WO2023116812A1 - Sulfonylurea compound - Google Patents

Sulfonylurea compound Download PDF

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Publication number
WO2023116812A1
WO2023116812A1 PCT/CN2022/140921 CN2022140921W WO2023116812A1 WO 2023116812 A1 WO2023116812 A1 WO 2023116812A1 CN 2022140921 W CN2022140921 W CN 2022140921W WO 2023116812 A1 WO2023116812 A1 WO 2023116812A1
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alkyl
membered
cycloalkyl
membered heterocycloalkyl
heterocycloalkyl
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PCT/CN2022/140921
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French (fr)
Chinese (zh)
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张立明
郝欣
吕玥
宋云鹏
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瑞石生物医药有限公司
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Publication of WO2023116812A1 publication Critical patent/WO2023116812A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom

Definitions

  • the present disclosure relates to the field of medicine, in particular to a sulfonylurea compound and its use and preparation method.
  • NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) is a protein coding gene, the protein belongs to nucleotide-binding and oligomerization domain-like receptors (nucleotide-binding and oligomerization domain-like receptors, NLRs ) family, also known as "pyosin domain protein 3" (Inoue et al, Immunology, 2013, 139, 1 1-18).
  • the gene encodes a protein that contains a pyridine domain, a nucleotide binding site domain (NBD), and a leucine-rich repeat (LRR) motif.
  • NBD nucleotide binding site domain
  • LRR leucine-rich repeat
  • NLRP3 In response to sterile inflammatory danger signals, NLRP3 interacts with adapter proteins, apoptosis-associated speck-like protein (ASC), and zymogen-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome then leads to the release of the inflammatory cytokines IL-1b and IL-18, and when dysregulated, NLRP3 inflammasome activation drives many diseases.
  • ASC apoptosis-associated speck-like protein
  • NLRP3 inflammasome pathway inhibitors it is necessary to provide new NLRP3 inflammasome pathway inhibitors to provide new options for the treatment of the above diseases.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • X1 is selected from S and O;
  • X 2 is CR 5 or N
  • a and B are each independently selected from NR 7 , C(R 4a ) 2 and O;
  • E and D are each independently selected from NR 7b , C(R 6a ) 2 and O;
  • R 3 is selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl; said C 1-6 alkyl, 3-6 membered cycloalkyl is optionally selected from one or more of C 1-6 Substituents of alkyl, 3-6 membered cycloalkyl, halogen, cyano, hydroxyl;
  • R 7 or R 7b are independently selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl Such as -COCH 3 , -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl, The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloal
  • R 7a is selected from hydrogen, cyano, hydroxyl, halogen and nitro; preferably R 7a is cyano or hydroxyl;
  • R 7c is independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkane Substituents of base, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, amino, cyano, nitro, hydroxyl; the C 1-6 alkyl, -OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered Heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl;
  • Each R 4a , R 4b , R 4c , R 4d , R 4e is the same or different, and each independently selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Heteroaryl, phenyl; -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkane Base, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 4f ;
  • R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; said -CONH 2 , C 1-6 alkyl,- OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Member heteroaryl and phenyl are optionally substituted by one or more R 5a ;
  • Each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, -CONH 2 , C 1-6 alkyl , -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 -6-membered heteroaryl, phenyl; said -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 6f
  • Z is N or CR 12 ;
  • R 12 is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen , cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a ; the C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally substituted by one or more R 12b ;
  • R 12b is selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered hetero Aryl and phenyl; said C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl optionally substituted by one or more R 12c ;
  • R 12a is selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino; said C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 Membered heterocycloalkyl and amino are optionally replaced by one or more selected from halogen, cyano, hydroxyl, amino, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl substituents are substituted;
  • R 8 , R 9 , R 10 , R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3- 6-membered heterocycloalkyl, 3-6-membered cycloalkyl, condensed ring formed by 3-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl Aryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl , a condensed ring formed by a 3-6 membered heterocycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membere
  • R 8 and R 9 together form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally replaced by One or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered
  • R 10 and R 11 together form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally replaced by One or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered
  • Each R 13b and R 13c are independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; the C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1- 6 alkylene-SO 2
  • Each R 13a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, C 1-6 alkylamino , Two C 1-6 alkylamino, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, -CONH 2 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; The amino, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered Cycloalkyl,
  • Each R 7c , R 4f , R 5a , R 6f , and R 12c are independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, amino, cyano, nitro, hydroxyl; the C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 Heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl;
  • R1 is not selected from Optionally substituted and optionally replaced by
  • R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2.
  • C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
  • R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene- SO 2 -3-6 membered heterocycloalkyl, The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 member
  • R 7a is as defined in claim 1, preferably R 7a is cyano;
  • R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
  • R is R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2.
  • C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
  • R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl , The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membere
  • R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
  • E and D are each independently selected from C(R 6a ) 2 and O, and only one of E and D is O;
  • R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2.
  • C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
  • R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
  • E and D are each independently selected from NR 7b , C(R 6a ) 2 and O, and only one of E and D is O;
  • R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2.
  • C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
  • R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl , -C 1-6 alkylene-3-6 membered cycloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen, -CO-C 1-6 alkyl such as -COCH 3 ;
  • R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
  • R 1 is selected from
  • E and D are each independently selected from NR 7b , C(R 6a ) 2 and O,
  • R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene- SO 2 -3-6 membered heterocycloalkyl, The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 member
  • R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
  • R 1 is selected from
  • R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
  • each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from hydrogen, halogen, Cyano, amino, nitro, hydroxyl, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkane base, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, phenyl group; the -CONH 2 , C 1-6 alkyl group, -OC 1-6 alkyl group , -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocyclo
  • R 6f is as defined in Formula 1.
  • each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from hydrogen, halogen, Cyano, amino, nitro, hydroxyl, -CONH 2 ; the -CONH 2 is optionally substituted by one or more R 6f ;
  • R 6f is as defined in Formula 1.
  • each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from C 1-6 Alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkane Base, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 6f ; R 6f is as defined in formula 1.
  • each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 6f ; R 6f is as shown in formula 1 definition.
  • each R 6f is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkane base, 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally replaced by one or multiple substituents selected from halogen, amino, cyano, nitro, hydroxyl.
  • R 6f is independently selected from halogen, amino, cyano, nitro, and hydroxyl.
  • R 6f is independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -O -3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, - O-3-6 membered heterocycloalkyl and 3-6 membered cycloalkyl are optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro and hydroxyl.
  • R 6d and R 6e are 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl together with the atoms connected to them; 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1- 6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl Substituents of radicals and phenyl groups are substituted.
  • R 6a form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with each other; the 3-8 membered cycloalkane A group or a 3-8 membered heterocycloalkyl group is optionally replaced by one or more groups selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl base replaced.
  • R 6b and R 6c form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered ring Alkyl or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl Substituents are substituted.
  • R 6d and R 6e form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkane A group or a 3-8 membered heterocycloalkyl group is optionally replaced by one or more groups selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl base replaced.
  • R 6d and R 6e form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkane A group or a 3-8 membered heterocycloalkyl group is optionally replaced by one or more groups selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl Substituted by a group; preferably R 6d and R 6e form a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkyl
  • R 7 is as defined in formula I, preferably R 7 is methyl
  • R 3 is as defined in formula I, preferably R 3 is methyl, propyl, isopropyl, hydroxyethyl;
  • R 4a , R 4b , R 4c , R 4d , R 4e are as defined in formula I, preferably R 4a , R 4b , R 4c , R 4d , R 4e are hydrogen.
  • R 2 is R 8 , R 9 , R 10 , R 11 are as defined in formula I.
  • R 2 is
  • R 8 and R 9 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group
  • the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6
  • R 10 and R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , condensed ring formed by 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 hetero A condensed ring formed by a cycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ;
  • R 12 , R 13a , R 13b are as defined in formula I.
  • R 2 is
  • R 8 and R 9 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group
  • the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6
  • R 10 and R 11 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group
  • the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6
  • R 12 , R 13b , R 13c are as defined in formula I.
  • R 2 is
  • Z is N or CR 12 ;
  • R 8 and R 9 form a 4-7 membered cycloalkyl group
  • the 4-7 membered cycloalkyl group is optionally selected from one or more halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 Substituted by heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 ; C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3- 6-membered cycloalkyl, 3-6-membered
  • R 10 and R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , condensed ring formed by 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 hetero
  • a condensed ring formed by a cycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ; R 12 , R
  • R 10 , R 11 , R 12 , R 13a , R 13b are as defined in formula I.
  • Z is N or CR 12 ;
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Elementary heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; said C 1-6 alkyl, halogenated C 1- 6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl,
  • R 10 is selected from condensed rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heteroaryl; the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl A condensed ring formed by a radical, a 5-6 membered heteroaryl is optionally substituted by one or more R 13a .
  • R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
  • R 12 , R 13a , R 13b are as defined in formula I.
  • Z is N or CR 12 ;
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Elementary heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; said C 1-6 alkyl, halogenated C 1- 6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl,
  • R 10 is selected from 5-6 membered heteroaryl optionally substituted by one or more R 13a ;
  • R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
  • R 12 , R 13a , R 13b are as defined in formula I.
  • R 2 is selected from
  • Z is N or CR 12 ;
  • R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
  • R 10a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl
  • n and m are independently selected from integers of 0-3; preferably n and m are independently selected from integers of 0-2;
  • R 8 , R 9 , R 12 , R 13a , R 13c are as defined in formula I;
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are as defined above.
  • Z is N or CR 12 ;
  • R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
  • n is an integer selected from 0-3;
  • R 12 , R 13a , R 13c , R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are as defined above.
  • Z is N.
  • Z is CR 12 ; R 12 is as defined in formula I.
  • R 12 is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3 -6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a ; the C 1- 6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally replaced by 1- 3 R 12b replaced;
  • R 12a and R 12b are as defined in formula I.
  • R 12 is selected from hydrogen, halogenated C 1-6 alkyl, hydroxyl substituted C 1-6 alkyl, cyano substituted C 1- 6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a , R 12a is as defined in formula I;
  • R 12 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, -OC 1-6 alkane base.
  • R 12a is selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino;
  • the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino are optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino ;
  • R 12a is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, 3-6 membered heterocycloalkyl.
  • R 12b is selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, -OC 1-6 alkyl, 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl and phenyl; said C 1-6 alkyl, -OC 1-6 alkyl, 3-6-membered cycloalkyl , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by 1-3 R 12c , R 12c is as defined in formula 1; preferably 12b is selected from halogen, cyano, Hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl substituted C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered Heterocycl
  • R 12c is independently selected from halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, -OC 1-6 Alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl.
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are independently selected from hydrogen, halogen, hydroxyl, cyano, Amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl; said C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkane
  • the group is optionally substituted by one or more R 13b , R 13b is as defined in formula I; preferably R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are independently selected from hydrogen, halogen, hydroxyl, Cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl; more preferably R 9a , R 9b , R 9c , R 9d , R 9e
  • R 13b is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, Halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl.
  • R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkane
  • the group, -OC 1-6 alkyl is optionally substituted by one or more R 13a , and R 13a is as defined in formula I.
  • R 11 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkane group; preferably R 11 is selected from hydrogen, methyl.
  • each R 13a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkylamino, di-C 1-6 Alkylamino, C 1-6 alkyl, -OC 1-6 alkyl; said amino, C 1-6 alkyl, -OC 1-6 alkyl are optionally selected from 1-3 C 1-6 Substituents of alkyl, cyano, hydroxyl, halogen, -OC 1-6 alkyl, halogenated C 1-6 alkyl, cyano substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl replaced.
  • each R 13a is independently selected from cyano, halogen, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, Methanesulfonyl, -CONH 2 , -CH 2 -SO 2 CH 3 , 3-6 membered heterocyclic group, amino group.
  • each R 13a is independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-5-6 Heteroaryl, -O-3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl; the C 1-6 alkyl, -OC 1-6 alkyl , -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl, optionally 1-3 selected from halogen , cyano, hydroxyl, C 1-6 alkyl substituents are substituted.
  • each R 13a is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, Aryl; the 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, and 5-6 membered heteroaryl group are optionally selected from C 1-6 alkyl group, cyano group, hydroxyl group, Halogen, -OC 1-6 alkyl, halogenated C 1-6 alkyl, cyano substituted C 1-6 alkyl.
  • R 10a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl , -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, halogen Substituted 3-6 membered cycloalkyl, halogenated 3-6 membered heterocycloalkyl.
  • R is optionally substituted , R 1 is not
  • R 2 is not
  • R is not optionally substituted
  • the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
  • the present disclosure also provides an isotope substitution of the compound as described in the first aspect or the second aspect, preferably, the isotope substitution is deuterium atom substitution
  • the present disclosure also provides a pharmaceutical composition, including at least one therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof as described in the first aspect and the second aspect, or the isotope as described in the third aspect Substitutes, and pharmaceutically acceptable excipients.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds or pharmaceutically acceptable salts or isotope substitutions thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds or pharmaceutically acceptable salts or isotopic substitutions thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides the compound described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of therapeutic and Use in medicine for diseases associated with NLRP3 activity.
  • the present disclosure also provides a method for preventing and/or treating diseases related to NLRP3 activity, which comprises administering a therapeutically effective amount of the compound described in the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof to a patient in need, Or the isotope substitution described in the third aspect, or the pharmaceutical composition described in the fourth aspect.
  • the present disclosure also provides a compound described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the third aspect, or the pharmaceutical composition described in the fourth aspect, which is used for preventing or Treatment of diseases associated with NLRP3 activity.
  • Diseases associated with NLRP3 activity include inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
  • the present disclosure also provides the compounds described in the first aspect and the second aspect or pharmaceutically acceptable salts thereof, or the isotope substitutions described in the third aspect or the pharmaceutical composition described in the fourth aspect in the preparation of treating inflammasome-related diseases, Use in medicine for immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
  • the present disclosure also provides the compound described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the third aspect or the pharmaceutical composition described in the fourth aspect, which are used to treat inflammasome-related Disease, immune disease, inflammatory disease, autoimmune disease and/or autoinflammatory disease.
  • the present disclosure also provides a method of treating and/or preventing inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases, which comprises administering a therapeutically effective amount of The first aspect, the compound of the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution of the third aspect, or the pharmaceutical composition of the fourth aspect.
  • the inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases may be specifically selected from: autoinflammatory fever syndrome (such as cryopyrin-related cycle syndrome), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease), inflammatory joint Inflammation-related diseases (such as gout, chondrocalcification, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation , type I or type II diabetes and its complications (such as nephropathy, retinopathy), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurode
  • acne hidradenitis suppurativa
  • asthma sarcoidosis
  • age-related macular degeneration e.g. myeloproliferative neoplasms, leukemia, myeloid Dysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer.
  • cancer-related diseases/conditions e.g. myeloproliferative neoplasms, leukemia, myeloid Dysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer.
  • compositions described in the present disclosure may be selected from inorganic or organic salts.
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are included in this within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or or both and Two configurations.
  • the bond configuration is not specified, i.e. the key The configuration of can be E type or Z type, or contain both E and Z configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • an “effective amount” or “therapeutically effective amount” as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl and its various branched isomers, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or Heterocycloalkyl is optionally substituted with halo, hydroxy, nitro, cyano or amino.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 6 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.
  • multicyclic cycloalkyls include spiro Cycloalkyls of rings, parallel rings and bridged rings.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo , cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl Or heterocycloalkyl is optionally substituted with halo, hydroxy, nitro, cyano or amino.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms.
  • Non-limiting examples of “heterocycloalkyl” include:
  • heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally Substituted by halogen, hydroxy, nitro, cyano or amino.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C -6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally Halogen, hydroxy, nitro, cyano or amino substituted.
  • cycloalkoxy and “heterocycloalkoxy” have the same definition as the above-mentioned "alkoxy”.
  • alkylthio refers to -S-(alkyl), wherein alkyl is as defined above.
  • alkylthio include: methylthio, ethylthio, propylthio, butylthio.
  • Alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from C 1-6 alkoxy, 3 to 6 membered cycloalkane group, 3 to 6 membered heterocycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 1-6 alkylthio, 3 to 6 membered cycloalkylthio, 3 to 6 Member heterocycloalkylthio, the alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio are optionally replaced by halogen , Hydroxy, cyano or amino.
  • cycloalkylthio and “heterocycloalkylthio” have the same definition as the above-mentioned “alkylthio”.
  • “Monovalent group” means that a compound is “formally” eliminated from a monovalent atom or group. "Subunit” or “divalent group” refers to a compound formed by “formally” eliminating two monovalent or one divalent atoms or atomic groups.
  • alkylene means what remains of an alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms.
  • An alkylene group having 1 to 6 carbon atoms include methylene (-CH 2 -), ethylene (eg -CH 2 CH 2 - or -CH(CH 3 )-).
  • the alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen , hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.
  • alkyleneoxy Similarly, the definitions of "alkyleneoxy”, “alkenylene”, “alkenyleneoxy”, “cycloalkylene”, and “heterocycloalkylene” are the same as “alkylene”.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated ⁇ -electron system, such as benzene base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C1-6 Alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 to 6-membered cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 6-membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-8 membered cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected from one or more halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.
  • the heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C alkane group or C 1-6 alkoxy group.
  • spiro refers to a compound in which two rings share one atom.
  • spirocycloalkyl groups include:
  • merged ring refers to a compound formed by combining two or more rings by sharing two adjacent atoms.
  • cycloalkyl groups include:
  • bridged ring refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • heterocyclic ring refers to atoms other than carbon atoms that make up the ring, and includes heterocycloalkyl and heteroaryl rings.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents.
  • two (2) hydrogens on the atom are replaced.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um column.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • compound 1d (25.0 g, 59.4 mmol) and acetonitrile (250 mL) were sequentially added into a 500 mL one-necked bottle. Cool down to 0°C, add 1,3-dichloro-5,5-dimethylhydantoin (23.4g, 118.9mmol), water (6mL) and acetic acid (6mL). Stir for 2 hours, concentrate under reduced pressure, add ethyl acetate (200 mL) and water (100 mL), dry the organic phase, filter, and concentrate under reduced pressure to obtain compound 1f (25 g, crude product), which is directly used in the next step.
  • compound 1i (30 mg, 0.12 mmol), tetrahydrofuran (2 mL), and sodium tert-butoxide (11.76 mg, 0.122 mmol) were added to a 10 mL one-necked bottle. Warm up to room temperature, stir for 30 minutes, add 1j (23 mg, 0.12 mmol), and stir for 4 hours.
  • compound 2k 150mg, 0.646mmol
  • tetrahydrofuran 5mL
  • sodium tert-butoxide 65mg, 0.68mmol
  • 1j (128mg, 0.646mmol) was added and stirred for 3 hours.
  • compound 4a (9.00g, 28.2mmol), tris(dibenzylideneacetone)dipalladium (1.29g, 1.41mmol), 4,5-bis(diphenylphosphine)-9 were added to the reaction flask, 9-Dimethylxanthene (1.63g, 2.82mmol), dioxane (100mL), N,N-diisopropylethylamine (9mL, 56.4mmol), under nitrogen atmosphere, add benzyl mercaptan ( 6mL, 56.4mmol), stirred at 80°C for 2 hours.
  • reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (system: 0.1% ammonia/acetonitrile/water to obtain the target product 4f (100 mg, yield: 30%); LC-MS m/z (ESI): 233.9 (M+H) + .
  • reaction solution was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 ⁇ m; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 50-70% B; flow 25ml/min ) was purified to obtain compound 4g (1.5 mg, yield: 2%).
  • LC-MS MS (ESI): m/z 474.2 (M+H+CH 3 CN) + .
  • Phosphorus pentachloride (10.5 g, 50.4 mmol) and pyridine (4.1 mL, 50.4 mmol) were added again, stirred for 2 hours, and the reaction was complete.
  • the aqueous phase was directly purified by reverse-phase column C18 (water/acetonitrile), lyophilized, and the residue was subjected to high-performance liquid chromatography (chromatographic column: Gilson-281, Xbridge 150*25mm, 5 ⁇ m; mobile phase: aqueous phase (10mM ammonia water) and acetonitrile, gradient ratio: 0-9min 6-36% B; flow 25ml/min) to obtain compound 5e (18mg, yield: 18.4%).
  • reaction solution was slowly poured into water (500 mL), then extracted three times with ethyl acetate (200 mL ⁇ 3), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography with eluent system (SiO 2 , 20%-25% ethyl acetate/petroleum ether) to obtain compound 6b (72 g, yield: 80.5%).
  • compound 19a (1.21g, 6.68mmol), compound 6f (2.00g, 6.68mmol), triethylamine (2.80mL, 20.1mmol) and N,N-dimethylformamide ( 10 mL), react at 100°C for 16 hours. Cool to room temperature and concentrate under reduced pressure. The crude product was subjected to preparative liquid chromatography (chromatographic column: Kromasil Eternity XT 250*80mm*10 ⁇ m; mobile phase: aqueous phase (10mM ammonium bicarbonate) and acetonitrile; gradient ratio: 0-20min 5-30% B; flow 140mL/ min) was purified to obtain compound 19b (600 mg, yield: 24.7%).
  • reaction solution was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 ⁇ m; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 45-60% B ; flow 25ml/min) to obtain compound 22 (19mg, 18.5%).
  • chromatographic column Waters, Xbridge 250*19mm, 10 ⁇ m; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 45-60% B ; flow 25ml/min
  • Compound 23 (11 mg, 19.5%) was prepared by reacting compound 2k with compound 3k using a synthesis method similar to that of Example 22.
  • Compound 25 (20 mg, 31.8%) was obtained by using the synthetic route of Example 4, replacing compound 1j with compound 3k in the sixth step.
  • compound 30c (380mg, 3.42mmol), dichloromethane (2mL), triethylamine (0.8mL, 5.4mmol), di-tert-butyl dicarbonate (0.9mL, 3.76mmol) were sequentially added to a 100mL single-necked bottle , stirred at room temperature for 1 hour. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system (SiO 2 , 10% ethyl acetate/petroleum ether) to obtain compound 30d (480 mg, yield: 55.4%).
  • compound 30i 500mg, 1.90mmol was dissolved in dichloromethane (2mL), the solution of compound 30i (500mg, 1.90mmol) in dichloromethane (2mL) was added dropwise to 7M ammonia methanol solution (20mL), stirred 1 hour. It was concentrated under reduced pressure and purified by reverse column C18 (water/acetonitrile, ammonia water system) to obtain compound 30j (150 mg, yield: 32.3%).
  • reaction solution was subjected to preparative liquid chromatography (column: Waters, Xbridge 250*19mm, 10 ⁇ m; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 45-60% B; flow 25ml/min ) was purified to obtain a crude product, which was exchanged with sodium ion exchange resin to obtain compound 30 (42 mg, yield: 23.5%).
  • Test Example 1 Inhibition of NLRP3 Inflammasome Activity in THP-1 Cells
  • THP-1 cells were resuspended in RPMI1640, 10% FBS, 1% P/S cell culture medium, and the cell density was adjusted to 1 ⁇ 10 6 cells/mL.
  • the culture dish was taken out , the supernatant and unattached cells were removed, the cells were digested and resuspended, and seeded at 96 in the orifice plate.
  • the cell plate was incubated overnight in the incubator, removed after 12 hours, removed the medium, added 50uL of fresh medium containing 200ng/mL LPS, and incubated in a cell incubator at 37°C and 5% carbon dioxide for 3.5 hours.
  • prepare a stock solution of the compound with a concentration of 30 mM in DMSO in a test tube then use DMSO as a solvent to gradually dilute the sample as required, and finally dilute it 333 times in the medium.
  • Table 1 shows the IC 50 values of compounds of the present invention for inhibiting NLRP3 inflammasome activity in THP-1 cells.
  • Table 1 The compounds of the present invention inhibit the IC50 value of NLRP3 inflammasome activity in THP-1 cells
  • Example number IC50 serial number IC50 Example 1 B Example 16 A Example 2 B Example 17 B Example 3 A Example 18 B Example 4 C Example 19 A Example 5 B Example 20 A Example 6 A Example 21 B Example 7 B Example 22 A Example 8 A Example 23 A Example 9 A Example 24 B Example 10 B Example 25 B Example 11 C Example 26 B Example 12 A Example 27 B Example 13 B Example 28 B Example 14 B Example 29 A Example 15 A Example 30 B Example 31 A Example 32 A Example 33 A Example 34 A Example 35 B Example 36 B Example 37 B Example 38 B
  • Test Example 2 Pharmacokinetic evaluation of the compound of the present invention
  • the dosage for intravenous injection was 1 mg/kg, and the dosage for intragastric administration was 3 mg /kg, the intravenous vehicle is 5% DMSO, 5% Solutol and 90% water, and the oral vehicle is 0.5% HPMC, 0.1% TW80 aqueous solution.
  • Plasma Blood was collected from the saphenous vein and centrifuged to obtain plasma, and the plasma concentration was determined using LC-MS/MS, and non-compartmental analysis was performed using Phoenix WinNonlin to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration ( C max ), half-life (T 1/2 ), area under the drug-time curve (AUC 0-t ), bioavailability (F), etc.
  • clearance Cl
  • C max peak concentration
  • T 1/2 half-life
  • AUC 0-t area under the drug-time curve
  • F bioavailability
  • Table 2 is the pharmacokinetic parameters of the compounds of the present invention in mice.
  • the disclosed compound has good pharmacokinetic absorption activity in mice, and has pharmacokinetic advantages.
  • the dosage for intravenous injection was 1 mg/kg, and the dosage for intragastric administration was 3 mg /kg, the intravenous vehicle is 5% DMSO, 5% Solutol and 90% water, and the oral vehicle is 0.5% HPMC, 0.1% TW80 aqueous solution.
  • Plasma Blood was collected from the saphenous vein and centrifuged to obtain plasma, and the plasma concentration was determined using LC-MS/MS, and non-compartmental analysis was performed using Phoenix WinNonlin to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration ( C max ), half-life (T 1/2 ), area under the drug-time curve (AUC 0-t ), bioavailability (F), etc.
  • clearance Cl
  • C max peak concentration
  • T 1/2 half-life
  • AUC 0-t area under the drug-time curve
  • F bioavailability
  • Table 3 is the pharmacokinetic parameters of the compounds of the present invention in rats.
  • the disclosed compound has good pharmacokinetic absorption activity in rats, and has pharmacokinetic advantages.

Abstract

The present disclosure provides a sulfonylurea compound. Specifically, provided are a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a use thereof in preparation of a drug for treating diseases associated with NLRP3 activity. Groups in formula (I) are as defined in the description.

Description

一种磺酰脲类化合物A sulfonylurea compound 技术领域technical field
本公开涉及医药领域，具体涉及一种磺酰脲类化合物及其用途和制备方法。The present disclosure relates to the field of medicine, in particular to a sulfonylurea compound and its use and preparation method.
背景技术Background technique
NOD样受体蛋白3(NOD-like receptor protein 3，NLRP3)是一种蛋白编码基因，该蛋白属于核苷酸结合和寡聚化域样受体(nucleotide-binding and oligomerization domain-like receptors，NLRs)家族，也被称为“含脓素域蛋白3”(Inoue et al，Immunology，2013，139，1 1-18)。该基因编码一种蛋白，该蛋白包含一个吡啶结构域，一个核苷酸结合位点结构域(NBD)，和一个富含亮氨酸的重复(LRR)基序。通过响应无菌的炎性危险信号，NLRP3与衔接蛋白、凋亡相关斑点样蛋白(ASC)以及酶原-1相互作用，形成NLRP3炎性体。之后，NLRP3炎性体的激活导致炎性细胞因子IL-1b和IL-18的释放，而当NLRP3炎性体的激活失调时，则会驱动许多疾病的发生。NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) is a protein coding gene, the protein belongs to nucleotide-binding and oligomerization domain-like receptors (nucleotide-binding and oligomerization domain-like receptors, NLRs ) family, also known as "pyosin domain protein 3" (Inoue et al, Immunology, 2013, 139, 1 1-18). The gene encodes a protein that contains a pyridine domain, a nucleotide binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with adapter proteins, apoptosis-associated speck-like protein (ASC), and zymogen-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome then leads to the release of the inflammatory cytokines IL-1b and IL-18, and when dysregulated, NLRP3 inflammasome activation drives many diseases.
研究表明，NLRP3炎性体的激活与多类疾病相关，包括：炎性体相关疾病、免疫性疾病如自身免疫性疾病、炎症性疾病如自身炎症性疾病。因此，需要提供新的NLRP3炎性体通路抑制剂，来为上述疾病的治疗提供新的可选方式。Studies have shown that the activation of NLRP3 inflammasome is associated with many types of diseases, including: inflammasome-related diseases, immune diseases such as autoimmune diseases, and inflammatory diseases such as autoinflammatory diseases. Therefore, it is necessary to provide new NLRP3 inflammasome pathway inhibitors to provide new options for the treatment of the above diseases.
发明内容Contents of the invention
第一方面，本公开提供一种如式I所示的化合物或其可药用盐，In a first aspect, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
其中R 1为
Figure PCTCN2022140921-appb-000001
where R1 is
Figure PCTCN2022140921-appb-000001
R 2为
Figure PCTCN2022140921-appb-000002
 R2 is
Figure PCTCN2022140921-appb-000002
X 1选自S和O； X1 is selected from S and O;
X 2为CR 5或N； X 2 is CR 5 or N;
A、B各自独立地选自NR 7、C(R 4a) 2和O； A and B are each independently selected from NR 7 , C(R 4a ) 2 and O;
E、D各自独立地选自NR 7b、C(R 6a) 2和O； E and D are each independently selected from NR 7b , C(R 6a ) 2 and O;
R 3选自氢、C 1-6烷基、3-6元环烷基；所述C 1-6烷基、3-6元环烷基任选被一个或多个选自C 1-6烷基、3-6元环烷基、卤素、氰基、羟基的取代基所取代； R 3 is selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl; said C 1-6 alkyl, 3-6 membered cycloalkyl is optionally selected from one or more of C 1-6 Substituents of alkyl, 3-6 membered cycloalkyl, halogen, cyano, hydroxyl;
R 7或R 7b独立地选自氢、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、硝基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基、
Figure PCTCN2022140921-appb-000003
所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基任选被一个或多个选自R 7c的取代基所取代； R 7 or R 7b are independently selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl Such as -COCH 3 , -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl,
Figure PCTCN2022140921-appb-000003
The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 CH 3 , -C 1-6 ethylene Alkyl-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl is optionally substituted by one or more substituents selected from R 7c ;
R 7a选自氢、氰基、羟基、卤素和硝基；优选R 7a为氰基或羟基； R 7a is selected from hydrogen, cyano, hydroxyl, halogen and nitro; preferably R 7a is cyano or hydroxyl;
R 7c独立地选自C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氨基、氰基、硝基、羟基的取代基所取代；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代； R 7c is independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkane Substituents of base, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, amino, cyano, nitro, hydroxyl; the C 1-6 alkyl, -OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered Heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl;
每个R 4a、R 4b、R 4c、R 4d、R 4e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 4f所取代； Each R 4a , R 4b , R 4c , R 4d , R 4e is the same or different, and each independently selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Heteroaryl, phenyl; -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkane Base, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 4f ;
或R 4a彼此间形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 4a form =S, =0, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl among each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally One or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl substituents;
或R 4b和R 4c、R 4d和R 4e与其相连的原子一起形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 4b and R 4c , R 4d and R 4e form =S, =O, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl together with the atoms connected to them; the 3-8 membered cycloalkyl Or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O- Substituents of 3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl replaced by
R 5选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 5a所取代； R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; said -CONH 2 , C 1-6 alkyl,- OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Member heteroaryl and phenyl are optionally substituted by one or more R 5a ;
每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、羟基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 6f所取代； Each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, -CONH 2 , C 1-6 alkyl , -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 -6-membered heteroaryl, phenyl; said -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 6f ;
或R 6a彼此间形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 6a form =S, =O, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl among each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally One or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl substituents;
或R 6b和R 6c、R 6d和R 6e与其相连的原子一起形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 6b and R 6c , R 6d and R 6e form =S, =O, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl together with the atoms connected to them; the 3-8 membered cycloalkyl Or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O- Substituents of 3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl replaced by
Z为N或CR 12； Z is N or CR 12 ;
R 12选自氢、C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、-CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a；所述C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2任选被一个或多个R 12b所取代； R 12 is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen , cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a ; the C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally substituted by one or more R 12b ;
R 12b选自卤素、氰基、羟基、氨基、C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基和苯基；所述C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基和苯基任选被一个或多个R 12c所取代； R 12b is selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered hetero Aryl and phenyl; said C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl optionally substituted by one or more R 12c ;
R 12a选自C 1-6烷基、3-6元环烷基、3-6元杂环烷基和氨基；所述C 1-6烷基、3-6元环烷基、3-6元杂环烷基和氨基任选被被一个或多个选自卤素、氰基、羟基、氨基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； R 12a is selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino; said C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 Membered heterocycloalkyl and amino are optionally replaced by one or more selected from halogen, cyano, hydroxyl, amino, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl substituents are substituted;
R 8、R 9、R 10、R 11独立地选自氢、卤素、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、3-6元杂环烷基、5-6元杂芳基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基、3-6元杂环烷基任选被一个或多个R 13a所取代； R 8 , R 9 , R 10 , R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3- 6-membered heterocycloalkyl, 3-6-membered cycloalkyl, condensed ring formed by 3-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl Aryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl , a condensed ring formed by a 3-6 membered heterocycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ;
或R 8和R 9与其相连的原子一起形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、 -SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； Or R 8 and R 9 together form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally replaced by One or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13b ;
或R 10和R 11与其相连的原子一起形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13c所取代； Or R 10 and R 11 together form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally replaced by One or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13c ;
每个R 13b、R 13c独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个选自卤素、羟基、氰基的取代基所取代； Each R 13b and R 13c are independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; the C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1- 6 alkylene-SO 2 CH 3 is optionally substituted by one or more substituents selected from halogen, hydroxyl, and cyano;
每个R 13a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、C 1-6烷基氨基、二C 1-6烷基氨基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基、5-6元杂芳基、-CONH 2、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述氨基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基、5-6元杂芳基、-CONH 2、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个选自C 1-6烷基、氰基、羟基、卤素、-O-C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基取代的C 1-6烷基的取代基所取代； Each R 13a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, C 1-6 alkylamino , Two C 1-6 alkylamino, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, -CONH 2 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; The amino, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -CONH 2 , -SO 2 -C 1- 6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 is optionally selected from one or more of C 1-6 alkyl, cyano, hydroxyl, halogen, -OC 1- Substituents of 6 alkyl, halogenated C 1-6 alkyl, cyano substituted C 1-6 alkyl substituted C 1-6 alkyl;
每个R 7c、R 4f、R 5a、R 6f、R 12c独立地选自C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氨基、氰基、硝基、羟基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代； Each R 7c , R 4f , R 5a , R 6f , and R 12c are independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, amino, cyano, nitro, hydroxyl; the C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 Heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl;
条件是：requirement is:
当R 2为任选取代的
Figure PCTCN2022140921-appb-000004
时，R 1不选自
Figure PCTCN2022140921-appb-000005
Figure PCTCN2022140921-appb-000006
任选取代的
Figure PCTCN2022140921-appb-000007
和任选取代的
Figure PCTCN2022140921-appb-000008
When R 2 is optionally substituted
Figure PCTCN2022140921-appb-000004
, R1 is not selected from
Figure PCTCN2022140921-appb-000005
Figure PCTCN2022140921-appb-000006
Optionally substituted
Figure PCTCN2022140921-appb-000007
and optionally replaced by
Figure PCTCN2022140921-appb-000008
在一些可实施方案中，式I所示的化合物或其可药用盐中，In some possible embodiments, in the compound represented by formula I or its pharmaceutically acceptable salt,
R 1为
Figure PCTCN2022140921-appb-000009
 R1 is
Figure PCTCN2022140921-appb-000009
R 5如式1中所定义，优选R 5选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被1-3个卤素、羟基、氰基所取代；更优选R 5选自氢、甲基、乙基、卤素、氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；最优选R 5为氢； R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2. C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
R 7b如式I中所定义，优选R 7b选自氢、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、硝基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基、
Figure PCTCN2022140921-appb-000010
Figure PCTCN2022140921-appb-000011
所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基任选被1-3个选自卤素、氰基、羟基的取代基所取代；更优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、
Figure PCTCN2022140921-appb-000012
R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene- SO 2 -3-6 membered heterocycloalkyl,
Figure PCTCN2022140921-appb-000010
Figure PCTCN2022140921-appb-000011
The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl such as- SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl optionally replaced by 1-3 members selected from halogen, Substituents of cyano group and hydroxyl group; more preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkane group, -C 1-6 alkylene-3-6 membered cycloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen,
Figure PCTCN2022140921-appb-000012
R 7a如权利要求1中所定义，优选地R 7a为氰基； R 7a is as defined in claim 1, preferably R 7a is cyano;
R 6a、R 6b、R 6c、R 6d、R 6e如式I中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 1为
Figure PCTCN2022140921-appb-000013
R 5如式1中所定义，优选R 5选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被1-3个卤素、羟基、氰基所取代；更优选R 5选自氢、甲基、乙基、卤素、 氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；最优选R 5为氢； In some possible embodiments, in the compound represented by formula I or its pharmaceutically acceptable salt, R is
Figure PCTCN2022140921-appb-000013
R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2. C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
R 7b如式I中所定义，优选R 7b选自氢、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、硝基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基、
Figure PCTCN2022140921-appb-000014
Figure PCTCN2022140921-appb-000015
所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基任选被1-3个选自卤素、氰基、羟基的取代基所取代；更优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、
Figure PCTCN2022140921-appb-000016
R 7a如权利要求1中所定义，优选地R 7a为氰基； R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl ,
Figure PCTCN2022140921-appb-000014
Figure PCTCN2022140921-appb-000015
The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl such as- SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl optionally replaced by 1-3 members selected from halogen, Substituents of cyano group and hydroxyl group; more preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkane group, -C 1-6 alkylene-3-6 membered cycloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen,
Figure PCTCN2022140921-appb-000016
R 7a is as defined in claim 1, preferably R 7a is cyano;
R 6a、R 6b、R 6c、R 6d、R 6e如式I中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 1为
Figure PCTCN2022140921-appb-000017
 R1 is
Figure PCTCN2022140921-appb-000017
E、D各自独立地选自C(R 6a) 2和O，且E、D中有且仅有一个为O； E and D are each independently selected from C(R 6a ) 2 and O, and only one of E and D is O;
R 5如式1中所定义，优选R 5选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被1-3个卤素、羟基、氰基所取代；更优选R 5选自氢、甲基、乙基、卤素、氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；最优选R 5为氢； R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2. C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
R 6a、R 6b、R 6c、R 6d、R 6e如式I中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 1为
Figure PCTCN2022140921-appb-000018
 R1 is
Figure PCTCN2022140921-appb-000018
E、D各自独立地选自NR 7b、C(R 6a) 2和O，且E、D中有且仅有一个为O； E and D are each independently selected from NR 7b , C(R 6a ) 2 and O, and only one of E and D is O;
R 5如式1中所定义，优选R 5选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被1-3个卤素、羟基、氰基所取代；更优选R 5选自氢、甲基、乙基、卤素、氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；最优选R 5为氢； R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH 2. C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by 1-3 halogen , hydroxyl, cyano; more preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano Base, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R is hydrogen;
R 7b如权利要求1中所定义，优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、-CO-C 1-6烷基如-COCH 3； R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl , -C 1-6 alkylene-3-6 membered cycloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen, -CO-C 1-6 alkyl such as -COCH 3 ;
R 6a、R 6b、R 6c、R 6d、R 6e如式I中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 1选自
Figure PCTCN2022140921-appb-000019
R 1 is selected from
Figure PCTCN2022140921-appb-000019
E、D各自独立地选自NR 7b、C(R 6a) 2和O， E and D are each independently selected from NR 7b , C(R 6a ) 2 and O,
R 7b如式I中所定义，优选R 7b选自氢、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、硝基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基、
Figure PCTCN2022140921-appb-000020
Figure PCTCN2022140921-appb-000021
所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基任选被1-3个选自卤素、氰基、羟基的取代基所取代；更优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、
Figure PCTCN2022140921-appb-000022
R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene- SO 2 -3-6 membered heterocycloalkyl,
Figure PCTCN2022140921-appb-000020
Figure PCTCN2022140921-appb-000021
The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl such as- SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl optionally replaced by 1-3 members selected from halogen, Substituents of cyano group and hydroxyl group; more preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkane group, -C 1-6 alkylene-3-6 membered cycloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen,
Figure PCTCN2022140921-appb-000022
R 6a、R 6b、R 6c、R 6d、R 6e如式I中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 1选自
Figure PCTCN2022140921-appb-000023
R 1 is selected from
Figure PCTCN2022140921-appb-000023
R 6a、R 6b、R 6c、R 6d、R 6e如式I中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、羟基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 6f所取代； In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from hydrogen, halogen, Cyano, amino, nitro, hydroxyl, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkane base, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, phenyl group; the -CONH 2 , C 1-6 alkyl group, -OC 1-6 alkyl group , -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, benzene The group is optionally substituted by one or more R 6f ;
R 6f如式1中所定义。 R 6f is as defined in Formula 1.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、羟基、-CONH 2；所述-CONH 2任选被一个或多个R 6f所取代； In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from hydrogen, halogen, Cyano, amino, nitro, hydroxyl, -CONH 2 ; the -CONH 2 is optionally substituted by one or more R 6f ;
R 6f如式1中所定义。 R 6f is as defined in Formula 1.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 6f所取代；R 6f如式1中所定义。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from C 1-6 Alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkane Base, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 6f ; R 6f is as defined in formula 1.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 6f所取代；R 6f如式1中所定义。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each is independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 6f ; R 6f is as shown in formula 1 definition.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 6f独立地选自C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代。 In some possible embodiments, in the compound shown in formula I or a pharmaceutically acceptable salt thereof, each R 6f is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkane base, 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally replaced by one or multiple substituents selected from halogen, amino, cyano, nitro, hydroxyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 6f独立地选自卤素、氨基、氰基、硝基、羟基。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 6f is independently selected from halogen, amino, cyano, nitro, and hydroxyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 6f独立地选自卤素、氰基、羟基、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基任选 被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 6f is independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -O -3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, - O-3-6 membered heterocycloalkyl and 3-6 membered cycloalkyl are optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro and hydroxyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 6a彼此间形成＝S、＝O。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 6a form =S, =O with each other.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 6b和R 6c形成＝S、＝O。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 6b and R 6c form =S, =O.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 6d和R 6e形成＝S、＝O。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 6d and R 6e form =S, =O.
在一些可实施方案中，式I所示的化合物或其可药用盐中，R 6d和R 6e与其相连的原子一起3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 6d and R 6e are 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl together with the atoms connected to them; 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1- 6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl Substituents of radicals and phenyl groups are substituted.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 6a彼此间形成3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代。 In some possible embodiments, in the compound represented by formula I or its pharmaceutically acceptable salt, R 6a form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with each other; the 3-8 membered cycloalkane A group or a 3-8 membered heterocycloalkyl group is optionally replaced by one or more groups selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl base replaced.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 6b和R 6c形成3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代。 In some possible embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R 6b and R 6c form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered ring Alkyl or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl Substituents are substituted.
在一些可实施方案，式I所示的化合物或其可药用盐中R 6d和R 6e形成3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代。 In some possible embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R 6d and R 6e form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkane A group or a 3-8 membered heterocycloalkyl group is optionally replaced by one or more groups selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl base replaced.
在一些可实施方案，式I所示的化合物或其可药用盐中R 6d和R 6e形成3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代；优选R 6d和R 6e形成3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基的取代基所取代。 In some possible embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R 6d and R 6e form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkane A group or a 3-8 membered heterocycloalkyl group is optionally replaced by one or more groups selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl Substituted by a group; preferably R 6d and R 6e form a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkyl group or 3-8 membered heterocycloalkyl group is optionally replaced by one or more members selected from halogen, cyanide Substituents of radical, amino, nitro, -CONH 2 , C 1-6 alkyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 1为
Figure PCTCN2022140921-appb-000024
 R1 is
Figure PCTCN2022140921-appb-000024
R 7如式I中所定义，优选R 7为甲基； R 7 is as defined in formula I, preferably R 7 is methyl;
R 3如式I中所定义，优选R 3为甲基、丙基、异丙基、羟基乙基； R 3 is as defined in formula I, preferably R 3 is methyl, propyl, isopropyl, hydroxyethyl;
R 4a、R 4b、R 4c、R 4d、R 4e如式I中所定义，优选R 4a、R 4b、R 4c、R 4d、R 4e为氢。 R 4a , R 4b , R 4c , R 4d , R 4e are as defined in formula I, preferably R 4a , R 4b , R 4c , R 4d , R 4e are hydrogen.
在上述提供的可实施方案的基础上，本公开针对R 2还提供了下述的技术方案。 On the basis of the possible implementation solutions provided above, the present disclosure also provides the following technical solutions for R 2 .
在一些可实施方案，式I所示的化合物或其可药用盐中，R 2为
Figure PCTCN2022140921-appb-000025
R 8、R 9、R 10、R 11如式I中所定义。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 2 is
Figure PCTCN2022140921-appb-000025
R 8 , R 9 , R 10 , R 11 are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 2为
Figure PCTCN2022140921-appb-000026
In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 2 is
Figure PCTCN2022140921-appb-000026
R 8和R 9形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代；优选R 8和R 9形成4元环烷基，所述4元环烷基任选被1-3个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基； R 8 and R 9 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkane Groups such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 are optionally substituted by one or more R 13b ; preferably R 8 and R 9 form a 4-membered cycloalkyl group, and the 4-membered Cycloalkyl is optionally replaced by 1-3 members selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl;
R 10、R 11独立地选自氢、卤素、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、3-6元杂环烷基、5-6元杂芳基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基、3-6元杂环烷基任选被一个或多个R 13a所取代； R 10 and R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , condensed ring formed by 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 hetero A condensed ring formed by a cycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ;
R 12、R 13a、R 13b如式I中所定义。 R 12 , R 13a , R 13b are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 2为
Figure PCTCN2022140921-appb-000027
In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 2 is
Figure PCTCN2022140921-appb-000027
R 8和R 9形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 8 and R 9 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkane Groups such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 are optionally substituted by one or more R 13b ;
R 10和R 11形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13c所取代； R 10 and R 11 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkane Groups such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 are optionally substituted by one or more R 13c ;
R 12、R 13b、R 13c如式I中所定义。 R 12 , R 13b , R 13c are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 2为
Figure PCTCN2022140921-appb-000028
In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 2 is
Figure PCTCN2022140921-appb-000028
Z为N或CR 12； Z is N or CR 12 ;
R 8和R 9形成4-7元环烷基，所述4-7元环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 8 and R 9 form a 4-7 membered cycloalkyl group, and the 4-7 membered cycloalkyl group is optionally selected from one or more halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 Substituted by heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 ; C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13b ;
R 10、R 11独立地选自氢、卤素、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、3-6元杂环烷基、5-6元杂芳基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基、3-6元杂环烷基任选被一个或多个R 13a所取代；R 12、R 13a、R 13b、如式I中所 定义； R 10 and R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , condensed ring formed by 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 hetero A condensed ring formed by a cycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ; R 12 , R 13a , R 13b , as defined in formula I;
R 10、R 11、R 12、R 13a、R 13b如式I中所定义。 R 10 , R 11 , R 12 , R 13a , R 13b are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 2为
Figure PCTCN2022140921-appb-000029
 R2 is
Figure PCTCN2022140921-appb-000029
Z为N或CR 12； Z is N or CR 12 ;
R 9a、R 9b、R 9c、R 9d、R 9e、R 9f各自独立地选自氢、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Elementary heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; said C 1-6 alkyl, halogenated C 1- 6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkane radical, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 optionally replaced by one or more R 13b replace;
R 10选自3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基；所述3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基任选被一个或多个R 13a所取代。 R 10 is selected from condensed rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heteroaryl; the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl A condensed ring formed by a radical, a 5-6 membered heteroaryl is optionally substituted by one or more R 13a .
R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
R 12、R 13a、R 13b如式I中所定义。 R 12 , R 13a , R 13b are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 2为
Figure PCTCN2022140921-appb-000030
 R2 is
Figure PCTCN2022140921-appb-000030
Z为N或CR 12； Z is N or CR 12 ;
R 9a、R 9b、R 9c、R 9d、R 9e、R 9f各自独立地选自氢、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Elementary heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; said C 1-6 alkyl, halogenated C 1- 6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkane radical, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 optionally replaced by one or more R 13b replace;
R 10选自任选被一个或多个R 13a所取代的5-6元杂芳基； R 10 is selected from 5-6 membered heteroaryl optionally substituted by one or more R 13a ;
R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选 被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
R 12、R 13a、R 13b如式I中所定义。 R 12 , R 13a , R 13b are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中R 2选自 In some possible embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R 2 is selected from
Figure PCTCN2022140921-appb-000031
Figure PCTCN2022140921-appb-000031
Z为N或CR 12； Z is N or CR 12 ;
R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
R 10a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13c所取代；R 10b选自C 1-6烷基，所述C 1-6烷基任选被C 3-6环烷基所取代； R 10a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13c ; R 10b is selected from C 1-6 alkyl, The C 1-6 alkyl is optionally substituted by a C 3-6 cycloalkyl;
n、m独立地选自0-3的整数；优选n、m独立地选自0-2的整数；n and m are independently selected from integers of 0-3; preferably n and m are independently selected from integers of 0-2;
R 8、R 9、R 12、R 13a、R 13c如式I中所定义； R 8 , R 9 , R 12 , R 13a , R 13c are as defined in formula I;
R 9a、R 9b、R 9c、R 9d、R 9e、R 9f如前所定义。 R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are as defined above.
在一些可实施方案，式I所示的化合物或其可药用盐中，In some possible embodiments, in a compound represented by formula I or a pharmaceutically acceptable salt thereof,
R 2为
Figure PCTCN2022140921-appb-000032
 R2 is
Figure PCTCN2022140921-appb-000032
Z为N或CR 12； Z is N or CR 12 ;
R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
n选自0-3的整数；n is an integer selected from 0-3;
R 12、R 13a、R 13c、R 9a、R 9b、R 9c、R 9d、R 9e、R 9f如前所定义。 R 12 , R 13a , R 13c , R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are as defined above.
在一些可实施方案，式I所示的化合物或其可药用盐中，Z为N。In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z is N.
在另一些可实施方案，式I所示的化合物或其可药用盐中，Z为CR 12；R 12如式I中所定义。 In other possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z is CR 12 ; R 12 is as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 12选自氢、C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、-CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a；所述C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2任选被1-3个R 12b所取代； In some possible embodiments, in the compound represented by formula I or its pharmaceutically acceptable salt, R 12 is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3 -6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a ; the C 1- 6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally replaced by 1- 3 R 12b replaced;
R 12a、R 12b如式I中所定义。 R 12a and R 12b are as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 12选自氢、卤代C 1-6烷基、羟基取代C 1-6烷基、氰基取代C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、-CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a，R 12a如式I中所定义； In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 12 is selected from hydrogen, halogenated C 1-6 alkyl, hydroxyl substituted C 1-6 alkyl, cyano substituted C 1- 6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a , R 12a is as defined in formula I;
优选R 12选自氢、卤素、C 1-6烷基、卤代C 1-6烷基、羟基取代C 1-6烷基、氰基取代C 1-6烷基、-O-C 1-6烷基。 Preferably R 12 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, -OC 1-6 alkane base.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 12a选自C 1-6烷基、3-6元环烷基、3-6元杂环烷基和氨基；所述C 1-6烷基、3-6元环烷基、3-6元杂环烷基和氨基任选被被一个或多个选自卤素、氰基、羟基、氨基的取代基所取代； In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 12a is selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino; The C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino are optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino ;
优选R 12a选自C 1-6烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、3-6元杂环烷基。 Preferably R 12a is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, 3-6 membered heterocycloalkyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 12b选自卤素、氰基、羟基、氨基、C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳 基和苯基；所述C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基和苯基任选被1-3个R 12c所取代，R 12c如式1中所定义；优选 12b选自卤素、氰基、羟基、氨基、C 1-6烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基和苯基。 In some possible embodiments, in the compound represented by formula I or its pharmaceutically acceptable salt, R 12b is selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, -OC 1-6 alkyl, 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl and phenyl; said C 1-6 alkyl, -OC 1-6 alkyl, 3-6-membered cycloalkyl , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by 1-3 R 12c , R 12c is as defined in formula 1; preferably 12b is selected from halogen, cyano, Hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl substituted C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered Heterocycloalkyl, 5-6 membered heteroaryl and phenyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 12c独立地选自卤素、氨基、氰基、硝基、羟基、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 12c is independently selected from halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, -OC 1-6 Alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 9a、R 9b、R 9c、R 9d、R 9e、R 9f独立地选自氢、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13b所取代，R 13b如式I中所定义；优选R 9a、R 9b、R 9c、R 9d、R 9e、R 9f独立地选自氢、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基；更优选R 9a、R 9b、R 9c、R 9d、R 9e、R 9f独立地选自氢、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基；最优选R 9a、R 9b、R 9c、R 9d、R 9e、R 9f为氢。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are independently selected from hydrogen, halogen, hydroxyl, cyano, Amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl; said C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkane The group is optionally substituted by one or more R 13b , R 13b is as defined in formula I; preferably R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are independently selected from hydrogen, halogen, hydroxyl, Cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl; more preferably R 9a , R 9b , R 9c , R 9d , R 9e , R 9f independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl; most preferably R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are hydrogen.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 13b独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 13b is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, Halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代，R 13a如式I中所定义。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkane The group, -OC 1-6 alkyl is optionally substituted by one or more R 13a , and R 13a is as defined in formula I.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 11选自氢、C 1-6烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基；优选R 11选自氢、甲基。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 11 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkane group; preferably R 11 is selected from hydrogen, methyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 13a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基氨基、二C 1-6烷基氨基、C 1-6烷基、-O-C 1-6烷基；所述氨基、C 1-6烷基、-O-C 1-6烷基任选被1-3个选自C 1-6烷基、氰基、羟基、卤素、-O-C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基、羟基取代的C 1-6烷基的取代基所取代。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, each R 13a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkylamino, di-C 1-6 Alkylamino, C 1-6 alkyl, -OC 1-6 alkyl; said amino, C 1-6 alkyl, -OC 1-6 alkyl are optionally selected from 1-3 C 1-6 Substituents of alkyl, cyano, hydroxyl, halogen, -OC 1-6 alkyl, halogenated C 1-6 alkyl, cyano substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl replaced.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 13a独立地选自氰基、卤素、羟基、C 1-6烷基、-O-C 1-6烷基、甲磺酰基、-CONH 2、-CH 2-SO 2CH 3、3-6元杂环基、氨基。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, each R 13a is independently selected from cyano, halogen, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, Methanesulfonyl, -CONH 2 , -CH 2 -SO 2 CH 3 , 3-6 membered heterocyclic group, amino group.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 13a独立地选自C 1-6烷基、-O-C 1-6烷基、-O-5-6元杂芳基、-O-3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基；所述C 1-6烷基、-O-C 1-6烷基、-O-5-6元杂芳基、-O-3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基任选1-3个选自卤素、氰基、羟基、C 1-6烷基的取代基所取代。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, each R 13a is independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-5-6 Heteroaryl, -O-3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl; the C 1-6 alkyl, -OC 1-6 alkyl , -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl, optionally 1-3 selected from halogen , cyano, hydroxyl, C 1-6 alkyl substituents are substituted.
在一些可实施方案，式I所示的化合物或其可药用盐中，每个R 13a独立地选自 3-6元环烷基、3-6元杂环烷基、5-6元杂芳基；所述3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自C 1-6烷基、氰基、羟基、卤素、-O-C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基所取代。 In some possible embodiments, in the compound represented by formula I or its pharmaceutically acceptable salt, each R 13a is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, Aryl; the 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, and 5-6 membered heteroaryl group are optionally selected from C 1-6 alkyl group, cyano group, hydroxyl group, Halogen, -OC 1-6 alkyl, halogenated C 1-6 alkyl, cyano substituted C 1-6 alkyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 10a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、卤代3-6元环烷基、卤代3-6元杂环烷基。 In some possible embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 10a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl , -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, halogen Substituted 3-6 membered cycloalkyl, halogenated 3-6 membered heterocycloalkyl.
在一些可实施方案，式I所示的化合物或其可药用盐中，R 2为任选取代的
Figure PCTCN2022140921-appb-000033
时，R 1不为
Figure PCTCN2022140921-appb-000034
In some possible embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R is optionally substituted
Figure PCTCN2022140921-appb-000033
, R 1 is not
Figure PCTCN2022140921-appb-000034
在一些可实施方案，式I所示的化合物或其可药用盐中，R 2不为
Figure PCTCN2022140921-appb-000035
In some possible embodiments, in the compound represented by formula I or its pharmaceutically acceptable salt, R 2 is not
Figure PCTCN2022140921-appb-000035
在一些可实施方案，式I所示的化合物或其可药用盐中，R 2不为任选取代的
Figure PCTCN2022140921-appb-000036
In some possible embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R is not optionally substituted
Figure PCTCN2022140921-appb-000036
第二方面，本公开还提供一种如下式所示的化合物或其可药用盐：In the second aspect, the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022140921-appb-000037
Figure PCTCN2022140921-appb-000037
Figure PCTCN2022140921-appb-000038
Figure PCTCN2022140921-appb-000038
Figure PCTCN2022140921-appb-000039
Figure PCTCN2022140921-appb-000039
Figure PCTCN2022140921-appb-000040
Figure PCTCN2022140921-appb-000040
Figure PCTCN2022140921-appb-000041
Figure PCTCN2022140921-appb-000041
Figure PCTCN2022140921-appb-000042
Figure PCTCN2022140921-appb-000042
第三方面，本公开还提供一种如第一方面或第二方面所述的化合物的同位素取代物，优选地，所述的同位素取代为氘原子取代In a third aspect, the present disclosure also provides an isotope substitution of the compound as described in the first aspect or the second aspect, preferably, the isotope substitution is deuterium atom substitution
第四方面，本公开还提供一种药物组合物，包括至少一种治疗有效量的如第一方面、第二方面所述的化合物或其可药用盐，或如第三方面所述的同位素取代物，以及药学上可接受的赋形剂。In the fourth aspect, the present disclosure also provides a pharmaceutical composition, including at least one therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof as described in the first aspect and the second aspect, or the isotope as described in the third aspect Substitutes, and pharmaceutically acceptable excipients.
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐或其同位素取代物。In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds or pharmaceutically acceptable salts or isotope substitutions thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds or pharmaceutically acceptable salts or isotopic substitutions thereof.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
第五方面，本公开还提供第一方面、第二方面所述的化合物或其可药用盐，或第三方面所述的同位素取代物，或第四方面所述药物组合物在制备治疗与NLRP3活性相关的疾病的药物中的用途。In the fifth aspect, the present disclosure also provides the compound described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of therapeutic and Use in medicine for diseases associated with NLRP3 activity.
本公开还提供一种预防和/或治疗与NLRP3活性相关的疾病的方法，其包括向有需要的患者施用治疗有效量的第一方面、第二方面所述的化合物或其可药用盐， 或第三方面所述的同位素取代物，或第四方面所述药物组合物。The present disclosure also provides a method for preventing and/or treating diseases related to NLRP3 activity, which comprises administering a therapeutically effective amount of the compound described in the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof to a patient in need, Or the isotope substitution described in the third aspect, or the pharmaceutical composition described in the fourth aspect.
本公开还提供一种第一方面、第二方面所述的化合物或其可药用盐，或第三方面所述的同位素取代物，或第四方面所述药物组合物，其用于预防或治疗与NLRP3活性相关的疾病。The present disclosure also provides a compound described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the third aspect, or the pharmaceutical composition described in the fourth aspect, which is used for preventing or Treatment of diseases associated with NLRP3 activity.
NLRP3活性相关的疾病包括炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病。Diseases associated with NLRP3 activity include inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
本公开还提供第一方面、第二方面所述的化合物或其可药用盐，或第三方面所述的同位素取代物或第四方面所述药物组合物在制备治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的药物中的用途。The present disclosure also provides the compounds described in the first aspect and the second aspect or pharmaceutically acceptable salts thereof, or the isotope substitutions described in the third aspect or the pharmaceutical composition described in the fourth aspect in the preparation of treating inflammasome-related diseases, Use in medicine for immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
本公开还提供第一方面、第二方面所述的化合物或其可药用盐，或第三方面所述的同位素取代物或第四方面所述药物组合物，其用于治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病。The present disclosure also provides the compound described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the third aspect or the pharmaceutical composition described in the fourth aspect, which are used to treat inflammasome-related Disease, immune disease, inflammatory disease, autoimmune disease and/or autoinflammatory disease.
本公开还提供一种治疗和/或预防炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的方法，其包括向有需要的患者施用治疗有效量的第一方面、第二方面所述的化合物或其可药用盐，或第三方面所述的同位素取代物，或第四方面所述药物组合物。The present disclosure also provides a method of treating and/or preventing inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases, which comprises administering a therapeutically effective amount of The first aspect, the compound of the second aspect or a pharmaceutically acceptable salt thereof, or the isotope substitution of the third aspect, or the pharmaceutical composition of the fourth aspect.
在一些实施方案中，所述炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病可具体选自：自身炎症发热综合征(如冷吡啉相关周期性综合征)、镰状细胞性贫血症、***性红斑狼疮、肝脏相关疾病(如慢性肝病、病毒性肝炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、酒精性肝病)、炎症性关节炎相关疾病(如痛风、软骨钙化病、骨关节炎、类风湿关节炎、急性或慢性关节炎)、肾脏相关疾病(如高草酸尿症、狼疮性肾炎、高血压性肾病、血液透析相关炎症、I型或II型糖尿病和其并发症(如肾病、视网膜病))、神经炎症相关疾病(如脑部感染、急性损伤、多发性硬化症，阿尔茨海默氏病和神经退行性疾病)、心血管及代谢相关紊乱或疾病(如降低心血管疾病风险(CvRR)、动脉粥样硬化、I型和II型糖尿病以及相关并发症、外周动脉疾病(PAD)、急性心力衰竭和高血压)、伤口愈合、疤痕形成、炎性皮肤疾病(例如痤疮、化脓性汗腺炎)、哮喘、结节病、年龄相关性黄斑变性、与癌症有关的疾病/病症(例如骨髓增生性肿瘤、白血病、骨髓增生异常综合症(MDS)、骨髓纤维化、肺癌、结肠癌)。In some embodiments, the inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases may be specifically selected from: autoinflammatory fever syndrome (such as cryopyrin-related cycle syndrome), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease), inflammatory joint Inflammation-related diseases (such as gout, chondrocalcification, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation , type I or type II diabetes and its complications (such as nephropathy, retinopathy), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases) , cardiovascular and metabolic related disorders or diseases (such as cardiovascular disease risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure and hypertension) , wound healing, scarring, inflammatory skin disorders (e.g. acne, hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, cancer-related diseases/conditions (e.g. myeloproliferative neoplasms, leukemia, myeloid Dysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer).
本公开中所述化合物可药用盐可选自无机盐或有机盐。Pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic or organic salts.
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物均在本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯 的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are included in this within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
本公开所述化合物的化学结构中，键
Figure PCTCN2022140921-appb-000043
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022140921-appb-000044
可以为
Figure PCTCN2022140921-appb-000045
或
Figure PCTCN2022140921-appb-000046
或者同时包含
Figure PCTCN2022140921-appb-000047
和
Figure PCTCN2022140921-appb-000048
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2022140921-appb-000049
并未指定构型，即键
Figure PCTCN2022140921-appb-000050
的构型可以为E型或Z型，或者同时包含E和Z两种构型。 In the chemical structures of the compounds described in this disclosure, the bond
Figure PCTCN2022140921-appb-000043
Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond
Figure PCTCN2022140921-appb-000044
can be
Figure PCTCN2022140921-appb-000045
or
Figure PCTCN2022140921-appb-000046
or both
Figure PCTCN2022140921-appb-000047
and
Figure PCTCN2022140921-appb-000048
Two configurations. In the chemical structures of the compounds described in this disclosure, the bond
Figure PCTCN2022140921-appb-000049
configuration is not specified, i.e. the key
Figure PCTCN2022140921-appb-000050
The configuration of can be E type or Z type, or contain both E and Z configurations.
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。The compounds and intermediates of the present disclosure may also exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine, lactam-lactim isomerization . An example of a lactam-lactim equilibrium is between A and B as shown below.
Figure PCTCN2022140921-appb-000051
Figure PCTCN2022140921-appb-000051
所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 The present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍 的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound of formula (I). Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。 "Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
术语解释Terminology Explanation
“药物组合物”表示含有一种或多种本文所述化合物或其可药用盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
“可药用赋形剂”包括但不限于任何批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。"Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。An "effective amount" or "therapeutically effective amount" as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氧代、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基或3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、氰基或氨基所取代。 "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl and its various branched isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or Heterocycloalkyl is optionally substituted with halo, hydroxy, nitro, cyano or amino.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃基团，环烷基环包含3至20个碳原子，优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、并环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独 立地选自卤素、羟基、氧代、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基或3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、氰基或氨基所取代。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; multicyclic cycloalkyls include spiro Cycloalkyls of rings, parallel rings and bridged rings. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo , cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl Or heterocycloalkyl is optionally substituted with halo, hydroxy, nitro, cyano or amino.
术语“杂环烷基”指饱和或部分不饱和单环或多环环状烃基团，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子。“杂环烷基”非限制性实例包括： The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include:
Figure PCTCN2022140921-appb-000052
Figure PCTCN2022140921-appb-000052
Figure PCTCN2022140921-appb-000053
等等。
Figure PCTCN2022140921-appb-000053
etc.
所述杂环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为杂环烷基，其非限制性实例包括：The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
Figure PCTCN2022140921-appb-000054
等。
Figure PCTCN2022140921-appb-000054
wait.
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基或3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、氰基或氨基所取代。 Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally Substituted by halogen, hydroxy, nitro, cyano or amino.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至7元环烷基或3至7元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、氰基或氨基所取代。 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C -6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally Halogen, hydroxy, nitro, cyano or amino substituted.
同理，“环烷氧基”、“杂环烷氧基”同上述“烷氧基”定义。Similarly, "cycloalkoxy" and "heterocycloalkoxy" have the same definition as the above-mentioned "alkoxy".
术语“烷硫基”指-S-(烷基)，其中烷基的定义如上所述。烷硫基的非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基。烷硫基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基、3至6元环烷氧基、3至6元杂环烷氧基、C 1-6烷硫基、3至6元环烷硫基、3至6元杂环烷硫基，所述烷氧基、环烷基、杂环烷基、环烷氧基、杂环氧基、烷硫基、环烷硫基、杂环烷硫基任选被卤素、羟基、氰基或氨基所取代。 The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio. Alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from C 1-6 alkoxy, 3 to 6 membered cycloalkane group, 3 to 6 membered heterocycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 1-6 alkylthio, 3 to 6 membered cycloalkylthio, 3 to 6 Member heterocycloalkylthio, the alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio are optionally replaced by halogen , Hydroxy, cyano or amino.
同理，“环烷硫基”、“杂环烷硫基”同上述“烷硫基”定义。Similarly, "cycloalkylthio" and "heterocycloalkylthio" have the same definition as the above-mentioned "alkylthio".
“一价基团”是指一个化合物从“形式上”消除一个单价的原子或基团。“亚基”或“二价基团”则是指化合物从“形式上”消除两个单价或一个双价形成的原子或原子团。"Monovalent group" means that a compound is "formally" eliminated from a monovalent atom or group. "Subunit" or "divalent group" refers to a compound formed by "formally" eliminating two monovalent or one divalent atoms or atomic groups.
术语“亚烷基”表示烷烃分子中去除2个氢原子后余下的部分，包括1至20个碳原子的直链和支链亚基团。含有1至6个碳原子的亚烷基，非限制性实施例包括亚甲基(-CH 2-)、亚乙基(如-CH 2CH 2-或-CH(CH 3)-)。如无特殊说明，亚烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氰基、氨基、C 1-6烷基或C 1-6烷氧基。 The term "alkylene" means what remains of an alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms. An alkylene group having 1 to 6 carbon atoms, non-limiting examples include methylene (-CH 2 -), ethylene (eg -CH 2 CH 2 - or -CH(CH 3 )-). Unless otherwise specified, the alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen , hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.
同理，“亚烷氧基”、“亚烯基”、“亚烯氧基”、“亚环烷基”、“亚杂环烷基”的定义如“亚烷基”。Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene", and "heterocycloalkylene" are the same as "alkylene".
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated π-electron system, such as benzene base and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2022140921-appb-000055
Figure PCTCN2022140921-appb-000055
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、3至6元环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、3至6元环烷氧基、3至6元杂环烷氧基、3至8元环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基或C 1-6烷氧基。 Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C1-6 Alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 to 6-membered cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 6-membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-8 membered cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected from one or more halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。 其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基(oxazolyl)、异噁唑基(isoxazolyl)、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、***基、吲唑基、苯并咪唑基、
Figure PCTCN2022140921-appb-000056
等。 The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl,
Figure PCTCN2022140921-appb-000056
wait.
所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2022140921-appb-000057
Figure PCTCN2022140921-appb-000057
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氰基、氨基、C 1-6烷基或C 1-6烷氧基。 Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C alkane group or C 1-6 alkoxy group.
术语“螺环”指两环共用一个原子的化合物。螺环烷基的非限制性实例包括：The term "spiro" refers to a compound in which two rings share one atom. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2022140921-appb-000058
Figure PCTCN2022140921-appb-000058
术语“并环”指两个或两个以上环通过共用两个相邻的原子并合而成的化合物。并环烷基的非限制性实例包括：The term "merged ring" refers to a compound formed by combining two or more rings by sharing two adjacent atoms. Non-limiting examples of cycloalkyl groups include:
Figure PCTCN2022140921-appb-000059
Figure PCTCN2022140921-appb-000059
术语“桥环”指两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的结构。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged ring" refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2022140921-appb-000060
Figure PCTCN2022140921-appb-000060
术语“杂环”指构成环的原子除碳原子外还有其他原子，其包括杂环烷基和杂芳环。The term "heterocyclic ring" refers to atoms other than carbon atoms that make up the ring, and includes heterocycloalkyl and heteroaryl rings.
术语“羟基”指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代”指＝O取代基。The term "oxo" refers to a =O substituent.
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。当取代基是酮或氧代(即，＝O)时，则原子上有两个(2个)氢被替代。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. When a substituent is keto or oxo (ie, =0), then two (2) hydrogens on the atom are replaced.
具体实施方式Detailed ways
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.
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)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is carried out with Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is four Methylsilane (TMS).
MS的测定用Shimadzu 2010 Mass Spectrometer或Agilent 6110A MSD质谱仪。MS was determined by Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱或Gilson-281 Waters Xbridge 150*25mm色谱柱或Gilson-281 Waters Xbridge 150*25mm色谱柱或Gilson-281 Phenomenex luna C18 250*50mm色谱柱)。Determination of HPLC using Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatography (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column or Gilson-281 Waters Xbridge 150 *25mm column or Gilson-281 Waters Xbridge 150*25mm column or Gilson-281 Phenomenex luna C18 250*50mm column).
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱。Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mm I.D., 3um, Chiralcel OD-3 100×4.6mm I.D., 3μm, ChiralCel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um column.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。The chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 Kinase average inhibition rate and IC 50 value were measured with NovoStar microplate reader (BMG Company, Germany).
本公开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 disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent The ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
实施例Example
实施例1Example 1
((3-氰基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)磺酰基)((1,2,3,5,6,7-六氢-s-indacen-4-基)氨甲酰基)胺钠盐((3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl)((1,2,3,5, 6,7-Hexahydro-s-indacen-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000061
Figure PCTCN2022140921-appb-000061
第一步first step
于室温，向1L反应瓶中加入化合物1a(50g,214mmol)、乙醇(500mL)、丙二腈(9.20g，139mmol)、二乙胺(16.6mL,160.8mmol)、硫单质(5.48g，161mmol)。氮气氛围下，升温至70℃，搅拌2小时。冷却至室温，过滤，收集滤饼并真空干燥，得到化合物1b(33g,产率：75.8％)。LC-MS m/z(ESI):314.1(M+H) +。 At room temperature, add compound 1a (50g, 214mmol), ethanol (500mL), malononitrile (9.20g, 139mmol), diethylamine (16.6mL, 160.8mmol), sulfur element (5.48g, 161mmol) into a 1L reaction flask ). Under a nitrogen atmosphere, the temperature was raised to 70° C. and stirred for 2 hours. Cool to room temperature, filter, collect the filter cake and dry in vacuo to obtain compound 1b (33 g, yield: 75.8%). LC-MS m/z (ESI): 314.1 (M+H) + .
第二步second step
于室温，向500mL的反应瓶中依次加入溴化铜(4.28g,19.1mmol)、亚硝酸叔丁酯(1.65g,16.0mmol)、乙腈(50mL)。氮气氛下，升温至65℃，加入化合物1b(5.0g,16.0mmol)，搅拌2小时。降至室温，加入水(100mL)，过滤，滤液用乙酸乙酯 (20mL×3)萃取。合并有机相，干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2，10％乙酸乙酯/石油醚)纯化，得到化合物1c(2.6g,产率：36％)。LC-MS m/z(ESI):378.0(M+H) +, At room temperature, copper bromide (4.28 g, 19.1 mmol), tert-butyl nitrite (1.65 g, 16.0 mmol), and acetonitrile (50 mL) were successively added into a 500 mL reaction flask. Under a nitrogen atmosphere, the temperature was raised to 65°C, compound 1b (5.0 g, 16.0 mmol) was added, and stirred for 2 hours. Cool down to room temperature, add water (100 mL), filter, and extract the filtrate with ethyl acetate (20 mL×3). The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (SiO 2 , 10% ethyl acetate/petroleum ether) to obtain compound 1c (2.6 g, yield: 36 %). LC-MS m/z(ESI):378.0(M+H) + ,
第三步third step
于室温，向1L单口瓶中加入化合物1c(23.0g,61.0mmol)、三(二亚苄基丙酮)二钯(2.79g,3.05mmol)、N,N-二异丙基乙胺(20.2mL,122mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(3.53g,6.10mmol)、二氧六环(300mL)和苄硫醇(15.1g,121.9mmol)。在氮气氛下，升温至100℃，搅拌2小时。降至室温，加入二氯甲烷(500mL)和水(300mL)，水相用二氯甲烷(200mL×3)萃取，收集有机相，减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2，10％乙酸乙酯/石油醚)纯化，得到化合物1d(25g,产率：97％)。 At room temperature, compound 1c (23.0g, 61.0mmol), tris(dibenzylideneacetone)dipalladium (2.79g, 3.05mmol), N,N-diisopropylethylamine (20.2mL , 122mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (3.53g, 6.10mmol), dioxane (300mL) and benzyl mercaptan (15.1g, 121.9mmol) . Under a nitrogen atmosphere, the temperature was raised to 100° C. and stirred for 2 hours. Cool down to room temperature, add dichloromethane (500mL) and water (300mL), extract the aqueous phase with dichloromethane (200mL×3), collect the organic phase, concentrate under reduced pressure, and use silica gel column chromatography to elute the residue from the system ( SiO 2 , 10% ethyl acetate/petroleum ether) to obtain compound 1d (25 g, yield: 97%).
1H NMR(400MHz,DMSO-d 6)δ7.42-7.21(m,10H),5.12(s,2H),4.59(s,2H),4.24(s,2H),3.68(s,2H),2.65(t,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.42-7.21(m,10H),5.12(s,2H),4.59(s,2H),4.24(s,2H),3.68(s,2H), 2.65(t,2H).
第四步the fourth step
于室温，向500mL单口瓶中依次加入化合物1d(25.0g,59.4mmol)、乙腈(250mL)。降温至0℃，加入1,3-二氯-5,5-二甲基海因(23.4g,118.9mmol)、水(6mL)和醋酸(6mL)。搅拌2小时，减压浓缩，加入乙酸乙酯(200mL)和水(100mL)，有机相干燥，过滤，减压浓缩，得到化合物1f(25g，粗品)，直接用于下一步。At room temperature, compound 1d (25.0 g, 59.4 mmol) and acetonitrile (250 mL) were sequentially added into a 500 mL one-necked bottle. Cool down to 0°C, add 1,3-dichloro-5,5-dimethylhydantoin (23.4g, 118.9mmol), water (6mL) and acetic acid (6mL). Stir for 2 hours, concentrate under reduced pressure, add ethyl acetate (200 mL) and water (100 mL), dry the organic phase, filter, and concentrate under reduced pressure to obtain compound 1f (25 g, crude product), which is directly used in the next step.
第五步the fifth step
于室温，在500mL三口瓶中加入化合物1f(10.0g,25.2mmol)、7M氨气的甲醇溶液(100mL，700mmol)。搅拌12小时，减压浓缩。加入甲醇(100mL)打浆，过滤，用甲醇(200mL)洗涤滤饼，收集滤饼，得到化合物1g(4.4g,产率：46.3％)。LC-MS m/z(ESI):378.2(M+H) +。 At room temperature, compound 1f (10.0 g, 25.2 mmol) and 7M methanolic ammonia solution (100 mL, 700 mmol) were added into a 500 mL three-neck flask. Stir for 12 hours and concentrate under reduced pressure. Methanol (100 mL) was added to make a slurry, filtered, the filter cake was washed with methanol (200 mL), and the filter cake was collected to obtain compound 1g (4.4 g, yield: 46.3%). LC-MS m/z (ESI): 378.2 (M+H) + .
第六步step six
于室温，向100mL单口瓶依次加入化合物1g(4.00g，10.6mmol)、溴化氢醋酸溶液(5mL,33％)、醋酸(15mL)，搅拌2小时。减压浓缩，加入甲醇(100mL)，缓慢加入碳酸钠固体至pH＝9，过滤，滤液减压浓缩，经反向柱C18(水/乙腈，氨水体系)纯化，得到化合物1h(600mg,产率：23.3％)。LC-MS m/z(ESI):244.0(M+H) +。 At room temperature, 1 g of compound (4.00 g, 10.6 mmol), hydrobromide acetic acid solution (5 mL, 33%), and acetic acid (15 mL) were sequentially added into a 100 mL single-necked bottle, and stirred for 2 hours. Concentrate under reduced pressure, add methanol (100mL), slowly add solid sodium carbonate to pH=9, filter, concentrate the filtrate under reduced pressure, and purify by reverse column C18 (water/acetonitrile, ammonia water system) to obtain compound 1h (600mg, yield : 23.3%). LC-MS m/z (ESI): 244.0 (M+H) + .
第七步step seven
向100mL单口瓶中加入化合物1h(2.00g,8.22mmol)、甲醇(20mL)、醋酸(2.4mL,41.1mmol)，搅拌10分钟，加入多聚甲醛(50mg)和氰基硼氢化钠(1.55g,24.7mmol)，室温搅拌1小时。加入7M氨的甲醇溶液(2mL)，减压浓缩，残余物经反向柱C18(水/乙腈，氨水体系)纯化，得到化合物1i(80mg,产率：3.8％)。LC-MS m/z(ESI):258.0(M+H) +。 Add compound 1h (2.00g, 8.22mmol), methanol (20mL), acetic acid (2.4mL, 41.1mmol) into a 100mL single-necked bottle, stir for 10 minutes, add paraformaldehyde (50mg) and sodium cyanoborohydride (1.55g , 24.7mmol), stirred at room temperature for 1 hour. 7M methanolic ammonia solution (2 mL) was added, concentrated under reduced pressure, and the residue was purified by reverse column C18 (water/acetonitrile, ammonia water system) to obtain compound 1i (80 mg, yield: 3.8%). LC-MS m/z (ESI): 258.0 (M+H) + .
第八步eighth step
0℃，向10mL单口瓶中加入化合物1i(30mg,0.12mmol)、四氢呋喃(2mL)、叔丁醇钠(11.76mg,0.122mmol)。升至室温，搅拌30分钟，加入1j(23mg,0.12mmol)，搅拌4小时。减压浓缩，残余物经制备液相色谱法(色谱柱：Waters，Xbridge 250*19mm，10μm；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-10min 50-70％B；flow 25ml/min)纯化，得到粗品，粗品经钠离子交换树脂交换后，得到化合物1(13.63mg,产率：23.7％)。At 0°C, compound 1i (30 mg, 0.12 mmol), tetrahydrofuran (2 mL), and sodium tert-butoxide (11.76 mg, 0.122 mmol) were added to a 10 mL one-necked bottle. Warm up to room temperature, stir for 30 minutes, add 1j (23 mg, 0.12 mmol), and stir for 4 hours. Concentrated under reduced pressure, the residue was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 50-70% B ; flow 25ml/min) was purified to obtain a crude product, which was exchanged with a sodium ion exchange resin to obtain compound 1 (13.63 mg, yield: 23.7%).
1H NMR(400MHz,DMSO-d 6)δ7.53(s,1H),6.78(s,1H),3.50(s,2H),2.75(t,4H),2.70-2.62(m,8H),2.35(s,3H),1.94-1.87(m,4H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.53(s,1H),6.78(s,1H),3.50(s,2H),2.75(t,4H),2.70-2.62(m,8H), 2.35(s,3H),1.94-1.87(m,4H).
LC-MS m/z(ESI):479.0(M+Na) +。 LC-MS m/z (ESI): 479.0 (M+Na) + .
实施例2Example 2
((1,2,3,5,6,7-六氢-s-indacen-4-基)氨基甲酰基)((6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)磺酰基)胺钠盐((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-methyl-4,5,6,7-tetrahydrothieno[2 ,3-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000062
Figure PCTCN2022140921-appb-000062
第一步first step
室温，在1L单口瓶中，加入化合物2a(31.0g,251.7mmol)、四氢呋喃(80mL)、硼烷二甲基硫醚络合物(252mL,504mmol)。氮气氛围下，升温至80℃，搅拌过夜。冷却至室温，滴加6M盐酸甲醇溶液(150mL,900mmol)，减压浓缩，残余物用二氯甲烷(300mL)打浆过滤，滤饼减压浓缩，得到化合物2b(35g,213.8mmol,产率：84.9％)。LC-MS:MS(ESI):m/z 128.2(M+H) +。 At room temperature, compound 2a (31.0 g, 251.7 mmol), tetrahydrofuran (80 mL), and borane dimethyl sulfide complex (252 mL, 504 mmol) were added to a 1 L single-necked bottle. Under a nitrogen atmosphere, the temperature was raised to 80 °C and stirred overnight. Cool to room temperature, add 6M hydrochloric acid methanol solution (150mL, 900mmol) dropwise, concentrate under reduced pressure, the residue is slurried and filtered with dichloromethane (300mL), and the filter cake is concentrated under reduced pressure to obtain compound 2b (35g, 213.8mmol, yield: 84.9%). LC-MS: MS (ESI): m/z 128.2 (M+H) + .
第二步second step
室温，在1L的单口瓶中加入化合物2b(32.0g,251.6mmol)和二氯甲烷(300mL)、三乙胺(88mL,633mmol)和二碳酸二叔丁酯(64mL,279mmol)。搅拌5小时。 倒入水(400mL)中，二氯甲烷(250mL×3)萃取，合并有机相，饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到化合物2c(41g,产率：72％)。LC-MS:MS(ESI):m/z 213.2(M-55+CH 3CN) +。 At room temperature, compound 2b (32.0 g, 251.6 mmol), dichloromethane (300 mL), triethylamine (88 mL, 633 mmol) and di-tert-butyl dicarbonate (64 mL, 279 mmol) were added into a 1 L one-necked bottle. Stir for 5 hours. Pour into water (400mL), extract with dichloromethane (250mL×3), combine the organic phases, wash with saturated brine (300mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 2c (41g, yield : 72%). LC-MS: MS (ESI): m/z 213.2 (M-55+CH 3 CN) + .
第三步third step
室温，在500mL单口瓶中依次加入化合物2c(82.0g,360.8mmol)、多聚甲醛(20.0g,190.4mmol)、对甲苯磺酸一水合物(1.04g,5.46mmol)和甲苯(200mL)。然后连接分水器回流管，氮气氛下，120℃搅拌2小时。减压浓缩，加入乙酸乙酯(200mL)，过滤，将滤液倒入水(500mL)中，用乙酸乙酯(400mL×3)萃取。有机相用饱和食盐水(400mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗产品。残余物用硅胶色谱法以洗脱体系(SiO 2,0-10％乙酸乙酯/石油醚)得到化合物2d(70g，产率：81.1％)。 At room temperature, compound 2c (82.0 g, 360.8 mmol), paraformaldehyde (20.0 g, 190.4 mmol), p-toluenesulfonic acid monohydrate (1.04 g, 5.46 mmol) and toluene (200 mL) were sequentially added into a 500 mL one-necked bottle. Then connect the return pipe of the water separator, and stir at 120° C. for 2 hours under nitrogen atmosphere. Concentrate under reduced pressure, add ethyl acetate (200 mL), filter, pour the filtrate into water (500 mL), and extract with ethyl acetate (400 mL×3). The organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The residue was chromatographed on silica gel with eluent system (SiO 2 , 0-10% ethyl acetate/petroleum ether) to obtain compound 2d (70 g, yield: 81.1%).
1H NMR(400MHz,DMSO-d 6)δ7.36(d,1H),6.85(d,1H),4.54(s,2H),3.58(t,2H),2.63(t,2H),1.42(m,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ7.36(d,1H),6.85(d,1H),4.54(s,2H),3.58(t,2H),2.63(t,2H),1.42( m, 9H).
第四步the fourth step
于室温，向500mL单口瓶中依次加入化合物2d(35g,117mmol)和4M盐酸1,4-二氧六环溶液(250mL)，搅拌2小时。减压浓缩。残余物用乙酸乙酯(400mL)打浆，过滤，得到化合物2e(20.5g,产率：99.7％)。At room temperature, compound 2d (35 g, 117 mmol) and 4M hydrochloric acid 1,4-dioxane solution (250 mL) were sequentially added into a 500 mL one-necked bottle, and stirred for 2 hours. Concentrate under reduced pressure. The residue was slurried with ethyl acetate (400 mL) and filtered to obtain compound 2e (20.5 g, yield: 99.7%).
1H NMR(400MHz,DMSO-d 6)δ9.71(s,2H),7.48(d,1H),6.93(d,1H),4.31(s,2H),3.35-3.32(m,2H),2.88(t,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ9.71(s,2H),7.48(d,1H),6.93(d,1H),4.31(s,2H),3.35-3.32(m,2H), 2.88(t,2H).
LC-MS:MS(ESI):m/z 140.2(M+H) +。 LC-MS: MS (ESI): m/z 140.2 (M+H) + .
第五步the fifth step
于室温，向50mL单口瓶中依次加入化合物2e(1.00g,5.69mmol)和三乙胺(632mg，6.26mmol)，并溶解于四氢呋喃(17mL)中。降到0℃后，缓慢加入乙酰氯(491mg,6.26mmol)，在室温，搅拌1小时。过滤，滤液加入乙酸乙酯(30mL)和水(15mL)，有机相干燥，过滤，滤液减压浓缩，残余物用硅胶色谱法以洗脱体系(SiO 2,0-10％乙酸乙酯/石油醚)纯化，得到化合物2f(1.03g，产率：99.8％)。LC-MS:MS(ESI):m/z 182.1(M+H) +。 At room temperature, compound 2e (1.00 g, 5.69 mmol) and triethylamine (632 mg, 6.26 mmol) were sequentially added into a 50 mL one-necked bottle, and dissolved in tetrahydrofuran (17 mL). After cooling down to 0°C, acetyl chloride (491mg, 6.26mmol) was added slowly, and stirred at room temperature for 1 hour. After filtration, ethyl acetate (30 mL) and water (15 mL) were added to the filtrate, the organic phase was dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel to elute the system (SiO 2 , 0-10% ethyl acetate/petroleum ether) to obtain compound 2f (1.03 g, yield: 99.8%). LC-MS: MS (ESI): m/z 182.1 (M+H) + .
第六步step six
于室温，在250mL的单口瓶中将化合物2f(2.4g，13.241mmol)溶解于二氯甲烷(60mL)中，加入醋酸酐(3.8mL,40.1mmol)。温度降至0℃，加入浓硫酸(0.7mL,14mmol)，室温搅拌12小时。减压浓缩，加入***(100mL)，过滤，滤饼用反向柱C18(水/乙腈，盐酸体系)纯化，到化合物2g(3.42g，产率：98.8％)。Compound 2f (2.4 g, 13.241 mmol) was dissolved in dichloromethane (60 mL) in a 250 mL one-necked bottle at room temperature, and acetic anhydride (3.8 mL, 40.1 mmol) was added. The temperature was lowered to 0°C, concentrated sulfuric acid (0.7 mL, 14 mmol) was added, and stirred at room temperature for 12 hours. Concentrate under reduced pressure, add diethyl ether (100 mL), filter, and the filter cake is purified by reverse column C18 (water/acetonitrile, hydrochloric acid system) to obtain compound 2g (3.42 g, yield: 98.8%).
1H NMR(400MHz,DMSO-d 6)δ6.84-6.83(m,1H),4.62-4.58(m,2H),3.68-3.63(m,2H),2.68-2.52(m,2H),2.09-2.06(m,3H)。 1 H NMR (400MHz,DMSO-d 6 )δ6.84-6.83(m,1H),4.62-4.58(m,2H),3.68-3.63(m,2H),2.68-2.52(m,2H),2.09 -2.06(m,3H).
第七步step seven
于室温，在250mL单口瓶中依次加入化合物2g(8.00g,30.6mmol)，并溶解 于二氯甲烷(80mL)。氮气氛下，加入五氯化磷(8.67g,41.6mmol)，室温搅拌20小时。倒入冰中，待恢复到室温后，加入二氯甲烷(200mL)，有机相干燥，过滤，滤液减压浓缩，得到产物2h(8.56g,粗品)，直接用于下一步。At room temperature, compound 2g (8.00g, 30.6mmol) was successively added into a 250mL one-necked bottle, and dissolved in dichloromethane (80mL). Under a nitrogen atmosphere, phosphorus pentachloride (8.67 g, 41.6 mmol) was added, and stirred at room temperature for 20 hours. Pour into ice, and after returning to room temperature, add dichloromethane (200 mL), dry the organic phase, filter, and concentrate the filtrate under reduced pressure to obtain the product 2h (8.56 g, crude product), which is directly used in the next step.
第八步eighth step
于室温，将化合物2h(12g，42.9mmol)溶解在二氯甲烷(10mL)中，并缓慢滴加到7M氨甲醇溶液(300mL，2100mmol)，搅拌1小时。过滤，用甲醇(10mL)洗涤滤饼，收集滤饼得到产物2i(10g，产率:89.6％)。LC-MS:MS(ESI):m/z 261.0(M+H) +。 Compound 2h (12 g, 42.9 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and slowly added dropwise to 7M ammonia in methanol solution (300 mL, 2100 mmol), and stirred for 1 hour. After filtration, the filter cake was washed with methanol (10 mL), and the filter cake was collected to obtain product 2i (10 g, yield: 89.6%). LC-MS: MS (ESI): m/z 261.0 (M+H) + .
第九步Ninth step
于室温，向100mL单口瓶中依次加入化合物2i(2.00g,7.68mmol)，20％的氢氧化钠的水溶液(10mL)，80℃，搅拌3小时。用2M的稀盐酸溶液调节pH＝7。向反应液中加入二氯甲烷/甲醇(10/1,20mL)的混合溶液萃取，有机相干燥，减压浓缩，得到产物2j(1.4g,产率：83.6％)。 1H NMR(400MHz,DMSO-d 6)δ7.59(s,2H),7.30(s,1H),3.91(s,2H),3.23(s,2H),2.95(t,2H),2.60-2.59(m,1H)。 At room temperature, compound 2i (2.00 g, 7.68 mmol) and 20% aqueous sodium hydroxide solution (10 mL) were successively added into a 100 mL one-necked bottle, stirred at 80° C. for 3 hours. Adjust pH=7 with 2M dilute hydrochloric acid solution. A mixed solution of dichloromethane/methanol (10/1, 20 mL) was added to the reaction solution for extraction, the organic phase was dried and concentrated under reduced pressure to obtain product 2j (1.4 g, yield: 83.6%). 1 H NMR (400MHz,DMSO-d 6 )δ7.59(s,2H),7.30(s,1H),3.91(s,2H),3.23(s,2H),2.95(t,2H),2.60- 2.59(m,1H).
第十步tenth step
于室温，向25mL单口瓶加入化合物2j(375mg,1.72mmol)、甲醇(3mL)、多聚甲醛(63mg,0.17mmol)、乙酸(0.2mL，3.4mmol)和氰基硼氢化钠(324mg,5.15mmol)，搅拌2小时。加入7M氨甲醇溶液(2mL)，减压浓缩。残余物经反相C18(水/乙腈，氨水体系)纯化，得到化合物2k(180mg,产率：45.1％)。LC-MS:MS(ESI):m/z 233.0(M+H) +。 At room temperature, compound 2j (375mg, 1.72mmol), methanol (3mL), paraformaldehyde (63mg, 0.17mmol), acetic acid (0.2mL, 3.4mmol) and sodium cyanoborohydride (324mg, 5.15 mmol), stirred for 2 hours. 7M ammonia in methanol solution (2 mL) was added, and concentrated under reduced pressure. The residue was purified by reverse phase C18 (water/acetonitrile, ammonia water system) to obtain compound 2k (180 mg, yield: 45.1%). LC-MS: MS (ESI): m/z 233.0 (M+H) + .
第十一步Eleventh step
于室温，在50mL单口瓶中加入化合物2k(150mg,0.646mmol)、四氢呋喃(5mL)，降温至0℃，加入叔丁醇钠(65mg,0.68mmol)，室温搅拌40分钟。再加入1j(128mg,0.646mmol)，搅拌3小时。减压浓缩，残余物经制备级液相色谱法(色谱柱：Waters，Xbridge 250*19mm，10μm；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-10min 40-65％B；flow 25ml/min)纯化得到粗品，粗品经钠离子交换树脂交换后，得到化合物2(114mg,收率：38.9％)。At room temperature, compound 2k (150mg, 0.646mmol) and tetrahydrofuran (5mL) were added to a 50mL single-necked bottle, cooled to 0°C, sodium tert-butoxide (65mg, 0.68mmol) was added, and stirred at room temperature for 40 minutes. 1j (128mg, 0.646mmol) was added and stirred for 3 hours. Concentrated under reduced pressure, the residue was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 40-65% B; flow 25ml/min) was purified to obtain the crude product, which was exchanged with sodium ion exchange resin to obtain compound 2 (114 mg, yield: 38.9%).
1H NMR(400MHz,DMSO-d 6)δ7.06(s,1H),6.77(s,1H),3.47(s,2H),2.76(m,4H),2.67(m,4H),2.58(m,4H),2.34(s,3H),2.03-1.81(m,4H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.06(s,1H),6.77(s,1H),3.47(s,2H),2.76(m,4H),2.67(m,4H),2.58( m, 4H), 2.34(s, 3H), 2.03-1.81(m, 4H).
LC-MS:MS(ESI):m/z 432.0(M+H) +。 LC-MS: MS (ESI): m/z 432.0 (M+H) + .
实施例3Example 3
N-(5-(2-氰基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-磺酰胺N-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5,6,7- Tetrahydrofuro[3,2-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000063
Figure PCTCN2022140921-appb-000063
第一步first step
在-78℃，向反应瓶中加入化合物3a(10g,65.12mmol)和四氢呋喃(100mL)，逐滴滴加,2.5M正丁基锂(28.6mL,71.63mmol)，搅拌1小时。将缓冲装置和尾气吸收装置接入反应体系后，向反应液中通入SO 2气体，保持温度在-30℃以下，搅拌0.5小时。反应液缓慢升温至室温，过滤，收集滤饼。滤饼用二氯甲烷(100mL)溶解后降温至0℃，加入N-氯代丁二酰亚胺(9.56g,71.63mmol)，室温下搅拌1小时，向反应液中加水(50mL)，二氯甲烷萃取(30mL×3)。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物3b(11g,产率:67％)。LC-MS m/z(ESI):251.8(M+H) +。 At -78°C, compound 3a (10 g, 65.12 mmol) and tetrahydrofuran (100 mL) were added dropwise to the reaction flask, 2.5M n-butyl lithium (28.6 mL, 71.63 mmol) was added dropwise, and stirred for 1 hour. After connecting the buffer device and tail gas absorption device into the reaction system, pass SO2 gas into the reaction solution, keep the temperature below -30°C, and stir for 0.5 hours. The reaction solution was slowly warmed to room temperature, filtered, and the filter cake was collected. The filter cake was dissolved in dichloromethane (100 mL) and cooled to 0°C, N-chlorosuccinimide (9.56 g, 71.63 mmol) was added, stirred at room temperature for 1 hour, water (50 mL) was added to the reaction solution, and two Chloromethane extraction (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3b (11 g, yield: 67%). LC-MS m/z (ESI): 251.8 (M+H) + .
第二步second step
于室温，向反应瓶中加入化合物3b(15g,59.51mmol)和吡啶(150mL)，降温至0℃，加入双-(4-甲氧基苄基)-胺(16.84g,65.46mmol)。恢复至室温搅拌12小时。减压浓缩，残余物用硅胶色谱法以洗脱体系(SiO 2,10-50％乙酸乙酯/石油醚)纯化，得到化合物3c(5g,产率:17.7％)。 At room temperature, compound 3b (15g, 59.51mmol) and pyridine (150mL) were added to the reaction flask, cooled to 0°C, and bis-(4-methoxybenzyl)-amine (16.84g, 65.46mmol) was added. Return to room temperature and stir for 12 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with an eluent system (SiO 2 , 10-50% ethyl acetate/petroleum ether) to obtain compound 3c (5 g, yield: 17.7%).
1H NMR(400MHz,CDCl 3)δ8.40(d,1H),7.39(dd,1H),7.23(d,1H),7.12-7.06(m,4H),6.78-6.72(m,4H),4.41(s,4H),3.76(s,6H).LC-MS m/z(ESI):472.9(M+H) +。 1 H NMR (400MHz, CDCl 3 )δ8.40(d,1H),7.39(dd,1H),7.23(d,1H),7.12-7.06(m,4H),6.78-6.72(m,4H), 4.41 (s, 4H), 3.76 (s, 6H). LC-MS m/z (ESI): 472.9 (M+H) + .
第三步third step
于室温，向反应瓶中加入化合物3c(5g,10.57mmol)和N,N-二甲基甲酰胺(50mL)，搅拌均匀后依次加入三乙胺(7.4mL,52.86mmol)、甲酸(2.43g,52.86mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.43g,0.53mmol)。氮气氛下，70℃搅拌3 小时。反应液减压浓缩后加入水(100mL)，用乙酸乙酯(100mL)萃取，有机相用无水硫酸钠干燥后，减压浓缩。残余物用硅胶柱色谱法以洗脱体系(SiO 2,40-50％乙酸乙酯/石油醚)纯化，得到产物3d(3g,产率:64.7％)。LC-MS m/z(ESI):439.1(M+H) +。 At room temperature, add compound 3c (5g, 10.57mmol) and N,N-dimethylformamide (50mL) into the reaction flask, stir well and then add triethylamine (7.4mL, 52.86mmol), formic acid (2.43g , 52.86mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.43g, 0.53mmol). Under nitrogen atmosphere, stir at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, extracted with ethyl acetate (100 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system (SiO 2 , 40-50% ethyl acetate/petroleum ether) to give product 3d (3 g, yield: 64.7%). LC-MS m/z (ESI): 439.1 (M+H) + .
第四步the fourth step
于室温，向反应瓶中加入化合物3d(100mg,0.23mol)、三甲基氧鎓四氟硼酸盐(34mg,0.23mmol)、二氯甲烷(5mL)，反应液室温搅拌3小时。减压浓缩，粗品用硅胶色谱法以洗脱体系(SiO 2,0-15％乙酸乙酯/石油醚)纯化，得到化合物3e(123mg,产率:99.8％)。LC-MS m/z(ESI):453.3(M) +。 At room temperature, compound 3d (100 mg, 0.23 mol), trimethyloxonium tetrafluoroborate (34 mg, 0.23 mmol), and dichloromethane (5 mL) were added to the reaction flask, and the reaction solution was stirred at room temperature for 3 hours. Concentrated under reduced pressure, the crude product was purified by silica gel chromatography with an eluent system (SiO 2 , 0-15% ethyl acetate/petroleum ether) to obtain compound 3e (123 mg, yield: 99.8%). LC-MS m/z (ESI): 453.3 (M) + .
第五步the fifth step
于室温，向反应瓶中加入化合物3e(123mg,0.27mmol)和甲醇(2mL)。搅拌至溶解，冰水浴降温至0℃，加入硼氢化钠(51mg,1.36mmol)。升温至50℃，搅拌2小时。反应液降至室温，加入到饱和氯化铵水溶液(10mL)中，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶色谱法以洗脱体系(SiO 2,0-15％乙酸乙酯/石油醚)纯化，得到化合物3f(50mg,产率:40.4％)。LC-MS m/z(ESI):457.3(M+H) +。 Compound 3e (123 mg, 0.27 mmol) and methanol (2 mL) were added to the reaction vial at room temperature. Stir until dissolved, cool down to 0°C in an ice-water bath, and add sodium borohydride (51 mg, 1.36 mmol). The temperature was raised to 50° C. and stirred for 2 hours. The reaction solution was cooled to room temperature, added to saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with an eluent system (SiO 2 , 0-15% ethyl acetate/petroleum ether) to obtain compound 3f (50 mg, yield: 40.4%). LC-MS m/z (ESI): 457.3 (M+H) + .
第六步step six
于室温，向反应瓶中加入化合物3f(200mg,0.44mmol)、二氯甲烷(5mL)、三氟乙酸(50mg,0.44mmol)。搅拌至溶解。室温搅拌48小时，将反应液减压浓缩，所得粗品用反相柱C18(乙腈/水)纯化，得到化合物3g(50mg,产率:52.8％)。LC-MS m/z(ESI):217.1(M+H) +。 At room temperature, compound 3f (200 mg, 0.44 mmol), dichloromethane (5 mL), trifluoroacetic acid (50 mg, 0.44 mmol) were added to the reaction vial. Stir until dissolved. After stirring at room temperature for 48 hours, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by reverse phase column C18 (acetonitrile/water) to obtain compound 3g (50 mg, yield: 52.8%). LC-MS m/z (ESI): 217.1 (M+H) + .
第七步step seven
于室温，向反应瓶中加入化合物3h(2.00g,9.43mmol)、化合物3i(2.17g,9.43mmol)、K 2CO 3(3.91mg,28.3mmol)、二氧六环(20mL)、H 2O(4mL)、[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷甲烷络合物(385mg,0.471mmol)，氮气置换3次，80℃搅拌2小时。反应液减压浓缩，加入水(100mL)和乙酸乙酯(100mL)，收集有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品用硅胶柱色谱法以洗脱体系(SiO 2,40％-50％乙酸乙酯/石油醚)纯化，得到产物3j(1.2g,产率：54.1％)。LC-MS m/z(ESI):236.2(M+H) +。 At room temperature, add compound 3h (2.00g, 9.43mmol), compound 3i (2.17g, 9.43mmol), K 2 CO 3 (3.91mg, 28.3mmol), dioxane (20mL), H 2 O (4 mL), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane methane complex (385 mg, 0.471 mmol), replaced with nitrogen three times, stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with eluent system (SiO 2 , 40%-50% ethyl acetate/petroleum ether) to obtain product 3j (1.2 g, yield: 54.1%). LC-MS m/z (ESI): 236.2 (M+H) + .
第八步eighth step
于室温，向反应瓶中加入化合物3j(30mg,0.13mmol)、四氢呋喃(1mL)、三乙胺(13mg,0.13mmol)，氮气氛下，温度降到0℃加入三光气(89mg,0.30mmol)，反应液在25℃搅拌0.5小时。将反应液浓缩得到化合物3k(33mg粗品)。Add compound 3j (30mg, 0.13mmol), tetrahydrofuran (1mL), triethylamine (13mg, 0.13mmol) to the reaction flask at room temperature, and add triphosgene (89mg, 0.30mmol) when the temperature drops to 0°C under nitrogen atmosphere , and the reaction solution was stirred at 25°C for 0.5 hours. The reaction solution was concentrated to obtain compound 3k (33 mg crude product).
第九步Ninth step
于室温，向反应瓶中加入化合物3g(30mg,0.12mmol)、四氢呋喃(1mL)，混合物冰水浴降至0℃后，加入叔丁醇钠(12mg,0.13mmol)。然后反应液在室温搅拌 0.5小时，随后加入化合物3k(33mg,0.13mmol)。反应液在室温搅拌4小时。减压浓缩，残余物经制备级液相色谱法(色谱柱：Waters，Xbridge 250*19mm，10μm；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-10min 30-50％B；flow 25ml/min)纯化，得到化合物3(8mg,14.5％)。At room temperature, compound 3g (30mg, 0.12mmol) and tetrahydrofuran (1mL) were added to the reaction flask, and after the mixture was cooled to 0°C in an ice-water bath, sodium tert-butoxide (12mg, 0.13mmol) was added. Then the reaction was stirred at room temperature for 0.5 hours, followed by the addition of compound 3k (33 mg, 0.13 mmol). The reaction was stirred at room temperature for 4 hours. Concentrated under reduced pressure, the residue was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 30-50% B; flow 25ml/min) was purified to obtain compound 3 (8mg, 14.5%).
1H NMR(400MHz,DMSO-d 6)δ8.64(d,1H),7.93(s,1H),7.64(d,1H),7.14(s,2H),6.34(s,1H),3.28(s,2H),2.86(m,8H),2.67(s,3H),2.04-1.97(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.64(d,1H),7.93(s,1H),7.64(d,1H),7.14(s,2H),6.34(s,1H),3.28( s,2H), 2.86(m,8H), 2.67(s,3H), 2.04-1.97(m,2H).
LC-MS:MS(ESI):m/z 478.2(M+H) +。 LC-MS: MS (ESI): m/z 478.2 (M+H) + .
实施例4Example 4
((1,2,3,5,6,7-六氢-s-indacen-4-基)氨基甲酰基)((5-甲基-4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-基)磺酰基)胺钠盐((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((5-methyl-4,5,6,7-tetrahydrothiazolo[5 ,4-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000064
Figure PCTCN2022140921-appb-000064
第一步first step
于室温，向反应瓶中加入化合物4a(9.00g,28.2mmol)、三(二亚苄基丙酮)二钯(1.29g,1.41mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(1.63g,2.82mmol)、二氧六环(100mL)、N,N-二异丙基乙胺(9mL,56.4mmol)，氮气氛下，加入苄硫醇(6mL,56.4mmol)，80℃搅拌2小时。反应液减压浓缩后加入水(100mL)，用乙酸乙酯(100mL×3)萃取，收集有机相用无水硫酸钠干燥后减压浓缩。残余物用硅胶柱色谱法以洗脱体系(SiO 2,20-40％乙酸乙酯/石油醚)纯化，得到目标产物4b(9g,产率：88.1％)。LC-MS m/z(ESI):363.5(M+H) +。 At room temperature, compound 4a (9.00g, 28.2mmol), tris(dibenzylideneacetone)dipalladium (1.29g, 1.41mmol), 4,5-bis(diphenylphosphine)-9 were added to the reaction flask, 9-Dimethylxanthene (1.63g, 2.82mmol), dioxane (100mL), N,N-diisopropylethylamine (9mL, 56.4mmol), under nitrogen atmosphere, add benzyl mercaptan ( 6mL, 56.4mmol), stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure and then added with water (100 mL), extracted with ethyl acetate (100 mL×3), and the collected organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system (SiO 2 , 20-40% ethyl acetate/petroleum ether) to obtain the target product 4b (9 g, yield: 88.1%). LC-MS m/z (ESI): 363.5 (M+H) + .
第二步second step
于室温，向反应瓶加入化合物4b(8.00g,22.1mmol)、乙腈(100mL)、醋酸(8mL)、H 2O(4mL)。搅拌均匀后降温至0℃，缓慢加入二氯海因(15.2g,77.2mmol)，搅拌2小时。加入水(200mL)，二氯甲烷(300mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物4c(6.5g)粗品，无需纯化，直接用于下一步反应。LC-MS m/z(ESI):380.0(M+H+CH 3CN) +。 Compound 4b (8.00 g, 22.1 mmol), acetonitrile (100 mL), acetic acid (8 mL), H 2 O (4 mL) were added to the reaction flask at room temperature. After stirring evenly, cool down to 0°C, slowly add dichlorohydantoin (15.2 g, 77.2 mmol), and stir for 2 hours. Add water (200mL), extract with dichloromethane (300mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude compound 4c (6.5g), which is directly used in the following One step reaction. LC-MS m/z (ESI): 380.0 (M+H+ CH3CN ) + .
第三步third step
于室温，向反应瓶中加入氨甲醇溶液(120mL)，在搅拌中分批加入化合物4c(6.5g)，室温搅拌过夜。反应液减压浓缩，粗品用硅胶色谱法以洗脱体系(SiO 2,0-40％乙酸乙酯/石油醚)纯化，得到化合物4d(5.5g,产率：89.8％)。LC-MS m/z(ESI)：320.1(M+H) +。 At room temperature, ammonia-methanol solution (120 mL) was added to the reaction flask, compound 4c (6.5 g) was added in batches while stirring, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography with an eluent system (SiO 2 , 0-40% ethyl acetate/petroleum ether) to obtain compound 4d (5.5 g, yield: 89.8%). LC-MS m/z (ESI): 320.1 (M+H) + .
第四步the fourth step
于室温，向反应瓶中加入化合物4d(1.00g,3.13mmol)和盐酸二氧六环溶液(13mL)，室温搅拌2小时。将反应液减压浓缩，得到化合物4e(600mg，产率:87.4％)。LC-MS m/z(ESI):219.9(M+H) +。 Add compound 4d (1.00 g, 3.13 mmol) and dioxane hydrochloride solution (13 mL) into the reaction flask at room temperature, and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 4e (600 mg, yield: 87.4%). LC-MS m/z (ESI): 219.9 (M+H) + .
第五步the fifth step
于室温，向反应瓶中加入化合物4e(500mg,1.96mmol)和甲醇(10mL)。搅拌至溶解后，加入醋酸钠(1.33g,9.78mmol)和少量醋酸将体系pH调至3-5，再加入多聚甲醛(579mg,1.56mmol)和2-甲基吡啶硼烷(209mg,1.96mmol)，室温搅拌2小时。反应液过滤，滤液减压浓缩，得到粗品用反相柱色谱法进行纯化(体系：0.1％氨水/乙腈/水，得到目标产物4f(100mg,产率：30％)；LC-MS m/z(ESI):233.9(M+H) +。 Compound 4e (500 mg, 1.96 mmol) and methanol (10 mL) were added to the reaction vial at room temperature. After stirring until dissolved, add sodium acetate (1.33g, 9.78mmol) and a small amount of acetic acid to adjust the pH of the system to 3-5, then add paraformaldehyde (579mg, 1.56mmol) and 2-picoline borane (209mg, 1.96 mmol), stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (system: 0.1% ammonia/acetonitrile/water to obtain the target product 4f (100 mg, yield: 30%); LC-MS m/z (ESI): 233.9 (M+H) + .
第六步step six
于室温，向反应瓶中加入化合物4f(40mg,0.17mmol)和四氢呋喃(1mL)，混合物冰水浴降至0℃后，加入叔丁醇钠(20mg,0.21mmol)，室温搅拌0.5小时，再将化合物1j(41mg,0.21mmol)的四氢呋喃(1mL)溶液缓慢加入，室温搅拌4小时。反应液经制备液相色谱(色谱柱：Waters，Xbridge 250*19mm，10μm；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-10min 50-70％B；flow 25ml/min)纯化，得到化合物4g(1.5mg,产率：2％)。LC-MS:MS(ESI):m/z 474.2(M+H+CH 3CN) +。 At room temperature, compound 4f (40mg, 0.17mmol) and tetrahydrofuran (1mL) were added to the reaction flask, and after the mixture was cooled to 0°C in an ice-water bath, sodium tert-butoxide (20mg, 0.21mmol) was added, stirred at room temperature for 0.5 hours, and then A solution of compound 1j (41 mg, 0.21 mmol) in tetrahydrofuran (1 mL) was added slowly and stirred at room temperature for 4 hours. The reaction solution was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 50-70% B; flow 25ml/min ) was purified to obtain compound 4g (1.5 mg, yield: 2%). LC-MS: MS (ESI): m/z 474.2 (M+H+CH 3 CN) + .
第七步step seven
装填好IR120阳离子交换树脂-钠型柱子后，分别用乙腈，水冲洗柱子，冲洗完毕后，将化合物4g(25.6mg,0.06mmol)用乙腈(2mL)溶解后滴加到柱子里，以洗脱体系(0:1-1:0，乙腈/水)冲洗柱子，洗脱下来的馏分加到第二根柱子上，将洗脱两次后的馏分合并冻干得到化合物4(14.03mg，产率：52.1％)。After filling the IR120 cation exchange resin-sodium column, wash the column with acetonitrile and water respectively. After washing, dissolve compound 4g (25.6mg, 0.06mmol) in acetonitrile (2mL) and add it dropwise to the column to elute System (0:1-1:0, acetonitrile/water) washes the column, and the eluted fraction is added to the second column, and the fractions eluted twice are combined and freeze-dried to obtain compound 4 (14.03 mg, yield : 52.1%).
1H NMR(400MHz,DMSO-d6)δ7.63(br s,1H),6.78(s,1H),3.71(s,2H),2.85-2.73(m,8H),2.68-2.64(m,4H),2.44(s,3H),1.94-1.84(m,4H)。LC-MS m/z(ESI):433.3(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.63(br s,1H),6.78(s,1H),3.71(s,2H),2.85-2.73(m,8H),2.68-2.64(m,4H) ,2.44(s,3H),1.94-1.84(m,4H). LC-MS m/z (ESI): 433.3 (M+H)+.
实施例5Example 5
((4-羟基-4-甲基-4,5,6,7-四氢苯并[b]噻吩-2-基)磺酰基)((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)胺钠盐((4-Hydroxy-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)sulfonyl)((5-(2-methoxypyridin-4-yl )-2,3-dihydro-1H-inden-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000065
Figure PCTCN2022140921-appb-000065
第一步first step
向250mL反应瓶，加入6,7-二氢-4(5H)-苯并噻吩酮(5a)(9.5g,62.4mmol)、二氯甲烷(100mL)，在-10℃，缓慢滴加氯磺酸(10.2g，87.4mmol)。滴加结束后，升温至室温，搅拌72小时。将上清液倒出，析出粘稠物溶于水中，冻干。残余物用反相C18纯化(0.225％甲酸/乙腈/水体系)，得到化合物5b(2.6g,产率：12.6％)。LC-MS m/z:230.9[M-H] -。 To a 250mL reaction flask, add 6,7-dihydro-4(5H)-benzothiophene (5a) (9.5g, 62.4mmol), dichloromethane (100mL), and slowly add chlorosulfur at -10°C Acid (10.2 g, 87.4 mmol). After completion of the dropwise addition, the temperature was raised to room temperature and stirred for 72 hours. The supernatant was poured out, and the precipitated sticky matter was dissolved in water and freeze-dried. The residue was purified by reverse phase C18 (0.225% formic acid/acetonitrile/water system) to obtain compound 5b (2.6 g, yield: 12.6%). LC-MS m/z: 230.9 [MH] - .
第二步second step
向100mL反应瓶，加入化合物5b(1.3g,81.2％purity,5.59mmol)、二氯甲烷(10mL)。冷却至0℃，加入五氯化磷(10.5g,50.4mmol)和吡啶(4.05mL,50.4mmol)。室温搅拌16小时。补加五氯化磷(10.5g,50.4mmol)和吡啶(4.1mL,50.4mmol)，搅拌2小时。再次补加五氯化磷(10.5g,50.4mmol)和吡啶(4.1mL,50.4mmol)，搅拌2小时，反应完全。向反应瓶中加入二氯甲烷(10mL)，冰浴下将反应液加入到氨气的四氢呋喃溶液(10mL，5mol/L)中，并补加氨水(10mL,25％)。室温搅拌0.5小时，过滤，滤饼用二氯甲烷(10mL)洗涤，滤液减压浓缩。残余物经柱层析色谱法分离(SiO2，30％乙酸乙酯/石油醚)。得到化合物5c(40mg)。 1HNMR(400MHz,DMSO-d 6)δ7.77(s,2H),7.60(s,1H),3.07(t,2H),2.26-2.19(m,2H),2.17-2.10(m,2H)。LC-MS m/z:230.0(M-H) -。 To a 100 mL reaction flask, compound 5b (1.3 g, 81.2% purity, 5.59 mmol), dichloromethane (10 mL) were added. Cool to 0 °C, add phosphorus pentachloride (10.5 g, 50.4 mmol) and pyridine (4.05 mL, 50.4 mmol). Stir at room temperature for 16 hours. Additional phosphorus pentachloride (10.5 g, 50.4 mmol) and pyridine (4.1 mL, 50.4 mmol) were added and stirred for 2 hours. Phosphorus pentachloride (10.5 g, 50.4 mmol) and pyridine (4.1 mL, 50.4 mmol) were added again, stirred for 2 hours, and the reaction was complete. Dichloromethane (10 mL) was added to the reaction flask, and the reaction solution was added to a solution of ammonia in tetrahydrofuran (10 mL, 5 mol/L) under ice cooling, and ammonia water (10 mL, 25%) was added. Stir at room temperature for 0.5 hour, filter, wash the filter cake with dichloromethane (10 mL), and concentrate the filtrate under reduced pressure. The residue was separated by column chromatography (SiO2, 30% ethyl acetate/petroleum ether). Compound 5c (40 mg) was obtained. 1 HNMR (400MHz,DMSO-d 6 )δ7.77(s,2H),7.60(s,1H),3.07(t,2H),2.26-2.19(m,2H),2.17-2.10(m,2H) . LC-MS m/z: 230.0 (MH) - .
第三步third step
向50mL反应瓶中，加入化合物5c(90mg,0.39mmol)和四氢呋喃(3mL)，降温至0℃，加入3M甲基溴化镁的THF溶液(1.9mL,5.7mmol)，室温搅拌1小时。加入饱和碳酸氢钠水溶液(2mL)，用乙酸乙酯(5mL×3)萃取，有机相用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物经用薄层色谱法以展开体系(石油醚:乙酸乙酯＝1:1)纯化，得到化合物5d(55mg，产率：57％)。 LC-MS m/z:246.1(M-H) -。 Add compound 5c (90 mg, 0.39 mmol) and tetrahydrofuran (3 mL) to a 50 mL reaction flask, cool down to 0°C, add 3M methylmagnesium bromide in THF (1.9 mL, 5.7 mmol), and stir at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (2 mL) was added, extracted with ethyl acetate (5 mL×3), the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 5d (55 mg, yield: 57%). LC-MS m/z: 246.1 (MH) - .
第四步the fourth step
向10mL反应瓶，加入化合物5d(65mg,74.1％purity,0.19mmol)、四氢呋喃(1mL)、化合物6n的四氢呋喃溶液(2mL,0.52mmol,0.26M四氢呋喃溶液)和1,8-二氮杂二环十一碳-7-烯(148mg,0.97mmol)。室温搅拌1小时，加水(5mL)，用乙酸乙酯萃取(1mL)。水相直接进行反相柱C18纯化(水/乙腈)，冻干，残余物用高效液相色谱法(色谱柱：Gilson-281，Xbridge 150*25mm，5μm；流动相：水相(10mM氨水)和乙腈，梯度配比：0-9min 6-36％B；flow 25ml/min)纯化，得到化合物5e(18mg，产率：18.4％)。To a 10 mL reaction flask, add compound 5d (65 mg, 74.1% purity, 0.19 mmol), THF (1 mL), compound 6n in THF (2 mL, 0.52 mmol, 0.26 M THF solution) and 1,8-diazabicyclo Undec-7-ene (148 mg, 0.97 mmol). Stir at room temperature for 1 hour, add water (5 mL), and extract with ethyl acetate (1 mL). The aqueous phase was directly purified by reverse-phase column C18 (water/acetonitrile), lyophilized, and the residue was subjected to high-performance liquid chromatography (chromatographic column: Gilson-281, Xbridge 150*25mm, 5 μm; mobile phase: aqueous phase (10mM ammonia water) and acetonitrile, gradient ratio: 0-9min 6-36% B; flow 25ml/min) to obtain compound 5e (18mg, yield: 18.4%).
1HNMR(400MHz,DMSO-d 6)δ9.48(s,1H),8.05(d,1H),7.33-7.29(m,2H),7.11-7.09(m,1H),7.06-7.01(m,1H),6.91(d,1H),6.75(s,1H),4.86(s,1H),3.85(s,3H),2.88(t,2H),2.80-2.70(m,2H),2.64-2.61(m,2H),1.99-1.92(m,3H),1.76-1.73(m,1H),1.69-1.64(m,2H),1.34(s,3H)。 1 HNMR (400MHz,DMSO-d 6 )δ9.48(s,1H),8.05(d,1H),7.33-7.29(m,2H),7.11-7.09(m,1H),7.06-7.01(m, 1H),6.91(d,1H),6.75(s,1H),4.86(s,1H),3.85(s,3H),2.88(t,2H),2.80-2.70(m,2H),2.64-2.61 (m,2H), 1.99-1.92(m,3H), 1.76-1.73(m,1H), 1.69-1.64(m,2H), 1.34(s,3H).
LC-MS m/z:512.1(M-H) -。 LC-MS m/z: 512.1 (MH) - .
第五步the fifth step
向8mL反应瓶，加入化合物5e(16mg,0.03mmol)和四氢呋喃(1mL)。降温至0℃，加入叔丁醇钠固体(2.99mg,0.03mmol)，搅拌5分钟。浓缩，经纯化得到产物5(7mg,产率：43.6％)。To an 8 mL reaction vial, compound 5e (16 mg, 0.03 mmol) and tetrahydrofuran (1 mL) were added. Cool down to 0°C, add solid sodium tert-butoxide (2.99 mg, 0.03 mmol), and stir for 5 minutes. Concentrated and purified to obtain product 5 (7 mg, yield: 43.6%).
1H NMR(400MHz,DMSO)δ8.06(d,1H),7.26(s,1H),7.22(s,1H),7.06(m,2H),6.95(s,1H),6.78(s,1H),4.82(s,1H),3.86(s,3H),3.31(s,2H),2.89(t,2H),2.78(d,2H),2.65(m,2H),1.98–1.93(m,2H),1.74(d,2H),1.35(s,3H)。 1 H NMR (400MHz,DMSO)δ8.06(d,1H),7.26(s,1H),7.22(s,1H),7.06(m,2H),6.95(s,1H),6.78(s,1H ),4.82(s,1H),3.86(s,3H),3.31(s,2H),2.89(t,2H),2.78(d,2H),2.65(m,2H),1.98–1.93(m, 2H), 1.74(d, 2H), 1.35(s, 3H).
LC-MS m/z:512.1(M-H) -。 LC-MS m/z: 512.1 (MH) - .
实施例6Example 6
((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)((5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)胺钠盐((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)((5-methyl-4,5,6,7 -Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000066
Figure PCTCN2022140921-appb-000066
Figure PCTCN2022140921-appb-000067
Figure PCTCN2022140921-appb-000067
第一步first step
于室温，在一个1L三口瓶中加入化合物6a(45g,323mmol)和四氢呋喃(500mL)。降温至0℃，滴加N,N-二异丙基乙胺(112mL,679mmol)和氯甲酸苄酯(50mL,356mmol)。升温至20℃，搅拌12小时。将反应液缓慢倒入水(500mL)中，然后用乙酸乙酯(200mL×3)萃取三次，合并乙酸乙酯相，用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱色谱法以洗脱体系(SiO 2,20％-25％乙酸乙酯/石油醚)纯化，得到化合物6b(72g，产率：80.5％)。 At room temperature, compound 6a (45 g, 323 mmol) and tetrahydrofuran (500 mL) were added into a 1 L three-neck flask. Cool down to 0° C., and add N,N-diisopropylethylamine (112 mL, 679 mmol) and benzyl chloroformate (50 mL, 356 mmol) dropwise. The temperature was raised to 20°C and stirred for 12 hours. The reaction solution was slowly poured into water (500 mL), then extracted three times with ethyl acetate (200 mL×3), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system (SiO 2 , 20%-25% ethyl acetate/petroleum ether) to obtain compound 6b (72 g, yield: 80.5%).
1HNMR(400MHz,CDCl 3)δ7.40-7.36(m,5H),7.14(d,1H),6.78(s,1H),5.20(s,2H),4.61(s,2H),3.83(s,2H),2.89(s,2H)。 1 HNMR (400MHz, CDCl 3 )δ7.40-7.36(m,5H),7.14(d,1H),6.78(s,1H),5.20(s,2H),4.61(s,2H),3.83(s ,2H), 2.89(s,2H).
LC-MS：m/z(ESI):274.0(M+H) +。 LC-MS: m/z (ESI): 274.0 (M+H) + .
第二步second step
向500mL三口烧瓶中加入化合物6b(24g,87.8mmol)和无水二氯甲烷(250mL)，降温至0℃，加入氯磺酸(6mL,92.2mmol)，反应5分钟。加入水(150mL)，减压浓缩除去二氯甲烷，水相用乙酸乙酯(300mL×3)萃取，合并有机相，干燥，过滤，滤液减压浓缩，得到粗品。粗品用反相柱C18(0.2％甲酸/乙腈/水)纯化，得到化合物6c(20g，产率：61.9％)。Add compound 6b (24g, 87.8mmol) and anhydrous dichloromethane (250mL) into a 500mL three-necked flask, cool down to 0°C, add chlorosulfonic acid (6mL, 92.2mmol), and react for 5 minutes. Water (150 mL) was added, dichloromethane was removed by concentration under reduced pressure, the aqueous phase was extracted with ethyl acetate (300 mL×3), the organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column C18 (0.2% formic acid/acetonitrile/water) to obtain compound 6c (20 g, yield: 61.9%).
1HNMR(400MHz,DMSO-d 6)δ7.39-7.32(m,5H),6.89(s,1H),5.13(s,2H),4.45-4.41(m,2H),3.68(s,2H),2.76-2.75(m,2H)。 1 HNMR(400MHz,DMSO-d 6 )δ7.39-7.32(m,5H),6.89(s,1H),5.13(s,2H),4.45-4.41(m,2H),3.68(s,2H) ,2.76-2.75(m,2H).
LC-MS：m/z(ESI):351.9(M+H) +。 LC-MS: m/z (ESI): 351.9 (M+H) + .
第三步third step
向1L三口瓶中加入化合物6c(20g,56.6mmol)和二氯甲烷(200mL)，降温至0℃，缓慢加入吡啶(13.7mL,170mmol)和五氯化磷(35.4g,170mmol)。升温至室 温，搅拌2小时。加入冰水(300mL)淬灭，搅拌5分钟，静置分液，水相用二氯甲烷(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物6d(37g，粗品)，直接用于下一步。Add compound 6c (20g, 56.6mmol) and dichloromethane (200mL) into a 1L three-necked flask, cool down to 0°C, and slowly add pyridine (13.7mL, 170mmol) and phosphorus pentachloride (35.4g, 170mmol). Warm to room temperature and stir for 2 hours. Add ice water (300mL) to quench, stir for 5 minutes, let stand to separate the liquids, extract the aqueous phase with dichloromethane (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 6d (37 g, crude product), used directly in the next step.
第四步the fourth step
向1L三口瓶中加入化合物6d(37g,99.5mmol)和四氢呋喃(250mL)，然后在0℃缓慢加入氨气/四氢呋喃溶液(99.5mL,199mmol,2M)，升至室温，搅拌12小时。减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2,45％-70％乙酸乙酯/石油醚)纯化，得到产物化合物6e(16g，产率：45.6％)。 Compound 6d (37g, 99.5mmol) and tetrahydrofuran (250mL) were added to a 1L three-necked flask, then ammonia/tetrahydrofuran solution (99.5mL, 199mmol, 2M) was slowly added at 0°C, raised to room temperature, and stirred for 12 hours. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography with an eluent system (SiO 2 , 45%-70% ethyl acetate/petroleum ether) to obtain the product compound 6e (16 g, yield: 45.6%).
1HNMR(400MHz,DMSO-d 6)δ7.61(s,2H),7.39-7.32(m,6H),5.13(s,2H),4.52-4.49(m,2H),3.71(s,2H),2.85(t,2H)。 1 HNMR(400MHz,DMSO-d 6 )δ7.61(s,2H),7.39-7.32(m,6H),5.13(s,2H),4.52-4.49(m,2H),3.71(s,2H) ,2.85(t,2H).
第五步the fifth step
于10℃，向250mL三口烧瓶中加入化合物6e(7g,19.9mmol)和无水二氯甲烷(70mL)，缓慢滴入氢溴酸/醋酸(15mL,33％)，在室温搅拌2小时。过滤，滤饼溶解在甲醇(80mL)中，缓慢加入碳酸钠固体至pH＝10，过滤，滤液减压浓缩，得到化合物6f(5g，粗品)，直接用于下一步。At 10°C, compound 6e (7g, 19.9mmol) and anhydrous dichloromethane (70mL) were added to a 250mL three-necked flask, hydrobromic acid/acetic acid (15mL, 33%) was slowly added dropwise, and stirred at room temperature for 2 hours. After filtration, the filter cake was dissolved in methanol (80 mL), solid sodium carbonate was slowly added to pH = 10, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6f (5 g, crude product), which was directly used in the next step.
第六步step six
于室温，向100mL单口瓶加入化合物6f(2.20g,10.1mmol)、甲醇(20mL)、醋酸(2.88mL,50.4mmol)、多聚甲醛(300mg,10.1mmol)和氰基硼氢化钠(1.27g,20.2mmol)，搅拌10小时。过滤，滤液减压浓缩，残余物用硅胶色谱法以洗脱体系(SiO 2,10-30％甲醇/二氯甲烷)纯化，得到化合物6g(2.2g,产率：81.4％)。 Add compound 6f (2.20g, 10.1mmol), methanol (20mL), acetic acid (2.88mL, 50.4mmol), paraformaldehyde (300mg, 10.1mmol) and sodium cyanoborohydride (1.27g , 20.2mmol), stirred for 10 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with an eluent system (SiO 2 , 10-30% methanol/dichloromethane) to obtain compound 6g (2.2 g, yield: 81.4%).
1HNMR(400MHz,CD 3OD)δ7.33(s,1H),3.88(s,2H),3.35-3.31(m,2H),3.25-3.21(m,2H),2.72(s,3H)。LC-MS m/z(ESI):233.0(M+H) +。 1 H NMR (400 MHz, CD 3 OD) δ 7.33 (s, 1H), 3.88 (s, 2H), 3.35-3.31 (m, 2H), 3.25-3.21 (m, 2H), 2.72 (s, 3H). LC-MS m/z (ESI): 233.0 (M+H) + .
第七步step seven
于室温，向250mL反应瓶中加入化合物6h(23.5g,176.440mmol)、三乙胺(31.9mL,229.37mmol)和二氯甲烷(150mL)。搅拌至溶解，在0℃逐滴滴加乙酸酐(19.1mL,202.91mmol)，反应液于0℃搅拌0.1小时后，室温搅拌1.4小时。向滤液中加水(25mL)，二氯甲烷萃取(10mL×3)，饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，过滤，、减压浓缩，残余物经柱层析色谱法(SiO 2,20-40％乙酸乙酯/石油醚)纯化，得到化合物6i(24.2g)。 Compound 6h (23.5 g, 176.440 mmol), triethylamine (31.9 mL, 229.37 mmol) and dichloromethane (150 mL) were added to a 250 mL reaction flask at room temperature. Stir until dissolved, then add acetic anhydride (19.1 mL, 202.91 mmol) dropwise at 0°C, and stir the reaction solution at 0°C for 0.1 hour, then at room temperature for 1.4 hours. Add water (25 mL) to the filtrate, extract with dichloromethane (10 mL×3), wash with saturated brine (20 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the residue is subjected to column chromatography ( SiO 2 , 20-40% ethyl acetate/petroleum ether) to obtain compound 6i (24.2 g).
1H NMR(400MHz,CDCl 3)δ7.73(d,J＝8.0Hz,1H),7.15(t,J＝7.6Hz,1H),7.03(d,J＝7.6Hz,1H),2.96(t,J＝7.2Hz,2H),2.82(t,J＝7.2Hz,2H),2.19(s,3H)2.08-2.15(m,2H)。LC-MS：m/z 176.3(M+H) +。 1 H NMR (400MHz, CDCl 3 ) δ7.73(d, J=8.0Hz, 1H), 7.15(t, J=7.6Hz, 1H), 7.03(d, J=7.6Hz, 1H), 2.96(t , J=7.2Hz, 2H), 2.82(t, J=7.2Hz, 2H), 2.19(s, 3H) 2.08-2.15(m, 2H). LC-MS: m/z 176.3 (M+H) + .
第八步eighth step
于室温，向100mL单口瓶中加入化合物6i(5g,28.534mmol)和甲苯(40mL)、对甲苯磺酸(2.99g,15.694mmol)、醋酸钯(0.30g,1.341mmol)，搅拌0.5小时，加入N-溴代丁二酰亚胺(4.32g,24.254mmol)，室温搅拌2小时。向反应液中加入硫 代硫酸钠水溶液(50mL)，乙酸乙酯萃取(20mL×3)，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物经柱层析色谱法(SiO 2,10％-50％乙酸乙酯/石油醚)纯化，得到化合物6j(4g)。LC-MS：m/z:254.1(M+H) +。 At room temperature, add compound 6i (5g, 28.534mmol), toluene (40mL), p-toluenesulfonic acid (2.99g, 15.694mmol), palladium acetate (0.30g, 1.341mmol) into a 100mL single-necked bottle, stir for 0.5 hours, add N-bromosuccinimide (4.32 g, 24.254 mmol), stirred at room temperature for 2 hours. Aqueous sodium thiosulfate solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography ( SiO2 , 10%-50% ethyl acetate/petroleum ether) to give compound 6j (4g). LC-MS: m/z: 254.1 (M+H) + .
第九步Ninth step
于室温，向500mL反应瓶中加入化合物6j(16g,62.960mmol)、乙醇(60mL)和36％～38％盐酸(90mL,2912.781mmol)。搅拌至溶解，反应液80℃搅拌36小时。减压浓缩，得到化合物6k(18g)。粗品无需纯化，直接用于下一步反应。LC-MS：m/z 212.2(M+H) +。 Add compound 6j (16 g, 62.960 mmol), ethanol (60 mL) and 36%-38% hydrochloric acid (90 mL, 2912.781 mmol) into a 500 mL reaction flask at room temperature. Stir until dissolved, and stir the reaction solution at 80°C for 36 hours. Concentration under reduced pressure gave compound 6k (18 g). The crude product was directly used in the next reaction without further purification. LC-MS: m/z 212.2 (M+H) + .
第十步tenth step
于室温，向250mL单口瓶中加入化合物6k(6g,19.803mol)、2-甲氧基吡啶-4-硼酸(6l)(3.63g,23.763mmol)、碳酸钾(8.76g,63.369mmol)、二氧六环(10mL)和水(10mL)，氮气氛下搅拌15分钟。加入[1,1-双(二苯基膦)二茂铁]二氯化钯(0.81g,0.990mmol)，反应液80℃搅拌36小时。向反应液中加入水(50mL)，乙酸乙酯萃取(40mL×3)，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤，减压减压浓缩。残余物经柱层析色谱法(SiO 2,15％乙酸乙酯/石油醚)纯化，得到化合物6m(3.08g)。 At room temperature, compound 6k (6g, 19.803mol), 2-methoxypyridine-4-boronic acid (6l) (3.63g, 23.763mmol), potassium carbonate (8.76g, 63.369mmol), di Hexane (10 mL) and water (10 mL) were stirred under nitrogen atmosphere for 15 minutes. [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.81 g, 0.990 mmol) was added, and the reaction solution was stirred at 80° C. for 36 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL×3), washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 15% ethyl acetate/petroleum ether) to obtain compound 6m (3.08 g).
1H NMR(400MHz,CDCl 3)δ8.22(dd,1H),7.01(dd,1H),6.98(d,1H),6.87–6.86(m,1H),6.77(d,1H),3.99(s,3H),3.50-3.91(m,2H),2.97(t,2H),2.77(t,2H),2.13-2.21(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ8.22(dd,1H),7.01(dd,1H),6.98(d,1H),6.87–6.86(m,1H),6.77(d,1H),3.99( s,3H), 3.50-3.91(m,2H), 2.97(t,2H), 2.77(t,2H), 2.13-2.21(m,2H).
LC-MS:m/z:241.3(M+H) +。 LC-MS: m/z: 241.3 (M+H) + .
第十一步Eleventh step
于室温，向50mL单口瓶中加入化合物6m(1g,4.161mmol)和四氢呋喃(15mL)，搅拌至溶解，冰水浴降温至0℃，加入三乙胺(1.23g,4.161mmol)和三光气(1.23g,4.161mmol)。室温搅拌0.5小时。反应液过滤，滤液减压浓缩，得到化合物6n(800mg)。粗品无需纯化，直接用于下一步反应。LC-MS:m/z:267.2(M+H) +。 At room temperature, add compound 6m (1g, 4.161mmol) and tetrahydrofuran (15mL) into a 50mL single-necked bottle, stir until dissolved, cool down to 0°C in an ice-water bath, add triethylamine (1.23g, 4.161mmol) and triphosgene (1.23 g, 4.161 mmol). Stir at room temperature for 0.5 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6n (800 mg). The crude product was directly used in the next reaction without further purification. LC-MS: m/z: 267.2 (M+H) + .
第十二步Twelfth step
于0℃，向50mL反应瓶中加入化合物6g(300mg,1.29mmol)、N,N-二甲基甲酰胺(5mL)、化合物6n(378mg,1.42mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(2.95g,19.4mmol)，升温至室温，搅拌1小时。加入水(10mL)和乙酸乙酯(10mL)，搅拌静置分液，水相用反相柱C18(体系：水/乙腈，梯度：乙腈20％～30％)纯化，得到化合物6o(100mg,产率：15.4％)。At 0°C, compound 6g (300mg, 1.29mmol), N,N-dimethylformamide (5mL), compound 6n (378mg, 1.42mmol) and 1,8-diazabicyclo[ 5.4.0] Undec-7-ene (2.95g, 19.4mmol), warmed up to room temperature, and stirred for 1 hour. Add water (10mL) and ethyl acetate (10mL), stir and stand still to separate the liquids, and the aqueous phase is purified by reverse-phase column C18 (system: water/acetonitrile, gradient: acetonitrile 20% to 30%) to obtain compound 6o (100mg, Yield: 15.4%).
1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),8.03(d,1H),7.21(s,1H),7.07(d,1H),7.02(d,1H),6.91(d,1H),6.88(s,1H),6.75(s,1H),3.85(s,3H),3.56-3.54(m,2H),2.76-2.74(m,4H),2.64-2.60(m,4H),2.34(s,3H),1.98-1.94(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ9.49(s,1H),8.03(d,1H),7.21(s,1H),7.07(d,1H),7.02(d,1H),6.91( d,1H),6.88(s,1H),6.75(s,1H),3.85(s,3H),3.56-3.54(m,2H),2.76-2.74(m,4H),2.64-2.60(m, 4H), 2.34(s, 3H), 1.98-1.94(m, 2H).
LC-MS m/z(ESI):499.0(M+H) +。 LC-MS m/z (ESI): 499.0 (M+H) + .
第十三步Step Thirteen
化合物6o(97.7mg,0.20mmol)溶解在2-甲基四氢呋喃(5mL)中，用饱和氯化钠溶液(2mL×3)洗涤，干燥，过滤，滤液减压浓缩，残余物溶解在四氢呋喃(0.3mL)中，降温至0℃，加入1M叔丁醇钠的四氢呋喃溶液(0.2mL,0.2mmol)，搅拌30分钟，减压浓缩，得到化合物6(55mg,产率51.1％)。Compound 6o (97.7mg, 0.20mmol) was dissolved in 2-methyltetrahydrofuran (5mL), washed with saturated sodium chloride solution (2mL×3), dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (0.3 mL), cooled to 0°C, added 1M sodium tert-butoxide in tetrahydrofuran (0.2 mL, 0.2 mmol), stirred for 30 minutes, and concentrated under reduced pressure to obtain compound 6 (55 mg, yield 51.1%).
1H NMR(400MHz,DMSO-d 6)δ8.02(d,1H),7.22(s,1H),7.06(d,1H),7.02(d,1H),6.92(d,1H),6.89(s,1H),6.75(s,1H),3.85(s,3H),2.88(t,2H),2.76-2.74(m,4H),2.67-2.60(m,4H),2.34(s,3H),1.99-1.94(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.02(d,1H),7.22(s,1H),7.06(d,1H),7.02(d,1H),6.92(d,1H),6.89( s,1H),6.75(s,1H),3.85(s,3H),2.88(t,2H),2.76-2.74(m,4H),2.67-2.60(m,4H),2.34(s,3H) ,1.99-1.94(m,2H).
LC-MS m/z(ESI):499.1(M+H) +。 LC-MS m/z (ESI): 499.1 (M+H) + .
实施例7Example 7
N-((1,2,3,5,6.7-六氢-s-indacen-4-基)氨甲酰基)-1-异丙基-5-甲基-4,5,6,7-四氢-1H-吡唑并[4,3-c]吡啶-3-磺酰胺N-((1,2,3,5,6.7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-5-methyl-4,5,6,7-tetra Hydrogen-1H-pyrazolo[4,3-c]pyridine-3-sulfonamide
Figure PCTCN2022140921-appb-000068
Figure PCTCN2022140921-appb-000068
第一步first step
于室温，向250mL反应瓶中加入化合物7a(4.4g,19.7mmol)、乙腈(50mL)和N-碘代丁二酰亚胺(8.87g,39.41mmol)。升温至60℃，搅拌16小时。加入饱和亚硫酸钠水溶液(50mL)淬灭。用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱色谱法以洗脱体系(SiO 2,0％-100％乙酸乙酯/石油醚)纯化，得到产物化合物7b(2.4g，产率：35％)。 Compound 7a (4.4 g, 19.7 mmol), acetonitrile (50 mL) and N-iodosuccinimide (8.87 g, 39.41 mmol) were added to a 250 mL reaction flask at room temperature. The temperature was raised to 60°C and stirred for 16 hours. Add saturated aqueous sodium sulfite (50 mL) to quench. Extracted with ethyl acetate (50 mL×3), combined the organic phases, washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system (SiO 2 , 0%-100% ethyl acetate/petroleum ether) to obtain the product compound 7b (2.4 g, yield: 35%).
1HNMR(400MHz,DMSO-d 6)δ12.97(s,1H)，4.11(s,2H),3.58(t,2H), 2.68-2.60(m,2H),1.42(s,9H)。LC-MS m/z(ESI):350.0(M+H) +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 4.11 (s, 2H), 3.58 (t, 2H), 2.68-2.60 (m, 2H), 1.42 (s, 9H). LC-MS m/z (ESI): 350.0 (M+H) + .
第二步second step
向100mL反应瓶，加入化合物7b(2.10g,6.01mmol)和N,N-二甲基甲酰胺(20mL)。降温至0℃，加入氢化钠(0.31g,7.82mmol,60％)和碘代异丙烷(1.53g,9.02mmol)，室温搅拌1小时。加入水(40mL)，用乙酸乙酯(20mL×3)萃取。有机相用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物7c和7c-1的混合物(2.05g,产率：87.2％)。LC-MS m/z(ESI)：392.0(M+H) +。 To a 100 mL reaction flask, compound 7b (2.10 g, 6.01 mmol) and N,N-dimethylformamide (20 mL) were added. Cool down to 0°C, add sodium hydride (0.31g, 7.82mmol, 60%) and iodoisopropane (1.53g, 9.02mmol), and stir at room temperature for 1 hour. Water (40 mL) was added and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of compounds 7c and 7c-1 (2.05 g, yield: 87.2%). LC-MS m/z (ESI): 392.0 (M+H) + .
第三步third step
向50mL反应瓶中加入化合物7c和7c-1的混合物(2.05g,5.24mmol)、对甲氧基苄硫醇(1.21g,7.86mmol)、三(二亚苄基丙酮)二钯(0.96g,1.05mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(961mg,1.05mmol)、二氧六环(20mL)和N,N-二异丙基乙胺(1.30mL,7.86mmol)。在氮气氛下，升温至100℃，搅拌16小时。降至室温，过滤，滤液减压浓缩。残余物用硅胶柱色谱法以洗脱体系(SiO 2,25％乙酸乙酯/石油醚)纯化，得到化合物7d和7d-1的混合物(1.6g，产率：73％)。LC-MS m/z(ESI)：418.1(M+H) +。 A mixture of compounds 7c and 7c-1 (2.05g, 5.24mmol), p-methoxybenzylthiol (1.21g, 7.86mmol), tris(dibenzylideneacetone)dipalladium (0.96g , 1.05mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (961mg, 1.05mmol), dioxane (20mL) and N,N-diisopropylethylamine (1.30 mL, 7.86 mmol). Under a nitrogen atmosphere, the temperature was raised to 100° C. and stirred for 16 hours. Cool down to room temperature, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography with eluent system (SiO 2 , 25% ethyl acetate/petroleum ether) to obtain a mixture of compounds 7d and 7d-1 (1.6 g, yield: 73%). LC-MS m/z (ESI): 418.1 (M+H) + .
第四步the fourth step
向50mL反应瓶中加入化合物7d和7d-1的混合物(1.2g,2.67mmol)、醋酸(15mL)和水(5mL)。降温至0℃，缓慢加入N-氯代丁二酰亚胺(2.50g,18.7mmol)，室温搅拌3小时。0℃将反应液加入到氨水(20mL，25％)中。减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2,50％乙酸乙酯/石油醚)纯化，得到化合物7e(90mg,收率:9.8％)和7e-1(240mg，收率:26.1％)。 To a 50 mL reaction flask was added a mixture of compounds 7d and 7d-1 (1.2 g, 2.67 mmol), acetic acid (15 mL) and water (5 mL). Cool down to 0°C, slowly add N-chlorosuccinimide (2.50 g, 18.7 mmol), and stir at room temperature for 3 hours. The reaction solution was added into aqueous ammonia (20 mL, 25%) at 0°C. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system (SiO 2 , 50% ethyl acetate/petroleum ether) to obtain compound 7e (90 mg, yield: 9.8%) and 7e-1 (240 mg, yield rate: 26.1%).
1H NMR(400MHz,CDCl 3)δ8.04(br s,2H),4.59(s,2H),4.46-4.35(m,1H),3.81-3.67(m,2H),2.72-2.70(m,2H),1.50-1.49(m,15H)。 1 H NMR (400MHz, CDCl 3 )δ8.04(br s,2H),4.59(s,2H),4.46-4.35(m,1H),3.81-3.67(m,2H),2.72-2.70(m, 2H), 1.50-1.49 (m, 15H).
LC-MS m/z(ESI):345.2(M+H) +。 LC-MS m/z (ESI): 345.2 (M+H) + .
第五步the fifth step
向50mL反应瓶中加入化合物7e(180mg,0.52mmol)、二氧六环(10mL)和6M盐酸(5mL,30mmol)，搅拌1小时。减压浓缩得到化合物7f(160mg，粗品)，直接用于下一步。Compound 7e (180 mg, 0.52 mmol), dioxane (10 mL) and 6M hydrochloric acid (5 mL, 30 mmol) were added to a 50 mL reaction flask, and stirred for 1 hour. Concentration under reduced pressure gave compound 7f (160 mg, crude product), which was directly used in the next step.
第六步step six
向25mL反应瓶中加入化合物7f(160mg,0.48mmol)、甲醇(10mL)、多聚甲醛(16.0mg,0.18mmol)、三乙胺(0.1mL,0.48mmol)和钯/碳(51mg,0.048mmol,10％)，氢气氛和室温搅拌5小时。过滤，滤液减压浓缩。残余物经高效液相色谱法((色谱柱:Waters Xbridge 150*25mm*5μm；流动相:水相(0.05％氨水)和乙腈，梯度配比:0-9min5-33％B；flow 25ml/min)纯化，得到化合物7g(60mg,收率:48.4％)。Add compound 7f (160 mg, 0.48 mmol), methanol (10 mL), paraformaldehyde (16.0 mg, 0.18 mmol), triethylamine (0.1 mL, 0.48 mmol) and palladium on carbon (51 mg, 0.048 mmol) to a 25 mL reaction vial ,10%), hydrogen atmosphere and room temperature stirring for 5 hours. Filter and concentrate the filtrate under reduced pressure. The residue is subjected to high performance liquid chromatography ((chromatographic column: Waters Xbridge 150*25mm*5 μ m; mobile phase: aqueous phase (0.05% ammoniacal liquor) and acetonitrile, gradient ratio: 0-9min5-33% B; flow 25ml/min ) was purified to obtain compound 7g (60 mg, yield: 48.4%).
1HNMR(400MHz,DMSO-d 6)δ7.31(s,1H),4.50-4.46(m,1H),3.40(s,2H), 2.74-2.71(m,2H),2.63-2.62(m,2H),2.36(s,3H),1.37(d,6H)。LC-MS m/z(ESI):259.1(M+H) +。 1 HNMR(400MHz,DMSO-d 6 )δ7.31(s,1H),4.50-4.46(m,1H),3.40(s,2H), 2.74-2.71(m,2H),2.63-2.62(m, 2H), 2.36(s, 3H), 1.37(d, 6H). LC-MS m/z (ESI): 259.1 (M+H) + .
第七步step seven
向25mL反应瓶中加入化合物7g(60mg,0.23mmol)、四氢呋喃(5mL)、化合物1j(69mg,0.35mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(106mg，0.70mmol)，室温搅拌1小时。减压浓缩，残余物经反相C18纯化(体系:水/乙腈，30％乙腈)，所得粗品经高效液相色谱法(色谱柱:Waters Xbridge 150*25mm*5μm；流动相:水相(10mM碳酸氢铵)和乙腈；梯度配比:0-10min 21-51％B；flow 25ml/min)分离纯化，得到化合物7(12mg,产率:10.9％)。Add compound 7g (60mg, 0.23mmol), tetrahydrofuran (5mL), compound 1j (69mg, 0.35mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene ( 106mg, 0.70mmol), stirred at room temperature for 1 hour. Concentrated under reduced pressure, the residue was purified by reverse phase C18 (system: water/acetonitrile, 30% acetonitrile), and the crude product obtained was subjected to high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5 μm; mobile phase: aqueous phase (10mM ammonium bicarbonate) and acetonitrile; gradient ratio: 0-10min 21-51% B; flow 25ml/min) separation and purification to obtain compound 7 (12mg, yield: 10.9%).
1H NMR(400MHz,DMSO-d 6)δ7.85(s,1H),6.89(s,1H),4.55-4.45(m,1H),3.64-3.56(m,2H),2.81-2.74(m,6H),2.63-2.55(m,6H),2.46-2.37(m,3H),1.98-1.81(m,4H),1.35(d,6H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.85(s,1H),6.89(s,1H),4.55-4.45(m,1H),3.64-3.56(m,2H),2.81-2.74(m ,6H), 2.63-2.55(m,6H), 2.46-2.37(m,3H), 1.98-1.81(m,4H), 1.35(d,6H).
LC-MS m/z(ESI)：458.2(M+H) +。 LC-MS m/z (ESI): 458.2 (M+H) + .
实施例8Example 8
N-((5-(2-氟吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-磺酰胺N-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5,6,7- Tetrahydrothieno[3,2-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000069
Figure PCTCN2022140921-appb-000069
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为2-氟-4-吡啶硼酸，制得化合物8(18mg，产率：12.5％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by 2-fluoro-4-pyridineboronic acid to obtain compound 8 (18mg, yield: 12.5%) .
1H NMR(400MHz,DMSO-d 6)δ8.10(d,1H),7.75(br s,1H),7.23(s,1H),7.18-7.05(m,4H),3.83(s,2H),3.12(s,3H),2.96-2.92(m,4H),2.77(s,2H),2.66(s,2H),2.02-1.95(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.10(d,1H),7.75(br s,1H),7.23(s,1H),7.18-7.05(m,4H),3.83(s,2H) ,3.12(s,3H),2.96-2.92(m,4H),2.77(s,2H),2.66(s,2H),2.02-1.95(m,2H).
LC-MS m/z(ESI):487.0(M+H) +。 LC-MS m/z (ESI): 487.0 (M+H) + .
实施例9Example 9
5-甲基-N-((5-(吡啶-3-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-磺酰胺5-Methyl-N-((5-(pyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4,5,6,7-tetrahydrothiophene And[3,2-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000070
Figure PCTCN2022140921-appb-000070
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为 吡啶-3-硼酸，制得化合物9(15mg，产率：8.6％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by pyridine-3-boronic acid to obtain compound 9 (15 mg, yield: 8.6%).
1H NMR(400MHz,DMSO-d 6)δ8.48-8.47(m,2H),7.66-7.64(m,1H),7.32-7.29(m,1H),7.17-7.13(m,2H),7.07(d,1H),3.67(s,2H),2.93-2.89(m,6H),2.73(t,2H),2.52(s,3H),1.99(m 2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.48-8.47(m,2H),7.66-7.64(m,1H),7.32-7.29(m,1H),7.17-7.13(m,2H),7.07 (d, 1H), 3.67 (s, 2H), 2.93-2.89 (m, 6H), 2.73 (t, 2H), 2.52 (s, 3H), 1.99 (m 2H).
LC-MS m/z(ESI):469.1(M+H) +。 LC-MS m/z (ESI): 469.1 (M+H) + .
实施例10Example 10
N-((5-(5-氟吡啶-3-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-5-甲基-4,5,6,7-四氢噻吩[3,2-c]吡啶-2-磺酰胺N-((5-(5-fluoropyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5,6,7- Tetrahydrothiophene[3,2-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000071
Figure PCTCN2022140921-appb-000071
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为5-氟-3-吡啶硼酸，制得化合物10(6mg，产率：3.2％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by 5-fluoro-3-pyridineboronic acid to obtain compound 10 (6mg, yield: 3.2%) .
1H NMR(400MHz,DMSO-d 6)δ8.45(d,1H),8.36(s,1H),7.61-7.60(m,1H),7.15-7.09(m,2H),7.01(s,1H),3.43(s,2H),2.92-2.87(m,6H),2.76(t,2H),2.52(s,3H),2.02-1.95(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.45(d,1H),8.36(s,1H),7.61-7.60(m,1H),7.15-7.09(m,2H),7.01(s,1H ), 3.43(s,2H), 2.92-2.87(m,6H), 2.76(t,2H), 2.52(s,3H), 2.02-1.95(m,2H).
LC-MS m/z(ESI):487.2(M+H) +。 LC-MS m/z (ESI): 487.2 (M+H) + .
实施例11Example 11
N-((5-(2-氰基嘧啶-5-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-磺酰胺N-((5-(2-cyanopyrimidin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5,6,7 -Tetrahydrothieno[3,2-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000072
Figure PCTCN2022140921-appb-000072
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为2-氰基嘧啶-5-硼酸频哪醇酯，制得化合物11(9mg，产率：6.3％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by 2-cyanopyrimidine-5-boronic acid pinacol ester to obtain compound 11 (9 mg, yield rate: 6.3%).
1H NMR(400MHz,DMSO-d 6)δ8.88(s,2H),7.75(s,1H),7.17(m,2H),6.91(s,1H),3.58(s,2H),2.92(t,2H),2.89-2.83(m,4H),2.81(t,2H),2.52(s,3H),2.04-1.96(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.88(s,2H),7.75(s,1H),7.17(m,2H),6.91(s,1H),3.58(s,2H),2.92( t,2H), 2.89-2.83(m,4H), 2.81(t,2H), 2.52(s,3H), 2.04-1.96(m,2H).
LC-MS m/z(ESI):495.3(M+H) +。 LC-MS m/z (ESI): 495.3 (M+H) + .
实施例12Example 12
((5-(3,6-二氢-2H-吡喃-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-5-甲基-4,5,6,7- 四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)胺钠盐((5-(3,6-Dihydro-2H-pyran-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5 ,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000073
Figure PCTCN2022140921-appb-000073
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸替换(6l)为3,6-二氢-2H-吡喃-4-硼酸频哪醇酯，制得化合物12(57mg，产率：81.1％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid was replaced by (6l) with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to obtain Compound 12 (57 mg, yield: 81.1%).
1H NMR(400MHz,DMSO-d 6)δ7.49(s,1H),7.23(s,1H),7.01-6.98(m,1H),6.89-6.86(m,1H),5.52(s,1H),4.07-4.05(m,2H),3.69-3.65(m,2H),3.52-3.51(m,2H),2.84-2.80(m,6H),2.68-2.63(m,2H),2.51(s,3H),2.14-2.13(m,2H),1.94-1.89(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.49(s,1H),7.23(s,1H),7.01-6.98(m,1H),6.89-6.86(m,1H),5.52(s,1H ),4.07-4.05(m,2H),3.69-3.65(m,2H),3.52-3.51(m,2H),2.84-2.80(m,6H),2.68-2.63(m,2H),2.51(s ,3H), 2.14-2.13(m,2H), 1.94-1.89(m,2H).
LC-MS m/z(ESI):474.1(M+H) +。 LC-MS m/z (ESI): 474.1 (M+H) + .
实施例13Example 13
N-((5-(6-氰基吡啶-3-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-磺酰胺N-((5-(6-cyanopyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5,6,7 -Tetrahydrothieno[3,2-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000074
Figure PCTCN2022140921-appb-000074
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为2-氰基-5-吡啶硼酸，制得化合物13(7mg，产率：6.2％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by 2-cyano-5-pyridineboronic acid to obtain compound 13 (7mg, yield: 6.2% ).
1H NMR(400MHz,DMSO-d 6)δ8.66(s,1H),7.91(s,2H),7.55(s,1H),7.12(dd,2H),6.89(s,1H),3.45(s,2H),2.91(t,2H),2.81-2.75(m,6H),2.42(s,3H),2.02-1.95(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.66(s,1H),7.91(s,2H),7.55(s,1H),7.12(dd,2H),6.89(s,1H),3.45( s, 2H), 2.91(t, 2H), 2.81-2.75(m, 6H), 2.42(s, 3H), 2.02-1.95(m, 2H).
LC-MS m/z(ESI):494.1(M+H) +。 LC-MS m/z (ESI): 494.1 (M+H) + .
实施例14Example 14
5-(4-(3-((5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)脲基)-2,3-二氢-1H-茚-5-基)吡啶酰胺5-(4-(3-((5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)ureido)-2,3 -Dihydro-1H-inden-5-yl)pyridineamide
Figure PCTCN2022140921-appb-000075
Figure PCTCN2022140921-appb-000075
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为(6-氨基甲酰基吡啶-3-基)硼酸，制得化合物14(10mg，产率：12.2％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by (6-carbamoylpyridin-3-yl)boronic acid to obtain compound 14 (10 mg, yield rate: 12.2%).
1H NMR(400MHz,DMSO-d 6)δ8.56(d,1H),8.13(s,1H),7.92(d,1H),7.83(dd, 1H),7.59(s,1H),7.42(br s,1H),7.11(dd,2H),6.93(s,1H),3.43(s,2H),2.91(t,2H),2.81-2.74(m,6H),2.41(s,3H),2.02-1.94(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.56(d,1H),8.13(s,1H),7.92(d,1H),7.83(dd,1H),7.59(s,1H),7.42( br s,1H),7.11(dd,2H),6.93(s,1H),3.43(s,2H),2.91(t,2H),2.81-2.74(m,6H),2.41(s,3H), 2.02-1.94 (m, 2H).
LC-MS m/z(ESI):512.3(M+H) +。 LC-MS m/z (ESI): 512.3 (M+H) + .
实施例15Example 15
((5-(2-氟吡啶-3-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)((5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)胺钠盐((5-(2-fluoropyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)((5-methyl-4,5,6,7-tetra Hydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000076
Figure PCTCN2022140921-appb-000076
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为2-氟-3-吡啶硼酸，制得化合物15(11mg，产率：56.8％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by 2-fluoro-3-pyridineboronic acid to obtain compound 15 (11 mg, yield: 56.8%) .
1H NMR(400MHz,DMSO-d 6)δ8.12(d,1H),7.73-7.71(m,1H),7.29(s,1H),7.22-7.17(m,1H),7.06(d,1H),7.00(d,1H),6.84(s,1H),3.32(s,2H),2.90(t,2H),2.82-2.73(m,4H),2.62(t,2H),2.35(s,3H),2.03-1.93(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.12(d,1H),7.73-7.71(m,1H),7.29(s,1H),7.22-7.17(m,1H),7.06(d,1H ),7.00(d,1H),6.84(s,1H),3.32(s,2H),2.90(t,2H),2.82-2.73(m,4H),2.62(t,2H),2.35(s, 3H), 2.03-1.93 (m, 2H).
LC-MS m/z(ESI):487.2(M+H) +。 LC-MS m/z (ESI): 487.2 (M+H) + .
实施例16Example 16
((5-(5-氰基吡啶-3-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)((5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)胺钠盐((5-(5-cyanopyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)((5-methyl-4,5,6,7- Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000077
Figure PCTCN2022140921-appb-000077
采用实施例6的合成路线，将第十步原料2-甲氧基吡啶-4-硼酸(6l)替换为5-氰基-3-吡啶硼酸，制得化合物16(16.93mg，产率：57.7％)。Using the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid (6l) was replaced by 5-cyano-3-pyridineboronic acid to obtain compound 16 (16.93mg, yield: 57.7 %).
1H NMR(400MHz,DMSO-d 6)δ8.80(d,1H),8.73(d,1H),8.12(t,1H),7.51(br s,1H),7.09(dd,2H),6.77(s,1H),3.31(s,2H),2.90(t,2H),2.81-2.74(m,4H),2.62(t,2H),2.35(s,3H),2.02-1.94(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.80(d,1H),8.73(d,1H),8.12(t,1H),7.51(br s,1H),7.09(dd,2H),6.77 (s,1H),3.31(s,2H),2.90(t,2H),2.81-2.74(m,4H),2.62(t,2H),2.35(s,3H),2.02-1.94(m,2H ).
LC-MS m/z(ESI):494.1(M+H) +。 LC-MS m/z (ESI): 494.1 (M+H) + .
实施例17Example 17
((5-(2-氰基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)((5-(2-(甲磺酰基)乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)胺钠盐((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)((5-(2-(methylsulfonyl)ethyl) -4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000078
Figure PCTCN2022140921-appb-000078
第一步first step
于室温，向10mL的反应瓶中加入化合物6f(300mg,1.0mmol)、无水乙醇(4mL)、三乙胺(0.6mL,4.0mmol)和化合物17a(128mg,1.2mmol)，升温至80℃，搅拌16小时。降至室温，减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2,100％乙酸乙酯/石油醚)纯化，得到化合物17b(200mg，产率61.5％)。 Add compound 6f (300mg, 1.0mmol), absolute ethanol (4mL), triethylamine (0.6mL, 4.0mmol) and compound 17a (128mg, 1.2mmol) to a 10mL reaction flask at room temperature, and heat up to 80°C , stirred for 16 hours. Cooled down to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system (SiO 2 , 100% ethyl acetate/petroleum ether) to obtain compound 17b (200 mg, yield 61.5%).
1H NMR(400MHz,DMSO-d 6)δ7.56(s,2H),7.23(s,1H),3.54(s,2H),3.37(t,2H),3.00(s,3H),3.91(t,2H),2.85-2.82(m,2H),2.80-2.77(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.56(s,2H),7.23(s,1H),3.54(s,2H),3.37(t,2H),3.00(s,3H),3.91( t,2H), 2.85-2.82(m,2H), 2.80-2.77(m,2H).
LC-MS m/z(ESI):324.9(M+H) +。 LC-MS m/z (ESI): 324.9 (M+H) + .
第二步second step
于室温，向25mL反应瓶中加入化合物17b(80mg,0.25mmol)和无水四氢呋喃(5mL)。冷却至0℃，缓慢滴加1M叔丁醇钠/四氢呋喃溶液(0.4mL,0.4mmol)。0℃反应0.5小时，加入化合物3k(156mg,0.296mmol)。室温反应1小时。加水(2mL)和甲基叔丁基醚(10mL)。水相冻干后经制备液相色谱(色谱柱：Waters Xbridge150*25mm*5um；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-9min 3-33％B；flow 25ml/min)纯化，得到化合物17c(40.48mg,产率:27.9％)。Compound 17b (80 mg, 0.25 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a 25 mL reaction flask at room temperature. After cooling to 0°C, 1M sodium tert-butoxide/tetrahydrofuran solution (0.4 mL, 0.4 mmol) was slowly added dropwise. After reacting at 0°C for 0.5 hours, compound 3k (156 mg, 0.296 mmol) was added. React at room temperature for 1 hour. Water (2 mL) and methyl tert-butyl ether (10 mL) were added. After the aqueous phase was lyophilized, it was subjected to preparative liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-9min 3-33% B; flow 25ml/ min) was purified to obtain compound 17c (40.48 mg, yield: 27.9%).
1H NMR(400MHz,DMSO-d 6)δ8.56(d,1H),7.90(s,1H),7.76(br s,1H),7.61-7.59(m,1H),7.13(s,2H),6.89(s,1H),3.48(s,2H),3.37(s,2H),3.02(s,3H),2.91(m,4H),2.80(m,6H),2.02-1.99(m,2H)。LC-MS m/z(ESI):586.3(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ8.56(d,1H),7.90(s,1H),7.76(br s,1H),7.61-7.59(m,1H),7.13(s,2H) ,6.89(s,1H),3.48(s,2H),3.37(s,2H),3.02(s,3H),2.91(m,4H),2.80(m,6H),2.02-1.99(m,2H ). LC-MS m/z (ESI): 586.3 (M+H) + .
第三步third step
将化合物17c(38mg)溶解在乙腈(1mL)中，滴加进IR120阳离子交换树脂-Na型柱子中，用乙腈:水＝0:1-20:80-40:60-50:50-1:0体系洗脱。合并馏分，冻干得到化合物17(40mg,产率:93.1％)。Compound 17c (38 mg) was dissolved in acetonitrile (1 mL), and added dropwise to an IR120 cation exchange resin-Na column, using acetonitrile:water=0:1-20:80-40:60-50:50-1: 0 system elution. Fractions were combined and lyophilized to obtain compound 17 (40 mg, yield: 93.1%).
1H NMR(400MHz,DMSO-d 6)δ8.55(d,1H),7.90(s,1H),7.61-7.59(m,2H),7.10(s,2H),6.80(s,1H),3.47(s,2H),3.38(s,2H),3.01(s,3H),2.91(t,4H),2.83-2.77(m,6H),2.03-1.95(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.55(d,1H),7.90(s,1H),7.61-7.59(m,2H),7.10(s,2H),6.80(s,1H), 3.47(s,2H), 3.38(s,2H), 3.01(s,3H), 2.91(t,4H), 2.83-2.77(m,6H), 2.03-1.95(m,2H).
LC-MS m/z(ESI):586.1(M+H) +。 LC-MS m/z (ESI): 586.1 (M+H) + .
实施例18Example 18
N-((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-5-(2-(甲磺酰基)乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-磺酰胺N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-(methylsulfonyl)ethyl base)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000079
Figure PCTCN2022140921-appb-000079
采用与实施例6相类似的合成方法，用化合物17b与化合物6n反应制得化合物18(20mg,产率：3.6％)。Compound 18 (20 mg, yield: 3.6%) was prepared by reacting compound 17b with compound 6n using a synthesis method similar to that of Example 6.
1H NMR(400MHz,DMSO-d 6)δ8.04(d,1H),7.74(s,1H),7.21(s,1H),7.17(d,1H),7.08(d,1H),6.83(d,1H),6.70(s,1H),3.85(s,3H),3.52(s,2H),3.37-3.30(m,2H),3.00(s,3H),2.93-2.89(m,4H),2.84-2.80(m,4H),2.71-2.67(m,2H),2.02-1.94(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.04(d,1H),7.74(s,1H),7.21(s,1H),7.17(d,1H),7.08(d,1H),6.83( d,1H),6.70(s,1H),3.85(s,3H),3.52(s,2H),3.37-3.30(m,2H),3.00(s,3H),2.93-2.89(m,4H) ,2.84-2.80(m,4H),2.71-2.67(m,2H),2.02-1.94(m,2H).
LC-MS m/z(ESI):591.4(M+H) +。 LC-MS m/z (ESI): 591.4 (M+H) + .
实施例19Example 19
((5-((3-(羟甲基)氧杂环丁烷-3-基)甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)胺钠盐((5-((3-(Hydroxymethyl)oxetan-3-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- Base)sulfonyl)((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000080
Figure PCTCN2022140921-appb-000080
第一步first step
于室温，向50mL单口瓶依次加入化合物19a(1.21g,6.68mmol)、化合物6f (2.00g,6.68mmol)、三乙胺(2.80mL,20.1mmol)和N,N-二甲基甲酰胺(10mL)，100℃反应16小时。冷却到室温，减压浓缩。粗品经制备液相色谱法(色谱柱:Kromasil Eternity XT 250*80mm*10μm；流动相:水相(10mM碳酸氢铵)和乙腈；梯度配比:0-20min 5-30％B；flow 140mL/min)纯化，得到化合物19b(600mg,产率：24.7％)。At room temperature, compound 19a (1.21g, 6.68mmol), compound 6f (2.00g, 6.68mmol), triethylamine (2.80mL, 20.1mmol) and N,N-dimethylformamide ( 10 mL), react at 100°C for 16 hours. Cool to room temperature and concentrate under reduced pressure. The crude product was subjected to preparative liquid chromatography (chromatographic column: Kromasil Eternity XT 250*80mm*10 μm; mobile phase: aqueous phase (10mM ammonium bicarbonate) and acetonitrile; gradient ratio: 0-20min 5-30% B; flow 140mL/ min) was purified to obtain compound 19b (600 mg, yield: 24.7%).
1H NMR(400MHz,DMSO-d 6)δ7.46(s,2H),7.23(s,1H),4.82(s,1H),4.36-4.28(m,4H),3.64(s,2H),3.42(s,2H),2.80(t,2H),2.77(s,2H),2.66(t,2H)。LC-MS m/z(ESI):319.1(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ7.46(s,2H),7.23(s,1H),4.82(s,1H),4.36-4.28(m,4H),3.64(s,2H), 3.42(s,2H), 2.80(t,2H), 2.77(s,2H), 2.66(t,2H). LC-MS m/z (ESI): 319.1 (M+H) + .
第二步second step
采用与实施例6相类似的合成方法，用化合物19b与化合物6n反应制得化合物19(93mg,产率:69.1％)。Compound 19 (93 mg, yield: 69.1%) was prepared by reacting compound 19b with compound 6n using a synthesis method similar to that of Example 6.
1H NMR(400MHz,DMSO-d 6)δ8.03(d,1H),7.26(s,1H),7.07(d,1H),7.02(d,1H),6.92-6.89(m,2H),6.76(s,1H),4.82(s,1H),4.35-4.30(m,4H),3.85(s,3H),3.65(s,2H),3.35(s,2H),2.88(t,2H),2.77-2.72(m,6H),2.65-2.62(m,2H),2.00-1.92(m,2H)。LC-MS m/z(ESI):585.1(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ8.03(d,1H),7.26(s,1H),7.07(d,1H),7.02(d,1H),6.92-6.89(m,2H), 6.76(s,1H),4.82(s,1H),4.35-4.30(m,4H),3.85(s,3H),3.65(s,2H),3.35(s,2H),2.88(t,2H) ,2.77-2.72(m,6H),2.65-2.62(m,2H),2.00-1.92(m,2H). LC-MS m/z (ESI): 585.1 (M+H) + .
实施例20Example 20
((5-(2-(氧杂环丁烷-3-基氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)((5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)胺钠盐((5-(2-(Oxetane-3-yloxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)((5- Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000081
Figure PCTCN2022140921-appb-000081
第一步first step
于室温，向25mL反应瓶中加入60％钠氢(32.9mg,0.822mmol)和四氢呋喃(5mL)。冷却到0℃，加入化合物20a(45.7mg,0.617mmol)。继续0℃下搅拌0.5小时，加入化合物8(200mg,0.411mmol)。室温搅拌8小时，反应液倒入冰水(5mL)，乙酸乙酯萃取(3mL×3)。有机相用饱和氯化钠水溶液洗涤(5mL×1)，无水硫酸钠干燥。过滤，减压浓缩，粗品经制备液相色谱(色谱柱:Waters Xbridge 150*50mm*10um；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-11min 15-45％B；flow 60mL/min)纯化，得到化合物20b(37mg,产率:16.7％)。To a 25 mL reaction flask was added 60% sodium hydrogen (32.9 mg, 0.822 mmol) and tetrahydrofuran (5 mL) at room temperature. After cooling to 0°C, compound 20a (45.7 mg, 0.617 mmol) was added. Stirring was continued at 0°C for 0.5 hours, and compound 8 (200 mg, 0.411 mmol) was added. After stirring at room temperature for 8 hours, the reaction solution was poured into ice water (5 mL), and extracted with ethyl acetate (3 mL×3). The organic phase was washed with saturated aqueous sodium chloride (5 mL×1), and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure, the crude product was subjected to preparative liquid chromatography (chromatographic column: Waters Xbridge 150*50mm*10um; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-11min 15-45% B; flow 60mL/min) to obtain compound 20b (37mg, yield: 16.7%).
1H NMR(400MHz,DMSO-d 6)δ8.01(d,1H),7.75(br s,1H),7.17-7.14(m,2H),7.08(d,1H),6.91(d,1H),6.82(s,1H),5.59-5.53(m,1H),4.91(t,2H),4.58(dd,2H), 3.74(s,2H),2.95-2.89(m,6H),2.73(t,2H),2.60(s,3H),2.02-1.95(m,2H)。LC-MS m/z(ESI):541.1(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ8.01(d,1H),7.75(br s,1H),7.17-7.14(m,2H),7.08(d,1H),6.91(d,1H) ,6.82(s,1H),5.59-5.53(m,1H),4.91(t,2H),4.58(dd,2H), 3.74(s,2H),2.95-2.89(m,6H),2.73(t ,2H), 2.60(s,3H), 2.02-1.95(m,2H). LC-MS m/z (ESI): 541.1 (M+H) + .
第二步second step
将化合物20b(37mg,0.068mmol)溶解在乙腈(1mL)中，滴加进IR120阳离子交换树脂-Na型柱子中，用乙腈:水＝1:0-0:1体系洗脱。合并馏分，冻干得到化合物20(32mg,产率:86.8％)。Compound 20b (37 mg, 0.068 mmol) was dissolved in acetonitrile (1 mL), added dropwise to IR120 cation exchange resin-Na column, and eluted with acetonitrile:water=1:0-0:1 system. Fractions were combined and lyophilized to obtain compound 20 (32 mg, yield: 86.8%).
1H NMR(400MHz,DMSO-d 6)δ7.98(d,1H),7.44(br s,1H),7.10(d,1H),7.06-7.02(m,2H),6.93(d,1H),6.82(s,1H),5.58-5.53(m,1H),4.89(t,2H),4.58(dd,2H),3.49(s,2H),2.89(t,2H),2.83-2.72(m,6H),2.44(s,3H),1.99-1.95(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.98(d,1H),7.44(br s,1H),7.10(d,1H),7.06-7.02(m,2H),6.93(d,1H) ,6.82(s,1H),5.58-5.53(m,1H),4.89(t,2H),4.58(dd,2H),3.49(s,2H),2.89(t,2H),2.83-2.72(m ,6H), 2.44(s,3H), 1.99-1.95(m,2H).
LC-MS m/z(ESI):541.2(M+H) +。 LC-MS m/z (ESI): 541.2 (M+H) + .
实施例21Example 21
((4-羟基-4-甲基-4,,5,6,7-四氢苯并呋喃-2-基)磺酰基)((5-(2-甲氧吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)胺钠盐((4-Hydroxy-4-methyl-4,,5,6,7-tetrahydrobenzofuran-2-yl)sulfonyl)((5-(2-methoxypyridin-4-yl)-2 ,3-Dihydro-1H-inden-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000082
Figure PCTCN2022140921-appb-000082
采用实施例5的合成路线，将第一步原料6,7-二氢-4(5H)-苯并噻吩酮(5a)替换为6,7-二氢-4(5H)-苯并呋喃酮，制得化合物21(17mg，产率：55％)。Using the synthetic route of Example 5, the first step raw material 6,7-dihydro-4(5H)-benzothiophenone (5a) was replaced by 6,7-dihydro-4(5H)-benzofuranone , Compound 21 (17 mg, yield: 55%) was prepared.
1H NMR(400MHz,DMSO-d 6)δ8.07(d,1H),7.36(s,1H),7.12-7.01(m,2H),6.98-6.90(m,1H),6.77(s,1H),6.51(s,1H),4.71(s,1H),3.86(s,3H),3.62-3.51(m,2H),2.88(t,2H),2.77(t,2H),2.05-1.89(m,3),1.79-1.64(m,2H),1.62-1.53(m,1H),1.31(s,3H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.07(d,1H),7.36(s,1H),7.12-7.01(m,2H),6.98-6.90(m,1H),6.77(s,1H ),6.51(s,1H),4.71(s,1H),3.86(s,3H),3.62-3.51(m,2H),2.88(t,2H),2.77(t,2H),2.05-1.89( m, 3), 1.79-1.64 (m, 2H), 1.62-1.53 (m, 1H), 1.31 (s, 3H).
LC-MS m/z(ESI):498.2(M+H) +。 LC-MS m/z (ESI): 498.2 (M+H) + .
实施例22Example 22
3-氰基-N-((5-(2-氰基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-磺酰胺3-cyano-N-((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-methyl-4, 5,6,7-Tetrahydrothieno[2,3-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000083
Figure PCTCN2022140921-appb-000083
Figure PCTCN2022140921-appb-000084
Figure PCTCN2022140921-appb-000084
于室温，向反应瓶中依次加入化合物1i(50mg,0.19mmol)和四氢呋喃(1mL)。冰水浴降至0℃后，加入叔丁醇钠(22mg,0.23mmol)，升至室温搅拌0.5小时，随后将化合物3k(60mg,0.23mmol)的四氢呋喃(1mL)溶液缓慢加入，室温搅拌3小时。反应完成后，反应液经制备液相色谱法(色谱柱：Waters，Xbridge 250*19mm，10μm；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-10min 45-60％B；flow 25ml/min)纯化，得到化合物22(19mg,18.5％)。At room temperature, compound 1i (50 mg, 0.19 mmol) and tetrahydrofuran (1 mL) were sequentially added to the reaction flask. After the ice-water bath was lowered to 0°C, sodium tert-butoxide (22 mg, 0.23 mmol) was added, raised to room temperature and stirred for 0.5 hours, then a solution of compound 3k (60 mg, 0.23 mmol) in tetrahydrofuran (1 mL) was slowly added, and stirred at room temperature for 3 hours . After the reaction was completed, the reaction solution was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 45-60% B ; flow 25ml/min) to obtain compound 22 (19mg, 18.5%).
1H NMR(400MHz,DMSO-d 6)δ8.60(d,1H),7.88(s,1H),7.62(s,1H),7.12(s,2H),3.10(s,2H),2.91(t,4H),2.82(d,4H),2.67(s,3H),2.06-1.97(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),7.88(s,1H),7.62(s,1H),7.12(s,2H),3.10(s,2H),2.91( t,4H), 2.82(d,4H), 2.67(s,3H), 2.06-1.97(m,2H).
LC-MS m/z(ESI):519.1(M+H) +。 LC-MS m/z (ESI): 519.1 (M+H) + .
实施例23Example 23
N-((5-(2-氰基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-磺酰胺N-((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-methyl-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000085
Figure PCTCN2022140921-appb-000085
采用与实施例22相类似的合成方法，将化合物2k与化合物3k反应制得化合物23(11mg,19.5％)。Compound 23 (11 mg, 19.5%) was prepared by reacting compound 2k with compound 3k using a synthesis method similar to that of Example 22.
1H NMR(400MHz,DMSO-d 6)δ8.59(d,1H),7.90(s,1H),7.60(d,1H),7.16(d,2H),7.02(s,1H),3.93(s,2H),3.02(s,2H),2.92(t,2H),2.80(t,2H),2.76-2.70(m,2H),2.62(s,3H),2.08-1.93(m,2H)。LC-MS m/z(ESI):494.2(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ8.59(d,1H),7.90(s,1H),7.60(d,1H),7.16(d,2H),7.02(s,1H),3.93( s,2H),3.02(s,2H),2.92(t,2H),2.80(t,2H),2.76-2.70(m,2H),2.62(s,3H),2.08-1.93(m,2H) . LC-MS m/z (ESI): 494.2 (M+H) + .
实施例24Example 24
N-((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-5-甲基-4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-磺酰胺N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000086
Figure PCTCN2022140921-appb-000086
Figure PCTCN2022140921-appb-000087
Figure PCTCN2022140921-appb-000087
采用实施例4的合成路线，将第六步化合物1j替换为化合物6n，制得化合物24(5mg,7.7％)。Compound 24 (5 mg, 7.7%) was obtained by using the synthetic route of Example 4, replacing compound 1j with compound 6n in the sixth step.
1H NMR(400MHz,DMSO-d 6)δ8.09(d,1H),7.11(d,1H),7.05(d,1H),6.95(d,1H),6.76(s,1H),3.87(s,3H),2.97(s,2H),2.89(t,2H),2.84-2.71(m,4H),2.62-2.53(m,5H),2.03-1.92(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.09(d,1H),7.11(d,1H),7.05(d,1H),6.95(d,1H),6.76(s,1H),3.87( s,3H), 2.97(s,2H), 2.89(t,2H), 2.84-2.71(m,4H), 2.62-2.53(m,5H), 2.03-1.92(m,2H).
LC-MS m/z(ESI):500.1(M+H) +。 LC-MS m/z (ESI): 500.1 (M+H) + .
实施例25Example 25
N-((5-(2-氰基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-5-甲基-4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-磺酰胺N-((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridine-2-sulfonamide
Figure PCTCN2022140921-appb-000088
Figure PCTCN2022140921-appb-000088
采用实施例4的合成路线，将第六步化合物1j替换为化合物3k，制得化合物25(20mg,31.8％)。Compound 25 (20 mg, 31.8%) was obtained by using the synthetic route of Example 4, replacing compound 1j with compound 3k in the sixth step.
1H NMR(400MHz,DMSO-d 6)δ8.63(d,1H),7.93(s,1H),7.64(s,1H),7.13(s,2H),4.09(s,2H),3.21(s,2H),2.92(m,4H),2.81(dd,2H),2.70(s,3H),2.04-1.95(m,2H)。LC-MS m/z(ESI):495.2(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ8.63(d,1H),7.93(s,1H),7.64(s,1H),7.13(s,2H),4.09(s,2H),3.21( s, 2H), 2.92 (m, 4H), 2.81 (dd, 2H), 2.70 (s, 3H), 2.04-1.95 (m, 2H). LC-MS m/z (ESI): 495.2 (M+H) + .
实施例26Example 26
((3-氰基-6-(氧杂环丁烷-3-基甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)磺酰基)((1,2,3,5,6,7-六氢-s-indacen-4-基)氨基甲酰基)胺钠盐((3-cyano-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl )((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000089
Figure PCTCN2022140921-appb-000089
采用实施例1的合成路线，将第七步原料多聚甲醛替换为氧杂环丁烷-3-甲醛，制得化合物26(14mg,收率：37.4％)。Using the synthetic route of Example 1, the raw material paraformaldehyde in the seventh step was replaced with oxetane-3-carbaldehyde to obtain compound 26 (14 mg, yield: 37.4%).
1H NMR(400MHz,DMSO-d 6)δ7.50(s,1H),6.77(s,1H),4.63(dd,2H),4.26(t,2H),3.53(s,2H),3.27-3.23(m,2H),2.81-2.66(m,11H),2.05-1.99(m,2H),1.93-1.88(m,4H)。LC-MS m/z(ESI):513.1(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ7.50(s,1H),6.77(s,1H),4.63(dd,2H),4.26(t,2H),3.53(s,2H),3.27- 3.23 (m, 2H), 2.81-2.66 (m, 11H), 2.05-1.99 (m, 2H), 1.93-1.88 (m, 4H). LC-MS m/z (ESI): 513.1 (M+H) + .
实施例27Example 27
((3-氰基-6-乙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)磺酰基)((1,2,3,5,6,7-六氢-s-indacen-4-基)氨基甲酰基)胺钠盐((3-cyano-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl)((1,2,3,5, 6,7-Hexahydro-s-indacen-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000090
Figure PCTCN2022140921-appb-000090
采用实施例1的合成路线，将第七步原料多聚甲醛替换为乙醛，制得化合物27(42mg,收率：56.2％)。Using the synthetic route of Example 1, the raw material paraformaldehyde in the seventh step was replaced with acetaldehyde to obtain compound 27 (42 mg, yield: 56.2%).
1H NMR(400MHz,DMSO-d 6)δ7.52(s,1H),6.77(s,1H),3.56(s,2H),2.75-2.53(m,14H),1.98-1.83(m,4H),1.06(t,3H)。LC-MS m/z(ESI):471.2(M+H) +。 1 H NMR (400MHz,DMSO-d 6 )δ7.52(s,1H),6.77(s,1H),3.56(s,2H),2.75-2.53(m,14H),1.98-1.83(m,4H ), 1.06(t,3H). LC-MS m/z (ESI): 471.2 (M+H) + .
实施例28Example 28
((6-乙酰基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)磺酰基)((1,2,3,5,6,7-六氢-s-indacen-4-基)氨基甲酰基)胺钠盐((6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl)((1,2,3,5,6,7-hexa Hydrogen-s-indacen-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000091
Figure PCTCN2022140921-appb-000091
0℃，向25mL单口瓶中加入化合物2i(100mg,0.384mmol)、四氢呋喃(2mL)、叔丁醇钠(37mg,0.38mmol)，室温搅拌40分钟。加入化合物1j(76mg,0.38mmol)， 搅拌3小时。减压浓缩，残余物经制备液相色谱法(色谱柱：Waters，Xbridge250*19mm，10μm；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-10min 30-65％B；flow 25ml/min)纯化，得到粗品，粗品经钠离子交换树脂交换后，得到化合物28(48mg,产率：26.0％)。Add compound 2i (100 mg, 0.384 mmol), tetrahydrofuran (2 mL), sodium tert-butoxide (37 mg, 0.38 mmol) into a 25 mL one-necked bottle at 0°C, and stir at room temperature for 40 minutes. Compound 1j (76 mg, 0.38 mmol) was added and stirred for 3 hours. Concentrated under reduced pressure, the residue was subjected to preparative liquid chromatography (chromatographic column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 30-65% B; flow 25ml/min) to obtain the crude product, which was exchanged with sodium ion exchange resin to obtain compound 28 (48 mg, yield: 26.0%).
1H NMR(400MHz,DMSO-d 6)δ7.43(s,1H),7.09(d,1H),6.77(s,1H),4.62(d,2H),3.75-3.57(m,2H),2.76(t,4H),2.68(t,6H),2.07(m,3H),1.94-1.87(m,4H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.43(s,1H),7.09(d,1H),6.77(s,1H),4.62(d,2H),3.75-3.57(m,2H), 2.76 (t, 4H), 2.68 (t, 6H), 2.07 (m, 3H), 1.94-1.87 (m, 4H).
LC-MS m/z(ESI):460.1(M+H) +。 LC-MS m/z (ESI): 460.1 (M+H) + .
实施例29Example 29
((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)((6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)磺酰基)胺钠盐((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)((6-methyl-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000092
Figure PCTCN2022140921-appb-000092
采用实施例2的合成路线，将第十一步化合物1j替换为化合物6n，制得化合物29(16mg,产率：14.1％)。Using the synthetic route of Example 2, compound 1j was replaced by compound 6n in the eleventh step to obtain compound 29 (16 mg, yield: 14.1%).
1H NMR(400MHz,DMSO-d 6)δ8.03(d,1H),7.25(s,1H),7.08(d,1H),7.03(d,1H),6.94(s,1H),6.92(d,1H),6.76(s,1H),3.85(s,3H),3.48(s,2H),2.89(t，2H),2.77(t,2H),2.59(s,4H),2.35(s,3H),2.03-1.88(m,2H)。LC-MS m/z(ESI):499.2(M+H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.03(d,1H),7.25(s,1H),7.08(d,1H),7.03(d,1H),6.94(s,1H),6.92( d,1H),6.76(s,1H),3.85(s,3H),3.48(s,2H),2.89(t,2H),2.77(t,2H),2.59(s,4H),2.35(s ,3H), 2.03-1.88(m,2H). LC-MS m/z (ESI): 499.2 (M+H).
实施例30Example 30
((6-乙酰基-4,5,6,7-四氢呋喃并[2,3-c]吡啶-2-基)磺酰基)((1,2,3,5,6,7-六氢-s-indacen-4-基)氨基甲酰基)胺钠盐((6-acetyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)sulfonyl)((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000093
Figure PCTCN2022140921-appb-000093
Figure PCTCN2022140921-appb-000094
Figure PCTCN2022140921-appb-000094
第一步first step
向单口瓶中依次加入化合物30a(8.00g，83.3mmol)、乙醇(100mL)、硝基甲烷(4.4mL,83mmol)，0℃加入10N氢氧化钠水溶液(8.3mL,83mmol)，搅拌1小时。将反应液倒入15％的盐酸水溶液(100mL)中，析出固体，过滤，将滤饼减压，干燥，得到产物30b(6g,产率：51.8％)。直接用于下一步。Compound 30a (8.00g, 83.3mmol), ethanol (100mL), nitromethane (4.4mL, 83mmol) were sequentially added to a one-necked flask, 10N aqueous sodium hydroxide solution (8.3mL, 83mmol) was added at 0°C, and stirred for 1 hour. The reaction solution was poured into 15% aqueous hydrochloric acid solution (100 mL), and a solid was precipitated, filtered, and the filter cake was decompressed and dried to obtain product 30b (6 g, yield: 51.8%). used directly in the next step.
第二步second step
向单口瓶中加入2.5M四氢铝锂的四氢呋喃溶液(6.4mL,16mmol)和2mL四氢呋喃，0℃滴加硫酸(0.4mL,8mmol)，搅拌20分钟。加入化合物30b(500mg,3.59mmol)的四氢呋喃(2mL)溶液，搅拌10分钟。加热至回流，搅拌5分钟。降到0℃，加入异丙醇(1.7mL,21.6mmol)和氢氧化钠(1.29g，32.3mmol)，过滤，用乙酸乙酯洗涤滤饼，收集滤液，减压浓缩，得到粗产物30c(380mg，粗品)，直接用于下一步反应。Add 2.5M tetrahydrofuran solution of lithium aluminum tetrahydrogen (6.4mL, 16mmol) and 2mL tetrahydrofuran to the one-necked flask, add sulfuric acid (0.4mL, 8mmol) dropwise at 0°C, and stir for 20 minutes. A solution of compound 30b (500 mg, 3.59 mmol) in tetrahydrofuran (2 mL) was added and stirred for 10 minutes. Heat to reflux and stir for 5 minutes. Cool down to 0°C, add isopropanol (1.7mL, 21.6mmol) and sodium hydroxide (1.29g, 32.3mmol), filter, wash the filter cake with ethyl acetate, collect the filtrate, and concentrate under reduced pressure to obtain the crude product 30c ( 380mg, crude product), directly used in the next reaction.
LC-MS m/z(ESI):112.1。LC-MS m/z (ESI): 112.1.
第三步third step
于室温，在100mL单口瓶中依次加入化合物30c(380mg,3.42mmol)、二氯甲烷(2mL)、三乙胺(0.8mL,5.4mmol)、二碳酸二叔丁酯(0.9mL,3.76mmol)，室温搅拌1小时。减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2，10％乙酸乙酯/石油醚)纯化，得到化合物30d(480mg，产率：55.4％)。 At room temperature, compound 30c (380mg, 3.42mmol), dichloromethane (2mL), triethylamine (0.8mL, 5.4mmol), di-tert-butyl dicarbonate (0.9mL, 3.76mmol) were sequentially added to a 100mL single-necked bottle , stirred at room temperature for 1 hour. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system (SiO 2 , 10% ethyl acetate/petroleum ether) to obtain compound 30d (480 mg, yield: 55.4%).
1H NMR(400MHz,CDCl 3)δ7.37(t,1H),7.27(s,1H),6.29(s,1H),4.59(s,1H),3.32-3.31(m,2H),2.61(t,2H),1.44(m,9H)。 1 H NMR (400MHz, CDCl 3 )δ7.37(t,1H),7.27(s,1H),6.29(s,1H),4.59(s,1H),3.32-3.31(m,2H),2.61( t,2H), 1.44(m,9H).
第四步the fourth step
于室温，向100mL单口瓶中依次加入化合物30d(380mg,1.80mmol)、甲苯(8mL)、多聚甲醛(34mg，0.95mmol)、对甲基苯磺酸(6mg，0.04mmol)，回流搅拌2小时。加水(10mL)和乙酸乙酯(20mL)，有机相用盐水(10mL)洗涤，收集有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2，10％乙酸乙酯/石油醚)纯化，得到化合物30e(200mg,产率：49.8％)。 At room temperature, sequentially add compound 30d (380mg, 1.80mmol), toluene (8mL), paraformaldehyde (34mg, 0.95mmol), p-toluenesulfonic acid (6mg, 0.04mmol) into a 100mL single-necked bottle, and stir at reflux for 2 Hour. Add water (10mL) and ethyl acetate (20mL), wash the organic phase with brine (10mL), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is eluted by silica gel column chromatography (SiO 2 , 10% ethyl acetate/petroleum ether) to obtain compound 30e (200 mg, yield: 49.8%).
1H NMR(400MHz,CDCl 3)δ7.28(d,1H),6.24(d,1H),4.44(s,2H),3.63(s,2H), 2.53-2.51(m,2H),1.48(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.28(d,1H),6.24(d,1H),4.44(s,2H),3.63(s,2H), 2.53-2.51(m,2H),1.48( s, 9H).
第五步the fifth step
于室温，在100mL单口瓶中依次加入化合物30e(3.93g,17.5mmol)、二氯甲烷(24mL)、三氟乙酸(8mL)，搅拌2小时。浓缩得到化合物30f(3.2g，粗品)，直接用于下一步。At room temperature, compound 30e (3.93 g, 17.5 mmol), dichloromethane (24 mL), and trifluoroacetic acid (8 mL) were sequentially added into a 100 mL one-necked bottle, and stirred for 2 hours. Concentration gave compound 30f (3.2 g, crude product), which was directly used in the next step.
LC-MS m/z(ESI)：124.4(M+H) +。 LC-MS m/z (ESI): 124.4 (M+H) + .
第六步step six
于室温，在250mL的单口瓶中，加入化合物30f(3.20g,16.3mmol)、四氢呋喃(90mL)、三乙胺(4mL,28.6mmol)，降到0℃，滴加乙酰氯(2mL,28.6mmol)，升至室温，搅拌1小时。过滤，向滤液加水(30mL)，用乙酸乙酯(30mL×3)萃取，减压浓缩，残余物用硅胶柱色谱法以洗脱体系(SiO 2，15％乙酸乙酯/石油醚)纯化，得到化合物30g(1.69g，产率：62.8％)。 At room temperature, in a 250mL one-necked bottle, add compound 30f (3.20g, 16.3mmol), tetrahydrofuran (90mL), triethylamine (4mL, 28.6mmol), drop to 0 ℃, add dropwise acetyl chloride (2mL, 28.6mmol ), warmed to room temperature, and stirred for 1 hour. After filtration, water (30 mL) was added to the filtrate, extracted with ethyl acetate (30 mL×3), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system (SiO 2 , 15% ethyl acetate/petroleum ether), Compound 30g (1.69g, yield: 62.8%) was obtained.
LC-MS m/z(ESI)：166.0(M+H) +。 LC-MS m/z (ESI): 166.0 (M+H) + .
第七步step seven
于室温，在50mL单口瓶中依次加入化合物30g(1.69g,10.2mmol)、二氯甲烷(10mL)。降温至0℃，加入氯磺酸(1.79g,15.3mmol)，于室温，搅拌10分钟。加入冰水(20mL)淬灭，水相用反向柱C18(水/乙腈，HCl体系)进行纯化，得到化合物30h(2.3g，产率：92.0％)。At room temperature, 30 g of compound (1.69 g, 10.2 mmol) and dichloromethane (10 mL) were sequentially added into a 50 mL one-necked bottle. Cool down to 0°C, add chlorosulfonic acid (1.79g, 15.3mmol), and stir at room temperature for 10 minutes. Ice water (20 mL) was added to quench, and the aqueous phase was purified by reverse column C18 (water/acetonitrile, HCl system) to obtain compound 30h (2.3 g, yield: 92.0%).
LC-MS m/z(ESI)：246.3(M+H) +。 LC-MS m/z (ESI): 246.3 (M+H) + .
第八步eighth step
于室温，向50mL单口瓶中依次加入化合物30h(600mg,2.45mmol)、二氯甲烷(12mL)，随后加入吡啶(0.2mL,2.7mmol)，在氮气氛下加入五氯化磷(764mg,3.67mmol)，搅拌12小时，将反应液倒入冰水(15mL)中，升至室温，用二氯甲烷(20mL)萃取，有机相干燥，过滤，滤液减压浓缩，得到产物30i(500mg，产率：77.4％)。At room temperature, compound 30h (600mg, 2.45mmol) and dichloromethane (12mL) were sequentially added to a 50mL single-necked bottle, followed by pyridine (0.2mL, 2.7mmol), and phosphorus pentachloride (764mg, 3.67mL) was added under a nitrogen atmosphere. mmol), stirred for 12 hours, the reaction solution was poured into ice water (15mL), raised to room temperature, extracted with dichloromethane (20mL), the organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain product 30i (500mg, product rate: 77.4%).
LC-MS m/z(ESI):264.2(M+H) +。 LC-MS m/z (ESI): 264.2 (M+H) + .
第九步Ninth step
于室温，化合物30i(500mg,1.90mmol)溶于二氯甲烷(2mL)，将化合物30i(500mg,1.90mmol)的二氯甲烷(2mL)溶液滴加到7M氨甲醇溶液(20mL)中，搅拌1小时。减压浓缩，用反向柱C18(水/乙腈，氨水体系)进行纯化，得到化合物30j(150mg，产率：32.3％)。At room temperature, compound 30i (500mg, 1.90mmol) was dissolved in dichloromethane (2mL), the solution of compound 30i (500mg, 1.90mmol) in dichloromethane (2mL) was added dropwise to 7M ammonia methanol solution (20mL), stirred 1 hour. It was concentrated under reduced pressure and purified by reverse column C18 (water/acetonitrile, ammonia water system) to obtain compound 30j (150 mg, yield: 32.3%).
LC-MS m/z(ESI)：245.3(M+H)。LC-MS m/z (ESI): 245.3 (M+H).
第十步tenth step
0℃下，在50mL单口瓶中加入化合物30j(100mg,0.384mmol)、四氢呋喃(2mL)，加入叔丁醇钠(19.7mg,0.205mmol)。于室温搅拌40分钟。加入化合物1j(40.8mg,0.205mmol)的四氢呋喃(2mL)。搅拌3小时。反应液经制备液相色谱(色谱柱： Waters，Xbridge 250*19mm，10μm；流动相：水相(0.05％氨水)和乙腈，梯度配比：0-10min 45-60％B；flow 25ml/min)纯化，得到粗品，粗品用钠离子交换树脂交换，得到化合物30(42mg，产率：23.5％)。At 0°C, compound 30j (100 mg, 0.384 mmol), tetrahydrofuran (2 mL) and sodium tert-butoxide (19.7 mg, 0.205 mmol) were added to a 50 mL single-necked bottle. Stir at room temperature for 40 minutes. Compound 1j (40.8 mg, 0.205 mmol) in tetrahydrofuran (2 mL) was added. Stir for 3 hours. The reaction solution was subjected to preparative liquid chromatography (column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 45-60% B; flow 25ml/min ) was purified to obtain a crude product, which was exchanged with sodium ion exchange resin to obtain compound 30 (42 mg, yield: 23.5%).
1H NMR(400MHz,DMSO-d 6)δ7.45(s,1H),6.77(s,1H),6.45(s,1H),4.51-4.46(m,2H),3.67-3.60(m,2H),2.75(m,4H),2.69-2.63(m,4H),2.39-2.33(m,2H),2.09-2.06(m,3H),1.98-1.81(m,4H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.45(s,1H),6.77(s,1H),6.45(s,1H),4.51-4.46(m,2H),3.67-3.60(m,2H ), 2.75 (m, 4H), 2.69-2.63 (m, 4H), 2.39-2.33 (m, 2H), 2.09-2.06 (m, 3H), 1.98-1.81 (m, 4H).
LC-MS m/z(ESI):444.2(M+H) +。 LC-MS m/z (ESI): 444.2 (M+H) + .
实施例31Example 31
((5-甲基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-基)磺酰基)((2,4,5,6-四氢-1H-环丁烷并[f]茚-3-基)氨基甲酰基)胺钠盐((5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H-cyclobutane Alk[f]inden-3-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000095
Figure PCTCN2022140921-appb-000095
第一步first step
将化合物3g(104mg,0.481mmol)溶解在无水四氢呋喃(5mL)中，降温至0℃，滴入叔丁醇钠溶液(0.5mL,0.5mmol,1M四氢呋喃溶液)，0℃搅拌半小时后，加入化合物31a(81mg,0.437mmol，采用专利申请“WO2020018975中说明书第339页的实施例141”公开的方法制备而得)，0℃继续反应半小时。反应液浓缩后，粗品经反相柱(0-23.5％，乙腈/0.2％氨水)纯化，得到化合物31b(70mg，产率：39.87％)。Compound 3g (104mg, 0.481mmol) was dissolved in anhydrous tetrahydrofuran (5mL), cooled to 0°C, sodium tert-butoxide solution (0.5mL, 0.5mmol, 1M tetrahydrofuran solution) was added dropwise, and stirred at 0°C for half an hour, Compound 31a (81mg, 0.437mmol, prepared by the method disclosed in the patent application "Example 141 on page 339 of the specification in WO2020018975") was added, and the reaction was continued at 0°C for half an hour. After the reaction solution was concentrated, the crude product was purified by reverse phase column (0-23.5%, acetonitrile/0.2% ammonia water) to obtain compound 31b (70 mg, yield: 39.87%).
1H NMR(400MHz,DMSO-d 6)δ7.69(s,1H),6.72(s,1H),6.58(s,1H),3.76(s,2H),3.06-3.00(m,2H),2.84-2.83(m,4H),2.78(t,2H),2.69-2.66(m,4H),2.49(s,3H),1.96-1.88(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.69(s,1H),6.72(s,1H),6.58(s,1H),3.76(s,2H),3.06-3.00(m,2H), 2.84-2.83 (m, 4H), 2.78 (t, 2H), 2.69-2.66 (m, 4H), 2.49 (s, 3H), 1.96-1.88 (m, 2H).
LC-MS m/z:402.2(M+H) +。 LC-MS m/z: 402.2 (M+H) + .
第二步second step
装填好两根IR120阳离子交换树脂-钠型柱子(高约15厘米)后，分别用去离子水(20mL)、乙腈(20mL)、去离子水(20mL)冲洗柱子，冲洗完毕后，将化合物31b(70mg,0.174mmol)用乙腈(2mL)溶解后滴加到柱子里，以洗脱体系(0:1-1:0，乙腈/水)冲洗柱子，洗脱下来的馏分加到第二根柱子上，将洗脱两次后的馏分合并，冻干，得到化合物31(49mg，产率：66.15％) 1H NMR(400MHz,DMSO-d 6)δ7.54(s,1H),6.52(s,1H),6.43(s,1H),3.22(s,2H),3.05-3.03(m,2H),2.82-2.75(m,4H), 2.69-2.62(m,6H),2.33(s,3H),1.97-1.87(m,2H)。 After filling two IR120 cation exchange resin-sodium columns (about 15 cm in height), wash the columns with deionized water (20mL), acetonitrile (20mL), and deionized water (20mL) respectively. After washing, compound 31b (70mg, 0.174mmol) was dissolved in acetonitrile (2mL) and added dropwise to the column, washed with the elution system (0:1-1:0, acetonitrile/water), and the eluted fraction was added to the second column Above, the fractions eluted twice were combined and lyophilized to obtain compound 31 (49 mg, yield: 66.15%) 1 H NMR (400 MHz, DMSO-d 6 ) δ7.54 (s, 1H), 6.52 (s ,1H),6.43(s,1H),3.22(s,2H),3.05-3.03(m,2H),2.82-2.75(m,4H), 2.69-2.62(m,6H),2.33(s,3H ), 1.97-1.87(m,2H).
LC-MS m/z(ESI):402.1(M+H) +。 LC-MS m/z (ESI): 402.1 (M+H) + .
实施例32Example 32
((5-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)((2,4,5,6-四氢-1H-环丁烷并[f]茚-3-基)氨基甲酰基)胺钠盐((5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H- Cyclobutano[f]inden-3-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000096
Figure PCTCN2022140921-appb-000096
采用实施例31的合成路线，将第一步化合物3g替换为化合物6g，制得化合物32(9mg，产率：6.3％)。Using the synthetic route of Example 31, compound 3g was replaced by compound 6g in the first step to obtain compound 32 (9 mg, yield: 6.3%).
1H NMR(400MHz,DMSO-d 6)δ7.42(s,1H)7.02(s,1H)6.51(s,1H)3.29(s,2H)3.03-3.09(m,2H)2.81(t,2H)2.77(t,2H)2.74(t,2H)2.67(t,2H)2.56(t,2H)2.32(s,3H)1.90(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.42(s,1H)7.02(s,1H)6.51(s,1H)3.29(s,2H)3.03-3.09(m,2H)2.81(t,2H ) 2.77 (t, 2H) 2.74 (t, 2H) 2.67 (t, 2H) 2.56 (t, 2H) 2.32 (s, 3H) 1.90 (m, 2H).
LC-MS m/z:418.0(M+H) +。 LC-MS m/z: 418.0 (M+H) + .
实施例33Example 33
((5-乙基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)((2,4,5,6-四氢-1H-环丁烷并[f]茚-3-基)氨基甲酰基)胺钠盐((5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H- Cyclobutano[f]inden-3-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000097
Figure PCTCN2022140921-appb-000097
第一步first step
向二甲基亚砜(15mL)中加入化合物6f(1g,3.34mmol)，冰水浴降温至0℃，缓慢加入氟化铯(0.76g,5.01mmol)，再加入碘乙烷(0.63g,4.01mmol)，自然升温至室温，20℃搅拌1小时。反应液不处理直接用反向柱色谱法(C18，30％，乙腈/0.2％氨水)纯化，得到化合物1b(220mg,产率26.7％)。Add compound 6f (1g, 3.34mmol) to dimethyl sulfoxide (15mL), cool down to 0°C in an ice-water bath, slowly add cesium fluoride (0.76g, 5.01mmol), then add iodoethane (0.63g, 4.01 mmol), naturally warmed to room temperature, and stirred for 1 hour at 20°C. The reaction solution was directly purified by reverse column chromatography (C18, 30%, acetonitrile/0.2% ammonia water) without any treatment to obtain compound 1b (220 mg, yield 26.7%).
1H NMR(400MHz,DMSO-d 6)δ7.55(s,2H),7.24(s,1H),3.43(s,2H),2.82(t,J＝5.6Hz,2H),2.70(t,J＝5.6Hz,2H),2.52(q,J＝7.2Hz,2H),1.07(t,J＝7.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ7.55(s, 2H), 7.24(s, 1H), 3.43(s, 2H), 2.82(t, J=5.6Hz, 2H), 2.70(t, J=5.6Hz, 2H), 2.52(q, J=7.2Hz, 2H), 1.07(t, J=7.2Hz, 3H).
LC-MS m/z(ESI)：247.1(M+H) +。 LC-MS m/z (ESI): 247.1 (M+H) + .
第二步second step
采用实施例31的合成路线，将第一步化合物3g替换为化合物33a，制得化合物33(55.91mg,产率14.4％)。Using the synthetic route of Example 31, the first step compound 3g was replaced by compound 33a to obtain compound 33 (55.91 mg, yield 14.4%).
1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),7.71(s,1H),7.30(s,1H),6.60(s,1H),3.93(s,2H),3.21-3.13(m,2H),3.08-3.03(m,2H),2.99-2.93(m,4H),2.85-2.80(m,2H),2.76(t,J＝7.6Hz,2H),2.65(t,J＝7.6Hz,2H),1.95-1.88(m,2H),1.18(t,J＝7.2Hz,3H)。 1 H NMR (400MHz,DMSO-d 6 )δ10.19(s,1H),7.71(s,1H),7.30(s,1H),6.60(s,1H),3.93(s,2H),3.21- 3.13(m,2H),3.08-3.03(m,2H),2.99-2.93(m,4H),2.85-2.80(m,2H),2.76(t,J＝7.6Hz,2H),2.65(t, J=7.6Hz, 2H), 1.95-1.88(m, 2H), 1.18(t, J=7.2Hz, 3H).
LC-MS m/z(ESI):432.2(M+H) +。 LC-MS m/z (ESI): 432.2 (M+H) + .
实施例34Example 34
((5-异丙基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)((2,4,5,6-四氢-1H-环丁烷并[f]茚-3-基)氨基甲酰基)胺钠盐((5-isopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H -Cyclobutane[f]inden-3-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000098
Figure PCTCN2022140921-appb-000098
采用实施例33的合成路线，将原料碘乙烷替换为碘代异丙烷，制得化合物34(86.82mg,产率12％) 1H NMR(400MHz,DMSO-d 6)δ7.58(s,1H),7.17(s,1H),6.56(s,1H),3.77(s,2H),3.17-3.14(m,1H),3.06-3.00(m,4H),2.87-2.83(m,4H),2.77(t,J＝7.2Hz,2H),2.67(t,J＝7.2Hz,2H),1.94-1.87(m,2H),1.13(d,J＝6.4Hz,6H)。 Using the synthetic route of Example 33, the raw material iodoethane was replaced by iodoisopropane to obtain compound 34 (86.82 mg, yield 12%) 1 H NMR (400MHz, DMSO-d 6 ) δ7.58(s, 1H),7.17(s,1H),6.56(s,1H),3.77(s,2H),3.17-3.14(m,1H),3.06-3.00(m,4H),2.87-2.83(m,4H) , 2.77 (t, J = 7.2Hz, 2H), 2.67 (t, J = 7.2Hz, 2H), 1.94-1.87 (m, 2H), 1.13 (d, J = 6.4Hz, 6H).
LC-MS m/z(ESI)：446.2(M+H) +。 LC-MS m/z (ESI): 446.2 (M+H) + .
实施例35Example 35
((5-氰基甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)磺酰基)((2,4,5,6-四氢-1H-环丁烷并[f]茚-3-基)氨基甲酰基)胺钠盐((5-cyanomethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro- 1H-Cyclobutano[f]inden-3-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000099
Figure PCTCN2022140921-appb-000099
采用实施例33的合成路线，将原料碘乙烷替换为溴乙腈，制得化合物35(18.61mg,产率39.85％)。Using the synthetic route of Example 33, the raw material iodoethane was replaced by bromoacetonitrile to obtain compound 35 (18.61 mg, yield 39.85%).
1H NMR(400MHz,DMSO-d 6)δ7.45(s,1H),7.08(s,1H),6.52(s,1H),3.90(s,2H),3.51(s,2H),3.08-3.03(m,2H),2.82-2.75(m,8H),2.67(t,J＝7.2Hz,2H),1.93-1.86(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.45(s,1H),7.08(s,1H),6.52(s,1H),3.90(s,2H),3.51(s,2H),3.08- 3.03 (m, 2H), 2.82-2.75 (m, 8H), 2.67 (t, J=7.2Hz, 2H), 1.93-1.86 (m, 2H).
LC-MS m/z(ESI):465.2(M+Na) +。 LC-MS m/z (ESI): 465.2 (M+Na) + .
实施例36Example 36
((5-乙基-4,5,6,7-四氢呋喃并[3,2-c]吡啶-2-基)磺酰基)((2,4,5,6-四氢-1H-环丁烷并[f]茚-3-基)氨基甲酰基)胺钠盐((5-Ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H-cyclobutane Alk[f]inden-3-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000100
Figure PCTCN2022140921-appb-000100
采用实施例3的合成路线，将第四步中原料三甲基氧鎓四氟硼酸盐替换为三乙基氧鎓四氟硼酸盐，第九步中原料3k替换为化合物31a，制得化合物36(18.61mg,产率39.85％)。Using the synthetic route of Example 3, the raw material trimethyloxonium tetrafluoroborate in the fourth step was replaced by triethyloxonium tetrafluoroborate, and the raw material 3k was replaced by compound 31a in the ninth step to obtain Compound 36 (18.61 mg, yield 39.85%).
1H NMR(400MHz,DMSO-d 6):δ7.60(br s,1H),6.54(s,2H),3.53-3.44(m,2H),3.07-3.02(m,2H),2.96-2.86(m,2H),2.82-2.76(m,4H),2.69-2.65(m,6H),1.91(quint,J＝7.2Hz,2H),1.10(t,J＝7.2Hz,3H)。 1 H NMR(400MHz,DMSO-d 6 ):δ7.60(br s,1H),6.54(s,2H),3.53-3.44(m,2H),3.07-3.02(m,2H),2.96-2.86 (m, 2H), 2.82-2.76 (m, 4H), 2.69-2.65 (m, 6H), 1.91 (quint, J=7.2Hz, 2H), 1.10 (t, J=7.2Hz, 3H).
LC-MS m/z(ESI)：416.0(M+H) +。 LC-MS m/z (ESI): 416.0 (M+H) + .
实施例37Example 37
((6-甲基-4,5,6,7-四氢呋喃并[2,3-c]吡啶-2-基)磺酰基)((2,4,5,6-四氢-1H-环丁烷并[f]茚-3-基)氨基甲酰基)胺钠盐((6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H-cyclobutane Alk[f]inden-3-yl)carbamoyl)amine sodium salt
Figure PCTCN2022140921-appb-000101
Figure PCTCN2022140921-appb-000101
采用实施例3的合成路线，将原料3a替换为呋喃并[2,3-C]吡啶，第九步中原料3k替换为31a，制得化合物37(38.36mg，产率：99.23％)。Using the synthetic route of Example 3, the raw material 3a was replaced by furo[2,3-C]pyridine, and the raw material 3k was replaced by 31a in the ninth step to obtain compound 37 (38.36 mg, yield: 99.23%).
1H NMR(400MHz,DMSO-d 6)δ7.54(s,1H),6.52(s,1H),6.46-6.45(m,1H),3.37(s,2H),3.04-3.03(m,2H),2.81-2.80(m,2H),2.77(t,2H),2.67(t,2H),2.57-2.54(m,2H),2.43-2.41(m,2H),2.35(s,3H),1.94-1.86(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.54(s,1H),6.52(s,1H),6.46-6.45(m,1H),3.37(s,2H),3.04-3.03(m,2H ),2.81-2.80(m,2H),2.77(t,2H),2.67(t,2H),2.57-2.54(m,2H),2.43-2.41(m,2H),2.35(s,3H), 1.94-1.86 (m, 2H).
LC-MS m/z(ESI):402.3(M+H) +。 LC-MS m/z (ESI): 402.3 (M+H) + .
实施例38Example 38
((1,2,3,5,6,7-六氢-s-indacen-4-基)氨基甲酰基)((6-甲基-4,5,6,7-四氢呋喃并[2,3-c]吡啶-2-基)磺酰基)胺钠盐((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-methyl-4,5,6,7-tetrahydrofuro[2,3 -c]pyridin-2-yl)sulfonyl)amine sodium salt
Figure PCTCN2022140921-appb-000102
Figure PCTCN2022140921-appb-000102
采用实施例37的合成路线，将原料31a替换为化合物1j，制得化合物38(110mg，产率：95.4％)。Using the synthetic route of Example 37, the starting material 31a was replaced by compound 1j to obtain compound 38 (110 mg, yield: 95.4%).
1H NMR(400MHz,DMSO-d 6)δ7.53(s,1H),6.77(s,1H),6.44(s,1H),3.36(s,2H),2.75(t,4H),2.65(t,4H),2.57-2.54(m,2H),2.43-2.40(m,2H),2.35(s,3H),1.94-1.87(m,4H)。 1 H NMR (400MHz,DMSO-d 6 )δ7.53(s,1H),6.77(s,1H),6.44(s,1H),3.36(s,2H),2.75(t,4H),2.65( t, 4H), 2.57-2.54(m, 2H), 2.43-2.40(m, 2H), 2.35(s, 3H), 1.94-1.87(m, 4H).
LC-MS m/z(ESI)：416.2(M+H) +。 LC-MS m/z (ESI): 416.2 (M+H) + .
生物学评价biological evaluation
测试例1：THP-1细胞中NLRP3炎症小体活性抑制实验Test Example 1: Inhibition of NLRP3 Inflammasome Activity in THP-1 Cells
1)实验材料1) Experimental materials
Figure PCTCN2022140921-appb-000103
Figure PCTCN2022140921-appb-000103
2)实验步骤2) Experimental steps
将THP-1细胞重悬于RPMI1640、10％FBS、1％P/S的细胞培养基中，调整细胞密度为1×10 6个/mL。将10mL THP-1细胞铺在直径10cm的细胞培养皿中，加入PMA分化处理，PMA的终浓度为10ng/mL。细胞在37℃，5％二氧化碳的细胞培养箱里孵育24小时后，取出培养皿，去除上清及未贴壁的细胞，将细胞消化 后重悬，以10 5个/孔的数量接种在96孔板中。细胞板放入培养箱中孵育过夜，12小时后取出，去掉培养基，加入50uL新鲜的含有200ng/mL LPS的培养基，置于37℃，5％二氧化碳的细胞培养箱里孵育3.5小时。同时，在试管中以DMSO配制浓度为30mM的化合物储备溶液，然后以DMSO为溶剂，根据需要梯度稀释样品，最后稀释333倍于培养基中。在96孔板中每孔转移50uL待测样品，于37℃，5％二氧化碳的细胞培养箱中孵育0.5小时。取出96孔板，再向每孔加入50uL含有15uM Negericin的培养基，于37℃，5％二氧化碳的细胞培养箱中孵育1小时。取出细胞板，离心后取上清，按照ELISA试剂盒说明书操作，检测IL-1β。细胞板中的细胞加入试剂，按照CellTiter-Glo Luminescent Cell Viability Assay Kit的说明书操作，检测细胞活性。 THP-1 cells were resuspended in RPMI1640, 10% FBS, 1% P/S cell culture medium, and the cell density was adjusted to 1×10 6 cells/mL. Spread 10 mL of THP-1 cells in a cell culture dish with a diameter of 10 cm, and add PMA for differentiation treatment, and the final concentration of PMA is 10 ng/mL. After the cells were incubated at 37°C in a 5% carbon dioxide incubator for 24 hours, the culture dish was taken out , the supernatant and unattached cells were removed, the cells were digested and resuspended, and seeded at 96 in the orifice plate. The cell plate was incubated overnight in the incubator, removed after 12 hours, removed the medium, added 50uL of fresh medium containing 200ng/mL LPS, and incubated in a cell incubator at 37°C and 5% carbon dioxide for 3.5 hours. At the same time, prepare a stock solution of the compound with a concentration of 30 mM in DMSO in a test tube, then use DMSO as a solvent to gradually dilute the sample as required, and finally dilute it 333 times in the medium. Transfer 50uL of the sample to be tested in each well of a 96-well plate, and incubate at 37°C for 0.5 hour in a cell culture incubator with 5% carbon dioxide. Take out the 96-well plate, add 50uL medium containing 15uM Negericin to each well, and incubate for 1 hour at 37°C in a cell culture incubator with 5% carbon dioxide. Take out the cell plate, take the supernatant after centrifugation, and follow the instructions of the ELISA kit to detect IL-1β. The cells in the cell plate were added with reagents, and the cell viability was detected according to the instructions of the CellTiter-Glo Luminescent Cell Viability Assay Kit.
表1为本发明化合物对THP-1细胞中NLRP3炎症小体活性抑制的IC 50值。 Table 1 shows the IC 50 values of compounds of the present invention for inhibiting NLRP3 inflammasome activity in THP-1 cells.
表1本发明化合物对THP-1细胞中NLRP3炎症小体活性抑制的IC 50值 Table 1 The compounds of the present invention inhibit the IC50 value of NLRP3 inflammasome activity in THP-1 cells
实施例编号Example number IC 50 IC50 编号serial number IC 50 IC50
实施例1Example 1 BB 实施例16Example 16 AA
实施例2Example 2 BB 实施例17Example 17 BB
实施例3Example 3 AA 实施例18Example 18 BB
实施例4Example 4 CC 实施例19Example 19 AA
实施例5Example 5 BB 实施例20Example 20 AA
实施例6Example 6 AA 实施例21Example 21 BB
实施例7Example 7 BB 实施例22Example 22 AA
实施例8Example 8 AA 实施例23Example 23 AA
实施例9Example 9 AA 实施例24Example 24 BB
实施例10Example 10 BB 实施例25Example 25 BB
实施例11Example 11 CC 实施例26Example 26 BB
实施例12Example 12 AA 实施例27Example 27 BB
实施例13Example 13 BB 实施例28Example 28 BB
实施例14Example 14 BB 实施例29Example 29 AA
实施例15Example 15 AA 实施例30Example 30 BB
实施例31Example 31 AA 实施例32Example 32 AA
实施例33Example 33 AA 实施例34Example 34 AA
实施例35Example 35 BB 实施例36Example 36 BB
实施例37Example 37 BB 实施例38Example 38 BB
注：A<0.1uM；0.1uM<B<1uM；1uM<C<10uMNote: A<0.1uM; 0.1uM<B<1uM; 1uM<C<10uM
结论：in conclusion:
测试例2：本发明化合物的药代动力学评价Test Example 2: Pharmacokinetic evaluation of the compound of the present invention
1)小鼠药代动力学评价1) Pharmacokinetic evaluation in mice
雄性CD-1小鼠(n＝3，6只/化合物，购自斯贝福(北京)生物技术有限公司)，将试验化合物溶解后得到澄清溶液，分别经尾静脉注射和灌胃给药。收集给药后5分钟、15分钟、0.5小时、1小时、2小时、4小时、8小时和24小时内的血浆样品，静脉注射给药剂量为1mg/kg，灌胃组给药剂量为3mg/kg，静脉溶媒为5％DMSO、5％Solutol和90％水，口服溶媒为0.5％HPMC、0.1％TW80水溶液。分别从隐静脉采血并离心后获得血浆，使用LC-MS/MS测定血药浓度，并使用Phoenix WinNonlin进行非房室分析来估计药代动力学参数如：清除率(Cl)，达峰浓度(C max)，半衰期(T 1/2)，药时曲线下面积(AUC 0-t)，生物利用度(F)等。 Male CD-1 mice (n=3, 6 mice/compound, purchased from Speiford (Beijing) Biotechnology Co., Ltd.), dissolved the test compound to obtain a clear solution, and administered it through tail vein injection and intragastric administration, respectively. Plasma samples were collected within 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. The dosage for intravenous injection was 1 mg/kg, and the dosage for intragastric administration was 3 mg /kg, the intravenous vehicle is 5% DMSO, 5% Solutol and 90% water, and the oral vehicle is 0.5% HPMC, 0.1% TW80 aqueous solution. Blood was collected from the saphenous vein and centrifuged to obtain plasma, and the plasma concentration was determined using LC-MS/MS, and non-compartmental analysis was performed using Phoenix WinNonlin to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration ( C max ), half-life (T 1/2 ), area under the drug-time curve (AUC 0-t ), bioavailability (F), etc.
表2为本发明化合物在小鼠体内的药代动力学参数。Table 2 is the pharmacokinetic parameters of the compounds of the present invention in mice.
表2 本发明化合物在小鼠体内的药代动力学参数Table 2 Pharmacokinetic parameters of compounds of the present invention in mice
Figure PCTCN2022140921-appb-000104
Figure PCTCN2022140921-appb-000104
注：i.g.灌胃给药；i.v.静脉给药。Note: i.g. intragastric administration; i.v. intravenous administration.
结论：本公开化合物在小鼠体内具有很好的药代吸收活性，具有药代动力学优势。Conclusion: The disclosed compound has good pharmacokinetic absorption activity in mice, and has pharmacokinetic advantages.
2)SD大鼠药代动力学评价2) Pharmacokinetic evaluation of SD rats
雄性SD大鼠(n＝3，6只/化合物，购自斯贝福(北京)生物技术有限公司)，将试验化合物溶解后得到澄清溶液，分别经尾静脉注射和灌胃给药。收集给药后5分钟、15分钟、0.5小时、1小时、2小时、4小时、8小时和24小时内的血浆样品，静脉注射给药剂量为1mg/kg，灌胃组给药剂量为3mg/kg，静脉溶媒为5％DMSO、5％Solutol和90％水，口服溶媒为0.5％HPMC、0.1％TW80水溶液。分别从隐静脉采血并离心后获得血浆，使用LC-MS/MS测定血药浓度，并使用Phoenix  WinNonlin进行非房室分析来估计药代动力学参数如：清除率(Cl)，达峰浓度(C max)，半衰期(T 1/2)，药时曲线下面积(AUC 0-t)，生物利用度(F)等。 Male SD rats (n=3, 6 rats/compound, purchased from Speifu (Beijing) Biotechnology Co., Ltd.), the test compound was dissolved to obtain a clear solution, which was injected into the tail vein and administered by intragastric administration, respectively. Plasma samples were collected within 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. The dosage for intravenous injection was 1 mg/kg, and the dosage for intragastric administration was 3 mg /kg, the intravenous vehicle is 5% DMSO, 5% Solutol and 90% water, and the oral vehicle is 0.5% HPMC, 0.1% TW80 aqueous solution. Blood was collected from the saphenous vein and centrifuged to obtain plasma, and the plasma concentration was determined using LC-MS/MS, and non-compartmental analysis was performed using Phoenix WinNonlin to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration ( C max ), half-life (T 1/2 ), area under the drug-time curve (AUC 0-t ), bioavailability (F), etc.
表3为本发明化合物在大鼠体内的药代动力学参数。Table 3 is the pharmacokinetic parameters of the compounds of the present invention in rats.
表3 本发明化合物在大鼠体内的药代动力学参数Table 3 Pharmacokinetic parameters of compounds of the present invention in rats
Figure PCTCN2022140921-appb-000105
Figure PCTCN2022140921-appb-000105
注：i.g.灌胃给药；i.v.静脉给药。Note: i.g. intragastric administration; i.v. intravenous administration.
结论：本公开化合物在大鼠体内具有很好的药代吸收活性，具有药代动力学优势。Conclusion: The disclosed compound has good pharmacokinetic absorption activity in rats, and has pharmacokinetic advantages.

Claims (47)

  1. 式I所示的化合物或其可药用盐，A compound represented by formula I or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022140921-appb-100001
    Figure PCTCN2022140921-appb-100001
    其中：in:
    R 1为
    Figure PCTCN2022140921-appb-100002
     R1 is
    Figure PCTCN2022140921-appb-100002
    R 2为
    Figure PCTCN2022140921-appb-100003
     R2 is
    Figure PCTCN2022140921-appb-100003
    X 1选自S和O； X1 is selected from S and O;
    X 2为CR 5或N； X 2 is CR 5 or N;
    A、B各自独立地选自NR 7、C(R 4a) 2和O； A and B are each independently selected from NR 7 , C(R 4a ) 2 and O;
    E、D各自独立地选自NR 7b、C(R 6a) 2和O； E and D are each independently selected from NR 7b , C(R 6a ) 2 and O;
    R 3选自氢、C 1-6烷基、3-6元环烷基；所述C 1-6烷基、3-6元环烷基任选被一个或多个选自C 1-6烷基、3-6元环烷基、卤素、氰基、羟基的取代基所取代； R 3 is selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl; said C 1-6 alkyl, 3-6 membered cycloalkyl is optionally selected from one or more of C 1-6 Substituents of alkyl, 3-6 membered cycloalkyl, halogen, cyano, hydroxyl;
    R 7或R 7b独立地选自氢、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、硝基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基、
    Figure PCTCN2022140921-appb-100004
    Figure PCTCN2022140921-appb-100005
    所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2、-CO-C 1-6烷基如-COCH 3、-SO 2-C 1-6烷基、-C 1-6亚烷基-SO 2CH 3、-C 1-6亚烷基-SO 2-3-6元杂环烷基任选被一个或多个选自R 7c的取代基所取代；     R 7 or R 7b are independently selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2 , -CO-C 1-6 alkyl Such as -COCH 3 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3- 6-membered heterocycloalkyl,
    Figure PCTCN2022140921-appb-100004
    Figure PCTCN2022140921-appb-100005
    The C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino, -CONH 2 , -CO-C 1-6 alkyl such as -COCH 3 , -SO 2 -C 1-6 alkyl, - C 1-6 alkylene-SO 2 CH 3 , -C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl is optionally substituted by one or more substituents selected from R 7c ;
    R 7a选自氢、氰基、羟基、卤素和硝基；优选R 7a为氰基或羟基； R 7a is selected from hydrogen, cyano, hydroxyl, halogen and nitro; preferably R 7a is cyano or hydroxyl;
    R 7c独立地选自C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氨基、氰基、硝基、羟基的取代基所取代；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元 杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代； R 7c is independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkane Substituents of base, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, amino, cyano, nitro, hydroxyl; the C 1-6 alkyl, -OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered Heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl;
    每个R 4a、R 4b、R 4c、R 4d、R 4e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 4f所取代； Each R 4a , R 4b , R 4c , R 4d , R 4e is the same or different, and each independently selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Heteroaryl, phenyl; -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkane Base, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 4f ;
    或R 4a彼此间形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 4a form =S, =0, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl among each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally One or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl substituents;
    或R 4b和R 4c、R 4d和R 4e与其相连的原子一起形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 4b and R 4c , R 4d and R 4e form =S, =O, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl together with the atoms connected to them; the 3-8 membered cycloalkyl Or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O- Substituents of 3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl replaced by
    R 5选自氢、卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 5a所取代； R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; said -CONH 2 , C 1-6 alkyl,- OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Member heteroaryl and phenyl are optionally substituted by one or more R 5a ;
    每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、羟基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 6f所取代； Each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, -CONH 2 , C 1-6 alkyl , -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 -6-membered heteroaryl, phenyl; said -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 6f ;
    或R 6a彼此间形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 6a form =S, =O, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl among each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally One or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl substituents;
    或R 6b和R 6c、R 6d和R 6e与其相连的原子一起形成＝S、＝O、3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； Or R 6b and R 6c , R 6d and R 6e form =S, =O, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl together with the atoms connected to them; the 3-8 membered cycloalkyl Or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O- Substituents of 3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl replaced by
    Z为N或CR 12； Z is N or CR 12 ;
    R 12选自氢、C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、-CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a；所述C 1-6 烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2任选被一个或多个R 12b所取代； R 12 is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen , cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a ; the C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally substituted by one or more R 12b ;
    R 12b选自卤素、氰基、羟基、氨基、C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基和苯基；所述C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基和苯基任选被一个或多个R 12c所取代； R 12b is selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered hetero Aryl and phenyl; said C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl optionally substituted by one or more R 12c ;
    R 12a选自C 1-6烷基、3-6元环烷基、3-6元杂环烷基和氨基；所述C 1-6烷基、3-6元环烷基、3-6元杂环烷基和氨基任选被被一个或多个选自卤素、氰基、羟基、氨基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； R 12a is selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino; said C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 Membered heterocycloalkyl and amino are optionally replaced by one or more selected from halogen, cyano, hydroxyl, amino, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl substituents are substituted;
    R 8、R 9、R 10、R 11独立地选自氢、卤素、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、3-6元环烷基、5-6元杂芳基、3-6元杂环烷基任选被一个或多个R 13a所取代； R 8 , R 9 , R 10 , R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3- 6-membered heterocycloalkyl, condensed ring formed by 3-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl Aryl; the C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 heterocycloalkane A condensed ring formed by a radical and a 5-6 membered heteroaryl group, a 3-6 membered cycloalkyl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ;
    或R 8和R 9与其相连的原子一起形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； Or R 8 and R 9 together form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally replaced by One or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13b ;
    或R 10和R 11与其相连的原子一起形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13c所取代； Or R 10 and R 11 together form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally replaced by One or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13c ;
    每个R 13b、R 13c独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个选自卤素、羟基、氰基的取代基所取代； Each R 13b and R 13c are independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; the C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1- 6 alkylene-SO 2 CH 3 is optionally substituted by one or more substituents selected from halogen, hydroxyl, and cyano;
    每个R 13a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、-O-3-6 元环烷基、C 1-6烷基氨基、二C 1-6烷基氨基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基、5-6元杂芳基、-CONH 2、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述氨基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基、5-6元杂芳基、-CONH 2、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个选自C 1-6烷基、氰基、羟基、卤素、-O-C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基取代的C 1-6烷基的取代基所取代； Each R 13a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, C 1-6 alkylamino , Two C 1-6 alkylamino, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, -CONH 2 , -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; The amino, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -CONH 2 , -SO 2 -C 1- 6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 is optionally selected from one or more of C 1-6 alkyl, cyano, hydroxyl, halogen, -OC 1- Substituents of 6 alkyl, halogenated C 1-6 alkyl, cyano substituted C 1-6 alkyl substituted C 1-6 alkyl;
    每个R 7c、R 4f、R 5a、R 6f、R 12c独立地选自C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氨基、氰基、硝基、羟基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代； Each R 7c , R 4f , R 5a , R 6f , and R 12c are independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, amino, cyano, nitro, hydroxyl; the C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 Heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl;
    条件是：requirement is:
    当R 2为任选取代的
    Figure PCTCN2022140921-appb-100006
    时，     When R 2 is optionally substituted
    Figure PCTCN2022140921-appb-100006
    hour,
    R 1不选自
    Figure PCTCN2022140921-appb-100007
    任选取代的
    Figure PCTCN2022140921-appb-100008
    和任选取代的
    Figure PCTCN2022140921-appb-100009
    R 1 is not selected from
    Figure PCTCN2022140921-appb-100007
    Optionally substituted
    Figure PCTCN2022140921-appb-100008
    and optionally replaced by
    Figure PCTCN2022140921-appb-100009
  2. 根据权利要求1所述的式I所示的化合物或其可药用盐，其中：The compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein:
    R 1为
    Figure PCTCN2022140921-appb-100010
     R1 is
    Figure PCTCN2022140921-appb-100010
    R 5如权利要求1中所定义，优选R 5选自氢、甲基、乙基、卤素、氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；更优选R 5为氢； R is as defined in claim 1, preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halo Cyclopropyl, halomethylcyclopropyl; More preferably R is hydrogen;
    R 7b如权利要求1中所定义，优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、-C 1-6亚烷基-SO 2CH 3、
    Figure PCTCN2022140921-appb-100011
    R 7a、R 6a、R 6b、R 6c、R 6d、R 6e如权利要求1中所定义。     R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl , -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxyl substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, -C 1-6 alkylene -SO 2 CH 3 .
    Figure PCTCN2022140921-appb-100011
    R 7a , R 6a , R 6b , R 6c , R 6d , R 6e are as defined in claim 1 .
  3. 根据权利要求1所述的式I所示的化合物或其可药用盐，其中：The compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein:
    R 1为
    Figure PCTCN2022140921-appb-100012
     R1 is
    Figure PCTCN2022140921-appb-100012
    R 5如权利要求1中所定义，优选R 5选自氢、甲基、乙基、卤素、氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；更优选R 5为氢； R is as defined in claim 1, preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halo Cyclopropyl, halomethylcyclopropyl; More preferably R is hydrogen;
    R 7b如权利要求1中所定义，优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、-C 1-6亚烷基-SO 2CH 3、
    Figure PCTCN2022140921-appb-100013
    更优选R 7b选自C 1-6烷基；     R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl , -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxyl substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, -C 1-6 alkylene -SO 2 CH 3 .
    Figure PCTCN2022140921-appb-100013
    More preferably R 7b is selected from C 1-6 alkyl;
    R 7a如权利要求1中所定义，优选地R 7a为氰基； R 7a is as defined in claim 1, preferably R 7a is cyano;
    R 6a、R 6b、R 6c、R 6d、R 6e如权利要求1中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in claim 1 .
  4. 根据权利要求1所述的式I所示的化合物或其可药用盐，其中：The compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein:
    R 1为
    Figure PCTCN2022140921-appb-100014
     R1 is
    Figure PCTCN2022140921-appb-100014
    E、D各自独立地选自C(R 6a) 2和O，且E、D中有且仅有一个为O； E and D are each independently selected from C(R 6a ) 2 and O, and only one of E and D is O;
    R 5如权利要求1中所定义，优选R 5选自氢、甲基、乙基、卤素、氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；更优选R 5为氢； R is as defined in claim 1, preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halo Cyclopropyl, halomethylcyclopropyl; More preferably R is hydrogen;
    R 6a、R 6b、R 6c、R 6d、R 6e如权利要求1中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in claim 1 .
  5. 根据权利要求1所述的式I所示的化合物或其可药用盐，其中：The compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein:
    R 1为
    Figure PCTCN2022140921-appb-100015
     R1 is
    Figure PCTCN2022140921-appb-100015
    E、D各自独立地选自NR 7b、C(R 6a) 2和O，且E、D中有且仅有一个为O； E and D are each independently selected from NR 7b , C(R 6a ) 2 and O, and only one of E and D is O;
    R 5如权利要求1中所定义，优选R 5选自氢、甲基、乙基、卤素、氰基、环丙基、亚甲基环丙基、卤代甲基、卤代乙基、卤代环丙基、卤代甲基环丙基；更优 选R 5为氢； R is as defined in claim 1, preferably R is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halo Cyclopropyl, halomethylcyclopropyl; More preferably R is hydrogen;
    R 7b如权利要求1中所定义，优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、-CO-C 1-6烷基如-COCH 3； R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl , -C 1-6 alkylene-3-6 membered cycloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen, -CO-C 1-6 alkyl such as -COCH 3 ;
    R 6a、R 6b、R 6c、R 6d、R 6e如权利要求1中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in claim 1 .
  6. 根据权利要求1所述的式I所示的化合物或其可药用盐，其中：The compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein:
    R 1选自
    Figure PCTCN2022140921-appb-100016
    R 1 is selected from
    Figure PCTCN2022140921-appb-100016
    E、D各自独立地选自NR 7b、C(R 6a) 2和O， E and D are each independently selected from NR 7b , C(R 6a ) 2 and O,
    R 7b如权利要求1中所定义，优选R 7b选自氢、C 1-6烷基、3-6元杂环烷基、-C 1-6亚烷基-3-6元杂环烷基、-C 1-6亚烷基-3-6元环烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、-CO-C 1-6烷基如-COCH 3；R 6a、R 6b、R 6c、R 6d、R 6e如权利要求1中所定义。 R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl , -C 1-6 alkylene-3-6 membered cycloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen, -CO-C 1-6 alkyl such as -COCH 3 ; R 6a , R 6b , R 6c , R 6d , R 6e are as defined in claim 1.
  7. 根据权利要求1所述的式I所示的化合物或其可药用盐，其中：The compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein:
    R 1选自
    Figure PCTCN2022140921-appb-100017
    R 1 is selected from
    Figure PCTCN2022140921-appb-100017
    R 6a、R 6b、R 6c、R 6d、R 6e如权利要求1中所定义。 R 6a , R 6b , R 6c , R 6d , R 6e are as defined in claim 1 .
  8. 根据权利要求1-7中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-7, wherein:
    每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、羟基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 6f所取代； Each R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, -CONH 2 , C 1-6 alkyl , -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 -6-membered heteroaryl, phenyl; said -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered hetero Cycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl are optionally substituted by one or more R 6f ;
    R 6f如权利要求1中所定义。 R 6f is as defined in claim 1 .
  9. 根据权利要求1-7中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-7, wherein:
    每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、氰基、氨基、硝基、羟基、-CONH 2；所述-CONH 2任选被一个或多个R 6f所取代； Each of R 6a , R 6b , R 6c , R 6d , and R 6e is the same or different, and each is independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, and -CONH 2 ; any of the -CONH 2 Optionally replaced by one or more R 6f ;
    R 6f如权利要求1中所定义。 R 6f is as defined in claim 1 .
  10. 根据权利要求1-7中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-7, wherein:
    每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一个或多个R 6f所取代； Each of R 6a , R 6b , R 6c , R 6d , and R 6e is the same or different, and each is independently selected from C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkane Base, -O-3-6 membered heterocycloalkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, phenyl group; said C 1-6 alkyl group , -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 -6-membered heteroaryl, phenyl is optionally substituted by one or more R 6f ;
    R 6f如权利要求1中所定义。 R 6f is as defined in claim 1 .
  11. 根据权利要求1-7中任一项所述的式I所示的化合物或其可药用盐，其中：每个R 6a、R 6b、R 6c、R 6d、R 6e相同或不同，且各自独立地选自氢、卤素、羟基、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 6f所取代； The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein: each of R 6a , R 6b , R 6c , R 6d , R 6e is the same or different, and each independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl; said C 1-6 alkyl, -OC 1-6 alkyl is optionally replaced by one or more R 6f replaced by
    R 6f如权利要求1中所定义。 R 6f is as defined in claim 1 .
  12. 根据权利要求1-11中任一项所述的式I所示的化合物或其可药用盐，其中：每个R 6f独立地选自C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代。 According to the compound shown in formula I according to any one of claims 1-11 or its pharmaceutically acceptable salt, wherein: each R 6f is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 The heteroaryl group is optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy.
  13. 根据权利要求1-11中任一项所述的式I所示的化合物或其可药用盐，其中：R 6f独立地选自卤素、氨基、氰基、硝基、羟基。 The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein: R 6f is independently selected from halogen, amino, cyano, nitro, hydroxyl.
  14. 根据权利要求1-11中任一项所述的式I所示的化合物或其可药用盐，其中：R 6f独立地选自卤素、氰基、羟基、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基任选被一个或多个选自卤素、氨基、氰基、硝基、羟基的取代基所取代。 According to any one of claims 1-11, the compound shown in formula I or a pharmaceutically acceptable salt thereof, wherein: R 6f is independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3 -6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl is optionally replaced by one or more substituents selected from halogen, amino, cyano, nitro, hydroxyl replace.
  15. 根据权利要求1-7中任一项所述的式I所示的化合物或其可药用盐，其中，R 6d和R 6e与其相连的原子一起3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代。 The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 6d and R 6e are 3-8-membered cycloalkyl or 3-8-membered together with the atoms connected to them. Heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 Alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl substituents are substituted.
  16. 根据权利要求1-7中任一项所述的式I所示的化合物或其可药用盐，其中：R 6a彼此间形成3-8元环烷基或3-8元杂环烷基，或R 6b和R 6c、R 6d和R 6e形成3-8 元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代。 According to the compound shown in formula I according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein: R 6a form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group, Or R 6b and R 6c , R 6d and R 6e form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkyl group or 3-8 membered heterocycloalkyl group is optionally By one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O- Substituents of 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl.
  17. 根据权利要求1-7中任一项所述的式I所示的化合物或其可药用盐，其中：R 6d和R 6e形成3-8元环烷基或3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基的取代基所取代； The compound shown in formula I according to any one of claims 1-7 or its pharmaceutically acceptable salt, wherein: R 6d and R 6e form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl ; The 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally replaced by one or more selected from halogen, cyano, amino, nitro, -CONH 2 , C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Substituents of heteroaryl and phenyl are substituted;
    优选R 6d和R 6e形成3-8元杂环烷基；所述3-8元环烷基或3-8元杂环烷基任选被一个或多个选自卤素、氰基、氨基、硝基、-CONH 2、C 1-6烷基的取代基所取代。 Preferably R 6d and R 6e form a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkyl group or 3-8 membered heterocycloalkyl group is optionally replaced by one or more members selected from halogen, cyano, amino, Nitro, -CONH 2 , C 1-6 alkyl substituents.
  18. 根据权利要求1所述的式I所示的化合物或其可药用盐，其中：The compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein:
    R 1为
    Figure PCTCN2022140921-appb-100018
     R1 is
    Figure PCTCN2022140921-appb-100018
    R 7如权利要求1中所定义，优选R 7为甲基； R 7 is as defined in claim 1, preferably R 7 is methyl;
    R 3如权利要求1中所定义，优选R 3为甲基、丙基、异丙基、羟基乙基； R 3 is as defined in claim 1, preferably R 3 is methyl, propyl, isopropyl, hydroxyethyl;
    R 4a、R 4b、R 4c、R 4d、R 4e根据权利要求1中所定义，优选R 4a、R 4b、R 4c、R 4d、R 4e为氢。 R 4a , R 4b , R 4c , R 4d , R 4e are as defined in claim 1, preferably R 4a , R 4b , R 4c , R 4d , R 4e are hydrogen.
  19. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2为
    Figure PCTCN2022140921-appb-100019
     R2 is
    Figure PCTCN2022140921-appb-100019
    R 8、R 9、R 10、R 11如权利要求1中所定义。 R 8 , R 9 , R 10 , R 11 are as defined in claim 1 .
  20. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2为
    Figure PCTCN2022140921-appb-100020
     R2 is
    Figure PCTCN2022140921-appb-100020
    R 8和R 9形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 8 and R 9 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkane Groups such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 are optionally substituted by one or more R 13b ;
    R 10、R 11独立地选自氢、卤素、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、3-6元杂环烷基、5-6元杂芳基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基、3-6元杂环烷基任选被一个或多个R 13a所取代； R 10 and R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , condensed ring formed by 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 hetero A condensed ring formed by a cycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ;
    R 12、R 13a、R 13b如权利要求1中所定义。 R 12 , R 13a , R 13b are as defined in claim 1 .
  21. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2为
    Figure PCTCN2022140921-appb-100021
     R2 is
    Figure PCTCN2022140921-appb-100021
    R 8和R 9形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 8 and R 9 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkane Groups such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 are optionally substituted by one or more R 13b ;
    R 10和R 11形成4-7元环烷基或5-6元杂环烷基，所述4-7元环烷基或5-6元杂环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂 环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13c所取代； R 10 and R 11 form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the 4-7 membered cycloalkyl group or 5-6 membered heterocycloalkyl group is optionally selected from one or more Halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C Substituted by 1-6 alkylene-SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkane Groups such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 are optionally substituted by one or more R 13c ;
    R 12、R 13b、R 13c如权利要求1中所定义。 R 12 , R 13b , R 13c are as defined in claim 1 .
  22. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2为
    Figure PCTCN2022140921-appb-100022
     R2 is
    Figure PCTCN2022140921-appb-100022
    Z为N或CR 12； Z is N or CR 12 ;
    R 8和R 9形成4-7元环烷基，所述4-7元环烷基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 8 and R 9 form a 4-7 membered cycloalkyl group, and the 4-7 membered cycloalkyl group is optionally selected from one or more halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 Substituted by heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 ; C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13b ;
    R 10、R 11独立地选自氢、卤素、C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、3-6元杂环烷基、5-6元杂芳基；所述C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基、3-6元杂环烷基任选被一个或多个R 13a所取代； R 10 and R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , condensed ring formed by 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; said C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 hetero A condensed ring formed by a cycloalkyl group and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group, and a 3-6 membered heterocycloalkyl group are optionally substituted by one or more R 13a ;
    R 10、R 11、R 12、R 13a、R 13b如权利要求1中所定义。 R 10 , R 11 , R 12 , R 13a , R 13b are as defined in claim 1 .
  23. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2为
    Figure PCTCN2022140921-appb-100023
     R2 is
    Figure PCTCN2022140921-appb-100023
    Z为N或CR 12； Z is N or CR 12 ;
    R 9a、R 9b、R 9c、R 9d、R 9e、R 9f各自独立地选自氢、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6 元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Elementary heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; said C 1-6 alkyl, halogenated C 1- 6- Alkyl, -OC 1-6- Alkyl, -O-3-6-membered Cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6-membered Cycloalkyl, 3-6-membered Heterocycloalkane radical, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 optionally replaced by one or more R 13b replace;
    R 10选自3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基；所述3-6元杂环烷基和5-6元杂芳基形成的稠环、5-6元杂芳基任选被一个或多个R 13a所取代； R 10 is selected from condensed rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heteroaryl; the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl A condensed ring formed by a group, a 5-6 membered heteroaryl group is optionally substituted by one or more R 13a ;
    R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
    R 12、R 13a、R 13b如权利要求1中所定义。 R 12 , R 13a , R 13b are as defined in claim 1 .
  24. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2为
    Figure PCTCN2022140921-appb-100024
     R2 is
    Figure PCTCN2022140921-appb-100024
    Z为N或CR 12； Z is N or CR 12 ;
    R 9a、R 9b、R 9c、R 9d、R 9e、R 9f各自独立地选自氢、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13b所取代； R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, - OC 1-6- membered alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 Elementary heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 ; said C 1-6 alkyl, halogenated C 1- 6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkane radical, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 optionally replaced by one or more R 13b replace;
    R 10选自任选被一个或多个R 13a所取代的5-6元杂芳基； R 10 is selected from 5-6 membered heteroaryl optionally substituted by one or more R 13a ;
    R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
    R 12、R 13a、R 13b如权利要求1中所定义。 R 12 , R 13a , R 13b are as defined in claim 1 .
  25. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2选自： R2 is selected from:
    Figure PCTCN2022140921-appb-100025
    Figure PCTCN2022140921-appb-100025
    Figure PCTCN2022140921-appb-100026
    Figure PCTCN2022140921-appb-100026
    Z为N或CR 12； Z is N or CR 12 ;
    R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
    R 10a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3的取代基所取代；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、-SO 2-C 1-6烷基如-SO 2CH 3、-C 1-6亚烷基-SO 2CH 3任选被一个或多个R 13c所取代； R 10a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene -SO 2 CH 3 substituents; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl, - O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2 -C 1-6 alkyl such as -SO 2 CH 3 , -C 1-6 alkylene-SO 2 CH 3 is optionally substituted by one or more R 13c ;
    R 10b选自C 1-6烷基，所述C 1-6烷基任选被C 3-6环烷基所取代； R 10b is selected from C 1-6 alkyl, the C 1-6 alkyl is optionally substituted by C 3-6 cycloalkyl;
    n、m独立地选自0-3的整数；优选n、m独立地选自0-2的整数；n and m are independently selected from integers of 0-3; preferably n and m are independently selected from integers of 0-2;
    R 8、R 9、R 12、R 13a、R 13c如权利要求1中所定义； R 8 , R 9 , R 12 , R 13a , R 13c are as defined in claim 1;
    R 9a、R 9b、R 9c、R 9d、R 9e、R 9f如权利要求23中所定义。 R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are as defined in claim 23.
  26. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中：According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 1-18, wherein:
    R 2为
    Figure PCTCN2022140921-appb-100027
     R2 is
    Figure PCTCN2022140921-appb-100027
    Z为N或CR 12； Z is N or CR 12 ;
    R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代； R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a ;
    n选自0-3的整数；n is an integer selected from 0-3;
    R 12、R 13a、R 13c如权利要求1中所定义； R 12 , R 13a , R 13c are as defined in claim 1;
    R 9a、R 9b、R 9c、R 9d、R 9e、R 9f如权利要求23中所定义。 R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are as defined in claim 23.
  27. 根据权利要求1-26中任一项所述的式I所示的化合物或其可药用盐，其中Z为N。The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, wherein Z is N.
  28. 根据权利要求1-26中任一项所述的式I所示的化合物或其可药用盐，其中Z为CR 12； The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, wherein Z is CR 12 ;
    R 12如权利要求1中所定义。 R 12 is as defined in claim 1 .
  29. 根据权利要求1-26中任一项所述的式I所示的化合物或其可药用盐，其中，R 12选自氢、C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、-CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a；所述C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、氨基、-CONH 2任选被1-3个R 12b所取代； The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, wherein R 12 is selected from hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a ; the C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 is optionally replaced by 1-3 R 12b ;
    R 12a、R 12b如权利要求1中所定义。 R 12a and R 12b are as defined in claim 1.
  30. 根据权利要求1-26中任一项所述的式I所示的化合物或其可药用盐，其中，R 12选自氢、卤代C 1-6烷基、羟基取代C 1-6烷基、氰基取代C 1-6烷基、-O-C 1-6烷基、3-6元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基、卤素、氰基、氨基、-CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a，R 12a如权利要求1中所定义； According to any one of claims 1-26, the compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from hydrogen, halogenated C 1-6 alkyl, hydroxyl substituted C 1-6 alkane group, cyano substituted C 1-6 alkyl, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, Cyano, amino, -CONH 2 , -SO 2 R 12a , -CH 2 -SO 2 R 12a , R 12a is as defined in claim 1;
    优选R 12选自氢、卤素、C 1-6烷基、卤代C 1-6烷基、羟基取代C 1-6烷基、氰基取代C 1-6烷基、-O-C 1-6烷基。 Preferably R 12 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, -OC 1-6 alkane base.
  31. 根据权利要求23-30中任一项所述的式I所示的化合物或其可药用盐，According to the compound shown in formula I or its pharmaceutically acceptable salt according to any one of claims 23-30,
    其中，R 9a、R 9b、R 9c、R 9d、R 9e、R 9f独立地选自氢、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13b所取代，R 13b如权利要求1中所定义； Wherein, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl; the C 1-6 alkyl, halogenated C 1-6 alkyl, -OC 1-6 alkyl are optionally substituted by one or more R 13b , R 13b as claimed as defined in 1;
    优选R 9a、R 9b、R 9c、R 9d、R 9e、R 9f为氢。 Preferably R 9a , R 9b , R 9c , R 9d , R 9e , R 9f are hydrogen.
  32. 根据权利要求1-31中任一项所述的式I所示的化合物或其可药用盐，R 13b独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基。 According to the compound shown in formula I or pharmaceutically acceptable salt thereof according to any one of claims 1-31, R 13b is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl.
  33. 根据权利要求1-18中任一项所述的式I所示的化合物或其可药用盐，其中R 11选自氢、卤素、C 1-6烷基、-O-C 1-6烷基；所述C 1-6烷基、-O-C 1-6烷基任选被一个或多个R 13a所取代，R 13a如权利要求1中所定义。 The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-18, wherein R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -OC 1-6 alkyl; The C 1-6 alkyl, -OC 1-6 alkyl is optionally substituted by one or more R 13a , and R 13a is as defined in claim 1.
  34. 根据权利要求1-20、23-33中任一项所述的式I所示的化合物或其可药用盐，其中R 11选自氢、C 1-6烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基；优选R 11选自氢、甲基。 According to the compound shown in formula I described in any one of claims 1-20, 23-33 or pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl; preferably R 11 is selected from hydrogen, methyl.
  35. 根据权利要求1-34中任一项所述的式I所示的化合物或其可药用盐，其中：每个R 13a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基氨基、二C 1-6烷基氨基、C 1-6烷基、-O-C 1-6烷基；所述氨基、C 1-6烷基、-O-C 1-6烷基任选被1-3个选自C 1-6烷基、氰基、羟基、卤素、-O-C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基、羟基取代的C 1-6烷基的取代基所取代。 The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein: each R 13a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkane Base amino, two C 1-6 alkyl amino, C 1-6 alkyl, -OC 1-6 alkyl; said amino, C 1-6 alkyl, -OC 1-6 alkyl are optionally replaced by 1- 3 are selected from C 1-6 alkyl, cyano, hydroxyl, halogen, -OC 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkyl substituted by cyano, C substituted by hydroxy Substituents of 1-6 alkyl groups.
  36. 根据权利要求1-34中任一项所述的式I所示的化合物或其可药用盐，其中：每个R 13a独立地选自氰基、卤素、羟基、C 1-6烷基、-O-C 1-6烷基、甲磺酰基、-CONH 2、-CH 2-SO 2CH 3、3-6元杂环基、氨基。 According to any one of claims 1-34, the compound shown by formula I or a pharmaceutically acceptable salt thereof, wherein: each R 13a is independently selected from cyano, halogen, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl group, methylsulfonyl group, -CONH 2 , -CH 2 -SO 2 CH 3 , 3-6 membered heterocyclic group, amino group.
  37. 根据权利要求1-34中任一项所述的式I所示的化合物或其可药用盐，其中：每个R 13a独立地选自C 1-6烷基、-O-C 1-6烷基、-O-5-6元杂芳基、-O-3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基；所述C 1-6烷基、-O-C 1-6烷基、-O-5-6元杂芳基、-O-3-6元杂环烷基、-O-C 1-6亚烷基-3-6元杂环烷基任选1-3个选自卤素、氰基、羟基、C 1-6烷基的取代基所取代。 The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein: each R 13a is independently selected from C 1-6 alkyl, -OC 1-6 alkyl , -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl; the C 1-6 alkyl , -OC 1-6 alkyl, -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -OC 1-6 alkylene-3-6 membered heterocycloalkyl Select 1-3 substituents selected from halogen, cyano, hydroxyl, C 1-6 alkyl to replace.
  38. 根据权利要求1-34中任一项所述的式I所示的化合物或其可药用盐，其中：每个R 13a独立地选自3-6元环烷基、3-6元杂环烷基、5-6元杂芳基；所述3-6元环烷基、3-6元杂环烷基、5-6元杂芳基任选被一个或多个选自C 1-6烷基、氰基、羟 基、卤素、-O-C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基所取代。 According to the compound shown in formula I according to any one of claims 1-34 or its pharmaceutically acceptable salt, wherein: each R 13a is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocycle Alkyl, 5-6 membered heteroaryl; The 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally selected from C 1-6 by one or more Alkyl, cyano, hydroxyl, halogen, -OC 1-6 alkyl, halogenated C 1-6 alkyl, cyano substituted C 1-6 alkyl.
  39. 根据权利要求25-38中任一项所述的式I所示的化合物或其可药用盐，其中：R 10a独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、-O-C 1-6烷基、-O-3-6元环烷基、-O-3-6元杂环烷基、3-6元环烷基、3-6元杂环烷基、卤代3-6元环烷基、卤代3-6元杂环烷基。 According to the compound shown in formula I or pharmaceutically acceptable salt thereof according to any one of claims 25-38, wherein: R 10a is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, Halogenated C 1-6 alkyl, -OC 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, halogenated 3-6-membered cycloalkyl, halogenated 3-6-membered heterocycloalkyl.
  40. 根据权利要求1-39中任一项所述的式I所示的化合物或其可药用盐，其中R 2为任选取代的
    Figure PCTCN2022140921-appb-100028
    时，R 1不为
    Figure PCTCN2022140921-appb-100029
    According to the compound shown in formula I or pharmaceutically acceptable salt thereof according to any one of claims 1-39, wherein R 2 is optionally substituted
    Figure PCTCN2022140921-appb-100028
    , R 1 is not
    Figure PCTCN2022140921-appb-100029
  41. 根据权利要求1-39中任一项所述的式I所示的化合物或其可药用盐，其中R 2不为
    Figure PCTCN2022140921-appb-100030
    According to the compound shown in formula I or pharmaceutically acceptable salt thereof according to any one of claims 1-39, wherein R 2 is not
    Figure PCTCN2022140921-appb-100030
  42. 根据权利要求1-39中任一项所述的式I所示的化合物或其可药用盐，其中R 2不为任选取代的
    Figure PCTCN2022140921-appb-100031
    According to the compound shown in formula I or pharmaceutically acceptable salt thereof according to any one of claims 1-39, wherein R 2 is not optionally substituted
    Figure PCTCN2022140921-appb-100031
  43. 根据权利要求1中所述的式I所示的化合物或其可药用盐，其选自：According to the compound shown in formula I described in claim 1 or its pharmaceutically acceptable salt, it is selected from:
    Figure PCTCN2022140921-appb-100032
    Figure PCTCN2022140921-appb-100032
    Figure PCTCN2022140921-appb-100033
    Figure PCTCN2022140921-appb-100033
    Figure PCTCN2022140921-appb-100034
    Figure PCTCN2022140921-appb-100034
    Figure PCTCN2022140921-appb-100035
    Figure PCTCN2022140921-appb-100035
    Figure PCTCN2022140921-appb-100036
    Figure PCTCN2022140921-appb-100036
    Figure PCTCN2022140921-appb-100037
    Figure PCTCN2022140921-appb-100037
  44. 一种根据权利要求1-43中任一项所述的式I所示的化合物或其可药用盐的同位素取代物，优选地，所述的同位素取代为氘原子取代。An isotopic substitution of the compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-43, preferably, the isotopic substitution is deuterium atom substitution.
  45. 一种药物组合物，其包含至少一种治疗有效量的如权利要求1-43中任一项所述的式I所示的化合物或其可药用盐，或如权利要求44所述的同位素取代物，以及药学上可接受的赋形剂。A pharmaceutical composition comprising at least one therapeutically effective amount of the compound shown in formula I as claimed in any one of claims 1-43 or a pharmaceutically acceptable salt thereof, or the isotope as claimed in claim 44 Substitutes, and pharmaceutically acceptable excipients.
  46. 权利要求1-43中任一项所述的式I所示的化合物或其可药用盐，或如权利要求44所述的同位素取代物，或权利要求45所述的药物组合物在制备治疗与NLRP3活性相关的疾病的药物中的用途。The compound shown in the formula I described in any one of claims 1-43 or its pharmaceutically acceptable salt, or the isotope substitution as described in claim 44, or the pharmaceutical composition described in claim 45 is in preparation treatment Use in medicine for diseases associated with NLRP3 activity.
  47. 权利要求1-43任一项所述的式I所示的化合物或其可药用盐，或如权利要求44所述的同位素取代物，或权利要求45所述的药物组合物在制备治疗炎性体相关疾病、免疫性疾病如自身免疫性疾病、炎症性疾病如自身炎症性疾病的药物中的用途。The compound shown in the formula I described in any one of claims 1-43 or its pharmaceutically acceptable salt, or the isotope substitution as described in claim 44, or the pharmaceutical composition described in claim 45 is in preparation treatment inflammation Use in drugs for sexually related diseases, immune diseases such as autoimmune diseases, and inflammatory diseases such as autoinflammatory diseases.
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CN110914256A (en) * 2017-07-07 2020-03-24 英夫拉索姆有限公司 Novel sulfonamide carboxamide compounds
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