,J＝7.8Hz,1H),7.21-7.16(m,1H),6.99(t,J＝8.9Hz,1H),5.99(s,1H),4.68(d,J＝16.4Hz,1H),4.45(d,J＝16.4Hz,1H),4.27(dd,J＝10.6,6.6Hz,1H),4.06(q,J＝7.0Hz,2H),3.85(dd,J＝10.6,4.1Hz,1H),3.78-3.72(m,1H),3.62-3.58(m,1H),3.34(d,J＝8.5Hz,1H),3.25-3.15(m,2H),2.64-2.58(m,1H),2.50-2.40(m,4H),1.10(t,J＝7.0Hz,3H)。 Compound 54 (30 mg). MS: 636.6 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.10(d,J=8.5Hz,2H),7.95(d,J=3.2Hz,1H),7.90(d,J=3.2Hz,1H),7.86 (d, J＝8.5Hz, 2H), 7.25(d, J＝7.8Hz, 1H), 7.21-7.16(m, 1H), 6.99(t, J＝8.9Hz, 1H), 5.99(s, 1H) ,4.68(d,J＝16.4Hz,1H),4.45(d,J＝16.4Hz,1H),4.27(dd,J＝10.6,6.6Hz,1H),4.06(q,J＝7.0Hz,2H) ,3.85(dd,J＝10.6,4.1Hz,1H),3.78-3.72(m,1H),3.62-3.58(m,1H),3.34(d,J＝8.5Hz,1H),3.25-3.15(m , 2H), 2.64-2.58 (m, 1H), 2.50-2.40 (m, 4H), 1.10 (t, J=7.0Hz, 3H).
实施例53Example 53
化合物55:Compound 55:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000285
Figure PCTCN2021135751-appb-000285
化合物55的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体48-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物55。Synthesis of compound 55 reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 48-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) was prepared to give a yellow solid Compound 55.
化合物55(33毫克)。MS:636.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.09(d,J＝8.4Hz,2H),7.97(d,J＝3.1Hz,1H),7.90(d,J＝3.1Hz,1H),7.86(d,J＝8.4Hz,2H),7.27(d,J＝7.9Hz,1H),7.23-7.17(m,1H),6.99(t,J＝8.9Hz,1H),5.99(d,J＝3.1Hz,1H),4.78–4.47(m,3H),4.34-4.27(m,1H),4.06(q,J＝7.1Hz,2H),3.94–3.79(m,2H),3.75-3.66(m,1H),3.45-3.35(m,1H),3.25-3.15(m,1H),2.70-2.60(m,1H),2.55-2.35(m,4H),1.09(t,J＝7.1Hz,3H)。 Compound 55 (33 mg). MS: 636.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.09(d,J=8.4Hz,2H),7.97(d,J=3.1Hz,1H),7.90(d,J=3.1Hz,1H),7.86 (d, J=8.4Hz, 2H), 7.27 (d, J=7.9Hz, 1H), 7.23-7.17 (m, 1H), 6.99 (t, J=8.9Hz, 1H), 5.99 (d, J= 3.1Hz, 1H), 4.78-4.47(m, 3H), 4.34-4.27(m, 1H), 4.06(q, J=7.1Hz, 2H), 3.94-3.79(m, 2H), 3.75-3.66(m ,1H),3.45-3.35(m,1H),3.25-3.15(m,1H),2.70-2.60(m,1H),2.55-2.35(m,4H),1.09(t,J=7.1Hz,3H ).
实施例54Example 54
化合物56:Compound 56:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000286
Figure PCTCN2021135751-appb-000286
化合物56的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物56。Synthesis of compound 56 reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) was prepared to give a yellow solid Compound 56.
化合物56(11.7毫克)。MS:636.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.29(s,1H),8.09(d,J＝8.3Hz,1H),7.98–7.84(m,3H),7.56(t,J＝8.0Hz,1H),7.26(d,J＝7.8Hz,1H),7.22-7.16(m,1H),6.99(t,J＝9.0Hz,1H),5.99(s,1H),4.55(br,2H),4.28-4.26(m,1H),4.07(q,J＝7.1Hz,2H),3.97-3.92(m,1H),3.72-3.68(m,1H),3.58-3.43(m,2H),3.25-3.13(m,2H),2.60-2.45(m,5H),1.11(t,J＝7.1Hz,3H)。 Compound 56 (11.7 mg). MS: 636.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.29(s,1H),8.09(d,J=8.3Hz,1H),7.98-7.84(m,3H),7.56(t,J=8.0Hz, 1H), 7.26(d, J=7.8Hz, 1H), 7.22-7.16(m, 1H), 6.99(t, J=9.0Hz, 1H), 5.99(s, 1H), 4.55(br, 2H), 4.28-4.26(m, 1H), 4.07(q, J=7.1Hz, 2H), 3.97-3.92(m, 1H), 3.72-3.68(m, 1H), 3.58-3.43(m, 2H), 3.25- 3.13 (m, 2H), 2.60-2.45 (m, 5H), 1.11 (t, J=7.1 Hz, 3H).
实施例55Example 55
化合物57:Compound 57:
3-氯-4-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Chloro-4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000287
Figure PCTCN2021135751-appb-000287
化合物57的合成参考化合物1，通过使用3-氯-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体50-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物57。Synthesis of compound 57 Reference compound 1 by using 3-chloro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid (Intermediate 50-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 57 was prepared as a yellow solid.
化合物57(72毫克)。MS:671.6(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.17(s,1H),8.06(d,J＝8.3Hz,1H),7.96(d,J＝3.0Hz,1H),7.86(d,J＝3.0Hz,1H),7.61(d,J＝8.3Hz,1H),7.27(d,J＝8.0Hz,1H),7.23-7.18(m,1H),6.99(t,J＝8.8Hz,1H),6.00(s,1H),4.67(d,J＝16.4Hz,1H),4.58(d,J＝16.4Hz,1H),4.23-4.19(m,1H),4.08(q,J＝7.3Hz,2H),3.90-3.86(m,1H),3.74-3.68(m,2H),3.52–3.39(m,1H),3.33-3.25(m,2H),2.69-2.65(m,1H),2.55-2.52(m,1H),2.46(s,3H),1.11(t,J＝7.3Hz,3H)。 Compound 57 (72 mg). MS: 671.6 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.17(s,1H),8.06(d,J=8.3Hz,1H),7.96(d,J=3.0Hz,1H),7.86(d,J= 3.0Hz, 1H), 7.61 (d, J=8.3Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.23-7.18 (m, 1H), 6.99 (t, J=8.8Hz, 1H) ,6.00(s,1H),4.67(d,J＝16.4Hz,1H),4.58(d,J＝16.4Hz,1H),4.23-4.19(m,1H),4.08(q,J＝7.3Hz, 2H), 3.90-3.86(m, 1H), 3.74-3.68(m, 2H), 3.52-3.39(m, 1H), 3.33-3.25(m, 2H), 2.69-2.65(m, 1H), 2.55- 2.52 (m, 1H), 2.46 (s, 3H), 1.11 (t, J=7.3Hz, 3H).
实施例56Example 56
化合物58:Compound 58:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-氟苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-fluorobenzoic acid
Figure PCTCN2021135751-appb-000288
Figure PCTCN2021135751-appb-000288
化合物58的合成参考化合物1，通过使用3-氟-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体51-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物58。Synthesis of compound 58 Reference compound 1 by using 3-fluoro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid (Intermediate 51-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 58 was prepared as a yellow solid.
化合物58(36毫克)。MS:654.6(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.99–7.83(m,4H),7.72(t,J＝7.9Hz,1H),7.27-7.16(m,2H),6.99(t,J＝8.9Hz,1H),6.00(s,1H),4.63(d,J＝16.4Hz,1H),4.55(d,J＝16.4Hz,1H),4.28-4.22(m,1H),4.08(q,J＝7.2Hz,2H),3.92–3.74(m,2H),3.68-3.62(m,1H),3.41–3.33(m,1H),3.21-3.26(m,2H),2.67-2.63(m,1H),2.54-2.49(m,1H),2.46(s,3H),1.11(t,J＝7.2Hz,3H)。 Compound 58 (36 mg). MS: 654.6 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.99-7.83(m,4H),7.72(t,J=7.9Hz,1H),7.27-7.16(m,2H),6.99(t,J=8.9 Hz,1H),6.00(s,1H),4.63(d,J＝16.4Hz,1H),4.55(d,J＝16.4Hz,1H),4.28-4.22(m,1H),4.08(q,J =7.2Hz,2H),3.92-3.74(m,2H),3.68-3.62(m,1H),3.41-3.33(m,1H),3.21-3.26(m,2H),2.67-2.63(m,1H) ), 2.54-2.49 (m, 1H), 2.46 (s, 3H), 1.11 (t, J=7.2Hz, 3H).
实施例57Example 57
化合物59:Compound 59:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-4-氟苯甲酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-4-fluorobenzoic acid
Figure PCTCN2021135751-appb-000289
Figure PCTCN2021135751-appb-000289
化合物59的合成参考化合物1，通过使用4-氟-3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体52-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物59。Synthesis of compound 59 Reference compound 1 by using 4-fluoro-3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl ) benzoic acid (Intermediate 52-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 59 as a yellow solid.
化合物59(73毫克)。MS:654.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.24(dd,J＝7.4,2.1Hz,1H),8.14–8.06(m,1H),7.98(d,J＝2.9Hz,1H),7.89(d,J＝2.9Hz,1H),7.40(t,J＝9.5Hz,1H),7.28(d,J＝7.8Hz,1H),7.23-7.18(M,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.67(d,J＝16.4Hz,1H),4.59(d,J＝16.4Hz,1H),4.24(dd,J＝10.4,6.6Hz,1H),4.09(q,J＝7.1Hz,2H),3.89(dd,J＝12.9,5.7Hz,1H),3.82–3.66(m,2H),3.49–3.39(m,1H),3.35-3.25(m,2H),2.71-2.63(m,1H),2.61–2.44(m,4H),1.11(t,J＝7.1Hz,3H)。 Compound 59 (73 mg). MS: 654.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.24(dd,J=7.4,2.1Hz,1H),8.14-8.06(m,1H),7.98(d,J=2.9Hz,1H),7.89( d, J=2.9Hz, 1H), 7.40 (t, J=9.5Hz, 1H), 7.28 (d, J=7.8Hz, 1H), 7.23-7.18 (M, 1H), 7.00 (t, J=8.9 Hz,1H),6.00(s,1H),4.67(d,J=16.4Hz,1H),4.59(d,J=16.4Hz,1H),4.24(dd,J=10.4,6.6Hz,1H), 4.09(q, J=7.1Hz, 2H), 3.89(dd, J=12.9, 5.7Hz, 1H), 3.82-3.66(m, 2H), 3.49-3.39(m, 1H), 3.35-3.25(m, 2H), 2.71-2.63 (m, 1H), 2.61-2.44 (m, 4H), 1.11 (t, J=7.1 Hz, 3H).
实施例58Example 58
化合物60:Compound 60:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-氟苯甲酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-fluorobenzoic acid
Figure PCTCN2021135751-appb-000290
Figure PCTCN2021135751-appb-000290
化合物60的合成参考化合物1，通过使用3-氟-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体53-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物60。Synthesis of compound 60 Reference compound 1 by using 3-fluoro-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid (Intermediate 53-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolino[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 60 was prepared as a yellow solid.
化合物60(52毫克)。MS:654.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.09-8.05(m,2H), 7.98(d,J＝3.1Hz,1H),7.94(d,J＝3.1Hz,1H),7.64–7.57(m,1H),7.29(d,J＝7.8Hz,1H),7.23-7.19(m,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.63(s,2H),4.31(dd,J＝10.4,7.1Hz,1H),4.08(q,J＝7.2Hz,2H),3.93(dd,J＝10.5,5.1Hz,1H),3.82(dd,J＝13.4,5.8Hz,1H),3.71-3.67(m,1H),3.57-3.53(m,1H),3.39-3.35(m,1H),3.27-3.20(m,1H),2.69–2.43(m,5H),1.11(t,J＝7.2Hz,3H)。 Compound 60 (52 mg). MS: 654.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.09-8.05(m,2H), 7.98(d,J=3.1Hz,1H),7.94(d,J=3.1Hz,1H),7.64-7.57( m, 1H), 7.29(d, J=7.8Hz, 1H), 7.23-7.19(m, 1H), 7.00(t, J=8.9Hz, 1H), 6.00(s, 1H), 4.63(s, 2H) ),4.31(dd,J=10.4,7.1Hz,1H),4.08(q,J=7.2Hz,2H),3.93(dd,J=10.5,5.1Hz,1H),3.82(dd,J=13.4, 5.8Hz, 1H), 3.71-3.67(m, 1H), 3.57-3.53(m, 1H), 3.39-3.35(m, 1H), 3.27-3.20(m, 1H), 2.69-2.43(m, 5H) , 1.11 (t, J=7.2Hz, 3H).
实施例59Example 59
化合物61:Compound 61:
3-氯-5-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Chloro-5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000291
Figure PCTCN2021135751-appb-000291
化合物61的合成参考化合物1，通过使用3-氯-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体54-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物61。Synthesis of compound 61 Reference compound 1 by using 3-chloro-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid (Intermediate 54-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 61 was prepared as a yellow solid.
化合物61(64毫克)。MS:670.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.24(d,J＝2.2Hz,1H),8.17(s,1H),8.00–7.91(m,2H),7.86(d,J＝2.2Hz,1H),7.28(d,J＝7.9Hz,1H),7.23-7.19(m,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.63(s,2H),4.30(dd,J＝10.2,7.0Hz,1H),4.07(q,J＝7.2Hz,2H),3.92(dd,J＝10.2,5.0Hz,1H),3.81(dd,J＝13.5,5.7Hz,1H),3.71-3.65(m,1H),3.56-3.51(m,1H),3.37-3.30(m,1H),3.27-3.19(m,1H),2.65-2.45(m,5H),1.11(t,J＝7.2Hz,3H)。 Compound 61 (64 mg). MS: 670.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.24(d,J=2.2Hz,1H),8.17(s,1H),8.00-7.91(m,2H),7.86(d,J=2.2Hz, 1H), 7.28(d, J=7.9Hz, 1H), 7.23-7.19(m, 1H), 7.00(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.63(s, 2H), 4.30(dd,J＝10.2,7.0Hz,1H),4.07(q,J＝7.2Hz,2H),3.92(dd,J＝10.2,5.0Hz,1H),3.81(dd,J＝13.5,5.7Hz ,1H),3.71-3.65(m,1H),3.56-3.51(m,1H),3.37-3.30(m,1H),3.27-3.19(m,1H),2.65-2.45(m,5H),1.11 (t, J=7.2 Hz, 3H).
实施例60Example 60
化合物62:Compound 62:
3-(3-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3 6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯基)丁酸3-(3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2- yl)-36-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl)butanoic acid
Figure PCTCN2021135751-appb-000292
Figure PCTCN2021135751-appb-000292
化合物62的合成参考化合物1，通过使用3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c] 吡啶-2-基)苯基)丁酸(中间体55-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物62。Synthesis of compound 62 Reference compound 1 by using 3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene yl) butyric acid (Intermediate 55-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) Preparation of yellow solid compound 62.
化合物62(60毫克)。MS:678.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(d,J＝3.1Hz,1H),7.85(d,J＝3.1Hz,1H),7.56(d,J＝8.2Hz,2H),7.28(dd,J＝14.7,8.0Hz,3H),7.18(q,J＝7.4Hz,1H),6.99(t,J＝9.0Hz,1H),5.97(s,1H),4.69–4.48(m,2H),4.16–4.02(m,3H),3.85–3.65(m,2H),3.53(d,J＝10.6Hz,1H),3.13(s,5H),2.53(dd,J＝26.8,11.1Hz,3H),2.44(s,3H),2.36(d,J＝15.4Hz,1H),1.28(d,J＝6.9Hz,3H),1.09(t,J＝7.1Hz,3H)。 Compound 62 (60 mg). MS: 678.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(d,J=3.1Hz,1H),7.85(d,J=3.1Hz,1H),7.56(d,J=8.2Hz,2H),7.28 (dd, J=14.7, 8.0Hz, 3H), 7.18 (q, J=7.4Hz, 1H), 6.99 (t, J=9.0Hz, 1H), 5.97 (s, 1H), 4.69–4.48 (m, 2H), 4.16–4.02 (m, 3H), 3.85–3.65 (m, 2H), 3.53 (d, J=10.6Hz, 1H), 3.13 (s, 5H), 2.53 (dd, J=26.8, 11.1Hz) , 3H), 2.44 (s, 3H), 2.36 (d, J=15.4Hz, 1H), 1.28 (d, J=6.9Hz, 3H), 1.09 (t, J=7.1Hz, 3H).
实施例61Example 61
化合物63:Compound 63:
2-(3-((3aS,7aR)-5-((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸2-(3-((3aS,7aR)-5-((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl)- 2-Methylpropionic acid
Figure PCTCN2021135751-appb-000293
Figure PCTCN2021135751-appb-000293
化合物63的合成参考化合物1，通过使用2-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2-甲基丙酸(中间体56-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物63。Synthesis of compound 63 Reference compound 1 by using 2-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene yl)-2-methylpropionic acid (Intermediate 56-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 63 was prepared as a yellow solid.
化合物63(60毫克)。MS:678.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98–7.87(m,2H),7.80(d,J＝2.2Hz,1H),7.58(d,J＝8.2Hz,1H),7.42(t,J＝8.0Hz,1H),7.35–7.25(m,2H),7.20(q,J＝7.4Hz,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.62(d,J＝5.9Hz,2H),4.33–4.23(m,1H),4.14–4.00(m,2H),3.91–3.78(m,2H),3.73–3.65(m,1H),3.46(t,J＝10.5Hz,2H),3.19(s,1H),2.68–2.42(m,5H),1.59(s,6H),1.11(dd,J＝8.1,6.5Hz,3H)。 Compound 63 (60 mg). MS: 678.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98-7.87(m,2H),7.80(d,J=2.2Hz,1H),7.58(d,J=8.2Hz,1H),7.42(t, J=8.0Hz, 1H), 7.35–7.25(m, 2H), 7.20(q, J=7.4Hz, 1H), 7.00(t, J=8.9Hz, 1H), 6.00(s, 1H), 4.62( d, J=5.9Hz, 2H), 4.33–4.23 (m, 1H), 4.14–4.00 (m, 2H), 3.91–3.78 (m, 2H), 3.73–3.65 (m, 1H), 3.46 (t, J=10.5Hz, 2H), 3.19 (s, 1H), 2.68–2.42 (m, 5H), 1.59 (s, 6H), 1.11 (dd, J=8.1, 6.5Hz, 3H).
实施例62Example 62
化合物64:Compound 64:
3-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸3-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid
Figure PCTCN2021135751-appb-000294
Figure PCTCN2021135751-appb-000294
化合物64的合成参考化合物1，通过使用3-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸(中间体57-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物64。Synthesis of compound 64 Reference compound 1 by using 3-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Benzoic acid (Intermediate 57-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 64 was prepared as a yellow solid.
化合物64(30毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.05–7.92(m,3H),7.87(d,J＝3.0Hz,1H),7.54(dt,J＝15.2,7.7Hz,2H),7.27–7.13(m,2H),6.99(t,J＝8.9Hz,1H),5.96(s,1H),4.75–4.61(m,2H),4.59(d,J＝7.6Hz,2H),4.07(q,J＝7.1Hz,2H),3.71(ddd,J＝25.1,12.3,6.2Hz,3H),3.30–3.00(m,4H),2.48(d,J＝25.0Hz,5H),1.10(t,J＝7.2Hz,3H)。 Compound 64 (30 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ8.05-7.92(m,3H),7.87(d,J=3.0Hz,1H),7.54(dt,J=15.2,7.7Hz,2H),7.27- 7.13(m, 2H), 6.99(t, J=8.9Hz, 1H), 5.96(s, 1H), 4.75–4.61(m, 2H), 4.59(d, J=7.6Hz, 2H), 4.07(q , J＝7.1Hz, 2H), 3.71(ddd, J＝25.1, 12.3, 6.2Hz, 3H), 3.30–3.00(m, 4H), 2.48(d, J＝25.0Hz, 5H), 1.10(t, J=7.2Hz, 3H).
实施例63Example 63
化合物65:Compound 65:
(E)-3-(3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙烯酸(E)-3-(3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl ) Phenyl) Acrylic
Figure PCTCN2021135751-appb-000295
Figure PCTCN2021135751-appb-000295
化合物65的合成参考化合物1，通过使用(E)-3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)丙烯酸(中间体58-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物65。Synthesis of compound 65 Reference compound 1 by using (E)-3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridine-2 -yl)phenyl)acrylic acid (intermediate 58-2) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate Body 1-4) was prepared to obtain compound 65 as a yellow solid.
化合物65(13毫克)。MS:662.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.95(t,J＝2.5Hz,2H),7.90(d,J＝2.8Hz,1H),7.80(dt,J＝7.2,2.1Hz,1H),7.69(d,J＝16.0Hz,1H),7.55–7.46(m,2H),7.28(d,J＝7.9Hz,1H),7.20(q,J＝7.4Hz,1H),7.00(t,J＝8.9Hz,1H),6.53(dd,J＝15.8,1.6Hz,1H),6.00(s,1H),4.71–4.54(m,2H),4.32(dd,J＝10.7,6.7Hz,1H),4.12–4.03(m,2H),3.84(s,2H),3.71(s,1H),3.39(t,J＝10.6Hz,1H),3.21(s,2H),2.65(d,J＝15.4Hz,1H),2.52(t,J＝8.3Hz,1H),2.46(d,J＝2.0Hz,3H),1.10(td,J＝7.1,1.6Hz,3H)。 Compound 65 (13 mg). MS: 662.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.95(t,J=2.5Hz,2H),7.90(d,J=2.8Hz,1H),7.80(dt,J=7.2,2.1Hz,1H) ,7.69(d,J＝16.0Hz,1H),7.55–7.46(m,2H),7.28(d,J＝7.9Hz,1H),7.20(q,J＝7.4Hz,1H),7.00(t, J=8.9Hz, 1H), 6.53 (dd, J=15.8, 1.6Hz, 1H), 6.00 (s, 1H), 4.71–4.54 (m, 2H), 4.32 (dd, J=10.7, 6.7Hz, 1H) ), 4.12–4.03(m, 2H), 3.84(s, 2H), 3.71(s, 1H), 3.39(t, J=10.6Hz, 1H), 3.21(s, 2H), 2.65(d, J= 15.4Hz, 1H), 2.52 (t, J=8.3Hz, 1H), 2.46 (d, J=2.0Hz, 3H), 1.10 (td, J=7.1, 1.6Hz, 3H).
实施例64Example 64
化合物66:Compound 66:
3-(3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2,2-二甲基丙酸3-(3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl) -2,2-Dimethylpropionic acid
Figure PCTCN2021135751-appb-000296
Figure PCTCN2021135751-appb-000296
化合物66的合成参考化合物1，通过使用3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-2,2-二甲基丙酸(中间体59-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物66。Synthesis of compound 66 Reference compound 1 by using 3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene yl)-2,2-dimethylpropionic acid (Intermediate 59-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoro Acetate salt (Intermediate 1-4) was prepared to give compound 66 as a yellow solid.
化合物66(33毫克)。MS:692.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.95(d,J＝3.1Hz,1H),7.88(d,J＝3.0Hz,1H),7.60–7.53(m,2H),7.35(t,J＝7.9Hz,1H),7.27(d,J＝7.8Hz,1H),7.20(q,J＝7.4Hz,1H),7.11(d,J＝7.6Hz,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.68–4.54(m,2H),4.25(dd,J＝10.6,6.5Hz,1H),4.08(q,J＝7.1Hz,2H),3.89–3.65(m,3H),3.45–3.32(m,2H),3.28–3.15(m,1H),2.91(s,2H),2.66–2.42(m,5H),1.18(d,J＝1.5Hz,6H),1.11(td,J＝7.1,1.4Hz,3H)。 Compound 66 (33 mg). MS: 692.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.95(d,J=3.1Hz,1H),7.88(d,J=3.0Hz,1H),7.60-7.53(m,2H),7.35(t, J=7.9Hz, 1H), 7.27(d, J=7.8Hz, 1H), 7.20(q, J=7.4Hz, 1H), 7.11(d, J=7.6Hz, 1H), 7.00(t, J= 8.9Hz, 1H), 5.99 (s, 1H), 4.68–4.54 (m, 2H), 4.25 (dd, J=10.6, 6.5Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 3.89– 3.65(m, 3H), 3.45-3.32(m, 2H), 3.28-3.15(m, 1H), 2.91(s, 2H), 2.66-2.42(m, 5H), 1.18(d, J=1.5Hz, 6H), 1.11 (td, J=7.1, 1.4Hz, 3H).
实施例65Example 65
化合物67:Compound 67:
4-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸4-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)benzoic acid
Figure PCTCN2021135751-appb-000297
Figure PCTCN2021135751-appb-000297
化合物67的合成参考化合物1，通过使用4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)苯甲酸(中间体60-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物67。Synthesis of compound 67 Reference compound 1 by using 4-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Benzoic acid (Intermediate 60-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 67 was prepared as a yellow solid.
化合物67(39毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.05(d,J＝8.0Hz,2H),7.94(d,J＝2.9Hz,1H),7.85(d,J＝2.9Hz,1H),7.43(d,J＝8.0Hz,2H),7.26–7.13(m,2H),6.99(t,J＝8.8Hz,1H),5.97(s,1H),4.74–4.61(m,2H),4.57(s,2H),4.07(q,J＝7.1Hz,2H),3.70(ddd,J＝24.2,12.2,6.5Hz,3H),3.15(d,J＝11.8Hz,4H),2.55–2.42(m,5H),1.10(t,J＝7.2Hz,3H)。 Compound 67 (39 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.05(d,J=8.0Hz,2H),7.94(d,J=2.9Hz,1H),7.85(d,J=2.9Hz,1H),7.43 (d, J=8.0Hz, 2H), 7.26–7.13 (m, 2H), 6.99 (t, J=8.8Hz, 1H), 5.97 (s, 1H), 4.74–4.61 (m, 2H), 4.57 ( s, 2H), 4.07 (q, J=7.1Hz, 2H), 3.70 (ddd, J=24.2, 12.2, 6.5Hz, 3H), 3.15 (d, J=11.8Hz, 4H), 2.55–2.42 (m , 5H), 1.10 (t, J=7.2Hz, 3H).
实施例66Example 66
化合物68:Compound 68:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-4-甲基苯甲酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-4-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000298
Figure PCTCN2021135751-appb-000298
化合物68的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-4-甲基苯甲酸(中间体61-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物68。Synthesis of compound 68 Reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-4-methyl benzoic acid (intermediate 61-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4 ) to obtain compound 68 as a yellow solid.
化合物68(55毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.00–7.94(m,3H),7.88(d,J＝3.0Hz,1H),7.48(d,J＝7.9Hz,1H),7.28(d,J＝7.8Hz,1H),7.24–7.17(m,1H),7.00(t,J＝8.9Hz,1H),6.01(s,1H),4.69(d,J＝16.5Hz,1H),4.61(d,J＝16.4Hz,1H),4.17-4.07(m,3H),3.91(dd,J＝13.1,6.0Hz,1H),3.77–3.66(m,2H),3.47(dd,J＝13.1,8.7Hz,1H),3.35-3.30(m,1H),2.72-2.64(m,1H),2.61–2.50(m,1H),2.47(s,3H),2.33(s,3H),1.12(t,J＝7.1Hz,3H)。 Compound 68 (55 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.00-7.94(m,3H),7.88(d,J=3.0Hz,1H),7.48(d,J=7.9Hz,1H),7.28(d, J=7.8Hz, 1H), 7.24–7.17(m, 1H), 7.00(t, J=8.9Hz, 1H), 6.01(s, 1H), 4.69(d, J=16.5Hz, 1H), 4.61( d, J=16.4Hz, 1H), 4.17-4.07 (m, 3H), 3.91 (dd, J=13.1, 6.0Hz, 1H), 3.77-3.66 (m, 2H), 3.47 (dd, J=13.1, 8.7Hz, 1H), 3.35-3.30(m, 1H), 2.72-2.64(m, 1H), 2.61-2.50(m, 1H), 2.47(s, 3H), 2.33(s, 3H), 1.12(t , J=7.1Hz, 3H).
实施例67Example 67
化合物69:Compound 69:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲氧基苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methoxy benzoic acid
Figure PCTCN2021135751-appb-000299
Figure PCTCN2021135751-appb-000299
化合物69的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲氧基苯甲酸(中间体62-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物69。Synthesis of compound 69 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methyl Oxybenzoic acid (Intermediate 62-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) Preparation of yellow solid compound 69.
化合物69(25毫克)。MS:666.2(M+H) +. 1H NMR(400MHz,Methanol-d 4)δ8.08(d,J＝2.8Hz,1H),7.99-7.96(m,2H),7.92(d,J＝3.1Hz,1H),7.28(d,J＝7.9Hz,1H),7.24–7.18(m,2H),7.00(t,J＝8.9Hz, 1H),5.99(s,1H),4.63(s,2H),4.24(dd,J＝10.5,6.8Hz,1H),4.07(q,J＝7.1Hz,2H),3.94(s,3H),3.86-3.80(m,2H),3.70-3.67(m,1H),3.53-3.47(m,1H),3.39–3.31(m,1H),3.27–3.14(m,1H),2.68–2.48(m,2H),2.46(s,3H),1.11(t,J＝7.1Hz,3H)。 Compound 69 (25 mg). MS: 666.2(M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ8.08(d,J=2.8Hz,1H),7.99-7.96(m,2H),7.92(d,J= 3.1Hz, 1H), 7.28(d, J=7.9Hz, 1H), 7.24–7.18(m, 2H), 7.00(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.63(s, 2H), 4.24(dd, J=10.5, 6.8Hz, 1H), 4.07(q, J=7.1Hz, 2H), 3.94(s, 3H), 3.86-3.80(m, 2H), 3.70-3.67(m ,1H),3.53-3.47(m,1H),3.39-3.31(m,1H),3.27-3.14(m,1H),2.68-2.48(m,2H),2.46(s,3H),1.11(t , J=7.1Hz, 3H).
实施例68Example 68
化合物70:Compound 70:
5-((3aS,7aR)-5-(((S)-3-(乙氧基羰基)-2-(3-氟-2-甲基苯基)-6-(噻唑-2-基)-2,5-二氢吡啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸5-((3aS,7aR)-5-(((S)-3-(ethoxycarbonyl)-2-(3-fluoro-2-methylphenyl)-6-(thiazol-2-yl) -2,5-Dihydropyridin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000300
Figure PCTCN2021135751-appb-000300
化合物70的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体63-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物70。Synthesis of compound 70 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methyl benzoic acid (Intermediate 63-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 70 as a yellow solid.
化合物70(55毫克)。MS:650.2(M+H) +. 1H NMR(400MHz,Methanol-d 4)δ8.18(d,J＝2.4Hz,1H),7.96(d,J＝3.1Hz,1H),7.92-7.88(m,2H),7.37(d,J＝8.4Hz,1H),7.28(d,J＝7.9Hz,1H),7.23-7.18(m,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.63(s,2H),4.26(dd,J＝10.4,6.9Hz,1H),4.07(q,J＝7.1Hz,2H),3.89-3.81(m,2H),3.75-3.65(m,1H),3.54-3.49(m,1H),3.37-3.30(m,1H),3.25-3.18(m,1H),2.68–2.39(m,8H),1.11(t,J＝7.1Hz,3H)。 Compound 70 (55 mg). MS: 650.2 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 ) δ 8.18 (d, J=2.4Hz, 1H), 7.96 (d, J=3.1Hz, 1H), 7.92-7.88 (m,2H),7.37(d,J=8.4Hz,1H),7.28(d,J=7.9Hz,1H),7.23-7.18(m,1H),7.00(t,J=8.9Hz,1H) ,5.99(s,1H),4.63(s,2H),4.26(dd,J=10.4,6.9Hz,1H),4.07(q,J=7.1Hz,2H),3.89-3.81(m,2H), 3.75-3.65(m, 1H), 3.54-3.49(m, 1H), 3.37-3.30(m, 1H), 3.25-3.18(m, 1H), 2.68-2.39(m, 8H), 1.11(t, J =7.1Hz, 3H).
实施例69Example 69
化合物71:Compound 71:
3-((3aS,7aR)-5-(((R)-6-(2-氯-4-氟苯基)-5-(甲氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3 ,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000301
Figure PCTCN2021135751-appb-000301
化合物71的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和 (R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸甲酯(中间体A5)代替(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1)制备得到黄色固体化合物71。Synthesis of compound 71 with reference to compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) and (R) -Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (intermediate A5) in place of (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Ethyl carboxylate (Intermediate A1) was prepared to give compound 71 as a yellow solid.
化合物71(14毫克)。MS:642.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.28(d,J＝2.1Hz,1H),8.14–8.08(m,1H),7.97–7.90(m,3H),7.60–7.49(m,2H),7.27(dd,J＝8.7,2.5Hz,1H),7.10(td,J＝8.3,2.5Hz,1H),6.18(s,1H),4.61(s,2H),4.28(dd,J＝10.4,7.0Hz,1H),3.93(dd,J＝10.9,4.9Hz,1H),3.76(d,J＝10.3Hz,1H),3.62(s,4H),3.50(s,1H),3.21(dt,J＝17.6,6.1Hz,1H),2.60(s,2H)。 Compound 71 (14 mg). MS: 642.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.28(d,J=2.1Hz,1H),8.14-8.08(m,1H),7.97-7.90(m,3H),7.60-7.49(m,2H) ), 7.27(dd, J=8.7, 2.5Hz, 1H), 7.10(td, J=8.3, 2.5Hz, 1H), 6.18(s, 1H), 4.61(s, 2H), 4.28(dd, J= 10.4,7.0Hz,1H),3.93(dd,J=10.9,4.9Hz,1H),3.76(d,J=10.3Hz,1H),3.62(s,4H),3.50(s,1H),3.21( dt, J=17.6, 6.1 Hz, 1H), 2.60 (s, 2H).
实施例70Example 70
化合物72:Compound 72:
3-((3aS,7aR)-5-(((R)-6-(2-溴代-4-氟苯基)-5-(甲氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((R)-6-(2-bromo-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000302
Figure PCTCN2021135751-appb-000302
化合物72的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和(R)-4-(2-溴-4-氟苯基)-6-(溴甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸甲酯(中间体A6)代替(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1)制备得到黄色固体化合物72。Synthesis of compound 72 with reference to compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) and (R) -4-(2-Bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (intermediate A6) in place of (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Ethyl carboxylate (Intermediate A1) was prepared to give compound 72 as a yellow solid.
化合物72(18毫克)。MS:686.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.28(s,1H),8.15–8.06(m,1H),7.96–7.91(m,3H),7.61–7.49(m,2H),7.45(dd,J＝8.4,2.6Hz,1H),7.15(dt,J＝9.6,4.8Hz,1H),6.17(s,1H),4.60(s,2H),4.32–4.24(m,1H),3.93(s,1H),3.75(d,J＝13.0Hz,1H),3.62(s,5H),3.49(s,1H),3.26–3.11(m,1H),2.65–2.41(m,2H)。 Compound 72 (18 mg). MS: 686.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.28(s,1H),8.15-8.06(m,1H),7.96-7.91(m,3H),7.61-7.49(m,2H),7.45(dd , J=8.4, 2.6Hz, 1H), 7.15(dt, J=9.6, 4.8Hz, 1H), 6.17(s, 1H), 4.60(s, 2H), 4.32–4.24(m, 1H), 3.93( s, 1H), 3.75 (d, J=13.0Hz, 1H), 3.62 (s, 5H), 3.49 (s, 1H), 3.26–3.11 (m, 1H), 2.65–2.41 (m, 2H).
实施例71Example 71
化合物73:Compound 73:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(4-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(4-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000303
Figure PCTCN2021135751-appb-000303
化合物73的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和(S)-6-(溴甲基)-4-(4-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A4)代替(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1)制备得到黄色固体化合物73。Synthesis of compound 73 reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) and (S) -6-(Bromomethyl)-4-(4-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (middle Body A4) instead of (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5 -Ethyl carboxylate (Intermediate A1) was prepared to give compound 73 as a yellow solid.
化合物73(19毫克)。MS:636.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.29(t,J＝1.9Hz,1H),8.10(ddd,J＝8.3,2.4,1.1Hz,1H),7.97–7.95(m,1H),7.94–7.91(m,2H),7.60–7.54(m,1H),7.43(dd,J＝8.4,5.8Hz,1H),6.97–6.89(m,2H),5.95(s,1H),4.61(s,2H),4.29(dd,J＝10.4,6.9Hz,1H),4.08(q,J＝7.1Hz,2H),3.93(dd,J＝10.3,5.0Hz,1H),3.80(dd,J＝13.2,5.9Hz,1H),3.72–3.62(m,1H),3.52(dd,J＝13.1,7.4Hz,1H),3.38–3.32(m,1H),3.28–3.16(m,1H),2.57(s,5H),1.12(t,J＝7.1Hz,3H)。 Compound 73 (19 mg). MS: 636.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.29(t,J=1.9Hz,1H),8.10(ddd,J=8.3,2.4,1.1Hz,1H),7.97-7.95(m,1H), 7.94–7.91 (m, 2H), 7.60–7.54 (m, 1H), 7.43 (dd, J=8.4, 5.8Hz, 1H), 6.97–6.89 (m, 2H), 5.95 (s, 1H), 4.61 ( s, 2H), 4.29 (dd, J=10.4, 6.9Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 3.93 (dd, J=10.3, 5.0Hz, 1H), 3.80 (dd, J =13.2,5.9Hz,1H),3.72-3.62(m,1H),3.52(dd,J=13.1,7.4Hz,1H),3.38-3.32(m,1H),3.28-3.16(m,1H), 2.57 (s, 5H), 1.12 (t, J=7.1 Hz, 3H).
实施例72Example 72
化合物74:Compound 74:
3-((3aS,7aR)-5-(((R)-6-(2-氯-4-氟苯基)-5-(乙氧基羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000304
Figure PCTCN2021135751-appb-000304
化合物74的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A3)代替(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1)制备得到黄色固体化合物74。Synthesis of compound 74 reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) and (R) -6-(Bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (intermediate A3) In place of (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Ethyl carboxylate (Intermediate A1) was prepared to give compound 74 as a yellow solid.
化合物74(29毫克)。MS:656.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.29(s,1H),8.03(d,J＝8.3Hz,1H),7.91(d,J＝7.8Hz,1H),7.68(s,2H),7.55(t,J＝8.0Hz,1H),7.45(dd,J＝8.7,6.2Hz,1H),7.22(dd,J＝8.8,2.5Hz,1H),7.09–7.01(m,1H),6.17(s,1H),4.24–3.88(m,6H),3.01–2.80(m,3H), 2.67(d,J＝5.8Hz,2H),2.31–2.13(m,2H),1.13(td,J＝7.1,1.5Hz,3H)。 Compound 74 (29 mg). MS: 656.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.29(s,1H),8.03(d,J=8.3Hz,1H),7.91(d,J=7.8Hz,1H),7.68(s,2H) ,7.55(t,J＝8.0Hz,1H),7.45(dd,J＝8.7,6.2Hz,1H),7.22(dd,J＝8.8,2.5Hz,1H),7.09–7.01(m,1H), 6.17(s, 1H), 4.24-3.88(m, 6H), 3.01-2.80(m, 3H), 2.67(d, J=5.8Hz, 2H), 2.31-2.13(m, 2H), 1.13(td, J=7.1, 1.5 Hz, 3H).
实施例73Example 73
化合物75:Compound 75:
3-((3aS,7aR)-5-(((S)-6-(3,4-二氟-2-甲基苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((S)-6-(3,4-difluoro-2-methylphenyl)-5-(ethoxycarbonyl)-2-(thiazole-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000305
Figure PCTCN2021135751-appb-000305
化合物75的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和(S)-6-(溴甲基)-4-(3,4-二氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A8)代替(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1)制备得到黄色固体化合物75。Synthesis of compound 75 reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) and (S) -6-(Bromomethyl)-4-(3,4-difluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Ester (Intermediate A8) in place of (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydro Pyrimidine-5-carboxylate ethyl ester (Intermediate A1) was prepared to give compound 75 as a yellow solid.
化合物75(39毫克)。MS:654.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.29(s,1H),8.13–8.08(m,1H),7.96–7.90(m,3H),7.57(t,J＝8.0Hz,1H),7.24(t,J＝6.9Hz,1H),7.09(q,J＝8.8Hz,1H),5.94(s,1H),4.57(s,2H),4.28(dd,J＝10.2,7.1Hz,1H),4.08(q,J＝7.1Hz,2H),3.93(dd,J＝10.0,5.4Hz,1H),3.73(d,J＝10.4Hz,1H),3.58(s,1H),3.46(d,J＝14.4Hz,1H),3.29–3.11(m,2H),2.69–2.39(m,5H),1.12(t,J＝7.1Hz,3H)。 Compound 75 (39 mg). MS: 654.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.29(s,1H),8.13-8.08(m,1H),7.96-7.90(m,3H),7.57(t,J=8.0Hz,1H), 7.24(t,J＝6.9Hz,1H),7.09(q,J＝8.8Hz,1H),5.94(s,1H),4.57(s,2H),4.28(dd,J＝10.2,7.1Hz,1H ), 4.08(q, J＝7.1Hz, 2H), 3.93(dd, J＝10.0, 5.4Hz, 1H), 3.73(d, J＝10.4Hz, 1H), 3.58(s, 1H), 3.46(d , J=14.4Hz, 1H), 3.29–3.11 (m, 2H), 2.69–2.39 (m, 5H), 1.12 (t, J=7.1Hz, 3H).
实施例74Example 74
化合物76:Compound 76:
3-((3aS,7aR)-5-(((R)-6-(2-氯-3-氟苯基)-5-(乙氧基羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((R)-6-(2-chloro-3-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000306
Figure PCTCN2021135751-appb-000306
化合物76的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和 (R)-6-(溴甲基)-4-(2-氯-3-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A2)代替(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1)制备得到黄色固体化合物76。Synthesis of compound 76 reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) and (R) -6-(Bromomethyl)-4-(2-chloro-3-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (intermediate A2) in place of (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Ethyl carboxylate (Intermediate A1) was prepared to give compound 76 as a yellow solid.
化合物76(19毫克)。MS:656.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.29(t,J＝1.9Hz,1H),8.13–8.08(m,1H),7.96(d,J＝3.1Hz,1H),7.95–7.91(m,2H),7.57(t,J＝8.0Hz,1H),7.39–7.33(m,2H),7.26–7.19(m,1H),6.24(s,1H),4.63(s,2H),4.29(dd,J＝10.3,6.9Hz,1H),4.06(q,J＝7.1Hz,2H),3.93(dd,J＝10.4,5.0Hz,1H),3.84–3.74(m,1H),3.66(s,1H),3.52(s,1H),3.38–3.32(m,1H),3.27–3.15(m,1H),2.67–2.43(m,2H),1.11(t,J＝7.1Hz,3H)。 Compound 76 (19 mg). MS: 656.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.29(t,J=1.9Hz,1H),8.13-8.08(m,1H),7.96(d,J=3.1Hz,1H),7.95-7.91( m, 2H), 7.57 (t, J=8.0Hz, 1H), 7.39–7.33 (m, 2H), 7.26–7.19 (m, 1H), 6.24 (s, 1H), 4.63 (s, 2H), 4.29 (dd,J＝10.3,6.9Hz,1H),4.06(q,J＝7.1Hz,2H),3.93(dd,J＝10.4,5.0Hz,1H),3.84–3.74(m,1H),3.66( s, 1H), 3.52 (s, 1H), 3.38–3.32 (m, 1H), 3.27–3.15 (m, 1H), 2.67–2.43 (m, 2H), 1.11 (t, J=7.1Hz, 3H) .
实施例75Example 75
化合物77:Compound 77:
3-((3aS,7aR)-5-(((R)-6-(2-溴-4-氟苯基)-5-(乙氧基羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-((3aS,7aR)-5-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000307
Figure PCTCN2021135751-appb-000307
化合物77的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体49-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和(R)-4-(2-溴-4-氟苯基)-6-(溴甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A7)代替(S)-6-(溴甲基)-4-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(中间体A1)制备得到黄色固体化合物77。Synthesis of compound 77 reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid (intermediate body 49-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) and (R) -4-(2-Bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (intermediate A7) in place of (S)-6-(bromomethyl)-4-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Ethyl carboxylate (Intermediate A1) was prepared to give compound 77 as a yellow solid.
化合物77(80毫克)。MS:700.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.29(t,J＝2.0Hz,1H),8.11(d,J＝8.4Hz,1H),8.00–7.90(m,3H),7.55(ddd,J＝9.9,8.3,5.7Hz,2H),7.46(dt,J＝8.4,2.5Hz,1H),7.16(td,J＝8.4,2.5Hz,1H),6.19(d,J＝2.4Hz,1H),4.65(s,2H),4.30(dd,J＝10.2,7.1Hz,1H),4.08(qd,J＝7.1,2.5Hz,2H),3.92(dd,J＝10.3,4.9Hz,1H),3.81(s,1H),3.70(s,1H),3.55(s,1H),3.43–3.33(m,1H),3.23(dd,J＝11.5,5.7Hz,1H),2.72–2.42(m,2H),1.12(td,J＝7.1,2.5Hz,3H)。 Compound 77 (80 mg). MS: 700.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.29(t,J=2.0Hz,1H),8.11(d,J=8.4Hz,1H),8.00-7.90(m,3H),7.55(ddd, J=9.9, 8.3, 5.7Hz, 2H), 7.46 (dt, J=8.4, 2.5Hz, 1H), 7.16 (td, J=8.4, 2.5Hz, 1H), 6.19 (d, J=2.4Hz, 1H) ),4.65(s,2H),4.30(dd,J＝10.2,7.1Hz,1H),4.08(qd,J＝7.1,2.5Hz,2H),3.92(dd,J＝10.3,4.9Hz,1H) ,3.81(s,1H),3.70(s,1H),3.55(s,1H),3.43–3.33(m,1H),3.23(dd,J=11.5,5.7Hz,1H),2.72–2.42(m , 2H), 1.12 (td, J=7.1, 2.5Hz, 3H).
实施例76Example 76
化合物78:Compound 78:
6-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸6-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)nicotinic acid
Figure PCTCN2021135751-appb-000308
Figure PCTCN2021135751-appb-000308
化合物78的合成参考化合物1，通过使用6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)烟酸(中间体64-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物78。Synthesis of compound 78 Reference compound 1 by using 6-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)nicotinic acid (intermediate body 64-2) instead of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4) was prepared to give a yellow solid Compound 78.
化合物78(67毫克)。MS:637.6(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ9.01(dd,J＝2.2,0.9Hz,1H),8.51(dt,J＝8.9,1.0Hz,1H),8.40(ddd,J＝8.8,2.3,0.9Hz,1H),7.94(dd,J＝3.1,0.9Hz,1H),7.89(dd,J＝3.2,1.0Hz,1H),7.28(dd,J＝8.0,1.3Hz,1H),7.21(td,J＝7.9,5.5Hz,1H),7.00(ddd,J＝9.5,8.0,1.3Hz,1H),5.99(s,1H),4.66–4.50(m,2H),4.42(dd,J＝11.9,6.8Hz,1H),4.16(dd,J＝11.9,4.8Hz,1H),4.07(q,J＝7.2Hz,2H),3.85–3.77(m,1H),3.65(d,J＝9.8Hz,1H),3.43(t,J＝10.6Hz,1H),3.19(dt,J＝18.3,6.0Hz,1H),2.64(s,1H),2.46(d,J＝2.0Hz,4H),1.10(td,J＝7.1,0.9Hz,3H)。 Compound 78 (67 mg). MS: 637.6 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 ) δ 9.01 (dd, J=2.2, 0.9 Hz, 1H), 8.51 (dt, J=8.9, 1.0 Hz, 1H), 8.40 (ddd, J=8.8, 2.3 ,0.9Hz,1H),7.94(dd,J＝3.1,0.9Hz,1H),7.89(dd,J＝3.2,1.0Hz,1H),7.28(dd,J＝8.0,1.3Hz,1H),7.21 (td, J=7.9, 5.5Hz, 1H), 7.00 (ddd, J=9.5, 8.0, 1.3Hz, 1H), 5.99 (s, 1H), 4.66–4.50 (m, 2H), 4.42 (dd, J =11.9,6.8Hz,1H),4.16(dd,J=11.9,4.8Hz,1H),4.07(q,J=7.2Hz,2H),3.85-3.77(m,1H),3.65(d,J= 9.8Hz, 1H), 3.43 (t, J=10.6Hz, 1H), 3.19 (dt, J=18.3, 6.0Hz, 1H), 2.64 (s, 1H), 2.46 (d, J=2.0Hz, 4H) , 1.10 (td, J=7.1, 0.9 Hz, 3H).
实施例77Example 77
化合物79:Compound 79:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲氧基苯甲酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methoxy benzoic acid
Figure PCTCN2021135751-appb-000309
Figure PCTCN2021135751-appb-000309
化合物79的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲氧基苯甲酸(中间体65-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物79。Synthesis of compound 79 Reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methyl Oxybenzoic acid (Intermediate 65-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 79 was prepared as a yellow solid.
化合物79(68.8毫克)。MS:666.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.97(d,J＝3.1Hz,1H),7.93(d,J＝3.1Hz,1H),7.80(dt,J＝7.2,1.9Hz,2H),7.49–7.44(m,1H),7.28(d,J＝7.8Hz,1H),7.21(td,J＝7.9,5.5Hz,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.63(s,2H),4.28(dd,J＝10.4,6.9Hz,1H),4.08(q,J＝7.1Hz,2H),3.88(s,4H),3.81(dd,J＝13.4,5.9Hz,1H),3.69(d,J＝9.9Hz,1H),3.56(s,1H),3.37(dd,J＝10.3,6.4Hz,1H),3.22(dt,J＝17.9,6.1Hz,1H),2.67–2.41(m,5H),1.11(t,J＝7.1Hz,3H)。 Compound 79 (68.8 mg). MS: 666.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.97(d,J=3.1Hz,1H),7.93(d,J=3.1Hz,1H),7.80(dt,J=7.2,1.9Hz,2H) ,7.49–7.44(m,1H),7.28(d,J＝7.8Hz,1H),7.21(td,J＝7.9,5.5Hz,1H),7.00(t,J＝8.9Hz,1H),5.99( s,1H),4.63(s,2H),4.28(dd,J=10.4,6.9Hz,1H),4.08(q,J=7.1Hz,2H),3.88(s,4H),3.81(dd,J =13.4,5.9Hz,1H),3.69(d,J=9.9Hz,1H),3.56(s,1H),3.37(dd,J=10.3,6.4Hz,1H),3.22(dt,J=17.9, 6.1Hz, 1H), 2.67–2.41 (m, 5H), 1.11 (t, J=7.1Hz, 3H).
实施例78Example 78
化合物80:Compound 80:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000310
Figure PCTCN2021135751-appb-000310
化合物80的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体66-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物80。Synthesis of compound 80 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methyl benzoic acid (Intermediate 66-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 80 as a yellow solid.
化合物80(48.8毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.06–7.99(m,1H),7.95(d,J＝3.2Hz,1H),7.88(d,J＝3.2Hz,1H),7.73–7.65(m,2H),7.28(d,J＝7.8Hz,1H),7.20(td,J＝8.0,5.5Hz,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.61(q,J＝16.4Hz,2H),4.30(dd,J＝10.6,6.5Hz,1H),4.07(q,J＝7.1Hz,2H),3.85(ddd,J＝14.6,12.0,4.8Hz,2H),3.79–3.67(m,1H),3.41–3.33(m,1H),3.25(dd,J＝18.0,6.7Hz,1H),2.63(s,4H),2.57–2.43(m,4H),1.10(t,J＝7.1Hz,3H)。 Compound 80 (48.8 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.06-7.99(m,1H),7.95(d,J=3.2Hz,1H),7.88(d,J=3.2Hz,1H),7.73-7.65( m, 2H), 7.28(d, J=7.8Hz, 1H), 7.20(td, J=8.0, 5.5Hz, 1H), 7.00(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.61(q,J＝16.4Hz,2H),4.30(dd,J＝10.6,6.5Hz,1H),4.07(q,J＝7.1Hz,2H),3.85(ddd,J＝14.6,12.0,4.8Hz , 2H), 3.79–3.67 (m, 1H), 3.41–3.33 (m, 1H), 3.25 (dd, J=18.0, 6.7Hz, 1H), 2.63 (s, 4H), 2.57–2.43 (m, 4H) ), 1.10 (t, J=7.1 Hz, 3H).
实施例79Example 79
化合物81:Compound 81:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000311
Figure PCTCN2021135751-appb-000311
化合物81的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸(中间体67-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物81。Synthesis of compound 81 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methyl benzoic acid (Intermediate 67-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 81 as a yellow solid.
化合物81(72.9毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.01(d,J＝1.9Hz,1H),7.99–7.92(m,2H),7.88(d,J＝3.2Hz,1H),7.42(d,J＝8.2Hz,1H),7.28(d,J＝7.8Hz,1H),7.20(td,J＝8.0,5.6Hz,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.73–4.55(m,2H),4.18(dd,J＝10.7,6.3Hz,1H), 4.09(q,J＝7.1Hz,2H),3.92(dd,J＝13.2,6.0Hz,1H),3.80–3.62(m,2H),3.47–3.35(m,1H),3.26(s,1H),2.69(t,J＝14.5Hz,1H),2.56(ddd,J＝15.3,10.2,4.6Hz,1H),2.47(d,J＝2.0Hz,3H),2.32(s,3H),1.12(t,J＝7.1Hz,3H)。 Compound 81 (72.9 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.01(d,J=1.9Hz,1H),7.99-7.92(m,2H),7.88(d,J=3.2Hz,1H),7.42(d, J=8.2Hz, 1H), 7.28(d, J=7.8Hz, 1H), 7.20(td, J=8.0, 5.6Hz, 1H), 7.00(t, J=8.9Hz, 1H), 6.00(s, 1H), 4.73–4.55(m, 2H), 4.18(dd, J=10.7, 6.3Hz, 1H), 4.09(q, J=7.1Hz, 2H), 3.92 (dd, J=13.2, 6.0Hz, 1H) ), 3.80–3.62 (m, 2H), 3.47–3.35 (m, 1H), 3.26 (s, 1H), 2.69 (t, J=14.5Hz, 1H), 2.56 (ddd, J=15.3, 10.2, 4.6 Hz, 1H), 2.47 (d, J=2.0 Hz, 3H), 2.32 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).
实施例80Example 80
化合物82:Compound 82:
3-((3aS，7aR)-5-(((S)-3-(乙氧基羰基)-2-(3-氟-2-甲基苯基)-6-(噻唑-2-基)-2,5-二氢吡啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲基苯甲酸3-((3aS,7aR)-5-(((S)-3-(ethoxycarbonyl)-2-(3-fluoro-2-methylphenyl)-6-(thiazol-2-yl) -2,5-Dihydropyridin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000312
Figure PCTCN2021135751-appb-000312
化合物82的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲基苯甲酸(中间体68-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物82。Synthesis of compound 82 Reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methyl benzoic acid (Intermediate 68-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 82 as a yellow solid.
化合物82(62.1毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.05(s,1H),7.81(s,1H),7.72(s,1H),7.67(d,J＝3.1Hz,1H),7.65(d,J＝3.1Hz,1H),7.17–7.08(m,2H),6.94-6.90(m,1H),5.97(s,1H),4.18(d,J＝17.1Hz,1H),4.08-4.03(m,4H),3.93(d,J＝17.1Hz,1H),2.99–2.78(m,3H),2.65(t,J＝5.9Hz,2H),2.51(d,J＝2.1Hz,3H),2.41(s,3H),2.31–2.12(m,2H),1.12(t,J＝7.1Hz,3H)。 Compound 82 (62.1 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.05(s,1H),7.81(s,1H),7.72(s,1H),7.67(d,J=3.1Hz,1H),7.65(d, J=3.1Hz, 1H), 7.17-7.08(m, 2H), 6.94-6.90(m, 1H), 5.97(s, 1H), 4.18(d, J=17.1Hz, 1H), 4.08-4.03(m ,4H),3.93(d,J＝17.1Hz,1H),2.99–2.78(m,3H),2.65(t,J＝5.9Hz,2H),2.51(d,J＝2.1Hz,3H),2.41 (s, 3H), 2.31–2.12 (m, 2H), 1.12 (t, J=7.1 Hz, 3H).
实施例81Example 81
化合物83:Compound 83:
4-((3aR,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000313
Figure PCTCN2021135751-appb-000313
化合物83的合成参考化合物1，通过使用4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基苯甲酸(中间体69-2)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间 体1-4)制备得到黄色固体化合物83。Synthesis of compound 83 Reference compound 1 by using 4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methyl benzoic acid (intermediate 69-2) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate 1-4 ) to obtain compound 83 as a yellow solid.
化合物83(56毫克)。MS:650.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.02(d,J＝1.9Hz,1H),7.96(dd,J＝8.0,2.3Hz,2H),7.87(d,J＝3.1Hz,1H),7.44(d,J＝8.2Hz,1H),7.28(d,J＝7.8Hz,1H),7.20(td,J＝7.9,5.5Hz,1H),7.00(t,J＝8.9Hz,1H),6.01(s,1H),4.76(d,J＝16.4Hz,1H),4.54(d,J＝16.4Hz,1H),4.16(dd,J＝10.7,6.4Hz,1H),4.09(q,J＝7.1Hz,2H),3.89(dd,J＝13.1,6.1Hz,1H),3.69(dd,J＝11.1,3.8Hz,2H),3.42(dd,J＝13.1,8.8Hz,1H),3.24(d,J＝11.3Hz,1H),2.66(ddd,J＝14.9,12.2,7.6Hz,1H),2.58–2.42(m,4H),2.32(s,3H),1.11(t,J＝7.1Hz,3H)。 Compound 83 (56 mg). MS: 650.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.02(d,J=1.9Hz,1H),7.96(dd,J=8.0,2.3Hz,2H),7.87(d,J=3.1Hz,1H) ,7.44(d,J＝8.2Hz,1H),7.28(d,J＝7.8Hz,1H),7.20(td,J＝7.9,5.5Hz,1H),7.00(t,J＝8.9Hz,1H) ,6.01(s,1H),4.76(d,J＝16.4Hz,1H),4.54(d,J＝16.4Hz,1H),4.16(dd,J＝10.7,6.4Hz,1H),4.09(q, J=7.1Hz, 2H), 3.89 (dd, J=13.1, 6.1Hz, 1H), 3.69 (dd, J=11.1, 3.8Hz, 2H), 3.42 (dd, J=13.1, 8.8Hz, 1H), 3.24(d, J=11.3Hz, 1H), 2.66(ddd, J=14.9, 12.2, 7.6Hz, 1H), 2.58–2.42(m, 4H), 2.32(s, 3H), 1.11(t, J= 7.1Hz, 3H).
实施例82Example 82
化合物84:Compound 84:
4-((3aR,7aS)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-氟苯甲酸4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-fluorobenzoic acid
Figure PCTCN2021135751-appb-000314
Figure PCTCN2021135751-appb-000314
化合物84的合成参考化合物1，通过使用3-氟-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体70-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物84。Synthesis of compound 84 Reference compound 1 by using 3-fluoro-4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid (Intermediate 70-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 84 was prepared as a yellow solid.
化合物84(56毫克)。MS:654.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.99–7.92(m,2H),7.91–7.84(m,2H),7.73(t,J＝7.9Hz,1H),7.28(d,J＝7.8Hz,1H),7.20(td,J＝8.0,5.5Hz,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.76(d,J＝16.4Hz,1H),4.53(d,J＝16.3Hz,1H),4.25(dd,J＝10.5,6.4Hz,1H),4.08(q,J＝7.1Hz,2H),3.92–3.78(m,2H),3.75–3.65(m,1H),3.42(dd,J＝13.1,8.4Hz,1H),3.27(d,J＝9.9Hz,1H),2.73–2.60(m,1H),2.57–2.43(m,4H),1.11(t,J＝7.1Hz,3H)。 Compound 84 (56 mg). MS: 654.2 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.99-7.92(m,2H),7.91-7.84(m,2H),7.73(t,J=7.9Hz,1H),7.28(d,J=7.8 Hz, 1H), 7.20(td, J＝8.0, 5.5Hz, 1H), 7.00(t, J＝8.9Hz, 1H), 6.00(s, 1H), 4.76(d, J＝16.4Hz, 1H), 4.53(d,J＝16.3Hz,1H),4.25(dd,J＝10.5,6.4Hz,1H),4.08(q,J＝7.1Hz,2H),3.92–3.78(m,2H),3.75–3.65 (m, 1H), 3.42 (dd, J=13.1, 8.4Hz, 1H), 3.27 (d, J=9.9Hz, 1H), 2.73–2.60 (m, 1H), 2.57–2.43 (m, 4H), 1.11 (t, J=7.1 Hz, 3H).
实施例83Example 83
化合物85:Compound 85:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,3-二甲基苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,3-di Toluic acid
Figure PCTCN2021135751-appb-000315
Figure PCTCN2021135751-appb-000315
化合物85的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,3-二甲基苯甲酸(中间体72-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物85。Synthesis of compound 85 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,3 -Dimethylbenzoic acid (Intermediate 72-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 85 was prepared as a yellow solid.
化合物85(36毫克)。MS:664.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.74(s,1H),7.70(d,J＝3.1Hz,1H),7.67(d,J＝3.1Hz,1H),7.66(d,J＝2.1Hz,1H),7.15-7.09(m,2H),6.96–6.89(m,1H),5.97(s,1H),4.17(d,J＝17.1Hz,1H),4.10–3.97(m,4H),3.94(d,J＝17.1Hz,1H),3.00–2.78(m,3H),2.65(t,J＝5.8Hz,2H),2.51(d,J＝2.0Hz,3H),2.42(s,3H),2.33(s,3H),2.27–2.13(m,2H),1.13(t,J＝7.1Hz,3H)。 Compound 85 (36 mg). MS: 664.2 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.74(s,1H),7.70(d,J=3.1Hz,1H),7.67(d,J=3.1Hz,1H),7.66(d,J= 2.1Hz, 1H), 7.15-7.09(m, 2H), 6.96-6.89(m, 1H), 5.97(s, 1H), 4.17(d, J=17.1Hz, 1H), 4.10-3.97(m, 4H) ),3.94(d,J＝17.1Hz,1H),3.00–2.78(m,3H),2.65(t,J＝5.8Hz,2H),2.51(d,J＝2.0Hz,3H),2.42(s , 3H), 2.33 (s, 3H), 2.27–2.13 (m, 2H), 1.13 (t, J=7.1 Hz, 3H).
实施例84Example 84
化合物86:Compound 86:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-氟-2-甲基苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-fluoro-2 -Toluic acid
Figure PCTCN2021135751-appb-000316
Figure PCTCN2021135751-appb-000316
化合物86的合成参考化合物1，通过使用3-氟-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体73-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物86。Synthesis of compound 86 Reference compound 1 by using 3-fluoro-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) -2-methylbenzoic acid (intermediate 73-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate Body 1-4) was prepared to obtain compound 86 as a yellow solid.
化合物86(30毫克)。MS:668.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.79(dd,J＝11.7,2.1Hz,1H),7.73–7.66(m,3H),7.14-7.10(m,2H),6.94-6.90(m,1H),5.97(s,1H),4.16(d,J＝17.1Hz,1H),4.10–3.97(m,4H),3.94(d,J＝17.1Hz,1H),2.98–2.77(m,3H),2.66(t,J＝5.7Hz,2H),2.51(d,J＝2.0Hz,3H),2.42(d,J＝2.1Hz,3H),2.30–2.11(m,2H),1.12(t,J＝7.1Hz,3H)。 Compound 86 (30 mg). MS: 668.2 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.79(dd,J=11.7,2.1Hz,1H),7.73-7.66(m,3H),7.14-7.10(m,2H),6.94-6.90(m ,1H),5.97(s,1H),4.16(d,J=17.1Hz,1H),4.10–3.97(m,4H),3.94(d,J=17.1Hz,1H),2.98–2.77(m, 3H), 2.66(t, J＝5.7Hz, 2H), 2.51(d, J＝2.0Hz, 3H), 2.42(d, J＝2.1Hz, 3H), 2.30–2.11(m, 2H), 1.12( t, J=7.1 Hz, 3H).
实施例85Example 85
化合物87:Compound 87:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,4-二甲基苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,4-di Toluic acid
Figure PCTCN2021135751-appb-000317
Figure PCTCN2021135751-appb-000317
化合物87的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,4-二甲基苯甲酸(中间体74-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物87。Synthesis of compound 87 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,4 -Dimethylbenzoic acid (Intermediate 74-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 87 was prepared as a yellow solid.
化合物87(40毫克)。MS:664.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.92(d,J＝3.1Hz,1H),7.70(d,J＝3.1Hz,1H),7.69(s,1H),7.24(s,1H),7.16–7.06(m,2H),6.94-6.90(m,1H),5.98(s,1H),4.19(d,J＝17.1Hz,1H),4.06(q,J＝7.1Hz,2H),3.97–3.80(m,3H),3.01–2.88(m,2H),2.85–2.77(m,1H),2.65(dd,J＝6.8,4.5Hz,2H),2.55(s,3H),2.51(d,J＝2.0Hz,3H),2.28(s,5H),1.13(t,J＝7.1Hz,3H)。 Compound 87 (40 mg). MS: 664.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.92(d,J=3.1Hz,1H),7.70(d,J=3.1Hz,1H),7.69(s,1H),7.24(s,1H) ,7.16–7.06(m,2H),6.94-6.90(m,1H),5.98(s,1H),4.19(d,J=17.1Hz,1H),4.06(q,J=7.1Hz,2H), 3.97–3.80 (m, 3H), 3.01–2.88 (m, 2H), 2.85–2.77 (m, 1H), 2.65 (dd, J=6.8, 4.5Hz, 2H), 2.55 (s, 3H), 2.51 ( d, J=2.0 Hz, 3H), 2.28 (s, 5H), 1.13 (t, J=7.1 Hz, 3H).
实施例86Example 86
化合物88:Compound 88:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,6-二甲基苯甲酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,6-di Toluic acid
Figure PCTCN2021135751-appb-000318
Figure PCTCN2021135751-appb-000318
化合物88的合成参考化合物1，通过使用3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,6-二甲基苯甲酸(中间体75-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物88。Synthesis of compound 88 Reference compound 1 by using 3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,6 -Dimethylbenzoic acid (Intermediate 75-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 88 was prepared as a yellow solid.
化合物88(70毫克)。MS:664.2(M+H) +。 Compound 88 (70 mg). MS: 664.2 (M+H) + .
实施例87Example 87
化合物89:Compound 89:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoro Methoxy)benzoic acid
Figure PCTCN2021135751-appb-000319
Figure PCTCN2021135751-appb-000319
化合物89的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸(中间体77-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物89。Synthesis of compound 89 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-( Trifluoromethoxy)benzoic acid (Intermediate 77-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate ( Intermediate 1-4) was prepared to obtain compound 89 as a yellow solid.
化合物89(20毫克)。MS:720.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.18(d,J＝2.8Hz,1H),8.05(dd,J＝9.0,2.7Hz,1H),7.68(s,2H),7.44(d,J＝8.9Hz,1H),7.19–7.06(m,2H),6.93(t,J＝9.0Hz,1H),5.97(s,1H),4.19(d,J＝17.1Hz,1H),4.11–3.91(m,5H),3.04–2.79(m,3H),2.74-2.63(m,2H),2.51(d,J＝2.0Hz,3H),2.31–2.14(m,2H),1.12(t,J＝7.1Hz,3H)。 Compound 89 (20 mg). MS: 720.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.18(d,J=2.8Hz,1H),8.05(dd,J=9.0,2.7Hz,1H),7.68(s,2H),7.44(d, J=8.9Hz, 1H), 7.19–7.06 (m, 2H), 6.93 (t, J=9.0Hz, 1H), 5.97 (s, 1H), 4.19 (d, J=17.1Hz, 1H), 4.11– 3.91(m, 5H), 3.04-2.79(m, 3H), 2.74-2.63(m, 2H), 2.51(d, J=2.0Hz, 3H), 2.31-2.14(m, 2H), 1.12(t, J=7.1Hz, 3H).
实施例88Example 88
化合物90:Compound 90:
4-((3aS,7aR)-5-((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-异丙基苯甲酸4-((3aS,7aR)-5-((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-isopropylbenzene Formic acid
Figure PCTCN2021135751-appb-000320
Figure PCTCN2021135751-appb-000320
化合物90的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-异丙基苯甲酸(中间体78-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物90。Synthesis of compound 90 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-iso Propylbenzoic acid (Intermediate 78-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) Preparation of yellow solid compound 90.
化合物90(10毫克)。MS:678.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.06(s,1H),7.89(dd,J＝8.8,5.6Hz,2H),7.81(d,J＝3.0Hz,1H),7.33(d,J＝8.2Hz,1H),7.22(d,J＝7.9Hz,1H),7.14(q,J＝ 7.4Hz,1H),6.93(t,J＝8.9Hz,1H),5.94(s,1H),4.64(d,J＝16.2Hz,1H),4.56(d,J＝16.4Hz,1H),4.05(dq,J＝21.5,7.2,6.8Hz,3H),3.88(dd,J＝13.0,6.0Hz,1H),3.71(d,J＝12.2Hz,1H),3.57(d,J＝11.2Hz,1H),3.37(dd,J＝13.1,9.0Hz,1H),3.27(d,J＝9.4Hz,2H),2.93(q,J＝6.9Hz,1H),2.69–2.34(m,5H),1.21(t,J＝6.1Hz,6H),1.05(t,J＝7.1Hz,3H)。 Compound 90 (10 mg). MS: 678.2 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ8.06(s,1H),7.89(dd,J=8.8,5.6Hz,2H),7.81(d,J=3.0Hz,1H),7.33(d, J=8.2Hz, 1H), 7.22(d, J=7.9Hz, 1H), 7.14(q, J=7.4Hz, 1H), 6.93(t, J=8.9Hz, 1H), 5.94(s, 1H) ,4.64(d,J＝16.2Hz,1H),4.56(d,J＝16.4Hz,1H),4.05(dq,J＝21.5,7.2,6.8Hz,3H),3.88(dd,J＝13.0,6.0 Hz, 1H), 3.71(d, J＝12.2Hz, 1H), 3.57(d, J＝11.2Hz, 1H), 3.37(dd, J＝13.1, 9.0Hz, 1H), 3.27(d, J＝9.4 Hz, 2H), 2.93 (q, J=6.9 Hz, 1H), 2.69–2.34 (m, 5H), 1.21 (t, J=6.1 Hz, 6H), 1.05 (t, J=7.1 Hz, 3H).
实施例89Example 89
化合物91:Compound 91:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoro Methyl)benzoic acid
Figure PCTCN2021135751-appb-000321
Figure PCTCN2021135751-appb-000321
化合物91的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸(中间体79-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物91。Synthesis of compound 91 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-( Trifluoromethyl)benzoic acid (Intermediate 79-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate Body 1-4) was prepared to obtain compound 91 as a yellow solid.
化合物91(15毫克)。MS:704.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.01(d,J＝11.5Hz,2H),7.77(d,J＝8.6Hz,1H),7.68(s,2H),7.18–7.09(m,2H),6.90-6.95(m,1H),5.97(s,1H),4.19(d,J＝17.1Hz,1H),4.11–3.95(m,5H),3.03–2.81(m,3H),2.71(q,J＝4.9Hz,2H),2.51(d,J＝2.0Hz,3H),2.36–2.12(m,2H),1.12(t,J＝7.1Hz,3H)。 Compound 91 (15 mg). MS: 704.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.01(d,J=11.5Hz,2H),7.77(d,J=8.6Hz,1H),7.68(s,2H),7.18-7.09(m, 2H), 6.90-6.95(m, 1H), 5.97(s, 1H), 4.19(d, J=17.1Hz, 1H), 4.11-3.95(m, 5H), 3.03-2.81(m, 3H), 2.71 (q, J=4.9 Hz, 2H), 2.51 (d, J=2.0 Hz, 3H), 2.36-2.12 (m, 2H), 1.12 (t, J=7.1 Hz, 3H).
实施例90Example 90
化合物92:Compound 92:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,6-二甲基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,6-di Toluic acid
Figure PCTCN2021135751-appb-000322
Figure PCTCN2021135751-appb-000322
化合物92的合成参考化合物1，通过使用4-((3aS，7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡 啶-2-基)-2,6-二甲基苯甲酸(中间体76-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物92。Synthesis of compound 92 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,6 -Dimethylbenzoic acid (Intermediate 76-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 92 was prepared as a yellow solid.
化合物92(35毫克)。MS:664.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.68(d,J＝3.2,0.9Hz,1H),7.61(d,J＝3.1Hz,1H),7.41(s,2H),7.09-7.14(m,2H),6.90-6.95(m,1H),5.97(s,1H),4.17(d,J＝17.1Hz,1H),4.10–3.91(m,5H),2.95-2.99(m,1H),2.79-2.85(m,2H),2.63-2.68(m,2H),2.51(d,J＝2.0Hz,3H),2.35(s,6H),2.29–2.12(m,2H),1.12(t,J＝7.1Hz,3H)。 Compound 92 (35 mg). MS: 664.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.68(d,J=3.2,0.9Hz,1H),7.61(d,J=3.1Hz,1H),7.41(s,2H),7.09-7.14( m,2H),6.90-6.95(m,1H),5.97(s,1H),4.17(d,J=17.1Hz,1H),4.10-3.91(m,5H),2.95-2.99(m,1H) ,2.79-2.85(m,2H),2.63-2.68(m,2H),2.51(d,J=2.0Hz,3H),2.35(s,6H),2.29-2.12(m,2H),1.12(t , J=7.1Hz, 3H).
实施例91Example 91
化合物93:Compound 93:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,5-二甲基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,5-di Toluic acid
Figure PCTCN2021135751-appb-000323
Figure PCTCN2021135751-appb-000323
化合物93的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,5-二甲基苯甲酸(中间体80-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物93。Synthesis of compound 93 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,5 -Dimethylbenzoic acid (Intermediate 80-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 93 was prepared as a yellow solid.
化合物93(12毫克)。MS:664.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.83–7.75(m,2H),7.72(d,J＝3.1Hz,1H),7.19–7.06(m,3H),6.89-6.94m,1H),5.98(s,1H),4.19(d,J＝17.1Hz,1H),4.06(q,J＝7.1Hz,2H),3.99–3.79(m,3H),3.04–2.89(m,2H),2.80–2.66(m,2H),2.63(q,J＝6.7,5.9Hz,1H),2.57–2.45(m,6H),2.27(s,5H),1.13(t,J＝7.1Hz,3H)。 Compound 93 (12 mg). MS: 664.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.83-7.75(m,2H),7.72(d,J=3.1Hz,1H),7.19-7.06(m,3H),6.89-6.94m,1H) ,5.98(s,1H),4.19(d,J=17.1Hz,1H),4.06(q,J=7.1Hz,2H),3.99-3.79(m,3H),3.04-2.89(m,2H), 2.80–2.66 (m, 2H), 2.63 (q, J=6.7, 5.9Hz, 1H), 2.57–2.45 (m, 6H), 2.27 (s, 5H), 1.13 (t, J=7.1Hz, 3H) .
实施例92Example 92
化合物94:Compound 94:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-氟-2-甲基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-fluoro-2 -Toluic acid
Figure PCTCN2021135751-appb-000324
Figure PCTCN2021135751-appb-000324
化合物94的合成参考化合物1，通过使用5-氟-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸(中间体81-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物94。Synthesis of compound 94 Reference compound 1 by using 5-fluoro-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) -2-methylbenzoic acid (intermediate 81-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate Body 1-4) was prepared to obtain compound 94 as a yellow solid.
化合物94(43毫克)。MS:668.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.79(d,J＝3.2Hz,1H),7.73–7.65(m,2H),7.40(d,J＝7.3Hz,1H),7.14-7.06(m,2H),6.94-6.89(m,1H),5.97(s,1H),4.18(d,J＝17.1Hz,1H),4.05(q,J＝7.1Hz,2H),4.02–3.86(m,3H),3.05–2.86(m,2H),2.82–2.57(m,4H),2.55(s,3H),2.50(d,J＝2.0Hz,3H),2.41–2.13(m,2H),1.12(t,J＝7.1Hz,3H) Compound 94 (43 mg). MS: 668.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.79(d,J=3.2Hz,1H),7.73-7.65(m,2H),7.40(d,J=7.3Hz,1H),7.14-7.06( m, 2H), 6.94-6.89 (m, 1H), 5.97 (s, 1H), 4.18 (d, J=17.1Hz, 1H), 4.05 (q, J=7.1Hz, 2H), 4.02–3.86 (m ,3H),3.05–2.86(m,2H),2.82–2.57(m,4H),2.55(s,3H),2.50(d,J=2.0Hz,3H),2.41–2.13(m,2H), 1.12(t,J=7.1Hz,3H)
实施例93Example 93
化合物95:Compound 95:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲氧基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methoxy benzoic acid
Figure PCTCN2021135751-appb-000325
Figure PCTCN2021135751-appb-000325
化合物95的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲氧基苯甲酸(中间体82-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物95。Synthesis of compound 95 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methyl Oxybenzoic acid (Intermediate 82-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 95 was prepared as a yellow solid.
化合物95(24毫克)。MS:666.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.75(d,J＝2.8Hz,2H),7.70(q,J＝2.7Hz,2H),7.40(d,J＝8.0Hz,1H),7.17–7.05(m,2H),6.92(t,J＝8.9Hz,1H),5.98(s,1H),4.17(d,J＝16.9Hz,1H),4.06(q,J＝7.1Hz,2H),3.97-3.80(m,5H),3.84(t,J＝8.1Hz,1H),3.02-2.83(m,2H),2.81–2.65(m,2H),2.65–2.56(m,1H),2.51(d,J＝2.0Hz,3H),2.45–2.29(m,1H),2.27-2.15(m,1H),1.13(t,J＝7.1Hz,3H)。 Compound 95 (24 mg). MS: 666.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.75(d,J=2.8Hz,2H),7.70(q,J=2.7Hz,2H),7.40(d,J=8.0Hz,1H),7.17 –7.05(m, 2H), 6.92(t, J=8.9Hz, 1H), 5.98(s, 1H), 4.17(d, J=16.9Hz, 1H), 4.06(q, J=7.1Hz, 2H) ,3.97-3.80(m,5H),3.84(t,J＝8.1Hz,1H),3.02-2.83(m,2H),2.81-2.65(m,2H),2.65-2.56(m,1H),2.51 (d, J=2.0 Hz, 3H), 2.45-2.29 (m, 1H), 2.27-2.15 (m, 1H), 1.13 (t, J=7.1 Hz, 3H).
实施例94Example 94
化合物96:Compound 96:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoro Methoxy)benzoic acid
Figure PCTCN2021135751-appb-000326
Figure PCTCN2021135751-appb-000326
化合物96的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲氧基)苯甲酸(中间体83-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物96。Synthesis of compound 96 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-( Trifluoromethoxy)benzoic acid (Intermediate 83-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate ( Intermediate 1-4) was prepared to obtain compound 96 as a yellow solid.
化合物96(124毫克)。MS:720.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.15–8.06(m,2H),7.96(d,J＝3.1Hz,1H),7.89(d,J＝3.1Hz,1H),7.70(dd,J＝8.9,2.1Hz,1H),7.27(d,J＝7.8Hz,1H),7.24–7.17(m,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.67–4.50(m,2H),4.33(dd,J＝10.5,6.6Hz,1H),4.07(q,J＝7.1Hz,2H),3.92–3.77(m,2H),3.77-3.64(m,1H),3.41-3.33(m,1H),3.27-3.18(m,2H),2.74-2.60(m,1H),2.57-2.43(m,4H),1.10(t,J＝7.1Hz,3H)。 Compound 96 (124 mg). MS: 720.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.15-8.06(m,2H),7.96(d,J=3.1Hz,1H),7.89(d,J=3.1Hz,1H),7.70(dd, J=8.9, 2.1Hz, 1H), 7.27(d, J=7.8Hz, 1H), 7.24–7.17(m, 1H), 7.00(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.67-4.50(m, 2H), 4.33(dd, J=10.5, 6.6Hz, 1H), 4.07(q, J=7.1Hz, 2H), 3.92-3.77(m, 2H), 3.77-3.64(m, 1H), 3.41-3.33(m, 1H), 3.27-3.18(m, 2H), 2.74-2.60(m, 1H), 2.57-2.43(m, 4H), 1.10(t, J=7.1Hz, 3H) .
实施例95Example 95
化合物97:Compound 97:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲氧基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methoxy benzoic acid
Figure PCTCN2021135751-appb-000327
Figure PCTCN2021135751-appb-000327
化合物97的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶 -2-基)-2-甲氧基苯甲酸(中间体84-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物97。Synthesis of compound 97 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methyl Oxybenzoic acid (Intermediate 84-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 97 was prepared as a yellow solid.
化合物97(14毫克)。MS:666.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.98–7.91(m,2H),7.89(d,J＝3.1Hz,1H),7.81(d,J＝2.0Hz,1H),7.28(d,J＝7.8Hz,1H),7.25–7.17(m,2H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.61(q,J＝16.4Hz,2H),4.33(dd,J＝10.6,6.5Hz,1H),4.07(q,J＝7.1Hz,2H),3.94(s,3H),3.92–3.80(m,2H),3.78-3.69(m,1H),3.41–3.33(m,1H),3.29-3.16(m,2H),2.74-2.60(m,1H),2.57–2.40(m,4H),1.11(t,J＝7.1Hz,3H)。 Compound 97 (14 mg). MS: 666.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.98-7.91(m,2H),7.89(d,J=3.1Hz,1H),7.81(d,J=2.0Hz,1H),7.28(d, J=7.8Hz, 1H), 7.25–7.17(m, 2H), 7.00(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.61(q, J=16.4Hz, 2H), 4.33( dd, J=10.6, 6.5Hz, 1H), 4.07 (q, J=7.1Hz, 2H), 3.94 (s, 3H), 3.92-3.80 (m, 2H), 3.78-3.69 (m, 1H), 3.41 -3.33(m,1H), 3.29-3.16(m,2H), 2.74-2.60(m,1H), 2.57-2.40(m,4H), 1.11(t,J=7.1Hz,3H).
实施例96Example 96
化合物98:Compound 98:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-isopropyl benzoic acid
Figure PCTCN2021135751-appb-000328
Figure PCTCN2021135751-appb-000328
化合物98的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸(中间体85-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物98。Synthesis of compound 98 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-iso Propylbenzoic acid (Intermediate 85-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 98 was prepared as a yellow solid.
化合物98(14.7毫克)。MS:678.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.91(d,J＝2.2Hz,1H),7.76(d,J＝8.5Hz,1H),7.65(d,J＝3.2Hz,1H),7.56(d,J＝3.1Hz,1H),7.50(dd,J＝8.6,2.2Hz,1H),7.12(dt,J＝8.0,5.6Hz,2H),6.90-6.95(m,1H),5.98(s,1H),4.19(d,J＝17.1Hz,1H),4.11–4.01(m,4H),3.98–3.80(m,2H),2.96-3.00(m,1H),2.93–2.77(m,2H),2.62-2.67(m,2H),2.51(s,3H),2.35–2.10(m,2H),1.21-1.26(m,6H),1.12(t,J＝7.1Hz,3H)。 Compound 98 (14.7 mg). MS: 678.2 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.91(d,J=2.2Hz,1H),7.76(d,J=8.5Hz,1H),7.65(d,J=3.2Hz,1H),7.56 (d, J=3.1Hz, 1H), 7.50 (dd, J=8.6, 2.2Hz, 1H), 7.12 (dt, J=8.0, 5.6Hz, 2H), 6.90-6.95 (m, 1H), 5.98( s, 1H), 4.19 (d, J=17.1Hz, 1H), 4.11–4.01 (m, 4H), 3.98–3.80 (m, 2H), 2.96–3.00 (m, 1H), 2.93–2.77 (m, 2H), 2.62-2.67(m, 2H), 2.51(s, 3H), 2.35-2.10(m, 2H), 1.21-1.26(m, 6H), 1.12(t, J=7.1Hz, 3H).
实施例97Example 97
化合物99:Compound 99:
2-环丙基-4-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸2-Cyclopropyl-4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole) -2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene Formic acid
Figure PCTCN2021135751-appb-000329
Figure PCTCN2021135751-appb-000329
化合物99的合成参考化合物1，通过使用2-环丙基-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体86-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物99。Synthesis of compound 99 Reference compound 1 by using 2-cyclopropyl-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridine-2- yl)benzoic acid (Intermediate 86-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 99 was prepared as a yellow solid.
化合物99(17毫克)。MS:676.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.96(d,J＝3.2Hz,1H),7.92(d,J＝8.5Hz,1H),7.89(d,J＝3.2Hz,1H),7.54(dd,J＝8.5,2.3Hz,1H),7.50(d,J＝2.3Hz,1H),7.28(d,J＝7.8Hz,1H),7.20(td,J＝7.9,5.4Hz,1H),7.00(t,J＝8.8Hz,1H),5.99(s,1H),4.65(d,J＝16.4Hz,1H),4.58(d,J＝16.4Hz,1H),4.29(dd,J＝10.6,6.5Hz,1H),4.07(q,J＝7.1Hz,2H),3.83(ddd,J＝19.4,11.5,4.9Hz,2H),3.71(s,1H),3.42-3.36(m,2H),3.22(d,J＝15.3Hz,1H),2.87–2.77(m,1H),2.63(d,J＝14.7Hz,1H),2.46(d,J＝2.0Hz,4H),1.10(t,J＝7.1Hz,3H),1.05-1.01(m,2H),0.74-0.70(m,2H)。 Compound 99 (17 mg). MS: 676.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.96(d,J=3.2Hz,1H),7.92(d,J=8.5Hz,1H),7.89(d,J=3.2Hz,1H),7.54 (dd, J=8.5, 2.3Hz, 1H), 7.50 (d, J=2.3Hz, 1H), 7.28 (d, J=7.8Hz, 1H), 7.20 (td, J=7.9, 5.4Hz, 1H) ,7.00(t,J＝8.8Hz,1H),5.99(s,1H),4.65(d,J＝16.4Hz,1H),4.58(d,J＝16.4Hz,1H),4.29(dd,J＝ 10.6,6.5Hz,1H),4.07(q,J=7.1Hz,2H),3.83(ddd,J=19.4,11.5,4.9Hz,2H),3.71(s,1H),3.42-3.36(m,2H) ), 3.22(d, J＝15.3Hz, 1H), 2.87–2.77(m, 1H), 2.63(d, J＝14.7Hz, 1H), 2.46(d, J＝2.0Hz, 4H), 1.10(t , J=7.1Hz, 3H), 1.05-1.01 (m, 2H), 0.74-0.70 (m, 2H).
实施例98Example 98
化合物100:Compound 100:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-(trifluoro Methyl)benzoic acid
Figure PCTCN2021135751-appb-000330
Figure PCTCN2021135751-appb-000330
化合物100的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-(三氟甲基)苯甲酸(中间体87-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物100。Synthesis of compound 100 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-( Trifluoromethyl)benzoic acid (Intermediate 87-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate Body 1-4) was prepared to obtain compound 100 as a yellow solid.
化合物100(71毫克)。MS:704.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.28(s,1H),7.90(d,J＝8.5,2.2Hz,1H),7.81(d,J＝8.5Hz,1H),7.68(d,J＝3.1Hz,1H),7.60(d,J＝3.1Hz,1H),7.10-7.15(m, 2H),6.90-6.95(m,1H),5.97(s,1H),4.18(d,J＝17.1Hz,1H),4.12–4.01(m,4H),3.96(d,J＝17.1Hz,1H),3.03–2.79(m,3H),2.65-2.70(m,2H),2.51(d,J＝2.0Hz,3H),2.19-2.29(m,2H),1.12(t,J＝7.1Hz,3H) Compound 100 (71 mg). MS: 704.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.28(s,1H),7.90(d,J=8.5,2.2Hz,1H),7.81(d,J=8.5Hz,1H),7.68(d, J=3.1Hz, 1H), 7.60(d, J=3.1Hz, 1H), 7.10-7.15(m, 2H), 6.90-6.95(m, 1H), 5.97(s, 1H), 4.18(d, J =17.1Hz,1H),4.12-4.01(m,4H),3.96(d,J=17.1Hz,1H),3.03-2.79(m,3H),2.65-2.70(m,2H),2.51(d, J=2.0Hz, 3H), 2.19-2.29(m, 2H), 1.12(t, J=7.1Hz, 3H)
实施例99Example 99
化合物101:Compound 101:
3-氯-4-((3aR,7aS)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Chloro-4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000331
Figure PCTCN2021135751-appb-000331
化合物101的合成参考化合物1，通过使用3-氯-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体88-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物101。Synthesis of compound 101 Reference compound 1 by using 3-chloro-4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid (Intermediate 88-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 101 was prepared as a yellow solid.
化合物101(21毫克)。MS:671.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.18(d,J＝1.8Hz,1H),8.07(d,J＝8.0,1H),7.95-7.96(d,J＝4.0Hz,1H),7.87-7.88(d,J＝4.0Hz,1H),7.63(d,J＝8.2Hz,1H),7.28(d,J＝7.9Hz,1H),7.17-7.23(m,1H),7.00(t,J＝8.0Hz,1H),6.01(s,1H),4.77(d,J＝16.2Hz,1H),4.54(d,J＝16.3Hz,1H),4.18-4.22(m,1H),4.06-4.12(q,J＝7.1Hz,2H),3.86-3.92(m,1H),3.69-3.76(m,2H),3.45-3.50(m,1H),3.31-3.35(m,2H),2.68(d,J＝15.6Hz,1H),2.60–2.41(m,4H),1.11(t,J＝7.1Hz,3H)。 Compound 101 (21 mg). MS: 671.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.18(d,J=1.8Hz,1H),8.07(d,J=8.0,1H),7.95-7.96(d,J=4.0Hz,1H), 7.87-7.88(d,J＝4.0Hz,1H),7.63(d,J＝8.2Hz,1H),7.28(d,J＝7.9Hz,1H),7.17-7.23(m,1H),7.00(t , J＝8.0Hz, 1H), 6.01(s, 1H), 4.77(d, J＝16.2Hz, 1H), 4.54(d, J＝16.3Hz, 1H), 4.18-4.22(m, 1H), 4.06 -4.12(q, J=7.1Hz, 2H), 3.86-3.92(m, 1H), 3.69-3.76(m, 2H), 3.45-3.50(m, 1H), 3.31-3.35(m, 2H), 2.68 (d, J=15.6 Hz, 1H), 2.60-2.41 (m, 4H), 1.11 (t, J=7.1 Hz, 3H).
实施例100Example 100
化合物102:Compound 102:
2-氯-4-((3aR,7aS)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸2-Chloro-4-((3aR,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzoic acid
Figure PCTCN2021135751-appb-000332
Figure PCTCN2021135751-appb-000332
化合物102的合成参考化合物1，通过使用2-氯-4-((3aR,7aS)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体89-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物102。Synthesis of compound 102 Reference compound 1 by using 2-chloro-4-((3aR,7aS)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Benzoic acid (Intermediate 89-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 102 was prepared as a yellow solid.
化合物102(21毫克)。MS:671.2(M+H) +。 Compound 102 (21 mg). MS: 671.2 (M+H) + .
实施例101Example 101
化合物103:Compound 103:
6-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)烟酸6-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)nicotinic acid
Figure PCTCN2021135751-appb-000333
Figure PCTCN2021135751-appb-000333
化合物103的合成参考化合物1，通过使用6-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)烟酸(中间体90-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物103。Synthesis of compound 103 Reference compound 1 by using 6-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Nicotinic acid (Intermediate 90-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolino[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) The compound 103 was prepared as a yellow solid.
化合物103(29毫克)。MS:651.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ9.07(d,J＝2.0Hz,1H),8.33(dd,J＝8.1,2.0Hz,1H),7.72(d,J＝3.2Hz,1H),7.69(d,J＝3.2Hz,1H),7.45(d,J＝8.1Hz,1H),7.16–7.05(m,2H),6.97–6.87(m,1H),5.95(s,1H),4.79(d,J＝15.8Hz,1H),4.66(d,J＝15.8Hz,1H),4.12(d,J＝16.8Hz,1H),4.04(q,J＝7.1Hz,2H),3.96(d,J＝16.8Hz,1H),3.61(dd,J＝10.0,7.1Hz,1H),3.47(dd,J＝10.0,6.2Hz,1H),2.93(dd,J＝12.4,5.2Hz,1H),2.85–2.58(m,4H),2.49(d,J＝2.0Hz,3H),2.41–2.11(m,2H),1.11(t,J＝7.1Hz,3H)。 Compound 103 (29 mg). MS: 651.2 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ9.07(d,J=2.0Hz,1H),8.33(dd,J=8.1,2.0Hz,1H),7.72(d,J=3.2Hz,1H) ,7.69(d,J=3.2Hz,1H),7.45(d,J=8.1Hz,1H),7.16–7.05(m,2H),6.97–6.87(m,1H),5.95(s,1H), 4.79(d,J＝15.8Hz,1H),4.66(d,J＝15.8Hz,1H),4.12(d,J＝16.8Hz,1H),4.04(q,J＝7.1Hz,2H),3.96( d, J＝16.8Hz, 1H), 3.61 (dd, J＝10.0, 7.1Hz, 1H), 3.47 (dd, J＝10.0, 6.2Hz, 1H), 2.93 (dd, J＝12.4, 5.2Hz, 1H) ), 2.85–2.58 (m, 4H), 2.49 (d, J=2.0Hz, 3H), 2.41–2.11 (m, 2H), 1.11 (t, J=7.1Hz, 3H).
实施例102Example 102
化合物104:Compound 104:
3-(3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯基)-3-甲基丁酸3-(3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)phenyl) -3-Methylbutyric acid
Figure PCTCN2021135751-appb-000334
Figure PCTCN2021135751-appb-000334
化合物104的合成参考化合物1，通过使用3-(3-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯基)-3-甲基丁酸(中间体91-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物104。Synthesis of compound 104 Reference compound 1 by using 3-(3-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl) Phenyl)-3-methylbutanoic acid (Intermediate 91-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetic acid The salt (intermediate 1-4) was prepared to give compound 104 as a yellow solid.
化合物104(92毫克)。MS:692.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.95(d,J＝3.1Hz,1H),7.88(d,J＝3.2Hz,1H),7.78(d,J＝2.0Hz,1H),7.50(d,J＝7.8Hz,1H),7.37(dt,J＝15.0,7.9Hz,2H),7.28(d,J＝7.8Hz,1H),7.24–7.14(m,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.68–4.51(m,2H),4.29(dd,J＝10.6,6.6Hz,1H),4.08(q,J＝7.1Hz,2H),3.98–3.64(m,3H),3.42(s,1H),3.20–3.15(m,1H),2.67(s,3H),2.46–2.11(m,4H),1.47(s,6H),1.11(t,J＝7.1Hz,3H)。 Compound 104 (92 mg). MS: 692.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.95(d,J=3.1Hz,1H),7.88(d,J=3.2Hz,1H),7.78(d,J=2.0Hz,1H),7.50 (d, J=7.8Hz, 1H), 7.37 (dt, J=15.0, 7.9Hz, 2H), 7.28 (d, J=7.8Hz, 1H), 7.24–7.14 (m, 1H), 7.00 (t, J=8.9Hz, 1H), 5.99(s, 1H), 4.68–4.51(m, 2H), 4.29(dd, J=10.6, 6.6Hz, 1H), 4.08(q, J=7.1Hz, 2H), 3.98–3.64 (m, 3H), 3.42 (s, 1H), 3.20–3.15 (m, 1H), 2.67 (s, 3H), 2.46–2.11 (m, 4H), 1.47 (s, 6H), 1.11 ( t, J=7.1 Hz, 3H).
实施例103Example 103
化合物105:Compound 105:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-isopropyl benzoic acid
Figure PCTCN2021135751-appb-000335
Figure PCTCN2021135751-appb-000335
化合物105的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-异丙基苯甲酸(中间体92-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物105。Synthesis of compound 105 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-iso Propylbenzoic acid (Intermediate 92-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) Preparation of yellow solid compound 105.
化合物105(9.2毫克)。MS:678.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.01(d,J＝2.5Hz,1H),7.97(d,J＝3.1Hz,1H),7.95–7.89(m,2H),7.54(d,J＝8.7Hz,1H),7.28(d,J＝7.8Hz,1H),7.25–7.16(m,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.63(s,2H),4.27(dd,J＝10.4,6.8Hz,1H),4.08(q,J＝7.1Hz,2H),3.93–3.65(m,2H),3.49(s,1H),3.20–3.15(m,3H),2.73–2.40(m,5H),1.26(d,J＝6.9Hz,6H),1.11(t,J＝7.1Hz,3H)。 Compound 105 (9.2 mg). MS: 678.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.01(d,J=2.5Hz,1H),7.97(d,J=3.1Hz,1H),7.95-7.89(m,2H),7.54(d, J=8.7Hz, 1H), 7.28(d, J=7.8Hz, 1H), 7.25–7.16(m, 1H), 7.00(t, J=8.9Hz, 1H), 5.99(s, 1H), 4.63( s, 2H), 4.27 (dd, J=10.4, 6.8Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 3.93–3.65 (m, 2H), 3.49 (s, 1H), 3.20–3.15 (m, 3H), 2.73–2.40 (m, 5H), 1.26 (d, J=6.9 Hz, 6H), 1.11 (t, J=7.1 Hz, 3H).
实施例104Example 104
化合物106:Compound 106:
3-环丙基-4-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸3-Cyclopropyl-4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole) -2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene Formic acid
Figure PCTCN2021135751-appb-000336
Figure PCTCN2021135751-appb-000336
化合物106的合成参考化合物1，通过使用3-环丙基-4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体93-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物106。Synthesis of compound 106 Reference compound 1 by using 3-cyclopropyl-4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridine-2- yl)benzoic acid (Intermediate 93-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) Preparation of yellow solid compound 106.
化合物106(19.2毫克)。MS:676.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.00–7.91(m,2H),7.88(dd,J＝3.2,1.1Hz,1H),7.80(d,J＝1.9Hz,1H),7.43(d,J＝8.2Hz,1H),7.28(d,J＝7.8Hz,1H),7.26–7.16(m,1H),7.00(t,J＝8.9Hz,1H),6.00(s,1H),4.65(q,J＝16.4Hz,3H),4.26(dd,J＝10.7,6.2Hz,1H),4.09(q,J＝7.1Hz,3H),3.93(d,J＝12.4Hz,1H),3.81–3.56(m,2H),3.51–3.35(m,1H),2.80–2.52(m,2H),2.47(d,J＝2.0Hz,4H),2.09–1.84(m,1H),1.12(t,J＝7.1Hz,4H),1.08–0.97(m,2H),0.83–0.67(m,3H)。 Compound 106 (19.2 mg). MS: 676.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.00-7.91(m,2H),7.88(dd,J=3.2,1.1Hz,1H),7.80(d,J=1.9Hz,1H),7.43( d, J=8.2Hz, 1H), 7.28 (d, J=7.8Hz, 1H), 7.26–7.16 (m, 1H), 7.00 (t, J=8.9Hz, 1H), 6.00 (s, 1H), 4.65(q,J＝16.4Hz,3H),4.26(dd,J＝10.7,6.2Hz,1H),4.09(q,J＝7.1Hz,3H),3.93(d,J＝12.4Hz,1H), 3.81–3.56 (m, 2H), 3.51–3.35 (m, 1H), 2.80–2.52 (m, 2H), 2.47 (d, J=2.0Hz, 4H), 2.09–1.84 (m, 1H), 1.12 ( t, J=7.1 Hz, 4H), 1.08-0.97 (m, 2H), 0.83-0.67 (m, 3H).
实施例105Example 105
化合物107:Compound 107:
2-环丙基-5-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸2-Cyclopropyl-5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole) -2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)benzene Formic acid
Figure PCTCN2021135751-appb-000337
Figure PCTCN2021135751-appb-000337
化合物107的合成参考化合物1，通过使用2-环丙基-5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)苯甲酸(中间体95-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物107。Synthesis of compound 107 Reference compound 1 by using 2-cyclopropyl-5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridine-2- yl)benzoic acid (Intermediate 95-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 107 was prepared as a yellow solid.
化合物107(18毫克)。MS:676.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.07(d,J＝2.5Hz,1H),7.97(d,J＝3.1Hz,1H),7.92(d,J＝3.1Hz,1H),7.87(dd,J＝8.6,2.5Hz,1H),7.28(d,J＝7.8Hz,1H),7.25–7.17(m,1H),7.12(d,J＝8.7Hz,1H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.63(s,2H),4.26(dd,J＝10.5,6.8Hz,1H),4.07(q,J＝7.1Hz,2H),3.89–3.79(m,2H),3.70(d,J＝9.0Hz,1H),3.55–3.44(m,1H),3.36(d,J＝9.9Hz,1H),3.21(dt,J＝18.7,6.8Hz,1H),2.74–2.65(m,1H),2.46(d,J＝2.0Hz,5H),1.11(t,J＝7.1Hz,3H),1.00(dt,J＝8.7,3.1Hz,2H),0.74–0.68(m,2H)。 Compound 107 (18 mg). MS: 676.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.07(d,J=2.5Hz,1H),7.97(d,J=3.1Hz,1H),7.92(d,J=3.1Hz,1H),7.87 (dd, J=8.6, 2.5Hz, 1H), 7.28 (d, J=7.8Hz, 1H), 7.25–7.17 (m, 1H), 7.12 (d, J=8.7Hz, 1H), 7.00 (t, J=8.9Hz, 1H), 5.99(s, 1H), 4.63(s, 2H), 4.26(dd, J=10.5, 6.8Hz, 1H), 4.07(q, J=7.1Hz, 2H), 3.89– 3.79(m,2H),3.70(d,J=9.0Hz,1H),3.55–3.44(m,1H),3.36(d,J=9.9Hz,1H),3.21(dt,J=18.7,6.8Hz ,1H),2.74–2.65(m,1H),2.46(d,J=2.0Hz,5H),1.11(t,J=7.1Hz,3H),1.00(dt,J=8.7,3.1Hz,2H) , 0.74–0.68 (m, 2H).
实施例106Example 106
化合物108:Compound 108:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-(三氟甲氧基)苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-(trifluoro Methoxy)benzoic acid
Figure PCTCN2021135751-appb-000338
Figure PCTCN2021135751-appb-000338
化合物108的合成参考化合物1，通过使用4-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-(三氟甲氧基)苯甲酸(中间体94-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物108。Synthesis of compound 108 Reference compound 1 by using 4-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-( Trifluoromethoxy)benzoic acid (Intermediate 94-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate ( Intermediate 1-4) was prepared to obtain compound 108 as a yellow solid.
化合物108(80毫克)。MS:720.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.04(d,J＝8.3Hz,1H),7.98(s,1H),7.91(d,J＝3.1Hz,1H),7.82(d,J＝3.0Hz,1H),7.67(d,J＝8.3Hz,1H),7.21(d,J＝7.9Hz,1H),7.13(q,J＝7.5Hz,1H),6.93(t,J＝8.9Hz,1H),5.93(s,1H),4.59(d,J＝16.4Hz,1H),4.51(d,J＝16.3Hz,1H),4.18(dd,J＝10.5,5.6Hz,1H),4.02(q,J＝7.1Hz,2H),3.84(d,J＝9.3Hz,1H),3.68(d,J＝ 12.6Hz,1H),3.60(d,J＝10.5Hz,1H),3.17(d,J＝11.8Hz,3H),2.58(d,J＝13.8Hz,1H),2.53–2.43(m,1H),2.39(s,3H),1.04(t,J＝7.1Hz,3H)。 Compound 108 (80 mg). MS: 720.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.04(d,J=8.3Hz,1H),7.98(s,1H),7.91(d,J=3.1Hz,1H),7.82(d,J= 3.0Hz, 1H), 7.67 (d, J=8.3Hz, 1H), 7.21 (d, J=7.9Hz, 1H), 7.13 (q, J=7.5Hz, 1H), 6.93 (t, J=8.9Hz) ,1H),5.93(s,1H),4.59(d,J＝16.4Hz,1H),4.51(d,J＝16.3Hz,1H),4.18(dd,J＝10.5,5.6Hz,1H),4.02 (q,J=7.1Hz,2H),3.84(d,J=9.3Hz,1H),3.68(d,J=12.6Hz,1H),3.60(d,J=10.5Hz,1H),3.17(d , J=11.8Hz, 3H), 2.58 (d, J=13.8Hz, 1H), 2.53–2.43 (m, 1H), 2.39 (s, 3H), 1.04 (t, J=7.1Hz, 3H).
实施例107Example 107
化合物109:Compound 109:
3-(5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸3-(5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2, 2-Dimethylpropionic acid
Figure PCTCN2021135751-appb-000339
Figure PCTCN2021135751-appb-000339
化合物109的合成参考化合物1，通过使用3-(5-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯基)-2,2-二甲基丙酸(中间体96-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物109。Synthesis of compound 109 Reference compound 1 by using 3-(5-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)- 2-Methylphenyl)-2,2-dimethylpropionic acid (Intermediate 96-1) in place of 4,5,6,7-tetrahydro-2H-pyrazoline[3,4-c]pyridine- 3-alcohol trifluoroacetate (intermediate 1-4) was prepared to give compound 109 as a yellow solid.
化合物109(70毫克)。MS:706.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.95(d,J＝3.0Hz,1H),7.88(d,J＝3.1Hz,1H),7.48(dd,J＝6.3,2.4Hz,2H),7.31–7.16(m,3H),7.00(t,J＝8.9Hz,1H),5.99(s,1H),4.60(q,J＝16.4Hz,2H),4.22(dd,J＝10.6,6.4Hz,1H),4.07(q,J＝7.2Hz,2H),3.89–3.79(m,1H),3.73(d,J＝11.1Hz,2H),3.37(d,J＝9.5Hz,1H),3.28–3.11(m,2H),2.98(s,2H),2.63(s,1H),2.46(d,J＝2.0Hz,4H),2.34(s,3H),1.20(s,6H),1.11(t,J＝7.1Hz,3H)。 Compound 109 (70 mg). MS: 706.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.95(d,J=3.0Hz,1H),7.88(d,J=3.1Hz,1H),7.48(dd,J=6.3,2.4Hz,2H) ,7.31–7.16(m,3H),7.00(t,J=8.9Hz,1H),5.99(s,1H),4.60(q,J=16.4Hz,2H),4.22(dd,J=10.6,6.4 Hz,1H),4.07(q,J＝7.2Hz,2H),3.89–3.79(m,1H),3.73(d,J＝11.1Hz,2H),3.37(d,J＝9.5Hz,1H), 3.28–3.11(m, 2H), 2.98(s, 2H), 2.63(s, 1H), 2.46(d, J=2.0Hz, 4H), 2.34(s, 3H), 1.20(s, 6H), 1.11 (t, J=7.1 Hz, 3H).
实施例108Example 108
化合物110:Compound 110:
1-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丙烷-1-羧酸1-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclopropane- 1-Carboxylic acid
Figure PCTCN2021135751-appb-000340
Figure PCTCN2021135751-appb-000340
化合物110的合成参考化合物1，通过使用1-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡 啶-2-基)甲基)环丙烷-1-羧酸(中间体97-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物110。Synthesis of compound 110 Reference compound 1 by using 1-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Cyclopropane-1-carboxylic acid (Intermediate 97-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate Body 1-4) was prepared to obtain compound 110 as a yellow solid.
化合物110(71毫克)。MS:614.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.99(dd,J＝3.1,1.0Hz,1H),7.89(d,J＝3.1Hz,1H),7.26(d,J＝7.7Hz,1H),7.24–7.15(m,1H),7.00(t,J＝8.9Hz,1H),5.98(s,1H),4.59(s,2H),4.07(q,J＝7.1Hz,2H),3.97–3.70(m,3H),3.70–3.45(m,2H),3.40–3.26(m,1H),3.19–2.96(m,3H),2.46(d,J＝2.0Hz,4H),1.35(s,2H),1.17–0.97(m,7H)。 Compound 110 (71 mg). MS: 614.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.99(dd,J=3.1,1.0Hz,1H),7.89(d,J=3.1Hz,1H),7.26(d,J=7.7Hz,1H) ,7.24–7.15(m,1H),7.00(t,J=8.9Hz,1H),5.98(s,1H),4.59(s,2H),4.07(q,J=7.1Hz,2H),3.97– 3.70(m,3H),3.70-3.45(m,2H),3.40-3.26(m,1H),3.19-2.96(m,3H),2.46(d,J=2.0Hz,4H),1.35(s, 2H), 1.17–0.97 (m, 7H).
实施例109Example 109
化合物111:Compound 111:
4-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-2-甲基苯甲酸4-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)-2 -Toluic acid
Figure PCTCN2021135751-appb-000341
Figure PCTCN2021135751-appb-000341
化合物111的合成参考化合物1，通过使用4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-2-甲基苯甲酸(中间体98-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物111。Synthesis of compound 111 Reference compound 1 by using 4-((((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) -2-methylbenzoic acid (intermediate 98-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate Body 1-4) was prepared to obtain compound 111 as a yellow solid.
化合物111(30毫克)。MS:664.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.93(d,J＝7.9Hz,1H),7.90(d,J＝3.1Hz,1H),7.83(d,J＝3.1Hz,1H),7.27–7.14(m,4H),6.98(t,J＝8.8Hz,1H),5.96(s,1H),4.73–4.38(m,5H),4.06(q,J＝7.1Hz,2H),3.74–3.44(m,2H),3.23–2.90(m,5H),2.58(s,3H),2.45(d,J＝2.0Hz,4H),1.10(t,J＝7.1Hz,3H)。 Compound 111 (30 mg). MS: 664.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.93(d,J=7.9Hz,1H),7.90(d,J=3.1Hz,1H),7.83(d,J=3.1Hz,1H),7.27 –7.14(m,4H),6.98(t,J=8.8Hz,1H),5.96(s,1H),4.73–4.38(m,5H),4.06(q,J=7.1Hz,2H),3.74– 3.44 (m, 2H), 3.23–2.90 (m, 5H), 2.58 (s, 3H), 2.45 (d, J=2.0Hz, 4H), 1.10 (t, J=7.1Hz, 3H).
实施例110Example 110
化合物112:Compound 112:
4-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-3-甲基苯甲酸4-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)-3 -Toluic acid
Figure PCTCN2021135751-appb-000342
Figure PCTCN2021135751-appb-000342
化合物112的合成参考化合物1，通过使用4-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)-3-甲基苯甲酸(中间体99-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物112。Synthesis of compound 112 Reference compound 1 by using 4-((((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) -3-methylbenzoic acid (intermediate 99-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate Body 1-4) was prepared to obtain compound 112 as a yellow solid.
化合物112(240毫克)。MS:664.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.88(s,1H),7.81(d,J＝8.0Hz,1H),7.73(d,J＝3.1Hz,1H),7.68(d,J＝3.1Hz,1H),7.29(d,J＝7.9Hz,1H),7.16–7.02(m,2H),6.91(dd,J＝9.9,7.8Hz,1H),5.94(s,1H),4.64(s,2H),4.15–3.94(m,3H),3.89–3.73(m,1H),3.43(dd,J＝10.1,7.1Hz,1H),3.21(dd,J＝10.3,5.9Hz,1H),2.93–2.63(m,3H),2.60–2.44(m,5H),2.38(s,3H),2.34–2.11(m,1H),1.11(t,J＝7.1Hz,3H)。 Compound 112 (240 mg). MS: 664.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.88(s,1H),7.81(d,J=8.0Hz,1H),7.73(d,J=3.1Hz,1H),7.68(d,J= 3.1Hz, 1H), 7.29(d, J=7.9Hz, 1H), 7.16–7.02(m, 2H), 6.91(dd, J=9.9, 7.8Hz, 1H), 5.94(s, 1H), 4.64( s, 2H), 4.15–3.94 (m, 3H), 3.89–3.73 (m, 1H), 3.43 (dd, J=10.1, 7.1Hz, 1H), 3.21 (dd, J=10.3, 5.9Hz, 1H) , 2.93–2.63 (m, 3H), 2.60–2.44 (m, 5H), 2.38 (s, 3H), 2.34–2.11 (m, 1H), 1.11 (t, J=7.1 Hz, 3H).
实施例111Example 111
化合物113和化合物114:Compound 113 and Compound 114:
4-((S)-1-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)乙基)苯甲酸和4-((R)-1-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)乙基)苯甲酸4-((S)-1-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-( Thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl) Ethyl)benzoic acid and 4-((R)-1-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylbenzene) yl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrrole[3,4-c] Pyridin-2-yl)ethyl)benzoic acid
Figure PCTCN2021135751-appb-000343
Figure PCTCN2021135751-appb-000343
化合物113和化合物114的合成参考化合物1，通过使用4-(1-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)乙基)苯甲酸(中间体100-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物113和化合物114。制备分离条件为：色谱柱：
Figure PCTCN2021135751-appb-000344
CSH TM Prep-C18(5μm，OBD TM 19*150mm)；柱温：室温；流速:40mL/min；波长:254nm；溶剂系统：乙腈和0.05％三氟乙酸水溶液，乙腈梯度为20％～60％。 Synthesis of compound 113 and compound 114 Reference compound 1 by using 4-(1-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridine-2- yl)ethyl)benzoic acid (intermediate 100-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (intermediate Compound 1-4) was prepared to obtain compound 113 and compound 114 as yellow solids. Preparative separation conditions are: chromatographic column:
Figure PCTCN2021135751-appb-000344
CSH TM Prep-C18 (5μm, OBD TM 19*150mm); column temperature: room temperature; flow rate: 40mL/min; wavelength: 254nm; solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution, acetonitrile gradient is 20%～60% .
化合物113(17毫克，保留时间4.341分钟)。MS:664.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.04(d,J＝8.2Hz,2H),7.98(d,J＝3.1Hz,1H),7.90(d,J＝3.1Hz,1H),7.46(d,J＝8.1Hz,2H),7.26(d,J＝7.8Hz,1H),7.24–7.15(m,1H),6.99(t,J＝9.0Hz,1H),5.98(s,1H),5.48(d,J＝7.1Hz,1H),4.67–4.55(m,2H),4.08(q,J＝7.1Hz,2H),3.85–3.67(m,2H),3.42(dd,J＝10.8,6.3Hz,1H),3.31(s,1H),3.24(dd,J＝21.1,11.6Hz,2H),3.00(s,1H),2.65–2.38(m,5H),1.67(d,J＝7.1Hz,3H),1.11(t,J＝7.1Hz,3H)。 Compound 113 (17 mg, retention time 4.341 min). MS: 664.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.04(d,J=8.2Hz,2H),7.98(d,J=3.1Hz,1H),7.90(d,J=3.1Hz,1H),7.46 (d, J=8.1Hz, 2H), 7.26 (d, J=7.8Hz, 1H), 7.24–7.15 (m, 1H), 6.99 (t, J=9.0Hz, 1H), 5.98 (s, 1H) , 5.48 (d, J=7.1Hz, 1H), 4.67–4.55 (m, 2H), 4.08 (q, J=7.1Hz, 2H), 3.85–3.67 (m, 2H), 3.42 (dd, J=10.8 ,6.3Hz,1H),3.31(s,1H),3.24(dd,J=21.1,11.6Hz,2H),3.00(s,1H),2.65–2.38(m,5H),1.67(d,J= 7.1Hz, 3H), 1.11 (t, J=7.1Hz, 3H).
化合物114(15毫克，保留时间4.522分钟)。MS:664.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.04(d,J＝8.2Hz,2H),7.98(d,J＝3.1Hz,1H),7.90(d,J＝3.1Hz,1H),7.46(d,J＝8.1Hz,2H),7.26(d,J＝7.8Hz,1H),7.24–7.15(m,1H),6.99(t,J＝9.0Hz,1H),5.98(s,1H),5.48(d,J＝7.1Hz,1H),4.67–4.55(m,2H),4.08(q,J＝7.1Hz,2H),3.85–3.67(m,2H),3.42(dd,J＝10.8,6.3Hz,1H),3.31(s,1H),3.24(dd,J＝21.1,11.6Hz,2H),3.00(s,1H),2.65–2.38(m,5H),1.67(d,J＝7.1Hz,3H),1.11(t,J＝7.1Hz,3H)。 Compound 114 (15 mg, retention time 4.522 min). MS: 664.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.04(d,J=8.2Hz,2H),7.98(d,J=3.1Hz,1H),7.90(d,J=3.1Hz,1H),7.46 (d, J=8.1Hz, 2H), 7.26 (d, J=7.8Hz, 1H), 7.24–7.15 (m, 1H), 6.99 (t, J=9.0Hz, 1H), 5.98 (s, 1H) , 5.48 (d, J=7.1Hz, 1H), 4.67–4.55 (m, 2H), 4.08 (q, J=7.1Hz, 2H), 3.85–3.67 (m, 2H), 3.42 (dd, J=10.8 ,6.3Hz,1H),3.31(s,1H),3.24(dd,J=21.1,11.6Hz,2H),3.00(s,1H),2.65–2.38(m,5H),1.67(d,J= 7.1Hz, 3H), 1.11 (t, J=7.1Hz, 3H).
实施例112Example 112
化合物115：Compound 115:
3-((3aS,7aR)-5-(((R)-6-(2-氯-3-氟苯基)-5-(乙氧基羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸3-((3aS,7aR)-5-(((R)-6-(2-chloro-3-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2-dimethyl propionic acid
Figure PCTCN2021135751-appb-000345
Figure PCTCN2021135751-appb-000345
化合物115的合成参考化合物49，通过使用中间体A2代替中间体A1制备得到黄色固体化合物115。Synthesis of compound 115 Referring to compound 49, compound 115 was prepared as a yellow solid by using intermediate A2 instead of intermediate A1.
化合物115(30毫克)。MS:637.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.95(d,J＝3.1Hz,1H),7.72(d,J＝3.1Hz,1H),7.31–7.20(m,2H),7.13(s,1H),6.22(s,1H),4.11(d,J＝17.1Hz,1H),4.03(q,J＝7.1Hz,2H),3.87(d,J＝17.1Hz,1H),3.68–3.57(m,2H),3.51–3.40(m,2H),2.89(dd,J＝12.3,5.3Hz,1H),2.75–2.45(m,4H),2.28–2.07(m,2H),1.24(d,J＝8.0Hz,6H),1.11(t,J＝7.1Hz,3H)。 Compound 115 (30 mg). MS: 637.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.95(d,J=3.1Hz,1H),7.72(d,J=3.1Hz,1H),7.31-7.20(m,2H),7.13(s, 1H), 6.22(s, 1H), 4.11(d, J=17.1Hz, 1H), 4.03(q, J=7.1Hz, 2H), 3.87(d, J=17.1Hz, 1H), 3.68–3.57( m, 2H), 3.51–3.40 (m, 2H), 2.89 (dd, J=12.3, 5.3Hz, 1H), 2.75–2.45 (m, 4H), 2.28–2.07 (m, 2H), 1.24 (d, J=8.0 Hz, 6H), 1.11 (t, J=7.1 Hz, 3H).
实施例113Example 113
化合物116：Compound 116:
3-((3aS,7aR)-5-(((S)-6-(3,4-二氟-2-甲基苯基-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧 啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸3-((3aS,7aR)-5-(((S)-6-(3,4-difluoro-2-methylphenyl-5-(ethoxycarbonyl)-2-(thiazol-2-yl) )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2- dimethylpropionic acid
Figure PCTCN2021135751-appb-000346
Figure PCTCN2021135751-appb-000346
化合物116的合成参考化合物49，通过使用中间体A8代替中间体A1制备得到黄色固体化合物116。Synthesis of compound 116 Referring to compound 49, compound 116 was prepared as a yellow solid by using intermediate A8 instead of intermediate A1.
化合物116(70毫克)。MS:634.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.93(d,J＝3.2Hz,1H),7.71(d,J＝3.1Hz,1H),7.07–6.96(m,2H),5.92(s,1H),4.16–4.01(m,3H),3.87(d,J＝17.1Hz,1H),3.67–3.56(m,2H),3.52–3.39(m,2H),2.88(dd,J＝12.3,5.2Hz,1H),2.75–2.57(m,2H),2.55(d,J＝2.4Hz,3H),2.52–2.43(m,1H),2.28–2.05(m,2H),1.23(d,J＝8.6Hz,6H),1.13(t,J＝7.1Hz,3H)。 Compound 116 (70 mg). MS: 634.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.93(d,J=3.2Hz,1H),7.71(d,J=3.1Hz,1H),7.07-6.96(m,2H),5.92(s, 1H), 4.16–4.01 (m, 3H), 3.87 (d, J=17.1Hz, 1H), 3.67–3.56 (m, 2H), 3.52–3.39 (m, 2H), 2.88 (dd, J=12.3, 5.2Hz, 1H), 2.75–2.57 (m, 2H), 2.55 (d, J=2.4Hz, 3H), 2.52–2.43 (m, 1H), 2.28–2.05 (m, 2H), 1.23 (d, J = 8.6 Hz, 6H), 1.13 (t, J=7.1 Hz, 3H).
实施例114Example 114
化合物117：Compound 117:
3-((3aS,7aR)-5-(((R)-6-(2-氯-4-氟苯基)-5-(乙氧基羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸3-((3aS,7aR)-5-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2-dimethyl propionic acid
Figure PCTCN2021135751-appb-000347
Figure PCTCN2021135751-appb-000347
化合物117的合成参考化合物49，通过使用中间体A3代替中间体A1制备得到黄色固体化合物117。Synthesis of compound 117 Referring to compound 49, compound 117 was prepared as a yellow solid by using intermediate A3 instead of intermediate A1.
化合物117(73毫克)。MS:637.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.95(d,J＝3.2Hz,1H),7.73(d,J＝3.1Hz,1H),7.41(dd,J＝8.7,6.1Hz,1H),7.22(dd,J＝8.7,2.6Hz,1H),7.04(td,J＝8.4,2.7Hz,1H),6.17(s,1H),4.15–4.00(m,3H),3.86(d,J＝17.1Hz,1H),3.69–3.58(m,2H),3.45(dd,J＝22.4,11.8Hz,2H),2.89(dd,J＝12.3,5.2Hz,1H),2.76–2.54(m,3H),2.53–2.45(m,1H),2.28–2.05(m,2H),1.24(d,J＝7.7Hz,6H),1.12(t,J＝7.1Hz,3H)。 Compound 117 (73 mg). MS: 637.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.95(d,J=3.2Hz,1H),7.73(d,J=3.1Hz,1H),7.41(dd,J=8.7,6.1Hz,1H) ,7.22(dd,J＝8.7,2.6Hz,1H),7.04(td,J＝8.4,2.7Hz,1H),6.17(s,1H),4.15–4.00(m,3H),3.86(d,J = 17.1Hz, 1H), 3.69–3.58 (m, 2H), 3.45 (dd, J=22.4, 11.8Hz, 2H), 2.89 (dd, J=12.3, 5.2Hz, 1H), 2.76–2.54 (m, 3H), 2.53–2.45 (m, 1H), 2.28–2.05 (m, 2H), 1.24 (d, J=7.7Hz, 6H), 1.12 (t, J=7.1Hz, 3H).
实施例115Example 115
化合物118：Compound 118:
4-((3aS,7aR)-5-(((R)-6-(2-氯-3-氟苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aR)-5-(((R)-6-(2-chloro-3-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3 ,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000348
Figure PCTCN2021135751-appb-000348
化合物118的合成参考化合物80，通过使用中间体A2代替中间体A1制备得到黄色固体化合物118。Synthesis of compound 118 Referring to compound 80, compound 118 was prepared as a yellow solid by using intermediate A2 instead of intermediate A1.
化合物118(53毫克)。MS:671.1(M+H) +。1H NMR(400MHz,Methanol-d 4)δ7.92(d,J＝8.5Hz,1H),7.65–7.51(m,4H),7.26–7.15(m,2H),7.06(dd,J＝9.2,6.3Hz,1H),6.15(s,1H),4.17–3.81(m,6H),2.97–2.45(m,9H),2.27–2.04(m,2H),1.03(t,J＝7.1Hz,3H)。 Compound 118 (53 mg). MS: 671.1 (M+H) + . 1H NMR(400MHz,Methanol-d 4 )δ7.92(d,J=8.5Hz,1H),7.65-7.51(m,4H),7.26-7.15(m,2H),7.06(dd,J=9.2, 6.3Hz, 1H), 6.15 (s, 1H), 4.17–3.81 (m, 6H), 2.97–2.45 (m, 9H), 2.27–2.04 (m, 2H), 1.03 (t, J=7.1Hz, 3H) ).
实施例116Example 116
化合物119：Compound 119:
4-((3aS,7aR)-5-(((R)-6-(2-氯-4-氟苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aR)-5-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3 ,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000349
Figure PCTCN2021135751-appb-000349
化合物119的合成参考化合物80，通过使用中间体A3代替中间体A1制备得到黄色固体化合物119。Synthesis of compound 119 Referring to compound 80, compound 119 was prepared as a yellow solid by using intermediate A3 instead of intermediate A1.
化合物119(42毫克)。MS:671.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.84(d,J＝8.5Hz,1H),7.66–7.51(m,4H),7.37(dd,J＝8.7,6.2Hz,1H),7.15(dd,J＝8.7,2.5Hz,1H),6.97(td,J＝8.4,2.4 Hz,1H),6.10(s,1H),4.14–3.81(m,6H),2.94–2.70(m,3H),2.65–2.49(m,5H),2.23–2.06(m,2H),1.05(t,J＝7.1Hz,3H)。 Compound 119 (42 mg). MS: 671.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.84(d,J=8.5Hz,1H),7.66-7.51(m,4H),7.37(dd,J=8.7,6.2Hz,1H),7.15( dd, J=8.7, 2.5Hz, 1H), 6.97 (td, J=8.4, 2.4 Hz, 1H), 6.10 (s, 1H), 4.14–3.81 (m, 6H), 2.94–2.70 (m, 3H) , 2.65–2.49 (m, 5H), 2.23–2.06 (m, 2H), 1.05 (t, J=7.1 Hz, 3H).
实施例117Example 117
化合物120：Compound 120:
4-((3aS,7aR)-5-(((S)-6-(3,4-二氟-2-甲基苯基-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aR)-5-(((S)-6-(3,4-difluoro-2-methylphenyl-5-(ethoxycarbonyl)-2-(thiazol-2-yl) )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methyl benzoic acid
Figure PCTCN2021135751-appb-000350
Figure PCTCN2021135751-appb-000350
化合物120的合成参考化合物80，通过使用中间体A8代替中间体A1制备得到黄色固体化合物120。Synthesis of compound 120 Referring to compound 80, compound 120 was prepared as a yellow solid by using intermediate A8 instead of intermediate A1.
化合物120(48毫克)。MS:668.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.88(d,J＝8.5Hz,1H),7.59(dd,J＝14.1,4.4Hz,3H),7.51(d,J＝3.0Hz,1H),7.02–6.89(m,2H),5.85(s,1H),4.10(d,J＝17.2Hz,1H),3.98(q,J＝7.1Hz,4H),3.87(d,J＝17.2Hz,1H),2.95–2.69(m,3H),2.59(dq,J＝9.9,6.0,5.3Hz,2H),2.55–2.45(m,6H),2.23–2.04(m,2H),1.06(t,J＝7.1Hz,3H)。 Compound 120 (48 mg). MS: 668.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.88(d,J=8.5Hz,1H),7.59(dd,J=14.1,4.4Hz,3H),7.51(d,J=3.0Hz,1H) ,7.02–6.89(m,2H),5.85(s,1H),4.10(d,J=17.2Hz,1H),3.98(q,J=7.1Hz,4H),3.87(d,J=17.2Hz, 1H), 2.95–2.69 (m, 3H), 2.59 (dq, J=9.9, 6.0, 5.3Hz, 2H), 2.55–2.45 (m, 6H), 2.23–2.04 (m, 2H), 1.06 (t, J=7.1Hz, 3H).
实施例118Example 118
化合物121：Compound 121:
4-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(4-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(4-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000351
Figure PCTCN2021135751-appb-000351
化合物121的合成参考化合物80，通过使用中间体A4代替中间体A1制备得到黄色固体化合物121。Synthesis of compound 121 Referring to compound 80, compound 121 was prepared as a yellow solid by using intermediate A4 instead of intermediate A1.
化合物121(41毫克)。MS:650.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.83(d,J＝8.4Hz,1H),7.61–7.48(m,4H),7.19(dd,J＝8.6,6.0Hz,1H),6.84(dd,J＝9.9,2.6Hz,1H),6.77(td,J＝8.6,2.6Hz,1H),5.85(s,1H),4.14–3.81(m,6H),2.88(dd,J＝12.1,4.5Hz,1H),2.84–2.69(m,2H),2.65–2.44(m,8H),2.23–2.02(m,2H),1.05(t,J＝7.1Hz,3H)。 Compound 121 (41 mg). MS: 650.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.83(d,J=8.4Hz,1H),7.61-7.48(m,4H),7.19(dd,J=8.6,6.0Hz,1H),6.84( dd, J=9.9, 2.6Hz, 1H), 6.77 (td, J=8.6, 2.6Hz, 1H), 5.85 (s, 1H), 4.14–3.81 (m, 6H), 2.88 (dd, J=12.1, 4.5Hz, 1H), 2.84–2.69 (m, 2H), 2.65–2.44 (m, 8H), 2.23–2.02 (m, 2H), 1.05 (t, J=7.1Hz, 3H).
实施例119Example 119
化合物122：Compound 122:
5-((3aS,7aR)-5-(((R)-6-(2-氯-3-氟苯基)-5-(乙氧基羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸5-((3aS,7aR)-5-(((R)-6-(2-chloro-3-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000352
Figure PCTCN2021135751-appb-000352
化合物122的合成参考化合物70，通过使用中间体A2代替中间体A1制备得到黄色固体化合物122。Synthesis of compound 122 Referring to compound 70, compound 122 was prepared as a yellow solid by using intermediate A2 instead of intermediate A1.
化合物122(48毫克)。MS:671.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.99(d,J＝2.3Hz,1H),7.74(dd,J＝8.4,2.2Hz,1H),7.66–7.58(m,2H),7.29–7.16(m,3H),7.06(td,J＝8.1,6.9,2.6Hz,1H),6.15(s,1H),4.09(d,J＝17.2Hz,1H),3.95(h,J＝8.2Hz,4H),3.86(d,J＝17.2Hz,1H),2.92–2.70(m,3H),2.58(d,J＝5.7Hz,2H),2.49(s,3H),2.13(dt,J＝25.8,6.6Hz,2H),1.04(t,J＝7.1Hz,3H)。 Compound 122 (48 mg). MS: 671.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.99(d,J=2.3Hz,1H),7.74(dd,J=8.4,2.2Hz,1H),7.66-7.58(m,2H),7.29- 7.16(m, 3H), 7.06(td, J=8.1, 6.9, 2.6Hz, 1H), 6.15(s, 1H), 4.09(d, J=17.2Hz, 1H), 3.95(h, J=8.2Hz ,4H),3.86(d,J＝17.2Hz,1H),2.92-2.70(m,3H),2.58(d,J＝5.7Hz,2H),2.49(s,3H),2.13(dt,J＝ 25.8, 6.6 Hz, 2H), 1.04 (t, J=7.1 Hz, 3H).
实施例120Example 120
化合物123：Compound 123:
5-((3aS,7aR)-5-(((R)-6-(2-氯-4-氟苯基)-5-(乙氧基羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸5-((3aS,7aR)-5-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000353
Figure PCTCN2021135751-appb-000353
化合物123的合成参考化合物70，通过使用中间体A3代替中间体A1制备得到黄色固体化合物123。Synthesis of compound 123 Referring to compound 70, compound 123 was prepared as a yellow solid by using intermediate A3 instead of intermediate A1.
化合物123(48毫克)。MS:671.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.00(d,J＝2.4Hz,1H),7.74(dd,J＝8.4,2.3Hz,1H),7.67–7.57(m,2H),7.37(dd,J＝8.7,6.1Hz,1H),7.25(d,J＝8.4Hz,1H),7.14(dd,J＝8.7,2.5Hz,1H),6.97(td,J＝8.4,2.5Hz,1H),6.10(s,1H),4.09(d,J＝17.2Hz,1H),3.97(dp,J＝16.3,9.0Hz,4H),3.85(d,J＝17.2Hz,1H),2.92–2.72(m,3H),2.58(t,J＝5.8Hz,2H),2.49(s,3H),2.23–2.06(m,2H),1.05(t,J＝7.1Hz,3H)。 Compound 123 (48 mg). MS: 671.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.00(d,J=2.4Hz,1H),7.74(dd,J=8.4,2.3Hz,1H),7.67-7.57(m,2H),7.37( dd,J＝8.7,6.1Hz,1H),7.25(d,J＝8.4Hz,1H),7.14(dd,J＝8.7,2.5Hz,1H),6.97(td,J＝8.4,2.5Hz,1H) ),6.10(s,1H),4.09(d,J＝17.2Hz,1H),3.97(dp,J＝16.3,9.0Hz,4H),3.85(d,J＝17.2Hz,1H),2.92–2.72 (m, 3H), 2.58 (t, J=5.8 Hz, 2H), 2.49 (s, 3H), 2.23-2.06 (m, 2H), 1.05 (t, J=7.1 Hz, 3H).
实施例121Example 121
化合物124：Compound 124:
5-((3aS,7aR)-5-(((S)-6-(3,4-二氟-2-甲基苯基-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸5-((3aS,7aR)-5-(((S)-6-(3,4-difluoro-2-methylphenyl-5-(ethoxycarbonyl)-2-(thiazol-2-yl) )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methyl benzoic acid
Figure PCTCN2021135751-appb-000354
Figure PCTCN2021135751-appb-000354
化合物124的合成参考化合物70，通过使用中间体A8代替中间体A1制备得到黄色固体化合物124。Synthesis of compound 124 Referring to compound 70, compound 124 was prepared as a yellow solid by using intermediate A8 instead of intermediate A1.
化合物124(21毫克)。MS:668.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.00(d,J＝2.4Hz,1H),7.72(dd,J＝8.3,2.3Hz,1H),7.59(q,J＝3.1Hz,2H),7.24(d,J＝8.4Hz,1H),6.97(dt,J＝22.7,8.8Hz,2H),5.84(s,1H),4.10(d,J＝17.2Hz,1H),4.05–3.81(m,5H),2.91–2.71(m,3H),2.67–2.38(m,8H),2.12(dp,J＝20.1,5.7,4.4Hz,2H),1.06(t,J＝7.1Hz,3H)。 Compound 124 (21 mg). MS: 668.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.00(d,J=2.4Hz,1H),7.72(dd,J=8.3,2.3Hz,1H),7.59(q,J=3.1Hz,2H) ,7.24(d,J＝8.4Hz,1H),6.97(dt,J＝22.7,8.8Hz,2H),5.84(s,1H),4.10(d,J＝17.2Hz,1H),4.05–3.81( m, 5H), 2.91–2.71 (m, 3H), 2.67–2.38 (m, 8H), 2.12 (dp, J=20.1, 5.7, 4.4Hz, 2H), 1.06 (t, J=7.1Hz, 3H) .
实施例122Example 122
化合物125：Compound 125:
5-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(4-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(4-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzene Formic acid
Figure PCTCN2021135751-appb-000355
Figure PCTCN2021135751-appb-000355
化合物125的合成参考化合物70，通过使用中间体A4代替中间体A1制备得到黄色固体化合物125。Synthesis of compound 125 Referring to compound 70, compound 125 was prepared as a yellow solid by using intermediate A4 instead of intermediate A1.
化合物125(20毫克)。MS:650.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.72(dd,J＝8.4,2.3Hz,1H),7.59(q,J＝3.1Hz,2H),7.29–7.16(m,2H),6.89–6.73(m,2H),5.85(s,1H),4.10(d,J＝17.1Hz,1H),4.04–3.82(m,5H),2.92–2.70(m,3H),2.63–2.42(m,8H),2.21–2.05(m,2H),1.06(t,J＝7.1Hz,3H)。 Compound 125 (20 mg). MS: 650.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.72(dd,J=8.4,2.3Hz,1H),7.59(q,J=3.1Hz,2H),7.29-7.16(m,2H),6.89- 6.73(m, 2H), 5.85(s, 1H), 4.10(d, J=17.1Hz, 1H), 4.04–3.82(m, 5H), 2.92–2.70(m, 3H), 2.63–2.42(m, 8H), 2.21–2.05 (m, 2H), 1.06 (t, J=7.1 Hz, 3H).
实施例123Example 123
化合物126：Compound 126:
3-((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(4-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2,2-二甲基丙酸3-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(4-fluoro-2-methylphenyl)-2-(thiazol-2-yl) -3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2,2-di Methylpropionic acid
Figure PCTCN2021135751-appb-000356
Figure PCTCN2021135751-appb-000356
化合物126的合成参考化合物49，通过使用中间体A4代替中间体A1制备得到黄色固体化合物126。Synthesis of compound 126 Referring to compound 49, compound 126 was prepared as a yellow solid by using intermediate A4 instead of intermediate A1.
化合物126(80毫克)。MS:616.1(M+H) +。 Compound 126 (80 mg). MS: 616.1 (M+H) + .
实施例124Example 124
化合物127：Compound 127:
1-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸1-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclobutane Alkane-1-carboxylic acid
Figure PCTCN2021135751-appb-000357
Figure PCTCN2021135751-appb-000357
化合物127的合成参考化合物1，通过使用1-(((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环丁烷-1-羧酸(中间体101-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物127。Synthesis of compound 127 Reference compound 1 by using 1-(((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Cyclobutane-1-carboxylic acid (Intermediate 101-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate ( Intermediate 1-4) was prepared to obtain compound 127 as a yellow solid.
化合物127(88毫克)。MS:628.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.91(d,J＝3.1Hz,1H),7.82(d,J＝3.0Hz,1H),7.20(d,J＝7.8Hz,1H),7.13(q,J＝7.5Hz,1H),6.93(t,J＝8.9Hz,1H),5.91(s,1H),4.60–4.47(m,2H),4.00(q,J＝7.1Hz,2H),3.88–3.58(m,5H),3.16(dd,J＝22.2,12.1Hz,3H),3.02–2.90(m,1H),2.51–2.30(m,7H),2.08–1.85(m,4H),1.03(t,J＝7.1Hz,3H)。 Compound 127 (88 mg). MS: 628.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.91(d,J=3.1Hz,1H),7.82(d,J=3.0Hz,1H),7.20(d,J=7.8Hz,1H),7.13 (q, J=7.5Hz, 1H), 6.93 (t, J=8.9Hz, 1H), 5.91 (s, 1H), 4.60–4.47 (m, 2H), 4.00 (q, J=7.1Hz, 2H) ,3.88–3.58(m,5H),3.16(dd,J=22.2,12.1Hz,3H),3.02–2.90(m,1H),2.51–2.30(m,7H),2.08–1.85(m,4H) , 1.03 (t, J=7.1 Hz, 3H).
实施例125Example 125
化合物128：Compound 128:
1-(((3aS,7aR)-5-(((S)-5-(乙氧基羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环戊烷-1-羧酸1-(((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl )-3,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl)cyclopenta Alkane-1-carboxylic acid
Figure PCTCN2021135751-appb-000358
Figure PCTCN2021135751-appb-000358
化合物128的合成参考化合物1，通过使用1-(((3As,7aR)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)甲基)环戊烷-1-羧酸(中间体102-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物128。Synthesis of compound 128 Reference compound 1 by using 1-(((3As,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)methyl) Cyclopentane-1-carboxylic acid (Intermediate 102-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate ( Intermediate 1-4) was prepared to obtain compound 128 as a yellow solid.
化合物128(18毫克)。MS:642.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.91(d,J＝3.1Hz,1H),7.83(d,J＝3.0Hz,1H),7.20(d,J＝7.8Hz,1H),7.13(q,J＝7.5Hz,1H),6.93(t,J＝8.9Hz,1H),5.92 (s,1H),4.61–4.47(m,2H),4.00(q,J＝7.1Hz,2H),3.79–3.60(m,4H),3.55(d,J＝13.9Hz,1H),3.34–3.24(m,2H),3.16(d,J＝9.7Hz,1H),2.97(dd,J＝11.9,5.5Hz,1H),2.38(d,J＝2.0Hz,5H),2.06(td,J＝11.1,5.4Hz,2H),1.67(dq,J＝11.1,5.9Hz,4H),1.55(dt,J＝13.4,6.3Hz,2H),1.03(t,J＝7.1Hz,3H)。 Compound 128 (18 mg). MS: 642.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.91(d,J=3.1Hz,1H),7.83(d,J=3.0Hz,1H),7.20(d,J=7.8Hz,1H),7.13 (q, J=7.5Hz, 1H), 6.93 (t, J=8.9Hz, 1H), 5.92 (s, 1H), 4.61–4.47 (m, 2H), 4.00 (q, J=7.1Hz, 2H) , 3.79–3.60 (m, 4H), 3.55 (d, J=13.9Hz, 1H), 3.34–3.24 (m, 2H), 3.16 (d, J=9.7Hz, 1H), 2.97 (dd, J=11.9 ,5.5Hz,1H),2.38(d,J＝2.0Hz,5H),2.06(td,J＝11.1,5.4Hz,2H),1.67(dq,J＝11.1,5.9Hz,4H),1.55(dt , J=13.4, 6.3Hz, 2H), 1.03 (t, J=7.1Hz, 3H).
实施例126Example 126
化合物129：Compound 129:
4-((3aS,7aS)-5-(((R)-6-(2-氯-3-氟苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aS)-5-(((R)-6-(2-chloro-3-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3 ,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000359
Figure PCTCN2021135751-appb-000359
化合物129的合成参考化合物1，通过使用2-甲基-4-((3aS,7aS)-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体103-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和中间体A2代替中间体A1制备得到黄色固体化合物129。Synthesis of compound 129 Reference compound 1 by using 2-methyl-4-((3aS,7aS)-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 103-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) and Intermediate Compound A2 was prepared in place of intermediate A1 to give compound 129 as a yellow solid.
化合物129(150毫克)。MS:652.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.01–7.95(m,2H),7.87(d,J＝3.1Hz,1H),7.62(d,J＝8.8Hz,2H),7.38–7.31(m,2H),7.26–7.20(m,1H),6.23(s,1H),4.69(d,J＝16.1Hz,1H),4.55(d,J＝16.1Hz,1H),4.20–4.01(m,3H),3.88–3.70(m,2H),3.66–3.59(m,1H),3.25–3.08(m,4H),2.53(d,J＝15.6Hz,1H),2.40(d,J＝14.0Hz,1H),1.10(t,J＝7.1Hz,3H)。 Compound 129 (150 mg). MS: 652.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.01-7.95(m,2H),7.87(d,J=3.1Hz,1H),7.62(d,J=8.8Hz,2H),7.38-7.31( m, 2H), 7.26–7.20 (m, 1H), 6.23 (s, 1H), 4.69 (d, J=16.1Hz, 1H), 4.55 (d, J=16.1Hz, 1H), 4.20–4.01 (m , 3H), 3.88–3.70 (m, 2H), 3.66–3.59 (m, 1H), 3.25–3.08 (m, 4H), 2.53 (d, J=15.6Hz, 1H), 2.40 (d, J=14.0 Hz, 1H), 1.10 (t, J=7.1 Hz, 3H).
实施例127Example 127
化合物130：Compound 130:
4-((3aS,7aS)-5-(((S)-6-(3,4-二氟-2-甲基苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aS)-5-(((S)-6-(3,4-difluoro-2-methylphenyl)-5-(ethoxycarbonyl)-2-(thiazole-2- (yl)-3,6-dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrrole[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000360
Figure PCTCN2021135751-appb-000360
化合物130的合成参考化合物1，通过使用2-甲基-4-((3aS,7aS)-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体103-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和中间体A8代替中间体A1制备得到黄色固体化合物130。Synthesis of compound 130 Reference compound 1 by using 2-methyl-4-((3aS,7aS)-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 103-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) and Intermediate Compound A8 was prepared in place of intermediate A1 to give compound 130 as a yellow solid.
化合物130(140毫克)。MS:650.7(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.02–7.95(m,2H),7.87(d,J＝3.1Hz,1H),7.63(d,J＝9.1Hz,2H),7.25(dd,J＝9.1,4.8Hz,1H),7.09(q,J＝8.9Hz,1H),5.93(s,1H),4.67(d,J＝16.1Hz,1H),4.53(d,J＝16.2Hz,1H),4.16(dd,J＝10.6,5.0Hz,1H),4.08(q,J＝7.1Hz,2H),3.86–3.72(m,2H),3.67–3.59(m,1H),3.16(dd,J＝19.5,10.2Hz,4H),2.61(s,3H),2.52(s,1H),2.39(td,J＝14.5,12.7,5.4Hz,1H),1.11(t,J＝7.1Hz,3H)。 Compound 130 (140 mg). MS: 650.7 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.02-7.95(m,2H),7.87(d,J=3.1Hz,1H),7.63(d,J=9.1Hz,2H),7.25(dd, J=9.1, 4.8Hz, 1H), 7.09(q, J=8.9Hz, 1H), 5.93(s, 1H), 4.67(d, J=16.1Hz, 1H), 4.53(d, J=16.2Hz, 1H), 4.16 (dd, J=10.6, 5.0Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 3.86–3.72 (m, 2H), 3.67–3.59 (m, 1H), 3.16 (dd , J＝19.5, 10.2Hz, 4H), 2.61(s, 3H), 2.52(s, 1H), 2.39(td, J＝14.5, 12.7, 5.4Hz, 1H), 1.11(t, J＝7.1Hz, 3H).
实施例128Example 128
化合物131：Compound 131:
4-((3aS,7aS)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基苯甲酸4-((3aS,7aS)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylbenzoic acid
Figure PCTCN2021135751-appb-000361
Figure PCTCN2021135751-appb-000361
化合物131的合成参考化合物1，通过使用2-甲基-4-((3aS,7aS)-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体103-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物131。Synthesis of compound 131 Reference compound 1 by using 2-methyl-4-((3aS,7aS)-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)benzoic acid (Intermediate 103-1) was prepared in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4) Compound 131 as a yellow solid.
化合物131(50毫克)。MS:632.7(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.02–7.95(m,2H), 7.86(d,J＝3.2Hz,1H),7.68–7.60(m,2H),7.28(d,J＝7.8Hz,1H),7.20(td,J＝8.0,5.6Hz,1H),7.00(t,J＝8.9Hz,1H),5.98(s,1H),4.67(d,J＝16.1Hz,1H),4.54(d,J＝16.1Hz,1H),4.16(dd,J＝10.6,5.0Hz,1H),4.07(q,J＝7.1Hz,2H),3.79(dd,J＝28.4,12.1Hz,2H),3.62(dd,J＝8.8,6.9Hz,1H),3.27–3.06(m,4H),2.61(s,3H),2.53(t,J＝13.5Hz,1H),2.40(d,J＝13.2Hz,1H),1.10(t,J＝7.1Hz,3H)。 Compound 131 (50 mg). MS: 632.7 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.02-7.95(m,2H), 7.86(d,J=3.2Hz,1H),7.68-7.60(m,2H),7.28(d,J=7.8 Hz, 1H), 7.20(td, J＝8.0, 5.6Hz, 1H), 7.00(t, J＝8.9Hz, 1H), 5.98(s, 1H), 4.67(d, J＝16.1Hz, 1H), 4.54(d,J＝16.1Hz,1H),4.16(dd,J＝10.6,5.0Hz,1H),4.07(q,J＝7.1Hz,2H),3.79(dd,J＝28.4,12.1Hz,2H) ), 3.62(dd, J=8.8, 6.9Hz, 1H), 3.27–3.06(m, 4H), 2.61(s, 3H), 2.53(t, J=13.5Hz, 1H), 2.40(d, J= 13.2Hz, 1H), 1.10 (t, J=7.1Hz, 3H).
实施例129Example 129
化合物132：Compound 132:
6-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-4-甲基烟酸6-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-4-methylnicotinic acid
Figure PCTCN2021135751-appb-000362
Figure PCTCN2021135751-appb-000362
化合物132的合成参考化合物1，通过使用6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)-4-甲基烟酸(中间体104-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物132。Synthesis of compound 132 Reference compound 1 by using 6-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-4- Methylnicotinic acid (Intermediate 104-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 132 was prepared as a yellow solid.
化合物132(45毫克)。MS:651.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.92(s,1H),8.36(s,1H),7.97(d,J＝3.1Hz,1H),7.91(d,J＝3.1Hz,1H),7.29(d,J＝7.8Hz,1H),7.26–7.17(m,1H),7.01(t,J＝8.9Hz,1H),6.00(s,1H),4.67–4.56(m,2H),4.40(dd,J＝11.9,6.8Hz,1H),4.18–4.03(m,3H),3.92–3.81(m,1H),3.71(s,1H),3.46(t,J＝10.9Hz,1H),3.21(d,J＝13.0Hz,1H),2.68(s,5H),1.11(t,J＝7.1Hz,3H)。 Compound 132 (45 mg). MS: 651.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.92(s,1H),8.36(s,1H),7.97(d,J=3.1Hz,1H),7.91(d,J=3.1Hz,1H) ,7.29(d,J=7.8Hz,1H),7.26–7.17(m,1H),7.01(t,J=8.9Hz,1H),6.00(s,1H),4.67–4.56(m,2H), 4.40(dd,J=11.9,6.8Hz,1H),4.18-4.03(m,3H),3.92-3.81(m,1H),3.71(s,1H),3.46(t,J=10.9Hz,1H) , 3.21 (d, J=13.0 Hz, 1H), 2.68 (s, 5H), 1.11 (t, J=7.1 Hz, 3H).
实施例130Example 130
化合物133：Compound 133:
6-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-5-甲基烟酸6-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-5-methylnicotinic acid
Figure PCTCN2021135751-appb-000363
Figure PCTCN2021135751-appb-000363
化合物133的合成参考化合物1，通过使用6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)-5-甲基烟酸(中间体105-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物133。Synthesis of compound 133 Reference compound 1 by using 6-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-5- Methylnicotinic acid (Intermediate 105-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 133 was prepared as a yellow solid.
化合物133(35毫克)。MS:651.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.92(d,J＝2.0Hz,1H),8.35(d,J＝2.0Hz,1H),8.00(d,J＝3.1Hz,1H),7.90(d,J＝3.1Hz,1H),7.30(d,J＝7.8Hz,1H),7.21(td,J＝7.9,5.4Hz,1H),7.01(t,J＝8.9Hz,1H),6.01(s,1H),4.74–4.60(m,2H),4.30(dd,J＝10.9,6.3Hz,1H),4.10(q,J＝7.1Hz,2H),3.98(td,J＝13.5,11.9,4.9Hz,2H),3.78(d,J＝11.4Hz,1H),3.52–3.42(m,1H),2.69(s,1H),2.61–2.44(m,4H),2.37(s,3H),1.12(t,J＝7.1Hz,3H)。 Compound 133 (35 mg). MS: 651.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.92(d,J=2.0Hz,1H),8.35(d,J=2.0Hz,1H),8.00(d,J=3.1Hz,1H),7.90 (d, J=3.1Hz, 1H), 7.30 (d, J=7.8Hz, 1H), 7.21 (td, J=7.9, 5.4Hz, 1H), 7.01 (t, J=8.9Hz, 1H), 6.01 (s, 1H), 4.74–4.60 (m, 2H), 4.30 (dd, J=10.9, 6.3Hz, 1H), 4.10 (q, J=7.1Hz, 2H), 3.98 (td, J=13.5, 11.9 ,4.9Hz,2H),3.78(d,J＝11.4Hz,1H),3.52-3.42(m,1H),2.69(s,1H),2.61-2.44(m,4H),2.37(s,3H) , 1.12 (t, J=7.1 Hz, 3H).
实施例131Example 131
化合物134：Compound 134:
6-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-甲基烟酸6-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-methylnicotinic acid
Figure PCTCN2021135751-appb-000364
Figure PCTCN2021135751-appb-000364
化合物134的合成参考化合物1，通过使用6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)-2-甲基烟酸(中间体106-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物134。Synthesis of compound 134 Reference compound 1 by using 6-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2- Methylnicotinic acid (Intermediate 106-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) The compound 134 was prepared as a yellow solid.
化合物134(90毫克)。MS:651.2(M+H) +。 1H NMR(400MHz,Methanol-d4)δ8.39–8.28(m,2H),7.98(d,J＝3.1Hz,1H),7.90(d,J＝3.1Hz,1H),7.30(d,J＝7.9Hz,1H),7.27–7.17(m,1H),7.01(t,J＝8.9Hz,1H),6.00(s,1H),4.64(s,2H),4.44(dd,J＝12.0,6.9Hz,1H),4.17(dd,J＝12.0,5.1Hz,1H),4.08 (q,J＝7.1Hz,2H),3.86(dd,J＝13.5,5.9Hz,1H),3.73(s,1H),3.63–3.46(m,1H),3.43–3.34(m,1H),3.21(dt,J＝17.7,6.3Hz,1H),2.79(s,3H),2.73–2.58(m,1H),2.47(d,J＝2.0Hz,4H),1.11(t,J＝7.1Hz,3H)。 Compound 134 (90 mg). MS: 651.2 (M+H) + . 1 H NMR(400MHz,Methanol-d4)δ8.39-8.28(m,2H),7.98(d,J=3.1Hz,1H),7.90(d,J=3.1Hz,1H),7.30(d,J =7.9Hz,1H),7.27–7.17(m,1H),7.01(t,J=8.9Hz,1H),6.00(s,1H),4.64(s,2H),4.44(dd,J=12.0, 6.9Hz, 1H), 4.17 (dd, J=12.0, 5.1Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 3.86 (dd, J=13.5, 5.9Hz, 1H), 3.73 (s, 1H), 3.63–3.46 (m, 1H), 3.43–3.34 (m, 1H), 3.21 (dt, J=17.7, 6.3Hz, 1H), 2.79 (s, 3H), 2.73–2.58 (m, 1H) , 2.47 (d, J=2.0 Hz, 4H), 1.11 (t, J=7.1 Hz, 3H).
实施例132Example 132
化合物135：Compound 135:
4-((3As,7aR)-5-(((R)-6-(2-氯-3-氟苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-2-氟苯甲酸4-((3As,7aR)-5-(((R)-6-(2-chloro-3-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3 ,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-2-fluorobenzoic acid
Figure PCTCN2021135751-appb-000365
Figure PCTCN2021135751-appb-000365
化合物135的合成参考化合物1，通过使用2-氟-4-((3As,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)苯甲酸(中间体107-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和中间体A2代替中间体A1制备得到黄色固体化合物135。Synthesis of compound 135 Reference compound 1 by using 2-fluoro-4-((3As,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl ) benzoic acid (Intermediate 107-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) and intermediate A2 instead of intermediate A1 were prepared to give compound 135 as a yellow solid.
化合物135(70毫克)。MS:675.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.00(t,J＝8.5Hz,1H),7.82(td,J＝11.9,2.5Hz,3H),7.56(dd,J＝8.7,2.1Hz,1H),7.33(q,J＝3.5,3.0Hz,2H),7.19(ddd,J＝9.4,6.0,3.7Hz,1H),6.23(s,1H),4.50(d,J＝16.6Hz,1H),4.44–4.34(m,1H),4.22(dd,J＝10.3,6.5Hz,1H),4.05(q,J＝7.1Hz,2H),3.91(dd,J＝10.3,4.4Hz,1H),3.60(d,J＝14.1Hz,1H),3.40(s,1H),3.26–3.05(m,3H),2.63–2.33(m,2H),1.10(t,J＝7.1Hz,3H)。 Compound 135 (70 mg). MS: 675.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.00(t,J=8.5Hz,1H),7.82(td,J=11.9,2.5Hz,3H),7.56(dd,J=8.7,2.1Hz, 1H), 7.33(q, J＝3.5, 3.0Hz, 2H), 7.19(ddd, J＝9.4, 6.0, 3.7Hz, 1H), 6.23(s, 1H), 4.50(d, J＝16.6Hz, 1H) ), 4.44–4.34 (m, 1H), 4.22 (dd, J=10.3, 6.5Hz, 1H), 4.05 (q, J=7.1Hz, 2H), 3.91 (dd, J=10.3, 4.4Hz, 1H) , 3.60 (d, J=14.1 Hz, 1H), 3.40 (s, 1H), 3.26–3.05 (m, 3H), 2.63–2.33 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
实施例133Example 133
化合物136：Compound 136:
5-((3aS,7aR)-5-(((S)-5-(乙氧羰基)-6-(3-氟-2-甲基苯基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基吡啶甲酸5-((3aS,7aR)-5-(((S)-5-(ethoxycarbonyl)-6-(3-fluoro-2-methylphenyl)-2-(thiazol-2-yl)- 3,6-Dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methylpicolinic acid
Figure PCTCN2021135751-appb-000366
Figure PCTCN2021135751-appb-000366
化合物136的合成参考化合物1，通过使用5-((3aS,7aR)-7a-氟-1-氧辛烷氢-2H-吡咯[3,4-c]吡啶-2-基)-3-甲基吡啶酸(中间体108-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)制备得到黄色固体化合物136。Synthesis of compound 136 Reference compound 1 by using 5-((3aS,7aR)-7a-fluoro-1-oxooctanehydro-2H-pyrro[3,4-c]pyridin-2-yl)-3-methyl pyridine acid (Intermediate 108-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1-4 ) to obtain compound 136 as a yellow solid.
化合物136(34毫克)。MS:651.2(M+H) +。 Compound 136 (34 mg). MS: 651.2 (M+H) + .
实施例134Example 134
化合物137：Compound 137:
6-((3aS,7aR)-5-(((R)-6-(2-氯-3-氟苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-7a-氟-1-氧代八氢-2H-吡咯[3,4-c]吡啶-2-基)-4-甲基烟酸6-((3aS,7aR)-5-(((R)-6-(2-chloro-3-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3 ,6-dihydropyrimidin-4-yl)methyl)-7a-fluoro-1-oxooctahydro-2H-pyrro[3,4-c]pyridin-2-yl)-4-methylnicotinic acid
Figure PCTCN2021135751-appb-000367
Figure PCTCN2021135751-appb-000367
化合物137的合成参考化合物1，通过使用6-((3aS,7aR)-7a-氟-1-氧代八氢-2H-吡咯并[3,4-c]吡啶-2-基)-4-甲基烟酸(中间体104-1)代替4,5,6,7-四氢-2H-吡唑啉[3,4-c]吡啶-3-醇三氟乙酸盐(中间体1-4)和中间体A2代替中间体A1制备得到黄色固体化合物137。Synthesis of compound 137 Reference compound 1 by using 6-((3aS,7aR)-7a-fluoro-1-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-4- Methylnicotinic acid (Intermediate 104-1) in place of 4,5,6,7-tetrahydro-2H-pyrazolin[3,4-c]pyridin-3-ol trifluoroacetate (Intermediate 1- 4) and intermediate A2 instead of intermediate A1 to prepare yellow solid compound 137.
化合物137(76毫克)。MS:672.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.36(s,1H),7.97(d,J＝3.1Hz,1H),7.91(d,J＝3.1Hz,1H),7.43–7.32(m,2H),7.27–7.20(m,1H),6.25(s,1H),4.68–4.55(m,2H),4.40(dd,J＝11.9,6.8Hz,1H),4.18–4.03(m,4H),3.84(d,J＝8.4Hz,1H),3.71(s,1H),3.45(s,1H),3.19(d,J＝17.3Hz,1H),2.68(s,5H),1.11(t,J＝7.1Hz,3H)。 Compound 137 (76 mg). MS: 672.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.36(s,1H),7.97(d,J=3.1Hz,1H),7.91(d,J=3.1Hz,1H),7.43-7.32(m, 2H), 7.27–7.20 (m, 1H), 6.25 (s, 1H), 4.68–4.55 (m, 2H), 4.40 (dd, J=11.9, 6.8Hz, 1H), 4.18–4.03 (m, 4H) ,3.84(d,J＝8.4Hz,1H),3.71(s,1H),3.45(s,1H),3.19(d,J＝17.3Hz,1H),2.68(s,5H),1.11(t, J=7.1Hz, 3H).
细胞水平药效评价Cell-level drug efficacy evaluation
本发明测试化合物在HepG2.2.15细胞中抗HBV(乙肝病毒)活性(表1)The anti-HBV (hepatitis B virus) activity of the test compounds of the present invention in HepG2.2.15 cells (Table 1)
HepG2.2.15细胞培养于10％的胎牛血清(Corning)、100U青霉素(Gibico)、100μg/mL链霉素(Gibico)和250μg/mL遗传霉素(Gibco)的DMEM(1X)+GlutaMAX TM-I培养基(Invitrogen)。 HepG2.2.15 cells were cultured in 10% fetal bovine serum (Corning), 100U penicillin (Gibico), 100 μg/mL streptomycin (Gibico) and 250 μg/mL geneticin (Gibco) in DMEM (1X) + GlutaMAX ™ - I medium (Invitrogen).
将HepG2.2.15细胞接种到96孔板中(每孔100μL培养基中4×10 4个细胞)，并且在37℃孵育过夜。称取待测试化合物，用DMSO配制为10mM母液。利用DMSO对待测定化合物按3.16倍进行梯度稀释，继续用培养基3.16倍梯度稀释化合物50倍，最后将稀释好的化合物加入到细胞板中，总体积为200μL，最后的DMSO浓度为1％。将加好药的96孔培养板移入37℃培养箱中培养5天。取2μL核酸释放剂加入到96孔PCR反应板中，取细胞上清和HBV定量标准品各2μL加入到相应的孔内，离心使充分混匀，室温孵育10min使核酸充分释放。用圣湘生物乙肝病毒荧光定量诊断试剂盒，通过荧光定量PCR(CFX Connect Real-Time System)将提取的样品进行HBV DNA定量。 HepG2.2.15 cells were seeded into 96-well plates ( 4 x 104 cells in 100 μL of medium per well) and incubated overnight at 37°C. Compounds to be tested were weighed and prepared as 10 mM stock solutions in DMSO. The compounds to be tested were diluted 3.16-fold in DMSO, and the compounds were further diluted 50-fold in a 3.16-fold gradient in the medium. Finally, the diluted compounds were added to the cell plate with a total volume of 200 μL, and the final DMSO concentration was 1%. The medicated 96-well culture plate was transferred to a 37°C incubator for 5 days. Add 2 μL of nucleic acid release agent to the 96-well PCR reaction plate, add 2 μL of cell supernatant and HBV quantitative standard to the corresponding wells, centrifuge to mix well, and incubate at room temperature for 10 minutes to fully release nucleic acids. The extracted samples were quantified for HBV DNA by fluorescent quantitative PCR (CFX Connect Real-Time System) using Shengxiang Bio-HBV Fluorescence Quantitative Diagnostic Kit.
以HBV的标准品的拷贝数(IU/ml)的对数(log10)横坐标，以对应的CT值为纵坐标建立标准曲线，样品的拷贝数将根据阳样品对应的CT和标曲换算得到，抑制率的百分数计算公式如下：Take the abscissa of the logarithm (log10) of the copy number (IU/ml) of the HBV standard, and establish a standard curve with the corresponding CT value on the ordinate. The copy number of the sample will be converted according to the CT and standard curve corresponding to the positive sample. , the percentage of inhibition rate is calculated as follows:
％抑制率＝100-100*(样本HBV的拷贝数-高浓度参考化合物列HBV拷贝数)/DMSO列HBV的拷贝数-高浓度参考化合物列HBV拷贝数)。% inhibition rate=100-100*(copy number of HBV in sample - copy number of HBV in high concentration reference compound column)/copy number of HBV in DMSO column - HBV copy number in high concentration reference compound column).
细胞水平细胞毒性评价(Cytotoxicity)Cytotoxicity assessment at the cellular level
本发明测试化合物对肝癌细胞HepG2.2.15的细胞毒性(表2)Cytotoxicity of test compounds of the present invention on hepatoma cells HepG2.2.15 (Table 2)
将HepG2.2.15细胞接种到96孔板中(每孔8000个细胞)，用化合物处理五天后，通过加入60μL的CellTiter Glo试剂(Promega)来测定细胞活力。将加入CellTiter Glo的细胞板在振板机上震荡20分钟，然后在室温10分钟稳定化学发光信号。用酶标仪(Bio-TeK SYNERGY NEO2)读取化学发光值。HepG2.2.15 cells were seeded into 96-well plates (8000 cells per well), and after five days of compound treatment, cell viability was determined by adding 60 μL of CellTiter Glo reagent (Promega). The cell plate with added CellTiter Glo was shaken on a shaker for 20 minutes and then stabilized for 10 minutes at room temperature for the chemiluminescent signal. The chemiluminescence value was read with a microplate reader (Bio-TeK SYNERGY NEO2).
50％细胞毒性对应的浓度(CC 50)通过graphpad prism软件来拟合，细胞毒性的计算公式为： The concentration corresponding to 50% cytotoxicity (CC 50 ) was fitted by graphpad prism software, and the calculation formula of cytotoxicity is:
细胞毒性％＝100-(样品孔化学发光值-空白培养基列的平均化学发光值)/(DMSO列的平均化学发光值-空白培养基列的平均化学发光值)*100% Cytotoxicity=100-(Chemiluminescence value of sample well-Mean chemiluminescence value of blank medium column)/(Mean chemiluminescence value of DMSO column-Mean chemiluminescence value of blank medium column)*100
表1：本发明测试化合物在HepG2.2.15细胞中抗HBV(乙肝病毒)活性Table 1: Anti-HBV (Hepatitis B Virus) Activity of Test Compounds of the Invention in HepG2.2.15 Cells
Example IDExample ID IC 50(HepG2.2.15,μM) IC50 (HepG2.2.15, μM) Example IDExample ID IC 50(HepG 2.2.15,μM) IC50 (HepG 2.2.15, μM)
化合物1Compound 1 0.0070.007 化合物52Compound 52 0.130.13
化合物2Compound 2 0.10.1 化合物53Compound 53 0.110.11
化合物3Compound 3 0.0320.032 化合物54Compound 54 0.0720.072
化合物4Compound 4 0.0410.041 化合物55Compound 55 0.0490.049
化合物5Compound 5 0.210.21 化合物56Compound 56 0.0690.069
化合物6Compound 6 0.130.13 化合物57Compound 57 0.110.11
化合物7Compound 7 0.0770.077 化合物58Compound 58 0.0970.097
化合物9Compound 9 0.130.13 化合物59Compound 59 0.200.20
化合物10Compound 10 0.130.13 化合物60Compound 60 0.0970.097
化合物11Compound 11 0.0740.074 化合物61Compound 61 0.130.13
化合物12Compound 12 0.0510.051 化合物62Compound 62 0.0520.052
化合物13Compound 13 0.130.13 化合物63Compound 63 0.0670.067
化合物15Compound 15 0.120.12 化合物64Compound 64 0.0710.071
化合物16Compound 16 0.180.18 化合物65Compound 65 0.0260.026
化合物17Compound 17 0.150.15 化合物66Compound 66 0.020.02
化合物18Compound 18 0.180.18 化合物67Compound 67 0.0170.017
化合物19Compound 19 0.120.12 化合物68Compound 68 0.0380.038
化合物20Compound 20 0.240.24 化合物69Compound 69 0.110.11
化合物21Compound 21 0.0990.099 化合物70Compound 70 0.0480.048
化合物22Compound 22 0.210.21 化合物71Compound 71 0.170.17
化合物23Compound 23 0.0690.069 化合物72Compound 72 0.140.14
化合物24Compound 24 0.480.48 化合物73Compound 73 0.0860.086
化合物25Compound 25 1.211.21 化合物74Compound 74 0.0990.099
化合物26Compound 26 0.1040.104 化合物75Compound 75 0.0910.091
化合物27Compound 27 0.0160.016 化合物76Compound 76 0.0260.026
化合物28Compound 28 0.0910.091 化合物77Compound 77 0.0710.071
化合物29Compound 29 0.130.13 化合物78Compound 78 0.0690.069
化合物30Compound 30 0.0700.070 化合物79Compound 79 0.0660.066
化合物31Compound 31 0.0350.035 化合物80Compound 80 0.0390.039
化合物32Compound 32 0.0550.055 化合物81Compound 81 0.0270.027
化合物33Compound 33 0.0660.066 化合物82Compound 82 0.0570.057
化合物34Compound 34 0.120.12 化合物85Compound 85 0.0760.076
化合物35Compound 35 0.0440.044 化合物86Compound 86 0.110.11
化合物36Compound 36 0.280.28 化合物87Compound 87 0.0700.070
化合物37Compound 37 0.0950.095 化合物89Compound 89 0.0650.065
化合物38Compound 38 0.120.12 化合物93Compound 93 0.0380.038
化合物39Compound 39 0.140.14 化合物94Compound 94 0.0730.073
化合物40Compound 40 0.0980.098 化合物95Compound 95 0.0570.057
化合物41Compound 41 0.120.12 化合物96Compound 96 0.1060.106
化合物42Compound 42 0.0490.049 化合物97Compound 97 0.0430.043
化合物43Compound 43 0.0940.094 化合物98Compound 98 0.0580.058
化合物44Compound 44 0.0660.066 化合物99Compound 99 0.0900.090
化合物45Compound 45 0.100.10 化合物100Compound 100 0.1560.156
化合物46Compound 46 0.240.24 化合物101Compound 101 0.1830.183
化合物47Compound 47 0.290.29 化合物102Compound 102 0.1790.179
化合物48Compound 48 0.0370.037 化合物104Compound 104 0.1400.140
化合物49Compound 49 0.0270.027 化合物105Compound 105 0.1690.169
化合物50Compound 50 0.1020.102 化合物106Compound 106 0.0370.037
化合物51Compound 51 0.180.18 化合物107Compound 107 0.1490.149
化合物108Compound 108 0.0510.051 化合物110Compound 110 0.0460.046
化合物111Compound 111 0.0410.041 化合物112Compound 112 0.0090.009
化合物113Compound 113 0.1210.121 化合物114Compound 114 0.020.02
化合物115Compound 115 0.0270.027 化合物116Compound 116 0.0250.025
化合物117Compound 117 0.040.04 化合物118Compound 118 0.0160.016
化合物119Compound 119 0.0310.031 化合物120Compound 120 0.0310.031
化合物121Compound 121 0.0850.085 化合物122Compound 122 0.0640.064
化合物123Compound 123 0.0840.084 化合物124Compound 124 0.0540.054
化合物126Compound 126 0.1580.158 化合物127Compound 127 0.0330.033
化合物128Compound 128 0.0230.023 化合物129Compound 129 0.0480.048
化合物130Compound 130 0.0580.058 化合物131Compound 131 0.0590.059
化合物132Compound 132 0.0430.043 化合物133Compound 133 0.0620.062
化合物134Compound 134 0.0690.069 化合物135Compound 135 0.0740.074
化合物136Compound 136 0.0690.069 化合物137Compound 137 0.0220.022
表2：本发明测试化合物对肝癌细胞HepG2.2.15的细胞毒性Table 2: Cytotoxicity of test compounds of the present invention on hepatoma cells HepG2.2.15
Figure PCTCN2021135751-appb-000368
Figure PCTCN2021135751-appb-000368
Figure PCTCN2021135751-appb-000369
Figure PCTCN2021135751-appb-000369
小鼠药代动力学(PK)评价Mouse Pharmacokinetic (PK) Evaluation
药代动力学实验委托美迪西普亚医药科技(上海)有限公司完成，受试动物为ICR小鼠(上海西普尔-必凯实验动物有限公司)。通过灌胃(po)向ICR小鼠给测试化合物。po的剂量是10mg/kg，溶媒系统为10％DMSO+40％PEG400+50％Saline(0.9％saline)。动物给药前禁食过夜(10-14小时)，给药4小时后给食。给药后在多个时间点(0.5，1，3，5小时)收集血液于肝素钠抗凝管中。小鼠经CO 2安乐死后，在多个时间点(0.5，1，3，5小时)采集肝脏。处理样品，以LC-MS/MS方法分析药物在血浆和肝脏中的浓度，用Phoenix WinNonlin计算药代参数。 Pharmacokinetic experiments were entrusted to Medicipua Pharmaceutical Technology (Shanghai) Co., Ltd. to complete, and the test animals were ICR mice (Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.). Test compounds were administered to ICR mice by gavage (po). The po dose was 10 mg/kg and the vehicle system was 10% DMSO + 40% PEG400 + 50% Saline (0.9% saline). Animals were fasted overnight (10-14 hours) prior to dosing and fed 4 hours after dosing. Blood was collected in heparin sodium anticoagulant tubes at various time points (0.5, 1, 3, 5 hours) after dosing. Livers were harvested at various time points (0.5, 1, 3, 5 hours) after mice were euthanized by CO2 . Samples were processed, drug concentrations in plasma and liver were analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated using Phoenix WinNonlin.
实验数据表明，本发明化合物在小鼠体内具有特殊的药代动力学性质，特别是肝脏药物浓度与血浆药物浓度比(L/P)较高，考虑到肝脏是HBV病毒的繁殖器官，预期在抗HBV病毒方面可以达到良好的药效和安全性。The experimental data show that the compounds of the present invention have special pharmacokinetic properties in mice, especially the ratio of liver drug concentration to plasma drug concentration (L/P) is high. Considering that the liver is the reproductive organ of HBV virus, it is expected that Good efficacy and safety can be achieved in anti-HBV virus.

Claims (12)

  1. 一种如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，A dihydropyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021135751-appb-100001
    Figure PCTCN2021135751-appb-100001
    其中，
    Figure PCTCN2021135751-appb-100002
    为
    Figure PCTCN2021135751-appb-100003
    in,
    Figure PCTCN2021135751-appb-100002
    for
    Figure PCTCN2021135751-appb-100003
    R 1为2-噻唑基，被一个或多个R 1a取代的2-噻唑基，R 1a独立地为卤素或甲基；当取代基为多个时，相同或不同； R 1 is 2-thiazolyl, 2-thiazolyl substituted by one or more R 1a , R 1a is independently halogen or methyl; when there are multiple substituents, they are the same or different;
    R 2，R 3，R 4独立地为H，卤素，甲基，-CN，甲基-O-或-CF 3； R 2 , R 3 , R 4 are independently H, halogen, methyl, -CN, methyl-O- or -CF 3 ;
    R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
    R 6为H，卤素，羟基、C 1-3烷基，环丙基； R 6 is H, halogen, hydroxyl, C 1-3 alkyl, cyclopropyl;
    R 7为H，卤素，C 1-3烷基，羟基，甲氧基，C 1-3烷基-O-C(＝O)-； R 7 is H, halogen, C 1-3 alkyl, hydroxy, methoxy, C 1-3 alkyl-OC(=O)-;
    或者，R 6和R 7与相连的碳原子一起可以形成：3-6元环烷基或3-6元杂环烷基；所述的3-6元杂环烷基中，杂原子选自N、O、S，杂原子个数为1或2； Alternatively, R 6 and R 7 together with the connected carbon atoms can form: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; in the 3-6 membered heterocycloalkyl, the heteroatom is selected from N, O, S, the number of heteroatoms is 1 or 2;
    R 9为H，甲基； R 9 is H, methyl;
    W为–N＝，-C(R 11R 12)-； W is -N=, -C(R 11 R 12 )-;
    R 11，R 12独立地为H，C 1-3烷基； R 11 , R 12 are independently H, C 1-3 alkyl;
    R 13为H、苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-；当取代基为多个时，相同或不同； R 13 is H, phenyl-L 1 -, pyridyl-L 2 -, 3-7-membered monocyclic cycloalkyl-L 3 -, C 1-6 alkyl-L 4 -, or, by one or Multiple R 1b substituted: C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 -, 3-7 membered monocyclic cycloalkyl-L 3 -; when substituent When there are multiple, the same or different;
    -L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、C 1-3亚烷基、R 8取代的C 1-3亚烷基；R 8独立地为C 1-4烷基、3-7元环烷基； -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently connecting bonds, C 1-3 alkylene, and R 8 substituted C 1-3 alkylene; R 8 is independently C 1-4 alkyl, 3-7 membered cycloalkyl;
    R 1b独立地为-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，OH，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-，卤素，C 1-6烷基，CN，C 1-3烷基磺酰基，3-7元环烷基；或者被一个或多个R 1c取代的：-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-，C 1-6烷基，C 1-3烷基磺酰基，3-7元环烷基；R 1c独立地为卤素、C 1- 4烷基、3-7元环烷基； R 1b is independently -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 - C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, OH, C 1-3 alkane Base-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, halogen, C 1-6 alkyl, CN, C 1-3 alkylsulfonyl, 3-7 membered ring Alkyl; or substituted by one or more R 1c : -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene) -CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1- 3 alkyl-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, C 1-6 alkyl, C 1-3 alkylsulfonyl, 3-7 membered cycloalkyl ; R 1c is independently halogen, C 1-4 alkyl, 3-7 membered cycloalkyl;
    Figure PCTCN2021135751-appb-100004
    表示单键或双键；
    Figure PCTCN2021135751-appb-100004
    Indicates a single bond or a double bond;
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  2. 如权利要求1所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，其特征在于，The dihydropyrimidine compound represented by formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that,
    和/或，R 1为2-噻唑基； and/or, R 1 is 2-thiazolyl;
    和/或，R 2，R 3，R 4独立地为H，卤素，甲基； and/or, R 2 , R 3 , R 4 are independently H, halogen, methyl;
    和/或，R 5为甲基或乙基； And/or, R 5 is methyl or ethyl;
    和/或，R 6为H，卤素，羟基、C 1-3烷基； And/or, R 6 is H, halogen, hydroxyl, C 1-3 alkyl;
    和/或，R 7为H，卤素，羟基，甲氧基，C 1-3烷基-O-C(＝O)-； and/or, R 7 is H, halogen, hydroxy, methoxy, C 1-3 alkyl-OC(=O)-;
    和/或，R 6和R 7与连接的碳一起形成3-6元杂环烷基； and/or, R and R together with the carbon to which they are attached form a 3-6 membered heterocycloalkyl;
    和/或，
    Figure PCTCN2021135751-appb-100005
    为
    Figure PCTCN2021135751-appb-100006
    and / or,
    Figure PCTCN2021135751-appb-100005
    for
    Figure PCTCN2021135751-appb-100006
    和/或，R 9为H； and/or, R 9 is H;
    和/或，R 11，R 12独立地为H； and/or, R 11 , R 12 are independently H;
    和/或，当W为N时，
    Figure PCTCN2021135751-appb-100007
    为
    Figure PCTCN2021135751-appb-100008
    and/or, when W is N,
    Figure PCTCN2021135751-appb-100007
    for
    Figure PCTCN2021135751-appb-100008
    和/或，当W为C(R 11R 12)时，
    Figure PCTCN2021135751-appb-100009
    为
    Figure PCTCN2021135751-appb-100010
    and/or, when W is C(R 11 R 12 ),
    Figure PCTCN2021135751-appb-100009
    for
    Figure PCTCN2021135751-appb-100010
    和/或，R 13为H，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-； and/or, R 13 is H, C 1-6 alkyl-L 4 -, or, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, Pyridyl-L 2 -, 3-7 membered monocyclic cycloalkyl-L 3 -;
    和/或，-L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、亚甲基、
    Figure PCTCN2021135751-appb-100011
    或-CH(CH 3)-；     And/or, -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linkage, a methylene group,
    Figure PCTCN2021135751-appb-100011
    or -CH( CH3 )-;
    和/或，R 1b独立地为-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，卤素，C 1-6烷基，3-7元环烷基；或者被一个或多个取代基R 1c取代的：C 1-3烷基-O-，C 1-6烷基； And/or, R 1b is independently -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene) -CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, C 1- 3 alkyl-O-, halogen, C 1-6 alkyl, 3-7 membered cycloalkyl; or substituted by one or more substituents R 1c : C 1-3 alkyl-O-, C 1- 6 alkyl;
    和/或，至少一个R 1b为-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基； And/or, at least one R 1b is -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene) -CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl;
    和/或，当W为N时，R 13为H，C 1-6烷基-L 4-； and/or, when W is N, R 13 is H, C 1-6 alkyl-L 4 -;
    和/或，当W为C(R 11R 12)、
    Figure PCTCN2021135751-appb-100012
    为
    Figure PCTCN2021135751-appb-100013
    时，R 13为H或被一个或多个R 1b取代的苯基-L 1-。     and/or, when W is C(R 11 R 12 ),
    Figure PCTCN2021135751-appb-100012
    for
    Figure PCTCN2021135751-appb-100013
    , R 13 is H or phenyl-L 1 - substituted with one or more R 1b .
  3. 如权利要求2所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，其特征在于，The dihydropyrimidine compound of formula I as claimed in claim 2 or a pharmaceutically acceptable salt thereof, characterized in that,
    当R 1a独立地为卤素时，所述的卤素为F、Cl、Br； When R 1a is independently halogen, the halogen is F, Cl, Br;
    和/或，R 2，R 3，R 4独立地为卤素时，所述的卤素为F、Cl、Br； And/or, when R 2 , R 3 , and R 4 are independently halogen, the halogen is F, Cl, or Br;
    和/或，当R 5为C 1-3烷基时，所述的C 1-3烷基为甲基、乙基、正丙基、异丙基； And/or, when R 5 is C 1-3 alkyl, the C 1-3 alkyl is methyl, ethyl, n-propyl, isopropyl;
    和/或，当R 6为C 1-3烷基时，所述的C 1-3烷基为甲基、乙基、正丙基、异丙基； And/or, when R 6 is C 1-3 alkyl, the C 1-3 alkyl is methyl, ethyl, n-propyl, isopropyl;
    和/或，当R 6为卤素时，所述的卤素为F、Cl、Br； And/or, when R 6 is halogen, the halogen is F, Cl, Br;
    和/或，当R 7为C 1-3烷基、C 1-3烷基-O-C(＝O)-时，所述的C 1-3烷基、C 1-3烷基-O-C(＝O)-里的C 1-3烷基为甲基、乙基、正丙基、异丙基； And/or, when R 7 is C 1-3 alkyl, C 1-3 alkyl-OC(=O)-, the C 1-3 alkyl, C 1-3 alkyl-OC(= C 1-3 alkyl in O)- is methyl, ethyl, n-propyl, isopropyl;
    和/或，当R 7为卤素时，所述的卤素为F、Cl、Br； And/or, when R 7 is halogen, the halogen is F, Cl, Br;
    和/或，当R 6和R 7与相连的碳原子一起可以形成3-6元杂环烷基时，所述的3-6元杂环烷基为氧杂环丙基； And/or, when R 6 and R 7 together with the connected carbon atoms can form a 3-6 membered heterocycloalkyl group, the 3-6 membered heterocycloalkyl group is oxacyclopropyl;
    和/或，当R 13为C 1-6烷基-L 4-，被一个或多个R 1b取代的C 1-6烷基-L 4-时，所述的C 1-6烷基-L 4-，被一个或多个R 1b取代的C 1-6烷基-L 4-里的C 1-6烷基独立地为甲基、乙基、正丙基、异丙基、异丁基、仲丁基或叔丁基； And/or, when R 13 is C 1-6 alkyl-L 4 -, C 1-6 alkyl-L 4 - substituted by one or more R 1b , the C 1-6 alkyl-L 4 - L 4 -, C 1-6 alkyl substituted by one or more R 1b - C 1-6 alkyl in L 4 - is independently methyl, ethyl, n-propyl, isopropyl, isobutyl base, sec-butyl or tert-butyl;
    和/或，当R 13为3-7元单环的环烷基-L 3-，被一个或多个R 1b取代的3-7元单环的环烷基时，所述的3-7元单环的环烷基-L 3-，被一个或多个R 1b取代的3-7元单环的环烷基里的3-7元单环的环烷基独立地为环丙基、环丁基、环戊基、环己基； And/or, when R 13 is a 3-7-membered monocyclic cycloalkyl-L 3 -, a 3-7-membered monocyclic cycloalkyl substituted by one or more R 1b , the 3-7 Monocyclic cycloalkyl-L 3 -, the 3-7-membered monocyclic cycloalkyl in the 3-7-membered monocyclic cycloalkyl substituted by one or more R 1b is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
    和/或，当-L 1-，-L 2-，-L 3-，-L 4-独立地为C 1-3亚烷基、R 8取代的C 1-3亚烷基时，所述的C 1-3亚烷基和R 8取代的C 1-3亚烷基里的C 1-3亚烷基为亚甲基、-CH 2CH 2-、-CH(CH 3)-、
    Figure PCTCN2021135751-appb-100014
    -CH(CH 3)CH 2-或-C(CH 3) 2-；     And/or, when -L 1 -, -L 2 -, -L 3 -, and -L 4 - are independently C 1-3 alkylene, R 8 substituted C 1-3 alkylene, the The C 1-3 alkylene group in the C 1-3 alkylene group and the C 1-3 alkylene group substituted by R 8 are methylene, -CH 2 CH 2 -, -CH(CH 3 )-,
    Figure PCTCN2021135751-appb-100014
    -CH( CH3 )CH2- or -C( CH3 ) 2- ;
    和/或，当R 8独立地为C 1-4烷基时，所述的C 1-4烷基为甲基、乙基、正丙基、异丙基、异丁基、仲丁基或叔丁基； And/or, when R 8 is independently C 1-4 alkyl, said C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
    和/或，当R 8独立地为3-7元环烷基时，所述的3-7元环烷基为环丙基、环丁基、环戊基、环己基、环庚基； And/or, when R 8 is independently a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl;
    和/或，当R 1b独立地为C 1-6烷基；或者被一个或多个R 1c取代的C 1-6烷基时，所述的C 1-6烷基，和被一个或多个R 1c取代的C 1-6烷基里的C 1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 1b is independently C 1-6 alkyl; or C 1-6 alkyl substituted by one or more R 1c , said C 1-6 alkyl, and by one or more The C 1-6 alkyl in the C 1-6 alkyl substituted by each R 1c is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl base;
    和/或，当R 1b独立地为-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-3亚烷基)-，C 1-3烷基磺酰基；或者被一个或多个R 1c取代的：-CO 2-C 1-3 烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-3亚烷基)-，C 1-3烷基磺酰基时，所述的-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1- 3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-，C 1-3烷基磺酰基，和被一个或多个R 1c取代的：-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2-C 1-3烷基，C 1-3烷基-O-，C 1-3烷基-O-(C 1-6亚烷基)-，C 1-3烷基磺酰基里的C 1-3烷基独立地为甲基、乙基、正丙基、异丙基； and/or, when R 1b is independently -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkene base)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-3 alkylene)-, C 1-3 alkyl sulfone Acyl; or substituted by one or more R 1c : -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2- 6 alkenylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-3 alkylene)-, C 1-3 In the case of alkylsulfonyl, the -CO 2 -C 1-3 alkyl group, -(C 1-6 alkylene group)-CO 2 -C 1-3 alkyl group, -(C 2-6 alkenylene group )-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-6 alkylene )-, C 1-3 alkylsulfonyl , and substituted by one or more R 1c : -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 Alkenylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-O-(C 1-6 alkylene)-, C 1-3 alkyl C 1-3 alkyl in the sulfonyl group is independently methyl, ethyl, n-propyl, isopropyl;
    和/或，当R 1b独立地为-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-，或者被一个或多个R 1c取代的：-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-时，所述的-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-，和被一个或多个R 1c取代的：-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，C 1-3烷基-O-(C 1-6亚烷基)-里的C 1-6亚烷基独立地为亚甲基，-CH 2CH 2-，-CH(CH 3)-，
    Figure PCTCN2021135751-appb-100015
    -CH(CH 3)CH 2-，-C(CH 3) 2-，
    Figure PCTCN2021135751-appb-100016
    and/or, when R 1b is independently -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 Alkyl-O-(C 1-6 alkylene)-, or substituted by one or more R 1c : -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene base)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 alkylene)-, the -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-(C 1-6 alkylene)-, and by one or more R 1c Substituted: -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, C 1-3 alkyl-O-( C 1-6 alkylene in C 1-6 alkylene)- is independently methylene, -CH 2 CH 2 -, -CH(CH 3 )-,
    Figure PCTCN2021135751-appb-100015
    -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -,
    Figure PCTCN2021135751-appb-100016
    和/或，当R 1b独立地为-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，或者被一个或多个R 1c取代的：-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基时，所述的-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基，和被一个或多个R 1c取代的：-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基里的C 2-6亚烯基独立地为
    Figure PCTCN2021135751-appb-100017
    或其顺反异构体；     and/or, when R 1b is independently -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, or by one or Multiple R 1c substituted: -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, the -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl, and substituted by one or more R 1c : -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl in C 2-6 alkenylene is independently
    Figure PCTCN2021135751-appb-100017
    or its cis-trans isomer;
    和/或，当R 1b独立地为3-7元环烷基，被一个或多个R 1c取代的3-7元环烷基时，所述的3-7元环烷基，和被一个或多个R 1c取代的3-7元环烷基里的3-7元环烷基独立地为环丙基、环丁基、环戊基； and/or, when R 1b is independently a 3-7 membered cycloalkyl, a 3-7 membered cycloalkyl substituted with one or more R 1c , said 3-7 membered cycloalkyl, and is replaced by a The 3-7-membered cycloalkyl in the 3-7-membered cycloalkyl substituted with more than one R 1c is independently cyclopropyl, cyclobutyl, and cyclopentyl;
    和/或，当R 1c独立地为卤素时，所述的卤素为F，Cl； and/or, when R 1c is independently halogen, the halogen is F, Cl;
    和/或，当R 1c独立地为C 1-4烷基时，所述的C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 1c is independently C 1-4 alkyl, the C 1-4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base, sec-butyl or tert-butyl;
    和/或，当R 1c独立地为3-7元环烷基时，所述的3-7元环烷基独立地为环丙基、环丁基、环戊基、环己基、环庚基； And/or, when R 1c is independently 3-7 membered cycloalkyl, said 3-7 membered cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl ;
    和/或，R 13为H，甲基，异丙基，
    Figure PCTCN2021135751-appb-100018
    Figure PCTCN2021135751-appb-100019
    and/or, R 13 is H, methyl, isopropyl,
    Figure PCTCN2021135751-appb-100018
    Figure PCTCN2021135751-appb-100019
    和/或，R 1b独立地为-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，C 1-3烷基-O-，C 1-6烷基，卤素，3-7元环烷基，或被一个或多个取代基R 1c取代的C 1-3烷基-O-； and/or, R 1b is independently -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, C 1-3 alkyl -O-, C 1-6 alkyl, halogen, 3-7 membered cycloalkyl, or C 1-3 alkyl-O- substituted by one or more substituents R 1c ;
    和/或，
    Figure PCTCN2021135751-appb-100020
    为
    Figure PCTCN2021135751-appb-100021
    and / or,
    Figure PCTCN2021135751-appb-100020
    for
    Figure PCTCN2021135751-appb-100021
  4. 如权利要求1所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，其特征在于，The dihydropyrimidine compound represented by formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that,
    Figure PCTCN2021135751-appb-100022
    为
    Figure PCTCN2021135751-appb-100023
    Figure PCTCN2021135751-appb-100022
    for
    Figure PCTCN2021135751-appb-100023
    和/或，
    Figure PCTCN2021135751-appb-100024
    为
    Figure PCTCN2021135751-appb-100025
    and / or,
    Figure PCTCN2021135751-appb-100024
    for
    Figure PCTCN2021135751-appb-100025
    和/或，R 6为H，F，OH，甲基； And/or, R 6 is H, F, OH, methyl;
    和/或，R 7为H，F，OH，甲氧基、甲氧基羰基； And/or, R 7 is H, F, OH, methoxy, methoxycarbonyl;
    和/或，R 1b独立地为F、Cl、甲基、异丙基、环丙基、甲基-O-、-O-CF 3、-CF 3、-CO 2H、
    Figure PCTCN2021135751-appb-100026
    Figure PCTCN2021135751-appb-100027
    Figure PCTCN2021135751-appb-100028
    例如，R 13为H、
    Figure PCTCN2021135751-appb-100029
    Figure PCTCN2021135751-appb-100030
    Figure PCTCN2021135751-appb-100031
    异丙基、
    Figure PCTCN2021135751-appb-100032
    Figure PCTCN2021135751-appb-100033
    Figure PCTCN2021135751-appb-100034
    甲基、
    Figure PCTCN2021135751-appb-100035
    Figure PCTCN2021135751-appb-100036
    and/or, R 1b is independently F, Cl, methyl, isopropyl, cyclopropyl, methyl-O-, -O-CF 3 , -CF 3 , -CO 2 H,
    Figure PCTCN2021135751-appb-100026
    Figure PCTCN2021135751-appb-100027
    Figure PCTCN2021135751-appb-100028
    For example, R 13 is H,
    Figure PCTCN2021135751-appb-100029
    Figure PCTCN2021135751-appb-100030
    Figure PCTCN2021135751-appb-100031
    Isopropyl,
    Figure PCTCN2021135751-appb-100032
    Figure PCTCN2021135751-appb-100033
    Figure PCTCN2021135751-appb-100034
    methyl,
    Figure PCTCN2021135751-appb-100035
    Figure PCTCN2021135751-appb-100036
    和/或，
    Figure PCTCN2021135751-appb-100037
    为
    Figure PCTCN2021135751-appb-100038
    Figure PCTCN2021135751-appb-100039
    例如
    Figure PCTCN2021135751-appb-100040
    Figure PCTCN2021135751-appb-100041
    Figure PCTCN2021135751-appb-100042
    又例如
    Figure PCTCN2021135751-appb-100043
    Figure PCTCN2021135751-appb-100044
    and / or,
    Figure PCTCN2021135751-appb-100037
    for
    Figure PCTCN2021135751-appb-100038
    Figure PCTCN2021135751-appb-100039
    E.g
    Figure PCTCN2021135751-appb-100040
    Figure PCTCN2021135751-appb-100041
    Figure PCTCN2021135751-appb-100042
    Another example
    Figure PCTCN2021135751-appb-100043
    Figure PCTCN2021135751-appb-100044
    Figure PCTCN2021135751-appb-100045
    Figure PCTCN2021135751-appb-100045
    Figure PCTCN2021135751-appb-100046
    Figure PCTCN2021135751-appb-100046
  5. 如权利要求1所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的二氢嘧啶类化合物可如下方案1、方案2、方案3、方案4、方案5；The dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the dihydropyrimidine compound represented by formula I can be as shown in Scheme 1, Option 2, Option 3, Option 4, Option 5;
    方案1、plan 1,
    R 1为2-噻唑基， R 1 is 2-thiazolyl,
    R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
    R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
    R 6为H，卤素，OH，C 1-3烷基； R 6 is H, halogen, OH, C 1-3 alkyl;
    R 7为H，F，OH，甲氧基、C 1-3烷基-O-C(＝O)-； R 7 is H, F, OH, methoxy, C 1-3 alkyl-OC(=O)-;
    或者，R 6和R 7与连接的碳一起形成3-6元杂环烷基； Alternatively, R6 and R7 together with the attached carbon form a 3-6 membered heterocycloalkyl;
    R 9为H； R 9 is H;
    W为C(R 11R 12)或-N＝； W is C(R 11 R 12 ) or -N=;
    R 11，R 12独立地为H； R 11 , R 12 are independently H;
    R 13为H，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-； R 13 is H, C 1-6 alkyl-L 4 -, or, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2- , 3-7 membered monocyclic cycloalkyl-L 3 -;
    -L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、C 1-3亚烷基； -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently connecting bonds, C 1-3 alkylene;
    R 1b独立地为卤素，C 1-6烷基，C 1-3烷基-O-，3-7元环烷基，CO 2H，-(C 2-6亚烯基)-CO 2H，-(C 1-6亚烷基)-CO 2H，-CO 2-C 1-3烷基，被一个或多个取代基R 1c取代的：C 1-3烷基-O-或C 1-6烷基；R 1c独立地为卤素；且至少一个R 1b为CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基； R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, CO 2 H, -(C 2-6 alkenylene)-CO 2 H , -(C 1-6 alkylene)-CO 2 H, -CO 2 -C 1-3 alkyl, substituted by one or more substituents R 1c : C 1-3 alkyl-O- or C 1-6 alkyl; R 1c is independently halogen; and at least one R 1b is CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, - (C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 -C 1-3 alkyl;
    Figure PCTCN2021135751-appb-100047
    为
    Figure PCTCN2021135751-appb-100048
    Figure PCTCN2021135751-appb-100047
    for
    Figure PCTCN2021135751-appb-100048
    方案2、Scenario 2,
    R 1为2-噻唑基， R 1 is 2-thiazolyl,
    R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
    R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
    R 6为H，F，OH，甲基； R 6 is H, F, OH, methyl;
    R 7为H，F，OH，甲氧基、C 1-3烷基-O-C(＝O)-； R 7 is H, F, OH, methoxy, C 1-3 alkyl-OC(=O)-;
    或者，R 6和R 7与连接的碳一起形成3元杂环烷基； Alternatively, R and R together with the attached carbon form a 3 - membered heterocycloalkyl;
    R 9为H； R 9 is H;
    W为C(R 11R 12)或N； W is C(R 11 R 12 ) or N;
    R 11，R 12独立地为H； R 11 , R 12 are independently H;
    R 13为H，C 1-6烷基-L 4-，或者，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基，3-7元单环的环烷基-L 3-； R 13 is H, C 1-6 alkyl-L 4 -, or, substituted with one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl, 3 -7-membered monocyclic cycloalkyl-L 3 -;
    -L 1-，-L 3-，-L 4-独立地为连接键、亚甲基、-CH(CH 3)-； -L 1 -, -L 3 -, -L 4 - are independently a linkage, a methylene group, -CH(CH 3 )-;
    R 1b独立地为卤素，C 1-6烷基，C 1-3烷基-O-，3-7元环烷基，-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，-CO 2-C 1-3烷基，3-7元环烷基，或被一个或多个R 1c取代的C 1-6烷基或C 1-3烷基-O-；R 1c独立地为卤素；且至少一个R 1b为CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H，-CO 2-C 1-3烷基； R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H, -CO 2 -C 1-3 alkyl, 3-7 membered cycloalkyl, or C 1-6 substituted with one or more R 1c Alkyl or C 1-3 alkyl-O-; R 1c is independently halogen; and at least one R 1b is CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2- 6 alkenylene) -CO 2 H, -CO 2 -C 1-3 alkyl;
    Figure PCTCN2021135751-appb-100049
    为
    Figure PCTCN2021135751-appb-100050
    Figure PCTCN2021135751-appb-100049
    for
    Figure PCTCN2021135751-appb-100050
    方案3、Option 3,
    R 1为2-噻唑基， R 1 is 2-thiazolyl,
    R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
    R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
    Figure PCTCN2021135751-appb-100051
    为
    Figure PCTCN2021135751-appb-100052
    Figure PCTCN2021135751-appb-100051
    for
    Figure PCTCN2021135751-appb-100052
    R 6为H，F，甲基； R 6 is H, F, methyl;
    R 9为H； R 9 is H;
    Figure PCTCN2021135751-appb-100053
    为
    Figure PCTCN2021135751-appb-100054
    Figure PCTCN2021135751-appb-100053
    for
    Figure PCTCN2021135751-appb-100054
    方案4、Option 4,
    Figure PCTCN2021135751-appb-100055
    为
    Figure PCTCN2021135751-appb-100056
    Figure PCTCN2021135751-appb-100055
    for
    Figure PCTCN2021135751-appb-100056
    R 1为2-噻唑基， R 1 is 2-thiazolyl,
    R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
    R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
    R 9为H； R 9 is H;
    R 13为H，被一个或多个R 1b取代的苯基-L 1-； R 13 is H, phenyl-L 1 - substituted by one or more R 1b ;
    -L 1-独立地为连接键、C 1-3亚烷基； -L 1 - is independently a linkage, C 1-3 alkylene;
    R 1b独立地为C 1-6烷基，C 1-3烷基-O-，-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H；且至少一个R 1b为-CO 2H，-(C 1-6亚烷基)-CO 2H，-(C 2-6亚烯基)-CO 2H； R 1b is independently C 1-6 alkyl, C 1-3 alkyl-O-, -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkene and at least one R 1b is -CO 2 H, -(C 1-6 alkylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 H ;
    Figure PCTCN2021135751-appb-100057
    为
    Figure PCTCN2021135751-appb-100058
    Figure PCTCN2021135751-appb-100057
    for
    Figure PCTCN2021135751-appb-100058
    方案5、Option 5.
    Figure PCTCN2021135751-appb-100059
    为
    Figure PCTCN2021135751-appb-100060
    Figure PCTCN2021135751-appb-100059
    for
    Figure PCTCN2021135751-appb-100060
    R 1为2-噻唑基， R 1 is 2-thiazolyl,
    R 2，R 3，R 4独立地为H，卤素，甲基； R 2 , R 3 , R 4 are independently H, halogen, methyl;
    R 5为C 1-3烷基； R 5 is C 1-3 alkyl;
    R 6为H，F，甲基； R 6 is H, F, methyl;
    R 7为H，F，OH，甲氧基、C 1-3烷基-O-C(＝O)-； R 7 is H, F, OH, methoxy, C 1-3 alkyl-OC(=O)-;
    R 6和R 7与连接的碳一起形成氧杂环丙基； R 6 and R 7 together with the attached carbon form oxanyl;
    R 9为H； R 9 is H;
    R 13为H，C 1-6烷基-L 4-，被一个或多个R 1b取代的：C 1-6烷基-L 4-，苯基-L 1-，吡啶基-L 2-，3-7元单环的环烷基-L 3-； R 13 is H, C 1-6 alkyl-L 4 -, substituted by one or more R 1b : C 1-6 alkyl-L 4 -, phenyl-L 1 -, pyridyl-L 2 - , 3-7 membered monocyclic cycloalkyl-L 3 -;
    -L 1-，-L 2-，-L 3-，-L 4-独立地为连接键、亚甲基、-CH(CH 3)-； -L 1 -, -L 2 -, -L 3 -, -L 4 - are independently a linkage, a methylene group, -CH(CH 3 )-;
    R 1b独立地为卤素，C 1-6烷基，C 1-3烷基-O-，3-7元环烷基，CO 2H，-(C 2-6亚烯基)-CO 2H，-(C 1-6亚烷基)-CO 2H，-CO 2-C 1-3烷基，被一个或多个取代基R 1c取代的：C 1-3烷基-O-或C 1-6烷基；R 1c独立地为卤素；且至少一个R 1b为-CO 2H，-CO 2-C 1-3烷基，-(C 1-6亚烷基)-CO 2H，-(C 1-6亚烷基)-CO 2-C 1-3烷基，-(C 2-6亚烯基)-CO 2H，-(C 2-6亚烯基)-CO 2-C 1-3烷基； R 1b is independently halogen, C 1-6 alkyl, C 1-3 alkyl-O-, 3-7 membered cycloalkyl, CO 2 H, -(C 2-6 alkenylene)-CO 2 H , -(C 1-6 alkylene)-CO 2 H, -CO 2 -C 1-3 alkyl, substituted by one or more substituents R 1c : C 1-3 alkyl-O- or C 1-6 alkyl; R 1c is independently halogen; and at least one R 1b is -CO 2 H, -CO 2 -C 1-3 alkyl, -(C 1-6 alkylene)-CO 2 H, -(C 1-6 alkylene)-CO 2 -C 1-3 alkyl, -(C 2-6 alkenylene)-CO 2 H, -(C 2-6 alkenylene)-CO 2 - C 1-3 alkyl;
    Figure PCTCN2021135751-appb-100061
    为
    Figure PCTCN2021135751-appb-100062
    Figure PCTCN2021135751-appb-100061
    for
    Figure PCTCN2021135751-appb-100062
  6. 如权利要求1所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的二氢嘧啶类化合物为如下任一化合物：The dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the dihydropyrimidine compound represented by formula I is any of the following compounds :
    Figure PCTCN2021135751-appb-100063
    Figure PCTCN2021135751-appb-100063
    Figure PCTCN2021135751-appb-100064
    Figure PCTCN2021135751-appb-100064
    Figure PCTCN2021135751-appb-100065
    Figure PCTCN2021135751-appb-100065
    Figure PCTCN2021135751-appb-100066
    Figure PCTCN2021135751-appb-100066
    Figure PCTCN2021135751-appb-100067
    Figure PCTCN2021135751-appb-100067
    Figure PCTCN2021135751-appb-100068
    Figure PCTCN2021135751-appb-100068
  7. 如权利要求1所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的二氢嘧啶类化合物为如下任一化合物：The dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the dihydropyrimidine compound represented by formula I is any of the following compounds :
    在下述条件下保留时间为4.341min的化合物
    Figure PCTCN2021135751-appb-100069
    其制备分离条件如下，     Compounds with a retention time of 4.341 min under the following conditions
    Figure PCTCN2021135751-appb-100069
    Its preparation and separation conditions are as follows,
    色谱柱：
    Figure PCTCN2021135751-appb-100070
    CSH TMPrep-C18(5μm，OBD TM19*150mm)；柱温：室温；流速:40mL/min；波长:254nm；溶剂系统：乙腈和0.05％三氟乙酸水溶液，乙腈梯度为20％～60％；     Column:
    Figure PCTCN2021135751-appb-100070
    CSH TM Prep-C18 (5μm, OBD TM 19*150mm); column temperature: room temperature; flow rate: 40mL/min; wavelength: 254nm; solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution, acetonitrile gradient is 20%～60% ;
    在下述条件下保留时间为4.522min的化合物
    Figure PCTCN2021135751-appb-100071
    其制备分离条件如下，     Compounds with a retention time of 4.522 min under the following conditions
    Figure PCTCN2021135751-appb-100071
    Its preparation and separation conditions are as follows,
    色谱柱：
    Figure PCTCN2021135751-appb-100072
    CSH TMPrep-C18(5μm，OBD TM19*150mm)；柱温：室温；流速:40mL/min；波长:254nm；溶剂系统：乙腈和0.05％三氟乙酸水溶液，乙腈梯度为20％～60％。     Column:
    Figure PCTCN2021135751-appb-100072
    CSH TM Prep-C18 (5μm, OBD TM 19*150mm); column temperature: room temperature; flow rate: 40mL/min; wavelength: 254nm; solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution, acetonitrile gradient is 20%～60% .
  8. 一种如权利要求1-7中任一项所述的如式I所示的二氢嘧啶类化合物的制备方法，其特征在于，在溶剂中，在缩合剂存在下，将如式VI所示的化合物与式X所示的化合物或其盐进行如下所示的胺化反应，得到所述的如式I所示的二氢嘧啶类化合物即可；A preparation method of a dihydropyrimidine compound shown in formula I as described in any one of claims 1-7, is characterized in that, in a solvent, in the presence of a condensing agent, as shown in formula VI The compound and the compound represented by the formula X or its salt are subjected to the amination reaction shown below to obtain the dihydropyrimidine compound shown in the formula I;
    Figure PCTCN2021135751-appb-100073
    Figure PCTCN2021135751-appb-100073
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 9、R 13、W、Z 1、Z 2、Z 3、
    Figure PCTCN2021135751-appb-100074
    和*的定义如权利要求1-7中任一项所述；     Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 13 , W, Z 1 , Z 2 , Z 3 ,
    Figure PCTCN2021135751-appb-100074
    and * are as defined in any one of claims 1-7;
    所述的缩合剂可为2,2,6,6-四甲基哌啶；所述的溶剂可为腈类溶剂和/或卤代烃类溶剂，例如乙腈和二氯甲烷，又例如其体积比为1:3；所述胺化反应的温度可为10℃～30℃；所述的缩合剂与所述的如下式X所示的化合物或其盐地摩尔比可为1.2:1；所述的如式VI所示的化合物与所述的如式X所示 的化合物或其盐地摩尔比可为1.1:1；所述的溶剂与所述的如式X所示的化合物的体积摩尔比可为8L/moL。The condensing agent can be 2,2,6,6-tetramethylpiperidine; the solvent can be nitrile solvents and/or halogenated hydrocarbon solvents, such as acetonitrile and dichloromethane, and the volume of The ratio is 1:3; the temperature of the amination reaction can be 10°C to 30°C; the molar ratio of the condensing agent to the compound represented by the following formula X or its salt can be 1.2:1; The molar ratio of the compound shown in the formula VI to the compound shown in the formula X or its salt can be 1.1:1; the volume mole of the solvent and the compound shown in the formula X The ratio can be 8L/moL.
  9. 一种如式X所示的化合物或其盐，A compound of formula X or a salt thereof,
    Figure PCTCN2021135751-appb-100075
    Figure PCTCN2021135751-appb-100075
    其中，R 6、R 7、R 9、R 13、W和
    Figure PCTCN2021135751-appb-100076
    的定义如权利要求1-7中任一方案所述；     wherein R 6 , R 7 , R 9 , R 13 , W and
    Figure PCTCN2021135751-appb-100076
    The definition is as described in any one of claims 1-7;
    例如，
    Figure PCTCN2021135751-appb-100077
    Figure PCTCN2021135751-appb-100078
    E.g,
    Figure PCTCN2021135751-appb-100077
    Figure PCTCN2021135751-appb-100078
    Figure PCTCN2021135751-appb-100079
    Figure PCTCN2021135751-appb-100079
    Figure PCTCN2021135751-appb-100080
    Figure PCTCN2021135751-appb-100080
  10. 一种药物组合物，其包含如权利要求1-7中任一项所述的式I所示的二氢嘧啶类化合物或其药学上可接受的盐，和，药用辅料；所述的如权利要求1-7中任一项所述的式I所示的二氢嘧啶类化合物或其药学上可接受的盐可为治疗有效量的。A pharmaceutical composition, it comprises the dihydropyrimidine compound shown in formula I as described in any one of claim 1-7 or its pharmaceutically acceptable salt, and, pharmaceutical adjuvant; The dihydropyrimidine compound represented by formula I according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof may be in a therapeutically effective amount.
  11. 一种如权利要求1-7中任一项所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐在制备HBV抑制剂中的应用。A use of a dihydropyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of an HBV inhibitor according to any one of claims 1-7.
  12. 一种如权利要求1-7中任一项所述的如式I所示的二氢嘧啶类化合物或其药学上可接受的盐在制备药物中的应用；所述的药物可为用于预防和/或治疗与HBV感染的药物。A use of a dihydropyrimidine compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of medicine as described in any one of claims 1-7; the medicine can be used for prevention and/or drugs to treat HBV infection.
PCT/CN2021/135751 2020-12-09 2021-12-06 Dihydropyrimidine compound, preparation method therefor, and application thereof WO2022121844A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180010983.5A CN115003673B (en) 2020-12-09 2021-12-06 Dihydropyrimidine compound, preparation method and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011449986.2 2020-12-09
CN202011449986 2020-12-09

Publications (1)

Publication Number Publication Date
WO2022121844A1 true WO2022121844A1 (en) 2022-06-16

Family

ID=81897768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/135751 WO2022121844A1 (en) 2020-12-09 2021-12-06 Dihydropyrimidine compound, preparation method therefor, and application thereof

Country Status (2)

Country Link
CN (2) CN114621219A (en)
WO (1) WO2022121844A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106061978A (en) * 2014-03-07 2016-10-26 豪夫迈·罗氏有限公司 Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CN107427514A (en) * 2015-03-16 2017-12-01 豪夫迈·罗氏有限公司 Use TLR7 activators and the combined therapy of HBV capsids assembling inhibitor
CN109678859A (en) * 2017-10-18 2019-04-26 广东东阳光药业有限公司 Dihydropyrimidines and its application in drug
CN109843296A (en) * 2016-06-10 2019-06-04 英安塔制药有限公司 B type hepatitis antivirus medicament
WO2020125729A1 (en) * 2018-12-20 2020-06-25 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis b infections
WO2020135439A1 (en) * 2018-12-25 2020-07-02 广东东阳光药业有限公司 Deuterated dihydropyrimidine compound and use thereof as drug

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106061978A (en) * 2014-03-07 2016-10-26 豪夫迈·罗氏有限公司 Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CN107427514A (en) * 2015-03-16 2017-12-01 豪夫迈·罗氏有限公司 Use TLR7 activators and the combined therapy of HBV capsids assembling inhibitor
CN109843296A (en) * 2016-06-10 2019-06-04 英安塔制药有限公司 B type hepatitis antivirus medicament
CN109678859A (en) * 2017-10-18 2019-04-26 广东东阳光药业有限公司 Dihydropyrimidines and its application in drug
WO2020125729A1 (en) * 2018-12-20 2020-06-25 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis b infections
WO2020135439A1 (en) * 2018-12-25 2020-07-02 广东东阳光药业有限公司 Deuterated dihydropyrimidine compound and use thereof as drug

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY ANONYMOUS : "1H-Pyrrolo[3,4-c]pyridin-1-one, octahydro-3,3-dimethyl- (CA INDEX NAME) OTHER CA INDEX NAMES: CN - Octahydro-3,3-dimethyl-1H-pyrrolo[3,4-c]pyridin-1-one MF - C9 H16 N2 O SR - Chemical Catalog Supplier: FCH Group LC - STN Files: CHEMCATS tektronix-4QCUHO2S ", XP055943371, retrieved from STN *

Also Published As

Publication number Publication date
CN115003673A (en) 2022-09-02
CN115003673B (en) 2023-08-11
CN114621219A (en) 2022-06-14

Similar Documents

Publication Publication Date Title
WO2021087018A1 (en) Pyridazinones as parp7 inhibitors
CN101998959B (en) Benzoxazole carboxamide inhibitors of poly(ADP-ribose)polymerase (PARP)
EP3558973A1 (en) Pyridine derivatives as immunomodulators
CA2829939C (en) Tricyclic gyrase inhibitors
CA3139526A1 (en) Triaryl compounds for treatment of pd-l1 diseases
CN114072135A (en) Compounds for treating PD-L1 diseases
KR20050057408A (en) Triazaspiro[5.5]undecane derivatives and drugs comprising the same as the active ingredient
JP2021195367A (en) Cyclopropyl dihydroquinoline sulfonamide compounds
KR20070026414A (en) Hiv integrase inhibitors
WO2013082345A1 (en) Aryl dihydropyridinone and piperidinone as mgat2 inhibitors
TW202128695A (en) Heteroaryl-biphenyl amines for the treatment of pd-l1 diseases
CA3104956C (en) Novel lxr modulators with bicyclic core moiety
CN101481323B (en) Benzo cyclohepten derivate, and preparation and medical use thereof
CN108341819B (en) Phosphodiesterase inhibitors and uses thereof
CN102372701A (en) Azabicyclo hexane derivative, preparation method, and application of azabicyclo hexane derivative in medicine
CN111718332B (en) 2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof
WO2018028491A1 (en) Indoleamine2,3-dioxygenase inhibitors and uses thereof in pharmacy
WO2022121844A1 (en) Dihydropyrimidine compound, preparation method therefor, and application thereof
TWI794994B (en) Pyrimidinamide compounds and their applications
WO2017008681A1 (en) Amide derivative, and preparation method and pharmaceutical use thereof
WO2022171072A1 (en) Dihydropyrimidine compound, preparation method therefor and application thereof
TWI811901B (en) A kind of pyrimidine formamide compound and application thereof
TW201400470A (en) 4-alkanoylamino-3-pyrazolone derivatives
WO2022052923A1 (en) Dihydropyrimidine compound and application thereof
CN116891437A (en) Amino acid derivative, pharmaceutical composition, preparation method and application thereof

Legal Events

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

Ref document number: 21902549

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21902549

Country of ref document: EP

Kind code of ref document: A1