WO2022089406A1 - Nitrogen-containing fused heterocyclic compound, and preparation method therefor and use thereof - Google Patents

Nitrogen-containing fused heterocyclic compound, and preparation method therefor and use thereof Download PDF

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Publication number
WO2022089406A1
WO2022089406A1 PCT/CN2021/126331 CN2021126331W WO2022089406A1 WO 2022089406 A1 WO2022089406 A1 WO 2022089406A1 CN 2021126331 W CN2021126331 W CN 2021126331W WO 2022089406 A1 WO2022089406 A1 WO 2022089406A1
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independently
alkyl
group
membered
butyl
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PCT/CN2021/126331
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French (fr)
Chinese (zh)
Inventor
马世超
付贤磊
赵梦溪
刘兰震
徐帅杰
刘绍军
刘艳超
张忠国
袁文佳
孙永丰
张海龙
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上海青煜医药科技有限公司
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Priority claimed from CN202111217906.5A external-priority patent/CN114478585A/en
Application filed by 上海青煜医药科技有限公司 filed Critical 上海青煜医药科技有限公司
Publication of WO2022089406A1 publication Critical patent/WO2022089406A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention discloses nitrogen-containing fused heterocyclic compounds, their stereoisomers, their tautomers or their pharmaceutically acceptable salts.
  • the present invention also provides a preparation method of the compound, a composition containing the compound and the use of the compound in preparing a medicine for treating diseases or conditions related to abnormal SHP2 activity.
  • the tyrosine phosphatase SHP2 consists of two N-terminal Src homology 2 domains (N-SH2 and C-SH2) and a protein tyrosine phosphatase catalytic domain (PTP).
  • N-SH2 can combine with PTP to form a ring structure, thereby hindering the binding of PTP to the substrate, so that the catalytic activity of the enzyme is inhibited; when the tyrosine of the upstream receptor protein is phosphorylated, N-SH2 When SH2 binds to it, the PTP catalytic domain is released to exert phosphatase activity.
  • SHP2 participates in multiple tumor cell signaling pathways, such as RTK/Ras/MAPK, JAK/STAT, and PI3K/Akt, by functioning downstream of the cytoplasm of many receptor tyrosine kinases.
  • RTK/Ras/MAPK RTK/Ras/MAPK
  • JAK/STAT JAK/STAT
  • PI3K/Akt PI3K/Akt
  • SHP2 is also involved in programmed death receptor 1 (PD1)-mediated suppression of the immune system.
  • PD1 programmed death receptor 1
  • SHP2 can dephosphorylate antigen receptor pathway proteins in T cells, thereby inhibiting T cell activation. Therefore, inhibition of SHP2 activity could reverse immunosuppression in the tumor microenvironment.
  • SHP2 is an important member of the protein tyrosine phosphatase family and is associated with many diseases in humans, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma and many more.
  • diseases in humans such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma and many more
  • the nitrogen-containing fused heterocyclic compound provided by the present invention is a brand-new SHP2 inhibitor, which exhibits good inhibitory activity on tumor cells and good druggability, and has broad prospects for drug development. Moreover, the preparation method of the compound is simple, which is favorable for industrial production.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a nitrogen-containing fused heterocyclic compound shown in formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt;
  • L 1 is a connecting bond, -O- or -S-;
  • Ring D is a connecting bond, C 4 -C 8 cycloalkyl, 5-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, 5-10-membered heterocyclyl acyl group, 5-10-membered heterocyclyl group and 5-6 membered heteroaryl group; in the heterocyclyl group, it contains 1-3 heteroatoms selected from the following group: N, O, S and P; in the heteroaryl group, 1-3 heteroatoms are selected from the group consisting of N, O and S;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R 1a2 , R 1a3 and R 1a5 are independently hydrogen, C 1 -C 4 alkyl, substituted or unsubstituted alkenyl, amide, C 3 -C 12 mono- or polyheterocycle, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered aryl substituted with one or more halogens or 5-6 membered heteroaryl substituted with one or more halogens or In the described single or polyheterocyclic group, 1-3 heteroatoms selected from the following group are included: N, O, S or P; in the described heteroaryl group, 1-3 heteroatoms selected from the following group are included. Heteroatom: N, O or S;
  • R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
  • R c is H or C 1 -C 4 alkyl
  • X 1 is CR 3 , and X 2 is CR 3 ; or, X 1 is N, and X 2 is CR 3 ; or, X 1 is CR 3 , and X 2 is N;
  • R 3 is independently hydrogen, halogen, amino, nitro, trifluoromethyl, C 3 -C 8 cycloalkyl, vinyl or C 1 -C 4 alkyl;
  • R 4 is independently hydrogen, halogen, C 1 -C 4 alkyl, amino, nitro, trifluoromethyl, C 1 -C 4 containing hydroxy or amino or halogen substituted alkyl;
  • o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen, halogen, C 1 -C 4 alkyl;
  • R 7 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino substituted C 1 -C 4 alkyl, amino substituted 3-12 membered cycloalkyl; R 8 is absent;
  • R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino, C 1 -C 4 alkyl substituted amino, C 1 - C 4 alkyl-O-substituted amino-;
  • p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
  • R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, halogen, amino, -NHR 9-1 , C 1 -C 4 alkyl;
  • R 9-1 is C 1 -C 4 alkyl
  • W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
  • R w is independently hydrogen or C 1 -C 4 alkyl
  • Ring H is independently absent or C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heteroaryl group; in the heterocyclic group, Contains 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, contains 1-3 heteroatoms selected from the following group: N, O, or S;
  • Z 1 is CR z1a R z1b or O
  • Z 2 is CR z2a R z2b or O
  • ring H is C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heterocyclic aryl group, Z 1 is CR z1a or N, and Z 2 is CR z2a or N, is a single bond; or Z 1 is C and Z 2 is C, is a double bond;
  • R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
  • r is independently 0, 1, 2, 3, or 4;
  • R 11-1 and R 11-2 are independently H or C 1 -C 4 alkyl
  • R 11-3 is independently H, C 1 -C 4 alkyl or CD 3 ;
  • R 11-4 is independently H or C 1 -C 4 alkyl
  • R 11-5 and R 11-6 are independently H or C 1 -C 4 alkyl
  • R 11-7 is independently halogen or amino
  • i is independently 0, 1, 2, 3, or 4;
  • R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
  • the nitrogen-containing fused heterocyclic compounds represented by formula I their stereoisomers, their tautomers or certain pharmaceutically acceptable salts thereof
  • These groups are defined as follows, and the unmentioned groups are described in any scheme of this application (hereinafter referred to as a certain preferred scheme of the present invention),
  • n1, n2, and n3 are independently 0, 1, 2, 3, or 4, and n1+n2 equals 0, 1, 2, 3, 4, 5, or 6; n1+n2+n3 equals 0, 1, 2 , 3, 4, 5 or 6;
  • Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms
  • Ring F is a 5-membered heteroaryl containing 1 to 4 N, S, O heteroatoms
  • n 0, 1, 2, 3, 4 or 5;
  • R 1a is independently halogen, C 1 -C 6 alkyl, amino;
  • L 1 is -S- or -O- (also for example -S-).
  • Ring D is a linking bond, C6 - C10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl and 5-6 membered heteroaryl.
  • R3 is independently hydrogen.
  • R 4 is independently hydrogen.
  • X 1 is CR 3 and X 2 is CR 3 .
  • X 1 is N and X 2 is CR 3 .
  • X 1 is CR 3 and X 2 is N.
  • n 0, 1 or 2.
  • R 1a2 is independently a 5-6 membered aryl group or a 5-6 membered aryl group substituted with one or more halogens.
  • R 1a3 and R 1a5 are independently H, C 1 -C 4 alkyl, 5-6 membered heteroaryl or
  • Ra is independently halogen.
  • o1 is either 0 or 1.
  • o2 is either 0 or 1.
  • p 1 or 2.
  • q 0 or 1.
  • R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, amino or -NHR 9-1 .
  • R 9a and R 9b one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group;
  • one is a hydrogen atom and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group.
  • R 10a and R 10b one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group.
  • W is independently a linker, -C( Rw ) 2- , -O-, or -NRw- .
  • Z 1 is CR z1a R z1b and Z 2 is O; alternatively, Z 1 is O and Z 2 is CR z2a R z2b .
  • Ring H is phenyl or 5-6 membered heteroaryl; eg, phenyl.
  • Rz1a and Rz1b alternatively, of Rz2a and Rz2b , one is hydrogen and the other is hydrogen or C1 - C4 alkyl; for example, Rz1a , Rz1b , Rz2a , Rz2b are independently hydrogen Atom, or R z1a is H, and R z1b is methyl.
  • r is independently 0 or 1; eg, 0.
  • W is the connection key; that is
  • W is a connecting key
  • p' is 0, and q is 1.
  • L 1 is a connecting key or -S-;
  • Ring D is a connecting bond, a C 6 -C 10 aryl group, a 5-10-membered heteroaryl group, a 5-10-membered heterocyclic group, and a 5-6-membered heteroaryl group; among the heterocyclic groups, 1-3 a heteroatom selected from the following group: N, O, S and P; the heteroaryl group contains 1-3 heteroatoms selected from the following group: N, O and S;
  • n 0, 1 or 2;
  • R 1a2 , R 1a3 and R 1a5 are independently hydrogen, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered aryl substituted with one or more halogens, or In the described heteroaryl group, contains 1-3 heteroatoms selected from the following group: N, O or S;
  • Ra is independently halogen
  • R c is H or C 1 -C 4 alkyl
  • X 1 is CR 3
  • X 2 is CR 3 ;
  • R 3 is independently hydrogen, halogen, amino or C 1 -C 4 alkyl
  • R 4 is independently hydrogen, halogen, amino, or C 1 -C 4 alkyl
  • o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen;
  • p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
  • R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, amino, or -NHR 9-1 ;
  • R 9-1 is C 1 -C 4 alkyl
  • W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
  • R w is independently hydrogen or C 1 -C 4 alkyl
  • Ring H is independently absent or a C 6 -C 10 aryl group, a 5-10 membered heteroaryl group; the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S;
  • Z 1 is CR z1a R z1b or O
  • Z 2 is CR z2a R z2b or O
  • R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
  • r is independently 0, 1, 2, 3, or 4;
  • R 11-1 and R 11-2 are independently H or C 1 -C 4 alkyl
  • R 11-3 is independently H, C 1 -C 4 alkyl or CD 3 ;
  • R 11-4 is independently H or C 1 -C 4 alkyl
  • R 11-5 and R 11-6 are independently H or C 1 -C 4 alkyl
  • R 11-7 is independently halogen or amino
  • i is independently 0, 1, 2, 3, or 4;
  • R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
  • R2 is Ring H is absent or is phenyl or 5-6 membered heteroaryl; p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2;
  • Ring H is phenyl or 5-6 membered heteroaryl
  • Z1 is C and Z2 is C, is a double bond; r is independently 0 or 1; such as 0;
  • R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl; for example, a hydrogen atom;
  • R 9a , R 9b , R 10a and R 10b are independently hydrogen or C 1 -C 4 alkyl; such as hydrogen;
  • p' is 0; q is 1; or p' is 1; q is 0;
  • R2 is q is 1 or 2; for example Another example Also for example
  • the nitrogen-containing fused heterocyclic compound represented by formula I of the present invention is represented by formula I-2;
  • L 1 is independently a connecting key, S;
  • n is independently 0, 1, 2, 3, 4, 5, or 6;
  • Ring D is independently phenyl, 5-6 membered heteroaryl or 5-10 membered heterocyclyl and 5-6 membered heteroaryl, preferably phenyl, pyrazinyl, pyridyl (eg )or
  • R 1a is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, amino, cyano, hydroxy, or, substituted with one or more R a : C 1 -C 6 Alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different;
  • R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
  • Ring H is selected from phenyl, 5-6 membered heteroaryl, preferably phenyl, pyridyl (eg ), pyrazinyl or thiazolyl (eg );
  • R 11 is independently selected from hydrogen atom, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
  • r is independently selected from 0, 1 and 2;
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • R 1a is independently halogen, amino or C 1 -C 6 alkyl
  • n is independently 0, 1, 2, 3, 4 or 5; for example n is independently 0, 1, 2 or 3;
  • Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms;
  • L 1 is a connection key, -O- or -S-;
  • X 1 is CR 3 and X 2 is CR 3 ; or, X 1 is N and X 2 is CR 3 ;
  • R3 and R4 are independently hydrogen ;
  • o1, o2 are independently 0, 1 or 2; e.g. 1;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently hydrogen;
  • R 9a , R 9b , R 10a and R 10b are independently a hydrogen atom, an amino group or a C 1 -C 4 alkyl group;
  • W is independently a connecting bond, -C(R w ) 2 -;
  • Ring H is independently absent or phenyl or 5-6 membered heteroaryl
  • Z 1 is CR z1a R z1b and Z 2 is O, or Z 1 is O and Z 2 is CR z2a R z2b ;
  • R z1a , R z1b , R z2a , R z2b are independently a hydrogen atom or a C 1 -C 4 alkyl group; is a single key;
  • ring H is phenyl or 5-6 membered heteroaryl
  • Z 1 and Z 2 are independently C, is a double bond
  • R 11 is independently a hydrogen atom, a halogen, a C 1 -C 6 alkyl group
  • r is independently 0, or 2;
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • the nitrogen-containing fused heterocyclic compounds represented by formula I their stereoisomers, their tautomers or certain pharmaceutically acceptable salts thereof.
  • L 1 is a connecting bond, -O- or -S-; for example, S;
  • R 1a is independently halogen, C 1 -C 6 alkyl, amino
  • Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms
  • n is independently 1 or 2; e.g. 2;
  • X 1 is CR 3
  • X 2 is CR 3
  • R 3 is independently hydrogen
  • R 4 is independently hydrogen
  • R2 is E.g
  • Ring H is independently phenyl or 5-10 membered heterocyclic aryl
  • p' is 0 and q is 1; or p' is 1 and q is 0;
  • R 9a is a hydrogen atom or a C 1 -C 4 alkyl group
  • r is independently 0 or 1;
  • R 11 is independently C 1 -C 4 alkyl
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • L 1 is a connecting key, -S-;
  • r is independently 0.
  • Ring D is a 5-10-membered heteroaryl group
  • the 5-10-membered heteroaryl group is a 6-membered heteroaryl group containing 1 to 3 N atoms; for example, pyridine, or for example
  • Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms.
  • Ring D is a 5-10-membered heteroaryl group
  • the 5-10-membered heteroaryl group is a 9-10-membered heteroaryl group containing 1 to 3 N atoms, such as benzopyrazolyl, benzopyridine base, for example
  • Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms
  • Ring F is a 5-membered heteroaryl group containing 1 to 4 N, S, O heteroatoms.
  • ring D is a C 6 -C 10 aryl group
  • the C 6 -C 10 aryl group is phenyl or naphthyl; for example, phenyl or
  • Ring D is a 5-10-membered heterocyclic group and a 5-6-membered heteroaryl group
  • the 5-10-membered heterocyclic group and the 5-6-membered heteroaryl group are Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms
  • R 1a is independently halogen
  • the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
  • R 1a is independently a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group eg methyl, ethyl, propyl, butyl, pentyl or hexyl
  • C 1 -C 6 alkyl C4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • eg methyl methyl, ethyl, propyl, butyl, pentyl or hexyl
  • C 1 -C 6 alkyl C4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • R 1a is independently a 3-8-membered heterocyclic group
  • the 3-8-membered heterocyclic group is independently a 3-5-membered heterocycloalkyl, such as pyrrolidinyl, and another example is
  • R 1a is independently a 3-8 membered heterocyclyl substituted with one or more R 1a4
  • the 3-8 membered heterocyclyl substituted with one or more R 1a4 is a 3-8 membered heterocyclyl substituted with one or more R 1a4 Substituted 3-5 membered heterocycloalkyl; for example
  • R 1a is independently -NR 1a3 R 1a5
  • the -NR 1a3 R 1a5 is -NH 2 , -NHCH 3 ,
  • R 1a is independently a 5-10-membered heteroaryl group
  • the 5-10-membered heteroaryl group is independently pyrazinyl, oxazolyl or benzoxazolyl, such as
  • R 1a is independently a C 1 -C 6 alkyl substituted with one or more Ra
  • the C 1 -C 6 alkyl substituted with one or more Ra is -CF 3 .
  • R 1a1 , R 1a4 , R 1a2 , R 1a3 or R 1a5 are independently C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl Propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.
  • R 1a2 , R 1a3 and R 1a5 are independently a 5- to 6-membered aryl group, the 5- to 6-membered aryl group is a phenyl group.
  • R 1a2 , R 1a3 and R 1a5 are independently 5-6 membered heteroaryl, the 5-6 membered heteroaryl is
  • R 1a2 , R 1a3 and R 1a5 are independently 5-6 membered aryl substituted with one or more halogens, the one or more halogen substituted 5-6 membered aryl groups are
  • R 1a2 , R 1a3 and R 1a5 are independently when, the for
  • the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
  • R c is independently C 1 -C 4 alkyl
  • said C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl, for example methyl or ethyl.
  • R 1a is independently located in the ortho, meta and para positions of the bond between ring D and L 1 , for example, when n is 2, R 1a is located in rings D and L
  • the ortho and para positions of the 1 linkage alternatively, R 1a is located in the ortho and meta positions of the ring D and L 1 linkage.
  • n is independently 0, 1, 2; eg, 1 or 2.
  • R 9a and R 9b are independently C 1 -C 4 alkyl
  • said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
  • R 9a-1 is a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
  • R 10a and R 10b are independently C 1 -C 4 alkyl
  • said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
  • R w is C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl.
  • the 5-6 membered heteroaryl group is a 6-membered heteroaryl group containing 1-2 N atoms, 1-3 members selected from N, O and 5-membered heteroaryl group of S atom; the 6-membered heteroaryl group such as pyridyl, pyrazinyl, such as The 5-membered heteroaryl group such as thiazolyl or pyrazolyl, such as a denotes a fused position.
  • ring H is a C6 - C10 aryl group
  • the C6 - C10 aryl group is phenyl or naphthyl, such as phenyl.
  • R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl groups
  • the C 1 -C 4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-propyl Butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
  • R11 is independently halogen
  • the halogen is chlorine or fluorine; eg chlorine.
  • R 11 is independently a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group eg methyl, ethyl, propyl, butyl, pentyl or hexyl
  • C 1 -C 6 alkyl C4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • eg methyl methyl, ethyl, propyl, butyl, pentyl or hexyl
  • C 1 -C 6 alkyl C4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • R 11 is independently C 1 -C 6 alkyl-O-
  • said C 1 -C 6 alkyl-O- eg methoxy, ethoxy, propoxy, butoxy, pentyl oxy or hexyloxy
  • is independently C 1 -C 4 alkyl-O- eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy
  • methoxy eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy
  • R 11 is independently a C 3 -C 8 cycloalkyl group
  • the C 3 -C 8 cycloalkyl group is a C 3 -C 5 cycloalkyl group, such as cyclopropyl, cyclobutyl or cycloalkyl amyl.
  • R 11 is independently a 3-7 membered heterocyclyl
  • the 3-7 membered heterocyclyl is the 3-7 membered heterocycloalkyl, eg
  • R 11 is independently -(CH 2 ) q NR 11-1 R 11-2 , the -(CH 2 ) q NR 11-1 R 11-2 is
  • R 11 is independently a C 1 -C 6 alkyl group substituted with a hydroxy group
  • the C 1 -C 6 alkyl group in the C 1 -C 6 alkyl group substituted with a hydroxy group is independently a C 1 -C 4 alkane base; e.g.
  • R 11 is independently a C 6 -C 10 aryl group that is unsubstituted or substituted with 1-4 R b
  • the C 6 -C 10 aryl group is phenyl
  • the C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
  • the C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
  • the C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
  • R 11-7 is independently halogen
  • the halogen is fluorine, chlorine or bromine; for example fluorine or chlorine.
  • R2 is Indicates the enantiomer, which is a mixture of the S and R configurations.
  • the nitrogen-containing fused heterocyclic compound represented by formula I its stereoisomer, its tautomer or its pharmaceutically acceptable salt
  • L 1 is a connecting bond, -O- or -S-;
  • Ring D is C 4 -C 8 cycloalkyl, 5-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl acyl group, 5-10 membered heterocyclyl group and 5-6 membered heteroaryl group;
  • the heterocyclyl group contains 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, it contains 1-3 heteroatoms selected from the group consisting of N, O, or S;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R 1a1 is independently halogen or C 1 -C 4 alkyl
  • R 1a2 is independently hydrogen, C 1 -C 4 alkyl, substituted or unsubstituted alkenyl, amide, C 3 -C 12 single or polyheterocycle; 5-6 membered aryl or heteroaryl;
  • R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
  • X 1 is CR 3 , and X 2 is CR 3 ; or, X 1 is N, and X 2 is CR 3 ; or, X 1 is CR 3 , and X 2 is N;
  • R 3 is independently hydrogen, halogen, amino, nitro, trifluoromethyl, C 3 -C 8 cycloalkyl, vinyl or C 1 -C 4 alkyl;
  • R 4 is independently hydrogen, halogen, C 1 -C 4 alkyl, amino, nitro, trifluoromethyl, C 1 -C 4 containing hydroxy or amino or halogen substituted alkyl;
  • o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen, halogen, C 1 -C 4 alkyl;
  • R 7 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino substituted C 1 -C 4 alkyl, amino substituted 3-12 membered cycloalkyl; R 8 is absent;
  • R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino, C 1 -C 4 alkyl substituted amino, C 1 - C 4 alkyl-O-substituted amino-;
  • p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
  • R 9a , R 9b , R 10a , R 10b are independently hydrogen, halogen, amino, C 1 -C 4 alkyl;
  • W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
  • R w is independently hydrogen, C 1 -C 4 alkyl
  • Ring H is independently absent or C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl, 5-10-membered heterocyclic aryl; among the heterocyclic groups , containing 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, containing 1-3 heteroatoms selected from the following group: N, O, or S;
  • Z 1 is CR z1a R z1b or O
  • Z 2 is CR z2a R z2b or O
  • ring H is C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heterocyclic aryl group, Z 1 is CR z1a or N, and Z 2 is CR z2a or N, is a single bond; or Z 1 is C and Z 2 is C, is a double bond;
  • R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
  • r is independently 0, 1, 2, 3 or and 4;
  • R 11 is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, nitro, C 3 -C 8 cycloalkyl, unsubstituted or 1 -Aryl substituted with 4 R b , 5-6 membered heteroaryl group containing 1-3 heteroatoms, or, substituted with one or more R b : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different; in the 5-6-membered aromatic hetero group, 1-3 heteroatoms are selected from the following group: N, O, S or P;
  • R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
  • n1 and n2 are independently 0, 1, 2, 3, or 4, and n1+n2 is equal to 0, 1, 2, 3, 4, 5, or 6;
  • Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms
  • Ring F is a 5-membered heteroaryl containing 1 to 4 N, S, O heteroatoms
  • n 0, 1, 2, 3, 4 or 5;
  • R 1a is independently halogen, C 1 -C 6 alkyl, amino;
  • L 1 is -S- or -O- (also for example -S-).
  • R 1a is independently halogen, C 1 -C 6 alkyl, amino; eg, halogen, amino.
  • Ring D is C6 - C10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl and 5-6 membered heteroaryl.
  • R3 is independently hydrogen.
  • R 4 is independently hydrogen.
  • X 1 is CR 3 and X 2 is CR 3 .
  • X 1 is N and X 2 is CR 3 .
  • X 1 is CR 3 and X 2 is N.
  • R 3a , R 3b , R 4a , R 4b are independently hydrogen; that is, R 2 is
  • R 5a , R 5b , R 6a and R 6b are independently hydrogen or C 1 -C 6 alkyl; eg, hydrogen.
  • o1 is 1.
  • o2 is 1.
  • p 1 or 2.
  • q is independently 1.
  • one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group; for example, one is a hydrogen atom, the other is a hydrogen atom, a C 1 -C 4 alkyl or amino.
  • R 10a and R 10b one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group.
  • R 10a and R 10b one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group.
  • W is independently a connecting bond, -C(R w ) 2 -.
  • Z 1 is CR z1a R z1b and Z 2 is O; alternatively, Z 1 is O and Z 2 is CR z2a R z2b .
  • Ring H is phenyl or 5-6 membered heteroaryl; eg, phenyl.
  • R z1a and R z1b are hydrogen and the other is hydrogen or C 1 -C 4 alkyl;
  • R z1a , R z1b , R z2a , and R z2b are independently hydrogen atoms.
  • r is independently 0 or 1; eg, 0.
  • R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl; eg, halogen.
  • W is the connection key; that is
  • R2 is Ring H is absent or is phenyl or 5-6 membered heteroaryl; p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2;
  • Ring H is phenyl or 5-6 membered heteroaryl
  • Z1 is C and Z2 is C, is a double bond; r is independently 0 or 1; such as 0;
  • R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl; for example, a hydrogen atom;
  • R 9a , R 9b , R 10a and R 10b are independently hydrogen or C 1 -C 4 alkyl; such as hydrogen;
  • p' is 0; p is 1; or p' is 1; q is 0;
  • R2 is q is 1 or 2; for example Another example Also for example
  • the nitrogen-containing fused heterocyclic compound represented by formula I of the present invention is represented by formula I-2;
  • L 1 is independently a connecting key, S;
  • n is independently 0, 1, 2, 3, 4, 5, or 6;
  • Ring D is independently phenyl, 5-6 membered heteroaryl or 5-10 membered heterocyclyl and 5-6 membered heteroaryl, preferably phenyl, pyrazinyl, pyridyl (eg )or
  • R 1a is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, amino, cyano, hydroxy, or, substituted with one or more R a : C 1 -C 6 Alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different;
  • R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
  • Ring H is selected from phenyl, 5-6 membered heteroaryl, preferably phenyl, pyridyl (eg ), pyrazinyl or thiazolyl (eg );
  • R 11 is independently selected from hydrogen atom, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
  • r is independently selected from 0, 1 and 2;
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • R 1a is independently halogen, amino or C 1 -C 6 alkyl
  • n is independently 0, 1, 2, 3, 4 or 5; for example n is independently 0, 1, 2 or 3;
  • Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms;
  • L 1 is a connection key, -O- or -S-;
  • X 1 is CR 3 and X 2 is CR 3 ; or, X 1 is N and X 2 is CR 3 ;
  • R3 and R4 are independently hydrogen ;
  • o1, o2 are independently 0, 1 or 2; e.g. 1;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently hydrogen;
  • R 9a , R 9b , R 10a and R 10b are independently a hydrogen atom, an amino group or a C 1 -C 4 alkyl group;
  • W is independently a connecting bond, -C(R w ) 2 -;
  • Ring H is independently absent or phenyl or 5-6 membered heteroaryl
  • Z 1 is CR z1a R z1b and Z 2 is O, or Z 1 is O and Z 2 is CR z2a R z2b ;
  • R z1a , R z1b , R z2a , R z2b are independently a hydrogen atom or a C 1 -C 4 alkyl group; is a single key;
  • ring H is phenyl or 5-6 membered heteroaryl
  • Z 1 and Z 2 are independently C, is a double bond
  • R 11 is independently a hydrogen atom, a halogen, a C 1 -C 6 alkyl group
  • r is independently 0, or 2;
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • the nitrogen-containing fused heterocyclic compounds represented by formula I their stereoisomers, their tautomers or some of their pharmaceutically acceptable salts.
  • L 1 is a connecting bond, -O- or -S-; for example, S;
  • R 1a is independently halogen, C 1 -C 6 alkyl, amino
  • Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms
  • n is independently 1 or 2; e.g. 2;
  • X 1 is CR 3
  • X 2 is CR 3
  • R 3 is independently hydrogen
  • R 4 is independently hydrogen
  • R2 is E.g
  • Ring H is independently phenyl or 5-10 membered heterocyclic aryl
  • p' is 0 and q is 1; or p' is 1 and q is 0;
  • R 9a is a hydrogen atom or a C 1 -C 4 alkyl group
  • r is independently 0 or 1;
  • R 11 is independently C 1 -C 4 alkyl
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • L 1 is a connecting key, -S-;
  • r is independently 0.
  • Ring D is a 5-10-membered heteroaryl group
  • the 5-10-membered heteroaryl group is a 6-membered heteroaryl group containing 1 to 3 N atoms; for example, pyridine, or for example
  • Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms.
  • ring D is a C 6 -C 10 aryl group
  • the C 6 -C 10 aryl group is phenyl or naphthyl; for example, phenyl or
  • Ring D is a 5-10-membered heterocyclic group and a 5-6-membered heteroaryl group
  • R 1a is independently halogen
  • the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
  • R 1a is independently a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group eg methyl, ethyl, propyl, butyl, pentyl or hexyl
  • C 1 -C 6 alkyl C4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • eg methyl methyl, ethyl, propyl, butyl, pentyl or hexyl
  • C 1 -C 6 alkyl C4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • R 1a is independently located in the ortho, meta and para positions of the bond between ring D and L 1 , for example, when n is 2, it is located in the adjacent ortho and Counterpoint.
  • n is independently 0, 1, 2; eg, 1 or 2.
  • R 9a and R 9b are independently C 1 -C 4 alkyl
  • said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
  • R 10a and R 10b are independently C 1 -C 4 alkyl
  • said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
  • the 5-6 membered heteroaryl group is a 6-membered heteroaryl group with 1-2 N atoms, 1-3 members selected from N, O and S Atomic 5-membered heteroaryl; said 6-membered heteroaryl such as pyridyl, pyrazinyl, such as The 5-membered heteroaryl group such as thiazolyl, such as a denotes a fused position.
  • R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • eg methyl e.g methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • R 11 is independently halogen, said halogen being chlorine, fluorine; for example chlorine.
  • R2 is E.g represents the enantiomer.
  • the nitrogen-containing fused heterocyclic compound represented by formula I of the present invention is any of the following compounds:
  • the nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts may have one or more chiral carbon atoms, so Optically pure isomers can be isolated, eg, pure enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
  • the nitrogen-containing fused heterocyclic compounds shown in formula I can be represented by a single Stereoisomers or their mixtures (eg racemates) exist.
  • stereoisomer refers to a cis-trans isomer or an optical isomer.
  • stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • the nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts described in the present invention can be prepared by methods similar to those known in the chemical field. Synthesis, its steps and conditions can refer to the steps and conditions of similar reactions in the art, especially the synthesis according to the description herein. Starting materials are typically from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online database).
  • the fused ring compound represented by formula I or a pharmaceutically acceptable salt thereof can also be prepared by the fused ring compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the salt of the compound is obtained by peripheral modification using conventional methods in the art to obtain other described fused ring compounds represented by formula I or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified.
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • the necessary starting materials or reagents for the preparation of compounds such as those of formula I are either commercially available or prepared by synthetic methods known in the art.
  • Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below.
  • the term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound.
  • Pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
  • salt formation examples include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid , mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
  • the fused ring compound shown in formula I may have one or more chiral carbon atoms, and thus can be separated into optically pure isomers, such as pure enantiomers, or racemates, or mixed isomers . Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
  • the chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and protecting groups including tert-butoxycarbonyl (Boc).
  • the above methods may additionally include steps before or after the steps specifically described herein, where appropriate protecting groups may be added or removed to obtain the target compound. Additionally, various synthetic steps can be performed alternately or sequentially to obtain the final target product.
  • the present invention provides the preparation method of the nitrogen-containing fused heterocyclic compound shown in formula I and its intermediate, which mainly includes the following aspects:
  • the present invention provides a method for preparing a nitrogen-containing fused heterocyclic compound represented by formula I.
  • the compound of formula I is a compound represented by general formula I', it comprises the following steps: The compound shown in ' is subjected to deprotection reaction to obtain the compound shown in formula I';
  • the present invention provides a compound of formula II',
  • the compound represented by the formula II'-a is selected from the following compounds:
  • the present invention provides a compound of formula III-3,
  • the present invention provides a method for preparing a compound of formula I.
  • the compound of formula I is a compound represented by general formula I-a or a compound represented by general formula I-b, it comprises the following steps:
  • Formula I-1 and the boronic acid shown in formula I-2 are subjected to coupling reaction to obtain formula I-a, or, formula I-1 is subjected to coupling reaction with thiol or sodium sulfide shown in formula I-3 to obtain formula I-b;
  • W 1 represents halogen or sulfonyl, preferably Br, I, or sulfonyl;
  • R is H or C 1 -C 4 alkyl;
  • X 1 , X 2 , ring D, n, R 4 , R 1a and R 2 is defined as above.
  • the present invention provides a method for preparing a compound of formula I, when the compound of formula I is a compound of general formula III, it comprises the following steps:
  • Intermediate III-1 is substituted by intermediate amine III-2 under basic conditions to obtain intermediate compound III-3, and then intermediate III-3 is subjected to coupling reaction with boronic acid, thiol or sodium sulfide to obtain formula III;
  • W 1 and W 2 represent halogen or sulfonyl, preferably chlorine, Br, I or sulfonyl;
  • R 6b , R 7 , and R 8 are as described above.
  • the present invention provides a preparation method of the compound of formula I, when the compound of formula I is , it includes the following steps:
  • V-1-a1 is obtained by subjecting intermediate C1 and amine under basic conditions, under suitable solvent and reaction temperature;
  • V-1-a1 is coupled with I-2 under alkaline conditions to obtain V-1-a2, and then the protective group Pg is removed under acidic conditions to obtain V-1-a. ;
  • V-1-b2 can be obtained by coupling V-1-a1 with the compound represented by formula I-3 in the presence of a catalyst under basic conditions; and then removing the protecting group Pg under acidic conditions to obtain V- 1-b can be;
  • the present invention provides an intermediate The synthetic method of (C1), it comprises the steps:
  • the C1-1 intermediate is obtained by combining 2-chloroaminopyrimidine compound C1-0 with a ring-closing reagent in a solvent at room temperature or under heating conditions; the C1-1 intermediate and an aqueous or alcoholic solution of ammonia are obtained at room temperature or under heating conditions Obtain C1-2 intermediate; C1-2 is obtained under basic conditions at room temperature or heated to C1-3; C1-3 is converted into C1;
  • W 1 and W 2 are defined as above.
  • the catalyst involved in the present invention is selected from: palladium/carbon, Raney nickel, tetrakis-triphenylphosphonium palladium, palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]bis Palladium chloride, [1,1'-bis(dibenzylphosphine)dichlorodipentyl iron palladium, tris(dibenzylideneacetone)dipalladium;
  • the solvent involved in the present invention is selected from: dichloromethane, chloroform C, methanol, ethanol, isopropanol, tert-butanol, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP , THF or a combination thereof.
  • the bases involved in the present invention include organic bases and inorganic bases;
  • the organic base involved in the present invention is preferably: TEA, DIPEA or a combination thereof;
  • the inorganic bases involved in the present invention are preferably: sodium hydride, n-butyllithium, lithium diisopropylamide, potassium acetate, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, tert-butanol Sodium, LiHMDS, LDA, Butyllithium, or a combination thereof.
  • the present invention also provides a pharmaceutical composition, comprising the above-mentioned nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable Accepted salts, and pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable adjuvants are preferably selected from diluents, absorbents, wetting agents, binders, disintegrants, and lubricants.
  • Said nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt can be a therapeutically effective amount.
  • the present invention also provides the nitrogen-containing fused heterocyclic compound shown in formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt or as previously described
  • the pharmaceutical composition described is used for the preparation of medicines.
  • the medicine can be a medicine for treating diseases or conditions related to abnormal SHP2 activity; preferably, the diseases or conditions include, but are not limited to, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, stomach cancer, anaplastic large cell lymphoma, or glioblastoma .
  • the present invention also provides a method for treating a disease or condition related to abnormal SHP2 activity, comprising administering to the patient a therapeutically effective amount of the nitrogen-containing fused heterocyclic compound shown in Formula I, its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • the disease or disorder includes, but is not limited to, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer , colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.
  • the present invention also provides a method for preventing and/or treating tumors, which comprises administering to a patient a therapeutically effective amount of the nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer isomers, tautomers or pharmaceutically acceptable salts thereof.
  • the tumor includes, but is not limited to, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma , squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.
  • the terms "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification.
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to OCH2- .
  • C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • Haldroxy refers to the -OH group.
  • Alkoxy means an alkyl group as defined below substituted with hydroxy (-OH).
  • Cyano refers to -CN.
  • Amino refers to -NH2 .
  • Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, eg, monoalkylamino, dialkylamino, alkyl amido, aralkylamino, heteroaralkylamino.
  • Carboxyl refers to -COOH.
  • amino refers to an amino-substituted carbonyl group.
  • sulfonamido refers to an amino-substituted sulfonyl group.
  • alkyl refers to a fully saturated straight or branched hydrocarbon chain group, Consists of only carbon and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is attached to the rest of the molecule by a single bond, such as including but not limited to Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl , n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • alkyl refers to a fully saturated straight or branched hydrocarbon chain group, Consists of only carbon and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to
  • alkenyl as a group or part of another group means consisting of carbon and hydrogen atoms only, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) a straight or branched hydrocarbon chain group, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butan- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • cyclohydrocarbyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include fused rings system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which is saturated or unsaturated and can be The carbon atoms are connected to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cyclic hydrocarbon group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene base, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzoyl Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl,
  • heterocyclyl as a group or part of another group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group.
  • the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon, or sulfur atoms of a can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • a stable 3- to 20-membered heterocycloalkyl consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alk-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, is
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H isoindolyl, 2-benzoxazolinone, 2H-1,4 - Benzoxazin-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen 5- to 16-membered conjugated ring system groups of heteroatoms of , oxygen and sulfur.
  • a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group The aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring.
  • a nitrogen, carbon or sulfur atom in a heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized.
  • a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazolyl, carboline, phenanthridine, phenanthroline, acridine base, phena
  • heteroarylalkyl refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.
  • “optionally” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not.
  • “optionally substituted aryl” means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
  • substituents described in the claims and description section of the present invention are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.
  • moiety refers to a specific fragment or functional group in a molecule.
  • a chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
  • the compounds of the present invention are intended to include both E- and Z-geometric isomers.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemic and optically pure forms.
  • the compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2 dichloroacetate, Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipic acid Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesul
  • “Pharmaceutically acceptable base addition salts” refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohe
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.
  • pharmaceutically acceptable excipient includes, but is not limited to, any adjuvant, carrier, excipient, glidant, enhancer approved by the relevant government agency as acceptable for human or livestock use.
  • Sweetening agents diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the "tumor” of the present invention includes, but is not limited to, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcoma, melanoma, articular chondroma, cholangiomas, leukemia, gastrointestinal Stromal tumor, diffuse large B cell lymphoma, follicular lymphoma and other lymphoma, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate Cancer, Liver Cancer, Skin Cancer, Epithelial Cell Cancer, Cervical Cancer, Ovarian Cancer, Colon Cancer, Nasopharyngeal Cancer, Brain Cancer, Bone Cancer, Esophageal Cancer, Melanoma, Kidney Cancer, Oral Cancer, Multiple Myeloma, Mesothelioma , malignant rhabdoid tumor, endo
  • prophylactic As used herein, the terms “prophylactic”, “preventing” and “preventing” include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition.
  • An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drug treatments obtained by admixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form.
  • unfixed combination refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • intermediate compound functional groups may need to be protected by suitable protecting groups.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effects of the present invention are: 1.
  • the nitrogen-containing fused heterocyclic compound disclosed in the present invention is a novel allosteric inhibitor, which can "lock" the basis of weak SHP2 activity by combining with the non-catalytic region of SHP2 state, so as to achieve the purpose of inhibiting its activity.
  • the fused ring compound disclosed by the invention overcomes the disadvantages of the general selectivity and poor druggability of the PTP catalytic region inhibitor, exhibits good biological activity and druggability, and has a good prospect for drug development.
  • the starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidder, Anegi, etc., or can be synthesized by known methods.
  • the ice bath refers to -5 degrees Celsius to 0 degrees Celsius
  • the room temperature refers to 10 degrees Celsius to 30 degrees Celsius
  • the reflux temperature generally refers to the reflux temperature of the solvent under normal pressure.
  • a reaction overnight refers to a time of 8-15 hours.
  • the specific operating temperature is not limited, and all are carried out at room temperature.
  • the separation and purification of intermediates and final products are carried out by normal-phase or reversed-phase chromatographic column separation or other suitable methods.
  • the normal phase flash chromatography column uses ethyl acetate and n-hexane or methanol and dichloromethane as mobile phases.
  • Reversed-phase preparative high pressure liquid chromatography (HPLC) was performed on a C18 column with UV detection at 214 nm and 254 nm with mobile phases A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% carbonic acid) ammonium hydrogen), B (acetonitrile).
  • Step 1 (S)-2-((tert-butyldimethylsilyl)oxy)ethyl propionate A1-1
  • Step 3 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) A1-3
  • reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (150 mL), brine (150 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure.
  • the crude product was purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give 4-((2S)-2-((tert-butyldicarbonate) Methylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)A1-3 (17 g, yield: 32%) as light red oil .
  • Step 4 ((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1 -4
  • Step 5 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1-5
  • Step 7 (S)-tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate A1-7
  • Step 8 (3S,4S)-4-((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-Butyl ester A1-8
  • reaction mixture was quenched with saturated brine solution at 0°C and stirred at room temperature for 15 minutes. After filtration, the solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate.
  • Step 9 (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)propane-2- Sulfenamide A1
  • methyl 6-amino-3-bromopicolinate (5.00 g, 21.6 mmol) followed by di-tert-butyl dicarbonate (9.68 g, 44.4 mmol) and triethylamine (4.38 g, 43.3 mmol) and 4-dimethylaminopyridine (0.132 g, 1.08 mmol) and tert-butanol (30 mL). Under nitrogen, the mixture was heated to 80°C and the reaction was stirred for 16 hours.
  • Step 4 tert-butyl 4-((3-bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-cyanopiperidine-1-carboxylate A45-4
  • tert-butyl 4-cyanopiperidine-1-carboxylate A45-3 (2.75 g, 13.1 mmol) and 30 mL of tetrahydrofuran solvent.
  • the mixture was cooled to -78°C with a dry ice ethanol bath, then lithium diisopropylamide (1.53 g, 14.3 mmol) was slowly added dropwise to the system under nitrogen, and the reaction was maintained at -78°C for 1 h.
  • Step 5 tert-butyl 2-((tert-butoxycarbonyl)amino)-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine ]-1'-carboxylate A45-5
  • Step 6 tert-butyl(S,Z)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl ⁇ sulfinyl>)imino)-5, 7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-6
  • Step 7 tert-butyl(5S)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl ⁇ sulfinyl>)amino)-5,7-di Hydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-7
  • Step 8 N-((S)-2-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidin]-5-yl)-2-methyl Propane-2-sulfinamide A45
  • Step 1 (3-bromo-6-chloropyridin-2-yl) methanol A53-1
  • methyl 3-bromo-6-chloropicoline (5.00 g, 20.0 mmol) followed by 20 mL of methanol.
  • Sodium borohydride (3.78 g, 99.8 mmol) was added portionwise under nitrogen at 0°C. The reaction was kept at 0°C for 5 minutes, and the mixture was slowly warmed to room temperature and stirred for 3 hours.
  • Step 3 1-(tert-butyl)4-ethyl 4-((3-bromo-6-chloropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate A53-3
  • Step 4 tert-butyl 2-chloro-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53- 4
  • Step 5 tert-butyl(S,Z)-5-((tert-butylsulfinyl ⁇ sulfinyl>)imino)-2-chloro-5,7-dihydrospiro[cyclopentadiene [b]pyridine-6,4'-piperidine]-1'-carboxylate A53-5
  • Step 6 tert-butyl(5S)-5-((tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-chloro-5,7-dihydrospiro[cyclopentadieno[b ]pyridine-6,4'-piperidine]-1'-carboxylate A53-6
  • Step 7 tert-butyl(5S)-5-((tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-(3-fluoroazetidin-1-yl)-5,7- Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-7
  • Step 8 N-((S)-2-(3-fluoroazetidin-1-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine ]-5-yl)-2-methylpropane-2-sulfinamide A53
  • Step 1 tert-butyl(5S)-5-((tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-hydrazino-5,7-dihydrospiro[cyclopentadieno[ b]pyridine-6,4'-piperidine]-1'-carboxylate A49-1
  • Step 2 tert-butyl(6S)-6-((tert-butylsulfinyl ⁇ sulfinyl>)amino)-6,8-dihydrospiro[cyclopentadieno[e][1, 2,4]Triazolo[4,3-a]pyridine-7,4'-piperidine]-1'-carboxylate A49-2
  • Step 3 N-((S)-6,8-dihydrospiro[cyclopentadieno[e][1,2,4]triazolo[4,3-a]pyridine-7,4'- Piperidin]-6-yl)-2-methylpropane-2-sulfinamide A49
  • Step 1 tert-butyl 2-methyl-4-carbonyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A48 -1
  • Step 2 tert-butyl(Z)-4-((tert-butylsulfinyl ⁇ sulfinyl>)imino)-2-methyl-4,6-dihydrospiro[cyclopentadieno [d]thiazole-5,4'-piperidine]-1'-carboxylate
  • Step 3 tert-butyl(4S)-4-((tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-methyl-4,6-dihydrospiro[cyclopentadieno[ d] Thiazole-5,4'-piperidine]-1'-carboxylate
  • Step 2 1-tert-Butyl-4-ethyl-4-[(2-chloro-1,3-thiazol-4-yl)methyl]piperidine-1,4-dicarboxylate A46-2
  • Step 3 tert-butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'- tert-Butyl Carboxylate A46-3
  • Step 4 tert-butyl(6)-2-chloro-6- ⁇ [(R)-2-methylpropane-2-sulfinyl]imino ⁇ -4,6-dihydrospiro[cyclopentadiene [d][1,3]thiazole 5,4'-piperidine]-1'-carboxylate tert-butyl ester A46-4
  • Step 1 tert-butyl(6)-2-methyl-6-[(R)-2-methylpropane-2-sulfinyl)imino]-4,6-dihydrospiro[cyclopentadiene [d][1,3]thiazole-5,4'-piperidine]-1'-carboxylate tert-butyl ester A47-1
  • Step 2 Obtain tert-butyl (S)-6-((((R)-tert-butylsulfinyl)amino)-2-methyl-4,6-dihydrospiro[ Cyclopentadiene[d]thiazole-5,4'-piperidine]-1'-carboxylate tert-butyl ester A47-2
  • Step 3 Deprotection according to the method of Step 8 of Example 2 to obtain (R)-2-methyl-N-((S)-2-methyl-4,6-dihydrospiro[cyclopentadieno[d] ]thiazol-5,4'-piperidin]-6-yl)propane-2-sulfinamide A47
  • Step 1 tert-butyl(R,Z)-6-((tert-butylsulfinyl ⁇ sulfinyl>)imino)-2-(dimethylamino)-4,6-dihydrospiro[ Cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A42-1
  • Step 2 Remove (R)-N-((S)-2-(dimethylamino)-4,6-dihydrospiro[cyclopentadieno[d] according to the methods of Step 7 and Step 8 of Example 2 ]thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A42
  • Step 1 tert-butyl(5S)-5-((tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno [b]pyridine-6,4'-piperidine]-1'-carboxylate A16-1
  • Step 2 Deprotection according to the method of Step 8 of Example 2 to obtain (R)-N-((S)-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6 ,4'-Piperidin]-5-yl)-2-methylpropane-2-sulfinamide A16
  • Step 1 4-((2-Bromophenyl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester A41-1
  • o-Bromoaniline 500 mg, 2.91 mmol
  • tert-butyl 4-oxopiperidine-1-carboxylate 666 mg, 3.34 mmol
  • trimethylsilane 331 mg, 3.34 mmol
  • the reaction solution was quenched with ammonia water, adjusted to neutrality, extracted with ethyl acetate, the organic phase was dried, concentrated, and the crude product was purified with a flash silica column to obtain a white solid 4-(( 2-Bromophenyl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester A41-1 (550 mg, 46.5% yield).
  • Step 2 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate tert-butyl ester A41-2
  • Step 3 1-Methyl 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate tert-butyl ester A41-3
  • Step 4 According to the method of Example 2, use 1-methyl 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate tert-butyl ester A41-3 as raw material to obtain intermediate (R)-2-methyl-N-((R)-1-methylspiro[indoline-2,4'-piperidin]-3-yl)propane-2-sulfinamide A41
  • Step 1 6-cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A13-1
  • Step 2 6-cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A13-1 is subjected to step 6 of Example 2, The method of step 7 and step 8 obtains the intermediate (R)-N-((S)-5-cyano-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl in three steps )-2-methylpropane-2-sulfinamide A13.
  • Step 1 1'-(tert-butoxycarbonyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxylic acid A21-1
  • 6-Cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A13-1 (420 mg, 1.29 mmol) was added to methanol To a mixed solvent of (15 mL) and water (15 mL), potassium hydroxide (0.72 g, 12.9 mmol) was added, followed by stirring at 70° C. for 15 hours. After cooling to room temperature, the pH was adjusted to 7 with saturated citric acid, then diluted with water (30 mL), and extracted with ethyl acetate (60 mL ⁇ 2).
  • Step 2 6-((methyl-d3)carbamoyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A21 -2
  • Step 3 6-((methyl-d3)carbamoyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A21 -2
  • the intermediate (S)-1-((((R)-tert-butylsulfinyl)amino)-N-(methyl-d3 is obtained through three steps of the method of step six, step seven and step eight of Example 2 )-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxamide
  • A21 The intermediate (S)-1-((((R)-tert-butylsulfinyl)amino)-N-(methyl-d3 is obtained through three steps of the method of step six, step seven and step eight of Example 2 )-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxamide A21
  • Step 1 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-4,6-dihydro Spiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1
  • Step 2 tert-butyl(S)-6-((((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-(2-hydroxypropan-2-yl)-4, 6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A29-2
  • Step 3 Deprotection according to the method of Example 2 to obtain intermediate (R)-N-((S)-2-(2-hydroxypropan-2-yl)-4,6-dihydrospiro[cyclopentadiene] [d]thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A29
  • Example 14 According to the methods of Example 5 and Example 13, intermediate (R)-N-((S)-2-(2-hydroxypropan-2-yl)-5,7-dihydrospiro[cyclo] can be obtained pentadieno[b]pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide A35
  • Step 1 tert-butyl(S)-6-(((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-formyl-4,6-dihydrospiro[cyclopentane Dieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-1
  • Step 2 tert-butyl(S)-6-((((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-(difluoromethyl)-4,6-dihydro Spiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-2
  • reaction solution was slowly added to an ice-water bath (10 mL) to quench, and the liquid was separated by stirring.
  • the aqueous phase was extracted with dichloromethane (10 mL) again, and the organic phases were combined with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL).
  • Step 3 Deprotection according to the method of Example 2 to obtain intermediate (R)-N-((S)-2-(difluoromethyl)-4,6-dihydrospiro[cyclopentadieno[d]] Thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A33
  • Step 1 tert-butyl-1-oxo-6-phenyl-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A18-1
  • tert-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A10- 1 is the starting material to obtain (R)-2-methyl-N-((S)-5-phenyl-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)propane -2-Sulfenamide A18
  • Step 1 tert-butyl(S)-6-((((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-(methylcarbamoyl)-4,6-di Hydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A55-1
  • Titanium (907mg, 3.19mmol), a pale yellow solution was obtained, reacted at 0-5°C for 15min, 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylidene Sulfuryl ⁇ sulfinyl>)amino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate
  • A29-1 (940 mg, 2.13 mmol) was dissolved in anhydrous methanol (9 mL) and slowly added dropwise to the reaction solution, reacted at 0-5 °C for 1 hour, sodium borohydride (161 mg, 4.26 mmol) was added, and then reacted at room temperature for 1 hour, LCMS showed the reaction completely.
  • Step 2 tert-butyl(S)-6-((((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-(methylcarbamoyl) according to the method of Example 2 -4,6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate
  • A55-1 removes the Boc protecting group to give (S)-6-( ((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-N-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperin pyridine]-2-carboxamide
  • A55-1 removes the Boc protecting group to give (S)-6-( ((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-N-methyl
  • Step 1 tert-butyl(S)-6-(((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-((methylamino)methyl)-4,6 -Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A56-1
  • Titanium (907mg, 3.19mmol), a pale yellow solution was obtained, reacted at 0-5°C for 15min, tert-butyl(S)-6-(((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino )-2-formyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-1 (940 mg, 2.13 mmol) dissolved in The reaction solution was slowly added dropwise to anhydrous methanol (9 mL), reacted at 0-5 °C for 1 hour, sodium borohydride (161 mg, 4.26 mmol) was added, and then reacted at room temperature for 1 hour.
  • Step 2 tert-butyl(S)-6-((((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-((methylamino)methane according to the method of Example 2 (R)-2 -Methyl-N-((S)-2-((methylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]- 4-yl)propane-2-sulfinamide A56
  • Step 1 tert-butyl(S)-6-(((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-((dimethylamino)methyl)-4,6 -Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A57-1
  • Step 2 tert-butyl(S)-6-((((R)-tert-butylsulfinyl ⁇ sulfinyl>)amino)-2-((dimethylamino)methyl according to the method of Example 2 (R)-N -((S)-2-((dimethylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-4-yl)- 2-Methylpropane-2-sulfinamide A57.
  • 2,3-Dichloro-4-iodopyridine (3.2g, 11.68mmol), palladium acetate (92mg, 0.41mmol), Xantphos (285mg, 0.49mmol), DIPEA were added to a dry 100mL round-bottomed flask in sequence under nitrogen protection (2.12 g, 16.46 mmol) and 1,4-dioxane (30 mL). The reaction mixture was stirred with heating at 100°C for 2 hours.
  • reaction solution was quenched with methanol (200 mL), the solvent was removed by rotary evaporation, water was added, extracted with ethyl acetate, the organic phase was washed, dried, and concentrated to obtain the crude product (2S,4R)-4-fluoro-2-(hydroxymethyl) ) tert-butyl pyrrolidine-1-carboxylate B4-1 (7.50 g, crude).
  • reaction solution was quenched by adding water, extracted with ethyl acetate, washed with the organic phase, dried and concentrated, and purified by column chromatography to obtain pure (2S,4R)-4-fluoro-2-((2-fluoro-4- Iodopyridin-3-yl)oxymethyl)pyrrolidine-1-carboxylate tert-butyl ester B4-2 (9.40 g, 61.9% yield).
  • Step 3 2-Fluoro-3-(((2S,4R)-4-fluoropyrrolidin-2-yl)oxymethyl)-4-iodopyridine ⁇ hydrochloride B4-3
  • (2S,4R)-4-fluoro-2-((2-fluoro-4-iodopyridin-3-yl)methoxy)pyrrolidine-1-carboxylate tert-butyl ester B4-2 (9.40 g, 21.4 mmol ) was added to a solution of hydrochloric acid in dioxane (4.00 M, 107 mL). The reaction solution was reacted at 25°C for 2 hours. The reaction was found to be complete by TLC monitoring. The reaction solution was filtered and the solid was collected.
  • Step 4 (6aS,8R)-8-Fluoro-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1 ,4]oxazine B4-4
  • Step 5 3-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrole[1,2-d][1, 4] Oxazin-4-yl)mercapto)propionic acid (2-ethylhexyl)ester B4-5

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Abstract

A nitrogen-containing fused heterocyclic compound, and a preparation method therefor and the use thereof. Provided are a nitrogen-containing fused heterocyclic compound as shown in formula I, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which can be used for preparing a drug for treating diseases or conditions related to an abnormal SHP2 activity, comprising cancer, etc.

Description

含氮稠杂环类化合物及其制备方法和应用Nitrogen-containing fused heterocyclic compounds and their preparation methods and applications
本申请要求申请日为2020/10/26的中国专利申请2020111558553和申请日为2021/10/19的中国申请2021112179065的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2020111558553 with the filing date of 2020/10/26 and Chinese application 2021112179065 with the filing date of 2021/10/19. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明公开了含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐。本发明也提供了该类化合物的制备方法、含有该类化合物的组合物以及该类化合物在制备治疗与SHP2活性异常相关疾病或病症的药物方面的用途。The invention discloses nitrogen-containing fused heterocyclic compounds, their stereoisomers, their tautomers or their pharmaceutically acceptable salts. The present invention also provides a preparation method of the compound, a composition containing the compound and the use of the compound in preparing a medicine for treating diseases or conditions related to abnormal SHP2 activity.
背景技术Background technique
酪氨酸磷酸酶SHP2由两个N-末端Src同源2结构域(N-SH2和C-SH2)和一个蛋白酪氨酸磷酸酶催化结构域(PTP)构成。在基础状态下，N-SH2能够与PTP结合形成一个环状结构，从而阻碍PTP与底物的结合，使得酶催化活性被抑制；当上游受体蛋白的酪氨酸被磷酸化后，N-SH2与之相结合，PTP催化域得到释放从而发挥出磷酸酶活性。The tyrosine phosphatase SHP2 consists of two N-terminal Src homology 2 domains (N-SH2 and C-SH2) and a protein tyrosine phosphatase catalytic domain (PTP). In the basal state, N-SH2 can combine with PTP to form a ring structure, thereby hindering the binding of PTP to the substrate, so that the catalytic activity of the enzyme is inhibited; when the tyrosine of the upstream receptor protein is phosphorylated, N-SH2 When SH2 binds to it, the PTP catalytic domain is released to exert phosphatase activity.
在细胞水平上，SHP2通过在诸多受体酪氨酸激酶的细胞质下游的功能作用，参与多个肿瘤细胞信号传导通路，如RTK/Ras/MAPK、JAK/STAT和PI3K/Akt等。通过对这些激酶以及信号通路的调控作用，SHP2与许多重要的细胞生命活动密切相关，如细胞增殖、迁移、分化、死亡、细胞因子的调控及肿瘤发生等等。At the cellular level, SHP2 participates in multiple tumor cell signaling pathways, such as RTK/Ras/MAPK, JAK/STAT, and PI3K/Akt, by functioning downstream of the cytoplasm of many receptor tyrosine kinases. Through the regulation of these kinases and signaling pathways, SHP2 is closely related to many important cell life activities, such as cell proliferation, migration, differentiation, death, regulation of cytokines and tumorigenesis.
同时，SHP2也参与程序性死亡受体1(PD1)介导的免疫系统抑制。T细胞的PD-1与PD-L1结合后，在细胞内能搞招募大量的SHP2。SHP2能够将T细胞内抗原受体通路蛋白去磷酸化，从而抑制T细胞的激活。因此，抑制SHP2的活性能够在肿瘤微环境中逆转免疫抑制。Meanwhile, SHP2 is also involved in programmed death receptor 1 (PD1)-mediated suppression of the immune system. After the PD-1 of T cells is combined with PD-L1, a large amount of SHP2 can be recruited in the cell. SHP2 can dephosphorylate antigen receptor pathway proteins in T cells, thereby inhibiting T cell activation. Therefore, inhibition of SHP2 activity could reverse immunosuppression in the tumor microenvironment.
SHP2是蛋白酪氨酸磷酸酶家族中的重要一员，与人类多种疾病相关，如努南综合征(Noonan Syndrome)、豹综合征(Leopard Syndrome)、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤等等。SHP2 is an important member of the protein tyrosine phosphatase family and is associated with many diseases in humans, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma and many more.
近期内发表的一系列专利，如WO2019/075265A1、WO2020/063760A1、WO2018/013597A1、WO2017/210134A1、WO2017/211303A1、WO2017/216706A1、WO 2016/203406A1、WO2016/203405A1、WO2016/203404A1、WO2015/107495A1、WO2015/107494A1和WO2015/107493A1等等，表明了SHP2作为一个新颖的可成药靶点，引起了越来越多的关注。目前在开发的SHP2变构抑制剂有多种，如诺华的TNO155、JAB-3068、RMC-4630、JAB-3312、RLY-1971等。目前该靶点在国内外还没有上市产品，同时初步的临床数据显示安全性并不好。因此开发出靶向SHP2的活性小分子药物，能够为患者提供更加安全有效的SHP2抑制剂具有非常重要的意义。近期内发表的一系列专利，如WO2019/075265A1、WO2020/063760A1、WO2018/013597A1、WO2017/210134A1、WO2017/211303A1、WO2017/216706A1、WO 2016/203406A1、WO2016/203405A1、WO2016/203404A1、WO2015/107495A1、 WO2015/107494A1 and WO2015/107493A1, etc., showed that SHP2 has attracted more and more attention as a novel druggable target. There are many SHP2 allosteric inhibitors currently under development, such as Novartis' TNO155, JAB-3068, RMC-4630, JAB-3312, RLY-1971 and so on. At present, there is no marketed product for this target at home and abroad, and preliminary clinical data show that the safety is not good. Therefore, it is of great significance to develop active small molecule drugs targeting SHP2 to provide patients with safer and more effective SHP2 inhibitors.
发明内容SUMMARY OF THE INVENTION
本发明提供的含氮稠杂环化合物是一类全新的SHP2抑制剂，表现出对肿瘤细胞很好的抑制活性且成药性好，具有广阔的药物开发前景。而且该类化合物的制备方法简单，有利于工业化生产。The nitrogen-containing fused heterocyclic compound provided by the present invention is a brand-new SHP2 inhibitor, which exhibits good inhibitory activity on tumor cells and good druggability, and has broad prospects for drug development. Moreover, the preparation method of the compound is simple, which is favorable for industrial production.
本发明是通过下述技术方案来解决上述技术问题的。The present invention solves the above-mentioned technical problems through the following technical solutions.
第一方面，本发明提供了一种如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；In a first aspect, the present invention provides a nitrogen-containing fused heterocyclic compound shown in formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt;
Figure PCTCN2021126331-appb-000001
Figure PCTCN2021126331-appb-000001
其中，in,
R 1为
Figure PCTCN2021126331-appb-000002
 R1 is
Figure PCTCN2021126331-appb-000002
其中，L 1为连接键、-O-或-S-； Wherein, L 1 is a connecting bond, -O- or -S-;
环D为连接键、C 4-C 8环烷基、5-6元单环杂环基、8-10元双环杂环基、C 6-C 10芳基、5-10元杂芳基、5-10元杂环基并苯基、5-10元杂环基并5-6元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S和P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O和S； Ring D is a connecting bond, C 4 -C 8 cycloalkyl, 5-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, 5-10-membered heterocyclyl acyl group, 5-10-membered heterocyclyl group and 5-6 membered heteroaryl group; in the heterocyclyl group, it contains 1-3 heteroatoms selected from the following group: N, O, S and P; in the heteroaryl group, 1-3 heteroatoms are selected from the group consisting of N, O and S;
n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
R 1a独立地为卤素、氰基、羟基、C 1-C 6烷基、C 1-C 6烷基-O-、C 3-C 8环烷基、3-8元杂环基、-C(＝O)OR 1a2、-NHC(＝O)R 1a2、-NR 1a3R 1a5、5-10元杂芳基、被一个或多个R 1a1取代的C 3-C 8环烷基、被一个或多个R 1a4取代的3-8元杂环基、或者，被一个或多个R a取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； R 1a is independently halogen, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, -C (=O)OR 1a2 , -NHC(=O)R 1a2 , -NR 1a3 R 1a5 , 5-10 membered heteroaryl, C 3 -C 8 cycloalkyl substituted by one or more R 1a1 , by one 3-8-membered heterocyclic group substituted by or more R 1a4 , or, substituted by one or more R a : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-; when the substituent is When more than one, the same or different; the heterocyclic group contains 1-3 heteroatoms selected from the following group: N, O, S or P; the heteroaryl group contains 1-3 heteroatoms a heteroatom selected from the group consisting of N, O or S;
R 1a1和R 1a4独立地为卤素、C 1-C 4烷基或氧代(＝O)； R 1a1 and R 1a4 are independently halogen, C 1 -C 4 alkyl or oxo (=O);
R 1a2、R 1a3和R 1a5独立地为氢、C 1-C 4烷基、取代或未取代的烯基、酰胺、C 3-C 12单或多杂环、5-6元的芳基、5-6元杂芳基、被一个或多个卤素取代的5-6元芳基或被一个或多个卤素取代的5-6元杂芳基或
Figure PCTCN2021126331-appb-000003
所述的单或多杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； R 1a2 , R 1a3 and R 1a5 are independently hydrogen, C 1 -C 4 alkyl, substituted or unsubstituted alkenyl, amide, C 3 -C 12 mono- or polyheterocycle, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered aryl substituted with one or more halogens or 5-6 membered heteroaryl substituted with one or more halogens or
Figure PCTCN2021126331-appb-000003
In the described single or polyheterocyclic group, 1-3 heteroatoms selected from the following group are included: N, O, S or P; in the described heteroaryl group, 1-3 heteroatoms selected from the following group are included. Heteroatom: N, O or S;
R a独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
R c为H或C 1-C 4烷基； R c is H or C 1 -C 4 alkyl;
X 1为CR 3，X 2为CR 3；或，X 1为N，X 2为CR 3；或，X 1为CR 3，X 2为N； X 1 is CR 3 , and X 2 is CR 3 ; or, X 1 is N, and X 2 is CR 3 ; or, X 1 is CR 3 , and X 2 is N;
R 3独立地为氢、卤素、氨基、硝基、三氟甲基、C 3-C 8的环烷基、乙烯基或C 1-C 4烷基； R 3 is independently hydrogen, halogen, amino, nitro, trifluoromethyl, C 3 -C 8 cycloalkyl, vinyl or C 1 -C 4 alkyl;
R 4独立地为氢、卤素、C 1-C 4烷基、氨基、硝基、三氟甲基、C 1-C 4含有羟基或氨基或卤素取代的烷基； R 4 is independently hydrogen, halogen, C 1 -C 4 alkyl, amino, nitro, trifluoromethyl, C 1 -C 4 containing hydroxy or amino or halogen substituted alkyl;
R 2为
Figure PCTCN2021126331-appb-000004
 R2 is
Figure PCTCN2021126331-appb-000004
o1、o2独立地为0、1或2；且o1+o2小于等于3；o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b独立地为氢、卤素、C 1-C 4烷基； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen, halogen, C 1 -C 4 alkyl;
Y＝N或C；Y=N or C;
当Y＝N时，R 7独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基取代的C 1-C 4烷基、氨基取代的3-12元环烷基；R 8不存在； When Y=N, R 7 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino substituted C 1 -C 4 alkyl, amino substituted 3-12 membered cycloalkyl; R 8 is absent;
当Y＝C时，R 7、R 8独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基、C 1-C 4烷基取代氨基、C 1-C 4烷基-O-取代氨基-； When Y=C, R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino, C 1 -C 4 alkyl substituted amino, C 1 - C 4 alkyl-O-substituted amino-;
或者，当Y＝C时，R 7和R 8与Y一起形成：
Figure PCTCN2021126331-appb-000005
Alternatively, when Y=C, R7 and R8 together with Y form:
Figure PCTCN2021126331-appb-000005
p、q独立地为0、1或2；且p+q小于等于3；p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
R 9a、R 9b、R 10a、R 10b独立地为氢、氘、卤素、氨基、-NHR 9-1、C 1-C 4烷基； R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, halogen, amino, -NHR 9-1 , C 1 -C 4 alkyl;
R 9-1为C 1-C 4烷基； R 9-1 is C 1 -C 4 alkyl;
W为连接键、-C(R w) 2-、-O-、-S-或-NR w-； W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
R w独立地为氢或C 1-C 4烷基； R w is independently hydrogen or C 1 -C 4 alkyl;
环H独立地为不存在或为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O、或S； Ring H is independently absent or C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heteroaryl group; in the heterocyclic group, Contains 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, contains 1-3 heteroatoms selected from the following group: N, O, or S;
当环H不存在时，Z 1为CR z1aR z1b或者O，Z 2为CR z2aR z2b或者O； When ring H does not exist, Z 1 is CR z1a R z1b or O, and Z 2 is CR z2a R z2b or O;
当环H为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂环芳基时，Z 1为CR z1a或者N，Z 2为CR z2a或者N，
Figure PCTCN2021126331-appb-000006
为单键；或者Z 1为C且Z 2为C，
Figure PCTCN2021126331-appb-000007
为双键； When ring H is C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heterocyclic aryl group, Z 1 is CR z1a or N, and Z 2 is CR z2a or N,
Figure PCTCN2021126331-appb-000006
is a single bond; or Z 1 is C and Z 2 is C,
Figure PCTCN2021126331-appb-000007
is a double bond;
R z1a、R z1b、R z2a、R z2b独立地为氢原子、卤素、C 1-C 4烷基； R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
r独立地为0、1、2、3或4；r is independently 0, 1, 2, 3, or 4;
R 11独立地为卤素、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-，硝基、C 3-C 8的环烷基、3-7元杂环 基、-(CH 2) iNR 11-1R 11-2、-C(＝O)N(R 11-3R 11-3)、
Figure PCTCN2021126331-appb-000008
被一个羟基取代的C 1-C 6烷基、未取代或被1-4个R b取代的C 6-C 10芳基、含有1-3个杂原子的5-6元的芳杂基，或者，被一个或多个R b取代的：C 1-C 6烷基、C 1-C 6烷基-O-、或者，被一个或多个R 11-7取代的3-7元杂环基；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述5-6元的芳杂基中，选自1-3个选自下组的杂原子：N、O、S或P； R 11 is independently halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, nitro, C 3 -C 8 cycloalkyl, 3-7 membered heterocycle group, -(CH 2 ) i NR 11-1 R 11-2 , -C(=O)N(R 11-3 R 11-3 ),
Figure PCTCN2021126331-appb-000008
C 1 -C 6 alkyl substituted with one hydroxyl group, C 6 -C 10 aryl group unsubstituted or substituted with 1-4 R b , 5-6 membered heteroaryl group containing 1-3 heteroatoms, Alternatively, substituted with one or more R b : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, or, 3-7 membered heterocycle substituted with one or more R 11-7 base; when there are multiple substituents, they are the same or different; the heterocyclic group contains 1-3 heteroatoms selected from the following group: N, O, S or P; the 5-6 membered In the heteroaryl group, 1-3 heteroatoms are selected from the following group: N, O, S or P;
R 11-1和R 11-2独立地为H或C 1-C 4烷基； R 11-1 and R 11-2 are independently H or C 1 -C 4 alkyl;
R 11-3独立地为H、C 1-C 4烷基或CD 3； R 11-3 is independently H, C 1 -C 4 alkyl or CD 3 ;
R 11-4独立地为H或C 1-C 4烷基； R 11-4 is independently H or C 1 -C 4 alkyl;
R 11-5和R 11-6独立地为H或C 1-C 4烷基； R 11-5 and R 11-6 are independently H or C 1 -C 4 alkyl;
R 11-7独立地为卤素或氨基； R 11-7 is independently halogen or amino;
i独立地为0、1、2、3或4；i is independently 0, 1, 2, 3, or 4;
R b独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-。 R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
在本发明某些优选实施方案中，所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐中的某些基团如下定义，未提及的基团同本申请任一方案所述(以下简称在本发明的某一优选方案中)，In certain preferred embodiments of the present invention, the nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or certain pharmaceutically acceptable salts thereof These groups are defined as follows, and the unmentioned groups are described in any scheme of this application (hereinafter referred to as a certain preferred scheme of the present invention),
Figure PCTCN2021126331-appb-000009
为：
Figure PCTCN2021126331-appb-000009
for:
Figure PCTCN2021126331-appb-000010
Figure PCTCN2021126331-appb-000010
其中，n1、n2和n3独立地为0、1、2、3或4，且n1+n2等于0、1、2、3、4、5或6；n1+n2+n3等于0、1、2、3、4、5或6；where n1, n2, and n3 are independently 0, 1, 2, 3, or 4, and n1+n2 equals 0, 1, 2, 3, 4, 5, or 6; n1+n2+n3 equals 0, 1, 2 , 3, 4, 5 or 6;
环E为含有1至3个N原子的6元杂芳基；环F为含有1至4个N、S、O杂原子的5元杂芳基；G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms; Ring F is a 5-membered heteroaryl containing 1 to 4 N, S, O heteroatoms; G is independently C, C(=O) , N, S or O heteroatoms or groups; G' is independently a linkage, C, C(=O), N, S or O atoms or groups;
例如，为
Figure PCTCN2021126331-appb-000011
n为0、1、2、3、4或5；R 1a独立地为卤素、C 1-C 6烷基、氨基； For example, for
Figure PCTCN2021126331-appb-000011
n is 0, 1, 2, 3, 4 or 5; R 1a is independently halogen, C 1 -C 6 alkyl, amino;
较佳地，为
Figure PCTCN2021126331-appb-000012
更佳地
Figure PCTCN2021126331-appb-000013
Preferably, for
Figure PCTCN2021126331-appb-000012
better
Figure PCTCN2021126331-appb-000013
在本发明的某一优选方案中，In a preferred solution of the present invention,
L 1为-S-或-O-(又例如-S-)。 L 1 is -S- or -O- (also for example -S-).
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 1a独立地为卤素、氨基、C 1-C 6烷基、3-8元杂环烷基、-NHC(＝O)R 1a2、-NHR 1a3、5-10元杂芳基、被一个或多个R 1a4取代的3-8元杂环烷基或被一个或多个R a取代的：C 1-C 6烷基；例如卤素、氨基。 R 1a is independently halogen, amino, C 1 -C 6 alkyl, 3-8 membered heterocycloalkyl, -NHC(=O)R 1a2 , -NHR 1a3 , 5-10 membered heteroaryl, by one or 3-8 membered heterocycloalkyl substituted with multiple R 1a4 or substituted with one or more R a : C 1 -C 6 alkyl; eg halogen, amino.
在本发明的某一优选方案中，In a preferred solution of the present invention,
环D为连接键、C 6-C 10芳基、5-10元杂芳基或5-10元杂环基并5-6元杂芳基。 Ring D is a linking bond, C6 - C10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl and 5-6 membered heteroaryl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 3独立地为氢。 R3 is independently hydrogen.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 4独立地为氢。 R 4 is independently hydrogen.
在本发明的某一优选方案中，In a preferred solution of the present invention,
X 1为CR 3，X 2为CR 3。 X 1 is CR 3 and X 2 is CR 3 .
在本发明的某一优选方案中，In a preferred solution of the present invention,
X 1为N，X 2为CR 3。 X 1 is N and X 2 is CR 3 .
在本发明的某一优选方案中，In a preferred solution of the present invention,
X 1为CR 3，X 2为N。 X 1 is CR 3 and X 2 is N.
在本发明的某一优选方案中，In a preferred solution of the present invention,
n为0、1或2个。n is 0, 1 or 2.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 1a2独立地为5-6元芳基或被一个或多个卤素取代的5-6元芳基。 R 1a2 is independently a 5-6 membered aryl group or a 5-6 membered aryl group substituted with one or more halogens.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 1a3和R 1a5独立地为H、C 1-C 4烷基、5-6元杂芳基或
Figure PCTCN2021126331-appb-000014
R 1a3 and R 1a5 are independently H, C 1 -C 4 alkyl, 5-6 membered heteroaryl or
Figure PCTCN2021126331-appb-000014
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 1a4独立地为氧代(＝O)。 R 1a4 is independently oxo (=O).
在本发明的某一优选方案中，In a preferred solution of the present invention,
R a独立地为卤素。 Ra is independently halogen.
在本发明的某一优选方案中，In a preferred solution of the present invention,
o1为0或1。o1 is either 0 or 1.
在本发明的某一优选方案中，In a preferred solution of the present invention,
o2为0或1。o2 is either 0 or 1.
在本发明的某一优选方案中，In a preferred solution of the present invention,
p为1或2。p is 1 or 2.
在本发明的某一优选方案中，In a preferred solution of the present invention,
q为0或1。q is 0 or 1.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 9a、R 9b、R 10a、R 10b独立地为氢、氘、氨基或-NHR 9-1。 R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, amino or -NHR 9-1 .
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 9a和R 9b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基； Among R 9a and R 9b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group;
例如一个为氢原子，另一个为氢原子、C 1-C 4烷基或氨基。 For example one is a hydrogen atom and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 10a和R 10b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基。 Among R 10a and R 10b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group.
在本发明的某一优选方案中，In a preferred solution of the present invention,
W独立地为连接键、-C(R w) 2-、-O-、或-NR w-。 W is independently a linker, -C( Rw ) 2- , -O-, or -NRw- .
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环H不存在时，Z 1为CR z1aR z1b，Z 2为O；或者，Z 1为O，Z 2为CR z2aR z2b。 When ring H is absent, Z 1 is CR z1a R z1b and Z 2 is O; alternatively, Z 1 is O and Z 2 is CR z2a R z2b .
在本发明的某一优选方案中，In a preferred solution of the present invention,
环H为苯基或5-6元杂芳基；例如苯基。Ring H is phenyl or 5-6 membered heteroaryl; eg, phenyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R z1a和R z1b中，或者，R z2a和R z2b中，一个为氢，另一个为氢或C 1-C 4烷基；例如，R z1a、R z1b、R z2a、R z2b独立地为氢原子、或R z1a为H，R z1b为甲基。 Of Rz1a and Rz1b , alternatively, of Rz2a and Rz2b , one is hydrogen and the other is hydrogen or C1 - C4 alkyl; for example, Rz1a , Rz1b , Rz2a , Rz2b are independently hydrogen Atom, or R z1a is H, and R z1b is methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
r独立地为0或1；例如0。r is independently 0 or 1; eg, 0.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 11独立地为卤素、氰基、C 1-C 6烷基、C 1-C 6烷基-O-、C 3-C 8的环烷基、3-7元杂环基、-(CH 2) q NR 11- 1R 11-2、-C(＝O)N(R 11-3R 11-3)、
Figure PCTCN2021126331-appb-000015
被一个羟基取代的C 1-C 6烷基、C 6-C 10芳基、被一个或多个R b取代的C 1-C 6烷基、被一个或多个R 11-7取代的3-7元杂环基。 R 11 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, 3-7 membered heterocyclyl, -(CH 2 ) q NR 11-1 R 11-2 , -C( = O)N(R 11-3 R 11-3 ),
Figure PCTCN2021126331-appb-000015
C 1 -C 6 alkyl substituted with one hydroxy, C 6 -C 10 aryl, C 1 -C 6 alkyl substituted with one or more R b , 3 substituted with one or more R 11-7 -7-membered heterocyclyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 2为
Figure PCTCN2021126331-appb-000016
Y＝C，R 7和R 8与Y一起形成：
Figure PCTCN2021126331-appb-000017
即
Figure PCTCN2021126331-appb-000018
 R2 is
Figure PCTCN2021126331-appb-000016
Y=C, R7 and R8 together with Y form:
Figure PCTCN2021126331-appb-000017
which is
Figure PCTCN2021126331-appb-000018
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000019
为
Figure PCTCN2021126331-appb-000020
即所述的如式I所示的含氮稠杂环类化合物为
Figure PCTCN2021126331-appb-000021
Figure PCTCN2021126331-appb-000019
for
Figure PCTCN2021126331-appb-000020
That is, the nitrogen-containing fused heterocyclic compounds shown in formula I are:
Figure PCTCN2021126331-appb-000021
其中，p’为0或1；q为0、1或2；且p’+q小于等于2；Wherein, p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2;
例如W为连接键；即
Figure PCTCN2021126331-appb-000022
再例如W为连接键，p’为0，q为1。 For example W is the connection key; that is
Figure PCTCN2021126331-appb-000022
For another example, W is a connecting key, p' is 0, and q is 1.
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000023
为
Figure PCTCN2021126331-appb-000024
其中，p’为0；q为0；W为-NR w-；即
Figure PCTCN2021126331-appb-000025
Figure PCTCN2021126331-appb-000023
for
Figure PCTCN2021126331-appb-000024
Among them, p' is 0; q is 0; W is -NR w -; namely
Figure PCTCN2021126331-appb-000025
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000026
为
Figure PCTCN2021126331-appb-000027
其中，p’为0；q为0；W为-O-；即
Figure PCTCN2021126331-appb-000028
Figure PCTCN2021126331-appb-000026
for
Figure PCTCN2021126331-appb-000027
Among them, p' is 0; q is 0; W is -O-; namely
Figure PCTCN2021126331-appb-000028
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 1为
Figure PCTCN2021126331-appb-000029
 R1 is
Figure PCTCN2021126331-appb-000029
其中，L 1为连接键或-S-； Wherein, L 1 is a connecting key or -S-;
环D为连接键、C 6-C 10芳基、5-10元杂芳基、5-10元杂环基并5-6元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S和P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O和S； Ring D is a connecting bond, a C 6 -C 10 aryl group, a 5-10-membered heteroaryl group, a 5-10-membered heterocyclic group, and a 5-6-membered heteroaryl group; among the heterocyclic groups, 1-3 a heteroatom selected from the following group: N, O, S and P; the heteroaryl group contains 1-3 heteroatoms selected from the following group: N, O and S;
n为0、1或2；n is 0, 1 or 2;
R 1a独立地为卤素、C 1-C 6烷基、3-8元杂环基、-C(＝O)OR 1a2、-NHC(＝O)R 1a2、-NR 1a3R 1a5、5-10元杂芳基、被一个或多个R 1a4取代的3-8元杂环基、或者，被一个或多个R a取代的：C 1-C 6烷基；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； R 1a is independently halogen, C 1 -C 6 alkyl, 3-8 membered heterocyclyl, -C(=O)OR 1a2 , -NHC(=O)R 1a2 , -NR 1a3 R 1a5 , 5-10 Membered heteroaryl, 3-8 membered heterocyclyl substituted by one or more R 1a4 , or, substituted by one or more R a : C 1 -C 6 alkyl; when there are multiple substituents, The same or different; the heterocyclic group contains 1-3 heteroatoms selected from the following group: N, O, S or P; the heteroaryl group contains 1-3 heteroatoms selected from the following group heteroatom: N, O or S;
R 1a4独立地为氧代(＝O)； R 1a4 is independently oxo (=O);
R 1a2、R 1a3和R 1a5独立地为氢、5-6元的芳基、5-6元杂芳基、被一个或多个卤素取代的5-6元芳 基或
Figure PCTCN2021126331-appb-000030
所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； R 1a2 , R 1a3 and R 1a5 are independently hydrogen, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered aryl substituted with one or more halogens, or
Figure PCTCN2021126331-appb-000030
In the described heteroaryl group, contains 1-3 heteroatoms selected from the following group: N, O or S;
R a独立地为卤素； Ra is independently halogen;
R c为H或C 1-C 4烷基； R c is H or C 1 -C 4 alkyl;
X 1为CR 3，X 2为CR 3； X 1 is CR 3 , X 2 is CR 3 ;
R 3独立地为氢、卤素、氨基或C 1-C 4烷基； R 3 is independently hydrogen, halogen, amino or C 1 -C 4 alkyl;
R 4独立地为氢、卤素、氨基或C 1-C 4烷基； R 4 is independently hydrogen, halogen, amino, or C 1 -C 4 alkyl;
R 2为
Figure PCTCN2021126331-appb-000031
 R2 is
Figure PCTCN2021126331-appb-000031
o1、o2独立地为0、1或2；且o1+o2小于等于3；o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b独立地为氢； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen;
Y＝N或C；Y=N or C;
当Y＝C时，R 7和R 8与Y一起形成：
Figure PCTCN2021126331-appb-000032
When Y=C, R7 and R8 together with Y form:
Figure PCTCN2021126331-appb-000032
p、q独立地为0、1或2；且p+q小于等于3；p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
R 9a、R 9b、R 10a、R 10b独立地为氢、氘、氨基或-NHR 9-1； R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, amino, or -NHR 9-1 ;
R 9-1为C 1-C 4烷基； R 9-1 is C 1 -C 4 alkyl;
W为连接键、-C(R w) 2-、-O-、-S-或-NR w-； W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
R w独立地为氢或C 1-C 4烷基； R w is independently hydrogen or C 1 -C 4 alkyl;
环H独立地为不存在或为C 6-C 10芳基、5-10元杂芳基；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； Ring H is independently absent or a C 6 -C 10 aryl group, a 5-10 membered heteroaryl group; the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S;
当环H不存在时，Z 1为CR z1aR z1b或者O，Z 2为CR z2aR z2b或者O； When ring H does not exist, Z 1 is CR z1a R z1b or O, and Z 2 is CR z2a R z2b or O;
当环H为C 6-C 10芳基、5-10元杂芳基时，Z 1为C且Z 2为C，
Figure PCTCN2021126331-appb-000033
为双键； When ring H is C 6 -C 10 aryl, 5-10 membered heteroaryl, Z 1 is C and Z 2 is C,
Figure PCTCN2021126331-appb-000033
is a double bond;
R z1a、R z1b、R z2a、R z2b独立地为氢原子、卤素、C 1-C 4烷基； R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
r独立地为0、1、2、3或4；r is independently 0, 1, 2, 3, or 4;
R 11独立地为卤素、氰基、C 1-C 6烷基、C 1-C 6烷基-O-，C 3-C 8的环烷基、3-7元杂环基、-(CH 2) iNR 11- 1R 11-2、-C(＝O)N(R 11-3R 11-3)、
Figure PCTCN2021126331-appb-000034
被一个羟基取代的C 1-C 6烷基、未取代或被1-4个R b取代的C 6-C 10芳基，或者，被一个或多个R b取代的：C 1-C 6烷基、或者，被一个或多个R 11- 7取代的3-7元杂环基；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述5-6元的芳杂基中，选自1-3个选自下组的杂原子：N、O、S或P； R 11 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, 3-7 membered heterocyclyl, -(CH 2 ) i NR 11-1 R 11-2 , -C( = O)N(R 11-3 R 11-3 ),
Figure PCTCN2021126331-appb-000034
C 1 -C 6 alkyl substituted with one hydroxy, C 6 -C 10 aryl unsubstituted or substituted with 1-4 R b , or, substituted with one or more R b : C 1 -C 6 Alkyl, or a 3-7 membered heterocyclic group substituted by one or more R 11-7 ; when there are multiple substituents, they are the same or different; among the heterocyclic groups, 1-3 optional groups are included A heteroatom from the following group: N, O, S or P; in the 5-6-membered aromatic hetero group, 1-3 heteroatoms are selected from the following group: N, O, S or P;
R 11-1和R 11-2独立地为H或C 1-C 4烷基； R 11-1 and R 11-2 are independently H or C 1 -C 4 alkyl;
R 11-3独立地为H、C 1-C 4烷基或CD 3； R 11-3 is independently H, C 1 -C 4 alkyl or CD 3 ;
R 11-4独立地为H或C 1-C 4烷基； R 11-4 is independently H or C 1 -C 4 alkyl;
R 11-5和R 11-6独立地为H或C 1-C 4烷基； R 11-5 and R 11-6 are independently H or C 1 -C 4 alkyl;
R 11-7独立地为卤素或氨基； R 11-7 is independently halogen or amino;
i独立地为0、1、2、3或4；i is independently 0, 1, 2, 3, or 4;
R b独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-。 R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 2为
Figure PCTCN2021126331-appb-000035
环H为不存在或为苯基或5-6元杂芳基；p’为0或1；q为0、1或2；且p’+q小于等于2； R2 is
Figure PCTCN2021126331-appb-000035
Ring H is absent or is phenyl or 5-6 membered heteroaryl; p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2;
例如，当环H为苯基或5-6元杂芳基时，For example, when Ring H is phenyl or 5-6 membered heteroaryl,
Z 1为C且Z 2为C，
Figure PCTCN2021126331-appb-000036
为双键；r独立地为0或1；例如0； Z1 is C and Z2 is C,
Figure PCTCN2021126331-appb-000036
is a double bond; r is independently 0 or 1; such as 0;
R 11独立地为氢原子、卤素、或C 1-C 6烷基；例如氢原子； R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl; for example, a hydrogen atom;
R 9a、R 9b、R 10a和R 10b独立地为氢或C 1-C 4烷基；例如氢； R 9a , R 9b , R 10a and R 10b are independently hydrogen or C 1 -C 4 alkyl; such as hydrogen;
p’为0；q为1；或p’为1；q为0；p' is 0; q is 1; or p' is 1; q is 0;
又例如，
Figure PCTCN2021126331-appb-000037
For another example,
Figure PCTCN2021126331-appb-000037
当环H为不存在时，When ring H is absent,
R 2为
Figure PCTCN2021126331-appb-000038
q为1或2；例如
Figure PCTCN2021126331-appb-000039
又例如
Figure PCTCN2021126331-appb-000040
还例如
Figure PCTCN2021126331-appb-000041
 R2 is
Figure PCTCN2021126331-appb-000038
q is 1 or 2; for example
Figure PCTCN2021126331-appb-000039
Another example
Figure PCTCN2021126331-appb-000040
Also for example
Figure PCTCN2021126331-appb-000041
在本发明的某一优选方案中，本发明所述的式I所示的含氮稠杂环类化合物为式为式I-2所示；In a preferred embodiment of the present invention, the nitrogen-containing fused heterocyclic compound represented by formula I of the present invention is represented by formula I-2;
Figure PCTCN2021126331-appb-000042
Figure PCTCN2021126331-appb-000042
其中，L 1独立为连接键、S； Wherein, L 1 is independently a connecting key, S;
n独立地为0、1、2、3、4、5或6；n is independently 0, 1, 2, 3, 4, 5, or 6;
环D独立地为苯基、5-6元杂芳基或5-10元杂环基并5-6元杂芳基，优选为苯基、吡嗪基、吡啶基(例如
Figure PCTCN2021126331-appb-000043
)或
Figure PCTCN2021126331-appb-000044
Ring D is independently phenyl, 5-6 membered heteroaryl or 5-10 membered heterocyclyl and 5-6 membered heteroaryl, preferably phenyl, pyrazinyl, pyridyl (eg
Figure PCTCN2021126331-appb-000043
)or
Figure PCTCN2021126331-appb-000044
R 1a独立地为卤素、C 1-C 6烷基、C 1-C 6烷基-O-、氨基、氰基、羟基，或者，被一个或多个R a取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同； R 1a is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, amino, cyano, hydroxy, or, substituted with one or more R a : C 1 -C 6 Alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different;
R a独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
环H选自苯基、5-6元杂芳基，优选苯基、吡啶基(例如
Figure PCTCN2021126331-appb-000045
)、吡嗪基或噻唑基(例如
Figure PCTCN2021126331-appb-000046
)； Ring H is selected from phenyl, 5-6 membered heteroaryl, preferably phenyl, pyridyl (eg
Figure PCTCN2021126331-appb-000045
), pyrazinyl or thiazolyl (eg
Figure PCTCN2021126331-appb-000046
);
R 11独立地为选自氢原子、卤素、硝基、氰基、C 1-C 6烷基、C 1-C 6烷氧基； R 11 is independently selected from hydrogen atom, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
r独立地选自0、1和2；r is independently selected from 0, 1 and 2;
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000047
为
Figure PCTCN2021126331-appb-000048
G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；
Figure PCTCN2021126331-appb-000047
for
Figure PCTCN2021126331-appb-000048
G is independently a C, C(=O), N, S or O heteroatom or group; G' is independently a linkage, C, C(=O), N, S or O atom or group;
R 1a独立地为卤素、氨基或C 1-C 6烷基； R 1a is independently halogen, amino or C 1 -C 6 alkyl;
n独立地为0、1、2、3、4或5；例如n独立地为0、1、2或3；n is independently 0, 1, 2, 3, 4 or 5; for example n is independently 0, 1, 2 or 3;
环E为含有1至3个N原子的6元杂芳基；G独立地为C、C(＝O)、N、S或O原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms; G is independently a C, C(=O), N, S or O atom or group; G' is independently a linkage, C, C (=O), N, S or O atom or group;
L 1为连接键、-O-或-S-； L 1 is a connection key, -O- or -S-;
X 1为CR 3，X 2为CR 3；或，X 1为N，X 2为CR 3； X 1 is CR 3 and X 2 is CR 3 ; or, X 1 is N and X 2 is CR 3 ;
R 3和R 4独立地为氢； R3 and R4 are independently hydrogen ;
R 2为
Figure PCTCN2021126331-appb-000049
Y＝C，R 7和R 8与Y一起形成：
Figure PCTCN2021126331-appb-000050
 R2 is
Figure PCTCN2021126331-appb-000049
Y=C, R7 and R8 together with Y form:
Figure PCTCN2021126331-appb-000050
o1、o2独立地为0、1或2；例如1；o1, o2 are independently 0, 1 or 2; e.g. 1;
R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a和R 6b独立地为氢； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently hydrogen;
q独立地为0、1或2；p’为0或1；q is independently 0, 1 or 2; p' is 0 or 1;
R 9a、R 9b、R 10a和R 10b独立地为氢原子、氨基或C 1-C 4烷基； R 9a , R 9b , R 10a and R 10b are independently a hydrogen atom, an amino group or a C 1 -C 4 alkyl group;
W独立地为连接键、-C(R w) 2-； W is independently a connecting bond, -C(R w ) 2 -;
环H独立地为不存在或者苯基或5-6元杂芳基；Ring H is independently absent or phenyl or 5-6 membered heteroaryl;
当环H不存在时，Z 1为CR z1aR z1b，Z 2为O，或者Z 1为O，Z 2为CR z2aR z2b； When ring H does not exist, Z 1 is CR z1a R z1b and Z 2 is O, or Z 1 is O and Z 2 is CR z2a R z2b ;
R z1a、R z1b、R z2a、R z2b独立地为氢原子或C 1-C 4烷基；
Figure PCTCN2021126331-appb-000051
为单键； R z1a , R z1b , R z2a , R z2b are independently a hydrogen atom or a C 1 -C 4 alkyl group;
Figure PCTCN2021126331-appb-000051
is a single key;
当环H为苯基或5-6元杂芳基时；Z 1和Z 2独立地为C，
Figure PCTCN2021126331-appb-000052
为双键； When ring H is phenyl or 5-6 membered heteroaryl; Z 1 and Z 2 are independently C,
Figure PCTCN2021126331-appb-000052
is a double bond;
R 11独立地为氢原子、卤素、C 1-C 6的烷基； R 11 is independently a hydrogen atom, a halogen, a C 1 -C 6 alkyl group;
r独立地为0、或2；r is independently 0, or 2;
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
在本发明某些优选实施方案中，所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，In certain preferred embodiments of the present invention, the nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or certain pharmaceutically acceptable salts thereof These groups are defined as follows (unmentioned groups are as described in any scheme of this application),
其中，in,
L 1为连接键、-O-或-S-；例如S； L 1 is a connecting bond, -O- or -S-; for example, S;
Figure PCTCN2021126331-appb-000053
为
Figure PCTCN2021126331-appb-000054
G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；
Figure PCTCN2021126331-appb-000053
for
Figure PCTCN2021126331-appb-000054
G is independently a C, C(=O), N, S or O heteroatom or group; G' is independently a linkage, C, C(=O), N, S or O atom or group;
R 1a独立地为卤素、C 1-C 6烷基、氨基； R 1a is independently halogen, C 1 -C 6 alkyl, amino;
环E为含有1至3个N原子的6元杂芳基；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms;
n独立地为1或2；例如2；n is independently 1 or 2; e.g. 2;
X 1为CR 3，X 2为CR 3；R 3独立地为氢；R 4独立地为氢； X 1 is CR 3 , X 2 is CR 3 ; R 3 is independently hydrogen; R 4 is independently hydrogen;
R 2为
Figure PCTCN2021126331-appb-000055
例如
Figure PCTCN2021126331-appb-000056
Figure PCTCN2021126331-appb-000057
 R2 is
Figure PCTCN2021126331-appb-000055
E.g
Figure PCTCN2021126331-appb-000056
Figure PCTCN2021126331-appb-000057
环H独立地为苯基或5-10元杂环芳基；Ring H is independently phenyl or 5-10 membered heterocyclic aryl;
p’为0，q为1；或p’为1，q为0；p' is 0 and q is 1; or p' is 1 and q is 0;
R 9a为氢原子或C 1-C 4烷基； R 9a is a hydrogen atom or a C 1 -C 4 alkyl group;
r独立地为0或1；r is independently 0 or 1;
R 11独立地为C 1-C 4烷基； R 11 is independently C 1 -C 4 alkyl;
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；The carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
较佳地，L 1为连接键、-S-； Preferably, L 1 is a connecting key, -S-;
R 2为
Figure PCTCN2021126331-appb-000058
 R2 is
Figure PCTCN2021126331-appb-000058
p’为0，q为1；p' is 0, q is 1;
r独立地为0。r is independently 0.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为5-10元杂芳基时，所述的5-10元杂芳基为含有1至3个N原子的6元杂芳基；例如吡啶，又例如
Figure PCTCN2021126331-appb-000059
When Ring D is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 6-membered heteroaryl group containing 1 to 3 N atoms; for example, pyridine, or for example
Figure PCTCN2021126331-appb-000059
例如，
Figure PCTCN2021126331-appb-000060
为
Figure PCTCN2021126331-appb-000061
环E为含有1至3个N原子的6元杂芳基。 E.g,
Figure PCTCN2021126331-appb-000060
for
Figure PCTCN2021126331-appb-000061
Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为5-10元杂芳基时，所述5-10元杂芳基为含有1至3个N原子的9-10元杂芳基，例如为苯并吡唑基、苯并吡啶基，又例如为
Figure PCTCN2021126331-appb-000062
When Ring D is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 9-10-membered heteroaryl group containing 1 to 3 N atoms, such as benzopyrazolyl, benzopyridine base, for example
Figure PCTCN2021126331-appb-000062
例如，
Figure PCTCN2021126331-appb-000063
为
Figure PCTCN2021126331-appb-000064
环E为含有1至3个N原子的6元杂芳基；环F为含有1至4个N、S、O杂原子的5元杂芳基。 E.g,
Figure PCTCN2021126331-appb-000063
for
Figure PCTCN2021126331-appb-000064
Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms; Ring F is a 5-membered heteroaryl group containing 1 to 4 N, S, O heteroatoms.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为C 6-C 10芳基时，所述的C 6-C 10芳基为苯基或萘基；例如苯基或
Figure PCTCN2021126331-appb-000065
When ring D is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is phenyl or naphthyl; for example, phenyl or
Figure PCTCN2021126331-appb-000065
例如，
Figure PCTCN2021126331-appb-000066
为
Figure PCTCN2021126331-appb-000067
又例如
Figure PCTCN2021126331-appb-000068
E.g,
Figure PCTCN2021126331-appb-000066
for
Figure PCTCN2021126331-appb-000067
Another example
Figure PCTCN2021126331-appb-000068
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为5-10元杂环基并5-6元杂芳基时，所述的5-10元杂环基并5-6元杂芳基为
Figure PCTCN2021126331-appb-000069
环E为含有1至3个N原子的6元杂芳基；G独立地为C、C(＝O)、N、S或O原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；例如，
Figure PCTCN2021126331-appb-000070
Figure PCTCN2021126331-appb-000071
When Ring D is a 5-10-membered heterocyclic group and a 5-6-membered heteroaryl group, the 5-10-membered heterocyclic group and the 5-6-membered heteroaryl group are
Figure PCTCN2021126331-appb-000069
Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms; G is independently a C, C(=O), N, S or O atom or group; G' is independently a linkage, C, C (=O), N, S or O atom or group; for example,
Figure PCTCN2021126331-appb-000070
Figure PCTCN2021126331-appb-000071
例如，
Figure PCTCN2021126331-appb-000072
为
Figure PCTCN2021126331-appb-000073
E.g,
Figure PCTCN2021126331-appb-000072
for
Figure PCTCN2021126331-appb-000073
或者，例如
Figure PCTCN2021126331-appb-000074
为
Figure PCTCN2021126331-appb-000075
又例如为
Figure PCTCN2021126331-appb-000076
or, for example
Figure PCTCN2021126331-appb-000074
for
Figure PCTCN2021126331-appb-000075
Another example is
Figure PCTCN2021126331-appb-000076
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟。 When R 1a is independently halogen, the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为C 1-C 6烷基时，所述的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；例如甲基。 When R 1a is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group (eg methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C 1 -C 6 alkyl C4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为3-8元杂环基时，所述3-8元杂环基独立地为3-5元杂环烷基，例如吡咯烷基，又例如为
Figure PCTCN2021126331-appb-000077
When R 1a is independently a 3-8-membered heterocyclic group, the 3-8-membered heterocyclic group is independently a 3-5-membered heterocycloalkyl, such as pyrrolidinyl, and another example is
Figure PCTCN2021126331-appb-000077
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为被一个或多个R 1a4取代的3-8元杂环基时，所述被一个或多个R 1a4取代的3-8元杂环基为被一个或多个R 1a4取代的3-5元杂环烷基；例如为
Figure PCTCN2021126331-appb-000078
When R 1a is independently a 3-8 membered heterocyclyl substituted with one or more R 1a4 , the 3-8 membered heterocyclyl substituted with one or more R 1a4 is a 3-8 membered heterocyclyl substituted with one or more R 1a4 Substituted 3-5 membered heterocycloalkyl; for example
Figure PCTCN2021126331-appb-000078
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为-NHC(＝O)R 1a2时，所述-NHC(＝O)R 1a2独立地为
Figure PCTCN2021126331-appb-000079
When R 1a is independently -NHC(=O)R 1a2 , said -NHC(=O)R 1a2 is independently
Figure PCTCN2021126331-appb-000079
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为-NR 1a3R 1a5时，所述-NR 1a3R 1a5为-NH 2、-NHCH 3、
Figure PCTCN2021126331-appb-000080
When R 1a is independently -NR 1a3 R 1a5 , the -NR 1a3 R 1a5 is -NH 2 , -NHCH 3 ,
Figure PCTCN2021126331-appb-000080
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为5-10元杂芳基时，所述5-10元杂芳基独立地为吡嗪基、噁唑基或苯并噁唑基，例如为
Figure PCTCN2021126331-appb-000081
When R 1a is independently a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is independently pyrazinyl, oxazolyl or benzoxazolyl, such as
Figure PCTCN2021126331-appb-000081
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为被一个或多个R a取代的C 1-C 6烷基时，所述被一个或多个R a取代的C 1-C 6烷基为-CF 3。 When R 1a is independently a C 1 -C 6 alkyl substituted with one or more Ra , the C 1 -C 6 alkyl substituted with one or more Ra is -CF 3 .
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a1、R 1a4、R 1a2、R 1a3或R 1a5独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为甲基、乙基、 正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如为甲基或乙基。 When R 1a1 , R 1a4 , R 1a2 , R 1a3 or R 1a5 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl Propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a2、R 1a3和R 1a5独立地为5-6元的芳基时，所述5-6元的芳基为苯基。 When R 1a2 , R 1a3 and R 1a5 are independently a 5- to 6-membered aryl group, the 5- to 6-membered aryl group is a phenyl group.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a2、R 1a3和R 1a5独立地为5-6元杂芳基，所述5-6元杂芳基为
Figure PCTCN2021126331-appb-000082
When R 1a2 , R 1a3 and R 1a5 are independently 5-6 membered heteroaryl, the 5-6 membered heteroaryl is
Figure PCTCN2021126331-appb-000082
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a2、R 1a3和R 1a5独立地为被一个或多个卤素取代的5-6元芳基，所述一个或多个卤素取代的5-6元芳基为
Figure PCTCN2021126331-appb-000083
When R 1a2 , R 1a3 and R 1a5 are independently 5-6 membered aryl substituted with one or more halogens, the one or more halogen substituted 5-6 membered aryl groups are
Figure PCTCN2021126331-appb-000083
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a2、R 1a3和R 1a5独立地为
Figure PCTCN2021126331-appb-000084
时，所述
Figure PCTCN2021126331-appb-000085
为
Figure PCTCN2021126331-appb-000086
When R 1a2 , R 1a3 and R 1a5 are independently
Figure PCTCN2021126331-appb-000084
when, the
Figure PCTCN2021126331-appb-000085
for
Figure PCTCN2021126331-appb-000086
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R a独立地为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟。 When Ra is independently halogen, the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R c独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如为甲基或乙基。 When R c is independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl, for example methyl or ethyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为苯基或6元杂芳基时，R 1a独立地位于环D与L 1连接键的邻位、间位及对位，例如当n为2时，R 1a位于环D与L 1连接键的邻位和对位、或者，R 1a位于环D与L 1连接键的邻位和间位。 When ring D is phenyl or 6-membered heteroaryl, R 1a is independently located in the ortho, meta and para positions of the bond between ring D and L 1 , for example, when n is 2, R 1a is located in rings D and L The ortho and para positions of the 1 linkage, alternatively, R 1a is located in the ortho and meta positions of the ring D and L 1 linkage.
在本发明的某一优选方案中，In a preferred solution of the present invention,
n独立地为0、1、2；例如1或2。n is independently 0, 1, 2; eg, 1 or 2.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 9a和R 9b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基。 When R 9a and R 9b are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 9a-1为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基。 When R 9a-1 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 10a和R 10b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基例如甲基、乙基、正丙基、异丙基、正 丁基、异丁基、仲丁基或叔丁基；又例如甲基。 When R 10a and R 10b are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R w为C 1-C 4烷基时，所述的C 1～C 4烷基例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基。 When R w is C 1 -C 4 alkyl, the C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环H独立地为5-6元杂芳基时，所述的5-6元杂芳基为含有1-2个N原子的6元杂芳基、1-3个选自N、O及S原子的5元杂芳基；所述的6元杂芳基例如吡啶基、吡嗪基，例如
Figure PCTCN2021126331-appb-000087
Figure PCTCN2021126331-appb-000088
所述的5元杂芳基例如噻唑基或吡唑基，例如
Figure PCTCN2021126331-appb-000089
a表示稠合位置。 When ring H is independently a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is a 6-membered heteroaryl group containing 1-2 N atoms, 1-3 members selected from N, O and 5-membered heteroaryl group of S atom; the 6-membered heteroaryl group such as pyridyl, pyrazinyl, such as
Figure PCTCN2021126331-appb-000087
Figure PCTCN2021126331-appb-000088
The 5-membered heteroaryl group such as thiazolyl or pyrazolyl, such as
Figure PCTCN2021126331-appb-000089
a denotes a fused position.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环H为C 6-C 10芳基时，所述C 6-C 10芳基为苯基或萘基，例如苯基。 When ring H is a C6 - C10 aryl group, the C6 - C10 aryl group is phenyl or naphthyl, such as phenyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R z1a、R z1b、R z2a、R z2b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基。 When R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl groups, the C 1 -C 4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-propyl Butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为卤素，所述的卤素为氯或氟；例如氯。 When R11 is independently halogen, the halogen is chlorine or fluorine; eg chlorine.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为C 1-C 6烷基时，所述的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；例如甲基。 When R 11 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group (eg methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C 1 -C 6 alkyl C4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); eg methyl.
当R 11独立地为C 1-C 6烷基-O-时，所述的C 1-C 6烷基-O-(例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基)独立地为C 1-C 4烷基-O-(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基)；例如甲氧基。 When R 11 is independently C 1 -C 6 alkyl-O-, said C 1 -C 6 alkyl-O- (eg methoxy, ethoxy, propoxy, butoxy, pentyl oxy or hexyloxy) is independently C 1 -C 4 alkyl-O- (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy); for example methoxy.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为C 3-C 8的环烷基时，所述C 3-C 8的环烷基为C 3-C 5的环烷基，例如为环丙基、环丁基或环戊基。 When R 11 is independently a C 3 -C 8 cycloalkyl group, the C 3 -C 8 cycloalkyl group is a C 3 -C 5 cycloalkyl group, such as cyclopropyl, cyclobutyl or cycloalkyl amyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为3-7元杂环基时，所述3-7元杂环基为所述3-7元杂环烷基，例如
Figure PCTCN2021126331-appb-000090
When R 11 is independently a 3-7 membered heterocyclyl, the 3-7 membered heterocyclyl is the 3-7 membered heterocycloalkyl, eg
Figure PCTCN2021126331-appb-000090
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为-(CH 2) qNR 11-1R 11-2时，所述-(CH 2) qNR 11-1R 11-2为
Figure PCTCN2021126331-appb-000091
When R 11 is independently -(CH 2 ) q NR 11-1 R 11-2 , the -(CH 2 ) q NR 11-1 R 11-2 is
Figure PCTCN2021126331-appb-000091
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为-C(＝O)N(R 11-3R 11-3)时，所述-C(＝O)N(R 11-3R 11-3)为
Figure PCTCN2021126331-appb-000092
Figure PCTCN2021126331-appb-000093
When R 11 is independently -C(=O)N(R 11-3 R 11-3 ), the -C(=O)N(R 11-3 R 11-3 ) is
Figure PCTCN2021126331-appb-000092
Figure PCTCN2021126331-appb-000093
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为
Figure PCTCN2021126331-appb-000094
时，所述
Figure PCTCN2021126331-appb-000095
为
Figure PCTCN2021126331-appb-000096
When R11 independently is
Figure PCTCN2021126331-appb-000094
when, the
Figure PCTCN2021126331-appb-000095
for
Figure PCTCN2021126331-appb-000096
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为
Figure PCTCN2021126331-appb-000097
时，所述
Figure PCTCN2021126331-appb-000098
为
Figure PCTCN2021126331-appb-000099
When R11 independently is
Figure PCTCN2021126331-appb-000097
when, the
Figure PCTCN2021126331-appb-000098
for
Figure PCTCN2021126331-appb-000099
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为被一个羟基取代的C 1-C 6烷基，所述被一个羟基取代的C 1-C 6烷基中C 1-C 6烷基独立地为C 1～C 4烷基；例如
Figure PCTCN2021126331-appb-000100
When R 11 is independently a C 1 -C 6 alkyl group substituted with a hydroxy group, the C 1 -C 6 alkyl group in the C 1 -C 6 alkyl group substituted with a hydroxy group is independently a C 1 -C 4 alkane base; e.g.
Figure PCTCN2021126331-appb-000100
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11独立地为未取代或被1-4个R b取代的C 6-C 10芳基时，所述C 6-C 10芳基为苯基。 When R 11 is independently a C 6 -C 10 aryl group that is unsubstituted or substituted with 1-4 R b , the C 6 -C 10 aryl group is phenyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当所述R 11-1和R 11-2独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基。 When the R 11-1 and R 11-2 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当所述R 11-3和R 11-4独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基。 When the R 11-3 and R 11-4 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当所述R 11-5和R 11-6独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基。 When the R 11-5 and R 11-6 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 11-7独立地为卤素，所述的卤素为氟、氯或溴；例如氟或氯。 When R 11-7 is independently halogen, the halogen is fluorine, chlorine or bromine; for example fluorine or chlorine.
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000101
为
Figure PCTCN2021126331-appb-000102
Figure PCTCN2021126331-appb-000103
Figure PCTCN2021126331-appb-000104
例如
Figure PCTCN2021126331-appb-000105
又例如
Figure PCTCN2021126331-appb-000106
Figure PCTCN2021126331-appb-000101
for
Figure PCTCN2021126331-appb-000102
Figure PCTCN2021126331-appb-000103
Figure PCTCN2021126331-appb-000104
E.g
Figure PCTCN2021126331-appb-000105
Another example
Figure PCTCN2021126331-appb-000106
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 1为
Figure PCTCN2021126331-appb-000107
Figure PCTCN2021126331-appb-000108
Figure PCTCN2021126331-appb-000109
 R1 is
Figure PCTCN2021126331-appb-000107
Figure PCTCN2021126331-appb-000108
Figure PCTCN2021126331-appb-000109
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000110
为
Figure PCTCN2021126331-appb-000111
Figure PCTCN2021126331-appb-000112
Figure PCTCN2021126331-appb-000113
Figure PCTCN2021126331-appb-000114
例如
Figure PCTCN2021126331-appb-000115
Figure PCTCN2021126331-appb-000116
Figure PCTCN2021126331-appb-000117
表示对映体，即为S构型和R构型的混合物。
Figure PCTCN2021126331-appb-000110
for
Figure PCTCN2021126331-appb-000111
Figure PCTCN2021126331-appb-000112
Figure PCTCN2021126331-appb-000113
Figure PCTCN2021126331-appb-000114
E.g
Figure PCTCN2021126331-appb-000115
Figure PCTCN2021126331-appb-000116
Figure PCTCN2021126331-appb-000117
Indicates the enantiomer, which is a mixture of the S and R configurations.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 2为
Figure PCTCN2021126331-appb-000118
Figure PCTCN2021126331-appb-000119
Figure PCTCN2021126331-appb-000120
Figure PCTCN2021126331-appb-000121
Figure PCTCN2021126331-appb-000122
Figure PCTCN2021126331-appb-000123
表示对映体，即为S构型和R构型的混合物。 R2 is
Figure PCTCN2021126331-appb-000118
Figure PCTCN2021126331-appb-000119
Figure PCTCN2021126331-appb-000120
Figure PCTCN2021126331-appb-000121
Figure PCTCN2021126331-appb-000122
Figure PCTCN2021126331-appb-000123
Indicates the enantiomer, which is a mixture of the S and R configurations.
在本发明的某一优选方案中，如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；In a certain preferred embodiment of the present invention, the nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt;
Figure PCTCN2021126331-appb-000124
Figure PCTCN2021126331-appb-000124
其中，in,
R 1为
Figure PCTCN2021126331-appb-000125
 R1 is
Figure PCTCN2021126331-appb-000125
其中，L 1为连接键、-O-或-S-； Wherein, L 1 is a connecting bond, -O- or -S-;
环D为C 4-C 8环烷基、5-6元单环杂环基、8-10元双环杂环基、C 6-C 10芳基、5-10元杂芳基、5-10元杂环基并苯基、5-10元杂环基并5-6元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O、或S； Ring D is C 4 -C 8 cycloalkyl, 5-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl acyl group, 5-10 membered heterocyclyl group and 5-6 membered heteroaryl group; the heterocyclyl group contains 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, it contains 1-3 heteroatoms selected from the group consisting of N, O, or S;
n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
R 1a独立地为卤素、氨基、氰基、羟基、C 1-C 6烷基、C 1-C 6烷基-O-、C 3-C 8环烷基、-C(＝O)OR 1a2、-NHC(＝O)R 1a2、被一个或多个R 1a1取代的C 3-C 8环烷基，或者，被一个或多个R a取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同； R 1a is independently halogen, amino, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, -C(=O)OR 1a2 , -NHC(=O)R 1a2 , C 3 -C 8 cycloalkyl substituted with one or more R 1a1 , or, substituted with one or more R a : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different;
R 1a1独立的为卤素或C 1-C 4烷基； R 1a1 is independently halogen or C 1 -C 4 alkyl;
R 1a2独立的为氢、C 1-C 4烷基、取代或未取代的烯基、酰胺、C 3-C 12单或多杂环；5-6元的芳基或杂芳基； R 1a2 is independently hydrogen, C 1 -C 4 alkyl, substituted or unsubstituted alkenyl, amide, C 3 -C 12 single or polyheterocycle; 5-6 membered aryl or heteroaryl;
R a独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
X 1为CR 3，X 2为CR 3；或，X 1为N，X 2为CR 3；或，X 1为CR 3，X 2为N； X 1 is CR 3 , and X 2 is CR 3 ; or, X 1 is N, and X 2 is CR 3 ; or, X 1 is CR 3 , and X 2 is N;
R 3独立地为氢、卤素、氨基、硝基、三氟甲基、C 3-C 8的环烷基、乙烯基或C 1-C 4烷基； R 3 is independently hydrogen, halogen, amino, nitro, trifluoromethyl, C 3 -C 8 cycloalkyl, vinyl or C 1 -C 4 alkyl;
R 4独立地为氢、卤素、C 1-C 4烷基、氨基、硝基、三氟甲基、C 1-C 4含有羟基或氨基或卤素取代的烷基； R 4 is independently hydrogen, halogen, C 1 -C 4 alkyl, amino, nitro, trifluoromethyl, C 1 -C 4 containing hydroxy or amino or halogen substituted alkyl;
R 2为
Figure PCTCN2021126331-appb-000126
 R2 is
Figure PCTCN2021126331-appb-000126
o1、o2独立地为0、1或2；且o1+o2小于等于3；o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b独立地为氢、卤素、C 1-C 4烷基； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen, halogen, C 1 -C 4 alkyl;
当Y＝N时，R 7独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基取代的C 1-C 4烷基、氨基取代的3-12元环烷基；R 8不存在； When Y=N, R 7 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino substituted C 1 -C 4 alkyl, amino substituted 3-12 membered cycloalkyl; R 8 is absent;
当Y＝C时，R 7、R 8独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基、C 1-C 4烷基取代氨基、C 1-C 4 烷基-O-取代氨基-； When Y=C, R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino, C 1 -C 4 alkyl substituted amino, C 1 - C 4 alkyl-O-substituted amino-;
或者当Y＝C时，R 7和R 8与Y一起形成：
Figure PCTCN2021126331-appb-000127
Or when Y=C, R7 and R8 together with Y form:
Figure PCTCN2021126331-appb-000127
p、q独立地为0、1或2；且p+q小于等于3；p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
R 9a、R 9b、R 10a、R 10b独立地为氢、卤素、氨基、C 1-C 4烷基； R 9a , R 9b , R 10a , R 10b are independently hydrogen, halogen, amino, C 1 -C 4 alkyl;
W为连接键、-C(R w) 2-、-O-、-S-或-NR w-； W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
R w独立地为氢、C 1-C 4烷基； R w is independently hydrogen, C 1 -C 4 alkyl;
环H独立地为不存在或为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂环芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O、或S； Ring H is independently absent or C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl, 5-10-membered heterocyclic aryl; among the heterocyclic groups , containing 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, containing 1-3 heteroatoms selected from the following group: N, O, or S;
当环H不存在时，Z 1为CR z1aR z1b或者O，Z 2为CR z2aR z2b或者O； When ring H does not exist, Z 1 is CR z1a R z1b or O, and Z 2 is CR z2a R z2b or O;
当环H为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂环芳基时，Z 1为CR z1a或者N，Z 2为CR z2a或者N，
Figure PCTCN2021126331-appb-000128
为单键；或者Z 1为C且Z 2为C，
Figure PCTCN2021126331-appb-000129
为双键； When ring H is C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heterocyclic aryl group, Z 1 is CR z1a or N, and Z 2 is CR z2a or N,
Figure PCTCN2021126331-appb-000128
is a single bond; or Z 1 is C and Z 2 is C,
Figure PCTCN2021126331-appb-000129
is a double bond;
R z1a、R z1b、R z2a、R z2b独立地为氢原子、卤素、C 1-C 4烷基； R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
r独立地为0、1、2、3或和4；r is independently 0, 1, 2, 3 or and 4;
R 11独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-，硝基、C 3-C 8的环烷基、未取代或1-4个R b取代的芳基、含有1-3杂原子的5-6元的芳杂基，或者，被一个或多个R b取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同；所述5-6元的芳杂基中，选自1-3个选自下组的杂原子：N、O、S或P； R 11 is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, nitro, C 3 -C 8 cycloalkyl, unsubstituted or 1 -Aryl substituted with 4 R b , 5-6 membered heteroaryl group containing 1-3 heteroatoms, or, substituted with one or more R b : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different; in the 5-6-membered aromatic hetero group, 1-3 heteroatoms are selected from the following group: N, O, S or P;
R b独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-。 R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000130
为：
Figure PCTCN2021126331-appb-000130
for:
Figure PCTCN2021126331-appb-000131
Figure PCTCN2021126331-appb-000131
其中，n1和n2独立地为0、1、2、3或4，且n1+n2等于0、1、2、3、4、5或6；wherein n1 and n2 are independently 0, 1, 2, 3, or 4, and n1+n2 is equal to 0, 1, 2, 3, 4, 5, or 6;
环E为含有1至3个N原子的6元杂芳基；环F为含有1至4个N、S、O杂原子的5元杂芳基；G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms; Ring F is a 5-membered heteroaryl containing 1 to 4 N, S, O heteroatoms; G is independently C, C(=O) , N, S or O heteroatoms or groups; G' is independently a linkage, C, C(=O), N, S or O atoms or groups;
例如，
Figure PCTCN2021126331-appb-000132
n为0、1、2、3、4或5；R 1a独立地为卤素、C 1-C 6烷基、氨基； E.g,
Figure PCTCN2021126331-appb-000132
n is 0, 1, 2, 3, 4 or 5; R 1a is independently halogen, C 1 -C 6 alkyl, amino;
较佳地，
Figure PCTCN2021126331-appb-000133
更佳地
Figure PCTCN2021126331-appb-000134
Preferably,
Figure PCTCN2021126331-appb-000133
better
Figure PCTCN2021126331-appb-000134
在本发明的某一优选方案中，In a preferred solution of the present invention,
L 1为-S-或-O-(又例如-S-)。 L 1 is -S- or -O- (also for example -S-).
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 1a独立地为卤素、C 1-C 6烷基、氨基；例如卤素、氨基。 R 1a is independently halogen, C 1 -C 6 alkyl, amino; eg, halogen, amino.
在本发明的某一优选方案中，In a preferred solution of the present invention,
环D为C 6-C 10芳基、5-10元杂芳基、或5-10元杂环基并5-6元杂芳基。 Ring D is C6 - C10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl and 5-6 membered heteroaryl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 3独立地为氢。 R3 is independently hydrogen.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 4独立地为氢。 R 4 is independently hydrogen.
在本发明的某一优选方案中，In a preferred solution of the present invention,
X 1为CR 3，X 2为CR 3。 X 1 is CR 3 and X 2 is CR 3 .
在本发明的某一优选方案中，In a preferred solution of the present invention,
X 1为N，X 2为CR 3。 X 1 is N and X 2 is CR 3 .
在本发明的某一优选方案中，In a preferred solution of the present invention,
X 1为CR 3，X 2为N。 X 1 is CR 3 and X 2 is N.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 3a、R 3b、R 4a、R 4b独立地为氢；即R 2为
Figure PCTCN2021126331-appb-000135
R 3a , R 3b , R 4a , R 4b are independently hydrogen; that is, R 2 is
Figure PCTCN2021126331-appb-000135
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 5a、R 5b、R 6a和R 6b独立地为氢或C 1-C 6烷基；例如氢。 R 5a , R 5b , R 6a and R 6b are independently hydrogen or C 1 -C 6 alkyl; eg, hydrogen.
在本发明的某一优选方案中，In a preferred solution of the present invention,
o1为1。o1 is 1.
在本发明的某一优选方案中，In a preferred solution of the present invention,
o2为1。o2 is 1.
在本发明的某一优选方案中，In a preferred solution of the present invention,
p为1或2。p is 1 or 2.
在本发明的某一优选方案中，In a preferred solution of the present invention,
q独立地为1。q is independently 1.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 9a和R 9b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基；例如一个为氢原子，另一个为氢原子、C 1-C 4烷基或氨基。 Among R 9a and R 9b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group; for example, one is a hydrogen atom, the other is a hydrogen atom, a C 1 -C 4 alkyl or amino.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 10a和R 10b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基。在本发明的某一优选方案中， Among R 10a and R 10b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group. In a preferred solution of the present invention,
W独立地为连接键、-C(R w) 2-。 W is independently a connecting bond, -C(R w ) 2 -.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环H不存在时，Z 1为CR z1aR z1b，Z 2为O；或者，Z 1为O，Z 2为CR z2aR z2b。 When ring H is absent, Z 1 is CR z1a R z1b and Z 2 is O; alternatively, Z 1 is O and Z 2 is CR z2a R z2b .
在本发明的某一优选方案中，In a preferred solution of the present invention,
环H为苯基或5-6元杂芳基；例如苯基。Ring H is phenyl or 5-6 membered heteroaryl; eg, phenyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R z1a和R z1b中，或者，R z2a和R z2b中，一个为氢，另一个为氢或C 1-C 4烷基； Of R z1a and R z1b , or, of R z2a and R z2b , one is hydrogen and the other is hydrogen or C 1 -C 4 alkyl;
例如，R z1a、R z1b、R z2a、R z2b独立地为氢原子。 For example, R z1a , R z1b , R z2a , and R z2b are independently hydrogen atoms.
在本发明的某一优选方案中，In a preferred solution of the present invention,
r独立地为0或1；例如0。r is independently 0 or 1; eg, 0.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 11独立地为氢原子、卤素、或C 1-C 6烷基；例如卤素。 R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl; eg, halogen.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 2为
Figure PCTCN2021126331-appb-000136
Y＝C，R 7和R 8与Y一起形成：
Figure PCTCN2021126331-appb-000137
即
Figure PCTCN2021126331-appb-000138
 R2 is
Figure PCTCN2021126331-appb-000136
Y=C, R7 and R8 together with Y form:
Figure PCTCN2021126331-appb-000137
which is
Figure PCTCN2021126331-appb-000138
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000139
为
Figure PCTCN2021126331-appb-000140
即所述的如式I所示的含氮稠杂环类化合物为
Figure PCTCN2021126331-appb-000141
Figure PCTCN2021126331-appb-000139
for
Figure PCTCN2021126331-appb-000140
That is, the nitrogen-containing fused heterocyclic compounds shown in formula I are:
Figure PCTCN2021126331-appb-000141
其中，p’为0或1；q为0、1或2；且p’+q小于等于2；Wherein, p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2;
例如W为连接键；即
Figure PCTCN2021126331-appb-000142
For example W is the connection key; that is
Figure PCTCN2021126331-appb-000142
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 2为
Figure PCTCN2021126331-appb-000143
环H为不存在或为苯基或5-6元杂芳基；p’为0或1；q为0、1或2；且p’+q小于等于2； R2 is
Figure PCTCN2021126331-appb-000143
Ring H is absent or is phenyl or 5-6 membered heteroaryl; p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2;
例如，当环H为苯基或5-6元杂芳基时，For example, when Ring H is phenyl or 5-6 membered heteroaryl,
Z 1为C且Z 2为C，
Figure PCTCN2021126331-appb-000144
为双键；r独立地为0或1；例如0； Z1 is C and Z2 is C,
Figure PCTCN2021126331-appb-000144
is a double bond; r is independently 0 or 1; such as 0;
R 11独立地为氢原子、卤素、或C 1-C 6烷基；例如氢原子； R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl; for example, a hydrogen atom;
R 9a、R 9b、R 10a和R 10b独立地为氢或C 1-C 4烷基；例如氢； R 9a , R 9b , R 10a and R 10b are independently hydrogen or C 1 -C 4 alkyl; such as hydrogen;
p’为0；p为1；或p’为1；q为0；p' is 0; p is 1; or p' is 1; q is 0;
又例如，
Figure PCTCN2021126331-appb-000145
For another example,
Figure PCTCN2021126331-appb-000145
当环H为不存在时，When ring H is absent,
R 2为
Figure PCTCN2021126331-appb-000146
q为1或2；例如
Figure PCTCN2021126331-appb-000147
又例如
Figure PCTCN2021126331-appb-000148
还例如
Figure PCTCN2021126331-appb-000149
 R2 is
Figure PCTCN2021126331-appb-000146
q is 1 or 2; for example
Figure PCTCN2021126331-appb-000147
Another example
Figure PCTCN2021126331-appb-000148
Also for example
Figure PCTCN2021126331-appb-000149
在本发明的某一优选方案中，本发明所述的式I所示的含氮稠杂环类化合物为式为式I-2所示；In a preferred embodiment of the present invention, the nitrogen-containing fused heterocyclic compound represented by formula I of the present invention is represented by formula I-2;
Figure PCTCN2021126331-appb-000150
Figure PCTCN2021126331-appb-000150
其中，L 1独立为连接键、S； Wherein, L 1 is independently a connecting key, S;
n独立地为0、1、2、3、4、5或6；n is independently 0, 1, 2, 3, 4, 5, or 6;
环D独立地为苯基、5-6元杂芳基或5-10元杂环基并5-6元杂芳基，优选为苯基、吡嗪基、吡啶基(例如
Figure PCTCN2021126331-appb-000151
)或
Figure PCTCN2021126331-appb-000152
Ring D is independently phenyl, 5-6 membered heteroaryl or 5-10 membered heterocyclyl and 5-6 membered heteroaryl, preferably phenyl, pyrazinyl, pyridyl (eg
Figure PCTCN2021126331-appb-000151
)or
Figure PCTCN2021126331-appb-000152
R 1a独立地为卤素、C 1-C 6烷基、C 1-C 6烷基-O-、氨基、氰基、羟基，或者，被一个或多个R a取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同； R 1a is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, amino, cyano, hydroxy, or, substituted with one or more R a : C 1 -C 6 Alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different;
R a独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
环H选自苯基、5-6元杂芳基，优选苯基、吡啶基(例如
Figure PCTCN2021126331-appb-000153
)、吡嗪基或噻唑基(例如
Figure PCTCN2021126331-appb-000154
)； Ring H is selected from phenyl, 5-6 membered heteroaryl, preferably phenyl, pyridyl (eg
Figure PCTCN2021126331-appb-000153
), pyrazinyl or thiazolyl (eg
Figure PCTCN2021126331-appb-000154
);
R 11独立地为选自氢原子、卤素、硝基、氰基、C 1-C 6烷基、C 1-C 6烷氧基； R 11 is independently selected from hydrogen atom, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
r独立地选自0、1和2；r is independently selected from 0, 1 and 2;
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000155
为
Figure PCTCN2021126331-appb-000156
G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；
Figure PCTCN2021126331-appb-000155
for
Figure PCTCN2021126331-appb-000156
G is independently a C, C(=O), N, S or O heteroatom or group; G' is independently a linkage, C, C(=O), N, S or O atom or group;
R 1a独立地为卤素、氨基或C 1-C 6烷基； R 1a is independently halogen, amino or C 1 -C 6 alkyl;
n独立地为0、1、2、3、4或5；例如n独立地为0、1、2或3；n is independently 0, 1, 2, 3, 4 or 5; for example n is independently 0, 1, 2 or 3;
环E为含有1至3个N原子的6元杂芳基；G独立地为C、C(＝O)、N、S或O原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms; G is independently a C, C(=O), N, S or O atom or group; G' is independently a linkage, C, C (=O), N, S or O atom or group;
L 1为连接键、-O-或-S-； L 1 is a connection key, -O- or -S-;
X 1为CR 3，X 2为CR 3；或，X 1为N，X 2为CR 3； X 1 is CR 3 and X 2 is CR 3 ; or, X 1 is N and X 2 is CR 3 ;
R 3和R 4独立地为氢； R3 and R4 are independently hydrogen ;
R 2为
Figure PCTCN2021126331-appb-000157
Y＝C，R 7和R 8与Y一起形成：
Figure PCTCN2021126331-appb-000158
 R2 is
Figure PCTCN2021126331-appb-000157
Y=C, R7 and R8 together with Y form:
Figure PCTCN2021126331-appb-000158
o1、o2独立地为0、1或2；例如1；o1, o2 are independently 0, 1 or 2; e.g. 1;
R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a和R 6b独立地为氢； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently hydrogen;
q独立地为0、1或2；p’为0或1；q is independently 0, 1 or 2; p' is 0 or 1;
R 9a、R 9b、R 10a和R 10b独立地为氢原子、氨基或C 1-C 4烷基； R 9a , R 9b , R 10a and R 10b are independently a hydrogen atom, an amino group or a C 1 -C 4 alkyl group;
W独立地为连接键、-C(R w) 2-； W is independently a connecting bond, -C(R w ) 2 -;
环H独立地为不存在或者苯基或5-6元杂芳基；Ring H is independently absent or phenyl or 5-6 membered heteroaryl;
当环H不存在时，Z 1为CR z1aR z1b，Z 2为O，或者Z 1为O，Z 2为CR z2aR z2b； When ring H does not exist, Z 1 is CR z1a R z1b and Z 2 is O, or Z 1 is O and Z 2 is CR z2a R z2b ;
R z1a、R z1b、R z2a、R z2b独立地为氢原子或C 1-C 4烷基；
Figure PCTCN2021126331-appb-000159
为单键； R z1a , R z1b , R z2a , R z2b are independently a hydrogen atom or a C 1 -C 4 alkyl group;
Figure PCTCN2021126331-appb-000159
is a single key;
当环H为苯基或5-6元杂芳基时；Z 1和Z 2独立地为C，
Figure PCTCN2021126331-appb-000160
为双键； When ring H is phenyl or 5-6 membered heteroaryl; Z 1 and Z 2 are independently C,
Figure PCTCN2021126331-appb-000160
is a double bond;
R 11独立地为氢原子、卤素、C 1-C 6的烷基； R 11 is independently a hydrogen atom, a halogen, a C 1 -C 6 alkyl group;
r独立地为0、或2；r is independently 0, or 2;
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
在本发明某些优选实施方案中，所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，In certain preferred embodiments of the present invention, the nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or some of their pharmaceutically acceptable salts These groups are defined as follows (unmentioned groups are as described in any scheme of this application),
其中，in,
L 1为连接键、-O-或-S-；例如S； L 1 is a connecting bond, -O- or -S-; for example, S;
Figure PCTCN2021126331-appb-000161
为
Figure PCTCN2021126331-appb-000162
G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；
Figure PCTCN2021126331-appb-000161
for
Figure PCTCN2021126331-appb-000162
G is independently a C, C(=O), N, S or O heteroatom or group; G' is independently a linkage, C, C(=O), N, S or O atom or group;
R 1a独立地为卤素、C 1-C 6烷基、氨基； R 1a is independently halogen, C 1 -C 6 alkyl, amino;
环E为含有1至3个N原子的6元杂芳基；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms;
n独立地为1或2；例如2；n is independently 1 or 2; e.g. 2;
X 1为CR 3，X 2为CR 3；R 3独立地为氢；R 4独立地为氢； X 1 is CR 3 , X 2 is CR 3 ; R 3 is independently hydrogen; R 4 is independently hydrogen;
R 2为
Figure PCTCN2021126331-appb-000163
例如
Figure PCTCN2021126331-appb-000164
Figure PCTCN2021126331-appb-000165
 R2 is
Figure PCTCN2021126331-appb-000163
E.g
Figure PCTCN2021126331-appb-000164
Figure PCTCN2021126331-appb-000165
环H独立地为苯基或5-10元杂环芳基；Ring H is independently phenyl or 5-10 membered heterocyclic aryl;
p’为0，q为1；或p’为1，q为0；p' is 0 and q is 1; or p' is 1 and q is 0;
R 9a为氢原子或C 1-C 4烷基； R 9a is a hydrogen atom or a C 1 -C 4 alkyl group;
r独立地为0或1；r is independently 0 or 1;
R 11独立地为C 1-C 4烷基； R 11 is independently C 1 -C 4 alkyl;
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；The carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
较佳地，L 1为连接键、-S-； Preferably, L 1 is a connecting key, -S-;
R 2为
Figure PCTCN2021126331-appb-000166
 R2 is
Figure PCTCN2021126331-appb-000166
p’为0，q为1；p' is 0, q is 1;
r独立地为0。r is independently 0.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为5-10元杂芳基时，所述的5-10元杂芳基为含有1至3个N原子的6元杂芳基；例如吡 啶，又例如
Figure PCTCN2021126331-appb-000167
When Ring D is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 6-membered heteroaryl group containing 1 to 3 N atoms; for example, pyridine, or for example
Figure PCTCN2021126331-appb-000167
例如，
Figure PCTCN2021126331-appb-000168
为
Figure PCTCN2021126331-appb-000169
环E为含有1至3个N原子的6元杂芳基。 E.g,
Figure PCTCN2021126331-appb-000168
for
Figure PCTCN2021126331-appb-000169
Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为C 6-C 10芳基时，所述的C 6-C 10芳基为苯基或萘基；例如苯基或
Figure PCTCN2021126331-appb-000170
When ring D is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is phenyl or naphthyl; for example, phenyl or
Figure PCTCN2021126331-appb-000170
例如，
Figure PCTCN2021126331-appb-000171
为
Figure PCTCN2021126331-appb-000172
又例如
Figure PCTCN2021126331-appb-000173
E.g,
Figure PCTCN2021126331-appb-000171
for
Figure PCTCN2021126331-appb-000172
Another example
Figure PCTCN2021126331-appb-000173
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为5-10元杂环基并5-6元杂芳基时，所述的5-10元杂环基并5-6元杂芳基为
Figure PCTCN2021126331-appb-000174
G独立地为C、C(＝O)、N、S或O原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；例如，
Figure PCTCN2021126331-appb-000175
When Ring D is a 5-10-membered heterocyclic group and a 5-6-membered heteroaryl group, the 5-10-membered heterocyclic group and the 5-6-membered heteroaryl group are
Figure PCTCN2021126331-appb-000174
G is independently a C, C(=O), N, S or O atom or group; G' is independently a bond, C, C(=O), N, S or O atom or group; for example,
Figure PCTCN2021126331-appb-000175
即，
Figure PCTCN2021126331-appb-000176
为
Figure PCTCN2021126331-appb-000177
例如，
Figure PCTCN2021126331-appb-000178
which is,
Figure PCTCN2021126331-appb-000176
for
Figure PCTCN2021126331-appb-000177
E.g,
Figure PCTCN2021126331-appb-000178
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟。 When R 1a is independently halogen, the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 1a独立地为C 1-C 6烷基时，所述的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；例如甲基。 When R 1a is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group (eg methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C 1 -C 6 alkyl C4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环D为苯基或6元杂芳基时，R 1a独立地位于环D与L 1连接键的邻位、间位及对位，例如当n 为2时，位于相邻的邻位和对位。 When ring D is phenyl or 6-membered heteroaryl, R 1a is independently located in the ortho, meta and para positions of the bond between ring D and L 1 , for example, when n is 2, it is located in the adjacent ortho and Counterpoint.
在本发明的某一优选方案中，In a preferred solution of the present invention,
n独立地为0、1、2；例如1或2。n is independently 0, 1, 2; eg, 1 or 2.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 9a和R 9b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基。 When R 9a and R 9b are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R 10a和R 10b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基。 When R 10a and R 10b are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl; another example is methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当环H独立地为5-6元杂芳基时，所述的5-6元杂芳基为1-2个N原子的6元杂芳基、1-3个选自N、O及S原子的5元杂芳基；所述的6元杂芳基例如吡啶基、吡嗪基，例如
Figure PCTCN2021126331-appb-000179
Figure PCTCN2021126331-appb-000180
所述的5元杂芳基例如噻唑基，例如
Figure PCTCN2021126331-appb-000181
a表示稠合位置。 When ring H is independently a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is a 6-membered heteroaryl group with 1-2 N atoms, 1-3 members selected from N, O and S Atomic 5-membered heteroaryl; said 6-membered heteroaryl such as pyridyl, pyrazinyl, such as
Figure PCTCN2021126331-appb-000179
Figure PCTCN2021126331-appb-000180
The 5-membered heteroaryl group such as thiazolyl, such as
Figure PCTCN2021126331-appb-000181
a denotes a fused position.
在本发明的某一优选方案中，In a preferred solution of the present invention,
当R z1a、R z1b、R z2a、R z2b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；例如甲基。 When R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); eg methyl.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 11独立地为卤素，所述的卤素为氯、氟；例如氯。 R 11 is independently halogen, said halogen being chlorine, fluorine; for example chlorine.
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000182
为
Figure PCTCN2021126331-appb-000183
例如
Figure PCTCN2021126331-appb-000184
又例如
Figure PCTCN2021126331-appb-000185
Figure PCTCN2021126331-appb-000182
for
Figure PCTCN2021126331-appb-000183
E.g
Figure PCTCN2021126331-appb-000184
Another example
Figure PCTCN2021126331-appb-000185
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 2为
Figure PCTCN2021126331-appb-000186
 R2 is
Figure PCTCN2021126331-appb-000186
在本发明的某一优选方案中，In a preferred solution of the present invention,
Figure PCTCN2021126331-appb-000187
为
Figure PCTCN2021126331-appb-000188
Figure PCTCN2021126331-appb-000189
例如
Figure PCTCN2021126331-appb-000190
Figure PCTCN2021126331-appb-000191
Figure PCTCN2021126331-appb-000192
表示对映体。
Figure PCTCN2021126331-appb-000187
for
Figure PCTCN2021126331-appb-000188
Figure PCTCN2021126331-appb-000189
E.g
Figure PCTCN2021126331-appb-000190
Figure PCTCN2021126331-appb-000191
Figure PCTCN2021126331-appb-000192
represents the enantiomer.
在本发明的某一优选方案中，In a preferred solution of the present invention,
R 2为
Figure PCTCN2021126331-appb-000193
Figure PCTCN2021126331-appb-000194
例如
Figure PCTCN2021126331-appb-000195
Figure PCTCN2021126331-appb-000196
Figure PCTCN2021126331-appb-000197
表示对映体。 R2 is
Figure PCTCN2021126331-appb-000193
Figure PCTCN2021126331-appb-000194
E.g
Figure PCTCN2021126331-appb-000195
Figure PCTCN2021126331-appb-000196
Figure PCTCN2021126331-appb-000197
represents the enantiomer.
在本发明的某一优选方案中，本发明所述的式I所示的含氮稠杂环类化合物为下列任一化合物：In a preferred embodiment of the present invention, the nitrogen-containing fused heterocyclic compound represented by formula I of the present invention is any of the following compounds:
Figure PCTCN2021126331-appb-000198
Figure PCTCN2021126331-appb-000198
Figure PCTCN2021126331-appb-000199
Figure PCTCN2021126331-appb-000199
Figure PCTCN2021126331-appb-000200
Figure PCTCN2021126331-appb-000200
Figure PCTCN2021126331-appb-000201
Figure PCTCN2021126331-appb-000201
Figure PCTCN2021126331-appb-000202
Figure PCTCN2021126331-appb-000202
Figure PCTCN2021126331-appb-000203
Figure PCTCN2021126331-appb-000203
Figure PCTCN2021126331-appb-000204
Figure PCTCN2021126331-appb-000204
Figure PCTCN2021126331-appb-000205
Figure PCTCN2021126331-appb-000205
Figure PCTCN2021126331-appb-000206
Figure PCTCN2021126331-appb-000206
Figure PCTCN2021126331-appb-000207
Figure PCTCN2021126331-appb-000207
Figure PCTCN2021126331-appb-000208
Figure PCTCN2021126331-appb-000208
Figure PCTCN2021126331-appb-000209
Figure PCTCN2021126331-appb-000209
Figure PCTCN2021126331-appb-000210
Figure PCTCN2021126331-appb-000210
本发明中，如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐可具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。In the present invention, the nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts may have one or more chiral carbon atoms, so Optically pure isomers can be isolated, eg, pure enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
本发明中，如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。In the present invention, the nitrogen-containing fused heterocyclic compounds shown in formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts, if there are stereoisomers, can be represented by a single Stereoisomers or their mixtures (eg racemates) exist. The term "stereoisomer" refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
由此，在本说明书通篇中，本领域技术人员可对所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐中所述基团及其取代基进行选择，以提供稳定的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐，包括但不限于本发明的实施例中所述的化合物。Therefore, throughout the present specification, those skilled in the art can describe the nitrogen-containing fused heterocyclic compounds shown in formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable compounds. The groups and their substituents in the accepted salts are selected to provide stable nitrogen-containing fused heterocyclic compounds of formula I, their stereoisomers, their tautomers, or their pharmaceutically acceptable compounds. Acceptable salts include, but are not limited to, the compounds described in the Examples of this invention.
本发明所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐可通过包括与化学领域公知方法相似的方法合成，其步骤和条件可参考本领域类似反应的步骤 和条件，特别是根据本文说明进行合成。起始原料通常是来自商业来源，例如Aldrich或可使用本领域技术人员公知的方法(通过SciFinder、Reaxys联机数据库得到)容易地制备。The nitrogen-containing fused heterocyclic compounds represented by formula I, their stereoisomers, their tautomers or their pharmaceutically acceptable salts described in the present invention can be prepared by methods similar to those known in the chemical field. Synthesis, its steps and conditions can refer to the steps and conditions of similar reactions in the art, especially the synthesis according to the description herein. Starting materials are typically from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online database).
本发明中，所述的如式I所示的稠环化合物或其药学上可接受的盐，也可以通过已制备得到的所述的如式I所示的稠环化合物或其药学上可接受的盐，采用本领域常规方法，经外周修饰进而得到其他所述的如式I所示的稠环化合物或其药学上可接受的盐。In the present invention, the fused ring compound represented by formula I or a pharmaceutically acceptable salt thereof can also be prepared by the fused ring compound represented by formula I or a pharmaceutically acceptable salt thereof. The salt of the compound is obtained by peripheral modification using conventional methods in the art to obtain other described fused ring compounds represented by formula I or a pharmaceutically acceptable salt thereof.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式I所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified. The following reaction schemes and examples serve to further illustrate the content of the present invention.
用于制备如式I中化合物的必要原料或试剂可以商购获得，或者通过本领域已知的合成方法制备。如下实验部分所描述的方法，可以制备游离碱或者其加酸所成盐的本发明的化合物。术语药学上可接受的盐指的是本文所定义的药学上可接受的盐，并且具有母体化合物所有的药学活性。药学上可接受的盐可以通过在有机碱的合适的有机溶剂中加入相应的酸，根据常规方法处理来制备药学上可接受的盐。The necessary starting materials or reagents for the preparation of compounds such as those of formula I are either commercially available or prepared by synthetic methods known in the art. Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound. Pharmaceutically acceptable salts The pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
成盐实例包括：与无机酸成盐，如盐酸、氢溴酸、硫酸、硝酸、磷酸；和有机酸所形成的盐，如醋酸、苯磺酸、苯甲酸、樟脑磺酸、柃檬酸、乙磺酸、富马酸、葡庚糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、黏糠酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、酒石酸、对甲苯磺酸或三甲基乙酸。Examples of salt formation include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid , mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
如式I所示的稠环化合物可能具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。The fused ring compound shown in formula I may have one or more chiral carbon atoms, and thus can be separated into optically pure isomers, such as pure enantiomers, or racemates, or mixed isomers . Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
本专利所述的合成路线中所用的化学品，包括溶剂，试剂，催化剂以及保护基团，脱保护基团，保护基团包括叔丁氧基羰基(Boc)。上述方法还可以另外包括在本文具体描述的步骤之前或之后的步骤，可以添加或除去合适的保护基团，以得到目标化合物。另外，各种合成步骤可以交替或顺次的进行以得到最终的目标产物。The chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and protecting groups including tert-butoxycarbonyl (Boc). The above methods may additionally include steps before or after the steps specifically described herein, where appropriate protecting groups may be added or removed to obtain the target compound. Additionally, various synthetic steps can be performed alternately or sequentially to obtain the final target product.
另一方面，本发明提供式I所示的含氮稠杂环类化合物及其中间体的制备方法，主要包括如下方面：On the other hand, the present invention provides the preparation method of the nitrogen-containing fused heterocyclic compound shown in formula I and its intermediate, which mainly includes the following aspects:
本发明提供一种如式I所示的含氮稠杂环类化合物的制备方法，当式I化合物为通式I’所示化合物时，其包括如下步骤：在酸性条件下，将如式II’所示的化合物进行脱除保护基反应，得到如式I’所示的化合物即可；The present invention provides a method for preparing a nitrogen-containing fused heterocyclic compound represented by formula I. When the compound of formula I is a compound represented by general formula I', it comprises the following steps: The compound shown in ' is subjected to deprotection reaction to obtain the compound shown in formula I';
Figure PCTCN2021126331-appb-000211
Figure PCTCN2021126331-appb-000211
其中，Pg选自保护基Boc、Ac、S(＝O) tBu；环H、R 1、X 1、X 2、R 4、W、Z 1、Z 2、o1、o2、p’、q、r、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b、R 9a、R 9b、R 10a、R 10b、R 11、*和
Figure PCTCN2021126331-appb-000212
的定义如上所述。 wherein, Pg is selected from protecting groups Boc, Ac, S(=O) t Bu; ring H, R 1 , X 1 , X 2 , R 4 , W, Z 1 , Z 2 , o1 , o2 , p′, q , r, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 9a , R 9b , R 10a , R 10b , R 11 , * and
Figure PCTCN2021126331-appb-000212
is defined as above.
本发明提供了一种如式II’所示的化合物，The present invention provides a compound of formula II',
Figure PCTCN2021126331-appb-000213
Figure PCTCN2021126331-appb-000213
其中，Pg选自保护基Boc、Ac、S(＝O) tBu；环H、R 1、X 1、X 2、R 4、W、Z 1、Z 2、o1、o2、p’、q、r、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b、R 9a、R 9b、R 10a、R 10b、R 11、*和
Figure PCTCN2021126331-appb-000214
的定义如上所述。 wherein, Pg is selected from protecting groups Boc, Ac, S(=O) t Bu; ring H, R 1 , X 1 , X 2 , R 4 , W, Z 1 , Z 2 , o1 , o2 , p′, q , r, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 9a , R 9b , R 10a , R 10b , R 11 , * and
Figure PCTCN2021126331-appb-000214
is defined as above.
在某一优选方案中，所述的式II’-a所示的化合物选自如下化合物：In a certain preferred embodiment, the compound represented by the formula II'-a is selected from the following compounds:
Figure PCTCN2021126331-appb-000215
Figure PCTCN2021126331-appb-000215
本发明提供了一种如式III-3所示的化合物，The present invention provides a compound of formula III-3,
Figure PCTCN2021126331-appb-000216
Figure PCTCN2021126331-appb-000216
其中，X 1、X 2、R 4、W 1、o1、R 5a、R 5b、R 6a、R 6b、Y、R 7、R 8的定义如上所述。 The definitions of X 1 , X 2 , R 4 , W 1 , o1 , R 5a , R 5b , R 6a , R 6b , Y, R 7 , and R 8 are as described above.
本发明提供了一种如式I化合物的制备方法，当式I化合物为通式I-a所示化合物或者通式I-b所示化合物时，其包括如下步骤：The present invention provides a method for preparing a compound of formula I. When the compound of formula I is a compound represented by general formula I-a or a compound represented by general formula I-b, it comprises the following steps:
Figure PCTCN2021126331-appb-000217
Figure PCTCN2021126331-appb-000217
式I-1与式I-2所示硼酸进行偶联反应后得到式I-a、或者，式I-1与式I-3所示硫醇或硫钠进行偶联反应后得到式I-b；Formula I-1 and the boronic acid shown in formula I-2 are subjected to coupling reaction to obtain formula I-a, or, formula I-1 is subjected to coupling reaction with thiol or sodium sulfide shown in formula I-3 to obtain formula I-b;
其中，W 1代表卤素或磺酰基，优选Br、I、或磺酰基；R为H或C 1-C 4烷基；X 1、X 2、环D、n、R 4、R 1a和R 2的定义如上所述。 Wherein, W 1 represents halogen or sulfonyl, preferably Br, I, or sulfonyl; R is H or C 1 -C 4 alkyl; X 1 , X 2 , ring D, n, R 4 , R 1a and R 2 is defined as above.
本发明提供了一种如式I化合物的制备方法，当式I化合物为通式III化合物时，其包括如下步骤：The present invention provides a method for preparing a compound of formula I, when the compound of formula I is a compound of general formula III, it comprises the following steps:
Figure PCTCN2021126331-appb-000218
Figure PCTCN2021126331-appb-000218
中间体III-1在碱性条件下被中间体胺III-2取代得到中间体化合物III-3，然后中间体III-3在与硼酸、硫醇或硫钠进行偶联反应后得到式III；Intermediate III-1 is substituted by intermediate amine III-2 under basic conditions to obtain intermediate compound III-3, and then intermediate III-3 is subjected to coupling reaction with boronic acid, thiol or sodium sulfide to obtain formula III;
其中，W 1和W 2代表卤素或磺酰基，优选氯、Br、I或磺酰基；X 1、X 2、Y、L 1、环D、o1、n、R 5a、R 5b、R 6a、R 6b、R 7、R 8的定义如上所述。 Wherein, W 1 and W 2 represent halogen or sulfonyl, preferably chlorine, Br, I or sulfonyl; X 1 , X 2 , Y, L 1 , ring D, o1 , n, R 5a , R 5b , R 6a , The definitions of R 6b , R 7 , and R 8 are as described above.
本发明提供了一种如式I化合物的制备方法，当式I化合物为
Figure PCTCN2021126331-appb-000219
时，其包括如下步骤： The present invention provides a preparation method of the compound of formula I, when the compound of formula I is
Figure PCTCN2021126331-appb-000219
, it includes the following steps:
将中间体C1和胺在碱性条件下，在合适的溶剂和反应温度下得到V-1-a1；V-1-a1 is obtained by subjecting intermediate C1 and amine under basic conditions, under suitable solvent and reaction temperature;
将V-1-a1在碱性条件下，在催化剂存在下与I-2通过偶联反应得到V-1-a2，然后在酸性条件下脱去保护基Pg，得到V-1-a即可；V-1-a1 is coupled with I-2 under alkaline conditions to obtain V-1-a2, and then the protective group Pg is removed under acidic conditions to obtain V-1-a. ;
或者，将V-1-a1与式I-3所示化合物在碱性条件下，在催化剂存在下通过偶联得到V-1-b2；然后在酸性条件下脱去保护基Pg，得到V-1-b即可；Alternatively, V-1-b2 can be obtained by coupling V-1-a1 with the compound represented by formula I-3 in the presence of a catalyst under basic conditions; and then removing the protecting group Pg under acidic conditions to obtain V- 1-b can be;
Figure PCTCN2021126331-appb-000220
Figure PCTCN2021126331-appb-000220
其中，Pg为N保护基，优选Boc、Ac、S(＝O)tBu；W 1和W 2代表卤素或磺酰基，优选氯、Br、I或磺酰基；R为H或C 1-C 4烷基；环D、环H、n、r、R 1a和R 11的定义如上所述。 Wherein, Pg is an N protecting group, preferably Boc, Ac, S(=O)tBu; W 1 and W 2 represent halogen or sulfonyl, preferably chlorine, Br, I or sulfonyl; R is H or C 1 -C 4 Alkyl; Ring D, Ring H, n, r, R 1a and R 11 are as defined above.
本发明提供了一种中间体
Figure PCTCN2021126331-appb-000221
(C1)的合成方法，其包括如下步骤： The present invention provides an intermediate
Figure PCTCN2021126331-appb-000221
The synthetic method of (C1), it comprises the steps:
将2-氯氨基嘧啶类化合物C1-0与关环试剂在溶剂中室温或加热的条件下得到C1-1中间体；将C1-1中间体与氨的水溶液或醇溶液室温或加热的条件下得到C1-2中间体；将C1-2在碱性条件下室温或加热得C1-3；将C1-3转化成C1；The C1-1 intermediate is obtained by combining 2-chloroaminopyrimidine compound C1-0 with a ring-closing reagent in a solvent at room temperature or under heating conditions; the C1-1 intermediate and an aqueous or alcoholic solution of ammonia are obtained at room temperature or under heating conditions Obtain C1-2 intermediate; C1-2 is obtained under basic conditions at room temperature or heated to C1-3; C1-3 is converted into C1;
Figure PCTCN2021126331-appb-000222
Figure PCTCN2021126331-appb-000222
其中，W 1、W 2定义如上所述。 Wherein, W 1 and W 2 are defined as above.
本发明所涉及到的催化剂选自：钯/碳、雷尼镍、四-三苯基磷钯、二氯化钯、[1,1′-双(二苯基膦 基)二茂铁]二氯化钯、[1,1′-双(二苄基膦)二氯二戊铁钯、三(二亚苄基丙酮)二钯；The catalyst involved in the present invention is selected from: palladium/carbon, Raney nickel, tetrakis-triphenylphosphonium palladium, palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]bis Palladium chloride, [1,1'-bis(dibenzylphosphine)dichlorodipentyl iron palladium, tris(dibenzylideneacetone)dipalladium;
本发明所涉及到的溶剂选自：二氯甲烷、氯仿C、甲醇、乙醇、异丙醇、叔丁醇、1,2-二氯乙烷、二氧六环、DMF、乙腈、DMSO、NMP、THF或其组合。The solvent involved in the present invention is selected from: dichloromethane, chloroform C, methanol, ethanol, isopropanol, tert-butanol, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP , THF or a combination thereof.
本发明所涉及到的碱包括有机碱和无机碱；The bases involved in the present invention include organic bases and inorganic bases;
本发明所涉及到的有机碱优选为：TEA、DIPEA或其组合；The organic base involved in the present invention is preferably: TEA, DIPEA or a combination thereof;
本发明所涉及到的无机碱优选为：氢化钠、正丁基锂、二异丙基氨基锂、醋酸钾、氢氧化锂、碳酸钾、碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠、LiHMDS、LDA、丁基锂或其组合。The inorganic bases involved in the present invention are preferably: sodium hydride, n-butyllithium, lithium diisopropylamide, potassium acetate, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, tert-butanol Sodium, LiHMDS, LDA, Butyllithium, or a combination thereof.
另一方面，本发明还提供一种药物组合物，包含如上所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐、以及药学上可接受的辅料。所述药学上可接受的辅料优先选自稀释剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂。所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐可为治疗有效量。On the other hand, the present invention also provides a pharmaceutical composition, comprising the above-mentioned nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable Accepted salts, and pharmaceutically acceptable excipients. The pharmaceutically acceptable adjuvants are preferably selected from diluents, absorbents, wetting agents, binders, disintegrants, and lubricants. Said nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt can be a therapeutically effective amount.
另一方面，本发明还提供了所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐或如前所述的药物组合物用于制备药物方面的用途。所述药物可为治疗与SHP2活性异常相关疾病或病症的药物；作为优选，所述疾病或病症包括但不局限于包括努南综合症、豹综合症、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤或成胶质细胞瘤。On the other hand, the present invention also provides the nitrogen-containing fused heterocyclic compound shown in formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt or as previously described The pharmaceutical composition described is used for the preparation of medicines. The medicine can be a medicine for treating diseases or conditions related to abnormal SHP2 activity; preferably, the diseases or conditions include, but are not limited to, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, stomach cancer, anaplastic large cell lymphoma, or glioblastoma .
另一方面，本发明还提供了一种治疗与SHP2活性异常相关疾病或病症的方法，其包括向患者施用治疗有效量的所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐。作为优选，所述疾病或病症包括但不局限于包括努南综合症、豹综合症、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤或成胶质细胞瘤。In another aspect, the present invention also provides a method for treating a disease or condition related to abnormal SHP2 activity, comprising administering to the patient a therapeutically effective amount of the nitrogen-containing fused heterocyclic compound shown in Formula I, its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof. Preferably, the disease or disorder includes, but is not limited to, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer , colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.
另一方面，本发明还提供了一种预防和/或治疗肿瘤的方法，其包括向患者施用治疗有效量的所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐。作为优选，所述肿瘤包括但不局限于包括青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤或成胶质细胞瘤。On the other hand, the present invention also provides a method for preventing and/or treating tumors, which comprises administering to a patient a therapeutically effective amount of the nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer isomers, tautomers or pharmaceutically acceptable salts thereof. Preferably, the tumor includes, but is not limited to, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma , squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.
术语说明Glossary
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, when used in reference to a specifically recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, the terms "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of," or "consisting of."
基团定义group definition
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于OCH 2-。 Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds. When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to OCH2- .
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。Section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings shown below unless specifically indicated otherwise.
在本申请中，术语“卤素”是指氟、氯、溴或碘。In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
“羟基”是指-OH基团。烷氧基”是指被羟基(-OH)取代的如下文所定义的烷基。"Hydroxy" refers to the -OH group. "Alkoxy" means an alkyl group as defined below substituted with hydroxy (-OH).
“羰基”是指-C(＝O)-基团。“氰基”是指-CN。"Carbonyl" refers to a -C(=O)- group. "Cyano" refers to -CN.
“氨基”是指-NH 2。 "Amino" refers to -NH2 .
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。"Substituted amino" means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, eg, monoalkylamino, dialkylamino, alkyl amido, aralkylamino, heteroaralkylamino.
“羧基”是指-COOH。"Carboxyl" refers to -COOH.
术语“酰胺基”表示氨基取代的羰基。The term "amido" refers to an amino-substituted carbonyl group.
术语“磺酰胺基”表示氨基取代的磺酰基。The term "sulfonamido" refers to an amino-substituted sulfonyl group.
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、 正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“烷基”指含有1至6个碳原子的烷基。In this application, the term "alkyl" as a group or part of another group (for example, in a halogen-substituted alkyl group, etc.) refers to a fully saturated straight or branched hydrocarbon chain group, Consists of only carbon and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is attached to the rest of the molecule by a single bond, such as including but not limited to Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl , n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc. For purposes of the present invention, the term "alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms.
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。In this application, the term "alkenyl" as a group or part of another group means consisting of carbon and hydrogen atoms only, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) a straight or branched hydrocarbon chain group, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butan- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
在本申请中，作为基团或是其它基团的一部分，术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烃基中的碳原子可以任选地被氧化。环烃基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。In this application, as a group or as part of another group, the term "cyclohydrocarbyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include fused rings system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which is saturated or unsaturated and can be The carbon atoms are connected to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cyclic hydrocarbon group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene base, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzoyl Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl , bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro- 4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。例如由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元杂环烷基。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。In this application, the term "heterocyclyl" as a group or part of another group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in this specification, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of a can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and through a single bond. In heterocyclyl containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. For example a stable 3- to 20-membered heterocycloalkyl consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alk-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl , phthalimide, etc.
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多 环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。As used herein, as a group or as part of another group, the term "aryl" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H isoindolyl, 2-benzoxazolinone, 2H-1,4 - Benzoxazin-3(4H)-one-7-yl and the like.
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。In this application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。In this application, as a group or part of another group, the term "heteroaryl" means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen 5- to 16-membered conjugated ring system groups of heteroatoms of , oxygen and sulfur. Unless specifically stated otherwise in this specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group The aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 selected heteroatoms. A stable 5- to 10-membered aromatic group from heteroatoms of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazolyl, carboline, phenanthridine, phenanthroline, acridine base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxtriazolyl, cinnoline, quinazolinyl, phenylthio, indolizine, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]Triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。在本申请中，“任选地”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In this application, the term "heteroarylalkyl" refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above. In this application, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
本发明权利要求书和说明书部分所述的“任选地”的取代基选自烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、氰基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烃基、任选取代的杂环烃基。The "optional" substituents described in the claims and description section of the present invention are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.
本发明的化合物的所有互变异构形式也将包含在本发明的范围内。本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体， 以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention. The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. The compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
本发明的取代基或代表符号，如Z 1、Z 2、X、Y、U、V、W 1、W 2、W 3、n、o、p、q、r、R 1、R 2a、R 2b、R 3a、R 3b、R 4、R 5、Pg1、Pg等，如未特别指出，相同的符号在不同地方代表相同的定义。 Substituents or representative symbols of the present invention, such as Z 1 , Z 2 , X, Y, U, V, W 1 , W 2 , W 3 , n, o, p, q, r, R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , Pg1 , Pg, etc., unless otherwise specified, the same symbols represent the same definitions in different places.
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives using, for example, chiral high performance liquid chromatography) ), see for example Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu.Rev.Anal.Chem.3 : 341-63, 2010; Fumiss et al.(eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc.Chem .Res.1990, 23, 128.
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2 dichloroacetate, Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipic acid Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate, Alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包 含的任意组分相互作用。在本申请中，“药学上可接受的赋形剂”包括但不限于任何被相关的政府理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、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。As used herein, the term "pharmaceutically acceptable" refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition. In this application, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, enhancer approved by the relevant government agency as acceptable for human or livestock use. Sweetening agents, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
本发明所述“肿瘤”包括但不限于脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌、多发性骨髓瘤、间皮瘤、恶性横纹肌样瘤、子宫内膜癌、头颈癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等疾病。The "tumor" of the present invention includes, but is not limited to, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcoma, melanoma, articular chondroma, cholangiomas, leukemia, gastrointestinal Stromal tumor, diffuse large B cell lymphoma, follicular lymphoma and other lymphoma, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate Cancer, Liver Cancer, Skin Cancer, Epithelial Cell Cancer, Cervical Cancer, Ovarian Cancer, Colon Cancer, Nasopharyngeal Cancer, Brain Cancer, Bone Cancer, Esophageal Cancer, Melanoma, Kidney Cancer, Oral Cancer, Multiple Myeloma, Mesothelioma , malignant rhabdoid tumor, endometrial cancer, head and neck cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma and other diseases.
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。As used herein, the terms "prophylactic", "preventing" and "preventing" include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.
本文所用的术语“治疗”和其它类似的同义词包括以下含义：As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing the emergence of a disease or disorder in mammals, particularly when such mammals are susceptible to, but have not been diagnosed with, the disease or disorder;
(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting the disease or disorder, i.e. arresting its development;
(iii)缓解疾病或病症，即使该疾病或病症的状态消退；或者(iii) alleviation of a disease or condition, even if the state of the disease or condition resolves; or
(iv)减轻该疾病或病症所造成的症状。(iv) alleviating symptoms caused by the disease or disorder.
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to at least one agent or compound sufficient to alleviate, to some extent, one or more symptoms of the disease or disorder being treated upon administration. amount. The result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition. An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays. The terms "administering," "administering," "administering," and the like, as used herein, refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基 甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。The terms "drug combination," "drug combination," "combination," "administration of other treatments," "administration of other therapeutic agents," etc. as used herein refer to drug treatments obtained by admixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form. The term "unfixed combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients. It will also be understood by those skilled in the art that in the methods described below, intermediate compound functional groups may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters. Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：1、本发明公开的含氮稠杂环化合物是一类新颖的变构抑制剂，能够通过与SHP2非催化区域的结合并“锁”住SHP2活性很弱的基础状态，从而达到抑制其活性的目的。本发明公开的稠环化合物克服了PTP催化区域抑制剂普遍的选择性和成药性差等缺点，表现了很好的生物活性及可成药性，具有很好的药物开发前景。The positive and progressive effects of the present invention are: 1. The nitrogen-containing fused heterocyclic compound disclosed in the present invention is a novel allosteric inhibitor, which can "lock" the basis of weak SHP2 activity by combining with the non-catalytic region of SHP2 state, so as to achieve the purpose of inhibiting its activity. The fused ring compound disclosed by the invention overcomes the disadvantages of the general selectivity and poor druggability of the PTP catalytic region inhibitor, exhibits good biological activity and druggability, and has a good prospect for drug development.
2、在相同条件的SHP2酶活性抑制实验、磷酸化蛋白激酶(p-ERK)细胞实验和MV-4-11细胞增殖实验等评价体系中，本发明与诺华所公开的临床化合物TNO155((3S,4S)-8-(6-氨基-5-((2-氨基-3-氯吡啶基-4-基)硫代)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺)相比，表现出了更优越的活性。2. In the evaluation system of SHP2 enzyme activity inhibition experiment, phosphorylated protein kinase (p-ERK) cell experiment and MV-4-11 cell proliferation experiment under the same conditions, the present invention and the clinical compound TNO155 ((3S) disclosed by Novartis ,4S)-8-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decane-4-amine) showed superior activity.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
下述实施例中所用的起始物可由化学品销售商如Aldrich、TCI、Alfa Aesar、毕得、安耐吉等处购得，或者可通过已知的方法来合成。The starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidder, Anegi, etc., or can be synthesized by known methods.
下述实施例中，冰浴是指-5摄氏度至0摄氏度，室温是指10摄氏度至30摄氏度，回流温度一般是指溶剂常压下溶剂回流温度。反应过夜是指时间为8-15小时。下述实施例中，未限定具体操作温度的，均在室温下进行。In the following examples, the ice bath refers to -5 degrees Celsius to 0 degrees Celsius, the room temperature refers to 10 degrees Celsius to 30 degrees Celsius, and the reflux temperature generally refers to the reflux temperature of the solvent under normal pressure. A reaction overnight refers to a time of 8-15 hours. In the following examples, the specific operating temperature is not limited, and all are carried out at room temperature.
下述实施例中，中间体和最终产物的分离提纯是通过正相或反相色谱柱分离或者其它合适的方法。正相快速色谱柱是用乙酸乙酯和正己烷或甲醇和二氯甲烷等作为流动相。反相制备性高压液相色谱(HPLC)是用C18柱并用UV 214nm和254nm来检测，其流动相为A(水和0.1％甲酸)、B(乙腈)或者流动相A(水和0.1％碳酸氢铵)、B(乙腈)。In the following examples, the separation and purification of intermediates and final products are carried out by normal-phase or reversed-phase chromatographic column separation or other suitable methods. The normal phase flash chromatography column uses ethyl acetate and n-hexane or methanol and dichloromethane as mobile phases. Reversed-phase preparative high pressure liquid chromatography (HPLC) was performed on a C18 column with UV detection at 214 nm and 254 nm with mobile phases A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% carbonic acid) ammonium hydrogen), B (acetonitrile).
各实施例中：LCMS仪器：Pump Agilent 1260UV检测器：Agilent 1260 DAD Mass Spectrometer API 3000In each example: LCMS Instrument: Pump Agilent 1260 UV Detector: Agilent 1260 DAD Mass Spectrometer API 3000
层析柱：Waters sunfire C18,4.6×50mm,5umChromatography column: Waters sunfire C18, 4.6×50mm, 5um
流动相：A-H2O(0.1％HCOOH)；B-乙腈NMRMobile phase: A-H2O (0.1% HCOOH); B-acetonitrile NMR
仪器：Bruker Ascend 400M( 1H NMR:400MHz； 13C NMR:100MHz)。 Apparatus: Bruker Ascend 400M ( 1 H NMR: 400 MHz; 13 C NMR: 100 MHz).
实施例1：(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺A1的制 备Example 1: (R)-2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2 - Preparation of sulfinamide A1
步骤一：(S)-2-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯A1-1Step 1: (S)-2-((tert-butyldimethylsilyl)oxy)ethyl propionate A1-1
Figure PCTCN2021126331-appb-000223
Figure PCTCN2021126331-appb-000223
向(S)-2-羟基丙酸乙酯(30g，254mmol)的二氯甲烷(300mL)溶液中加入咪唑(2.75g，304.9mmol)并冷却至0℃。向该溶液中分批加入叔丁基二甲基甲硅烷基氯(46.0g，304.9mmol)，并在室温下搅拌16小时。通过TLC分析判断反应完成后，将反应混合物用水淬灭并用二氯甲烷(2×100mL)萃取。将合并的有机层用无水硫酸钠干燥。过滤并减压浓缩，得到(S)-2-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯A1-1(50g，产率84％)，为无色液体。To a solution of (S)-ethyl 2-hydroxypropionate (30 g, 254 mmol) in dichloromethane (300 mL) was added imidazole (2.75 g, 304.9 mmol) and cooled to 0 °C. To the solution was added tert-butyldimethylsilyl chloride (46.0 g, 304.9 mmol) in portions and stirred at room temperature for 16 hours. After the reaction was judged to be complete by TLC analysis, the reaction mixture was quenched with water and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave (S)-ethyl 2-((tert-butyldimethylsilyl)oxy)propanoate A1-1 (50 g, 84% yield) as a colorless liquid.
1H NMR(400MHz,CDCl 3)δ4.32-4.27(m,1H),4.21-4.12(m,2H),1.37(d,J＝6.8Hz,3H),1.27(d,J＝7.2Hz,3H),0.90(s,9H),0.08(s,6H)ppm. 1 H NMR (400 MHz, CDCl 3 ) δ 4.32-4.27 (m, 1H), 4.21-4.12 (m, 2H), 1.37 (d, J=6.8 Hz, 3H), 1.27 (d, J=7.2 Hz, 3H),0.90(s,9H),0.08(s,6H)ppm.
步骤二：(S)-2-((叔丁基二甲基硅烷基)氧基)丙醛A1-2Step 2: (S)-2-((tert-butyldimethylsilyl)oxy)propionaldehyde A1-2
Figure PCTCN2021126331-appb-000224
Figure PCTCN2021126331-appb-000224
在-78℃下向(S)-2-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯A1-1(25g，107.6mmol)的二乙醚(500mL)溶液中缓慢滴加加入氢化二异丁基铝(1M己烷溶液)(129mL，129.1mmol)，并在-78℃下搅拌1小时。通过TLC分析确认反应完成后，使反应混合物温热至-40℃，反应用罗谢尔盐(1L)的饱和水溶液淬灭，然后加入乙醚(500mL)。将所得混合物在室温下搅拌2小时。然后用乙醚(200mL)萃取。有机层用饱和盐水(250mL)洗涤，用Na 2SO 4干燥，过滤并减压浓缩，得到(S)-2-((叔丁基二甲基硅烷基)氧基)丙醛A1-2(19g，收率：94％)。 A solution of (S)-ethyl 2-((tert-butyldimethylsilyl)oxy)propionate A1-1 (25 g, 107.6 mmol) in diethyl ether (500 mL) was slowly added dropwise at -78°C Diisobutylaluminum hydride (1M in hexanes) (129 mL, 129.1 mmol) was added and stirred at -78°C for 1 hour. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was allowed to warm to -40°C, the reaction was quenched with a saturated aqueous solution of Rochelle's salt (1 L), and ether (500 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. It was then extracted with ether (200 mL). The organic layer was washed with saturated brine (250 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (S)-2-((tert-butyldimethylsilyl)oxy)propanal A1-2( 19 g, yield: 94%).
1H NMR(400MHz,CDCl 3)δ9.61(s,1H),4.12-4.06(m,1H),1.27(d,J＝6.8Hz,3H),0.91(s,9H),0.10(s,6H)ppm. 1 H NMR (400MHz, CDCl 3 ) δ 9.61(s, 1H), 4.12-4.06(m, 1H), 1.27(d, J=6.8Hz, 3H), 0.91(s, 9H), 0.10(s, 6H)ppm.
步骤三：4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-(叔丁基)A1-3Step 3: 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) A1-3
Figure PCTCN2021126331-appb-000225
Figure PCTCN2021126331-appb-000225
在0℃下向搅拌的1-(叔丁基)-4-乙基哌啶-1,4-二羧酸酯(30g，116.6mmol)的THF(250mL)溶液中加入二异丙基氨化锂(2M，在THF中)(93.3mL，186.6mmol)，并继续在0℃下搅拌30分钟。然后加入(S)-2-((叔丁基二甲基硅烷基)氧基)丙醛A1-2(22g，116.6mmol)的THF(50mL)溶 液。所得反应混合物在0℃下搅拌1小时，然后在室温下保持1小时。通过TLC分析判断反应完成后，将反应混合物用饱和NH 4Cl溶液淬灭并用乙酸乙酯(2×250mL)萃取。将合并的有机层用水(150mL)，盐水(150mL)洗涤，无水硫酸钠干燥。过滤并减压浓缩。粗产物通过硅胶(60-120目)柱色谱法纯化，使用25％乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱剂，得到4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-(叔丁基)A1-3(17g，收率：32％)，为浅红色油状物。 To a stirred solution of 1-(tert-butyl)-4-ethylpiperidine-1,4-dicarboxylate (30 g, 116.6 mmol) in THF (250 mL) at 0 °C was added diisopropylamination Lithium (2M in THF) (93.3 mL, 186.6 mmol) and continued stirring at 0 °C for 30 min. Then a solution of (S)-2-((tert-butyldimethylsilyl)oxy)propanal A1-2 (22 g, 116.6 mmol) in THF (50 mL) was added. The resulting reaction mixture was stirred at 0°C for 1 hour and then kept at room temperature for 1 hour. After the reaction was judged to be complete by TLC analysis, the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (150 mL), brine (150 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give 4-((2S)-2-((tert-butyldicarbonate) Methylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)A1-3 (17 g, yield: 32%) as light red oil .
1H NMR(400MHz,CDCl 3)δ4.29-4.09(m,2H),3.96-3.94(m,2H),3.86-3.80(m,1H),3.56-3.54(m,1H),2.86-2.76(m,2H),2.46(d,J＝5.2Hz,1H),2.16-2.13(m,1H),2.13-2.04(m,1H),1.77-1.60(m,2H),1.46(s,9H),1.29-1.24(m,3H),1.12(d,J＝4Hz,3H),0.89(s,9H),0.05(s,6H)ppm；LCMS:m/z 346[M-100] +. 1 H NMR (400MHz, CDCl 3 ) δ 4.29-4.09(m, 2H), 3.96-3.94(m, 2H), 3.86-3.80(m, 1H), 3.56-3.54(m, 1H), 2.86-2.76 (m, 2H), 2.46(d, J=5.2Hz, 1H), 2.16-2.13(m, 1H), 2.13-2.04(m, 1H), 1.77-1.60(m, 2H), 1.46(s, 9H) ), 1.29-1.24(m, 3H), 1.12(d, J=4Hz, 3H), 0.89(s, 9H), 0.05(s, 6H) ppm; LCMS: m/z 346[M-100] + .
步骤四：((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯A1-4Step 4: ((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1 -4
Figure PCTCN2021126331-appb-000226
Figure PCTCN2021126331-appb-000226
向搅拌的溶液中加入4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-(叔丁基)A1-3(5g，11.21mmol)在THF(50mL)中的溶液中分批加入LiBH 4(0.73g，33.65mmol)并在室温下搅拌16小时。反应完毕后，将反应混合物在0℃用饱和NaHCO 3溶液淬灭，并在室温搅拌15分钟。滤出沉淀的固体，水相用乙酸乙酯(2×50mL)萃取。合并的有机层用无水硫酸钠干燥。过滤并减压浓缩得到的粗产物通过硅胶(100-200目)柱色谱纯化，使用25％乙酸乙酯的石油醚溶液梯度混合物作为洗脱液，得到((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯A1-4(3g，收率：66％)。 To the stirred solution was added 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylic acid 1-(tert. To a solution of butyl) A1-3 (5 g, 11.21 mmol) in THF (50 mL) was added LiBH4 (0.73 g, 33.65 mmol) portionwise and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO 3 solution at 0 °C and stirred at room temperature for 15 minutes. The precipitated solid was filtered off and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (100-200 mesh) using a gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give ((2S)-2-((tert-butyl) (3 g, yield: 66%).
1H NMR(400MHz,CDCl 3)δ4.55(t,J＝4.8Hz,1H),4.43(d,J＝6.4Hz,1H),3.52-3.47(m,5H),3.31-3.28(m,1H),3.05-3.01(m,2H),1.58-1.49(m,2H),1.42-1.38(m,11H),1.11(d,J＝6.4Hz,3H),0.85(m,9H),0.04(s,6H)ppm；LC-MS:m/z 404.3[M+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ 4.55 (t, J=4.8 Hz, 1H), 4.43 (d, J=6.4 Hz, 1H), 3.52-3.47 (m, 5H), 3.31-3.28 (m, 1H), 3.05-3.01(m, 2H), 1.58-1.49(m, 2H), 1.42-1.38(m, 11H), 1.11(d, J=6.4Hz, 3H), 0.85(m, 9H), 0.04 (s,6H)ppm; LC-MS: m/z 404.3 [M+H] + .
步骤五：4-((2S)-1,2-二羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯A1-5Step 5: 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1-5
Figure PCTCN2021126331-appb-000227
Figure PCTCN2021126331-appb-000227
((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯A1-4(25g，61.93mmol)的THF(500mL)溶液中加入四丁基氟化胺(1M在THF中)(93mL，92.89mmol)，并将所得反应混合物在室温下搅拌2小时。通过TLC分析判断反应完成后，将反应混合物用饱和的NaHCO 3溶液淬灭并用乙酸乙酯(2×500mL)萃取。合并的有机相用无水硫酸钠干燥。过滤并减压浓 缩得到的粗产品用硅胶(60-120目)柱色谱法纯化粗产物，使用70-90％乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱液，得到4-((2S)-1,2-二羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯A1-5(12g，收率：67％)，为无色液体。 ((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1-4( To a solution of 25 g, 61.93 mmol) in THF (500 mL) was added tetrabutylamine fluoride (1 M in THF) (93 mL, 92.89 mmol) and the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was judged to be complete by TLC analysis, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (2 x 500 mL). The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 70-90% ethyl acetate in petroleum ether as eluent to give 4-(( 2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester A1-5 (12 g, yield: 67%), a colorless liquid.
1H NMR(400MHz,DMSO-d 6)δ4.72(t,J＝4.8Hz,1H),4.61(d,J＝5.2Hz,1H),4.50(d,J＝7.2Hz,1H),3.72-3.68(m,1H),3.53-3.44(m,4H),3.11-2.98(m,3H),1.68-1.53(m,2H),1.42-1.35(m,11H),1.10(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 290.1[M+H] +。 1 H NMR (400MHz, DMSO-d 6 ) δ 4.72 (t, J=4.8Hz, 1H), 4.61 (d, J=5.2Hz, 1H), 4.50 (d, J=7.2Hz, 1H), 3.72 -3.68(m, 1H), 3.53-3.44(m, 4H), 3.11-2.98(m, 3H), 1.68-1.53(m, 2H), 1.42-1.35(m, 11H), 1.10(d, J= 6.4 Hz, 3H) ppm; LC-MS: m/z 290.1 [M+H] + .
步骤六：(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯A1-6Step 6: (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate tert-butyl ester A1-6
Figure PCTCN2021126331-appb-000228
Figure PCTCN2021126331-appb-000228
在0℃下向搅拌的NaH(60％，在矿物油中)(1.45g，60.5mmol)的THF(30mL)悬浮液中加入4-((2S)-1,2-二羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯A1-5(5g,17.3mmol)和对甲苯磺酰氯(3.29g，17.3mmol)的THF(20mL)溶液中，并将得到的反应混合物在0℃反应3小时。反应完成后，将反应混合物在-20℃下用饱和NH 4Cl溶液(250mL)淬灭，并用乙酸乙酯(2×50mL)萃取。合并的有机层用无水硫酸钠干燥。过滤并减压浓缩得到的粗产品用硅胶(100-200目)柱色谱法纯化，使用40％乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱剂，得到(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯A1-6(2.1g，收率：44％)。 To a stirred suspension of NaH (60% in mineral oil) (1.45 g, 60.5 mmol) in THF (30 mL) at 0 °C was added 4-((2S)-1,2-dihydroxypropyl)- 4-(Hydroxymethyl)piperidine-1-carboxylate tert-butyl ester A1-5 (5 g, 17.3 mmol) and p-toluenesulfonyl chloride (3.29 g, 17.3 mmol) in THF (20 mL), and the resulting reaction The mixture was reacted at 0°C for 3 hours. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution (250 mL) at -20 °C and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 40% ethyl acetate in petroleum ether as eluent to give (3S)-4-hydroxy- 3-Methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate tert-butyl ester A1-6 (2.1 g, yield: 44%).
1H NMR(400MHz,CDCl 3)δ3.83-3.62(m,5H),3.43(d,J＝6.0,1H),3.07-2.97(m,2H),1.72-1.55(m,3H),1.51-1.42(m,11H),1.33(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 172.2[M-100] +。 1 H NMR (400 MHz, CDCl 3 ) δ 3.83-3.62 (m, 5H), 3.43 (d, J=6.0, 1H), 3.07-2.97 (m, 2H), 1.72-1.55 (m, 3H), 1.51 -1.42 (m, 11H), 1.33 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 172.2 [M-100] + .
步骤七：(S)-叔丁基-3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯A1-7Step 7: (S)-tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate A1-7
Figure PCTCN2021126331-appb-000229
Figure PCTCN2021126331-appb-000229
将(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯A1-6(2.1g，7.74mmol)加入到四氢呋喃(50mL)溶液中，并保持搅拌1小时。反应完毕后，减压蒸馏除去溶剂。所得残余产物通过硅胶(100-200目)柱色谱纯化，使用30％乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱剂，接着用0.1％甲酸和乙腈作为洗脱剂的快速色谱法纯化得到(S)-叔丁基-3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯A1-7(1.2g，收率：57％)。(3S)-4-Hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate tert-butyl ester A1-6 (2.1 g, 7.74 mmol) was added to tetrahydrofuran (50 mL) solution and kept stirring for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The resulting residual product was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 30% ethyl acetate in petroleum ether as eluent, followed by flash chromatography using 0.1% formic acid and acetonitrile as eluents Obtained (S)-tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate A1-7 (1.2 g, yield: 57 %).
1H NMR(400MHz,CDCl 3)δ4.20(d,J＝9.5Hz,1H),3.94-3.90(m,4H),3.16-3.10(m,1H),3.03-2.97(m,1H),1.81-1.75(m,1H),1.67-1.62(m,1H),1.61-1.57(m,1H),1.42-1.45(m,10H),1.32(d,J＝6.0Hz,3H)ppm；LC-MS:m/z 214.1[M-55] +。 1 H NMR (400MHz, CDCl 3 ) δ 4.20 (d, J=9.5Hz, 1H), 3.94-3.90 (m, 4H), 3.16-3.10 (m, 1H), 3.03-2.97 (m, 1H), 1.81-1.75(m,1H),1.67-1.62(m,1H),1.61-1.57(m,1H),1.42-1.45(m,10H),1.32(d,J=6.0Hz,3H)ppm; LC -MS: m/z 214.1[M-55] + .
步骤八：(3S,4S)-4-((R)-叔丁基亚磺酰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯A1-8Step 8: (3S,4S)-4-((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-Butyl ester A1-8
Figure PCTCN2021126331-appb-000230
Figure PCTCN2021126331-appb-000230
(S)-叔-丁基-3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯A1-7(1.2g，4.46mmol)在THF(15mL)中的搅拌溶液分别为加入(R)-2-甲基丙烷-2-亚磺酰胺(1.07g，8.91mmol)和钛酸四乙酯(4.07g，17.84mmol)。所得反应混合物在90℃下搅拌20小时。将反应混合物冷却至-4℃，加入MeOH(2mL)，然后分批加入LiBH 4(282mg，12.99mmol)并在相同温度下保持搅拌1小时。反应完毕后，将反应混合物在0℃下用饱和盐水溶液淬灭，并在室温下搅拌15分钟。过滤，溶液用乙酸乙酯(2×50mL)萃取。合并的有机层用无水硫酸钠干燥。过滤并减压浓缩得到的粗产品用0.1％甲酸和乙腈作为洗脱液的GRACE快速色谱法纯化粗产物，得到(3S,4S)-4-((R)-叔丁基亚磺酰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯A1-8(1.2g,收率：72％)。 (S)-tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate A1-7 (1.2 g, 4.46 mmol) in To a stirred solution in THF (15 mL) was added (R)-2-methylpropane-2-sulfinamide (1.07 g, 8.91 mmol) and tetraethyl titanate (4.07 g, 17.84 mmol), respectively. The resulting reaction mixture was stirred at 90°C for 20 hours. The reaction mixture was cooled to -4°C, MeOH (2 mL) was added, then LiBH4 (282 mg, 12.99 mmol) was added in portions and kept stirring at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated brine solution at 0°C and stirred at room temperature for 15 minutes. After filtration, the solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by GRACE flash chromatography with 0.1% formic acid and acetonitrile as eluent to give (3S,4S)-4-((R)-tert-butylsulfinyl)amino )-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester A1-8 (1.2 g, yield: 72%).
1H NMR(400MHz,CDCl 3)δ4.20-4.15(m,1H),3.90-3.84(m,2H),3.63-3.59(m,1H),3.49-3.43(m,1H),3.31-3.29(m,1H),2.95-2.81(m,2H),1.90-1.71(m,2H),1.49-1.40(m,11H),1.25(s,9H),1.19(d,J＝6.5Hz,3H)ppm；LC-MS:m/z 375.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ 4.20-4.15 (m, 1H), 3.90-3.84 (m, 2H), 3.63-3.59 (m, 1H), 3.49-3.43 (m, 1H), 3.31-3.29 (m,1H),2.95-2.81(m,2H),1.90-1.71(m,2H),1.49-1.40(m,11H),1.25(s,9H),1.19(d,J=6.5Hz,3H ) ppm; LC-MS: m/z 375.2 [M+H] + .
步骤九：(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺A1Step 9: (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)propane-2- Sulfenamide A1
Figure PCTCN2021126331-appb-000231
Figure PCTCN2021126331-appb-000231
向(3S,4S)-4-((R)-叔丁基亚磺酰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯A1-8(1.1g，2.936mmol)的二氯甲烷(10mL)溶液中滴加三氟乙酸(1.12mL，14.68mmol)并在室温下搅拌6小时。反应完毕后，将反应混合物减压浓缩得到的粗产品用0.1％甲酸和乙腈的色谱法纯化粗产物，得到(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺A1(850mg，收率：72％)。To (3S,4S)-4-((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl To a solution of ester A1-8 (1.1 g, 2.936 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.12 mL, 14.68 mmol) dropwise and stirred at room temperature for 6 hours. After the reaction was completed, the crude product obtained by concentrating the reaction mixture under reduced pressure was purified by chromatography with 0.1% formic acid and acetonitrile to obtain (R)-2-methyl-N-((3S,4S)-3-methyl -2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide A1 (850 mg, yield: 72%).
1H NMR(400MHz,DMSO-d 6)δ8.40(brs,D 2O Exchangeable,1H),8.30(brs,D 2O Exchangeable,1H),5.28(d,J＝12.0Hz,1H),4.13-4.09(m,1H),3.77(d,J＝9.0Hz,1H),3.50-3.45(m,2H),3.29-3.26(m,1H),3.19-3.15(m,1H),2.94-2.85(m,2H),1.87-1.80(m,2H),1.69-1.59(m,2H),1.17(s,9H),1.08(d,J＝6.0Hz,3H)ppm；LC-MS:m/z 275.2[M+H] +。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.40 (brs, D 2 O Exchangeable, 1H), 8.30 (brs, D 2 O Exchangeable, 1H), 5.28 (d, J=12.0 Hz, 1H), 4.13 -4.09(m, 1H), 3.77(d, J=9.0Hz, 1H), 3.50-3.45(m, 2H), 3.29-3.26(m, 1H), 3.19-3.15(m, 1H), 2.94-2.85 (m, 2H), 1.87-1.80 (m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J=6.0Hz, 3H) ppm; LC-MS: m/ z 275.2[M+H] + .
实施例2：中间体叔-丁基(5S)-2-((叔-丁氧基羰基)氨基)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-5,7- 二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45的制备Example 2: Intermediate tert-butyl(5S)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl<sulfinyl>)amino)-5, Preparation of 7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45
步骤一：甲基3-溴-6-((叔-丁氧基羰基)氨基)甲基吡啶酸酯A45-1Step 1: Methyl 3-bromo-6-((tert-butoxycarbonyl)amino)picolinate A45-1
Figure PCTCN2021126331-appb-000232
Figure PCTCN2021126331-appb-000232
向干燥的100mL烧瓶中依次加入甲基6-氨基-3-溴甲基吡啶酸酯(5.00g,21.6mmol)和二-叔-丁基二碳酸酯(9.68g,44.4mmol)和三乙胺(4.38g,43.3mmol)和4-二甲氨基吡啶(0.132g,1.08mmol)和叔丁醇(30mL)。在氮气条件下，将混合物加热至80℃，并搅拌反应16小时。反应完毕后，真空浓缩，得到的浓缩物加入100mL的水，并使用乙酸乙酯(3×100mL)萃取，饱和食盐水洗涤并混合有机层，经无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(30％至40％梯度的乙酸乙酯：石油醚)，得到淡黄色油状物甲基3-溴-6-((叔-丁氧基羰基)氨基)甲基吡啶酸酯A45-1(5.77g,收率：80.5％)。To a dry 100 mL flask were added methyl 6-amino-3-bromopicolinate (5.00 g, 21.6 mmol) followed by di-tert-butyl dicarbonate (9.68 g, 44.4 mmol) and triethylamine (4.38 g, 43.3 mmol) and 4-dimethylaminopyridine (0.132 g, 1.08 mmol) and tert-butanol (30 mL). Under nitrogen, the mixture was heated to 80°C and the reaction was stirred for 16 hours. After the reaction was completed, concentrated in vacuo, the obtained concentrate was added with 100 mL of water, extracted with ethyl acetate (3×100 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain The residue was purified by silica gel chromatography (30% to 40% gradient of ethyl acetate:petroleum ether) to give methyl 3-bromo-6-((tert-butoxycarbonyl)amino)methyl as a pale yellow oil Pyridine ester A45-1 (5.77 g, yield: 80.5%).
LC-MS:m/z 331.1[M+H] +。 LC-MS: m/z 331.1 [M+H] + .
步骤二：叔-丁基(5-溴-6-(羟基甲基)吡啶-2-基)氨基甲酸酯A45-2Step 2: tert-butyl (5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate A45-2
Figure PCTCN2021126331-appb-000233
Figure PCTCN2021126331-appb-000233
向干燥的100mL烧瓶中依次加入甲基3-溴-6-((叔-丁氧基羰基)氨基)甲基吡啶酸酯A45-1(5.77g,17.4mmol)和20mL甲醇。在0℃氮气条件下，分批加入硼氢化钠(3.30g,87.1mmol)。保持0℃反应5分钟，将混合物缓慢升至室温搅拌反应3小时。反应完毕后，将混合物缓慢倒入饱和氯化铵的水溶液中，然后使用乙酸乙酯(3×100mL)萃取，混合有机层并使用饱和食盐水洗涤，经无水硫酸钠干燥，过滤并浓缩得到叔-丁基(5-溴-6-(羟基甲基)吡啶-2-基)氨基甲酸酯A45-2(4.31g，产率81.59％)。To a dry 100 mL flask were added methyl 3-bromo-6-((tert-butoxycarbonyl)amino)picolinate A45-1 (5.77 g, 17.4 mmol) followed by 20 mL of methanol. Sodium borohydride (3.30 g, 87.1 mmol) was added portionwise under nitrogen at 0°C. The reaction was kept at 0°C for 5 minutes, and the mixture was slowly warmed to room temperature and stirred for 3 hours. After the reaction was completed, the mixture was slowly poured into a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (3×100 mL), the organic layers were mixed and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain tert-Butyl(5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate A45-2 (4.31 g, 81.59% yield).
LC-MS:m/z 303.1[M+H] +。 LC-MS: m/z 303.1 [M+H] + .
步骤三：(3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基甲磺酸酯A45-3Step 3: (3-bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate A45-3
Figure PCTCN2021126331-appb-000234
Figure PCTCN2021126331-appb-000234
0℃下，在干燥的250mL烧瓶中依次加入叔-丁基(5-溴-6-(羟基甲基)吡啶-2-基)氨基甲酸酯A45-2(4.31g,14.2mmol)、甲磺酸酐(3.71g,21.3mmol)和30mL二氯甲烷溶剂并搅拌，缓慢滴加入三乙胺(4.32g,42.7mmol)。该混合物在氮气的保护下自然升至室温反应2小时。反应结束后，向该混合体系中加入100mL的水，用二氯甲烷(3x100mL)萃取。合并的有机相用Na 2SO 4干燥，过滤，滤 液减压浓缩，将得到的残留物通过硅胶色谱法纯化(30％至40％梯度的乙酸乙酯：石油醚)，得到无色油状物(3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基甲磺酸酯A45-3(4.53g,收率：83.7％)。 At 0 °C, in a dry 250 mL flask were sequentially added tert-butyl (5-bromo-6-(hydroxymethyl) pyridin-2-yl) carbamate A45-2 (4.31 g, 14.2 mmol), methyl methacrylate Sulfonic anhydride (3.71 g, 21.3 mmol) and 30 mL of dichloromethane solvent were stirred, and triethylamine (4.32 g, 42.7 mmol) was slowly added dropwise. The mixture was naturally warmed to room temperature under nitrogen protection for 2 hours. After the reaction was completed, 100 mL of water was added to the mixed system, followed by extraction with dichloromethane (3×100 mL). The combined organic phases were dried over Na2SO4 , filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (30% to 40% gradient of ethyl acetate:petroleum ether) to give a colorless oil ( 3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate A45-3 (4.53 g, yield: 83.7%).
LC-MS:m/z 381.2[M+H] +. LC-MS: m/z 381.2[M+H] + .
步骤四：叔-丁基4-((3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基)-4-氰基哌啶-1-羧酸酯A45-4Step 4: tert-butyl 4-((3-bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-cyanopiperidine-1-carboxylate A45-4
Figure PCTCN2021126331-appb-000235
Figure PCTCN2021126331-appb-000235
向干燥的100mL三口烧瓶中依次加入叔-丁基4-氰基哌啶-1-羧酸酯A45-3(2.75g,13.1mmol)和30mL的四氢呋喃溶剂。将该混合物用干冰乙醇浴降温至-78℃，然后在氮气条件下，将二异丙基氨基锂(1.53g,14.3mmol)缓慢滴加入该体系，维持-78℃反应1h。用20mL四氢呋喃溶解(3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基甲磺酸酯(4.53g,11.9mmol)并缓慢滴加入前一混合体系中，保持温度不变反应0.5h，后自然升至室温继续反应1h。反应完毕后，将混合物倒入100mL的水中，使用乙酸乙酯(3×100mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(50％至60％梯度的乙酸乙酯：石油醚)得到白色固体叔-丁基4-((3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基)-4-氰基哌啶-1-羧酸酯A45-4(2.01g,收率：17.0％)。Into a dry 100 mL three-necked flask were sequentially added tert-butyl 4-cyanopiperidine-1-carboxylate A45-3 (2.75 g, 13.1 mmol) and 30 mL of tetrahydrofuran solvent. The mixture was cooled to -78°C with a dry ice ethanol bath, then lithium diisopropylamide (1.53 g, 14.3 mmol) was slowly added dropwise to the system under nitrogen, and the reaction was maintained at -78°C for 1 h. (3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methanesulfonate (4.53g, 11.9mmol) was dissolved in 20mL of tetrahydrofuran and slowly added dropwise to the previous mixed system , keep the temperature unchanged for 0.5h, and then naturally rise to room temperature to continue the reaction for 1h. After the reaction was completed, the mixture was poured into 100 mL of water, extracted with ethyl acetate (3×100 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was chromatographed on silica gel Purification (50% to 60% gradient of ethyl acetate:petroleum ether) afforded tert-butyl 4-((3-bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl as a white solid )methyl)-4-cyanopiperidine-1-carboxylate A45-4 (2.01 g, yield: 17.0%).
LC-MS:m/z 495.1[M+H] +. LC-MS: m/z 495.1[M+H] + .
步骤五：叔-丁基2-((叔-丁氧基羰基)氨基)-5-羰基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-5Step 5: tert-butyl 2-((tert-butoxycarbonyl)amino)-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine ]-1'-carboxylate A45-5
Figure PCTCN2021126331-appb-000236
Figure PCTCN2021126331-appb-000236
向干燥的15mL微波管中依次加入叔-丁基4-((3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基)-4-氰基哌啶-1-羧酸酯A45-4(1.00g,2.02mmol)，二(DI-叔-丁基(4-二甲氨基苯基)膦)二氯钯(143mg,2.02mmol)，N,N-二异丙基乙基胺(1.31g,10.1mmol)，N,N-二甲基乙酰胺(10mL)和水(1mL)。然后在氮气条件下，将混合物加热至130℃搅拌16小时。反应完毕后，将混合物冷却至室温再将混合物真空浓缩，并饱和碳酸氢钠溶液淬灭反应，使用乙酸乙酯(3×80mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(90％至100％梯度的乙酸乙酯：石油醚)得到白色固体叔-丁基2-((叔-丁氧基羰基)氨基)-5-羰基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-5(200mg,收率：23.7％)。Into a dry 15mL microwave tube was sequentially added tert-butyl 4-((3-bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-cyanopiperidine -1-Carboxylate A45-4 (1.00 g, 2.02 mmol), bis(DI-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (143 mg, 2.02 mmol), N,N- Diisopropylethylamine (1.31 g, 10.1 mmol), N,N-dimethylacetamide (10 mL) and water (1 mL). The mixture was then heated to 130°C under nitrogen and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and then concentrated in vacuo, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×80 mL), washed with saturated brine, mixed with organic layers, and dried over anhydrous sodium sulfate , filtered and concentrated, and the resulting residue was purified by silica gel chromatography (90% to 100% gradient of ethyl acetate:petroleum ether) to give tert-butyl 2-((tert-butoxycarbonyl)amino) as a white solid -5-Carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-5 (200 mg, yield: 23.7%) .
LC-MS:m/z 418.1[M+H] +. LC-MS: m/z 418.1[M+H] + .
步骤六：叔-丁基(S,Z)-2-((叔-丁氧基羰基)氨基)-5-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-5,7-二氢 螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-6Step 6: tert-butyl(S,Z)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl<sulfinyl>)imino)-5, 7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-6
Figure PCTCN2021126331-appb-000237
Figure PCTCN2021126331-appb-000237
向干燥的15mL微波管中依次加入叔-丁基2-((叔-丁氧基羰基)氨基)-5-羰基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-5(200mg,0.48mmol)，(R)-2-甲基丙烷-2-亚磺酰胺(116mg,0.96mmol)和钛酸四乙酯(1mL)。然后在氮气条件下，将混合物加热至100℃搅拌7天。反应完毕后，将混合物冷却至室温再将混合物倒入水中淬灭反应，垫硅藻土抽滤，滤饼用乙酸乙酯洗涤，收集滤液，加入80mL水，并使用乙酸乙酯(3×50mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(20％至30％梯度的甲醇：乙酸乙酯)得到白色固体叔-丁基(S,Z)-2-((叔-丁氧基羰基)氨基)-5-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-6(58mg,收率：23.3％)。Into a dry 15 mL microwave tube was sequentially added tert-butyl 2-((tert-butoxycarbonyl)amino)-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6 ,4'-piperidine]-1'-carboxylate A45-5 (200mg, 0.48mmol), (R)-2-methylpropane-2-sulfinamide (116mg, 0.96mmol) and tetraethyl titanate ester (1 mL). The mixture was then heated to 100°C under nitrogen and stirred for 7 days. After the reaction was completed, the mixture was cooled to room temperature and then poured into water to quench the reaction, filtered through a pad of celite with suction, the filter cake was washed with ethyl acetate, the filtrate was collected, 80 mL of water was added, and ethyl acetate (3×50 mL) ) extraction, washed with saturated brine and combined the organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, the resulting residue was purified by silica gel chromatography (20% to 30% gradient of methanol: ethyl acetate) to give a white solid tertiary -Butyl(S,Z)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl<sulfinyl>)imino)-5,7-dihydro Spiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-6 (58 mg, yield: 23.3%).
LC-MS:m/z 521.1[M+H] +. LC-MS: m/z 521.1[M+H] + .
步骤七：叔-丁基(5S)-2-((叔-丁氧基羰基)氨基)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-7Step 7: tert-butyl(5S)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl<sulfinyl>)amino)-5,7-di Hydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-7
Figure PCTCN2021126331-appb-000238
Figure PCTCN2021126331-appb-000238
向干燥的50mL三口烧瓶中依次加入叔-丁基(S,Z)-2-((叔-丁氧基羰基)氨基)-5-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-6(58.0mg,0.11mmol)和四氢呋喃(10mL)。然后在氮气条件下，将混合物用干冰乙醇浴降温至-78℃，滴加入二异丁基氢化铝(23.5mg,0.17mmol)，保持此温度搅拌反应1h。反应完毕后，将混合物倒入80mL饱和氯化铵水溶液中淬灭，并使用乙酸乙酯(3×50mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(30％至40％梯度的甲醇：乙酸乙酯)得到白色固体叔-丁基(5S)-2-((叔-丁氧基羰基)氨基)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A45-7(40mg,收率：69.6％)。To a dry 50mL three-necked flask, successively added tert-butyl(S,Z)-2-((tert-butoxycarbonyl)amino)-5-((tert-butylsulfinyl<sulfinyl>) imino)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A45-6 (58.0 mg, 0.11 mmol) and tetrahydrofuran ( 10mL). Then, under nitrogen, the mixture was cooled to -78°C with a dry ice ethanol bath, and diisobutylaluminum hydride (23.5 mg, 0.17 mmol) was added dropwise, and the reaction was stirred at this temperature for 1 h. After the reaction was completed, the mixture was poured into 80 mL of saturated aqueous ammonium chloride solution to quench, and extracted with ethyl acetate (3×50 mL), washed with saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (30% to 40% gradient of methanol:ethyl acetate) to give tert-butyl(5S)-2-((tert-butoxycarbonyl)amino)-5- as a white solid ((tert-Butylsulfinyl<sulfinyl>)amino)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylic acid Ester A45-7 (40 mg, yield: 69.6%).
LC-MS:m/z 523.1[M+H] +. LC-MS: m/z 523.1[M+H] + .
步骤八：N-((S)-2-氨基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺A45Step 8: N-((S)-2-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidin]-5-yl)-2-methyl Propane-2-sulfinamide A45
Figure PCTCN2021126331-appb-000239
Figure PCTCN2021126331-appb-000239
按照实施例1步骤七的方法脱去Boc保护基得到N-((S)-2-氨基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺A45。Remove the Boc protecting group according to the method of step 7 of Example 1 to obtain N-((S)-2-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine ]-5-yl)-2-methylpropane-2-sulfinamide A45.
LC-MS:m/z 323.2[M+H] +. LC-MS: m/z 323.2[M+H] + .
按照实施例2的方法,以1-溴-4-(溴甲基)苯为原料可以得到中间体叔丁基6-溴-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A10-1、叔-丁基(S)-6-溴-1-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸酯 A10-2和(R)-N-((S)-5-溴-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺A10。 According to the method of Example 2, the intermediate tert-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-carboxylate tert-butyl ester A10-1, tert-butyl(S)-6-bromo-1-(((R)-tert-butylsulfinyl<sulfinyl >) amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate A10-2 and (R)-N-((S)-5-bromo-1 ,3-Dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide A10.
Figure PCTCN2021126331-appb-000240
Figure PCTCN2021126331-appb-000240
实施例3：中间体叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯的制备A53Example 3: Intermediate tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5,7-dihydrospiro[cyclopentadiene Preparation of [b]pyridine-6,4'-piperidine]-1'-carboxylate A53
步骤一：(3-溴-6-氯吡啶-2-基)甲醇A53-1Step 1: (3-bromo-6-chloropyridin-2-yl) methanol A53-1
Figure PCTCN2021126331-appb-000241
Figure PCTCN2021126331-appb-000241
向干燥的100mL烧瓶中依次加入甲基3-溴-6-氯甲基吡啶酸酯(5.00g,20.0mmol)和20mL甲醇。在0℃氮气条件下，分批加入硼氢化钠(3.78g,99.8mmol)。保持0℃反应5分钟，将混合物缓慢升至室温搅拌反应3小时。反应完毕后，将混合物缓慢倒入饱和氯化铵的水溶液中，然后使用乙酸乙酯(3×100mL)萃取，混合有机层并使用饱和食盐水洗涤，经无水硫酸钠干燥，过滤并浓缩 得到(3-溴-6-氯吡啶-2-基)甲醇A53-1(4.46g，产率90.4％)。To a dry 100 mL flask was added methyl 3-bromo-6-chloropicoline (5.00 g, 20.0 mmol) followed by 20 mL of methanol. Sodium borohydride (3.78 g, 99.8 mmol) was added portionwise under nitrogen at 0°C. The reaction was kept at 0°C for 5 minutes, and the mixture was slowly warmed to room temperature and stirred for 3 hours. After the reaction was completed, the mixture was slowly poured into a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (3×100 mL), the organic layers were mixed and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain (3-Bromo-6-chloropyridin-2-yl)methanol A53-1 (4.46 g, 90.4% yield).
LC-MS:m/z 221.9[M+H] +. LC-MS: m/z 221.9 [M+H] + .
步骤二：(3-溴-6-氯吡啶-2-基)甲基甲磺酸酯A53-2Step 2: (3-bromo-6-chloropyridin-2-yl) methylmethanesulfonate A53-2
Figure PCTCN2021126331-appb-000242
Figure PCTCN2021126331-appb-000242
0℃下，在干燥的250mL烧瓶中依次加入(3-溴-6-氯吡啶-2-基)甲醇A53-1(4.46g,20.1mmol)、甲磺酸酐(3.88g,22.3mmol)和30mL二氯甲烷溶剂并搅拌，缓慢滴加入三乙胺(4.06g,40.1mmol)。该混合物在氮气的保护下自然升至室温反应2小时。反应结束后，向该混合体系中加入100mL的水，用二氯甲烷(3x100mL)萃取。合并的有机相用Na 2SO 4干燥，过滤，滤液减压浓缩，将得到的残留物通过硅胶色谱法纯化(30％至40％梯度的乙酸乙酯：石油醚)，得到无色油状物(3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基甲磺酸酯A53-2(4.85g,收率：80.5％)。 At 0 °C, in a dry 250 mL flask were sequentially added (3-bromo-6-chloropyridin-2-yl) methanol A53-1 (4.46 g, 20.1 mmol), methanesulfonic anhydride (3.88 g, 22.3 mmol) and 30 mL With dichloromethane solvent and stirring, triethylamine (4.06 g, 40.1 mmol) was slowly added dropwise. The mixture was naturally warmed to room temperature under nitrogen protection for 2 hours. After the reaction was completed, 100 mL of water was added to the mixed system, followed by extraction with dichloromethane (3×100 mL). The combined organic phases were dried over Na2SO4 , filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (30% to 40% gradient of ethyl acetate:petroleum ether) to give a colorless oil ( 3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate A53-2 (4.85 g, yield: 80.5%).
LC-MS:m/z 299.9[M+H] +. LC-MS: m/z 299.9 [M+H] + .
步骤三：1-(叔-丁基)4-乙基4-((3-溴-6-氯吡啶-2-基)甲基)哌啶-1,4-二羧酸酯A53-3Step 3: 1-(tert-butyl)4-ethyl 4-((3-bromo-6-chloropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate A53-3
Figure PCTCN2021126331-appb-000243
Figure PCTCN2021126331-appb-000243
向干燥的100mL三口烧瓶中依次加入1-(叔-丁基)4-乙基哌啶-1,4-二羧酸酯A53-2(5.40g,21.0mmol)和30mL的四氢呋喃溶剂。将该混合物用干冰乙醇浴降温至-78℃，然后在氮气条件下，将二异丙基氨基锂(2.77g,25.8mmol)缓慢滴加入该体系，维持-78℃反应1h。用20mL四氢呋喃溶解(3-溴-6-((叔-丁氧基羰基)氨基)吡啶-2-基)甲基甲磺酸酯(4.85g,16.1mmol)并缓慢滴加入前一混合体系中，保持温度不变反应0.5h，后自然升至室温继续反应1h。反应完毕后，将混合物倒入100mL的水中，使用乙酸乙酯(3×100mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(50％至60％梯度的乙酸乙酯：石油醚)得到白色固体1-(叔-丁基)4-乙基4-((3-溴-6-氯吡啶-2-基)甲基)哌啶-1,4-二羧酸酯A53-3(5.85g,收率：78.5％)。Into a dry 100 mL three-necked flask were sequentially added 1-(tert-butyl) 4-ethylpiperidine-1,4-dicarboxylate A53-2 (5.40 g, 21.0 mmol) and 30 mL of tetrahydrofuran solvent. The mixture was cooled to -78°C with a dry ice ethanol bath, then lithium diisopropylamide (2.77 g, 25.8 mmol) was slowly added dropwise to the system under nitrogen, and the reaction was maintained at -78°C for 1 h. (3-Bromo-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methylmethanesulfonate (4.85g, 16.1mmol) was dissolved in 20mL of tetrahydrofuran and slowly added dropwise to the previous mixed system , keep the temperature unchanged for 0.5h, and then naturally rise to room temperature to continue the reaction for 1h. After the reaction was completed, the mixture was poured into 100 mL of water, extracted with ethyl acetate (3×100 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was chromatographed on silica gel Purification (50% to 60% gradient of ethyl acetate:petroleum ether) afforded 1-(tert-butyl)4-ethyl 4-((3-bromo-6-chloropyridin-2-yl)methane as a white solid yl)piperidine-1,4-dicarboxylate A53-3 (5.85 g, yield: 78.5%).
LC-MS:m/z 461.1[M+H] +. LC-MS: m/z 461.1[M+H] + .
步骤四：叔-丁基2-氯-5-羰基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-4Step 4: tert-butyl 2-chloro-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53- 4
Figure PCTCN2021126331-appb-000244
Figure PCTCN2021126331-appb-000244
向干燥的100mL三口烧瓶中依次加入1-(叔-丁基)4-乙基4-((3-溴-6-氯吡啶-2-基)甲基)哌啶-1,4-二羧酸酯A53-3(1.00g,2.17mmol)和10mL的四氢呋喃，用干冰乙醇浴降温至-78℃，然后在氮气条件下，将正丁基锂(0.21g,3.25mmol)缓慢滴加入该混合体系中。保持-78℃搅拌1.5小时。反应完毕后，将混合物倒入饱和氯化铵水溶液淬灭反应，使用乙酸乙酯(3×80mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(90％至100％梯度的乙酸乙酯：石油醚)得到白色固体叔-丁基2-氯-5-羰基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-4(188mg,收率：25.7％)。Into a dry 100mL three-necked flask was sequentially added 1-(tert-butyl)4-ethyl4-((3-bromo-6-chloropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate Ester A53-3 (1.00 g, 2.17 mmol) and 10 mL of tetrahydrofuran were cooled to -78 °C with a dry ice ethanol bath, and then n-butyllithium (0.21 g, 3.25 mmol) was slowly added dropwise to the mixture under nitrogen. in the system. Keep stirring at -78°C for 1.5 hours. After the reaction was completed, the mixture was poured into a saturated aqueous ammonium chloride solution to quench the reaction, extracted with ethyl acetate (3×80 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (90% to 100% gradient of ethyl acetate:petroleum ether) to give tert-butyl 2-chloro-5-carbonyl-5,7-dihydrospiro[cyclopentadienyl as a white solid. [b] Pyridine-6,4'-piperidine]-1'-carboxylate A53-4 (188 mg, yield: 25.7%).
LC-MS:m/z 337.1[M+H] +. LC-MS: m/z 337.1[M+H] + .
步骤五：叔-丁基(S,Z)-5-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-5Step 5: tert-butyl(S,Z)-5-((tert-butylsulfinyl<sulfinyl>)imino)-2-chloro-5,7-dihydrospiro[cyclopentadiene [b]pyridine-6,4'-piperidine]-1'-carboxylate A53-5
Figure PCTCN2021126331-appb-000245
Figure PCTCN2021126331-appb-000245
向干燥的15mL微波管中依次加入叔-丁基2-氯-5-羰基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-4(188mg,0.56mmol)，(R)-2-甲基丙烷-2-亚磺酰胺(136mg,1.12mmol)和钛酸四乙酯(1mL)。然后在氮气条件下，将混合物加热至100℃搅拌3小时。反应完毕后，将混合物冷却至室温再将混合物倒入水中淬灭反应，垫硅藻土抽滤，滤饼用乙酸乙酯洗涤，收集滤液，加入80mL水，并使用乙酸乙酯(3×50mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(20至30％梯度的甲醇：乙酸乙酯)得到白色固体叔-丁基(S,Z)-5-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-5(100mg,收率：40.6％)。Into a dry 15 mL microwave tube was sequentially added tert-butyl 2-chloro-5-carbonyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1' - Carboxylate A53-4 (188 mg, 0.56 mmol), (R)-2-methylpropane-2-sulfinamide (136 mg, 1.12 mmol) and tetraethyl titanate (1 mL). The mixture was then heated to 100°C under nitrogen and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and then poured into water to quench the reaction, filtered through a pad of celite with suction, the filter cake was washed with ethyl acetate, the filtrate was collected, 80 mL of water was added, and ethyl acetate (3×50 mL) ) extraction, washed with saturated brine and combined the organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, the resulting residue was purified by silica gel chromatography (20 to 30% gradient of methanol:ethyl acetate) to give a white solid tert- Butyl(S,Z)-5-((tert-butylsulfinyl<sulfinyl>)imino)-2-chloro-5,7-dihydrospiro[cyclopentadieno[b]pyridine -6,4'-Piperidine]-1'-carboxylate A53-5 (100 mg, yield: 40.6%).
LC-MS:m/z 440.1[M+H] +. LC-MS: m/z 440.1[M+H] + .
步骤六：叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6Step 6: tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5,7-dihydrospiro[cyclopentadieno[b ]pyridine-6,4'-piperidine]-1'-carboxylate A53-6
Figure PCTCN2021126331-appb-000246
Figure PCTCN2021126331-appb-000246
向干燥的50mL三口烧瓶中依次加入叔-丁基(S,Z)-5-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-5(100mg,0.23mmol)和四氢呋喃(10mL)。然后在氮气条件下，将混合物用干冰乙醇浴降温至-78℃，滴加入二异丁基氢化铝(49.1mg,0.35mmol)，保持此温度搅拌反应1h。反应完毕后，将混合物倒入80mL饱和氯化铵水溶液中淬灭，并使用乙酸乙酯(3×50mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(30％至40％梯度的甲醇：乙酸乙酯)得到白色固体叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6(53mg,收率：53.0％)。Into a dry 50mL three-necked flask, successively added tert-butyl(S,Z)-5-((tert-butylsulfinyl<sulfinyl>)imino)-2-chloro-5,7-dihydro Spiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-5 (100 mg, 0.23 mmol) and tetrahydrofuran (10 mL). Then, under nitrogen, the mixture was cooled to -78°C with a dry ice ethanol bath, and diisobutylaluminum hydride (49.1 mg, 0.35 mmol) was added dropwise, and the reaction was stirred at this temperature for 1 h. After the reaction was completed, the mixture was poured into 80 mL of saturated aqueous ammonium chloride solution for quenching, and extracted with ethyl acetate (3×50 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (30% to 40% gradient of methanol:ethyl acetate) to give tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>) as a white solid ) amino)-2-chloro-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (53 mg, yield: 53.0%).
LC-MS:m/z 442.1[M+H] +. LC-MS: m/z 442.1[M+H] + .
步骤七：叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(3-氟吖丁啶-1-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-7Step 7: tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-(3-fluoroazetidin-1-yl)-5,7- Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-7
Figure PCTCN2021126331-appb-000247
Figure PCTCN2021126331-appb-000247
在氮气保护下，向干燥的50mL单口烧瓶中依次加入叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6(50mg,0.114mmol)、3-氟吖丁啶盐酸(19.0mg,0.17mmol)、DIEA(44.0mg,0.341mmol)和乙腈(2mL)，然后在90℃下搅拌反应2小时。反应完毕后，将获得的残留物倒入水(20mL)，于室温下搅拌5分钟。然后用乙酸乙酯(3x50mL)萃取，将合并的有机相用MgSO 4干燥，过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(20％至30％梯度的甲醇/乙酸乙酯)，得到白色固体叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(3-氟吖丁啶-1-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-7(47.6mg,收率：87.3％)。 Under nitrogen protection, add tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5,7- Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (50 mg, 0.114 mmol), 3-fluoroazetidine hydrochloride (19.0 mg, 0.17 mmol), DIEA (44.0 mg, 0.341 mmol) and acetonitrile (2 mL), then the reaction was stirred at 90°C for 2 hours. After completion of the reaction, the obtained residue was poured into water (20 mL) and stirred at room temperature for 5 minutes. It was then extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (20% to 30% gradient methanol/ethyl acetate), tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-(3-fluoroazetidin-1-yl)-5,7- was obtained as a white solid Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-7 (47.6 mg, yield: 87.3%).
LCMS:m/z 481.1[M+H] +. LCMS: m/z 481.1[M+H] + .
步骤八：N-((S)-2-(3-氟吖丁啶-1-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺A53Step 8: N-((S)-2-(3-fluoroazetidin-1-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine ]-5-yl)-2-methylpropane-2-sulfinamide A53
Figure PCTCN2021126331-appb-000248
Figure PCTCN2021126331-appb-000248
按照实施例1步骤七的方法脱去Boc保护基得到N-((S)-2-(3-氟吖丁啶-1-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺A53。Remove the Boc protecting group according to the method of Step 7 of Example 1 to obtain N-((S)-2-(3-fluoroazetidin-1-yl)-5,7-dihydrospiro[cyclopentadieno[ b] Pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide A53.
LCMS:m/z 381.2[M+H] +. LCMS: m/z 381.2[M+H] + .
按照实施例3的合成路线和方法，用相应的原料和试剂制备得到如下螺环胺类中间体：According to the synthetic route and method of Example 3, the following spirocyclic amine intermediates were prepared with corresponding raw materials and reagents:
Figure PCTCN2021126331-appb-000249
Figure PCTCN2021126331-appb-000249
实施例4：中间体叔-丁基(6S)-6-((叔-丁基亚硫酰基<亚磺酰>)氨基)-6,8-二氢螺[环戊二烯并[e][1,2,4]三唑并[4,3-a]吡啶-7,4'-哌啶]-1'-羧酸酯A49的制备Example 4: Intermediate tert-butyl(6S)-6-((tert-butylsulfinyl<sulfinyl>)amino)-6,8-dihydrospiro[cyclopentadieno[e] Preparation of [1,2,4]Triazolo[4,3-a]pyridine-7,4'-piperidine]-1'-carboxylate A49
步骤一：叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-肼基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A49-1Step 1: tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-hydrazino-5,7-dihydrospiro[cyclopentadieno[ b]pyridine-6,4'-piperidine]-1'-carboxylate A49-1
Figure PCTCN2021126331-appb-000250
Figure PCTCN2021126331-appb-000250
在氮气保护下，向干燥的50mL单口烧瓶中依次加入叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6(50mg,0.114mmol)、水合肼(18.3mg,0.342mmol)和乙腈(2mL)，然后在90℃下搅拌反应48小时。反应完毕后，将混合物减压浓缩得到粗品叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-肼基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A49-1(20mg)。Under nitrogen protection, tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5,7- Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (50 mg, 0.114 mmol), hydrazine hydrate (18.3 mg, 0.342 mmol) and acetonitrile (2 mL), then the reaction was stirred at 90°C for 48 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-hydrazino-5,7-dihydro Spiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A49-1 (20 mg).
LCMS:m/z 438.1[M+H] +. LCMS: m/z 438.1[M+H] + .
步骤二：叔-丁基(6S)-6-((叔-丁基亚硫酰基<亚磺酰>)氨基)-6,8-二氢螺[环戊二烯并[e][1,2,4]三唑并[4,3-a]吡啶-7,4'-哌啶]-1'-羧酸酯A49-2Step 2: tert-butyl(6S)-6-((tert-butylsulfinyl<sulfinyl>)amino)-6,8-dihydrospiro[cyclopentadieno[e][1, 2,4]Triazolo[4,3-a]pyridine-7,4'-piperidine]-1'-carboxylate A49-2
Figure PCTCN2021126331-appb-000251
Figure PCTCN2021126331-appb-000251
在氮气保护下，向干燥的50mL单口烧瓶中依次加入粗品叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-肼基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A49-1(20mg)和原甲酸三甲酯(5mL)，然后在80℃下搅拌反应2小时。反应完毕后，将混合物倒入水中淬灭，用乙酸乙酯(3x50mL)萃取，将合并的有机相用MgSO 4干燥，过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(30％至40％梯度的甲醇/乙酸乙酯)，得到白色固体叔-丁基(6S)-6-((叔-丁基亚硫酰基<亚磺酰>)氨基)-6,8-二氢螺[环戊二烯并[e][1,2,4]三唑并[4,3-a]吡啶-7,4'-哌啶]-1'-羧酸酯A49-2(13mg，25.6％) Under nitrogen protection, the crude tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-hydrazino-5 was sequentially added to a dry 50mL single-necked flask, 7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A49-1 (20 mg) and trimethyl orthoformate (5 mL), then at 80 The reaction was stirred at °C for 2 hours. After the reaction was complete, the mixture was quenched by pouring into water, extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (30% to 40% gradient methanol/ethyl acetate) to give tert-butyl(6S)-6-((tert-butylsulfinyl<sulfinyl>)amino)-6,8-dihydrospiro[ Cyclopentadieno[e][1,2,4]triazolo[4,3-a]pyridine-7,4'-piperidine]-1'-carboxylate A49-2 (13 mg, 25.6% )
LCMS:m/z 448.1[M+H] +. LCMS: m/z 448.1[M+H] + .
步骤三：N-((S)-6,8-二氢螺[环戊二烯并[e][1,2,4]三唑并[4,3-a]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A49Step 3: N-((S)-6,8-dihydrospiro[cyclopentadieno[e][1,2,4]triazolo[4,3-a]pyridine-7,4'- Piperidin]-6-yl)-2-methylpropane-2-sulfinamide A49
Figure PCTCN2021126331-appb-000252
Figure PCTCN2021126331-appb-000252
按照实施例1步骤七的方法脱去Boc保护基得到N-((S)-6,8-二氢螺[环戊二烯并[e][1,2,4]三唑并[4,3-a]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A49。Remove the Boc protecting group according to the method of Step 7 of Example 1 to obtain N-((S)-6,8-dihydrospiro[cyclopentadieno[e][1,2,4]triazolo[4, 3-a]Pyridin-7,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A49.
LCMS:m/z 348.2[M+H] +. LCMS: m/z 348.2[M+H] + .
实施例5：中间体叔-丁基(4S)-4-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯的制备A48Example 5: Intermediate tert-butyl(4S)-4-((tert-butylsulfinyl<sulfinyl>)amino)-2-methyl-4,6-dihydrospiro[cyclopentadi] Preparation of Eno[d]thiazole-5,4'-piperidine]-1'-carboxylate A48
步骤一：叔-丁基2-甲基-4-羰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A48-1Step 1: tert-butyl 2-methyl-4-carbonyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A48 -1
Figure PCTCN2021126331-appb-000253
Figure PCTCN2021126331-appb-000253
向干燥的10mL微波管中依次加入叔-丁基2-氯-4-羰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯(220mg,0.642mmol)，2,4,6-三甲基-1,3,5,2,4,6-三噁三硼己环(403mg,3.21mmol)，[1,1'-二(二苯基膦基)二茂铁]二氯钯(II)(47.0mg,0.0642mmol)，碳酸钾(266mg,1.93mmol)，1,4-二氧六环(1mL)和水(0.2mL)。然后在氮气条件下，将混合物加热至90℃搅拌16小时。反应完毕后，将混合物冷却至室温，并用饱和碳酸氢钠溶液淬灭反应，使用乙酸乙酯(3×80mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(60％至70％梯度的乙酸乙酯：石油醚)得到白色固体叔-丁基2-甲基-4-羰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯(84.0mg,收率：40.6％)。To a dry 10 mL microwave tube, add tert-butyl 2-chloro-4-carbonyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1' - Carboxylic acid ester (220 mg, 0.642 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboroxane (403 mg, 3.21 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (47.0 mg, 0.0642 mmol), potassium carbonate (266 mg, 1.93 mmol), 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was then heated to 90°C and stirred for 16 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×80 mL), washed with saturated brine and mixed with organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, The resulting residue was purified by silica gel chromatography (60% to 70% gradient of ethyl acetate:petroleum ether) to give tert-butyl 2-methyl-4-carbonyl-4,6-dihydrospiro[cyclo] as a white solid Pentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate (84.0 mg, yield: 40.6%).
LC-MS:m/z 323.1[M+H] +. LC-MS: m/z 323.1[M+H] + .
步骤二：叔-丁基(Z)-4-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯Step 2: tert-butyl(Z)-4-((tert-butylsulfinyl<sulfinyl>)imino)-2-methyl-4,6-dihydrospiro[cyclopentadieno [d]thiazole-5,4'-piperidine]-1'-carboxylate
Figure PCTCN2021126331-appb-000254
Figure PCTCN2021126331-appb-000254
向干燥的10mL微波管中依次加入叔-丁基2-甲基-4-羰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯(84.0mg,0.260mmol)，(R)-2-甲基丙烷-2-亚磺酰胺(63.2mg,0.521mmol)和钛酸四 乙酯(1mL)。然后在氮气条件下，将混合物加热至100℃搅拌3小时。反应完毕后，将混合物冷却至室温再将混合物倒入水中淬灭反应，垫硅藻土抽滤，滤饼用乙酸乙酯洗涤，收集滤液，加入80mL水，并使用乙酸乙酯(3×50mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(20％至30％梯度的甲醇：乙酸乙酯)得到白色固体叔-丁基(Z)-4-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯(56.0mg,收率：52.6％)。To a dry 10 mL microwave tube, add tert-butyl 2-methyl-4-carbonyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1 sequentially '-carboxylate (84.0 mg, 0.260 mmol), (R)-2-methylpropane-2-sulfinamide (63.2 mg, 0.521 mmol) and tetraethyl titanate (1 mL). The mixture was then heated to 100°C under nitrogen and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and then poured into water to quench the reaction, filtered through a pad of celite with suction, the filter cake was washed with ethyl acetate, the filtrate was collected, 80 mL of water was added, and ethyl acetate (3×50 mL) ) extraction, washed with saturated brine and combined the organic layers, dried over anhydrous sodium sulfate, filtered and concentrated, the resulting residue was purified by silica gel chromatography (20% to 30% gradient of methanol: ethyl acetate) to give a white solid tertiary -Butyl(Z)-4-((tert-butylsulfinyl<sulfinyl>)imino)-2-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole -5,4'-Piperidine]-1'-carboxylate (56.0 mg, yield: 52.6%).
LC-MS:m/z 426.1[M+H] +. LC-MS: m/z 426.1[M+H] + .
步骤三：叔-丁基(4S)-4-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯Step 3: tert-butyl(4S)-4-((tert-butylsulfinyl<sulfinyl>)amino)-2-methyl-4,6-dihydrospiro[cyclopentadieno[ d] Thiazole-5,4'-piperidine]-1'-carboxylate
Figure PCTCN2021126331-appb-000255
Figure PCTCN2021126331-appb-000255
向干燥的50mL三口烧瓶中依次加入叔-丁基(Z)-4-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯(56.0mg,0.130mmol)和四氢呋喃(10mL)。然后在氮气条件下，将混合物用干冰乙醇浴降温至-78℃，滴加入二异丁基氢化铝(37.0mg,0.26mmol)，保持此温度搅拌反应1h。反应完毕后，将混合物倒入80mL饱和氯化铵水溶液中淬灭，并使用乙酸乙酯(3×50mL)萃取，饱和食盐水洗涤并混合有机层，无水硫酸钠干燥，过滤并浓缩，将得到的残留物通过硅胶色谱法纯化(30％至40％梯度的甲醇：乙酸乙酯)得到白色固体叔-丁基(4S)-4-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯(50mg,收率：89.9％)。Into a dry 50mL three-necked flask, successively added tert-butyl(Z)-4-((tert-butylsulfinyl<sulfinyl>)imino)-2-methyl-4,6-dihydrospiro [Cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate (56.0 mg, 0.130 mmol) and tetrahydrofuran (10 mL). Then, under nitrogen, the mixture was cooled to -78°C with a dry ice ethanol bath, and diisobutylaluminum hydride (37.0 mg, 0.26 mmol) was added dropwise, and the reaction was stirred at this temperature for 1 h. After the reaction was completed, the mixture was poured into 80 mL of saturated aqueous ammonium chloride solution to quench, and extracted with ethyl acetate (3×50 mL), washed with saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (30% to 40% gradient of methanol:ethyl acetate) to give tert-butyl(4S)-4-((tert-butylsulfinyl<sulfinyl>) as a white solid )amino)-2-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate (50 mg, yield: 89.9% ).
LC-MS:m/z 428.1[M+H] +. LC-MS: m/z 428.1[M+H] + .
按照实施例5的合成路线和方法，用相应的原料和试剂制备得到如下螺环胺类中间体：According to the synthetic route and method of Example 5, the following spirocyclic amine intermediates were prepared with corresponding raw materials and reagents:
Figure PCTCN2021126331-appb-000256
Figure PCTCN2021126331-appb-000256
Figure PCTCN2021126331-appb-000257
Figure PCTCN2021126331-appb-000257
Figure PCTCN2021126331-appb-000258
Figure PCTCN2021126331-appb-000258
Figure PCTCN2021126331-appb-000259
Figure PCTCN2021126331-appb-000259
实施例6：(R)-N-((S)-2-氯-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A46的制备Example 6: (R)-N-((S)-2-Chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-yl) - Preparation of 2-methylpropane-2-sulfinamide A46
步骤一：2-氯-4-(氯甲基)-1,3-噻唑A46-1Step 1: 2-Chloro-4-(chloromethyl)-1,3-thiazole A46-1
Figure PCTCN2021126331-appb-000260
Figure PCTCN2021126331-appb-000260
将(2-氯-1,3-噻唑-4-基)甲醇(2.00g,13.37mmol)溶于二氯甲烷(20ml)中，0℃下滴加氯化亚砜(3.18g，26.74mmol)，然后0℃搅拌反应3h。LC-MS检测反应完全，冷却到室温加水淬灭，碳酸氢钠调PH到中性，二氯甲烷(100mL x2)萃取两次，有机相合并后用饱和食盐水洗涤，有机相分离后用无水硫酸钠干燥，过滤并浓缩，拌样过柱(石油醚:乙酸乙酯＝20:1)得黄色油状物2-氯-4-(氯甲基)-1,3-噻唑A46-1(2.00g，89.02％)。(2-Chloro-1,3-thiazol-4-yl)methanol (2.00g, 13.37mmol) was dissolved in dichloromethane (20ml), thionyl chloride (3.18g, 26.74mmol) was added dropwise at 0°C , and then stirred at 0 °C for 3 h. LC-MS detected that the reaction was complete, cooled to room temperature and quenched with water, adjusted pH to neutrality with sodium bicarbonate, extracted twice with dichloromethane (100 mL x 2), combined the organic phases and washed with saturated brine, and separated the organic phases with dried over sodium sulfate, filtered and concentrated, mixed with sample and passed through column (petroleum ether:ethyl acetate=20:1) to obtain 2-chloro-4-(chloromethyl)-1,3-thiazole A46-1( 2.00 g, 89.02%).
LC-MS:[M+H] +＝168.1。 LC-MS: [M+H] + =168.1.
步骤二：1-叔丁基-4-乙基-4-[(2-氯-1,3-噻唑-4-基)甲基]哌啶-1,4-二羧酸酯A46-2Step 2: 1-tert-Butyl-4-ethyl-4-[(2-chloro-1,3-thiazol-4-yl)methyl]piperidine-1,4-dicarboxylate A46-2
Figure PCTCN2021126331-appb-000261
Figure PCTCN2021126331-appb-000261
将化合物1-叔丁基-4-乙基哌啶-1,4-二羧酸酯(3.74g,14.55mmol)溶于四氢呋喃(20ml)，与-78℃干冰乙醇浴中，慢慢滴加二异丙基氨基锂(8.39mL,16.79mmol)，并搅拌一小时。然后2-氯-4-(氯甲基)-1,3-噻唑A46-1(1.88g,11.19mmol)溶于5mL四氢呋喃滴加到反应液中，并在-78 °下继续反应2小时。LC-MS检测反应完毕，用饱和氯化铵溶液淬灭反应，然后乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱(石油醚：乙酸乙酯1:1)得到产物1-叔丁基-4-乙基-4-[(2-氯-1,3-噻唑-4-基)甲基]哌啶-1,4-二羧酸酯A46-2(2.98g,68.48％)。 The compound 1-tert-butyl-4-ethylpiperidine-1,4-dicarboxylate (3.74g, 14.55mmol) was dissolved in tetrahydrofuran (20ml), and it was slowly added dropwise to a -78°C dry ice ethanol bath Lithium diisopropylamide (8.39 mL, 16.79 mmol) and stirred for one hour. Then 2-chloro-4-(chloromethyl)-1,3-thiazole A46-1 (1.88 g, 11.19 mmol) was dissolved in 5 mL of tetrahydrofuran and added dropwise to the reaction solution, and the reaction was continued at -78 ° for 2 hours. LC-MS detected the completion of the reaction, quenched the reaction with saturated ammonium chloride solution, then extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and used a silica gel column (petroleum ether:ethyl acetate 1:1) to obtain Product 1-tert-Butyl-4-ethyl-4-[(2-chloro-1,3-thiazol-4-yl)methyl]piperidine-1,4-dicarboxylate A46-2 (2.98g , 68.48%).
LC-MS:[M+H] +＝389.1。 LC-MS: [M+H] + =389.1.
步骤三：叔丁基2-氯-6-氧代-4,6-二氢螺[环戊二烯并[d][1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A46-3Step 3: tert-butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'- tert-Butyl Carboxylate A46-3
Figure PCTCN2021126331-appb-000262
Figure PCTCN2021126331-appb-000262
将化合物1-叔丁基-4-乙基-4-[(2-氯-1,3-噻唑-4-基)甲基]哌啶-1,4-二羧酸酯A46-2(2.98g，7.66mmol)溶于20mL四氢呋喃中，与-78℃干冰乙醇浴中，慢慢滴加LDA(5.75mL，11.49mmol)， 并搅拌一小时。LC-MS检测反应完毕，用饱和氯化铵溶液淬灭反应，然后乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱(石油醚：乙酸乙酯10:1)得到产物叔丁基2-氯-6-氧代-4,6-二氢螺[环戊二烯并[d][1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A46-3(0.44g，16.75％)。The compound 1-tert-butyl-4-ethyl-4-[(2-chloro-1,3-thiazol-4-yl)methyl]piperidine-1,4-dicarboxylate A46-2 (2.98 g, 7.66 mmol) was dissolved in 20 mL of tetrahydrofuran, and LDA (5.75 mL, 11.49 mmol) was slowly added dropwise to a -78°C dry ice ethanol bath and stirred for one hour. LC-MS detected the completion of the reaction, quenched the reaction with saturated ammonium chloride solution, then extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and obtained by silica gel column (petroleum ether:ethyl acetate 10:1) Product tert-Butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-Butyl ester A46-3 (0.44 g, 16.75%).
LC-MS:m/z 343.1[M+H] +. LC-MS: m/z 343.1[M+H] + .
步骤四：叔丁基(6)-2-氯-6-{[(R)-2-甲基丙烷-2-亚磺酰基]亚氨基}-4,6-二氢螺[环戊二烯并[d][1,3]噻唑5,4'-哌啶]-1'-羧酸叔丁酯A46-4Step 4: tert-butyl(6)-2-chloro-6-{[(R)-2-methylpropane-2-sulfinyl]imino}-4,6-dihydrospiro[cyclopentadiene [d][1,3]thiazole 5,4'-piperidine]-1'-carboxylate tert-butyl ester A46-4
Figure PCTCN2021126331-appb-000263
Figure PCTCN2021126331-appb-000263
将叔丁基2-氯-6-氧代-4,6-二氢螺[环戊二烯并[d][1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A46-3(440mg,1.28mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(310.27mg,2.56mmol)加入到钛酸四乙酯(10mL)中，氮气保护下加热到90℃反应15h。反应完毕，冷却至室温加入乙酸乙酯(50mL)稀释，加入饱和食盐水(25mL)，有白色固体析出。将混合物过滤，滤饼用乙酸乙酯洗涤。滤液用饱和食盐水洗，有机相分液后用无水硫酸纳干燥，过滤浓缩。粗品通过硅胶色谱法纯化得到浅黄固体叔丁基(6)-2-氯-6-{[(R)-2-甲基丙烷-2-亚磺酰基]亚氨基}-4,6-二氢螺[环戊二烯并[d][1,3]噻唑5,4'-哌啶]-1'-羧酸叔丁酯A46-4(0.48g，收率：84.08％)。tert-Butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'-carboxylic acid Tert-butyl ester A46-3 (440 mg, 1.28 mmol) and (R)-2-methylpropane-2-sulfinamide (310.27 mg, 2.56 mmol) were added to tetraethyl titanate (10 mL) under nitrogen protection Heated to 90°C for 15h. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate (50 mL), and saturated brine (25 mL) was added, and a white solid was precipitated. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl(6)-2-chloro-6-{[(R)-2-methylpropane-2-sulfinyl]imino}-4,6-dihydro as a pale yellow solid Spiro[cyclopentadieno[d][1,3]thiazole 5,4'-piperidine]-1'-carboxylate tert-butyl ester A46-4 (0.48 g, yield: 84.08%).
LCMS:m/z 468.1[M+Na] +。 LCMS: m/z 468.1 [M+Na] + .
按照实施例2步骤七和步骤八的方法得到(R)-N-((S)-2-氯-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A46(R)-N-((S)-2-chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-dihydrospiro[cyclopentadieno[d]thiazole-5,4'- Piperidin]-6-yl)-2-methylpropane-2-sulfinamide A46
Figure PCTCN2021126331-appb-000264
Figure PCTCN2021126331-appb-000264
LC-MS:m/z 348.9[M+H] +. LC-MS: m/z 348.9 [M+H] + .
按照实施例6的方法,用相应的原料和试剂制备得到中间体(R)-N-((S)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A54According to the method of Example 6, the intermediate (R)-N-((S)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4' was prepared with corresponding raw materials and reagents -Piperidin]-6-yl)-2-methylpropane-2-sulfinamide A54
Figure PCTCN2021126331-appb-000265
Figure PCTCN2021126331-appb-000265
LC-MS:m/z 314.1[M+H] +. LC-MS: m/z 314.1[M+H] + .
实施例7：(R)-N-((S)-2-氯-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A47的制备Example 7: (R)-N-((S)-2-Chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-yl) Preparation of -2-methylpropane-2-sulfinamide A47
步骤一：叔丁基(6)-2-甲基-6-[(R)-2-甲基丙烷-2-亚磺酰基)亚氨基]-4,6-二氢螺[环戊二烯并[d][1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A47-1Step 1: tert-butyl(6)-2-methyl-6-[(R)-2-methylpropane-2-sulfinyl)imino]-4,6-dihydrospiro[cyclopentadiene [d][1,3]thiazole-5,4'-piperidine]-1'-carboxylate tert-butyl ester A47-1
Figure PCTCN2021126331-appb-000266
Figure PCTCN2021126331-appb-000266
将叔-丁基(R,Z)-6-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A46-4(100mg,0.22mmol),三甲基环三硼氧烷(55.23mg,0.44mmol),Pd(dppf)Cl 2(16.10mg,0.022mmol)和碳酸钾(91.22mg，0.66mmol)加入到1,4-二氧六环(4mL)-水(1mL)中，氮气保护下加热到90℃反应15h。反应完毕，粗品通过硅胶色谱法纯化得到叔丁基(6)-2-甲基-6-[(R)-2-甲基丙烷-2-亚磺酰基)亚氨基]-4,6-二氢螺[环戊二烯并[d][1,3]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A47-1(41.55mg，收率：44.38％). tert-butyl(R,Z)-6-((tert-butylsulfinyl<sulfinyl>)imino)-2-methyl-4,6-dihydrospiro[cyclopentadienyl [d] Thiazole-5,4'-piperidine]-1'-carboxylate A46-4 (100mg, 0.22mmol), Trimethylcyclotriboroxane (55.23mg, 0.44mmol), Pd(dppf) Cl 2 (16.10 mg, 0.022 mmol) and potassium carbonate (91.22 mg, 0.66 mmol) were added to 1,4-dioxane (4 mL)-water (1 mL), heated to 90° C. for 15 h under nitrogen protection. After completion of the reaction, the crude product was purified by silica gel chromatography to obtain tert-butyl(6)-2-methyl-6-[(R)-2-methylpropane-2-sulfinyl)imino]-4,6-di Hydrospiro[cyclopentadieno[d][1,3]thiazole-5,4'-piperidine]-1'-carboxylate tert-butyl ester A47-1 (41.55 mg, yield: 44.38%).
LCMS:m/z 426.1[M+H] +. LCMS: m/z 426.1[M+H] + .
步骤二：按照实施例二步骤七的方法得到叔丁基(S)-6-(((R)-叔丁基亚磺酰基)氨基)-2-甲基-4,6-二氢螺[环戊二烯[d]噻唑-5,4'-哌啶]-1'-羧酸叔丁酯A47-2Step 2: Obtain tert-butyl (S)-6-((((R)-tert-butylsulfinyl)amino)-2-methyl-4,6-dihydrospiro[ Cyclopentadiene[d]thiazole-5,4'-piperidine]-1'-carboxylate tert-butyl ester A47-2
Figure PCTCN2021126331-appb-000267
Figure PCTCN2021126331-appb-000267
1H NMR(400MHz,DMSO-d 6)δ5.85(d,J＝9.9Hz,1H),4.36(d,J＝9.8Hz,1H),3.79(d,J＝14.2Hz,2H),2.97(s,2H),2.74(d,J＝16.2Hz,1H),2.66(d,J＝15.6Hz,1H),2.62(s,3H),1.68(t,J＝10.6Hz,1H),1.56(dd,J＝10.7,4.3Hz,3H),1.40(s,9H),1.12(s,9H)ppm；LC-MS:[M+H] +＝428.1 1 H NMR (400MHz, DMSO-d 6 ) δ 5.85 (d, J=9.9Hz, 1H), 4.36 (d, J=9.8Hz, 1H), 3.79 (d, J=14.2Hz, 2H), 2.97 (s, 2H), 2.74(d, J＝16.2Hz, 1H), 2.66(d, J＝15.6Hz, 1H), 2.62(s, 3H), 1.68(t, J＝10.6Hz, 1H), 1.56 (dd, J=10.7, 4.3 Hz, 3H), 1.40 (s, 9H), 1.12 (s, 9H) ppm; LC-MS: [M+H] + =428.1
步骤三：按照实施例二步骤八的方法脱保护得到(R)-2-甲基-N-((S)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)丙烷-2-亚磺酰胺A47Step 3: Deprotection according to the method of Step 8 of Example 2 to obtain (R)-2-methyl-N-((S)-2-methyl-4,6-dihydrospiro[cyclopentadieno[d] ]thiazol-5,4'-piperidin]-6-yl)propane-2-sulfinamide A47
Figure PCTCN2021126331-appb-000268
Figure PCTCN2021126331-appb-000268
LC-MS:[M+H] +＝328.1 LC-MS: [M+H] + = 328.1
按照实施例7的方法,用相应的原料和试剂制备得到中间体(R)-2-甲基-N-((S)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-4-基)丙烷-2-亚磺酰胺A48According to the method of Example 7, the intermediate (R)-2-methyl-N-((S)-2-methyl-4,6-dihydrospiro[cyclopentadiene] was prepared with corresponding raw materials and reagents [d]thiazol-5,4'-piperidin]-4-yl)propane-2-sulfinamide A48
Figure PCTCN2021126331-appb-000269
Figure PCTCN2021126331-appb-000269
LC-MS:[M+H] +＝328.1 LC-MS: [M+H] + = 328.1
实施例8：中间体(R)-N-((S)-2-(二甲氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A42Example 8: Intermediate (R)-N-((S)-2-(dimethylamino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine ]-6-yl)-2-methylpropane-2-sulfinamide A42
步骤一：叔-丁基(R,Z)-6-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-(二甲氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A42-1Step 1: tert-butyl(R,Z)-6-((tert-butylsulfinyl<sulfinyl>)imino)-2-(dimethylamino)-4,6-dihydrospiro[ Cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A42-1
Figure PCTCN2021126331-appb-000270
Figure PCTCN2021126331-appb-000270
反应瓶加入叔-丁基(R,Z)-6-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-氯-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A46-4(1g，2.24mmol)和CH3CN(10mL)，淡黄色悬浮液，原料未完全溶解，加入二甲胺的THF溶液(1.7mL，3.40mmol)，悬浮液变澄清溶液，氩气保护加热至75℃，反应2小时，LCMS显示反应完全，反应液冷至室温，浓缩，粗品柱层析(300-400目硅胶，乙酸乙酯洗脱)纯化得到叔-丁基(R,Z)-6-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)-2-(二甲氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A42-1(845mg，82％收率)，为淡黄色泡沫状固体。Add tert-butyl(R,Z)-6-((tert-butylsulfinyl<sulfinyl>)imino)-2-chloro-4,6-dihydrospiro[cyclopentadiene to the reaction flask and [d]thiazole-5,4'-piperidine]-1'-carboxylate A46-4 (1 g, 2.24 mmol) and CH3CN (10 mL), pale yellow suspension, the starting material was not completely dissolved, dimethylamine was added of THF solution (1.7 mL, 3.40 mmol), the suspension became a clear solution, heated to 75 °C under argon protection, reacted for 2 hours, LCMS showed that the reaction was complete, the reaction solution was cooled to room temperature, concentrated, and the crude product was subjected to column chromatography (300-400 (mesh silica gel, ethyl acetate elution) to obtain tert-butyl(R,Z)-6-((tert-butylsulfinyl<sulfinyl>)imino)-2-(dimethylamino)- 4,6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A42-1 (845 mg, 82% yield) as pale yellow foam solid.
1H NMR(400MHz,DMSO-d 6)δ4.06–3.87(m,2H),3.16(s,6H),3.04–2.83(m,2H),2.98(s,2H), 2.81(d,J＝2.0Hz,2H),1.86–1.70(m,2H),1.52–1.44(m,1H),1.41(s,9H),1.12(s,9H)ppm；LCMS:m/z 455.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ4.06-3.87(m,2H), 3.16(s,6H), 3.04-2.83(m,2H), 2.98(s,2H), 2.81(d,J = 2.0Hz, 2H), 1.86–1.70 (m, 2H), 1.52–1.44 (m, 1H), 1.41 (s, 9H), 1.12 (s, 9H) ppm; LCMS: m/z 455.1 [M+H ] + .
步骤二：按照实施例二步骤七和步骤八的方法脱得到(R)-N-((S)-2-(二甲氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A42Step 2: Remove (R)-N-((S)-2-(dimethylamino)-4,6-dihydrospiro[cyclopentadieno[d] according to the methods of Step 7 and Step 8 of Example 2 ]thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A42
Figure PCTCN2021126331-appb-000271
Figure PCTCN2021126331-appb-000271
LCMS:m/z 357.2[M+H] +. LCMS: m/z 357.2[M+H] + .
实施例9：中间体N-((S)-2-环丙基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺A16的合成Example 9: Intermediate N-((S)-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-yl) Synthesis of -2-methylpropane-2-sulfinamide A16
步骤一：叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-环丙基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A16-1Step 1: tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno [b]pyridine-6,4'-piperidine]-1'-carboxylate A16-1
Figure PCTCN2021126331-appb-000272
Figure PCTCN2021126331-appb-000272
反应瓶加入叔-丁基(S)-5-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A53-6(1g粗品，2.3mmol)，环丙基硼酸(400mg，4.6mmol)，碳酸钾(952mg，6.9mmol)，Pd(dppf)Cl 2(165mg，0.2mmol)和1,4-二氧六环(10mL)，氩气保护下加热至105℃，反应过夜，LCMS显示反应完全，反应液冷至室温，旋去1,4-二氧六环，加入乙酸乙酯(50ml)溶解和水(50ml)，过滤，把不溶物除去，分液，有机相浓缩得粗品柱层析(300-400目硅胶，洗脱剂为石油醚:乙酸乙酯＝1:1)纯化得到叔-丁基(5S)-5-((叔-丁基亚硫酰基<亚磺酰>)氨基)-2-环丙基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯A16-1(205mg，20％收率)，为白色固体。 Add tert-butyl(S)-5-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-5,7-dihydrospiro[cyclopentanedi] to the reaction flask Eno[b]pyridine-6,4'-piperidine]-1'-carboxylate A53-6 (1 g crude, 2.3 mmol), cyclopropylboronic acid (400 mg, 4.6 mmol), potassium carbonate (952 mg, 6.9 mmol), Pd(dppf)Cl 2 (165mg, 0.2mmol) and 1,4-dioxane (10mL), heated to 105°C under argon protection, reacted overnight, LCMS showed that the reaction was complete, the reaction solution was cooled to room temperature , spin off 1,4-dioxane, add ethyl acetate (50ml) to dissolve and water (50ml), filter, remove the insolubles, separate the layers, and concentrate the organic phase to obtain the crude product by column chromatography (300-400 mesh silica gel) , the eluent is petroleum ether: ethyl acetate=1:1) and purified to obtain tert-butyl(5S)-5-((tert-butylsulfinyl<sulfinyl>)amino)-2-cyclopropane yl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-1'-carboxylate A16-1 (205 mg, 20% yield) as a white solid .
1H NMR(400MHz,DMSO-d 6)δ7.44(dd,J＝7.8,0.9Hz,1H),7.10(d,J＝7.8Hz,1H),5.68(d,J＝10.3Hz,1H),4.35(d,J＝10.3Hz,1H),3.85(d,J＝13.1Hz,2H),2.94(t,J＝20.7Hz,3H),2.67(d,J＝16.6Hz,1H),2.05(td,J＝8.2,4.0Hz,1H),1.77(s,1H),1.60(d,J＝13.9Hz,1H),1.41(s,10H),1.19(s,10H),0.98–0.75(m,4H)ppm；LCMS:m/z 448.2[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.44 (dd, J=7.8, 0.9 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 5.68 (d, J=10.3 Hz, 1H) ,4.35(d,J＝10.3Hz,1H),3.85(d,J＝13.1Hz,2H),2.94(t,J＝20.7Hz,3H),2.67(d,J＝16.6Hz,1H),2.05 (td, J=8.2, 4.0Hz, 1H), 1.77(s, 1H), 1.60(d, J=13.9Hz, 1H), 1.41(s, 10H), 1.19(s, 10H), 0.98–0.75( m, 4H) ppm; LCMS: m/z 448.2 [M+H] + .
步骤二：按照实施例二步骤八的方法脱保护得到(R)-N-((S)-2-环丙基-5,7-二氢螺[环戊二烯并[b] 吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺A16Step 2: Deprotection according to the method of Step 8 of Example 2 to obtain (R)-N-((S)-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6 ,4'-Piperidin]-5-yl)-2-methylpropane-2-sulfinamide A16
Figure PCTCN2021126331-appb-000273
Figure PCTCN2021126331-appb-000273
LCMS:m/z 348.2[M+H] +. LCMS: m/z 348.2[M+H] + .
按照实施例9的合成路线和方法，用相应的原料和试剂制备得到中间体(R)-2-甲基-N-((S)-2-甲基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)丙烷-2-亚磺酰胺A37According to the synthetic route and method of Example 9, the intermediate (R)-2-methyl-N-((S)-2-methyl-5,7-dihydrospiro[cyclic] was prepared with corresponding raw materials and reagents. Pentadieno[b]pyridin-6,4'-piperidin]-5-yl)propane-2-sulfinamide A37
Figure PCTCN2021126331-appb-000274
Figure PCTCN2021126331-appb-000274
LCMS:m/z 322.2[M+H] +. LCMS: m/z 322.2[M+H] + .
实施例10：中间体(R)-2-甲基-N-((R)-1-甲基螺[二氢吲哚-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺A41Example 10: Intermediate (R)-2-methyl-N-((R)-1-methylspiro[indoline-2,4'-piperidin]-3-yl)propane-2- Sulfenamide A41
步骤一：4-((2-溴苯基)氨基)-4-氰基哌啶-1-甲酸叔丁酯A41-1Step 1: 4-((2-Bromophenyl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester A41-1
Figure PCTCN2021126331-appb-000275
Figure PCTCN2021126331-appb-000275
将邻溴苯胺(500mg，2.91mmol)和4-氧代哌啶-1-甲酸叔丁酯(666mg，3.34mmol)和三甲基氰硅烷(331mg，3.34mmol)溶于醋酸(5mL)中，在30℃下，搅拌24小时，LCMS监测反应结束，反应液用氨水淬灭，调至中性，乙酸乙酯萃取，有机相干燥，浓缩，粗品用快速硅胶柱纯化得到白色固体4-((2-溴苯基)氨基)-4-氰基哌啶-1-甲酸叔丁酯A41-1(550mg，收率46.5％)。o-Bromoaniline (500 mg, 2.91 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (666 mg, 3.34 mmol) and trimethylsilane (331 mg, 3.34 mmol) were dissolved in acetic acid (5 mL), At 30 ° C, stirring for 24 hours, LCMS monitoring the end of the reaction, the reaction solution was quenched with ammonia water, adjusted to neutrality, extracted with ethyl acetate, the organic phase was dried, concentrated, and the crude product was purified with a flash silica column to obtain a white solid 4-(( 2-Bromophenyl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester A41-1 (550 mg, 46.5% yield).
1H NMR(400MHz,CDCl 3)δ7.55-7.48(m,1H),7.27-7.23(m,1H),7.22-7.16(m,1H),6.82-6.74(m,1H),4.40(br s,1H),4.01-3.80(m,2H),3.50-3.22(m,2H),2.49-2.23(m,2H),1.98-1.81(m,2H),1.48(s,9H)ppm；LCMS：m/z 326.0[M-56+H] +. 1 H NMR (400MHz, CDCl 3 )δ7.55-7.48(m,1H), 7.27-7.23(m,1H), 7.22-7.16(m,1H), 6.82-6.74(m,1H), 4.40(br s,1H),4.01-3.80(m,2H),3.50-3.22(m,2H),2.49-2.23(m,2H),1.98-1.81(m,2H),1.48(s,9H)ppm; LCMS : m/z 326.0[M-56+H] + .
步骤二：3-氧代螺环[二氢吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-2Step 2: 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate tert-butyl ester A41-2
Figure PCTCN2021126331-appb-000276
Figure PCTCN2021126331-appb-000276
将4-((2-溴苯基)氨基)-4-氰基哌啶-1-甲酸叔丁酯A41-1(15.0g，39.4mmoL)，二异丙基乙胺(20.4g，157mmol)和二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(2.79g，3.94mmol)加入到N,N-二甲基乙酰胺(100mL)和水(4.00mL)溶液中，氮气置换三次，在125℃下12小时，LCMS监测反应结束，反应液用乙酸乙酯稀释，饱和食盐水洗涤，有机相干燥，浓缩，粗品用快速硅胶柱纯化得到黄色油状物3-氧代螺环[二氢吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-2(10.2g，67.8％收率)。4-((2-Bromophenyl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester A41-1 (15.0 g, 39.4 mmol), diisopropylethylamine (20.4 g, 157 mmol) and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (2.79 g, 3.94 mmol) was added to N,N-dimethylacetamide (100 mL) and water ( 4.00mL) solution, nitrogen was replaced three times, at 125 ° C for 12 hours, LCMS monitoring the end of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried, concentrated, and the crude product was purified with a flash silica column to obtain a yellow oil. 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate tert-butyl ester A41-2 (10.2 g, 67.8% yield).
1H NMR(400MHz,CDCl 3)δ7.59(d,J＝7.8Hz,1H),7.47-7.38(m,1H),6.87(d,J＝8.3Hz,1H),6.81(t,J＝7.4Hz,1H),5.46(s,1H),4.21-4.04(m,2H),3.21-3.06(m,2H),1.95-1.85(m,2H),1.47(s,9H),1.45-1.38(m,2H)ppm；LCMS:m/z 203.1[M-100+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J=7.8 Hz, 1H), 7.47-7.38 (m, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.81 (t, J= 7.4Hz, 1H), 5.46(s, 1H), 4.21-4.04(m, 2H), 3.21-3.06(m, 2H), 1.95-1.85(m, 2H), 1.47(s, 9H), 1.45-1.38 (m,2H)ppm; LCMS: m/z 203.1[M-100+H] + .
步骤三：1-甲基3-氧代螺环[二氢吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-3Step 3: 1-Methyl 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate tert-butyl ester A41-3
Figure PCTCN2021126331-appb-000277
Figure PCTCN2021126331-appb-000277
在0℃下，将双(三甲基硅基)氨基钠的四氢呋喃溶液(1M，20.0mL)滴加到3-氧代螺环[二氢吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-2(5.00g，16.5mmol)的四氢呋喃溶液(40.0mL)中，在0℃下，搅拌20分钟后，向上述反应液中缓慢滴加碘甲烷(6.00g，42.2mmol)的四氢呋喃(15.0mL)溶液，继续在0℃下，搅拌2小时。LCMS监测反应结束，反应液用水淬灭，乙酸乙酯萃取，有机相干燥，浓缩，粗品用快速硅胶柱纯化得到黄色固体1-甲基3-氧代螺环[二氢吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-3(3.50g，62.6％收率)。A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 20.0 mL) was added dropwise to 3-oxospiro[indoline-2,4'-piperidine]-1 at 0 °C To the tetrahydrofuran solution (40.0 mL) of '-tert-butyl formate A41-2 (5.00 g, 16.5 mmol), at 0 °C, after stirring for 20 minutes, methyl iodide (6.00 g, 42.2 mmol) was slowly added dropwise to the above reaction solution. mmol) in tetrahydrofuran (15.0 mL) and stirring was continued at 0°C for 2 hours. The end of the reaction was monitored by LCMS, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was dried, concentrated, and the crude product was purified with a flash silica gel column to obtain a yellow solid 1-methyl 3-oxospiro[indoline-2,4] '-Piperidine]-1'-carboxylate tert-butyl ester A41-3 (3.50 g, 62.6% yield).
1H NMR(400MHz,CDCl 3)δ7.60-7.55(m,1H),7.52-7.44(m,1H),6.77-6.70(m,2H),4.10-4.00(m,2H),3.74-3.63(m,2H),2.89(s,3H),1.94-1.83(m,2H),1.50(s,9H),1.49-1.44(m,2H)ppm；LCMS:m/z 261.3[M-56+H] +. 1 H NMR (400MHz, CDCl 3 ) δ 7.60-7.55 (m, 1H), 7.52-7.44 (m, 1H), 6.77-6.70 (m, 2H), 4.10-4.00 (m, 2H), 3.74-3.63 (m,2H),2.89(s,3H),1.94-1.83(m,2H),1.50(s,9H),1.49-1.44(m,2H)ppm; LCMS: m/z 261.3[M-56+ H] + .
步骤四：按照实施例2的方法以1-甲基3-氧代螺环[二氢吲哚-2,4'-哌啶]-1'-甲酸叔丁酯A41-3为原料可以得到中间体(R)-2-甲基-N-((R)-1-甲基螺[二氢吲哚-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺A41Step 4: According to the method of Example 2, use 1-methyl 3-oxospiro[indoline-2,4'-piperidine]-1'-carboxylate tert-butyl ester A41-3 as raw material to obtain intermediate (R)-2-methyl-N-((R)-1-methylspiro[indoline-2,4'-piperidin]-3-yl)propane-2-sulfinamide A41
Figure PCTCN2021126331-appb-000278
Figure PCTCN2021126331-appb-000278
LC-MS:m/z 322.2[M+H] +. LC-MS: m/z 322.2[M+H] + .
实施例11：中间体(R)-N-((S)-5-氰基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺A13的合成Example 11: Intermediate (R)-N-((S)-5-cyano-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methyl Synthesis of Propane-2-sulfinamide A13
步骤一：6-氰基-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1Step 1: 6-cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A13-1
Figure PCTCN2021126331-appb-000279
Figure PCTCN2021126331-appb-000279
将叔丁基6-溴-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A10-1(500mg，1.31mmol)溶于N,N-二甲基甲酰胺(15mL)中，加入氰化锌(307.7mg，2.62mmol)。四三苯基膦钯(151.38mg,0.13mmol)氮气保护下100℃反应15小时后，反应完毕。过硅胶柱(石油醚：乙酸乙酯5:1)得到6-氰基-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1(420mg，98.23％)。Dissolve tert-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A10-1 (500 mg, 1.31 mmol) To N,N-dimethylformamide (15 mL) was added zinc cyanide (307.7 mg, 2.62 mmol). Tetrakistriphenylphosphine palladium (151.38 mg, 0.13 mmol) was reacted at 100° C. for 15 hours under nitrogen protection, and the reaction was completed. Silica gel column (petroleum ether:ethyl acetate 5:1) to obtain 6-cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tertiary Butyl ester A13-1 (420 mg, 98.23%).
LCMS:m/z 271.1[M-55] + 。 LCMS: m/z 271.1 [M-55] + .
步骤二：6-氰基-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1经过实施例2步骤六、步骤七和步骤八的方法三步得到中间体(R)-N-((S)-5-氰基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺A13。Step 2: 6-cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A13-1 is subjected to step 6 of Example 2, The method of step 7 and step 8 obtains the intermediate (R)-N-((S)-5-cyano-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl in three steps )-2-methylpropane-2-sulfinamide A13.
Figure PCTCN2021126331-appb-000280
Figure PCTCN2021126331-appb-000280
LCMS:m/z 332.1[M+1] + 。 LCMS: m/z 332.1[M+1] + .
按照实施例11的方法可以得到中间体N-(5-氰基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺A12According to the method of Example 11, the intermediate N-(5-cyano-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2- Sulfenamide A12
Figure PCTCN2021126331-appb-000281
Figure PCTCN2021126331-appb-000281
Figure PCTCN2021126331-appb-000282
LCMS:m/z 332.1[M+1] + 。
Figure PCTCN2021126331-appb-000282
LCMS: m/z 332.1[M+1] + .
实施例12：中间体(S)-1-(((R)-叔丁基亚磺酰基)氨基)-N-(甲基-d3)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺A21的合成Example 12: Intermediate (S)-1-(((R)-tert-butylsulfinyl)amino)-N-(methyl-d3)-1,3-dihydrospiro[indene-2,4 Synthesis of '-piperidine]-6-carboxamide A21
步骤一：1'–(叔丁氧基羰基)-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-6-羧酸A21-1Step 1: 1'-(tert-butoxycarbonyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxylic acid A21-1
Figure PCTCN2021126331-appb-000283
Figure PCTCN2021126331-appb-000283
将6-氰基-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A13-1(420mg，1.29mmol)加入到甲醇(15mL)和水(15mL)的混合溶剂中，然后加入氢氧化钾(0.72g,12.9mmol)并在70℃下搅拌15小时。冷却至室温后，用饱和柠檬酸将PH调至7，然后加水(30mL)稀释，用乙酸乙酯(60mLX2)萃取。合并的有机层用盐水(80mL)洗涤，经无水硫酸钠干燥，过滤并在减压下浓缩得到1'-(叔丁氧基羰基)-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-6-羧酸(420mg,94.4％)，其无需任何进一步纯化即可用于下一步骤。6-Cyano-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A13-1 (420 mg, 1.29 mmol) was added to methanol To a mixed solvent of (15 mL) and water (15 mL), potassium hydroxide (0.72 g, 12.9 mmol) was added, followed by stirring at 70° C. for 15 hours. After cooling to room temperature, the pH was adjusted to 7 with saturated citric acid, then diluted with water (30 mL), and extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-1-oxo-1,3-dihydrospiro[ Indene-2,4'-piperidine]-6-carboxylic acid (420 mg, 94.4%) was used in the next step without any further purification.
LCMS:m/z 290.1[M-55] +。 LCMS: m/z 290.1 [M-55] + .
步骤二：6-((甲基-d3)氨基甲酰基)-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A21-2Step 2: 6-((methyl-d3)carbamoyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A21 -2
Figure PCTCN2021126331-appb-000284
Figure PCTCN2021126331-appb-000284
在圆底烧瓶中，将1'-(叔丁氧基羰基)-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-6-羧酸A21-1(300mg,0.87mmol)溶解在无水N,N,-二甲基甲酰胺(5mL)中。依次加入甲烷-d 3-胺(73.65mg,1.05mmol)、 HATU(496.2mg,1.31mmo)和二异丙基乙胺(225mg,1.74mmol)。室温下搅拌1小时，然后通过硅胶柱(二氯甲烷:甲醇20:1)纯化得到6-((甲基-d3)氨基甲酰基)-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A21-2(220mg，69.96％)。 In a round bottom flask, 1'-(tert-butoxycarbonyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxylic acid A21-1 ( 300 mg, 0.87 mmol) was dissolved in dry N,N,-dimethylformamide (5 mL). Methane- d3 -amine (73.65 mg, 1.05 mmol), HATU (496.2 mg, 1.31 mmol) and diisopropylethylamine (225 mg, 1.74 mmol) were added sequentially. Stir at room temperature for 1 hour, then purify by silica gel column (dichloromethane:methanol 20:1) to give 6-((methyl-d3)carbamoyl)-1-oxo-1,3-dihydrospiro[indene -2,4'-Piperidine]-1'-carboxylate tert-butyl ester A21-2 (220 mg, 69.96%).
LC-MS:m/z 384.1[M+Na] +. LC-MS: m/z 384.1[M+Na] + .
步骤三：6-((甲基-d3)氨基甲酰基)-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A21-2经过实施例2步骤六、步骤七和步骤八的方法三步得到中间体(S)-1-(((R)-叔丁基亚磺酰基)氨基)-N-(甲基-d3)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺A21Step 3: 6-((methyl-d3)carbamoyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A21 -2 The intermediate (S)-1-((((R)-tert-butylsulfinyl)amino)-N-(methyl-d3 is obtained through three steps of the method of step six, step seven and step eight of Example 2 )-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxamide A21
Figure PCTCN2021126331-appb-000285
Figure PCTCN2021126331-appb-000285
LC-MS:m/z 367.2[M+H] +. LC-MS: m/z 367.2[M+H] + .
按照实施例12的合成路线和方法，用相应的原料和试剂制备得到如下螺环胺类中间体：According to the synthetic route and method of Example 12, the following spirocyclic amine intermediates were prepared with corresponding raw materials and reagents:
Figure PCTCN2021126331-appb-000286
Figure PCTCN2021126331-appb-000286
实施例13：中间体(R)-N-((S)-2-(2-羟基丙烷-2-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A29的合成Example 13: Intermediate (R)-N-((S)-2-(2-hydroxypropan-2-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5, Synthesis of 4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A29
步骤一：1'-(叔-丁基)2-甲基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1Step 1: 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-4,6-dihydro Spiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1
Figure PCTCN2021126331-appb-000287
Figure PCTCN2021126331-appb-000287
50mL反应瓶中加入叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-氯-4,6-二氢螺[环戊二 烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A46-5(300mg，0.670mmol)和甲醇(9mL)，淡黄色溶液，加入Et3N(136mg，1.34mmol)和Pd(dppf)Cl2(98mg，0.134mmol)，砖红色反应液CO置换，CO(45psi)45℃反应2小时，LCMS显示原料反应完全，反应液冷却至室温，硅藻土过滤，滤饼用甲醇(10mL X 4)洗涤，浓缩，粗品prep-HPLC制备得到1'-(叔-丁基)2-甲基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1,为淡黄色固体(63mg,20％收率)。Add tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-chloro-4,6-dihydrospiro[cyclic to the 50mL reaction flask Pentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A46-5 (300 mg, 0.670 mmol) and methanol (9 mL), pale yellow solution, was added Et3N (136 mg, 1.34 mmol) ) and Pd(dppf)Cl2 (98mg, 0.134mmol), the brick red reaction solution was replaced by CO, CO (45psi) was reacted at 45°C for 2 hours, LCMS showed that the reaction of the raw materials was complete, the reaction solution was cooled to room temperature, filtered through celite, and the filter cake Washed with methanol (10 mL × 4), concentrated, and the crude product was prepared by prep-HPLC to give 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylsulfinyl< Sulfinyl>)amino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1, which is pale Yellow solid (63 mg, 20% yield).
LC-MS:m/z 416.2[M-55] +； 1H NMR(400MHz,DMSO-d 6)δ5.84(d,J＝9.9Hz,1H),4.31(d,J＝9.8Hz,1H),4.00(s,3H),3.94–3.65(m,2H),2.99(s,2H),2.72–2.56(m,2H),1.72–1.48(m,4H),1.41(s,10H),1.12(s,9H). LC-MS: m/z 416.2 [M-55] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 5.84 (d, J=9.9 Hz, 1H), 4.31 (d, J=9.8 Hz, 1H ),4.00(s,3H),3.94–3.65(m,2H),2.99(s,2H),2.72–2.56(m,2H),1.72–1.48(m,4H),1.41(s,10H), 1.12(s,9H).
步骤二：叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(2-羟基丙烷-2-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A29-2Step 2: tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-(2-hydroxypropan-2-yl)-4, 6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A29-2
Figure PCTCN2021126331-appb-000288
Figure PCTCN2021126331-appb-000288
50mL反应瓶中加入1'-(叔-丁基)2-甲基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1(400mg，0.82mmol)和无水THF(8mL)，淡黄色溶液，氩气保护冷至0-5℃，慢慢加入MeMgBr(5mL，5.00mmol，1M in THF)，室温反应1.5小时，补加MeMgBr(3.2mL，3.20mmol，1M in THF)，继续反应1.5小时，慢慢加入饱和NH4Cl溶液(10mL)淬灭反应，放气明显，搅拌分液，水相用乙酸乙酯(10mL)萃取，合并有机相用饱和氯化钠(15mL)洗涤，干燥浓缩，粗品柱层析(300-400目硅胶，石油醚:四氢呋喃＝1:1)纯化得到80mg叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(2-羟基丙烷-2-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A29-2，淡黄色固体,20％收率。1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-4,6- Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1 (400 mg, 0.82 mmol) and anhydrous THF (8 mL), light The yellow solution was cooled to 0-5°C under argon protection, and MeMgBr (5 mL, 5.00 mmol, 1M in THF) was slowly added, and the reaction was carried out at room temperature for 1.5 hours. MeMgBr (3.2 mL, 3.20 mmol, 1M in THF) was added, and the reaction was continued. After 1.5 hours, saturated NH4Cl solution (10 mL) was slowly added to quench the reaction, the gas was obviously released, the liquid was separated by stirring, the aqueous phase was extracted with ethyl acetate (10 mL), the combined organic phases were washed with saturated sodium chloride (15 mL), dried and concentrated , the crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: tetrahydrofuran=1:1) to obtain 80 mg of tert-butyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl Acyl>)amino)-2-(2-hydroxypropan-2-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxy Ester A29-2, pale yellow solid, 20% yield.
LC-MS:m/z 416.2[M-55] +； 1H NMR(400MHz,DMSO-d 6)δ6.01–5.77(m,2H),4.38(d,J＝9.7Hz,1H),3.82(d,J＝16.6Hz,2H),2.84–2.58(m,3H),1.74–1.50(m,5H),1.48(s,5H),1.41(s,9H),1.36(s,3H),1.14(s,9H). LC-MS: m/z 416.2[M-55] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.01-5.77 (m, 2H), 4.38 (d, J=9.7 Hz, 1H), 3.82 (d, J=16.6Hz, 2H), 2.84–2.58 (m, 3H), 1.74–1.50 (m, 5H), 1.48 (s, 5H), 1.41 (s, 9H), 1.36 (s, 3H), 1.14(s, 9H).
步骤三：按照实施例2的方法脱保护得到中间体(R)-N-((S)-2-(2-羟基丙烷-2-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A29Step 3: Deprotection according to the method of Example 2 to obtain intermediate (R)-N-((S)-2-(2-hydroxypropan-2-yl)-4,6-dihydrospiro[cyclopentadiene] [d]thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A29
Figure PCTCN2021126331-appb-000289
Figure PCTCN2021126331-appb-000289
LC-MS:m/z 372.2[M+H] + LC-MS: m/z 372.2[M+H] +
实施例14按照实施例5和实施例13的方法可以得到中间体(R)-N-((S)-2-(2-羟基丙烷-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺A35Example 14 According to the methods of Example 5 and Example 13, intermediate (R)-N-((S)-2-(2-hydroxypropan-2-yl)-5,7-dihydrospiro[cyclo] can be obtained pentadieno[b]pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide A35
Figure PCTCN2021126331-appb-000290
Figure PCTCN2021126331-appb-000290
LC-MS:m/z 366.2[M+H] + LC-MS: m/z 366.2[M+H] +
实施例15中间体(R)-N-((S)-2-(二氟甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A33的合成Example 15 Intermediate (R)-N-((S)-2-(difluoromethyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine Synthesis of ]-6-yl)-2-methylpropane-2-sulfinamide A33
步骤一：叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-甲酰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1Step 1: tert-butyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-formyl-4,6-dihydrospiro[cyclopentane Dieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-1
Figure PCTCN2021126331-appb-000291
Figure PCTCN2021126331-appb-000291
干燥的100mL圆底烧瓶中加入1'-(叔-丁基)2-甲基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1(1.3g，2.7mmol)和甲苯(26mL)，得到淡黄色溶液，氩气保护下冷至-70℃，慢慢滴入DIBAL-H(6.7mL，6.7mmol，1M in hexane)，反应1小时，LCMS显示只有少量原料反应，补加DIBAL-H(3.5mL，3.5mmol，1M in hexane)，继续反应1小时，LCMS显示剩余少量原料，且有少量过度还原产物存在。往反应液中慢慢加入5％柠檬酸水溶液淬灭反应(检测水相发现有较多脱Boc产物，Rt＝2.17min)，加入乙酸乙酯(40mL)和饱和食盐水(20mL)，搅拌分液，有机相干燥浓缩，粗品柱层析(300-400目硅胶，石油醚:四氢呋喃＝2:1)纯化得到496mg淡黄色泡沫状固体，水相用饱和碳酸氢钠溶液调至pH＝8左右，加入Boc酸酐反应至原料消失，后处理粗品柱层析(300-400目硅胶，石油醚:四氢呋喃＝2:1)纯化得到叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-甲酰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1(238mg，收率62％)，为淡黄色泡沫状固体。Into a dry 100 mL round bottom flask was added 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-4 ,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1 (1.3 g, 2.7 mmol) and toluene (26 mL) , a pale yellow solution was obtained, cooled to -70°C under the protection of argon, DIBAL-H (6.7mL, 6.7mmol, 1M in hexane) was slowly added dropwise, and the reaction was carried out for 1 hour. H (3.5 mL, 3.5 mmol, 1 M in hexane), the reaction was continued for 1 hour, LCMS showed a small amount of starting material remaining, and a small amount of overreduced product was present. Slowly add 5% citric acid aqueous solution to the reaction solution to quench the reaction (detect the aqueous phase and find that there are more de-Boc products, Rt=2.17min), add ethyl acetate (40mL) and saturated brine (20mL), stir to separate The organic phase was dried and concentrated, and the crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: tetrahydrofuran=2:1) to obtain 496 mg of pale yellow foamy solid, and the aqueous phase was adjusted to pH=8 with saturated sodium bicarbonate solution , Boc acid anhydride was added to react until the raw materials disappeared, and the crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: tetrahydrofuran=2:1) to obtain tert-butyl (S)-6-(((R)-tert-butyl) -Butylsulfinyl<sulfinyl>)amino)-2-formyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'- Carboxylic acid ester A33-1 (238 mg, yield 62%) as pale yellow foamy solid.
LC-MS:m/z 342.2[M-100+H] +； 1H NMR(400MHz,DMSO-d 6)δ9.89(s,1H),6.10(d,J＝10.1Hz,1H),4.61(d,J＝10.0Hz,1H),3.82(d,J＝15.8Hz,2H),3.12–2.78(m,4H),1.74–1.58(m,4H),1.41(s,9H),1.15(s,9H)ppm. LC-MS: m/z 342.2 [M-100+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 6.10 (d, J=10.1 Hz, 1H), 4.61 (d, J=10.0Hz, 1H), 3.82 (d, J=15.8Hz, 2H), 3.12–2.78 (m, 4H), 1.74–1.58 (m, 4H), 1.41 (s, 9H), 1.15 ( s,9H)ppm.
步骤二：叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(二氟甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-2Step 2: tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-(difluoromethyl)-4,6-dihydro Spiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-2
Figure PCTCN2021126331-appb-000292
Figure PCTCN2021126331-appb-000292
50mL圆底烧瓶中加入叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-甲酰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1(300mg，0.68mmol)和二氯甲烷(6mL)，淡黄色溶液，慢慢加入二乙胺基三氟化硫(219mg，1.36mmol)，室温反应1小时。反应液慢慢加入到冰水浴(10mL)中淬灭，搅拌分液，水相再次用二氯甲烷(10mL)萃取，合并有机相用饱和碳酸氢钠溶液(15mL)和饱和食盐水(15mL)洗涤，干燥浓缩，粗品(和小试批次合并)柱层析(300-400目硅胶，石油醚:四氢呋喃＝5:2)纯化得到叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(二氟甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-2(156mg，收率42％)，为淡黄色固体。To a 50mL round-bottomed flask, add tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-formyl-4,6-dihydrospiro [Cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-1 (300 mg, 0.68 mmol) and dichloromethane (6 mL), pale yellow solution, slowly added Diethylaminosulfur trifluoride (219 mg, 1.36 mmol) was reacted at room temperature for 1 hour. The reaction solution was slowly added to an ice-water bath (10 mL) to quench, and the liquid was separated by stirring. The aqueous phase was extracted with dichloromethane (10 mL) again, and the organic phases were combined with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL). Washed, dried and concentrated, the crude product (combined with the small batch) was purified by column chromatography (300-400 mesh silica gel, petroleum ether:tetrahydrofuran=5:2) to obtain tert-butyl(S)-6-((((R)) -tert-Butylsulfinyl<sulfinyl>)amino)-2-(difluoromethyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperin pyridine]-1'-carboxylate A33-2 (156 mg, 42% yield) as a pale yellow solid.
LC-MS:m/z 364.2[M-100+H] +； 1H NMR(400MHz,DMSO-d 6)δ7.30(t,J＝56Hz,1H),6.06(d,J＝10.1Hz,1H),4.54(d,J＝10.2Hz,1H),3.81(d,J＝15.5Hz,2H),3.14–2.73(m,4H),1.79–1.50(m,5H),1.41(s,9H),1.14(s,9H)ppm. LC-MS: m/z 364.2 [M-100+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.30 (t, J=56 Hz, 1H), 6.06 (d, J=10.1 Hz, 1H), 4.54(d, J＝10.2Hz, 1H), 3.81(d, J＝15.5Hz, 2H), 3.14-2.73(m, 4H), 1.79-1.50(m, 5H), 1.41(s, 9H) ),1.14(s,9H)ppm.
步骤三：按照实施例2的方法脱保护得到中间体(R)-N-((S)-2-(二氟甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺A33Step 3: Deprotection according to the method of Example 2 to obtain intermediate (R)-N-((S)-2-(difluoromethyl)-4,6-dihydrospiro[cyclopentadieno[d]] Thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide A33
Figure PCTCN2021126331-appb-000293
Figure PCTCN2021126331-appb-000293
LC-MS:m/z 364.2[M+H] +. LC-MS: m/z 364.2[M+H] + .
实施例16中间体(R)-2-甲基-N-((S)-5-苯基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺A18Example 16 Intermediate (R)-2-methyl-N-((S)-5-phenyl-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)propane -2-Sulfenamide A18
步骤一：叔丁基-1-氧代-6-苯基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A18-1Step 1: tert-butyl-1-oxo-6-phenyl-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A18-1
Figure PCTCN2021126331-appb-000294
Figure PCTCN2021126331-appb-000294
在50mL双口瓶中加入叔丁基6-溴-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A10-1(200mg,0.53mmol),苯硼酸(96.93mg,0.80mmol),Pd(dppf)Cl 2(38.78mg,0.053mmol),碳酸钾(219.75mg,1.59mmol)和1，4-二氧六环-水(4mL-1mL)，氮气保护下于90℃搅拌2小时，反应完全后用乙酸乙酯和水萃取，有机层用饱和食盐水洗涤后旋干，粗品用快速分离柱(石油醚：乙酸 乙酯10:1)得到叔丁基-1-氧代-6-苯基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A18-1(200mg，收率99.97％)。 Add tert-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A10-1( 200mg, 0.53mmol), phenylboronic acid (96.93mg, 0.80mmol), Pd(dppf)Cl 2 (38.78mg, 0.053mmol), potassium carbonate (219.75mg, 1.59mmol) and 1,4-dioxane-water (4mL-1mL), stirred at 90°C for 2 hours under nitrogen protection, extracted with ethyl acetate and water after the reaction was completed, the organic layer was washed with saturated brine and then spin-dried, and the crude product was used with a rapid separation column (petroleum ether: ethyl acetate) 10:1) to obtain tert-butyl-1-oxo-6-phenyl-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A18-1( 200 mg, yield 99.97%).
LCMS:m/z 348.2[M+H] +. LCMS: m/z 348.2[M+H] + .
按照实施例2的方方，以叔丁基6-溴-1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯A10-1为原料可以得到(R)-2-甲基-N-((S)-5-苯基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺A18According to the recipe of Example 2, tert-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester A10- 1 is the starting material to obtain (R)-2-methyl-N-((S)-5-phenyl-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)propane -2-Sulfenamide A18
Figure PCTCN2021126331-appb-000295
Figure PCTCN2021126331-appb-000295
LCMS:m/z 382.57[M+H] +. LCMS: m/z 382.57[M+H] + .
实施例17中间体(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-N-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-2-甲酰胺A55Example 17 Intermediate (S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-N-methyl-4,6-dihydrospiro[cyclopentadiene [d]thiazole-5,4'-piperidine]-2-carboxamide A55
步骤一：叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(甲基氨基甲酰)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A55-1Step 1: tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-(methylcarbamoyl)-4,6-di Hydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A55-1
Figure PCTCN2021126331-appb-000296
Figure PCTCN2021126331-appb-000296
干燥的50mL双口烧瓶中加入MeNH 2/THF(10.6mL，10.60mmol，1M in THF)和无水甲醇(9mL)，氩气保护下冷至0-5℃，慢慢滴入四异丙醇钛(907mg，3.19mmol)，得到淡黄色溶液，0-5℃反应15min，1'-(叔-丁基)2-甲基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1',2-二羧酸酯A29-1(940mg，2.13mmol)溶于无水甲醇(9mL)后慢慢滴入反应液，0-5℃反应1小时，硼氢化钠(161mg，4.26mmol)加入，随后室温反应1小时，LCMS显示反应完全。加入二氯甲烷(40mL)稀释反应液，然后慢慢加入水(30mL)淬灭反应，搅拌15分钟后硅藻土过滤，滤饼用二氯甲烷(15mL X 4)洗涤，滤液用饱和食盐水(30mL X 2)洗涤，干燥浓缩，粗品柱层析(300-400目硅胶，二氯甲烷：甲醇(V/V)＝50:1)纯化得到叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(甲基氨基甲酰)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A55-1淡黄色泡沫状固体(162mg，收率17.2％)。 MeNH 2 /THF (10.6 mL, 10.60 mmol, 1 M in THF) and anhydrous methanol (9 mL) were added to a dry 50 mL two-necked flask, cooled to 0-5 °C under argon protection, and tetraisopropanol was slowly added dropwise. Titanium (907mg, 3.19mmol), a pale yellow solution was obtained, reacted at 0-5°C for 15min, 1'-(tert-butyl)2-methyl(S)-6-(((R)-tert-butylidene Sulfuryl<sulfinyl>)amino)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1',2-dicarboxylate A29-1 (940 mg, 2.13 mmol) was dissolved in anhydrous methanol (9 mL) and slowly added dropwise to the reaction solution, reacted at 0-5 °C for 1 hour, sodium borohydride (161 mg, 4.26 mmol) was added, and then reacted at room temperature for 1 hour, LCMS showed the reaction completely. Dichloromethane (40 mL) was added to dilute the reaction solution, and then water (30 mL) was slowly added to quench the reaction. After stirring for 15 minutes, celite was filtered. The filter cake was washed with dichloromethane (15 mL×4), and the filtrate was washed with saturated brine. (30mL×2) washed, dried and concentrated, and the crude product was purified by column chromatography (300-400 mesh silica gel, dichloromethane:methanol (V/V)=50:1) to obtain tert-butyl (S)-6-(( (R)-tert-butylsulfinyl<sulfinyl>)amino)-2-(methylcarbamoyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5, 4'-Piperidine]-1'-carboxylate A55-1 pale yellow foamy solid (162 mg, 17.2% yield).
LC-MS:m/z 371.2[M-100+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.79(q,J＝4.7Hz,1H),6.01(d,J＝10.1Hz,1H),4.52(d,J＝10.0Hz,1H),3.98–3.68(m,2H),3.16–2.81(m,3H),2.83–2.60(m,4H),1.86–1.50(m,4H),1.41(s,9H),1.14(s,9H). LC-MS: m/z 371.2 [M-100+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (q, J=4.7 Hz, 1H), 6.01 (d, J=10.1 Hz ,1H),4.52(d,J＝10.0Hz,1H),3.98-3.68(m,2H),3.16-2.81(m,3H),2.83-2.60(m,4H),1.86-1.50(m,4H) ),1.41(s,9H),1.14(s,9H).
步骤二：按照实施例2的方法叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-(甲基 氨基甲酰)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A55-1脱去Boc保护基得到(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-N-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-2-甲酰胺A55Step 2: tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-(methylcarbamoyl) according to the method of Example 2 -4,6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A55-1 removes the Boc protecting group to give (S)-6-( ((R)-tert-butylsulfinyl<sulfinyl>)amino)-N-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperin pyridine]-2-carboxamide A55
Figure PCTCN2021126331-appb-000297
Figure PCTCN2021126331-appb-000297
LC-MS:m/z 371.2[M+H] +； LC-MS: m/z 371.2 [M+H] + ;
实施例18中间体(R)-2-甲基-N-((S)-2-((甲基氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-4-基)丙烷-2-亚磺酰胺A56Example 18 Intermediate (R)-2-methyl-N-((S)-2-((methylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole -5,4'-Piperidin]-4-yl)propane-2-sulfinamide A56
步骤一：叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-((甲基氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1Step 1: tert-butyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-((methylamino)methyl)-4,6 -Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A56-1
Figure PCTCN2021126331-appb-000298
Figure PCTCN2021126331-appb-000298
干燥的50mL双口烧瓶中加入MeNH 2/THF(10.6mL，10.60mmol，1M in THF)和无水甲醇(9mL)，氩气保护下冷至0-5℃，慢慢滴入四异丙醇钛(907mg，3.19mmol)，得到淡黄色溶液，0-5℃反应15min，叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-甲酰基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A33-1(940mg，2.13mmol)溶于无水甲醇(9mL)后慢慢滴入反应液，0-5℃反应1小时，硼氢化钠(161mg，4.26mmol)加入，随后室温反应1小时，LCMS显示反应完全。加入二氯甲烷(40mL)稀释反应液，然后慢慢加入水(30mL)淬灭反应，搅拌15分钟后硅藻土过滤，滤饼用二氯甲烷(15mL X 4)洗涤，滤液用饱和食盐水(30mL X 2)洗涤，干燥浓缩，粗品柱层析(300-400目硅胶，二氯甲烷：甲醇(V/V)＝9:1)纯化得到叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-((甲基氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1(472mg，收率48％)，为淡黄色固体。 MeNH 2 /THF (10.6 mL, 10.60 mmol, 1 M in THF) and anhydrous methanol (9 mL) were added to a dry 50 mL two-necked flask, cooled to 0-5 °C under argon protection, and tetraisopropanol was slowly added dropwise. Titanium (907mg, 3.19mmol), a pale yellow solution was obtained, reacted at 0-5°C for 15min, tert-butyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino )-2-formyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A33-1 (940 mg, 2.13 mmol) dissolved in The reaction solution was slowly added dropwise to anhydrous methanol (9 mL), reacted at 0-5 °C for 1 hour, sodium borohydride (161 mg, 4.26 mmol) was added, and then reacted at room temperature for 1 hour. LCMS showed that the reaction was complete. Dichloromethane (40 mL) was added to dilute the reaction solution, and then water (30 mL) was slowly added to quench the reaction. After stirring for 15 minutes, celite was filtered. The filter cake was washed with dichloromethane (15 mL×4), and the filtrate was washed with saturated brine. (30mL×2) washed, dried and concentrated, and the crude product was purified by column chromatography (300-400 mesh silica gel, dichloromethane:methanol (V/V)=9:1) to obtain tert-butyl (S)-6-(( (R)-tert-Butylsulfinyl<sulfinyl>)amino)-2-((methylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole- 5,4'-Piperidine]-1'-carboxylate A56-1 (472 mg, yield 48%) as pale yellow solid.
LC-MS:m/z 401.2[M-55] +； 1H NMR(400MHz,DMSO-d 6)δ5.85(d,J＝10.0Hz,1H),4.38(d,J＝9.9Hz,1H),3.92-3.74(m,4H),3.10–2.80(m,2H),2.79–2.60(m,2H),2.33(s,3H),1.75–1.48(m,4H),1.41(s,9H),1.28(s,1H),1.13(s,9H). LC-MS: m/z 401.2 [M-55] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 5.85 (d, J=10.0 Hz, 1H), 4.38 (d, J=9.9 Hz, 1H ),3.92-3.74(m,4H),3.10-2.80(m,2H),2.79-2.60(m,2H),2.33(s,3H),1.75-1.48(m,4H),1.41(s,9H) ),1.28(s,1H),1.13(s,9H).
步骤二：按照实施例2的方法叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-((甲基氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1脱去Boc保护基得到(R)-2-甲基-N-((S)-2-((甲基氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-4-基)丙烷-2-亚磺酰胺A56Step 2: tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-((methylamino)methane according to the method of Example 2 (R)-2 -Methyl-N-((S)-2-((methylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]- 4-yl)propane-2-sulfinamide A56
Figure PCTCN2021126331-appb-000299
Figure PCTCN2021126331-appb-000299
LC-MS:m/z 357.2[M+H] +. LC-MS: m/z 357.2[M+H] + .
实施例19中间体(R)-N-((S)-2-((二甲氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-4-基)-2-甲基丙烷-2-亚磺酰胺A57Example 19 Intermediate (R)-N-((S)-2-((dimethylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4' -Piperidin]-4-yl)-2-methylpropane-2-sulfinamide A57
步骤一：叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-((二甲氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A57-1Step 1: tert-butyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-((dimethylamino)methyl)-4,6 -Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A57-1
Figure PCTCN2021126331-appb-000300
Figure PCTCN2021126331-appb-000300
50mL反应瓶加入叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-((甲基氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A56-1(250mg，0.547mmol)和无水甲醇(10mL)，淡黄色溶液，加入多聚甲醛(99mg，3.28mmol)，NaBH 3CN(206mg，3.28mmol)和醋酸(197mg，3.28mmol)，悬浮反应1h，LCMS只有少量原料转化，补加多聚甲醛(99mg，3.28mmol)，NaBH 3CN(206mg，3.28mmol)和醋酸(197mg，3.28mmol)，悬浮液继续反应1小时，LCMS显示反应完全。反应液中加入二氯甲烷(40mL)稀释，慢慢加入饱和NaHCO 3溶液(40mL)，搅拌分液，水相用二氯甲烷(30mL)萃取，合并有机相用brine(30mL)洗涤，干燥浓缩，粗品柱层析(300-400目硅胶，二氯甲烷:甲醇＝15:1)纯化得到叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-((二甲氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A57-1(232mg，90％收率)，为类白色固体。 50mL reaction flask was added with tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-((methylamino)methyl)-4, 6-Dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylate A56-1 (250 mg, 0.547 mmol) and anhydrous methanol (10 mL), pale yellow The solution was added with paraformaldehyde (99mg, 3.28mmol), NaBH 3 CN (206mg, 3.28mmol) and acetic acid (197mg, 3.28mmol), the suspension reaction was carried out for 1h, only a small amount of raw materials were converted by LCMS, and paraformaldehyde (99mg, 3.28mmol) was added. mmol), NaBH3CN (206 mg, 3.28 mmol) and acetic acid (197 mg, 3.28 mmol), the suspension was reacted for 1 hour, and LCMS showed that the reaction was complete. Dichloromethane (40 mL) was added to the reaction solution to dilute, and saturated NaHCO 3 solution (40 mL) was added slowly, and the liquid was separated by stirring. The aqueous phase was extracted with dichloromethane (30 mL), and the combined organic phases were washed with brine (30 mL), dried and concentrated. , the crude product was purified by column chromatography (300-400 mesh silica gel, dichloromethane:methanol=15:1) to obtain tert-butyl(S)-6-(((R)-tert-butylsulfinyl<sulfinyl Acyl>)amino)-2-((dimethylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-1'-carboxylic acid Ester A57-1 (232 mg, 90% yield) as an off-white solid.
LC-MS:m/z 471.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ5.88(d,J＝10.0Hz,1H),4.39(d,J＝9.9Hz,1H),3.92–2.74(m,2H),3.68(s,2H),3.10–2.82(m,2H),2.81–2.62(m,2H),2.25(s,6H),1.72–1.48(m,4H),1.40(s,9H),1.12(s,9H)ppm. LC-MS: m/z 471.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 5.88 (d, J=10.0 Hz, 1H), 4.39 (d, J=9.9 Hz, 1H ), 3.92–2.74(m, 2H), 3.68(s, 2H), 3.10–2.82(m, 2H), 2.81–2.62(m, 2H), 2.25(s, 6H), 1.72–1.48(m, 4H ),1.40(s,9H),1.12(s,9H)ppm.
步骤二：按照实施例2的方法叔-丁基(S)-6-(((R)-叔-丁基亚硫酰基<亚磺酰>)氨基)-2-((二甲氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-1'-羧酸酯A57-1脱去Boc保护基得到(R)-N-((S)-2-((二甲氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-4-基)-2-甲基丙烷-2-亚磺酰胺A57。Step 2: tert-butyl(S)-6-((((R)-tert-butylsulfinyl<sulfinyl>)amino)-2-((dimethylamino)methyl according to the method of Example 2 (R)-N -((S)-2-((dimethylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-4-yl)- 2-Methylpropane-2-sulfinamide A57.
Figure PCTCN2021126331-appb-000301
Figure PCTCN2021126331-appb-000301
LC-MS:m/z 371.2[M+H] +. LC-MS: m/z 371.2[M+H] + .
实施例20中间体3-氯-2-甲基吡啶-4-硫醇钠B2的合成Example 20 Synthesis of intermediate 3-chloro-2-methylpyridine-4-sodium thiolate B2
步骤一：甲基3-((2,3-二氯吡啶-4-基)硫代)丙酸酯B2-1Step 1: Methyl 3-((2,3-dichloropyridin-4-yl)thio)propionate B2-1
Figure PCTCN2021126331-appb-000302
Figure PCTCN2021126331-appb-000302
氮气保护下向干燥的100mL圆底烧瓶中依次加入2,3-二氯-4-碘吡啶(3.2g,11.68mmol)，醋酸钯(92mg，0.41mmol)，Xantphos(285mg,0.49mmol)，DIPEA(2.12g,16.46mmol)和1，4-二氧六环(30mL)。此反应混合物在100℃加热搅拌2小时。过滤并减压浓缩，得到的残留物通过硅胶色谱法纯化(0至30％梯度的乙酸乙酯/石油醚)，得到甲基3-((2,3-二氯吡啶-4-基)硫代)丙酸酯B2-1(2.9g，收率：76％)。2,3-Dichloro-4-iodopyridine (3.2g, 11.68mmol), palladium acetate (92mg, 0.41mmol), Xantphos (285mg, 0.49mmol), DIPEA were added to a dry 100mL round-bottomed flask in sequence under nitrogen protection (2.12 g, 16.46 mmol) and 1,4-dioxane (30 mL). The reaction mixture was stirred with heating at 100°C for 2 hours. Filtration and concentration under reduced pressure gave a residue that was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/petroleum ether) to give methyl 3-((2,3-dichloropyridin-4-yl)thio substituted) propionate B2-1 (2.9 g, yield: 76%).
LCMS:m/z 266.1[M+H] +. LCMS: m/z 266.1[M+H] + .
步骤二：3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯B2-2Step 2: methyl 3-((3-chloro-2-methylpyridin-4-yl)thio) propionate B2-2
Figure PCTCN2021126331-appb-000303
Figure PCTCN2021126331-appb-000303
氮气保护下向干燥的100mL圆底烧瓶中依次加入3-((2,3-二氯吡啶-4-基)硫基)丙酸甲酯B2-1(500mg,1.88mmol)，Pd(PPh 3) 4(217mg,0.188mmol)，三甲基环三硼氧烷(354mg,2.82mmol)，碳酸钾(389mg,2.82mmol)和1,4-二氧六环(10mL)。此反应混合物在氮气保护下100℃加热搅拌6小时。过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至40％梯度的乙酸乙酯/石油醚)，得到3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯B2-2(320mg，收率：69％)。 Into a dry 100mL round-bottomed flask under nitrogen protection, methyl 3-((2,3-dichloropyridin-4-yl)sulfanyl)propanoate B2-1 (500mg, 1.88mmol), Pd(PPh 3 ) 4 (217 mg, 0.188 mmol), trimethylcyclotriboroxane (354 mg, 2.82 mmol), potassium carbonate (389 mg, 2.82 mmol) and 1,4-dioxane (10 mL). The reaction mixture was heated and stirred at 100°C for 6 hours under nitrogen protection. The resulting residue, which was filtered and concentrated under reduced pressure, was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give 3-((3-chloro-2-methylpyridin-4-yl)thio methyl) propionate B2-2 (320 mg, yield: 69%).
步骤二：3-氯-2-甲基吡啶-4-硫醇钠B2Step 2: Sodium 3-chloro-2-methylpyridine-4-thiolate B2
Figure PCTCN2021126331-appb-000304
Figure PCTCN2021126331-appb-000304
向干燥的100mL圆底烧瓶中依次加入3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯(320mg,1.30mmol)和四氢呋喃(10mL)，然后再室温下缓慢滴加乙醇钠的乙醇溶液(21％,2mL)，该反应液在室温搅拌1小时。减压下浓缩，然后加入二氯甲烷(10mL)，析出大量棕色固体，过滤，并用二氯甲烷洗涤，干燥后得到3-氯-2-甲基吡啶-4-硫醇钠B2(200mg,收率：85％)。Methyl 3-((3-chloro-2-methylpyridin-4-yl)sulfanyl)propanoate (320 mg, 1.30 mmol) and tetrahydrofuran (10 mL) were added to a dry 100 mL round bottom flask, followed by room temperature A solution of sodium ethoxide in ethanol (21%, 2 mL) was slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. Concentrated under reduced pressure, then dichloromethane (10 mL) was added, a large amount of brown solid was precipitated, filtered, washed with dichloromethane, and dried to obtain sodium 3-chloro-2-methylpyridine-4-thiolate B2 (200 mg, collected rate: 85%).
1H NMR(400MHz,DMSO-d 6)δ7.37(d,J＝4.8Hz,1H),6.97(d,J＝4.8Hz,1H),2.31(s,3H)ppm；LCMS:m/z 160.0[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.37 (d, J=4.8 Hz, 1H), 6.97 (d, J=4.8 Hz, 1H), 2.31 (s, 3H) ppm; LCMS: m/z 160.0[M+H] + .
按照实施例20的方法，用相应的原料和试剂可以合成得到如下中间体：According to the method of Example 20, the following intermediates can be synthesized with corresponding raw materials and reagents:
Figure PCTCN2021126331-appb-000305
Figure PCTCN2021126331-appb-000305
实施例21中间体(6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]恶嗪-4-硫化钾B4的合成Example 21 Intermediate (6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4 Synthesis of ]oxazine-4-potassium sulfide B4
步骤一：(2S,4R)-4-氟-2-(羟甲基)吡咯烷-1-甲酸叔丁酯B4-1Step 1: (2S,4R)-4-Fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester B4-1
Figure PCTCN2021126331-appb-000306
Figure PCTCN2021126331-appb-000306
在0℃下向(2S,4R)-1-(叔丁氧羰基)-4-氟吡咯烷-2-甲酸(8.00g，34.3mmol)的四氢呋喃(90.0mL)溶液中滴加硼烷·二甲硫醚(10.0M，10.2mL)溶液。反应液在25℃下反应4小时。TLC监测发现反应完毕。反应液用甲醇(200mL)淬灭，旋蒸除去溶剂之后加水，再用乙酸乙酯萃取，有机相洗涤，干燥，浓缩得到粗品产物(2S,4R)-4-氟-2-(羟甲基)吡咯烷-1-甲酸叔丁酯B4-1(7.50g，粗品)。To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (8.00 g, 34.3 mmol) in tetrahydrofuran (90.0 mL) was added dropwise borane·diol at 0°C Methyl sulfide (10.0 M, 10.2 mL) solution. The reaction solution was reacted at 25°C for 4 hours. TLC monitoring showed that the reaction was complete. The reaction solution was quenched with methanol (200 mL), the solvent was removed by rotary evaporation, water was added, extracted with ethyl acetate, the organic phase was washed, dried, and concentrated to obtain the crude product (2S,4R)-4-fluoro-2-(hydroxymethyl) ) tert-butyl pyrrolidine-1-carboxylate B4-1 (7.50 g, crude).
19F NMR(377MHz,DMSO-d 6)δ-174.85,-175.11ppm； 1H NMR(400MHz,DMSO-d 6)δ5.22(d,J＝53.2Hz,1H),4.81-4.71(m,1H),3.90-3.77(m,1H),3.77-3.59(m,1H),3.59-3.41(m,2H),3.32-3.18 (m,1H),2.24-1.99(m,2H),1.40(s,9H)ppm. 19 F NMR (377MHz, DMSO-d 6 ) δ-174.85, -175.11 ppm; 1 H NMR (400 MHz, DMSO-d 6 ) δ 5.22 (d, J=53.2 Hz, 1H), 4.81-4.71 (m, 1H),3.90-3.77(m,1H),3.77-3.59(m,1H),3.59-3.41(m,2H),3.32-3.18(m,1H),2.24-1.99(m,2H),1.40( s,9H)ppm.
步骤二：(2S,4R)-4-氟-2-((2-氟-4-碘吡啶-3-基)氧甲基)吡咯烷-1-甲酸叔丁酯B4-2Step 2: (2S,4R)-4-fluoro-2-((2-fluoro-4-iodopyridin-3-yl)oxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester B4-2
Figure PCTCN2021126331-appb-000307
Figure PCTCN2021126331-appb-000307
在25℃条件下向(2S,4R)-4-氟-2-(羟甲基)吡咯烷-1-甲酸叔丁酯B4-1(7.50g，34.2mmol)的四氢呋喃(100mL)溶液中加入偶氮二甲酸二乙酯(8.94g，51.3mmol)，三苯基膦(13.5g，51.3mmol)和2-氟-3羟-4碘吡啶(8.01g，33.5mmol)。反应16小时后，TLC监测发现反应完全。向反应液中加水淬灭，再用乙酸乙酯萃取，有机相洗涤，干燥浓缩，通过柱层析纯化得到纯品(2S,4R)-4-氟-2-((2-氟-4-碘吡啶-3-基)氧甲基)吡咯烷-1-羧酸叔丁酯B4-2(9.40g，61.9％收率)。To a solution of (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester B4-1 (7.50 g, 34.2 mmol) in tetrahydrofuran (100 mL) was added at 25°C Diethyl azodicarboxylate (8.94 g, 51.3 mmol), triphenylphosphine (13.5 g, 51.3 mmol) and 2-fluoro-3hydroxy-4iodopyridine (8.01 g, 33.5 mmol). After 16 hours of reaction, TLC monitoring showed that the reaction was complete. The reaction solution was quenched by adding water, extracted with ethyl acetate, washed with the organic phase, dried and concentrated, and purified by column chromatography to obtain pure (2S,4R)-4-fluoro-2-((2-fluoro-4- Iodopyridin-3-yl)oxymethyl)pyrrolidine-1-carboxylate tert-butyl ester B4-2 (9.40 g, 61.9% yield).
19F NMR(377MHz,CHLOROFORM-d)δ-77.82,-77.95,-176.08,-176.83ppm； 1H NMR(400MHz,CHLOROFORM-d)δ7.61-7.53(m,2H),5.37-5.17(m,1H),4.62-4.21(m,3H),4.10-3.81(m,1H),3.71-3.52(m,1H),2.65-2.43(m,2H),1.47(s,9H)ppm；LCMS:m/z 384.9[M+H-56] +. 19 F NMR (377MHz, CHLOROFORM-d)δ-77.82,-77.95,-176.08,-176.83ppm; 1 H NMR (400MHz, CHLOROFORM-d)δ7.61-7.53(m,2H),5.37-5.17(m ,1H),4.62-4.21(m,3H),4.10-3.81(m,1H),3.71-3.52(m,1H),2.65-2.43(m,2H),1.47(s,9H)ppm; LCMS: m/z 384.9[M+H-56] + .
步骤三：2-氟-3-(((2S,4R)-4-氟吡咯烷-2-基)氧甲基)-4-碘吡啶·盐酸盐B4-3Step 3: 2-Fluoro-3-(((2S,4R)-4-fluoropyrrolidin-2-yl)oxymethyl)-4-iodopyridine·hydrochloride B4-3
Figure PCTCN2021126331-appb-000308
Figure PCTCN2021126331-appb-000308
将(2S,4R)-4-氟-2-((2-氟-4-碘吡啶-3-基)甲氧基)吡咯烷-1-甲酸叔丁酯B4-2(9.40g，21.4mmol)加入到盐酸的二氧六环(4.00M，107mL)溶液中。反应液在25℃下反应2小时。TLC监测发现反应完全。反应液过滤并收集固体。固体真空干燥后，得到产物2-氟-3-((2S,4R)-4-氟吡咯烷-2-基)甲氧基)-4-碘吡啶·盐酸盐B4-3(7.50g，粗品)。(2S,4R)-4-fluoro-2-((2-fluoro-4-iodopyridin-3-yl)methoxy)pyrrolidine-1-carboxylate tert-butyl ester B4-2 (9.40 g, 21.4 mmol ) was added to a solution of hydrochloric acid in dioxane (4.00 M, 107 mL). The reaction solution was reacted at 25°C for 2 hours. The reaction was found to be complete by TLC monitoring. The reaction solution was filtered and the solid was collected. After the solid was dried in vacuo, the product 2-fluoro-3-((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-4-iodopyridine·hydrochloride B4-3 (7.50 g, Crude).
19F NMR(377MHz,DMSO-d 6)δ-79.14,-173.98ppm； 1H NMR(400MHz,DMSO-d 6)δ10.50-10.16(m,1H),10.02-9.64(m,1H),7.85-7.79(m,1H),7.71-7.62(m,1H),5.62-5.41(m,1H),4.52-4.45(m,2H),4.11(br s,1H),3.71-3.52(m,2H),2.48(br s,1H),2.29-2.08(m,1H)ppm；LCMS:m/z 340.9[M+H] +. 19 F NMR (377MHz, DMSO-d 6 )δ-79.14,-173.98ppm; 1 H NMR (400MHz, DMSO-d 6 )δ 10.50-10.16(m,1H),10.02-9.64(m,1H), 7.85-7.79(m, 1H), 7.71-7.62(m, 1H), 5.62-5.41(m, 1H), 4.52-4.45(m, 2H), 4.11(br s, 1H), 3.71-3.52(m, 2H), 2.48(br s, 1H), 2.29-2.08(m, 1H) ppm; LCMS: m/z 340.9[M+H] + .
步骤四：(6aS,8R)-8-氟-4-碘-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]恶嗪B4-4Step 4: (6aS,8R)-8-Fluoro-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1 ,4]oxazine B4-4
Figure PCTCN2021126331-appb-000309
Figure PCTCN2021126331-appb-000309
向2-氟-3-((2S,4R)-4-氟吡咯烷-2-基)甲氧基)-4-碘吡啶·盐酸盐B4-3(7.50g，20.0mmol)的乙醇(100mL)溶液中加入碳酸钾(12.2g，88.2mmol)。反应液在25℃下反应14小时。LCMS监测发现反应完毕。将反应液浓缩除去溶剂，然后用水和乙酸乙酯萃取。有机相用饱和食盐水洗涤，干燥，过滤，浓缩。粗品通过柱层析纯化得到(6aS,8R)-8-氟-4-碘-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]恶嗪B4-4(6.20g，87.5％收率)。To 2-fluoro-3-((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-4-iodopyridine·hydrochloride B4-3 (7.50 g, 20.0 mmol) in ethanol ( 100 mL) solution was added potassium carbonate (12.2 g, 88.2 mmol). The reaction solution was reacted at 25°C for 14 hours. LCMS monitoring found that the reaction was complete. The reaction solution was concentrated to remove the solvent, and then extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried, filtered and concentrated. The crude product was purified by column chromatography to give (6aS,8R)-8-fluoro-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2- d] [1,4]oxazine B4-4 (6.20 g, 87.5% yield).
19F NMR(377MHz,CDCl 3)δ-172.93ppm； 1H NMR(400MHz,CDCl 3)δ7.41(d,J＝5.6Hz,1H),6.94(d,J＝5.6Hz,1H),5.53-5.35(m,1H),4.65(dd,J＝10.4,3.6Hz,1H),4.12-4.02(m,1H),3.98-3.91(m,1H),3.90-3.81(m,1H),3.52(t,J＝10.0Hz,1H),2.52-2.41(m,1H),1.74-1.57(m,1H)ppm；LCMS:m/z 321.2[M+H] +. 19 F NMR (377 MHz, CDCl 3 ) δ-172.93 ppm; 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J=5.6 Hz, 1H), 6.94 (d, J=5.6 Hz, 1H), 5.53 -5.35(m,1H),4.65(dd,J=10.4,3.6Hz,1H),4.12-4.02(m,1H),3.98-3.91(m,1H),3.90-3.81(m,1H),3.52 (t, J=10.0Hz, 1H), 2.52-2.41 (m, 1H), 1.74-1.57 (m, 1H) ppm; LCMS: m/z 321.2[M+H] + .
步骤五：3-(((6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯[1,2-d][1,4]恶嗪-4-基)巯基)丙酸(2-乙基己基)酯B4-5Step 5: 3-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrole[1,2-d][1, 4] Oxazin-4-yl)mercapto)propionic acid (2-ethylhexyl)ester B4-5
Figure PCTCN2021126331-appb-000310
Figure PCTCN2021126331-appb-000310
向(6aS,8R)-8-氟-4-碘-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]恶嗪B4-4(1.00g，3.12mmol)的二氧六环(10mL)溶液中加入N,N-二异丙基乙胺(1.21g，9.37mmol)、三(二亚苄基丙酮)二钯(143mg，156umol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(90.4mg，156umol)和3-巯基丙酸-2-乙基-己酯(1.02g，4.69mmol)。反应液在25℃下反应14小时。TLC监测反应完毕。反应液除去溶剂，残渣通过柱层析纯化得到3-(((6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯[1,2-d][1,4]恶嗪-4-基)巯基)丙酸(2-乙基己基)酯B4-5(1.26g，98.2％收率)。To (6aS,8R)-8-fluoro-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4 ] To a solution of oxazine B4-4 (1.00g, 3.12mmol) in dioxane (10mL) was added N,N-diisopropylethylamine (1.21g, 9.37mmol), tris(dibenzylideneacetone) Dipalladium (143 mg, 156 umol), 4,5-bis(diphenylphosphonium)-9,9-dimethylxanthene (90.4 mg, 156 umol) and 2-ethyl-hexyl 3-mercaptopropionate (1.02 g, 4.69 mmol). The reaction solution was reacted at 25°C for 14 hours. The completion of the reaction was monitored by TLC. The solvent was removed from the reaction solution, and the residue was purified by column chromatography to obtain 3-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrole[ 1,2-d][1,4]oxazin-4-yl)mercapto)propionic acid (2-ethylhexyl)ester B4-5 (1.26 g, 98.2% yield).
19F NMR(377MHz,CDCl 3)δ-172.97ppm； 1H NMR(400MHz,CDCl 3)δ7.63(d,J＝5.2Hz,1H),6.41(d,J＝5.2Hz,1H),5.43-5.25(m,1H),4.59-4.53(m,1H),3.99-3.75(m,5H),3.41(t,J＝10.0Hz,1H),3.13(t,J＝8.0Hz,2H),2.62(t,J＝8.0Hz,2H),2.43-2.32(m,1H),1.69-1.59(m,2H),1.58-1.45(m,2H),1.24-1.16(m,6H),0.82(t,J＝7.2Hz,6H)ppm. 19 F NMR (377 MHz, CDCl 3 ) δ-172.97 ppm; 1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (d, J=5.2 Hz, 1 H), 6.41 (d, J=5.2 Hz, 1 H), 5.43 -5.25(m,1H),4.59-4.53(m,1H),3.99-3.75(m,5H),3.41(t,J=10.0Hz,1H),3.13(t,J=8.0Hz,2H), 2.62(t, J＝8.0Hz, 2H), 2.43-2.32(m, 1H), 1.69-1.59(m, 2H), 1.58-1.45(m, 2H), 1.24-1.16(m, 6H), 0.82( t,J=7.2Hz,6H)ppm.
步骤六：(6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]恶嗪-4-硫化钾B4Step Six: (6aS,8R)-8-Fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxa oxazine-4-potassium sulfide B4
Figure PCTCN2021126331-appb-000311
Figure PCTCN2021126331-appb-000311
在-10℃下，向2-3-(((6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯[1,2-d][1,4]恶嗪-4-基)巯基)丙酸(2-乙基己基)酯(1.26g，3.07mmol)的四氢呋喃(8mL)溶液中加入叔丁醇钾溶液(1M，3.38mL，3.38mmol)。反应液在0℃下反应1小时。TLC监测反应完毕，加入乙酸乙酯淬灭，然后过滤，收集固体。固体洗涤，干燥后即得产物(6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]恶嗪-4-硫化钾(700mg，82.0％收率)。2-3-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrole[1,2 -d][1,4]oxazin-4-yl)mercapto)propionate (2-ethylhexyl)ester (1.26 g, 3.07 mmol) in tetrahydrofuran (8 mL) was added potassium tert-butoxide solution (1 M, 3.38 mL, 3.38 mmol). The reaction solution was reacted at 0°C for 1 hour. The completion of the reaction was monitored by TLC, quenched by the addition of ethyl acetate, and the solid was collected by filtration. The solid was washed and dried to obtain the product (6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][ 1,4]oxazine-4-potassium sulfide (700 mg, 82.0% yield).
19F NMR(377MHz,DMSO-d 6)δ-172.09ppm； 1H NMR(400MHz,DMSO-d 6)δ6.94(d,J＝5.6Hz,1H),6.35(d,J＝5.2Hz,1H),5.46-5.27(m,1H),4.36(dd,J＝10.0,3.6Hz,1H),3.76-3.67(m,1H),3.66-3.55(m,2H),3.08(t,J＝9.6Hz,1H),2.31-2.19(m,1H),1.80-1.60(m,1H)ppm；LCMS:m/z 227.3[M-39+2H] + 19 F NMR (377 MHz, DMSO-d 6 ) δ-172.09 ppm; 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.94 (d, J=5.6 Hz, 1H), 6.35 (d, J=5.2 Hz, 1H), 5.46-5.27(m, 1H), 4.36(dd, J=10.0, 3.6Hz, 1H), 3.76-3.67(m, 1H), 3.66-3.55(m, 2H), 3.08(t, J= 9.6Hz, 1H), 2.31-2.19(m, 1H), 1.80-1.60(m, 1H) ppm; LCMS: m/z 227.3[M-39+2H] +
按照实施例21的方法，用相应的原料和试剂可以合成得到中间体(S)-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]噁嗪-4-硫醇B3According to the method of Example 21, the intermediate (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2 can be synthesized by using the corresponding raw materials and reagents -d][1,4]oxazine-4-thiol B3
Figure PCTCN2021126331-appb-000312
Figure PCTCN2021126331-appb-000312
LCMS:m/z 209.1LCMS: m/z 209.1
实施例22中间体2-氯-3-(吡咯烷-1-基)苯硫酚B10的合成Example 22 Synthesis of intermediate 2-chloro-3-(pyrrolidin-1-yl)thiophenol B10
步骤一：叔丁基(2-氯-3-碘苯基)硫醚B10-1Step 1: tert-butyl (2-chloro-3-iodophenyl) sulfide B10-1
Figure PCTCN2021126331-appb-000313
Figure PCTCN2021126331-appb-000313
在-5℃下向3-(叔丁基硫基)-2-氯-苯胺(5.00g,23.18mmol)的盐酸溶液(12M,25.0mL)滴加亚硝酸钠的水溶液(1.92g,27.8mmol,10mL),搅拌30分钟后加入碘化钾的水溶液(7.69g,46.3mmol,10mL),混合物在-5℃搅拌30分钟。反应完后用亚硫酸钠淬灭，萃取并干燥，经快速硅胶柱得叔丁基(2-氯-3-碘苯基)硫醚B10-1(5.00g,15.3mmol,66.05％产率)。To a solution of 3-(tert-butylthio)-2-chloro-aniline (5.00 g, 23.18 mmol) in hydrochloric acid (12 M, 25.0 mL) was added dropwise an aqueous solution of sodium nitrite (1.92 g, 27.8 mmol) at -5°C , 10 mL), after stirring for 30 minutes, an aqueous solution of potassium iodide (7.69 g, 46.3 mmol, 10 mL) was added, and the mixture was stirred at -5° C. for 30 minutes. After the reaction, it was quenched with sodium sulfite, extracted and dried to obtain tert-butyl (2-chloro-3-iodophenyl) sulfide B10-1 (5.00 g, 15.3 mmol, 66.05% yield) through a flash silica gel column.
1H NMR(400MHz,DMSO-d 6)δ7.98(dd,J＝1.3,7.9Hz,1H),7.67(dd,J＝1.3,7.6Hz,1H),7.09(t,J＝7.8Hz,1H),1.28(s,9H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.98 (dd, J=1.3, 7.9 Hz, 1H), 7.67 (dd, J=1.3, 7.6 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 1.28(s, 9H).
步骤二：1-(3-(叔丁基硫基)-2-氯苯基)吡咯烷B10-2Step 2: 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidine B10-2
Figure PCTCN2021126331-appb-000314
Figure PCTCN2021126331-appb-000314
将叔丁基(2-氯-3-碘苯基)硫醚B10-1(2.00g,6.12mmol)，四氢吡咯(870mg,12.25mmol)，叔丁醇钾(2.06g,18.3mmol)，2-双环己基膦-2，6-二异丙氧基-1,1-联苯(285mg,612umol)，RuPhos-Pd-G3(512mg，612umol)和二甲苯(10mL)的混合物在氮气氛围下120℃下搅拌18个小时。反应结束后，水洗、 萃取干燥浓缩后经快速硅胶柱和prep-HPLC纯化得1-(3-(叔丁基硫基)-2-氯苯基)吡咯烷B10-2(250mg，15.1％产率)。The tert-butyl (2-chloro-3-iodophenyl) sulfide B10-1 (2.00 g, 6.12 mmol), tetrahydropyrrole (870 mg, 12.25 mmol), potassium tert-butoxide (2.06 g, 18.3 mmol), A mixture of 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (285mg, 612umol), RuPhos-Pd-G3 (512mg, 612umol) and xylene (10mL) under nitrogen atmosphere Stir at 120°C for 18 hours. After the reaction, washed with water, extracted, dried and concentrated, purified by flash silica gel column and prep-HPLC to obtain 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidine B10-2 (250 mg, 15.1% yield). Rate).
1H NMR(400MHz,DMSO-d 6)δ7.22-7.13(m,2H),7.06(dd,J＝2.4,7.4Hz,1H),3.26(br t,J＝6.5Hz,4H),1.91-1.83(m,4H),1.28(s,9H)ppm；LCMS:m/z 270.2[M+H] + 1 H NMR (400MHz, DMSO-d 6 ) δ 7.22-7.13 (m, 2H), 7.06 (dd, J=2.4, 7.4Hz, 1H), 3.26 (br t, J=6.5Hz, 4H), 1.91 -1.83(m,4H),1.28(s,9H)ppm; LCMS: m/z 270.2[M+H] +
步骤三：2-氯-3-(吡咯烷-1-基)苯硫酚B10Step 3: 2-Chloro-3-(pyrrolidin-1-yl)thiophenol B10
Figure PCTCN2021126331-appb-000315
Figure PCTCN2021126331-appb-000315
在100℃下将1-(3-(叔丁基硫基)-2-氯苯基)吡咯烷B10-2(250mg，0.93mmol)的盐酸溶液(12M，2mL)在氮气氛围下搅拌1小时。反应完全后用碳酸氢钠溶液淬灭、萃取、选干得2-氯-3-(吡咯烷-1-基)苯硫酚B10(190mg,收率96.0％)。A solution of 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidine B10-2 (250 mg, 0.93 mmol) in hydrochloric acid (12 M, 2 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h . After the reaction was completed, it was quenched with sodium bicarbonate solution, extracted, and dried to obtain 2-chloro-3-(pyrrolidin-1-yl)thiophenol B10 (190 mg, yield 96.0%).
1H NMR(400MHz,DMSO-d 6)δ7.04-6.98(m,2H),6.79-6.69(m,1H),5.46(s,1H),3.28-3.13(m,4H),1.93-1.78(m,4H)ppm；LCMS:m/z 213.9[M+H] + 1 H NMR (400MHz, DMSO-d 6 ) δ 7.04-6.98(m, 2H), 6.79-6.69(m, 1H), 5.46(s, 1H), 3.28-3.13(m, 4H), 1.93-1.78 (m,4H)ppm; LCMS: m/z 213.9[M+H] +
实施例23中间体1-(2-氯-3-巯基苯基)吡咯烷-2-酮B9Example 23 Intermediate 1-(2-chloro-3-mercaptophenyl)pyrrolidin-2-one B9
步骤一：1-(3-(叔丁基硫基)-2-氯苯基)吡咯烷-2-酮B9-1Step 1: 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidin-2-one B9-1
Figure PCTCN2021126331-appb-000316
Figure PCTCN2021126331-appb-000316
将碘化亚铜(117mg，0.612mmol)，碳酸钾(846mg，6.12mmol)加入到甲苯(10mL)中，氮气置换，然后加入N,N'-二甲基乙二胺(108mg，1.22mmol)，叔丁基(2-氯-3-碘苯基)硫醚B10-1(1.00g，3.06mmol)和吡咯烷-2-酮(781.67mg，9.18mmol)的甲苯(10mL)溶液，氮气氛围下，100℃反应16小时。TLC监测发现原料有剩余。反应液真空浓缩，通过柱层析纯化，得到灰白色固体产物1-(3-(叔丁基硫基)-2-氯苯基)吡咯烷-2-酮B9-1(400mg，33.6％收率，73％纯度)。Cuprous iodide (117 mg, 0.612 mmol), potassium carbonate (846 mg, 6.12 mmol) were added to toluene (10 mL), nitrogen purged, followed by N,N'-dimethylethylenediamine (108 mg, 1.22 mmol) , tert-butyl (2-chloro-3-iodophenyl) sulfide B10-1 (1.00 g, 3.06 mmol) and pyrrolidin-2-one (781.67 mg, 9.18 mmol) in toluene (10 mL) under nitrogen atmosphere at 100°C for 16 hours. TLC monitoring revealed that the starting material was left over. The reaction solution was concentrated in vacuo and purified by column chromatography to obtain 1-(3-(tert-butylthio)-2-chlorophenyl)pyrrolidin-2-one B9-1 as an off-white solid product (400 mg, 33.6% yield). , 73% pure).
1H NMR(400MHz,DMSO-d 6)δ7.66(dd,J＝7.6,2.0Hz,1H),7.46-7.41(m,2H),3.70-3.65(m,2H),2.43-2.38(m,2H),2.17-2.12(m,2H),1.32-1.27(m,9H)ppm；LCMS:m/z 284.2[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.66 (dd, J=7.6, 2.0 Hz, 1H), 7.46-7.41 (m, 2H), 3.70-3.65 (m, 2H), 2.43-2.38 (m ,2H),2.17-2.12(m,2H),1.32-1.27(m,9H)ppm; LCMS: m/z 284.2[M+H] + .
步骤二：1-(2-氯-3-巯基苯基)吡咯烷-2-酮B9Step 2: 1-(2-Chloro-3-mercaptophenyl)pyrrolidin-2-one B9
Figure PCTCN2021126331-appb-000317
Figure PCTCN2021126331-appb-000317
将1-(3-(叔丁基硫基)-2-氯苯基)吡咯烷-2-酮B9-1(370mg，1.30mmol)和浓盐酸(4.0mL)的混合物，在氮气氛围下100℃反应1小时。LCMS监测发现反应完全。在-10℃氮气氛围下，将反应液滴加到饱和碳酸氢钠(40mL)溶液中，调节pH至1，然后过滤，滤饼用水洗涤，干燥，得到白色固体产物1-(2-氯-3-巯基苯基)吡咯烷-2-酮B9(210mg，54.7％收率)。A mixture of 1-(3-(tert-butylsulfanyl)-2-chlorophenyl)pyrrolidin-2-one B9-1 (370 mg, 1.30 mmol) and concentrated hydrochloric acid (4.0 mL) was added under nitrogen for 100 °C to react for 1 hour. The reaction was found to be complete by LCMS monitoring. Under a nitrogen atmosphere at -10°C, the reaction was added dropwise to saturated sodium bicarbonate (40 mL) solution to adjust the pH to 1, then filtered, the filter cake was washed with water, and dried to obtain a white solid product 1-(2-chloro- 3-Mercaptophenyl)pyrrolidin-2-one B9 (210 mg, 54.7% yield).
1H NMR(400MHz,CHLOROFORM-d)δ7.36-7.28(m,1H),7.19(t,J＝7.8Hz,1H),7.14-7.05(m,1H),3.97(s,1H),3.82-3.71(m,2H),2.64-2.53(m,2H),2.33-2.19(m,2H)ppm；LCMS:m/z 228.2[M+H] +. 1H NMR(400MHz, CHLOROFORM-d)δ7.36-7.28(m,1H),7.19(t,J=7.8Hz,1H),7.14-7.05(m,1H),3.97(s,1H),3.82- 3.71(m,2H), 2.64-2.53(m,2H), 2.33-2.19(m,2H)ppm; LCMS: m/z 228.2[M+H] + .
实施例24中间体2-氯-3-(吡嗪-2-基氨基)苯硫酚B6Example 24 Intermediate 2-chloro-3-(pyrazin-2-ylamino)thiophenol B6
步骤一：N-(3-(叔丁巯基)-2-氯苯基)吡嗪-2-胺B6-1Step 1: N-(3-(tert-butylmercapto)-2-chlorophenyl)pyrazine-2-amine B6-1
Figure PCTCN2021126331-appb-000318
Figure PCTCN2021126331-appb-000318
将2-氯吡嗪(1.27g，11.2mmol)，3-(叔丁基硫基)-2-氯苯胺(1.50g，6.95mmol)，叔丁醇钠(935mg，9.37mmol)，和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(804mg，1.39mmol)加入甲苯(40.0mL)中，置换氮气三次，再在氮气氛围下加入三(二亚苄基丙酮)二钯(636mg，0.659mmol)，120℃反应1.5小时，LCMS检测反应结束，饱和食盐水洗涤，有机相减压浓缩，粗品用快速硅胶柱纯化得到N-(3-(叔丁巯基)-2-氯苯基)吡嗪-2-胺B6-1(1.50g，66.1％收率)。2-Chloropyrazine (1.27 g, 11.2 mmol), 3-(tert-butylthio)-2-chloroaniline (1.50 g, 6.95 mmol), sodium tert-butoxide (935 mg, 9.37 mmol), and 4, 5-Bis(diphenylphosphorus)-9,9-dimethylxanthene (804 mg, 1.39 mmol) was added to toluene (40.0 mL), nitrogen was replaced three times, and tris(dibenzylidene) was added under nitrogen atmosphere Acetone) dipalladium (636 mg, 0.659 mmol), reacted at 120 ° C for 1.5 hours, LCMS detected the end of the reaction, washed with saturated brine, the organic phase was concentrated under reduced pressure, and the crude product was purified by flash silica gel column to obtain N-(3-(tert-butylmercapto) -2-Chlorophenyl)pyrazin-2-amine B6-1 (1.50 g, 66.1% yield).
1H NMR(400MHz,DMSO-d 6)δ8.95(s,1H),8.39(d,J＝1.3Hz,1H),8.08(dd,J＝1.4,2.7Hz,1H),8.00(dd,J＝1.6,8.2Hz,1H),7.97(d,J＝2.8Hz,1H),7.43-7.38(m,1H),7.36-7.28(m,1H),1.31(s,9H)ppm；LCMS m/z 294.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 8.39 (d, J=1.3Hz, 1H), 8.08 (dd, J=1.4, 2.7Hz, 1H), 8.00 (dd, J=1.6, 8.2Hz, 1H), 7.97 (d, J=2.8Hz, 1H), 7.43-7.38 (m, 1H), 7.36-7.28 (m, 1H), 1.31 (s, 9H) ppm; LCMS m /z 294.1[M+H] + .
步骤二:2-氯-3-(吡嗪-2-基氨基)苯硫酚B6Step 2: 2-chloro-3-(pyrazin-2-ylamino) thiophenol B6
Figure PCTCN2021126331-appb-000319
Figure PCTCN2021126331-appb-000319
将N-(3-(叔丁硫基)-2-氯苯基)吡嗪-2-胺B6-1(1.20g，4.08mmol)加入到100mL三口烧瓶中，氮气置换三次，加入浓盐酸(40.0mL)，100℃下反应1小时，LCMS检测反应结束，加饱和碳酸氢钠水溶液淬灭，有机相萃取，减压浓缩，粗品用快速硅胶柱纯化得到2-氯-3-(吡嗪-2-基氨基)苯硫酚B6(162mg，15.9％收率)。N-(3-(tert-butylthio)-2-chlorophenyl)pyrazine-2-amine B6-1 (1.20g, 4.08mmol) was added to a 100mL three-necked flask, nitrogen was replaced three times, concentrated hydrochloric acid ( 40.0 mL), reacted at 100 ° C for 1 hour, LCMS detected the end of the reaction, quenched with saturated aqueous sodium bicarbonate solution, extracted with the organic phase, concentrated under reduced pressure, and the crude product was purified with a flash silica column to obtain 2-chloro-3-(pyrazine- 2-ylamino)thiophenol B6 (162 mg, 15.9% yield).
1H NMR(400MHz,DMSO-d 6)δ8.89(s,1H),8.36(d,J＝1.3Hz,1H),8.07(dd,J＝1.3,2.6Hz,1H),7.96(d,J＝2.6Hz,1H),7.67(dd,J＝1.2,8.1Hz,1H),7.27(dd,J＝1.3,7.8Hz,1H),7.20-7.12(m,1H),5.76(s,1H)ppm；LCMS m/z 237.8[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.89 (s, 1H), 8.36 (d, J=1.3 Hz, 1H), 8.07 (dd, J=1.3, 2.6 Hz, 1H), 7.96 (d, J=2.6Hz, 1H), 7.67(dd, J=1.2, 8.1Hz, 1H), 7.27(dd, J=1.3, 7.8Hz, 1H), 7.20-7.12(m, 1H), 5.76(s, 1H) )ppm; LCMS m/z 237.8[M+H] + .
实施例25中间体3-氯-2-(吡嗪-2-基)吡啶-4-硫钾盐B8Example 25 Intermediate 3-chloro-2-(pyrazin-2-yl)pyridine-4-sulfur potassium salt B8
步骤一：3-((2,3-二氯吡啶-4-基)硫基)丙酸-2-乙基己酯B8-1Step 1: 3-((2,3-Dichloropyridin-4-yl)thio)propionic acid-2-ethylhexyl ester B8-1
Figure PCTCN2021126331-appb-000320
Figure PCTCN2021126331-appb-000320
将2,3-二氯-4-碘吡啶(5.5g，20.1mmol)，3-巯基丙酸-2-乙基己酯(5.7g，26.1mmol)，三(二亚苄基丙酮)二钯(368mg，401μmol),4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(232mg，401μmol)和N,N-二异丙基乙胺(7.79g，60.2mmol)溶于二氧六环(50mL)，抽置换氮气三次，反应液升温至108℃下反应2小时，LCMS检测无原料剩余，反应液过滤浓缩，浓缩物用快速硅胶柱纯化得到3-((2,3-二氯吡啶-4-基)硫基)丙酸-2-乙基己酯B8-1(4.62g，63.1％收率)。2,3-Dichloro-4-iodopyridine (5.5 g, 20.1 mmol), 2-ethylhexyl 3-mercaptopropionate (5.7 g, 26.1 mmol), tris(dibenzylideneacetone)dipalladium (368 mg, 401 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (232 mg, 401 μmol) and N,N-diisopropylethylamine (7.79 g, 60.2 mmol) ) was dissolved in dioxane (50 mL), and the nitrogen was replaced by suction three times. The reaction solution was heated to 108 ° C and reacted for 2 hours. LCMS detected no raw materials remaining. The reaction solution was filtered and concentrated, and the concentrate was purified with a fast silica gel column to obtain 3-(( 2,3-Dichloropyridin-4-yl)thio)propanoate-2-ethylhexyl ester B8-1 (4.62 g, 63.1% yield).
1H NMR(400MHz,CHLOROFORM-d)δ8.16(d,J＝5.3Hz,1H),7.04(d,J＝5.3Hz,1H),4.08-4.04(m,2H),3.30-3.23(m,2H),2.79-2.73(m,2H),1.61-1.54(m,1H),1.31-1.27(m,7H),0.93-0.86(m,7H)ppm. 1 H NMR(400MHz, CHLOROFORM-d)δ8.16(d,J=5.3Hz,1H),7.04(d,J=5.3Hz,1H),4.08-4.04(m,2H),3.30-3.23(m ,2H),2.79-2.73(m,2H),1.61-1.54(m,1H),1.31-1.27(m,7H),0.93-0.86(m,7H)ppm.
步骤二：3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫基)丙酸-2-乙基己酯B8-2Step 2: 3-((3-Chloro-2-(pyrazin-2-yl)pyridin-4-yl)thio)propionic acid-2-ethylhexyl ester B8-2
Figure PCTCN2021126331-appb-000321
Figure PCTCN2021126331-appb-000321
在反应瓶中依次加入3-((2,3-二氯吡啶-4-基)硫基)丙酸-2-乙基己酯B8-1(2.00g,5.49mmol)，2-(三丁基锡烷基)吡嗪(2.43g，6.59mmol)，碘化亚铜(83.6mg，439umol)，四三苯基磷钯(507mg，439umol)溶于二甲苯(20mL)中，抽置换氮气三次。反应液于氮气氛围下升温至160℃反8小时，降温至120℃再反应16小时。TLC监测反应结束后，降至室温，过滤浓缩，浓缩物用快速硅胶柱纯化得到3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫基)丙酸-2-乙基己酯B8-2(590mg，1.45mmol,26.3％收率)。3-((2,3-dichloropyridin-4-yl)sulfanyl)propionic acid-2-ethylhexyl ester B8-1 (2.00g, 5.49mmol), 2-(tributyltin) were sequentially added to the reaction flask Alkyl)pyrazine (2.43 g, 6.59 mmol), cuprous iodide (83.6 mg, 439 umol), tetrakistriphenylphosphonium palladium (507 mg, 439 umol) were dissolved in xylene (20 mL), and the nitrogen was pumped three times. The reaction solution was heated to 160°C for 8 hours under nitrogen atmosphere, then cooled to 120°C and reacted for 16 hours. After the reaction was monitored by TLC, it was cooled to room temperature, filtered and concentrated, and the concentrate was purified by flash silica gel column to obtain 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)sulfanyl)propionic acid -2-Ethylhexyl ester B8-2 (590 mg, 1.45 mmol, 26.3% yield).
1H NMR(400MHz,CHLOROFORM-d)δ8.98(br s,1H),8.74(br s,1H),8.66(br s,1H),8.47(d,J＝4.9Hz,1H),7.25(d,J＝4.9Hz,1H),4.07-4.04(m,2H),3.53-3.48(m,2H),2.86-2.81(m,2H),1.63-1.57(m,1H),1.33-1.27(m,7H),0.93-0.88(m,7H)ppm. 1 H NMR(400MHz, CHLOROFORM-d)δ8.98(br s,1H),8.74(br s,1H),8.66(br s,1H),8.47(d,J＝4.9Hz,1H),7.25( d, J＝4.9Hz, 1H), 4.07-4.04(m, 2H), 3.53-3.48(m, 2H), 2.86-2.81(m, 2H), 1.63-1.57(m, 1H), 1.33-1.27( m,7H),0.93-0.88(m,7H)ppm.
步骤三：3-氯-2-(吡嗪-2-基)吡啶-4-硫钾盐B8Step 3: 3-Chloro-2-(pyrazin-2-yl)pyridine-4-sulfur potassium salt B8
Figure PCTCN2021126331-appb-000322
Figure PCTCN2021126331-appb-000322
将3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫基)丙酸-2-乙基己酯B8-2(560mg,1.37mmol)的四氢呋喃(15mL)溶液降温至-68℃，然后将叔丁醇钾的四氢呋喃溶液(1M，2.75mL)滴加到反应体系中。逐步升温至25℃，反应12小时。LCMS监测反应结束后，过滤浓缩。粗产品用乙酸乙酯打浆纯化，得到黄色固体产物3-氯-2-(吡嗪-2-基)吡啶-4-硫钾盐B8(270mg，87.9％收率)。3-((3-Chloro-2-(pyrazin-2-yl)pyridin-4-yl)sulfanyl)propanoate-2-ethylhexyl ester B8-2 (560 mg, 1.37 mmol) in tetrahydrofuran (15 mL) ) solution was cooled to -68°C, and then a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 2.75 mL) was added dropwise to the reaction system. The temperature was gradually raised to 25°C, and the reaction was carried out for 12 hours. After the reaction was monitored by LCMS, it was filtered and concentrated. The crude product was purified by slurrying with ethyl acetate to give 3-chloro-2-(pyrazin-2-yl)pyridine-4-sulfur potassium salt B8 (270 mg, 87.9% yield) as a yellow solid product.
1H NMR(400MHz,DMSO-d 6)δ8.80-8.78(m,1H),8.72-8.69(m,1H),8.62(d,J＝2.5Hz,1H),7.87(d,J＝4.8Hz,1H),6.46(d,J＝4.8Hz,1H)ppm；LCMS:m/z 224.[M-K+2H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.80-8.78 (m, 1H), 8.72-8.69 (m, 1H), 8.62 (d, J=2.5Hz, 1H), 7.87 (d, J=4.8 Hz,1H),6.46(d,J=4.8Hz,1H)ppm; LCMS: m/z 224.[M-K+2H] + .
实施例26中间体2-氯-3-(恶唑-2-基)苯硫酚B12Example 26 Intermediate 2-chloro-3-(oxazol-2-yl)thiophenol B12
步骤一：2-(3-(叔丁硫基)-2-氯苯基)恶唑B12-1Step 1: 2-(3-(tert-butylthio)-2-chlorophenyl)oxazole B12-1
Figure PCTCN2021126331-appb-000323
Figure PCTCN2021126331-appb-000323
将恶唑(267mg，3.86mmoL)溶于四氢呋喃(9mL)中，在氮气条件下降温至-70℃，滴加正丁基锂四氢呋喃溶液(2.5M，1.85mL)并在此温度下反应30分钟，然后滴加氯化锌四氢呋喃溶液(2M，5.79mL)，随后升温至20℃，加入四三苯基膦钯(223mg，0.19mmoL)和(2-氯-3碘苯基)叔丁基硫醚(900mg，2.76mmoL)，升温至60℃反应4小时，TLC和LCMS监测反应完毕，降至室温，淬灭，萃取，过滤，洗涤，干燥浓缩，用快速硅胶柱纯化得到2-(3-(叔丁硫基)-2-氯苯基)恶唑B12-1(500mg，65.05％收率)。Oxazole (267 mg, 3.86 mmol) was dissolved in tetrahydrofuran (9 mL), the temperature was lowered to -70°C under nitrogen, n-butyllithium tetrahydrofuran solution (2.5 M, 1.85 mL) was added dropwise and the reaction was carried out at this temperature for 30 minutes , then dropwise added zinc chloride tetrahydrofuran solution (2M, 5.79mL), then warmed to 20°C, added tetrakistriphenylphosphine palladium (223mg, 0.19mmol) and (2-chloro-3-iodophenyl)tert-butyl sulfide Ether (900 mg, 2.76 mmol), warmed to 60 °C and reacted for 4 hours, monitored by TLC and LCMS, cooled to room temperature, quenched, extracted, filtered, washed, dried and concentrated, and purified with a flash silica column to obtain 2-(3- (tert-Butylthio)-2-chlorophenyl)oxazole B12-1 (500 mg, 65.05% yield).
1H NMR(400MHz,CHLOROFORM-d)δ7.93(dd,J＝1.7,7.8Hz,1H),7.82(d,J＝0.8Hz,1H),7.79(dd,J＝1.7,7.7Hz,1H),7.38-7.30(m,2H),1.38(s,9H)ppm；LCMS:m/z 268.1[M+H] +. 1 H NMR (400MHz, CHLOROFORM-d) δ7.93 (dd, J=1.7, 7.8Hz, 1H), 7.82 (d, J=0.8Hz, 1H), 7.79 (dd, J=1.7, 7.7Hz, 1H) ), 7.38-7.30(m, 2H), 1.38(s, 9H) ppm; LCMS: m/z 268.1[M+H] + .
步骤二：2-氯-3-(恶唑-2-基)苯硫酚B12Step 2: 2-Chloro-3-(oxazol-2-yl)thiophenol B12
Figure PCTCN2021126331-appb-000324
Figure PCTCN2021126331-appb-000324
将2-(3-(叔丁硫基)-2-氯苯基)恶唑B12-1(500mg，1.87mmoL)溶于浓盐酸(10mL,35％纯度)在氮气气氛下升温至100℃反应1小时，TLC和LCMS监测反应完毕，降温至室温，淬灭，萃取，过滤，洗涤，干燥浓缩，用快速硅胶柱纯化得到2-氯-3-(恶唑-2-基)苯硫酚B12(200mg，50.1％收率)2-(3-(tert-butylthio)-2-chlorophenyl)oxazole B12-1 (500 mg, 1.87 mmol) was dissolved in concentrated hydrochloric acid (10 mL, 35% purity) and heated to 100 °C under nitrogen atmosphere for reaction After 1 hour, TLC and LCMS monitored the completion of the reaction, cooled to room temperature, quenched, extracted, filtered, washed, dried and concentrated, and purified by flash silica column to obtain 2-chloro-3-(oxazol-2-yl)thiophenol B12 (200mg, 50.1% yield)
1H NMR(400MHz,CHLOROFORM-d)δ7.84(s,1H),7.79(d,J＝7.8Hz,1H),7.49(d,J＝7.9Hz,1H),7.37(s,1H),7.32-7.26(m,1H),4.07(s,1H)ppm；LCMS:m/z 212.1[M+H] +. 1 H NMR(400MHz, CHLOROFORM-d)δ7.84(s,1H),7.79(d,J=7.8Hz,1H),7.49(d,J=7.9Hz,1H),7.37(s,1H), 7.32-7.26(m,1H),4.07(s,1H)ppm; LCMS: m/z 212.1[M+H] + .
按照实施例26的方法，用相应的原料可以合成得到中间体3-(苯并[d]恶唑-2-基)-2-氯苯硫酚B13According to the method of Example 26, the intermediate 3-(benzo[d]oxazol-2-yl)-2-chlorothiophenol B13 can be synthesized with corresponding raw materials
Figure PCTCN2021126331-appb-000325
Figure PCTCN2021126331-appb-000325
1H NMR(400MHz,CHLOROFORM-d)δ7.91(dd,J＝1.4,7.8Hz,1H),7.89-7.84(m,1H),7.67-7.61(m,1H),7.54(dd,J＝1.5,7.9Hz,1H),7.46-7.39(m,2H),7.30(t,J＝7.9Hz,1H),4.08(s,1H)ppm；LCMS:m/z 262.0[M+H] +. 1 H NMR(400MHz, CHLOROFORM-d)δ7.91(dd,J=1.4,7.8Hz,1H),7.89-7.84(m,1H),7.67-7.61(m,1H),7.54(dd,J= 1.5,7.9Hz,1H),7.46-7.39(m,2H),7.30(t,J=7.9Hz,1H),4.08(s,1H)ppm; LCMS: m/z 262.0[M+H] + .
实施例27 2-氯-N-(2-氯-3-巯苯基)-3-氟苯甲酰胺B11Example 27 2-Chloro-N-(2-chloro-3-mercaptophenyl)-3-fluorobenzamide B11
步骤一：2-氯-3-氟苯甲酰氯B11-1Step 1: 2-Chloro-3-fluorobenzoyl chloride B11-1
Figure PCTCN2021126331-appb-000326
Figure PCTCN2021126331-appb-000326
将2-氯-3-氟苯甲酸(500mg，2.86mmol)溶于SOCl 2(10mL)，再加入N,N-二甲基甲酰胺(104mg，1.43mmol)，在氮气氛围下80℃反应1小时后，TLC监测反应完全。反应液浓缩，得到黄色胶状产物2-氯-3-氟苯甲酰氯B11-1(550mg，粗品)。 2-Chloro-3-fluorobenzoic acid (500 mg, 2.86 mmol) was dissolved in SOCl 2 (10 mL), then N,N-dimethylformamide (104 mg, 1.43 mmol) was added, and the reaction was carried out at 80 ° C under nitrogen atmosphere for 1 After hours, the reaction was complete by TLC monitoring. The reaction solution was concentrated to obtain 2-chloro-3-fluorobenzoyl chloride B11-1 (550 mg, crude product) as a yellow gum product.
步骤二：N-(3-(叔丁硫基)-2-氯苯基)-2-氯-3-氟苯甲酰胺B11-2Step 2: N-(3-(tert-butylthio)-2-chlorophenyl)-2-chloro-3-fluorobenzamide B11-2
Figure PCTCN2021126331-appb-000327
Figure PCTCN2021126331-appb-000327
将3-(叔丁硫基)-2-氯苯胺B11-1(491mg，2.28mmol)溶于二氯甲烷(5mL)溶液中，在0℃下加入吡啶(676mg，8.55mmo)和2-氯-3-氟苯甲酰(550mg，2.85mmol)，在20℃下反应12小时。LCMS监测到目标产物，反应液浓缩，通过柱层析纯化，得到黄色固体产物N-(3-(叔丁硫基)-2-氯苯基)-2-氯-3-氟苯甲酰胺B11-2(480mg，40.7％收率)。3-(tert-Butylthio)-2-chloroaniline B11-1 (491 mg, 2.28 mmol) was dissolved in dichloromethane (5 mL) solution, pyridine (676 mg, 8.55 mmol) and 2-chloroaniline were added at 0°C -3-Fluorobenzoyl (550 mg, 2.85 mmol), reacted at 20°C for 12 hours. The target product was detected by LCMS, the reaction solution was concentrated, and purified by column chromatography to obtain a yellow solid product N-(3-(tert-butylthio)-2-chlorophenyl)-2-chloro-3-fluorobenzamide B11 -2 (480 mg, 40.7% yield).
1H NMR(400MHz,CDCl 3)δ8.63(d,J＝8.0Hz,1H),8.54(br s,1H),7.59(d,J＝7.6Hz,1H),7.51-7.47(m,1H),7.43-7.37(m,1H),7.36-7.29(m,2H),1.36(s,9H)ppm；LCMS:m/z 372.0[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (d, J=8.0 Hz, 1H), 8.54 (br s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.51-7.47 (m, 1H) ), 7.43-7.37(m, 1H), 7.36-7.29(m, 2H), 1.36(s, 9H) ppm; LCMS: m/z 372.0[M+H] + .
步骤三：2-氯-N-(2-氯-3-巯苯基)-3-氟苯甲酰胺B11Step 3: 2-Chloro-N-(2-Chloro-3-mercaptophenyl)-3-fluorobenzamide B11
Figure PCTCN2021126331-appb-000328
Figure PCTCN2021126331-appb-000328
将N-(3-(叔丁硫基)-2-氯苯基)-2-氯-3-氟苯甲酰胺(350mg，940umol)溶于三氟乙酸(67.5mmol，5mL)，在氮气氛围下110℃反应3小时。向反应液中加入水(10mL)，过滤，固体洗涤，冻干，得到纯品黄色固体产物2-氯-N-(2-氯-3-巯苯基)-3-氟苯甲酰胺B11(270mg，85.4％收率)。Dissolve N-(3-(tert-butylthio)-2-chlorophenyl)-2-chloro-3-fluorobenzamide (350 mg, 940 umol) in trifluoroacetic acid (67.5 mmol, 5 mL) under nitrogen atmosphere The reaction was carried out at 110°C for 3 hours. Water (10 mL) was added to the reaction solution, filtered, the solid was washed, and lyophilized to obtain a pure yellow solid product 2-chloro-N-(2-chloro-3-mercaptophenyl)-3-fluorobenzamide B11 ( 270 mg, 85.4% yield).
1H NMR(400MHz,DMSO-d 6)δ10.44(d,J＝32.8Hz,1H),7.66-7.21(m,6H),5.91(s,1H)ppm；LSMC:m/z 316.1[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (d, J=32.8 Hz, 1H), 7.66-7.21 (m, 6H), 5.91 (s, 1H) ppm; LSMC: m/z 316.1 [M +H] + .
按照实施例26的方法，用相应的原料可以合成得到中间体N-(2-氯-3-巯基苯基)苯酰胺B7According to the method of Example 26, the intermediate N-(2-chloro-3-mercaptophenyl)benzamide B7 can be synthesized with corresponding raw materials
Figure PCTCN2021126331-appb-000329
Figure PCTCN2021126331-appb-000329
LCMS:m/z 264.02[M+H] + LCMS: m/z 264.02[M+H] +
实施例28N,N-二(叔丁氧羰基)-(2-胺-3-氯吡啶-4-基)硼酸C2Example 28N,N-bis(tert-butoxycarbonyl)-(2-amine-3-chloropyridin-4-yl)boronic acid C2
步骤一：4-溴-3-氯吡啶-2-胺C2-1Step 1: 4-Bromo-3-chloropyridin-2-amine C2-1
Figure PCTCN2021126331-appb-000330
Figure PCTCN2021126331-appb-000330
四氟闷罐中，将4-溴-3-氯-2-氟吡啶(500mg，2.38mmol)溶于氨水(4.00mL)中，升温至100℃，反应2小时，降至常温，LCMS检测反应结束。用二氯甲烷萃取、饱和食盐水洗涤、减压浓缩，得到粗品4-溴-3-氯吡啶-2-胺C2-1(415mg，粗品)。4-Bromo-3-chloro-2-fluoropyridine (500mg, 2.38mmol) was dissolved in ammonia water (4.00mL) in a tetrafluoro jar, heated to 100°C, reacted for 2 hours, cooled to room temperature, and the reaction was detected by LCMS. Finish. It was extracted with dichloromethane, washed with saturated brine, and concentrated under reduced pressure to obtain crude 4-bromo-3-chloropyridin-2-amine C2-1 (415 mg, crude).
1H NMR(400MHz,CHLOROFORM-d)δ7.77(d,J＝5.4Hz,1H),6.92(d,J＝5.4Hz,1H),5.11(br s,2H)ppm。LCMS:m/z 207.0[M+H] +. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (d, J=5.4 Hz, 1H), 6.92 (d, J=5.4 Hz, 1H), 5.11 (br s, 2H) ppm. LCMS: m/z 207.0[M+H] + .
步骤二：N,N-二(叔丁氧羰基)-4-溴-3-氯吡啶-2-胺C2-2Step 2: N,N-bis(tert-butoxycarbonyl)-4-bromo-3-chloropyridine-2-amine C2-2
Figure PCTCN2021126331-appb-000331
Figure PCTCN2021126331-appb-000331
将4-溴-3-氯吡啶-2-胺C2-1(3.81g，18.4mmol)、Boc酸酐(10.0g，45.9mmol)、4-二甲氨基吡啶(3.37g，27.6mmol)溶于二氯甲烷(40.0mL)中，在20℃下反应12小时，LCMS检测反应结束。用二氯甲烷萃取、饱和食盐水洗涤、减压浓缩，用硅胶柱纯化得到N,N-二(叔丁氧羰基)-4-溴-3-氯吡啶-2-胺C2-2(5.95g，收率78.8％)。4-Bromo-3-chloropyridin-2-amine C2-1 (3.81 g, 18.4 mmol), Boc anhydride (10.0 g, 45.9 mmol), 4-dimethylaminopyridine (3.37 g, 27.6 mmol) were dissolved in di In methyl chloride (40.0 mL), the reaction was carried out at 20° C. for 12 hours, and the reaction was completed by LCMS detection. Extracted with dichloromethane, washed with saturated brine, concentrated under reduced pressure, and purified with silica gel column to obtain N,N-bis(tert-butoxycarbonyl)-4-bromo-3-chloropyridin-2-amine C2-2 (5.95 g , the yield is 78.8%).
1H NMR(400MHz,DMSO-d 6)δ8.35(d,J＝5.3Hz,1H),7.93(d,J＝5.1Hz,1H),1.36(s,18H)ppm；LCMS:m/z 253.1[M+H-156] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35 (d, J=5.3 Hz, 1H), 7.93 (d, J=5.1 Hz, 1H), 1.36 (s, 18H) ppm; LCMS: m/z 253.1[M+H-156] + .
步骤三：N,N-二(叔丁氧羰基)-(2-胺-3-氯吡啶-4-基)硼酸C2Step 3: N,N-bis(tert-butoxycarbonyl)-(2-amine-3-chloropyridin-4-yl)boronic acid C2
Figure PCTCN2021126331-appb-000332
Figure PCTCN2021126331-appb-000332
将N,N-二(叔丁氧羰基)-4-溴-3-氯吡啶-2-胺C2-2(500mg，1.23mmol)，联硼酸频那醇酯(374mg，1.47mmol)，醋酸钾(361mg，3.68mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(200mg，0.245mmol)，溶于1,4-二氧六环(5.00mL)，温度升温至100℃于氮气氛围下反应12小时，LCMS检测反应结束。乙酸乙酯萃取，饱和食盐水洗涤、减压浓缩，用HPLC纯化得到N,N-二(叔丁氧羰基)-(2-胺-3-氯吡啶-4-基)硼酸C2-3(240mg，收率45.8％)。N,N-bis(tert-butoxycarbonyl)-4-bromo-3-chloropyridin-2-amine C2-2 (500 mg, 1.23 mmol), pinacol biboronate (374 mg, 1.47 mmol), potassium acetate (361 mg, 3.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (200 mg, 0.245 mmol) in 1,4-dioxane Hexacyclic (5.00 mL) was heated to 100° C. and reacted under nitrogen atmosphere for 12 hours. LCMS detected the end of the reaction. Extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and purified by HPLC to obtain N,N-bis(tert-butoxycarbonyl)-(2-amine-3-chloropyridin-4-yl)boronic acid C2-3 (240 mg , the yield is 45.8%).
1H NMR(400MHz,DMSO-d 6)δ＝8.76(br s,2H),8.37-8.33(m,1H),7.43-7.39(m,1H),1.40-1.34(m,18H)ppm；LCMS:m/z 216.7[M-156+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ=8.76 (br s, 2H), 8.37-8.33 (m, 1H), 7.43-7.39 (m, 1H), 1.40-1.34 (m, 18H) ppm; LCMS :m/z 216.7[M-156+H] + .
按照实施例28的方法，用相应的中间体或原料可以合成得到如下中间体：According to the method of Example 28, the following intermediates can be synthesized with corresponding intermediates or raw materials:
Figure PCTCN2021126331-appb-000333
Figure PCTCN2021126331-appb-000333
Figure PCTCN2021126331-appb-000334
Figure PCTCN2021126331-appb-000334
实施例29中间体2-氯-5-碘-1,2a1,4-三氮杂环戊[cd]茚C1的合成Example 29 Synthesis of intermediate 2-chloro-5-iodo-1,2a1,4-triazacyclopenta[cd]indene C1
步骤一：5-氯-8-碘咪唑并[1,2-a]吡啶-3-羧酸乙酯C1-1Step 1: Ethyl 5-chloro-8-iodoimidazo[1,2-a]pyridine-3-carboxylate C1-1
Figure PCTCN2021126331-appb-000335
Figure PCTCN2021126331-appb-000335
在100mL单口闷罐中依次加入6-氯-3-碘吡啶-2-胺(10g，39.30mmol),2-氯-3-氧代丙酸乙酯(7.69g,51.09mmol)和乙醇(50mL).反应混合物在105℃加热搅拌反应70小时。冷却至室温后，直接加入硅胶旋干。粗品在硅胶上纯化(乙酸乙酯：石油醚＝3：10)，得到白色固体5-氯-8-碘咪唑并[1,2-a]吡啶-3-羧酸乙酯C1-1(8.6g,收率：62％)。6-Chloro-3-iodopyridin-2-amine (10g, 39.30mmol), 2-chloro-3-oxopropionic acid ethyl ester (7.69g, 51.09mmol) and ethanol (50mL) were successively added to a 100mL single-necked stuffy pot ). The reaction mixture was heated and stirred at 105°C for 70 hours. After cooling to room temperature, directly add silica gel and spin dry. The crude product was purified on silica gel (ethyl acetate:petroleum ether=3:10) to give ethyl 5-chloro-8-iodoimidazo[1,2-a]pyridine-3-carboxylate C1-1 (8.6 g, yield: 62%).
1H NMR(400MHz,DMSO-d 6)δ8.27(s,1H),8.05(d,J＝7.8Hz,1H),7.17(d,J＝7.8Hz,1H),4.36(t,J＝7.1Hz,2H),1.34(t,J＝7.1Hz,3H)ppm；LCMS:m/z 350.9[M+H] +。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.36 (t, J= 7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z 350.9 [M+H] + .
步骤二：5-氨基-8-碘咪唑并[1,2-a]吡啶-3-羧酸甲酯C1-2Step 2: Methyl 5-amino-8-iodoimidazo[1,2-a]pyridine-3-carboxylate C1-2
Figure PCTCN2021126331-appb-000336
Figure PCTCN2021126331-appb-000336
在100mL单口闷罐中依次加入5-氯-8-碘咪唑并[1,2-a]吡啶-3-羧酸乙酯C1-1(7.6g,21.68mmol)和7mol/L氨的甲醇溶液(50mL)。反应混合物在75℃加热搅拌反应16个小时。冷却至室温后，直接加入硅胶旋干。粗品在硅胶上纯化(乙酸乙酯：石油醚＝3：10)，得到淡黄色固体5-氨基-8-碘咪唑并[1,2-a]吡啶-3-羧酸甲酯C1-2(1.3g,收率：19％)。A methanol solution of 5-chloro-8-iodoimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester C1-1 (7.6g, 21.68mmol) and 7mol/L ammonia was sequentially added to a 100mL single-necked stuffy tank (50 mL). The reaction mixture was heated and stirred at 75°C for 16 hours. After cooling to room temperature, directly add silica gel and spin dry. The crude product was purified on silica gel (ethyl acetate:petroleum ether=3:10) to give 5-amino-8-iodoimidazo[1,2-a]pyridine-3-carboxylic acid methyl ester C1-2( 1.3g, yield: 19%).
1H NMR(400MHz,DMSO-d 6)δ8.35(s,1H),8.00(s,2H),7.79(d,J＝8.2Hz,1H),6.13(d,J＝8.2Hz,1H),3.86(s,3H)ppm；LCMS:m/z 317.9[M+H] +。 1 H NMR (400MHz, DMSO-d 6 )δ8.35(s,1H),8.00(s,2H),7.79(d,J=8.2Hz,1H),6.13(d,J=8.2Hz,1H) , 3.86 (s, 3H) ppm; LCMS: m/z 317.9 [M+H] + .
步骤三：5-碘-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-醇C1-3Step 3: 5-iodo-1,2a1,4-triazacyclopentadieno[cd]inden-2-ol C1-3
Figure PCTCN2021126331-appb-000337
Figure PCTCN2021126331-appb-000337
在100mL单口闷罐中依次加入5-氨基-8-碘咪唑并[1,2-a]吡啶-3-羧酸甲酯C1-2(1g,3.15mmol)，30％甲醇钠的甲醇溶液(1.13g,6.31mmol)和甲醇(20mL)。反应混合物在80℃加热搅拌反应16个小时。冷却至室温后，直接加入硅胶旋干。粗品在硅胶上纯化(乙酸乙酯：甲醇＝10：1)，得到5-碘-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-醇C1-3(250mg,收率：28％)。5-amino-8-iodoimidazo[1,2-a]pyridine-3-carboxylate methyl ester C1-2 (1 g, 3.15 mmol), 30% methanol solution of sodium methoxide ( 1.13 g, 6.31 mmol) and methanol (20 mL). The reaction mixture was heated and stirred at 80°C for 16 hours. After cooling to room temperature, directly add silica gel and spin dry. The crude product was purified on silica gel (ethyl acetate:methanol=10:1) to give 5-iodo-1,2a1,4-triazacyclopentadieno[cd]inden-2-ol C1-3 (250 mg, Yield: 28%).
1H NMR(400MHz,DMSO-d 6)δ12.35(s,1H),8.41(d,J＝1.2Hz,1H),8.18(d,J＝7.7Hz,1H),6.87(d,J＝7.7Hz,1H)ppm；LCMS:m/z 285.9[M+H] +。 1 H NMR (400MHz, DMSO-d 6 )δ12.35(s, 1H), 8.41(d, J=1.2Hz, 1H), 8.18(d, J=7.7Hz, 1H), 6.87(d, J= 7.7 Hz, 1 H) ppm; LCMS: m/z 285.9 [M+H] + .
步骤四：2-氯-5-碘-1,2a1,4-三氮杂环戊[cd]茚C1Step 4: 2-Chloro-5-iodo-1,2a1,4-triazacyclopenta[cd]indene C1
Figure PCTCN2021126331-appb-000338
Figure PCTCN2021126331-appb-000338
在50mL单口烧瓶中依次加入5-碘-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-醇C1-3(140mg,0.49mmol)，N,N-二异丙基乙胺(630mg,4.9mmol)和三氯氧磷(20mL)。反应混合物在130℃加热搅拌反应16个小时。冷却至室温后，减压蒸馏得到粗产品。粗品在硅胶上纯化(乙酸乙酯：石油醚＝3：10)，得到灰色固体2-氯-5-碘-1,2a1,4-三氮杂环戊二烯并[cd]茚C1(40mg,收率：27％)。5-iodo-1,2a1,4-triazacyclopentadieno[cd]inden-2-ol C1-3 (140mg, 0.49mmol), N,N-diisopropyl were added to a 50mL single-necked flask in turn Ethylamine (630 mg, 4.9 mmol) and phosphorus oxychloride (20 mL). The reaction mixture was heated and stirred at 130°C for 16 hours. After cooling to room temperature, the crude product was obtained by distillation under reduced pressure. The crude product was purified on silica gel (ethyl acetate:petroleum ether=3:10) to give 2-chloro-5-iodo-1,2a1,4-triazacyclopentadieno[cd]indene C1 (40 mg) as a grey solid , yield: 27%).
1H NMR(400MHz,DMSO-d 6)δ9.02(s,1H),8.63(d,J＝8.2Hz,1H),8.03(d,J＝8.2Hz,1H)ppm；LCMS:m/z 303.9[M+H] +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.02 (s, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H) ppm; LCMS: m/z 303.9[M+H] + .
实施例30(S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺D1Example 30 (S)-1'-(5-(2,3-dichlorophenyl)-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1,3- Dihydrospiro[indene-2,4'-piperidine]-1-amine D1
步骤一：(R)-N-((S)-1'-(5-碘-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺D1-1Step 1: (R)-N-((S)-1'-(5-iodo-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1,3-dihydro Spiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide D1-1
Figure PCTCN2021126331-appb-000339
Figure PCTCN2021126331-appb-000339
在氮气保护下，向干燥的50mL单口烧瓶中依次加入2-氯-5-碘-1,2a1,4-三氮杂环戊[cd]茚(C1) (20mg,0.07mmol)、(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(26mg,0.07mmol)、DIEA(18mg,0.14mmol)和MeCN(5mL)，然后在90℃下搅拌反应2小时。反应完毕后，将获得的残留物倒入水(10mL)，于室温下搅拌5分钟。然后用乙酸乙酯(3x50mL)萃取，将合并的有机相用MgSO 4干燥，过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至80％梯度的乙酸乙酯/石油醚)，得到淡黄色固体(R)-N-((S)-1'-(5-碘-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺D1-1(22mg,收率：58％)。 Under nitrogen protection, 2-chloro-5-iodo-1,2a1,4-triazacyclopenta[cd]indene (C1) (20mg, 0.07mmol), (R) was added to a dry 50mL single-necked flask in sequence -N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (26 mg, 0.07 mmol), DIEA (18 mg, 0.14 mmol) and MeCN (5 mL), then the reaction was stirred at 90°C for 2 hours. After completion of the reaction, the obtained residue was poured into water (10 mL) and stirred at room temperature for 5 minutes. It was then extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0 to 80% gradient of ethyl acetate/petroleum ether), A pale yellow solid was obtained (R)-N-((S)-1'-(5-iodo-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1,3-di Hydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide D1-1 (22 mg, yield: 58%).
LC-MS:m/z 574.1[M+H] +. LC-MS: m/z 574.1[M+H] + .
步骤二：(R)-N-((S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺D1-2Step 2: (R)-N-((S)-1'-(5-(2,3-dichlorophenyl)-1,2a1,4-triazacyclopenta[cd]indane-2- D1-2
Figure PCTCN2021126331-appb-000340
Figure PCTCN2021126331-appb-000340
在20mL的封管中室温下依次加入(R)-N-((S)-1'-(5-碘-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺D1-1(22mg，0.05mmol)，1,4-二氧六环(2mL)，纯净水(0.5mL)，(2,3-二氯苯基)硼酸(25mg，0.12mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(9mg，0.012mmol)和碳酸钾(50mg，0.36mmol)。氮气鼓泡一分钟，封管加热至80摄氏度，反应6小时。反应完毕，向反应液中加入20mL水并用乙酸乙酯(50mL×3)萃取。有机相依次用水(20mL×1)，饱和食盐水(20mL×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱法(石油醚：乙酸乙酯＝1：1)得到粗产物(R)-N-((S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺D1-2(20mg，产率：72％)，为淡黄色固体。(R)-N-((S)-1'-(5-iodo-1,2a1,4-triazacyclopenta[cd]indan-2-yl) was added to a 20 mL sealed tube at room temperature. -1,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide D1-1 (22 mg, 0.05 mmol), 1,4- Dioxane (2 mL), purified water (0.5 mL), (2,3-dichlorophenyl)boronic acid (25 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (9 mg, 0.012 mmol) and potassium carbonate (50 mg, 0.36 mmol). Nitrogen was bubbled for one minute, the tube was sealed and heated to 80 degrees Celsius, and the reaction was carried out for 6 hours. After the reaction was completed, 20 mL of water was added to the reaction solution and extracted with ethyl acetate (50 mL×3). The organic phase was washed successively with water (20 mL×1) and saturated brine (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product (R)-N-((S)-1'-(5-(2,3-dichlorophenyl)-1) was obtained by column chromatography (petroleum ether:ethyl acetate=1:1), 2a1,4-Triazacyclopenta[cd]indan-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane- 2-Sulfinamide D1-2 (20 mg, yield: 72%) as pale yellow solid.
LC-MS:m/z 560.1[M+H] +. LC-MS: m/z 560.1[M+H] + .
步骤三：(S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮杂环戊[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺D1Step 3: (S)-1'-(5-(2,3-dichlorophenyl)-1,2a1,4-triazacyclopenta[cd]inden-2-yl)-1,3-di Hydrospiro[indene-2,4'-piperidine]-1-amine D1
Figure PCTCN2021126331-appb-000341
Figure PCTCN2021126331-appb-000341
在氮气保下向50mL的单口烧瓶中依次加入(R)-N-((S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(20mg,0.035mmol)和甲醇(0.5mL)，在室温下滴加盐酸1，4-二氧六环溶液(0.05mL,4M)，该混合物在室温下搅拌反应1小时。 反应完毕后，冷却至室温,过滤并在减压浓缩得到的残留物通过高效液相制备色谱纯化得到(S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮杂环戊[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺D1(6mg，收率：37％)。Add (R)-N-((S)-1'-(5-(2,3-dichlorophenyl)-1,2a1,4-triazaheterocycle to a 50 mL single-necked flask under nitrogen atmosphere Penta[cd]indan-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (20mg, 0.035 mmol) and methanol (0.5 mL), hydrochloric acid 1,4-dioxane solution (0.05 mL, 4 M) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was cooled to room temperature, filtered and concentrated under reduced pressure. The residue obtained was purified by preparative high performance liquid chromatography to obtain (S)-1'-(5-(2,3-dichlorophenyl)-1,2a1 ,4-Triazacyclopenta[cd]inden-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine D1 (6 mg, yield: 37%) .
1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),7.98(d,J＝7.8Hz,1H),7.83(dd,J＝8.0,1.6Hz,1H),7.71(dd,J＝7.7,1.6Hz,1H),7.58(t,J＝7.9Hz,1H),7.45-7.34(m,2H),7.25(pd,J＝7.8,3.6Hz,3H),4.57(s,1H),4.15(s,1H),3.97(s,1H),3.60(s,2H),3.23(d,J＝15.7Hz,1H),2.78(d,J＝15.7Hz,1H),2.35-1.66(m,5H)ppm；LC-MS:m/z 488.1[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.83 (dd, J=8.0, 1.6 Hz, 1H), 7.71 (dd, J=7.7, 1.6Hz, 1H), 7.58(t, J=7.9Hz, 1H), 7.45-7.34(m, 2H), 7.25(pd, J=7.8, 3.6Hz, 3H), 4.57(s, 1H) ), 4.15(s, 1H), 3.97(s, 1H), 3.60(s, 2H), 3.23(d, J=15.7Hz, 1H), 2.78(d, J=15.7Hz, 1H), 2.35-1.66 (m,5H)ppm; LC-MS: m/z 488.1 [M+H] + .
实施例31(3S,4S)-8-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊烷[cd]茚-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 31 (3S,4S)-8-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentane[cd]inden-2-yl) -3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
步骤一：按照实施例30步骤一的方法，可以得到中间体(R)-N-((3S,4S)-8-(5-碘-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺酰胺D2-1Step 1: According to the method of Step 1 of Example 30, intermediate (R)-N-((3S,4S)-8-(5-iodo-1,2a1,4-triazacyclopentadiene can be obtained [cd]Inden-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide D2-1
Figure PCTCN2021126331-appb-000342
Figure PCTCN2021126331-appb-000342
LC-MS:m/z 546.1[M+H] +. LC-MS: m/z 546.1[M+H] + .
步骤二：(R)-N-((3S,4S)-8-(5-((2,3-二氯苯基)硫基)-1,2a1,4-三氮杂环戊烷[cd]茚-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺胺D2-2Step 2: (R)-N-((3S,4S)-8-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentane [cd ]Inden-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfinamide D2-2
Figure PCTCN2021126331-appb-000343
Figure PCTCN2021126331-appb-000343
在氮气保下向100mL的单口烧瓶中依次加入粗品(R)-N-((3S,4S)-8-(5-碘-1,2a1,4-三氮杂环戊烷[cd]茚-2-基)-3-甲基-2氧-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺胺D2-1(30mg，0.055mmol)、2,3-二氯苯硫醇(20mg,0.11mmol)、Pd 2(dba) 3(10mg,0.01mmol)、Xantphos(11mg,0.020mmol)、DIPEA(26mg,0.20mmol)和1,4-二氧六环溶液(5mL),该混合物在氮气保护下加热100℃搅拌反应6小时。反应完毕后，冷却至室温,过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至30％梯度的乙酸乙酯/甲醇)，得到(R)-N-((3S,4S)-8-(5-((2,3-二氯苯基)硫基)-1,2a1,4-三氮杂环戊烷[cd]茚-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺胺D2-2(20mg，收率：61.5％)。 The crude product (R)-N-((3S,4S)-8-(5-iodo-1,2a1,4-triazacyclopentane [cd]indene- 2-yl)-3-methyl-2oxo-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide D2-1 (30 mg, 0.055 mmol), 2 , 3-Dichlorobenzenethiol (20 mg, 0.11 mmol), Pd 2 (dba) 3 (10 mg, 0.01 mmol), Xantphos (11 mg, 0.020 mmol), DIPEA (26 mg, 0.20 mmol) and 1,4-dioxo Hexacyclic solution (5 mL), the mixture was heated at 100 °C under nitrogen protection and stirred for 6 hours. After the reaction was complete, cooled to room temperature, filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/methanol) to give (R)-N-((3S,4S) -8-(5-((2,3-Dichlorophenyl)sulfanyl)-1,2a1,4-triazacyclopentane[cd]inden-2-yl)-3-methyl-2- Oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfenamide D2-2 (20 mg, yield: 61.5%).
LC-MS:m/z 592.2[M+H] +. LC-MS: m/z 592.2[M+H] + .
步骤三：(3S,4S)-8-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊烷[cd]茚-2-基)-3-甲基-2-氧杂-8-氮 杂螺[4.5]癸烷-4-胺Step 3: (3S,4S)-8-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentane[cd]inden-2-yl) -3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
按照实施例30步骤三相同的方法(R)-N-((3S,4S)-8-(5-((2,3-二氯苯基)硫基)-1,2a1,4-三氮杂环戊烷[cd]茚-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺胺D2-2脱除亚磺酰基后得到(3S,4S)-8-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊烷[cd]茚-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Follow the same method as step 3 of Example 30 (R)-N-((3S,4S)-8-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazine Cyclopentane[cd]inden-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide After removal of the sulfinyl group from D2-2, (3S,4S)-8-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentane [cd ]Inden-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
Figure PCTCN2021126331-appb-000344
Figure PCTCN2021126331-appb-000344
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.09(d,J＝7.8Hz,1H),7.41(dd,J＝8.0,1.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.08(t,J＝8.0Hz,1H),6.51(dd,J＝8.1,1.4Hz,1H),4.29-4.05(m,2H),3.96(s,1H),3.86-3.63(m,3H),3.53(d,J＝8.6Hz,1H),2.99(d,J＝5.1Hz,1H),2.02-1.39(m,6H),1.10(d,J＝6.4Hz,3H)ppm；LCMS:m/z 487.9[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.41 (dd, J=8.0, 1.4Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 7.08(t, J=8.0Hz, 1H), 6.51(dd, J=8.1, 1.4Hz, 1H), 4.29-4.05(m, 2H), 3.96(s, 1H), 3.86-3.63(m, 3H), 3.53(d, J=8.6Hz, 1H), 2.99(d, J=5.1Hz, 1H), 2.02-1.39(m, 6H), 1.10(d, J=6.4Hz) ,3H)ppm; LCMS: m/z 487.9[M+H] + .
采用实施例31相同的制备方法，使用实施例29得到的中间体C1、螺环胺中间体A1-A57以及硫酚中间体B2-B14或硫钠和商业化硫酚制备如下化合物：Using the same preparation method of Example 31, using the intermediate C1 obtained in Example 29, the spirocyclic amine intermediate A1-A57 and the thiophenol intermediate B2-B14 or sodium sulfide and commercial thiophenol to prepare the following compounds:
实施例32 1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 32 1'-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-1, 3-Dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000345
Figure PCTCN2021126331-appb-000345
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.10(d,J＝7.8Hz,1H),7.42(dd,J＝8.1,1.4Hz,1H),7.34(dd,J＝8.3,4.3Hz,2H),7.26-7.16(m,3H),7.09(t,J＝8.1Hz,1H),6.51(dd,J＝8.1,1.3Hz,1H),4.54(s,1H),4.09(s,1H),3.96(s,1H),3.72(s,2H),3.15(s,1H),2.75(d,J＝15.7Hz,1H),1.75(d,J＝52.2Hz,4H),1.28(d,J＝40.3Hz,2H)ppm；LCMS:m/z 520.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.10 (d, J=7.8Hz, 1H), 7.42 (dd, J=8.1, 1.4Hz, 1H), 7.34 (dd, J=8.3, 4.3Hz, 2H), 7.26-7.16(m, 3H), 7.09(t, J=8.1Hz, 1H), 6.51(dd, J=8.1, 1.3Hz, 1H), 4.54(s, 1H) ), 4.09(s, 1H), 3.96(s, 1H), 3.72(s, 2H), 3.15(s, 1H), 2.75(d, J=15.7Hz, 1H), 1.75(d, J=52.2Hz ,4H),1.28(d,J=40.3Hz,2H)ppm; LCMS: m/z 520.1[M+H] + .
实施例33 1'-(5-((2-氨基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺环[茚-2,4'-哌啶]-1-胺Example 33 1'-(5-((2-Amino-3-chloropyridin-4-yl)sulfanyl)-1,2a1,4-triazacyclopenta[cd]indan-2-yl)- 1,3-Dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000346
Figure PCTCN2021126331-appb-000346
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.09(d,J＝7.8Hz,1H),7.51(d,J＝5.3Hz,1H),7.38-7.30(m,2H),7.20(qd,J＝6.3,5.6,3.4Hz,3H),6.38(s,2H),5.55(d,J＝5.4Hz,1H),4.54(s,1H),4.10(s, 1H),3.92(s,1H),3.84-3.63(m,1H),3.63-3.42(m,1H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.7Hz,1H),2.03-1.68(m,4H),1.46-1.02(m,2H)ppm；LCMS:m/z 502.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ8.57(s, 1H), 8.09(d, J=7.8Hz, 1H), 7.51(d, J=5.3Hz, 1H), 7.38-7.30(m, 2H), 7.20(qd, J=6.3, 5.6, 3.4Hz, 3H), 6.38(s, 2H), 5.55(d, J=5.4Hz, 1H), 4.54(s, 1H), 4.10(s, 1H ),3.92(s,1H),3.84-3.63(m,1H),3.63-3.42(m,1H),3.17(d,J=15.7Hz,1H),2.72(d,J=15.7Hz,1H) ,2.03-1.68(m,4H),1.46-1.02(m,2H)ppm; LCMS: m/z 502.1[M+H] + .
实施例34 1'-(5-((2-甲基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺环[茚-2,4'-哌啶]-1-胺Example 34 1'-(5-((2-methyl-3-chloropyridin-4-yl)sulfanyl)-1,2a1,4-triazacyclopenta[cd]indan-2-yl) -1,3-Dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000347
Figure PCTCN2021126331-appb-000347
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.13(d,J＝7.8Hz,1H),7.98(d,J＝5.4Hz,1H),7.36(d,J＝7.8Hz,2H),7.29-7.18(m,3H),6.28(d,J＝5.3Hz,1H),4.55(s,1H),4.10(s,1H),4.00(s,1H),3.74(s,1H),3.55(s,1H),3.19(d,J＝15.9Hz,1H),2.78(d,J＝15.8Hz,1H),2.57(s,3H),2.00-1.66(m,3H),1.41-1.21(m,1H)ppm；LCMS:m/z 501.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57(s, 1H), 8.13(d, J=7.8Hz, 1H), 7.98(d, J=5.4Hz, 1H), 7.36(d, J= 7.8Hz, 2H), 7.29-7.18(m, 3H), 6.28(d, J=5.3Hz, 1H), 4.55(s, 1H), 4.10(s, 1H), 4.00(s, 1H), 3.74( s,1H),3.55(s,1H),3.19(d,J=15.9Hz,1H),2.78(d,J=15.8Hz,1H),2.57(s,3H),2.00-1.66(m,3H) ), 1.41-1.21(m,1H)ppm; LCMS: m/z 501.1[M+H] + .
实施例35(S)-1'-(5-((2-甲基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺环[茚-2,4'-哌啶]-1-胺Example 35 (S)-1'-(5-((2-methyl-3-chloropyridin-4-yl)sulfanyl)-1,2a1,4-triazacyclopenta[cd]indan- 2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000348
Figure PCTCN2021126331-appb-000348
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.13(d,J＝7.8Hz,1H),7.98(d,J＝5.4Hz,1H),7.36(d,J＝7.8Hz,2H),7.29-7.18(m,3H),6.28(d,J＝5.3Hz,1H),4.55(s,1H),4.10(s,1H),4.00(s,1H),3.74(s,1H),3.55(s,1H),3.19(d,J＝15.9Hz,1H),2.78(d,J＝15.8Hz,1H),2.57(s,3H),2.00-1.66(m,3H),1.41-1.21(m,1H)ppm；LCMS:m/z 501.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57(s, 1H), 8.13(d, J=7.8Hz, 1H), 7.98(d, J=5.4Hz, 1H), 7.36(d, J= 7.8Hz, 2H), 7.29-7.18(m, 3H), 6.28(d, J=5.3Hz, 1H), 4.55(s, 1H), 4.10(s, 1H), 4.00(s, 1H), 3.74( s,1H),3.55(s,1H),3.19(d,J=15.9Hz,1H),2.78(d,J=15.8Hz,1H),2.57(s,3H),2.00-1.66(m,3H) ), 1.41-1.21(m,1H)ppm; LCMS: m/z 501.1[M+H] + .
实施例36 1'-(5-(萘-1-基硫基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺环[茚-2,4'-哌啶]-1-胺Example 36 1'-(5-(naphthalen-1-ylthio)-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1,3-dihydrospiro[ Indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000349
Figure PCTCN2021126331-appb-000349
1H NMR(400MHz,DMSO-d 6)δ8.53(s,1H),8.45-8.38(m,1H),8.04-7.97(m,1H),7.89(dd,J＝6.6,2.8Hz,1H),7.80(d,J＝7.8Hz,1H),7.61(tt,J＝7.0,5.2Hz,2H),7.47-7.37(m,2H),7.36-7.29(m,1H),7.25-7.16(m,4H),4.48(s,1H),4.08(s,1H),3.92(s,1H),3.65(s,1H),3.51(s,1H),3.16(d,J＝15.7Hz,1H),2.71(d,J＝15.7Hz,1H),2.05-1.55(m,4H),1.24(s,2H)ppm；LCMS:m/z 502.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.45-8.38 (m, 1H), 8.04-7.97 (m, 1H), 7.89 (dd, J=6.6, 2.8Hz, 1H ),7.80(d,J=7.8Hz,1H),7.61(tt,J=7.0,5.2Hz,2H),7.47-7.37(m,2H),7.36-7.29(m,1H),7.25-7.16( m, 4H), 4.48(s, 1H), 4.08(s, 1H), 3.92(s, 1H), 3.65(s, 1H), 3.51(s, 1H), 3.16(d, J＝15.7Hz, 1H ), 2.71(d, J=15.7Hz, 1H), 2.05-1.55(m, 4H), 1.24(s, 2H) ppm; LCMS: m/z 502.1[M+H] + .
实施例37 1'-(5-(((S)-6a,7,8,9-四氢-6H-吡啶[3,2-b]吡咯[1,2-d][1,4]恶嗪-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺环[茚-2,4'-哌啶]-1-胺Example 37 1'-(5-(((S)-6a,7,8,9-tetrahydro-6H-pyridine[3,2-b]pyrrole[1,2-d][1,4]oxa oxazin-4-yl)thio)-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine ]-1-amine
Figure PCTCN2021126331-appb-000350
Figure PCTCN2021126331-appb-000350
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.02(d,J＝7.8Hz,1H),7.32(dd,J＝10.9,6.7Hz,3H),7.20(qd,J＝6.7,5.6,3.8Hz,3H),5.56(d,J＝5.5Hz,1H),4.65(dd,J＝10.3,3.6Hz,1H),4.52(s,1H),4.08(s,1H),3.92(s,1H),3.68(ddd,J＝9.6,5.8,3.6Hz,2H),3.57(ddd,J＝10.6,8.2,2.4Hz,2H),3.50-3.40(m,2H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.7Hz,1H),2.19-2.07(m,2H),2.06-1.85(m,4H),1.69(s,1H),1.57-1.46(m,1H),1.27(d,J＝26.2Hz,2H)ppm；LCMS:m/z 550.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.02 (d, J=7.8Hz, 1H), 7.32 (dd, J=10.9, 6.7Hz, 3H), 7.20 (qd, J=6.7, 5.6, 3.8Hz, 3H), 5.56(d, J=5.5Hz, 1H), 4.65(dd, J=10.3, 3.6Hz, 1H), 4.52(s, 1H), 4.08(s, 1H) ),3.92(s,1H),3.68(ddd,J=9.6,5.8,3.6Hz,2H),3.57(ddd,J=10.6,8.2,2.4Hz,2H),3.50-3.40(m,2H), 3.17(d,J=15.7Hz,1H),2.72(d,J=15.7Hz,1H),2.19-2.07(m,2H),2.06-1.85(m,4H),1.69(s,1H),1.57 -1.46(m,1H),1.27(d,J=26.2Hz,2H)ppm; LCMS: m/z 550.1[M+H] + .
实施例38 1'-(5-(((6aS,8R)-8-氟-6a，7,8,9-四氢-6H-吡啶[3,2-b]吡咯[1,2-d][1,4]恶嗪-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-1,3-二氢螺环[茚-2,4'-哌啶]-1-胺Example 38 1'-(5-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyridine[3,2-b]pyrrole[1,2-d] [1,4]oxazin-4-yl)thio)-1,2a1,4-triazacyclopenta[cd]indan-2-yl)-1,3-dihydrospiro[indene-2 ,4'-Piperidin]-1-amine
Figure PCTCN2021126331-appb-000351
Figure PCTCN2021126331-appb-000351
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.03(d,J＝7.8Hz,1H),7.40-7.27(m,3H),7.26-7.12(m,3H),5.62(d,J＝5.5Hz,1H),5.48(d,J＝52.7Hz,1H),4.71(dd,J＝10.4,3.7Hz,1H),4.53(s,1H),4.09(s,1H),4.00-3.88(m,2H),3.84-3.61(m,3H),3.53(t,J＝9.9Hz,2H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.7Hz,1H),2.42-2.33(m,1H),2.30-1.57(m,6H),1.27(d,J＝25.6Hz,1H)ppm；LCMS:m/z 568.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.54(s, 1H), 8.03(d, J=7.8Hz, 1H), 7.40-7.27(m, 3H), 7.26-7.12(m, 3H), 5.62(d,J＝5.5Hz,1H),5.48(d,J＝52.7Hz,1H),4.71(dd,J＝10.4,3.7Hz,1H),4.53(s,1H),4.09(s,1H) ), 4.00-3.88(m, 2H), 3.84-3.61(m, 3H), 3.53(t, J=9.9Hz, 2H), 3.17(d, J=15.7Hz, 1H), 2.72(d, J= 15.7Hz, 1H), 2.42-2.33(m, 1H), 2.30-1.57(m, 6H), 1.27(d, J=25.6Hz, 1H) ppm; LCMS: m/z 568.1[M+H] + .
实施例39 1'-(5-((2-氨基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-7-胺Example 39 1'-(5-((2-amino-3-chloropyridin-4-yl)sulfanyl)-1,2a1,4-triazacyclopenta[cd]inden-2-yl)-5 ,7-Dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000352
Figure PCTCN2021126331-appb-000352
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.37(d,J＝4.4Hz,1H),8.09(d,J＝7.8Hz,1H),7.64(d,J＝7.5Hz,1H),7.51(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.19(dd,J＝7.3,5.1Hz,1H),6.37(s,2H),5.55(d,J＝5.4Hz,1H),3.97(s,1H),3.69(d,J＝41.8Hz,4H),3.20-3.10(m,2H),2.81-2.66(m,2H),1.98(dd,J＝21.7,14.2Hz,4H)ppm；LCMS:m/z 503.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.64 (d, J= 7.5Hz, 1H), 7.51 (d, J=5.4Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 7.19 (dd, J=7.3, 5.1Hz, 1H), 6.37 (s, 2H) ,5.55(d,J＝5.4Hz,1H),3.97(s,1H),3.69(d,J＝41.8Hz,4H),3.20-3.10(m,2H),2.81-2.66(m,2H), 1.98(dd,J=21.7,14.2Hz,4H)ppm; LCMS: m/z 503.1[M+H] + .
实施例40(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚-2-基)-5,7-二氢螺环[c]吡啶-6,4'-哌啶]-7-胺Example 40 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)sulfanyl)-1,2a1,4-triazacyclopenta[cd]indene-2- yl)-5,7-dihydrospiro[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000353
Figure PCTCN2021126331-appb-000353
1H NMR(400MHz,DMSO-d 6)δ8.49(s,1H),8.42(s,1H),8.31(d,J＝4.9Hz,1H),8.02(d,J＝7.8Hz,1H),7.44(d,J＝5.4Hz,1H),7.26(d,J＝7.8Hz,1H),7.20(d,J＝4.8Hz,1H),6.31(s,2H),5.47(d,J＝5.4Hz,1H),4.42(s,1H),3.96(s,2H),3.72-3.61(m,1H),3.48(s,1H),3.11(d,J＝16.5Hz,1H),2.69(d,J＝16.5Hz,1H),2.02-1.63(m,5H),1.16(s,1H)ppm；LCMS:m/z 503.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.49(s, 1H), 8.42(s, 1H), 8.31(d, J=4.9Hz, 1H), 8.02(d, J=7.8Hz, 1H) ,7.44(d,J＝5.4Hz,1H),7.26(d,J＝7.8Hz,1H),7.20(d,J＝4.8Hz,1H),6.31(s,2H),5.47(d,J＝ 5.4Hz, 1H), 4.42(s, 1H), 3.96(s, 2H), 3.72-3.61(m, 1H), 3.48(s, 1H), 3.11(d, J=16.5Hz, 1H), 2.69( d, J=16.5Hz, 1H), 2.02-1.63 (m, 5H), 1.16 (s, 1H) ppm; LCMS: m/z 503.1[M+H] + .
实施例41(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚满-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-7-胺Example 41 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopenta[cd]indan-2 -yl)-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000354
Figure PCTCN2021126331-appb-000354
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.37(d,J＝4.4Hz,1H),8.09(d,J＝7.8Hz,1H),7.64(d,J＝7.3Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.19(dd,J＝7.4,5.0Hz,1H),6.37(s,2H),5.56(t,J＝6.3Hz,1H),4.44(s,1H),4.08(s,1H),3.98(s,1H),3.69(d,J＝42.9Hz,3H),3.15(d,J＝16.0Hz,1H),2.75(d,J＝16.0Hz,1H),1.95(s,2H),1.75(s,1H),1.31(d,J＝62.6Hz,2H)ppm；LCMS:m/z 503.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.64 (d, J= 7.3Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 7.19 (dd, J=7.4, 5.0Hz, 1H), 6.37 (s, 2H) ,5.56(t,J＝6.3Hz,1H),4.44(s,1H),4.08(s,1H),3.98(s,1H),3.69(d,J＝42.9Hz,3H),3.15(d, J=16.0Hz, 1H), 2.75(d, J=16.0Hz, 1H), 1.95(s, 2H), 1.75(s, 1H), 1.31(d, J=62.6Hz, 2H) ppm; LCMS: m /z 503.1[M+H] + .
实施例42 1'-(5-((2-氨基-3-氯吡啶-4-基)硫基)-1,2a1,4-三氮杂环戊[cd]茚-2-基)-5,7-二氢螺[环戊][b]吡啶-6,4'-哌啶]-5-胺Example 42 1'-(5-((2-amino-3-chloropyridin-4-yl)sulfanyl)-1,2a1,4-triazacyclopenta[cd]inden-2-yl)-5 ,7-Dihydrospiro[cyclopenta][b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000355
Figure PCTCN2021126331-appb-000355
1H NMR(400MHz,DMSO-d 6)δ8.62(s,1H),8.56(d,J＝4.2Hz,1H),8.38(s,2H),8.13(d,J＝7.8Hz,1H),7.91(d,J＝7.4Hz,1H),7.52(d,J＝5.5Hz,1H),7.39(d,J＝7.9Hz,1H),7.38–7.30(m,1H),6.48(s,2H),5.56(d,J＝5.5Hz,1H),4.54(s,1H),4.11(s,2H),3.80(s,1H),3.57(s,1H),3.20(d,J＝16.9Hz,2H),2.00(d,J＝66.6Hz,3H),1.73(d,J＝24.2Hz,2H)；LCMS:m/z 503.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.62(s, 1H), 8.56(d, J=4.2Hz, 1H), 8.38(s, 2H), 8.13(d, J=7.8Hz, 1H) ,7.91(d,J＝7.4Hz,1H),7.52(d,J＝5.5Hz,1H),7.39(d,J＝7.9Hz,1H),7.38–7.30(m,1H),6.48(s, 2H), 5.56(d, J=5.5Hz, 1H), 4.54(s, 1H), 4.11(s, 2H), 3.80(s, 1H), 3.57(s, 1H), 3.20(d, J=16.9 Hz, 2H), 2.00(d, J=66.6Hz, 3H), 1.73(d, J=24.2Hz, 2H); LCMS: m/z 503.1[M+H] + .
实施例43(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 43 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000356
Figure PCTCN2021126331-appb-000356
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.09(d,J＝7.8Hz,1H),7.51(d,J＝5.4Hz,1H),7.33(d,J＝7.2Hz,2H),7.21(dt,J＝9.3,3.5Hz,3H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.54(s,1H),4.10(s,1H),3.95(s,1H),3.74(s,1H),3.53(d,J＝11.9Hz,1H),3.18(d,J＝15.8Hz,1H),2.74(d,J＝15.7Hz, 1H),1.80(d,J＝49.9Hz,5H)ppm；LCMS:m/z 502.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.51 (d, J=5.4 Hz, 1H), 7.33 (d, J= 7.2Hz, 2H), 7.21(dt, J=9.3, 3.5Hz, 3H), 6.38(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.54(s, 1H), 4.10(s, 1H), 3.95(s, 1H), 3.74(s, 1H), 3.53(d, J=11.9Hz, 1H), 3.18(d, J=15.8Hz, 1H), 2.74(d, J=15.7Hz, 1H), 1.80(d, J=49.9Hz, 5H)ppm; LCMS: m/z 502.1[M+H] + .
实施例44(S)-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡嗪-6,4'-哌啶]-5-胺Example 44 (S)-1'-(5-((3-Chloro-2-methylpyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd] inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyrazin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000357
Figure PCTCN2021126331-appb-000357
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.40(s,2H),8.12(d,J＝7.8Hz,1H),7.97(d,J＝5.4Hz,1H),7.36(d,J＝7.8Hz,1H),6.28(d,J＝5.4Hz,1H),4.51–4.45(m,1H),4.04(s,2H),3.71(d,J＝42.9Hz,4H),2.57(s,3H),2.00(d,J＝7.4Hz,4H),1.82–1.72(m,2H)ppm；LCMS:[M+H] +＝503.1. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57(s, 1H), 8.40(s, 2H), 8.12(d, J=7.8Hz, 1H), 7.97(d, J=5.4Hz, 1H) ,7.36(d,J＝7.8Hz,1H),6.28(d,J＝5.4Hz,1H),4.51–4.45(m,1H),4.04(s,2H),3.71(d,J＝42.9Hz, 4H), 2.57 (s, 3H), 2.00 (d, J=7.4Hz, 4H), 1.82–1.72 (m, 2H) ppm; LCMS: [M+H] + =503.1.
实施例45(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡嗪-6,4'-哌啶]-5-胺Example 45 (S)-1'-(5-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyrazin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000358
Figure PCTCN2021126331-appb-000358
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.40(q,J＝2.9Hz,2H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.34(d,J＝7.8Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.46(s,2H),4.03(s,3H),3.72(d,J＝49.2Hz,4H),2.03–1.88(m,4H)ppm；LCMS:[M+H] +＝504.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57(s, 1H), 8.40(q, J=2.9Hz, 2H), 8.09(d, J=7.8Hz, 1H), 7.50(d, J= 5.4Hz, 1H), 7.34(d, J=7.8Hz, 1H), 6.38(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.46(s, 2H), 4.03(s, 3H) , 3.72 (d, J=49.2Hz, 4H), 2.03–1.88 (m, 4H) ppm; LCMS: [M+H] + = 504.1
实施例46(S)-1'-(5-((3-氨基-2-氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-7-胺Example 46 (S)-1'-(5-((3-amino-2-chlorophenyl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene-2- yl)-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000359
Figure PCTCN2021126331-appb-000359
1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝15.3Hz,2H),8.31(d,J＝4.8Hz,1H),7.90(d,J＝7.8Hz,1H),7.21(dd,J＝10.4,6.4Hz,2H),6.67(d,J＝7.9Hz,1H),6.51(d,J＝8.2Hz,1H),5.69(d,J＝7.7Hz,1H),5.43(s,2H),4.42(s,2H),3.95(s,2H),3.62–3.58(m,1H),3.11(d,J＝16.9Hz,1H),2.69(d,J＝16.4Hz,1H),1.69(d,J＝77.8Hz,5H),1.27(s,1H)ppm；LCMS:[M+H] +＝502.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (d, J=15.3 Hz, 2H), 8.31 (d, J=4.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.21 (dd,J＝10.4,6.4Hz,2H),6.67(d,J＝7.9Hz,1H),6.51(d,J＝8.2Hz,1H),5.69(d,J＝7.7Hz,1H),5.43 (s, 2H), 4.42 (s, 2H), 3.95 (s, 2H), 3.62–3.58 (m, 1H), 3.11 (d, J=16.9Hz, 1H), 2.69 (d, J=16.4Hz, 1H), 1.69 (d, J=77.8Hz, 5H), 1.27 (s, 1H) ppm; LCMS: [M+H] + =502.1
实施例47 1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-d-5-胺Example 47 1'-(5-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-d-5-amine
Figure PCTCN2021126331-appb-000360
Figure PCTCN2021126331-appb-000360
1H NMR(400MHz,DMSO-d 6)δ8.50(s,1H),8.27(dd,J＝5.0,1.5Hz,1H),8.02(d,J＝7.8Hz,1H),7.60(d,J＝6.2Hz,1H),7.44(d,J＝5.4Hz,1H),7.26(d,J＝7.8Hz,1H),7.13(dd,J＝7.4,5.0Hz,1H),6.30(s,2H),5.48(d,J＝5.4Hz,1H),4.46(s,1H),4.03(s,1H),3.65(s,1H),3.47(s,1H),3.12(s,1H),2.77(d,J＝16.3Hz,1H),1.81(s,4H),1.66(s,2H)ppm；LCMS:[M+H] +＝504.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (s, 1H), 8.27 (dd, J=5.0, 1.5 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.60 (d, J=6.2Hz, 1H), 7.44(d, J=5.4Hz, 1H), 7.26(d, J=7.8Hz, 1H), 7.13(dd, J=7.4, 5.0Hz, 1H), 6.30(s, 2H), 5.48(d, J=5.4Hz, 1H), 4.46(s, 1H), 4.03(s, 1H), 3.65(s, 1H), 3.47(s, 1H), 3.12(s, 1H), 2.77(d, J=16.3Hz, 1H), 1.81(s, 4H), 1.66(s, 2H) ppm; LCMS: [M+H] + =504.1.
实施例48(R)-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 48(R)-1'-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000361
Figure PCTCN2021126331-appb-000361
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.09(d,J＝7.8Hz,1H),7.41(dd,J＝8.0,1.4Hz,1H),7.33(d,J＝7.8Hz,2H),7.20(qd,J＝6.5,5.5,3.4Hz,3H),7.08(t,J＝8.0Hz,1H),6.51(dd,J＝8.1,1.4Hz,1H),4.53(s,1H),4.09(s,1H),3.93(s,1H),3.85–3.60(m,1H),3.52(d,J＝12.5Hz,1H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.8Hz,1H),2.04–1.57(m,4H),1.23(s,2H)ppm；LCMS:[M+H] +＝520.1. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.41 (dd, J=8.0, 1.4Hz, 1H), 7.33 (d, J＝7.8Hz, 2H), 7.20(qd, J＝6.5, 5.5, 3.4Hz, 3H), 7.08(t, J＝8.0Hz, 1H), 6.51(dd, J＝8.1, 1.4Hz, 1H), 4.53(s, 1H), 4.09(s, 1H), 3.93(s, 1H), 3.85–3.60(m, 1H), 3.52(d, J=12.5Hz, 1H), 3.17(d, J=15.7Hz , 1H), 2.72 (d, J=15.8Hz, 1H), 2.04–1.57 (m, 4H), 1.23 (s, 2H) ppm; LCMS: [M+H] + = 520.1.
实施例49(S)-1'-(5-((2-(三氟甲基)吡啶-3-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 49 (S)-1'-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,2a1,4-triazacyclopentadieno[cd] inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000362
Figure PCTCN2021126331-appb-000362
1H NMR(400MHz,DMSO-d 6)δ8.53(s,1H),8.47(dd,J＝4.4,1.4Hz,1H),8.10(d,J＝7.8Hz,1H),7.41(dd,J＝8.3,4.5Hz,1H),7.37–7.29(m,3H),7.20(qd,J＝6.4,5.4,3.3Hz,3H),4.53(s,1H),4.09(s,1H),3.93(s,1H),3.72(d,J＝26.3Hz,1H),3.53(s,1H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.7Hz,1H),1.81(d,J＝50.7Hz,5H),1.28(s,1H)ppm；LCMS:[M+H] +＝521.4 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.47 (dd, J=4.4, 1.4 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.41 (dd, J=8.3, 4.5Hz, 1H), 7.37–7.29 (m, 3H), 7.20 (qd, J=6.4, 5.4, 3.3Hz, 3H), 4.53 (s, 1H), 4.09 (s, 1H), 3.93 (s,1H),3.72(d,J=26.3Hz,1H),3.53(s,1H),3.17(d,J=15.7Hz,1H),2.72(d,J=15.7Hz,1H),1.81 (d, J=50.7Hz, 5H), 1.28 (s, 1H) ppm; LCMS: [M+H] + =521.4
实施例50(S)-1'-(5-((2-氯-3-(吡嗪-2-基氨基)苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 50 (S)-1'-(5-((2-chloro-3-(pyrazin-2-ylamino)phenyl)thio)-1,2a1,4-triazacyclopentadiene [cd]inden-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000363
Figure PCTCN2021126331-appb-000363
1H NMR(400MHz,DMSO-d 6)δ9.02(s,1H),8.55(s,1H),8.41(d,J＝1.5Hz,1H),8.12–8.04(m,2H),7.98(d,J＝2.7Hz,1H),7.68(dd,J＝8.2,1.4Hz,1H),7.33(dd,J＝7.0,2.4Hz,2H),7.20(pd,J＝7.3,3.3Hz,3H),7.04(t,J＝8.1Hz,1H),6.29(dd,J＝8.0,1.4Hz,1H),4.53(s,1H),4.09(s,1H),3.92(s,1H),3.69(s,1H),3.53(s,1H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.7Hz,1H),2.20(s,1H),2.03–1.55(m,4H)ppm；LCMS:[M+H] +＝521.1 1 H NMR (400MHz, DMSO-d 6 )δ9.02(s,1H),8.55(s,1H),8.41(d,J=1.5Hz,1H),8.12-8.04(m,2H),7.98( d, J=2.7Hz, 1H), 7.68 (dd, J=8.2, 1.4Hz, 1H), 7.33 (dd, J=7.0, 2.4Hz, 2H), 7.20 (pd, J=7.3, 3.3Hz, 3H) ),7.04(t,J=8.1Hz,1H),6.29(dd,J=8.0,1.4Hz,1H),4.53(s,1H),4.09(s,1H),3.92(s,1H),3.69 (s, 1H), 3.53 (s, 1H), 3.17 (d, J=15.7Hz, 1H), 2.72 (d, J=15.7Hz, 1H), 2.20 (s, 1H), 2.03–1.55 (m, 4H) ppm; LCMS: [M+H] + =521.1
实施例51(S)-N-(3-((2-(7-氨基-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-1'-基)环戊二烯并[cd]茚-5-基)硫代)-2-氯苯基)苯酰胺Example 51(S)-N-(3-((2-(7-Amino-5,7-dihydrospiro[cyclopentadieno[c]pyridine-6,4'-piperidine]-1' -yl)cyclopentadieno[cd]inden-5-yl)thio)-2-chlorophenyl)benzamide
Figure PCTCN2021126331-appb-000364
Figure PCTCN2021126331-appb-000364
1H NMR(400MHz,DMSO-d 6)δ10.11(s,1H),8.49(s,1H),8.43(s,1H),8.32(d,J＝4.9Hz,1H),8.02(d,J＝7.8Hz,1H),7.97–7.91(m,2H),7.56(t,J＝7.3Hz,1H),7.49(t,J＝7.4Hz,2H),7.31–7.25(m,2H),7.21(d,J＝4.8Hz,1H),7.05(t,J＝8.0Hz,1H),6.41(dd,J＝8.1,1.3Hz,1H),4.43(s,1H),3.97(s,2H),3.66(s,1H),3.48(s,1H),3.10(s,1H),2.71(d,J＝16.5Hz,1H),1.70(d,J＝70.1Hz,6H)ppm；LCMS:[M+H] +＝606.2 1 H NMR (400MHz, DMSO-d 6 )δ 10.11(s, 1H), 8.49(s, 1H), 8.43(s, 1H), 8.32(d, J=4.9Hz, 1H), 8.02(d, J=7.8Hz, 1H), 7.97–7.91 (m, 2H), 7.56 (t, J=7.3Hz, 1H), 7.49 (t, J=7.4Hz, 2H), 7.31–7.25 (m, 2H), 7.21(d,J＝4.8Hz,1H),7.05(t,J＝8.0Hz,1H),6.41(dd,J＝8.1,1.3Hz,1H),4.43(s,1H),3.97(s,2H ), 3.66(s, 1H), 3.48(s, 1H), 3.10(s, 1H), 2.71(d, J=16.5Hz, 1H), 1.70(d, J=70.1Hz, 6H) ppm; LCMS: [M+H] + = 606.2
实施例52(S)-1'-(5-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 52 (S)-1'-(5-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)thio)-1,2a1,4-triazacyclopenta Dieno[cd]inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000365
Figure PCTCN2021126331-appb-000365
1H NMR(400MHz,DMSO-d 6)δ9.06(d,J＝1.6Hz,1H),8.87(dd,J＝2.6,1.6Hz,1H),8.81(d,J＝2.5Hz,1H),8.52(s,1H),8.20(d,J＝4.8Hz,1H),8.08(d,J＝7.8Hz,1H),7.39(d,J＝4.9Hz,1H),7.34(d,J＝7.4Hz,2H),7.24–7.15(m,3H),4.54(s,1H),4.09(s,1H),3.96(s,1H),3.73(d,J＝23.0Hz,1H),3.54(s,1H),3.18(d,J＝15.7Hz,1H),2.75(d,J＝15.8Hz,1H),1.99–1.65(m,3H),1.34(s,1H)ppm；LCMS:[M+H] +＝565.2 1 H NMR (400MHz, DMSO-d 6 ) δ 9.06 (d, J=1.6Hz, 1H), 8.87 (dd, J=2.6, 1.6Hz, 1H), 8.81 (d, J=2.5Hz, 1H) ,8.52(s,1H),8.20(d,J＝4.8Hz,1H),8.08(d,J＝7.8Hz,1H),7.39(d,J＝4.9Hz,1H),7.34(d,J＝ 7.4Hz, 2H), 7.24–7.15(m, 3H), 4.54(s, 1H), 4.09(s, 1H), 3.96(s, 1H), 3.73(d, J=23.0Hz, 1H), 3.54( s, 1H), 3.18 (d, J=15.7Hz, 1H), 2.75 (d, J=15.8Hz, 1H), 1.99–1.65 (m, 3H), 1.34 (s, 1H) ppm; LCMS: [M +H] + = 565.2
实施例53(S)-1-(3-((2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)环戊二烯并[cd]茚-5-基)硫代)-2-氯苯基)Example 53 (S)-1-(3-((2-(1-amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)cyclopentadieno [cd]Inden-5-yl)thio)-2-chlorophenyl)
Figure PCTCN2021126331-appb-000366
Figure PCTCN2021126331-appb-000366
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.09(d,J＝7.8Hz,1H),7.33(dd,J＝7.0,3.2Hz,2H),7.24–7.17(m,4H),7.11(t,J＝7.9Hz,1H),6.49(dd,J＝8.0,1.6Hz,1H),4.53(s,1H),4.09(s,1H),3.93(s,1H),3.71(t,J＝6.9Hz,3H),3.53(s,1H),3.17(d,J＝15.7Hz,1H),2.73(d,J＝15.7Hz,1H),2.44(d,J＝8.1Hz,2H),2.26–2.06(m,3H),1.82(s,4H)ppm；LCMS:[M+H] +＝569.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.33 (dd, J=7.0, 3.2Hz, 2H), 7.24-7.17 ( m, 4H), 7.11(t, J=7.9Hz, 1H), 6.49(dd, J=8.0, 1.6Hz, 1H), 4.53(s, 1H), 4.09(s, 1H), 3.93(s, 1H) ),3.71(t,J＝6.9Hz,3H),3.53(s,1H),3.17(d,J＝15.7Hz,1H),2.73(d,J＝15.7Hz,1H),2.44(d,J = 8.1Hz, 2H), 2.26–2.06 (m, 3H), 1.82 (s, 4H) ppm; LCMS: [M+H] + =569.1
实施例54(S)-1'-(5-((2-氯-3-(吡咯烷-1-基)苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 54 (S)-1'-(5-((2-chloro-3-(pyrrolidin-1-yl)phenyl)thio)-1,2a1,4-triazacyclopentadieno [cd]inden-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000367
Figure PCTCN2021126331-appb-000367
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.02(d,J＝7.9Hz,1H),7.32(t,J＝7.5Hz,2H),7.21(qd,J＝6.5,5.2,3.2Hz,3H),6.90(t,J＝8.0Hz,1H),6.77(dd,J＝8.3,1.4Hz,1H),5.98(dd,J＝7.9,1.3Hz,1H),4.53(s,1H),4.09(s,1H),3.95(s,1H),3.69(s,1H),3.51(s,1H),3.31(s,4H),3.17(d,J＝15.7Hz,1H),2.74(d,J＝15.8Hz,1H),2.07–1.64(m,8H),1.23(s,2H)ppm；LCMS:[M+H] +＝555.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.02 (d, J=7.9Hz, 1H), 7.32 (t, J=7.5Hz, 2H), 7.21 (qd, J= 6.5,5.2,3.2Hz,3H),6.90(t,J＝8.0Hz,1H),6.77(dd,J＝8.3,1.4Hz,1H),5.98(dd,J＝7.9,1.3Hz,1H), 4.53(s, 1H), 4.09(s, 1H), 3.95(s, 1H), 3.69(s, 1H), 3.51(s, 1H), 3.31(s, 4H), 3.17(d, J=15.7Hz , 1H), 2.74 (d, J=15.8Hz, 1H), 2.07–1.64 (m, 8H), 1.23 (s, 2H) ppm; LCMS: [M+H] + = 555.2
实施例55(R)-1'-(5-((2-(三氟甲基)吡啶-3-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-7-胺Example 55 (R)-1'-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,2a1,4-triazacyclopentadieno[cd] inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000368
Figure PCTCN2021126331-appb-000368
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.50–8.45(m,2H),8.38(d,J＝4.7Hz,1H),8.10(d,J＝7.8Hz,1H),7.41(dd,J＝8.2,4.5Hz,1H),7.36–7.31(m,2H),7.27(d,J＝4.8Hz,1H),4.48(s,1H),4.03(s,3H),3.75(s,1H),3.16(s,1H),2.75(s,1H),1.76(d,J＝56.4Hz,6H)ppm；LCMS:[M+H] +＝522.1 1 H NMR (400MHz, DMSO-d 6 )δ8.54(s,1H),8.50-8.45(m,2H),8.38(d,J=4.7Hz,1H),8.10(d,J=7.8Hz, 1H), 7.41(dd, J=8.2, 4.5Hz, 1H), 7.36–7.31(m, 2H), 7.27(d, J=4.8Hz, 1H), 4.48(s, 1H), 4.03(s, 3H) ), 3.75(s, 1H), 3.16(s, 1H), 2.75(s, 1H), 1.76(d, J=56.4Hz, 6H) ppm; LCMS: [M+H] + =522.1
实施例56(S)-2-氯-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 56 (S)-2-Chloro-1'-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000369
Figure PCTCN2021126331-appb-000369
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.10(d,J＝7.8Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.34(d,J＝7.8Hz,1H),7.08(t,J＝8.1Hz,1H),6.51(dd,J＝8.1,1.2Hz,1H),4.35(s,1H),4.04(s,2H),3.74(s,3H),2.33(s,2H),2.05–1.88(m,2H),1.75(s,3H)ppm；LCMS:[M+H] +＝561.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.10 (d, J=7.8Hz, 1H), 7.42 (dd, J=8.0, 1.3Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 7.08(t, J=8.1Hz, 1H), 6.51(dd, J=8.1, 1.2Hz, 1H), 4.35(s, 1H), 4.04(s, 2H), 3.74( s, 3H), 2.33 (s, 2H), 2.05–1.88 (m, 2H), 1.75 (s, 3H) ppm; LCMS: [M+H] + = 561.1
实施例57(S)-N-(3-((2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)环戊二烯并[cd]茚-5-基)硫代)-2-氯苯基)-2-氯-3-氟苯酰胺Example 57(S)-N-(3-((2-(1-Amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)cyclopentadieno [cd]Inden-5-yl)thio)-2-chlorophenyl)-2-chloro-3-fluorobenzamide
Figure PCTCN2021126331-appb-000370
Figure PCTCN2021126331-appb-000370
1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),8.55(s,1H),8.09(d,J＝7.8Hz,1H),7.55(dt,J＝16.5,7.9Hz,3H),7.43(d,J＝7.7Hz,1H),7.33(t,J＝6.6Hz,2H),7.26–7.16(m,3H),7.12(t,J＝8.0Hz,1H),6.47(d,J＝7.9Hz,1H),4.54(s,1H),4.11(s,2H),3.91(s,1H),3.69(s,2H),3.51(s,1H),1.82(d,J＝55.8Hz,6H)ppm；LCMS:[M+H] +＝657.1 1 H NMR (400MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 8.55 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.55 (dt, J=16.5, 7.9Hz, 3H), 7.43(d, J＝7.7Hz, 1H), 7.33(t, J＝6.6Hz, 2H), 7.26–7.16(m, 3H), 7.12(t, J＝8.0Hz, 1H), 6.47( d, J=7.9Hz, 1H), 4.54(s, 1H), 4.11(s, 2H), 3.91(s, 1H), 3.69(s, 2H), 3.51(s, 1H), 1.82(d, J =55.8Hz, 6H)ppm; LCMS: [M+H] + =657.1
实施例58(S)-1'-(5-((2-(三氟甲基)吡啶-3-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-7-胺Example 58 (S)-1'-(5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,2a1,4-triazacyclopentadieno[cd] inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000371
Figure PCTCN2021126331-appb-000371
1H NMR(400MHz,DMSO-d 6)δ8.56–8.44(m,3H),8.38(d,J＝4.9Hz,1H),8.11(d,J＝7.8Hz,1H),7.41(dd,J＝8.3,4.5Hz,1H),7.37–7.30(m,2H),7.27(d,J＝4.9Hz,1H),4.49(s,1H),4.02(s,2H),3.72(d,J＝29.5Hz,1H),3.55(s,1H),3.18(d,J＝16.5Hz,1H),2.76(d,J＝16.5Hz,1H),2.26–1.54(m,5H),1.30(dd,J＝41.0,12.4Hz,1H)ppm；LCMS:[M+H] +＝522.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56-8.44 (m, 3H), 8.38 (d, J=4.9Hz, 1H), 8.11 (d, J=7.8Hz, 1H), 7.41 (dd, J=8.3, 4.5Hz, 1H), 7.37–7.30(m, 2H), 7.27(d, J=4.9Hz, 1H), 4.49(s, 1H), 4.02(s, 2H), 3.72(d, J =29.5Hz,1H),3.55(s,1H),3.18(d,J=16.5Hz,1H),2.76(d,J=16.5Hz,1H),2.26–1.54(m,5H),1.30(dd , J=41.0, 12.4Hz, 1H) ppm; LCMS: [M+H] + =522.1
实施例59(S)-1'-(5-((2-氯-3-(噁唑-2-基)苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二 氢螺[茚-2,4'-哌啶]-1-胺Example 59 (S)-1'-(5-((2-Chloro-3-(oxazol-2-yl)phenyl)thio)-1,2a1,4-triazacyclopentadieno [cd]inden-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000372
Figure PCTCN2021126331-appb-000372
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.36(d,J＝0.8Hz,1H),8.12(d,J＝7.8Hz,1H),7.69(dd,J＝7.7,1.5Hz,1H),7.50(d,J＝0.8Hz,1H),7.34(dd,J＝8.0,4.3Hz,2H),7.24–7.18(m,4H),6.69(dd,J＝8.1,1.5Hz,1H),4.54(s,1H),4.10(s,1H),3.94(s,1H),3.73(s,1H),3.53(s,3H),3.17(d,J＝15.7Hz,1H),2.74(d,J＝15.8Hz,1H),1.77(d,J＝64.2Hz,3H),1.25(d,J＝13.3Hz,1H)ppm；LCMS:[M+H] +＝553.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.36 (d, J=0.8Hz, 1H), 8.12 (d, J=7.8Hz, 1H), 7.69 (dd, J= 7.7, 1.5Hz, 1H), 7.50 (d, J=0.8Hz, 1H), 7.34 (dd, J=8.0, 4.3Hz, 2H), 7.24–7.18 (m, 4H), 6.69 (dd, J=8.1 ,1.5Hz,1H),4.54(s,1H),4.10(s,1H),3.94(s,1H),3.73(s,1H),3.53(s,3H),3.17(d,J=15.7Hz ,1H),2.74(d,J=15.8Hz,1H),1.77(d,J=64.2Hz,3H),1.25(d,J=13.3Hz,1H)ppm; LCMS: [M+H] + = 553.1
实施例60(S)-1'-(5-((3-(苯并[d]噁唑-2-基)-2-氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 60 (S)-1'-(5-((3-(benzo[d]oxazol-2-yl)-2-chlorophenyl)thio)-1,2a1,4-triaza Cyclopentadieno[cd]inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000373
Figure PCTCN2021126331-appb-000373
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.15(d,J＝7.8Hz,1H),7.95–7.90(m,1H),7.90–7.84(m,2H),7.50(dtd,J＝16.2,7.4,1.4Hz,2H),7.36(d,J＝7.8Hz,1H),7.34–7.31(m,1H),7.29(t,J＝7.9Hz,1H),7.19(ddt,J＝11.5,8.0,4.2Hz,3H),6.78(dd,J＝8.1,1.5Hz,1H),4.55(s,1H),4.10(s,1H),3.92(s,1H),3.73(d,J＝29.9Hz,1H),3.54(s,1H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.7Hz,1H),1.84(d,J＝102.3Hz,5H),1.27(d,J＝29.3Hz,1H)ppm；LCMS:[M+H] +＝603.2 1 H NMR (400MHz, DMSO-d 6 )δ8.56(s, 1H), 8.15(d, J=7.8Hz, 1H), 7.95-7.90(m, 1H), 7.90-7.84(m, 2H), 7.50 (dtd, J=16.2, 7.4, 1.4Hz, 2H), 7.36 (d, J=7.8Hz, 1H), 7.34–7.31 (m, 1H), 7.29 (t, J=7.9Hz, 1H), 7.19 (ddt, J=11.5, 8.0, 4.2Hz, 3H), 6.78(dd, J=8.1, 1.5Hz, 1H), 4.55(s, 1H), 4.10(s, 1H), 3.92(s, 1H), 3.73(d,J＝29.9Hz,1H),3.54(s,1H),3.17(d,J＝15.7Hz,1H),2.72(d,J＝15.7Hz,1H),1.84(d,J＝102.3 Hz, 5H), 1.27 (d, J=29.3Hz, 1H) ppm; LCMS: [M+H] + =603.2
实施例61 6-溴-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 61 6-Bromo-1'-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000374
Figure PCTCN2021126331-appb-000374
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.09(d,J＝7.8Hz,1H),7.47(s,1H),7.44–7.40(m,1H),7.34(t,J＝9.1Hz,2H),7.19(d,J＝7.9Hz,1H),7.08(t,J＝8.1Hz,1H),6.51(d,J＝7.1Hz,1H),4.53(s,1H),4.06(d,J＝30.5Hz,2H),3.92(s,1H),3.66(s,1H),3.14(d,J＝15.9Hz,1H),2.68(s,1H),1.86(d,J＝86.7Hz,6H)ppm；LCMS:[M+H] +＝598.1 1 H NMR (400MHz, DMSO-d 6 )δ8.55(s,1H),8.09(d,J=7.8Hz,1H),7.47(s,1H),7.44-7.40(m,1H),7.34( t, J＝9.1Hz, 2H), 7.19(d, J＝7.9Hz, 1H), 7.08(t, J＝8.1Hz, 1H), 6.51(d, J＝7.1Hz, 1H), 4.53(s, 1H), 4.06(d, J＝30.5Hz, 2H), 3.92(s, 1H), 3.66(s, 1H), 3.14(d, J＝15.9Hz, 1H), 2.68(s, 1H), 1.86( d, J=86.7Hz, 6H)ppm; LCMS: [M+H] + =598.1
实施例62 1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1,6-二胺Example 62 1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-1,3-dihydrospiro[indene-2,4'-piperidine]-1,6-diamine
Figure PCTCN2021126331-appb-000375
Figure PCTCN2021126331-appb-000375
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.3Hz,1H),7.32(d,J＝7.8Hz,1H),6.86(d,J＝7.9Hz,1H),6.55(s,1H),6.42–6.36(m,3H),5.54(d,J＝5.4Hz,1H),4.86(s,2H),4.54(s,1H),4.08(s,1H),3.78(s,1H),3.75–3.63(m,1H),2.99(d,J＝15.0Hz,1H),1.70(s,4H),1.22(d,J＝9.3Hz,2H)ppm；LCMS:[M+H] +＝517.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.3 Hz, 1H), 7.32 (d, J= 7.8Hz, 1H), 6.86(d, J=7.9Hz, 1H), 6.55(s, 1H), 6.42–6.36(m, 3H), 5.54(d, J=5.4Hz, 1H), 4.86(s, 2H), 4.54(s, 1H), 4.08(s, 1H), 3.78(s, 1H), 3.75–3.63(m, 1H), 2.99(d, J=15.0Hz, 1H), 1.70(s, 4H) ), 1.22 (d, J=9.3 Hz, 2H) ppm; LCMS: [M+H] + =517.1
实施例63 1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲腈Example 63 1-Amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carbonitrile
Figure PCTCN2021126331-appb-000376
Figure PCTCN2021126331-appb-000376
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.09(d,J＝7.9Hz,1H),7.71(s,1H),7.67(d,J＝7.7Hz,1H),7.50(d,J＝5.4Hz,1H),7.44(d,J＝7.8Hz,1H),7.33(d,J＝8.0Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.53(s,1H),4.11(s,1H),3.98(s,1H),3.76–3.68(m,1H),3.51(s,1H),3.29(s,1H),2.79(s,1H),1.77(s,4H),1.26–1.10(m,2H)ppm；LCMS:[M+H] +＝527.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57(s, 1H), 8.09(d, J=7.9Hz, 1H), 7.71(s, 1H), 7.67(d, J=7.7Hz, 1H) ,7.50(d,J＝5.4Hz,1H),7.44(d,J＝7.8Hz,1H),7.33(d,J＝8.0Hz,1H),6.38(s,2H),5.54(d,J＝ 5.4Hz, 1H), 4.53(s, 1H), 4.11(s, 1H), 3.98(s, 1H), 3.76–3.68(m, 1H), 3.51(s, 1H), 3.29(s, 1H), 2.79 (s, 1H), 1.77 (s, 4H), 1.26–1.10 (m, 2H) ppm; LCMS: [M+H] + = 527.1
实施例64(R)-1-(3-((2-(7-氨基-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-1'-基)环戊二烯并[cd]茚-5-基)硫代)-2-氯苯基)吡咯烷-2-酮Example 64(R)-1-(3-((2-(7-Amino-5,7-dihydrospiro[cyclopentadieno[c]pyridine-6,4'-piperidine]-1' -yl)cyclopentadieno[cd]inden-5-yl)thio)-2-chlorophenyl)pyrrolidin-2-one
Figure PCTCN2021126331-appb-000377
Figure PCTCN2021126331-appb-000377
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.49(s,1H),8.38(d,J＝4.9Hz,1H),8.09(d,J＝7.8Hz,1H),7.34(d,J＝7.8Hz,1H),7.27(d,J＝4.9Hz,1H),7.18(dd,J＝7.8,1.6Hz,1H),7.11(t,J＝7.9Hz,1H),6.48(dd,J＝8.0,1.6Hz,1H),4.50(s,1H),4.05(d,J＝24.2Hz,2H),3.71(t,J＝6.9Hz,3H),3.59–3.52(m,1H),3.18(d,J＝16.5Hz,1H),2.76(d,J＝16.5Hz,1H),2.45(t,J＝8.0Hz,2H),2.17(p,J＝7.5Hz,3H),1.77(d,J＝64.9Hz,4H),1.39–1.21(m,1H)ppm；LCMS:[M+H] +＝570.2 1 H NMR (400MHz, DMSO-d 6 )δ8.55(s,1H),8.49(s,1H),8.38(d,J=4.9Hz,1H),8.09(d,J=7.8Hz,1H) ,7.34(d,J＝7.8Hz,1H),7.27(d,J＝4.9Hz,1H),7.18(dd,J＝7.8,1.6Hz,1H),7.11(t,J＝7.9Hz,1H) ,6.48(dd,J＝8.0,1.6Hz,1H),4.50(s,1H),4.05(d,J＝24.2Hz,2H),3.71(t,J＝6.9Hz,3H),3.59–3.52( m, 1H), 3.18 (d, J=16.5Hz, 1H), 2.76 (d, J=16.5Hz, 1H), 2.45 (t, J=8.0Hz, 2H), 2.17 (p, J=7.5Hz, 3H), 1.77 (d, J=64.9Hz, 4H), 1.39–1.21 (m, 1H) ppm; LCMS: [M+H] + =570.2
实施例65(R)-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,6-二氢螺[环戊二烯并[b]吡啶-7,4'-哌啶]-6-胺Example 65 (R)-1'-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-5,6-dihydrospiro[cyclopentadieno[b]pyridin-7,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000378
Figure PCTCN2021126331-appb-000378
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.35(d,J＝4.0Hz,1H),8.10(d,J＝7.8Hz,1H),7.66(d,J＝6.6Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.34(d,J＝7.8Hz,1H),7.19(dd,J＝7.5,5.0Hz,1H), 7.09(t,J＝8.1Hz,1H),6.52(dd,J＝8.1,1.3Hz,1H),4.47(s,2H),4.31(s,1H),4.04(s,3H),3.45(s,1H),3.13(s,1H),2.68(dd,J＝15.4,7.3Hz,1H),2.02(dd,J＝17.9,10.5Hz,2H),1.75(s,2H)ppm；LCMS:[M+H] +＝521.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.35 (d, J=4.0 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.66 (d, J= 6.6Hz, 1H), 7.42(dd, J=8.0, 1.3Hz, 1H), 7.34(d, J=7.8Hz, 1H), 7.19(dd, J=7.5, 5.0Hz, 1H), 7.09(t, J=8.1Hz, 1H), 6.52(dd, J=8.1, 1.3Hz, 1H), 4.47(s, 2H), 4.31(s, 1H), 4.04(s, 3H), 3.45(s, 1H), 3.13(s, 1H), 2.68(dd, J=15.4, 7.3Hz, 1H), 2.02(dd, J=17.9, 10.5Hz, 2H), 1.75(s, 2H) ppm; LCMS: [M+H] + = 521.1
实施例66(R)-1'-(5-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-7-胺Example 66(R)-1'-(5-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)thio)-1,2a1,4-triazacyclopenta Dieno[cd]inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000379
Figure PCTCN2021126331-appb-000379
1H NMR(400MHz,DMSO-d 6)δ9.07(d,J＝1.6Hz,1H),8.87(dd,J＝2.6,1.6Hz,1H),8.81(d,J＝2.5Hz,1H),8.52(d,J＝11.9Hz,2H),8.39(d,J＝4.9Hz,1H),8.20(d,J＝4.8Hz,1H),8.08(d,J＝7.8Hz,1H),7.39(d,J＝4.9Hz,1H),7.34(d,J＝7.8Hz,1H),7.28(d,J＝4.9Hz,1H),4.51(s,1H),4.05(s,2H),3.73(s,1H),3.56(s,1H),3.19(d,J＝16.6Hz,1H),2.78(d,J＝16.5Hz,1H),1.78(d,J＝72.2Hz,5H),1.35(s,1H)ppm；LCMS:[M+H] +＝566.1 1 H NMR (400MHz, DMSO-d 6 ) δ 9.07 (d, J=1.6Hz, 1H), 8.87 (dd, J=2.6, 1.6Hz, 1H), 8.81 (d, J=2.5Hz, 1H) ,8.52(d,J＝11.9Hz,2H),8.39(d,J＝4.9Hz,1H),8.20(d,J＝4.8Hz,1H),8.08(d,J＝7.8Hz,1H),7.39 (d, J=4.9Hz, 1H), 7.34(d, J=7.8Hz, 1H), 7.28(d, J=4.9Hz, 1H), 4.51(s, 1H), 4.05(s, 2H), 3.73 (s,1H),3.56(s,1H),3.19(d,J=16.6Hz,1H),2.78(d,J=16.5Hz,1H),1.78(d,J=72.2Hz,5H),1.35 (s, 1H) ppm; LCMS: [M+H] + =566.1
实施例67 1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺Example 67 1-Amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxamide
Figure PCTCN2021126331-appb-000380
Figure PCTCN2021126331-appb-000380
1H NMR(400MHz,DMSO-d 6)δ8.56(d,J＝7.9Hz,1H),8.09(d,J＝7.8Hz,1H),7.90(s,1H),7.86(s,1H),7.72(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.7Hz,1H),7.30–7.23(m,2H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.54(s,1H),4.11(s,1H),3.94(s,1H),3.79–3.68(m,1H),3.52(d,J＝11.3Hz,1H),3.20(d,J＝16.2Hz,1H),2.75(d,J＝16.1Hz,1H),1.83(d,J＝59.7Hz,4H),1.23(s,2H)ppm；LCMS:[M+H] +＝545.2 1 H NMR (400MHz, DMSO-d 6 )δ8.56(d,J=7.9Hz,1H),8.09(d,J=7.8Hz,1H),7.90(s,1H),7.86(s,1H) ,7.72(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.7Hz,1H),7.30–7.23(m,2H),6.38(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.54(s, 1H), 4.11(s, 1H), 3.94(s, 1H), 3.79–3.68(m, 1H), 3.52(d, J =11.3Hz,1H),3.20(d,J=16.2Hz,1H),2.75(d,J=16.1Hz,1H),1.83(d,J=59.7Hz,4H),1.23(s,2H)ppm ; LCMS: [M+H] + =545.2
实施例68(1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)二甲基膦氧化Example 68 (1-Amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd] Inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-6-yl)dimethylphosphine oxidation
Figure PCTCN2021126331-appb-000381
Figure PCTCN2021126331-appb-000381
1H NMR(400MHz,DMSO-d 6)δ8.61–8.51(m,1H),8.09(d,J＝7.8Hz,1H),7.73(d,J＝11.3Hz,1H),7.58(dd,J＝11.0,7.9Hz,1H),7.50(d,J＝5.4Hz,1H),7.34(dd,J＝11.6,7.8Hz,2H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.62–4.45(m,1H),4.17–4.00(m,1H),3.96(s,1H),3.82–3.63(m,1H),3.64–3.47(m,1H),3.22(d,J＝16.1Hz,1H),2.76(d,J＝15.9Hz,1H),2.04–1.93(m,1H),1.92–1.68(m,3H),1.63(d,J＝13.2Hz,6H),1.35–1.16(m,2H)ppm；LCMS:[M+H] +＝578.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.61-8.51 (m, 1H), 8.09 (d, J=7.8Hz, 1H), 7.73 (d, J=11.3Hz, 1H), 7.58 (dd, J=11.0,7.9Hz,1H),7.50(d,J=5.4Hz,1H),7.34(dd,J=11.6,7.8Hz,2H),6.38(s,2H),5.54(d,J=5.4 Hz, 1H), 4.62–4.45 (m, 1H), 4.17–4.00 (m, 1H), 3.96 (s, 1H), 3.82–3.63 (m, 1H), 3.64–3.47 (m, 1H), 3.22 ( d, J=16.1Hz, 1H), 2.76 (d, J=15.9Hz, 1H), 2.04–1.93 (m, 1H), 1.92–1.68 (m, 3H), 1.63 (d, J=13.2Hz, 6H) ), 1.35–1.16 (m, 2H) ppm; LCMS: [M+H] + =578.1
实施例69(S)-2-氯-1'-(5-((2,3-二氯苯基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺 [环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 69 (S)-2-Chloro-1'-(5-((2,3-dichlorophenyl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000382
Figure PCTCN2021126331-appb-000382
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.10(d,J＝7.8Hz,1H),7.73(d,J＝7.9Hz,1H),7.42(d,J＝7.0Hz,1H),7.36–7.29(m,2H),7.08(t,J＝8.1Hz,1H),6.51(d,J＝7.2Hz,1H),4.51(s,1H),4.08(s,1H),3.95(s,1H),3.63(d,J＝57.9Hz,3H),2.09(s,2H),1.81(d,J＝41.8Hz,5H)ppm；LCMS:[M+H] +＝555.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.10 (d, J=7.8Hz, 1H), 7.73 (d, J=7.9Hz, 1H), 7.42 (d, J= 7.0Hz, 1H), 7.36–7.29(m, 2H), 7.08(t, J=8.1Hz, 1H), 6.51(d, J=7.2Hz, 1H), 4.51(s, 1H), 4.08(s, 1H), 3.95(s, 1H), 3.63(d, J=57.9Hz, 3H), 2.09(s, 2H), 1.81(d, J=41.8Hz, 5H) ppm; LCMS: [M+H] + =555.1
实施例70 1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-N,N-二甲基-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺Example 70 1-Amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-N,N-dimethyl-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxamide
Figure PCTCN2021126331-appb-000383
Figure PCTCN2021126331-appb-000383
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝8.6Hz,2H),7.27(d,J＝7.6Hz,1H),7.21(d,J＝7.6Hz,1H),6.36(s,2H),5.55(d,J＝5.3Hz,1H),4.54(s,2H),4.13(s,2H),3.93(s,1H),3.17(d,J＝5.4Hz,1H),2.86(d,J＝59.6Hz,6H),2.72(s,1H),1.80(d,J＝33.3Hz,4H),1.48(s,2H)ppm；LCMS:[M+H] +＝573.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.33 (d, J= 8.6Hz, 2H), 7.27(d, J＝7.6Hz, 1H), 7.21(d, J＝7.6Hz, 1H), 6.36(s, 2H), 5.55(d, J＝5.3Hz, 1H), 4.54 (s, 2H), 4.13(s, 2H), 3.93(s, 1H), 3.17(d, J=5.4Hz, 1H), 2.86(d, J=59.6Hz, 6H), 2.72(s, 1H) , 1.80(d, J=33.3Hz, 4H), 1.48(s, 2H) ppm; LCMS: [M+H] + =573.1
实施例71(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 71 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000384
Figure PCTCN2021126331-appb-000384
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.34(d,J＝4.2Hz,1H),8.09(d,J＝7.8Hz,1H),7.67(d,J＝7.3Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.19(dd,J＝7.5,5.0Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.53(s,1H),4.10(s,1H),3.96(s,1H),3.74(d,J＝14.7Hz,1H),3.67–3.45(m,2H),1.99–1.67(m,5H),1.23(s,2H)ppm；LCMS:[M+H] +＝503.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.34 (d, J=4.2 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.67 (d, J= 7.3Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 7.19 (dd, J=7.5, 5.0Hz, 1H), 6.38 (s, 2H) ,5.54(d,J＝5.4Hz,1H),4.53(s,1H),4.10(s,1H),3.96(s,1H),3.74(d,J＝14.7Hz,1H),3.67–3.45( m, 2H), 1.99–1.67 (m, 5H), 1.23 (s, 2H) ppm; LCMS: [M+H] + = 503.1
实施例72(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-N-甲基-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 72 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-N-methyl-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000385
Figure PCTCN2021126331-appb-000385
1H NMR(400MHz,DMSO-d 6)δ8.55(d,J＝15.7Hz,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.9Hz,2H),7.23(d,J＝19.4Hz,3H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.28(s,1H),4.00(s,1H),3.75(dd,J＝26.2,14.0Hz,3H),3.09(d,J＝15.8Hz,1H),2.76(d,J＝16.0Hz,1H),2.41(s,3H),1.65(d,J＝26.2Hz,4H),1.23(s,1H)ppm；LCMS:[M+H] +＝517.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (d, J=15.7 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.33 (d, J=7.9Hz, 2H), 7.23 (d, J=19.4Hz, 3H), 6.37 (s, 2H), 5.54 (d, J=5.4Hz, 1H), 4.28 (s, 1H), 4.00 (s,1H),3.75(dd,J=26.2,14.0Hz,3H),3.09(d,J=15.8Hz,1H),2.76(d,J=16.0Hz,1H),2.41(s,3H) , 1.65 (d, J=26.2Hz, 4H), 1.23 (s, 1H) ppm; LCMS: [M+H] + =517.1
实施例73(S)-1'-(5-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 73 (S)-1'-(5-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)thio)-1,2a1,4-triazacyclopenta Dieno[cd]inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000386
Figure PCTCN2021126331-appb-000386
1H NMR(400MHz,DMSO-d 6)δ9.07(d,J＝1.5Hz,1H),8.87(dd,J＝2.6,1.6Hz,1H),8.81(d,J＝2.6Hz,1H),8.53(s,1H),8.34(dd,J＝5.4,1.5Hz,1H),8.21(d,J＝4.9Hz,1H),8.08(d,J＝7.8Hz,1H),7.67(d,J＝7.5Hz,1H),7.39(d,J＝4.9Hz,1H),7.34(d,J＝7.8Hz,1H),7.19(dd,J＝7.5,5.0Hz,1H),4.55(s,1H),4.10(s,1H),3.96(s,1H),3.72(s,1H),3.19(s,1H),2.84(d,J＝16.3Hz,1H),1.90(s,5H),1.27(s,1H)ppm；LCMS:[M+H] +＝566.1 1 H NMR (400MHz, DMSO-d 6 ) δ 9.07 (d, J=1.5Hz, 1H), 8.87 (dd, J=2.6, 1.6Hz, 1H), 8.81 (d, J=2.6Hz, 1H) ,8.53(s,1H),8.34(dd,J＝5.4,1.5Hz,1H),8.21(d,J＝4.9Hz,1H),8.08(d,J＝7.8Hz,1H),7.67(d, J=7.5Hz, 1H), 7.39(d, J=4.9Hz, 1H), 7.34(d, J=7.8Hz, 1H), 7.19(dd, J=7.5, 5.0Hz, 1H), 4.55(s, 1H), 4.10(s, 1H), 3.96(s, 1H), 3.72(s, 1H), 3.19(s, 1H), 2.84(d, J＝16.3Hz, 1H), 1.90(s, 5H), 1.27(s,1H)ppm; LCMS: [M+H] + =566.1
实施例74(S)-1'-(5-(喹啉-4-基硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 74 (S)-1'-(5-(quinolin-4-ylthio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-1, 3-Dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000387
Figure PCTCN2021126331-appb-000387
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.48(d,J＝4.8Hz,1H),8.32(dd,J＝8.4,1.4Hz,1H),8.19(d,J＝7.8Hz,1H),8.05(dd,J＝8.4,1.3Hz,1H),7.86(ddd,J＝8.3,6.9,1.4Hz,1H),7.75(ddd,J＝8.3,6.9,1.3Hz,1H),7.37(dd,J＝13.2,6.4Hz,2H),7.27–7.20(m,3H),6.63(d,J＝4.8Hz,1H),4.56(d,J＝12.3Hz,1H),4.10(s,1H),4.00(s,1H),3.72(s,1H),3.55(s,1H),3.19(d,J＝15.7Hz,1H),2.78(d,J＝15.7Hz,1H),1.79(dd,J＝75.7,28.9Hz,4H),1.37(s,2H)ppm；LCMS:[M+H] +＝503.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.32 (dd, J=8.4, 1.4 Hz, 1H), 8.19 (d, J=7.8Hz, 1H), 8.05 (dd, J=8.4, 1.3Hz, 1H), 7.86 (ddd, J=8.3, 6.9, 1.4Hz, 1H), 7.75 (ddd, J=8.3, 6.9, 1.3Hz) ,1H),7.37(dd,J＝13.2,6.4Hz,2H),7.27–7.20(m,3H),6.63(d,J＝4.8Hz,1H),4.56(d,J＝12.3Hz,1H) ,4.10(s,1H),4.00(s,1H),3.72(s,1H),3.55(s,1H),3.19(d,J＝15.7Hz,1H),2.78(d,J＝15.7Hz, 1H), 1.79 (dd, J=75.7, 28.9Hz, 4H), 1.37 (s, 2H) ppm; LCMS: [M+H] + =503.1
实施例75(S)-N-(1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)甲磺酰胺Example 75 (S)-N-(1-amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopenta Dieno[cd]inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-6-yl)methanesulfonamide
Figure PCTCN2021126331-appb-000388
Figure PCTCN2021126331-appb-000388
1H NMR(400MHz,DMSO-d 6)δ8.62–8.49(m,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.32(d,J＝7.8Hz,1H),7.22–7.12(m,2H),7.02(dd,J＝8.0,1.9Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.62–4.45(m,1H),4.17–3.97(m,1H),3.87(s,1H),3.78–3.71(m,1H),3.66–3.44(m,1H),3.12(d,J＝15.6Hz,1H),2.94(s,3H),2.65(d,J＝15.8Hz,1H),2.00–1.89(m,1H),1.90–1.63(m,3H),1.27–1.21(m,2H)ppm；LCMS:[M+H] +＝595.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.62-8.49 (m, 1H), 8.08 (d, J=7.8Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.32 (d, J=7.8Hz, 1H), 7.22–7.12(m, 2H), 7.02(dd, J=8.0, 1.9Hz, 1H), 6.38(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.62–4.45 (m, 1H), 4.17–3.97 (m, 1H), 3.87 (s, 1H), 3.78–3.71 (m, 1H), 3.66–3.44 (m, 1H), 3.12 (d, J=15.6 Hz, 1H), 2.94 (s, 3H), 2.65 (d, J=15.8Hz, 1H), 2.00–1.89 (m, 1H), 1.90–1.63 (m, 3H), 1.27–1.21 (m, 2H) ppm; LCMS: [M+H] + =595.1
实施例76 1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-5-胺Example 76 1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000389
Figure PCTCN2021126331-appb-000389
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.45–8.39(m,2H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.36–7.30(m,2H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.55(s,1H),4.12(s,1H),3.95(s,1H),3.77–3.71(m,1H),3.54(s,1H),3.21(s,1H),2.74(d,J＝15.9Hz,1H),1.99(s,5H),1.23(s,1H)ppm；LCMS:[M+H] +＝503.1 1 H NMR (400MHz, DMSO-d 6 )δ8.57(s,1H),8.45-8.39(m,2H),8.09(d,J=7.8Hz,1H),7.50(d,J=5.4Hz, 1H), 7.36–7.30(m, 2H), 6.38(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.55(s, 1H), 4.12(s, 1H), 3.95(s, 1H) ), 3.77–3.71(m, 1H), 3.54(s, 1H), 3.21(s, 1H), 2.74(d, J=15.9Hz, 1H), 1.99(s, 5H), 1.23(s, 1H) ppm; LCMS: [M+H] + =503.1
实施例77(S)-1'-(5-(((6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]噁嗪-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 77(S)-1'-(5-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[ 1,2-d][1,4]oxazin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-5,7- Dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000390
Figure PCTCN2021126331-appb-000390
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.35(dd,J＝5.2,1.6Hz,1H),8.03(d,J＝7.8Hz,1H),7.68(d,J＝7.5Hz,1H),7.33(dd,J＝15.6,6.6Hz,2H),7.20(dd,J＝7.5,5.0Hz,1H),5.61(d,J＝5.5Hz,1H),5.56–5.40(m,1H),4.71(dd,J＝10.2,3.6Hz,1H),4.54(s,1H),4.09(s,1H),3.99(s,1H),3.95–3.86(m,1H),3.80–3.76(m,1H),3.69(d,J＝2.1Hz,1H),3.60–3.47(m,3H),3.21(d,J＝16.4Hz,1H),2.85(d,J＝16.4Hz,1H),2.37(s,2H),1.84(dddd,J＝43.3,14.4,10.6,3.9Hz,5H),1.28(s,1H)ppm；LCMS:[M+H] +＝569.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.35 (dd, J=5.2, 1.6 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.5Hz, 1H), 7.33 (dd, J=15.6, 6.6Hz, 2H), 7.20 (dd, J=7.5, 5.0Hz, 1H), 5.61 (d, J=5.5Hz, 1H), 5.56– 5.40(m, 1H), 4.71(dd, J=10.2, 3.6Hz, 1H), 4.54(s, 1H), 4.09(s, 1H), 3.99(s, 1H), 3.95–3.86(m, 1H) ,3.80–3.76(m,1H),3.69(d,J=2.1Hz,1H),3.60–3.47(m,3H),3.21(d,J=16.4Hz,1H),2.85(d,J=16.4 Hz, 1H), 2.37(s, 2H), 1.84(dddd, J=43.3, 14.4, 10.6, 3.9Hz, 5H), 1.28(s, 1H) ppm; LCMS: [M+H] + =569.1
实施例78 1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-4-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 78 1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-4-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000391
Figure PCTCN2021126331-appb-000391
1H NMR(400MHz,DMSO-d 6)δ8.58–8.51(m,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.32(d,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),6.93(d,J＝7.4Hz,1H),6.81(d,J＝8.1Hz,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.50(s,1H),4.07(s,1H),3.89(s,1H),3.79(s,3H),3.72(s,1H),3.53(s,1H),3.08(dd,J＝15.5,8.5Hz,1H),2.59(d,J＝15.3Hz,1H),1.75(d,J＝79.7Hz,5H),1.30(dd,J＝40.0,13.6Hz,1H)ppm；LCMS:[M+H] +＝532.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58-8.51 (m, 1H), 8.08 (d, J=7.8Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.32 (d, J=7.8Hz, 1H), 7.19(t, J=7.8Hz, 1H), 6.93(d, J=7.4Hz, 1H), 6.81(d, J=8.1Hz, 1H), 6.37(s, 2H) ,5.54(d,J＝5.4Hz,1H),4.50(s,1H),4.07(s,1H),3.89(s,1H),3.79(s,3H),3.72(s,1H),3.53( s, 1H), 3.08 (dd, J=15.5, 8.5Hz, 1H), 2.59 (d, J=15.3Hz, 1H), 1.75 (d, J=79.7Hz, 5H), 1.30 (dd, J=40.0 , 13.6Hz, 1H)ppm; LCMS: [M+H] + =532.1
实施例79(S)-1'-(5-((2,3-二氢呋喃并[2,3-b]吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 79 (S)-1'-(5-((2,3-dihydrofuro[2,3-b]pyridin-4-yl)thio)-1,2a1,4-triazacycle pentadieno[cd]inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000392
Figure PCTCN2021126331-appb-000392
1H NMR(400MHz,DMSO-d 6)δ8.66(s,3H),8.54(dd,J＝4.9,1.6Hz,1H),8.12(d,J＝7.8Hz,1H),8.01(dd,J＝7.7,1.6Hz,1H),7.64–7.57(m,1H),7.37(d,J＝7.8Hz,1H),7.36–7.32(m,1H),6.04(d,J ＝5.6Hz,1H),4.61(t,J＝8.6Hz,3H),4.51(s,1H),4.18(s,1H),3.78(s,1H),3.22–3.11(m,3H),1.81(d,J＝83.4Hz,4H)ppm；LCMS:[M+H] +＝496.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 3H), 8.54 (dd, J=4.9, 1.6 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.01 (dd, J=7.7, 1.6Hz, 1H), 7.64–7.57 (m, 1H), 7.37 (d, J=7.8Hz, 1H), 7.36–7.32 (m, 1H), 6.04 (d, J=5.6Hz, 1H) ), 4.61(t, J=8.6Hz, 3H), 4.51(s, 1H), 4.18(s, 1H), 3.78(s, 1H), 3.22–3.11(m, 3H), 1.81(d, J= 83.4Hz, 4H)ppm; LCMS: [M+H] + =496.1
实施例80(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-6-甲基-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 80 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-6-methyl-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000393
Figure PCTCN2021126331-appb-000393
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.31(d,J＝7.8Hz,1H),7.15–7.06(m,2H),6.98(d,J＝7.5Hz,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.61–4.41(m,1H),4.18–3.95(m,1H),3.86(s,1H),3.81–3.53(m,2H),3.10(d,J＝15.5Hz,1H),2.64(d,J＝15.7Hz,1H),2.29(s,3H),2.06–1.58(m,5H),1.38–1.23(m,1H)ppm；LCMS:[M+H] +＝516.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.31 (d, J= 7.8Hz, 1H), 7.15–7.06 (m, 2H), 6.98 (d, J=7.5Hz, 1H), 6.37 (s, 2H), 5.54 (d, J=5.4Hz, 1H), 4.61–4.41 ( m, 1H), 4.18–3.95 (m, 1H), 3.86 (s, 1H), 3.81–3.53 (m, 2H), 3.10 (d, J=15.5Hz, 1H), 2.64 (d, J=15.7Hz) , 1H), 2.29 (s, 3H), 2.06–1.58 (m, 5H), 1.38–1.23 (m, 1H) ppm; LCMS: [M+H] + = 516.1
实施例81(S)-(1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)甲醇Example 81 (S)-(1-amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadiene [cd]inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-6-yl)methanol
Figure PCTCN2021126331-appb-000394
Figure PCTCN2021126331-appb-000394
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.35–7.27(m,2H),7.15(q,J＝7.6Hz,2H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),5.12(s,1H),4.60–4.50(m,1H),4.48(s,2H),4.16–3.97(m,1H),3.93(s,1H),3.79–3.64(m,1H),3.58–3.49(m,1H),3.14(d,J＝15.6Hz,1H),2.70(d,J＝15.8Hz,1H),2.05–1.91(m,1H),1.91–1.61(m,4H),1.40–1.25(m,1H)ppm；LCMS:[M+H] +＝532.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.08 (d, J=7.8Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.35-7.27 (m, 2H), 7.15(q, J=7.6Hz, 2H), 6.37(s, 2H), 5.54(d, J=5.4Hz, 1H), 5.12(s, 1H), 4.60–4.50(m, 1H), 4.48(s, 2H), 4.16-3.97(m, 1H), 3.93(s, 1H), 3.79-3.64(m, 1H), 3.58-3.49(m, 1H), 3.14(d, J=15.6Hz, 1H), 2.70 (d, J=15.8Hz, 1H), 2.05–1.91 (m, 1H), 1.91–1.61 (m, 4H), 1.40–1.25 (m, 1H) ppm; LCMS: [M+H] + = 532.1
实施例82(R)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺Example 82(R)-1'-(5-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine
Figure PCTCN2021126331-appb-000395
Figure PCTCN2021126331-appb-000395
1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),8.11(d,J＝7.8Hz,1H),7.51(d,J＝5.4Hz,1H),7.39–7.32(m,2H),7.17(t,J＝7.8Hz,1H),6.90(t,J＝7.4Hz,1H),6.82(d,J＝8.0Hz,1H),6.37(s,2H),5.55(d,J＝5.4Hz,1H),4.53(s,2H),4.15(s,2H),3.76(d,J＝76.3Hz,3H),1.94(d,J＝43.0Hz,4H)ppm；LCMS:[M+H] +＝504.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.11 (d, J=7.8Hz, 1H), 7.51 (d, J=5.4Hz, 1H), 7.39-7.32 (m, 2H), 7.17(t, J＝7.8Hz, 1H), 6.90(t, J＝7.4Hz, 1H), 6.82(d, J＝8.0Hz, 1H), 6.37(s, 2H), 5.55(d, J=5.4Hz, 1H), 4.53(s, 2H), 4.15(s, 2H), 3.76(d, J=76.3Hz, 3H), 1.94(d, J=43.0Hz, 4H) ppm; LCMS: [ M+H] + = 504.0
实施例83(R)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3H-螺[呋喃并[2,3-b]吡啶-2,4'-哌啶]-3-胺Example 83 (R)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-3H-spiro[furo[2,3-b]pyridin-2,4'-piperidin]-3-amine
Figure PCTCN2021126331-appb-000396
Figure PCTCN2021126331-appb-000396
1H NMR(400MHz,DMSO-d 6)δ8.62(s,1H),8.11(d,J＝7.8Hz,1H),8.03(dd,J＝5.1,1.4Hz,1H), 7.73(d,J＝6.8Hz,1H),7.51(d,J＝5.4Hz,1H),7.38(d,J＝7.8Hz,1H),6.94(dd,J＝7.1,5.2Hz,1H),6.37(s,2H),5.55(d,J＝5.4Hz,1H),4.56(s,2H),4.19(s,2H),3.77(d,J＝79.0Hz,3H),1.95(d,J＝32.4Hz,4H)ppm；LCMS:[M+H] +＝505.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 8.11 (d, J=7.8Hz, 1H), 8.03 (dd, J=5.1, 1.4Hz, 1H), 7.73 (d, J=6.8Hz, 1H), 7.51(d, J=5.4Hz, 1H), 7.38(d, J=7.8Hz, 1H), 6.94(dd, J=7.1, 5.2Hz, 1H), 6.37(s, 2H), 5.55(d, J＝5.4Hz, 1H), 4.56(s, 2H), 4.19(s, 2H), 3.77(d, J＝79.0Hz, 3H), 1.95(d, J＝32.4Hz, 4H) ppm; LCMS: [M+H] + =505.0
实施例84(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-6-苯基-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 84 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-6-phenyl-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000397
Figure PCTCN2021126331-appb-000397
1H NMR(400MHz,DMSO-d 6)δ8.58(s,1H),8.09(d,J＝7.8Hz,1H),7.65(dd,J＝12.0,4.8Hz,3H),7.55–7.42(m,4H),7.34(dd,J＝14.8,7.6Hz,3H),6.37(s,2H),5.55(d,J＝5.4Hz,1H),4.55(s,1H),4.15–4.07(m,1H),4.00(s,1H),3.75(s,1H),3.56(s,1H),3.21(d,J＝15.7Hz,1H),2.77(d,J＝15.9Hz,1H),1.85(d,J＝48.8Hz,5H),1.36(s,1H)ppm；LCMS:[M+H] +＝578.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.65 (dd, J=12.0, 4.8Hz, 3H), 7.55-7.42 ( m, 4H), 7.34(dd, J=14.8, 7.6Hz, 3H), 6.37(s, 2H), 5.55(d, J=5.4Hz, 1H), 4.55(s, 1H), 4.15–4.07(m ,1H),4.00(s,1H),3.75(s,1H),3.56(s,1H),3.21(d,J=15.7Hz,1H),2.77(d,J=15.9Hz,1H),1.85 (d, J=48.8Hz, 5H), 1.36 (s, 1H) ppm; LCMS: [M+H] + =578.1
实施例85(S)-1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲腈Example 85 (S)-1-Amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno [cd]inden-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carbonitrile
Figure PCTCN2021126331-appb-000398
Figure PCTCN2021126331-appb-000398
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.09(d,J＝7.8Hz,1H),7.71(s,1H),7.66(d,J＝7.5Hz,1H),7.50(d,J＝5.2Hz,1H),7.44(d,J＝7.6Hz,1H),7.33(d,J＝7.7Hz,1H),6.37(s,2H),5.55(d,J＝5.2Hz,1H),4.53(s,1H),4.23–3.88(m,3H),3.71(d,J＝28.9Hz,2H),1.84(d,J＝54.1Hz,5H),1.27(dd,J＝49.4,27.0Hz,2H)ppm；LCMS:[M+H] +＝527.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56(s, 1H), 8.09(d, J=7.8Hz, 1H), 7.71(s, 1H), 7.66(d, J=7.5Hz, 1H) ,7.50(d,J＝5.2Hz,1H),7.44(d,J＝7.6Hz,1H),7.33(d,J＝7.7Hz,1H),6.37(s,2H),5.55(d,J＝ 5.2Hz, 1H), 4.53(s, 1H), 4.23–3.88(m, 3H), 3.71(d, J=28.9Hz, 2H), 1.84(d, J=54.1Hz, 5H), 1.27(dd, J = 49.4, 27.0 Hz, 2H) ppm; LCMS: [M+H] + =527.1
实施例86(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-2,5-二胺Example 86 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-2,5-diamine
Figure PCTCN2021126331-appb-000399
Figure PCTCN2021126331-appb-000399
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.31(dd,J＝12.0,8.0Hz,2H),6.36(s,2H),6.25(d,J＝8.2Hz,1H),5.72(s,2H),5.54(d,J＝5.4Hz,1H),4.48(s,1H),4.05(s,1H),3.78(s,3H),3.56(s,2H),1.87–1.76(m,2H),1.64(s,2H),1.42(d,J＝29.3Hz,2H)ppm；LCMS:[M+H] +＝518.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.31 (dd, J= 12.0, 8.0Hz, 2H), 6.36(s, 2H), 6.25(d, J=8.2Hz, 1H), 5.72(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.48(s, 1H), 4.05(s, 1H), 3.78(s, 3H), 3.56(s, 2H), 1.87–1.76(m, 2H), 1.64(s, 2H), 1.42(d, J=29.3Hz, 2H )ppm; LCMS: [M+H] + =518.1
实施例87(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-6-氟-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 87 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-6-fluoro-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000400
Figure PCTCN2021126331-appb-000400
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.32(d,J＝7.8Hz,1H),7.22(dd,J＝8.1,5.2Hz,1H),7.09(d,J＝7.2Hz,1H),7.02–6.92(m,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.53(s,1H),4.18–3.98(m,1H),3.90(s,1H),3.74–3.46(m,2H),3.14(d,J ＝15.6Hz,1H),2.66(d,J＝15.3Hz,1H),2.03–1.90(m,1H),1.88–1.65(m,2H),1.35–1.22(m,1H)ppm；LCMS:[M+H] +＝520.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.32 (d, J= 7.8Hz, 1H), 7.22(dd, J=8.1, 5.2Hz, 1H), 7.09(d, J=7.2Hz, 1H), 7.02–6.92(m, 1H), 6.37(s, 2H), 5.54( d, J=5.4Hz, 1H), 4.53 (s, 1H), 4.18–3.98 (m, 1H), 3.90 (s, 1H), 3.74–3.46 (m, 2H), 3.14 (d, J=15.6Hz) , 1H), 2.66 (d, J=15.3Hz, 1H), 2.03–1.90 (m, 1H), 1.88–1.65 (m, 2H), 1.35–1.22 (m, 1H) ppm; LCMS: [M+H ] + = 520.1
实施例88(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3-氟-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 88 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-3-fluoro-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000401
Figure PCTCN2021126331-appb-000401
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.31(s,1H),8.09(d,J＝7.8Hz,1H),7.55(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.53(s,1H),4.10(s,1H),3.99(s,1H),3.74(d,J＝31.8Hz,1H),3.64–3.44(m,2H),1.85(d,J＝46.6Hz,5H),1.42–1.11(m,2H)ppm；LCMS:[M+H] +＝521.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57(s, 1H), 8.31(s, 1H), 8.09(d, J=7.8Hz, 1H), 7.55(d, J=7.8Hz, 1H) ,7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.53(s,1H) ,4.10(s,1H),3.99(s,1H),3.74(d,J=31.8Hz,1H),3.64–3.44(m,2H),1.85(d,J=46.6Hz,5H),1.42– 1.11 (m, 2H) ppm; LCMS: [M+H] + =521.2
实施例89(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3-甲基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 89 (S)-1'-(5-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-3-methyl-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000402
Figure PCTCN2021126331-appb-000402
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.17(s,1H),8.09(d,J＝7.8Hz,1H),7.54–7.46(m,2H),7.33(d,J＝7.8Hz,1H),6.37(s,2H),5.55(t,J＝6.5Hz,1H),4.52(s,1H),4.09(s,1H),3.93(s,1H),3.79–3.68(m,1H),3.53(s,1H),3.13(s,1H),2.77(d,J＝16.2Hz,1H),2.28(s,3H),1.98–1.63(m,5H),1.28(d,J＝37.5Hz,1H)ppm；LCMS:[M+H] +＝517.2 1 H NMR (400MHz, DMSO-d 6 )δ8.56(s,1H),8.17(s,1H),8.09(d,J=7.8Hz,1H),7.54-7.46(m,2H),7.33( d, J=7.8Hz, 1H), 6.37(s, 2H), 5.55(t, J=6.5Hz, 1H), 4.52(s, 1H), 4.09(s, 1H), 3.93(s, 1H), 3.79–3.68 (m, 1H), 3.53 (s, 1H), 3.13 (s, 1H), 2.77 (d, J=16.2Hz, 1H), 2.28 (s, 3H), 1.98–1.63 (m, 5H) , 1.28(d, J=37.5Hz, 1H) ppm; LCMS: [M+H] + =517.2
实施例90(R)-1-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1',3'-二氢螺[吖丁啶并-3,2'-茚]-1'-胺Example 90(R)-1-(5-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene- 2-yl)-1',3'-dihydrospiro[azetidino-3,2'-indene]-1'-amine
Figure PCTCN2021126331-appb-000403
Figure PCTCN2021126331-appb-000403
1H NMR(400MHz,DMSO-d 6)δ8.37(s,1H),8.10(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.40–7.34(m,2H),7.26–7.17(m,3H),6.37(s,2H),5.51(d,J＝5.4Hz,1H),4.67(d,J＝9.3Hz,1H),4.48(d,J＝9.2Hz,1H),4.37(d,J＝9.3Hz,1H),4.24(s,1H),3.99(d,J＝9.3Hz,1H),3.36(d,J＝15.7Hz,1H),3.18–3.14(m,1H),2.51(s,2H)ppm；LCMS:[M+H] +＝474.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.37 (s, 1H), 8.10 (d, J=7.8Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.40-7.34 (m, 2H), 7.26–7.17(m, 3H), 6.37(s, 2H), 5.51(d, J=5.4Hz, 1H), 4.67(d, J=9.3Hz, 1H), 4.48(d, J=9.2 Hz, 1H), 4.37(d, J＝9.3Hz, 1H), 4.24(s, 1H), 3.99(d, J＝9.3Hz, 1H), 3.36(d, J＝15.7Hz, 1H), 3.18– 3.14 (m, 1H), 2.51 (s, 2H) ppm; LCMS: [M+H] + =474.1
实施例91(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-甲基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 91 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-methyl-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000404
Figure PCTCN2021126331-appb-000404
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.08(d,J＝7.8Hz,1H),7.55(d,J＝7.7Hz,1H),7.50(d,J＝5.4Hz,1H),7.32(d,J＝7.8Hz,1H),7.04(d,J＝7.7Hz,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.66–4.38(m,1H),4.22–3.97(m,1H),3.91(s,1H),3.83–3.62(m,1H),3.59–3.45(m,1H),3.14(d,J＝16.3Hz,1H),2.78(d,J＝16.3Hz,1H),2.43(s,3H),2.09–1.57(m,5H),1.40–1.25(m,1H)ppm；LCMS: [M+H] +＝517.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.08 (d, J=7.8Hz, 1H), 7.55 (d, J=7.7Hz, 1H), 7.50 (d, J= 5.4Hz, 1H), 7.32 (d, J=7.8Hz, 1H), 7.04 (d, J=7.7Hz, 1H), 6.37 (s, 2H), 5.54 (d, J=5.4Hz, 1H), 4.66 –4.38(m,1H),4.22-3.97(m,1H),3.91(s,1H),3.83-3.62(m,1H),3.59-3.45(m,1H),3.14(d,J=16.3Hz ,1H),2.78(d,J＝16.3Hz,1H),2.43(s,3H),2.09–1.57(m,5H),1.40–1.25(m,1H)ppm; LCMS: [M+H] + =517.1
实施例92(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1-甲基-4,6-二氢-1H-螺[环戊二烯并[c]吡唑-5,4'-哌啶]-4-胺Example 92 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-1-methyl-4,6-dihydro-1H-spiro[cyclopentadieno[c]pyrazol-5,4'-piperidin]-4-amine
Figure PCTCN2021126331-appb-000405
Figure PCTCN2021126331-appb-000405
1H NMR(400MHz,DMSO-d 6)δ8.09(d,J＝7.9Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.17(s,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.43(s,1H),4.06(s,1H),3.76(s,1H),3.70(s,5H),2.76(q,J＝15.6Hz,2H),1.94(s,1H),1.71(s,3H)ppm；LCMS:[M+H] +＝506.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J=7.9 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.17 (s, 1H), 6.37(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.43(s, 1H), 4.06(s, 1H), 3.76(s, 1H), 3.70(s, 5H), 2.76 (q, J=15.6Hz, 2H), 1.94 (s, 1H), 1.71 (s, 3H) ppm; LCMS: [M+H] + =506.1
实施例93(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3-(三氟甲基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 93 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-3-(trifluoromethyl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000406
Figure PCTCN2021126331-appb-000406
1H NMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.58(s,1H),8.18–8.05(m,2H),7.50(d,J＝5.4Hz,1H),7.34(d,J＝7.8Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.65–4.46(m,1H),4.18(s,1H),4.15–4.01(m,1H),3.87–3.66(m,1H),3.62–3.47(m,1H),3.25–3.16(m,1H),3.03(d,J＝17.1Hz,1H),2.00–1.68(m,3H),1.50–1.26(m,1H)ppm；LCMS:[M+H] +＝571.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.79(s, 1H), 8.58(s, 1H), 8.18-8.05(m, 2H), 7.50(d, J=5.4Hz, 1H), 7.34( d, J=7.8Hz, 1H), 6.38 (s, 2H), 5.54 (d, J=5.4Hz, 1H), 4.65–4.46 (m, 1H), 4.18 (s, 1H), 4.15–4.01 (m , 1H), 3.87–3.66 (m, 1H), 3.62–3.47 (m, 1H), 3.25–3.16 (m, 1H), 3.03 (d, J=17.1Hz, 1H), 2.00–1.68 (m, 3H ), 1.50–1.26(m,1H)ppm; LCMS: [M+H] + =571.1
实施例94(S)-(1-氨基-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)二甲基膦氧化Example 94 (S)-(1-amino-1'-(5-((3-chloro-2-methylpyridin-4-yl)thio)-1,2a1,4-triazacyclopentadiene Eno[cd]inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-6-yl)dimethylphosphine oxidation
Figure PCTCN2021126331-appb-000407
Figure PCTCN2021126331-appb-000407
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.12(d,J＝7.8Hz,1H),7.97(d,J＝5.3Hz,1H),7.73(d,J＝11.3Hz,1H),7.61–7.56(m,1H),7.36(s,2H),6.27(d,J＝5.2Hz,1H),4.53(s,1H),4.16–4.08(m,1H),3.96(s,1H),3.79–3.72(m,1H),3.53(s,1H),3.20(s,1H),2.76(d,J＝16.1Hz,1H),2.57(s,3H),1.90(s,5H),1.65(s,3H),1.61(s,3H),1.31–1.24(m,1H)ppm；LCMS:[M+H] +＝577.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.97 (d, J=5.3 Hz, 1H), 7.73 (d, J= 11.3Hz, 1H), 7.61–7.56 (m, 1H), 7.36 (s, 2H), 6.27 (d, J=5.2Hz, 1H), 4.53 (s, 1H), 4.16–4.08 (m, 1H), 3.96(s, 1H), 3.79–3.72(m, 1H), 3.53(s, 1H), 3.20(s, 1H), 2.76(d, J=16.1Hz, 1H), 2.57(s, 3H), 1.90 (s, 5H), 1.65 (s, 3H), 1.61 (s, 3H), 1.31–1.24 (m, 1H) ppm; LCMS: [M+H] + = 577.1
实施例95(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3-甲氧基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 95 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-3-methoxy-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000408
Figure PCTCN2021126331-appb-000408
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.09(d,J＝7.8Hz,1H),8.04(d,J＝2.6Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.30(s,1H),6.39(s,2H),5.54(d,J＝5.4Hz,1H),4.53(s,1H),4.09(s,2H),3.93(s,1H),3.81(s,3H),3.51(s,1H),3.15(s,1H),2.75(d,J＝16.1Hz,1H),1.84(d,J＝53.9Hz,5H),1.26(s,1H)ppm；LCMS:[M+H] +＝533.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 8.04 (d, J=2.6 Hz, 1H), 7.50 (d, J= 5.4Hz, 1H), 7.33(d, J=7.8Hz, 1H), 7.30(s, 1H), 6.39(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.53(s, 1H) ,4.09(s,2H),3.93(s,1H),3.81(s,3H),3.51(s,1H),3.15(s,1H),2.75(d,J＝16.1Hz,1H),1.84( d, J=53.9Hz, 5H), 1.26 (s, 1H)ppm; LCMS: [M+H] + =533.1
实施例96(R)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1-甲基螺[二氢吲哚-2,4'-哌啶]-3-胺Example 96(R)-1'-(5-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-1-methylspiro[indoline-2,4'-piperidin]-3-amine
Figure PCTCN2021126331-appb-000409
Figure PCTCN2021126331-appb-000409
1H NMR(400MHz,DMSO-d 6)δ8.57(d,J＝32.3Hz,1H),8.09(d,J＝7.8Hz,1H),7.51(d,J＝5.4Hz,1H),7.34(s,1H),7.23(d,J＝7.1Hz,1H),7.06(t,J＝7.6Hz,1H),6.62(t,J＝7.3Hz,1H),6.40(d,J＝7.2Hz,3H),5.54(d,J＝5.3Hz,1H),4.71(s,2H),4.30(s,1H),4.18(s,2H),3.89(s,2H),3.52(s,2H),2.58(s,3H),1.96(d,J＝24.8Hz,2H)ppm；LCMS:[M+H] +＝517.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, J=32.3 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.51 (d, J=5.4 Hz, 1H), 7.34 (s,1H),7.23(d,J=7.1Hz,1H),7.06(t,J=7.6Hz,1H),6.62(t,J=7.3Hz,1H),6.40(d,J=7.2Hz ,3H),5.54(d,J＝5.3Hz,1H),4.71(s,2H),4.30(s,1H),4.18(s,2H),3.89(s,2H),3.52(s,2H) , 2.58(s, 3H), 1.96(d, J=24.8Hz, 2H) ppm; LCMS: [M+H] + =517.1
实施例97(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-3-氯-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 97 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-3-chloro-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000410
Figure PCTCN2021126331-appb-000410
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.38(d,J＝2.3Hz,1H),8.09(d,J＝7.9Hz,1H),7.78–7.71(m,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.54(d,J＝13.1Hz,1H),4.09(s,1H),4.00(s,1H),3.87–3.66(m,1H),3.53(d,J＝12.2Hz,1H),3.21(d,J＝16.5Hz,1H),2.84(d,J＝16.5Hz,1H),1.83(d,J＝37.9Hz,3H),1.25(d,J＝12.6Hz,1H)ppm；LCMS:[M+H] +＝537.1 1 H NMR (400MHz, DMSO-d 6 )δ8.57(s,1H),8.38(d,J=2.3Hz,1H),8.09(d,J=7.9Hz,1H),7.78-7.71(m, 1H), 7.50(d, J＝5.4Hz, 1H), 7.33(d, J＝7.8Hz, 1H), 6.38(s, 2H), 5.54(d, J＝5.4Hz, 1H), 4.54(d, J=13.1Hz, 1H), 4.09(s, 1H), 4.00(s, 1H), 3.87–3.66(m, 1H), 3.53(d, J=12.2Hz, 1H), 3.21(d, J=16.5 Hz, 1H), 2.84 (d, J=16.5Hz, 1H), 1.83 (d, J=37.9Hz, 3H), 1.25 (d, J=12.6Hz, 1H) ppm; LCMS: [M+H] + =537.1
实施例98(S)-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1-甲基-4,6-二氢-1H-螺[环戊二烯并[c]吡唑-5,4'-哌啶]-4-胺Example 98 (S)-1'-(5-((3-Chloro-2-methylpyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd] Inden-2-yl)-1-methyl-4,6-dihydro-1H-spiro[cyclopentadieno[c]pyrazol-5,4'-piperidin]-4-amine
Figure PCTCN2021126331-appb-000411
Figure PCTCN2021126331-appb-000411
1H NMR(400MHz,DMSO-d 6)δ8.57(d,J＝14.3Hz,1H),8.12(d,J＝7.8Hz,1H),7.97(d,J＝5.4Hz,1H),7.35(d,J＝7.8Hz,1H),7.16(s,1H),6.27(d,J＝5.3Hz,1H),4.45(s,1H),4.07(s,1H),3.76(s,2H),3.71(d,J＝5.0Hz,3H),3.65–3.49(m,1H),2.80(d,J＝15.7Hz,1H),2.74(s,1H),2.57(s,3H),1.90(s,2H),1.73(d,J＝19.7Hz,4H)ppm；LCMS:[M+H] +＝505.2 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, J=14.3 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.97 (d, J=5.4 Hz, 1H), 7.35 (d, J=7.8Hz, 1H), 7.16(s, 1H), 6.27(d, J=5.3Hz, 1H), 4.45(s, 1H), 4.07(s, 1H), 3.76(s, 2H) ,3.71(d,J＝5.0Hz,3H),3.65–3.49(m,1H),2.80(d,J＝15.7Hz,1H),2.74(s,1H),2.57(s,3H),1.90( s, 2H), 1.73 (d, J=19.7Hz, 4H) ppm; LCMS: [M+H] + =505.2
实施例99(S)-1'-(5-((3-氯-2-甲基吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-2,5-二胺Example 99 (S)-1'-(5-((3-Chloro-2-methylpyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd] inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-2,5-diamine
Figure PCTCN2021126331-appb-000412
Figure PCTCN2021126331-appb-000412
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.12(d,J＝7.8Hz,1H),7.97(d,J＝5.3Hz,1H),7.36–7.30(m,2H),6.28–6.24(m,2H),5.77(s,2H),4.50(s,1H),4.06(s,1H),3.77(d,J＝34.9Hz,3H),3.57(s,1H),2.57(s,3H),1.87–1.76(m,3H),1.63(s,2H),1.43(s,2H)ppm；LCMS:[M+H] +＝517.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.12 (d, J=7.8Hz, 1H), 7.97 (d, J=5.3Hz, 1H), 7.36-7.30 (m, 2H), 6.28–6.24(m, 2H), 5.77(s, 2H), 4.50(s, 1H), 4.06(s, 1H), 3.77(d, J=34.9Hz, 3H), 3.57(s, 1H) ), 2.57(s, 3H), 1.87–1.76(m, 3H), 1.63(s, 2H), 1.43(s, 2H) ppm; LCMS: [M+H] + = 517.1
实施例100(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-N2,N2-二甲基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-2,5-二胺Example 100(S)-1'-(5-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-N2,N2-dimethyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-2,5-diamine
Figure PCTCN2021126331-appb-000413
Figure PCTCN2021126331-appb-000413
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.43(d,J＝8.5Hz,1H),7.33(d,J＝7.8Hz,1H),6.43(d,J＝8.4Hz,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.50(s,1H),4.07(s,1H),3.82(s,1H),3.74(d,J＝18.0Hz,1H),3.56(s,1H),3.00(s,7H),2.70(d,J＝16.4Hz,1H),2.41(s,2H),1.92–1.77(m,2H),1.64(s,1H),1.39(s,1H)ppm；LCMS:[M+H] +＝546.2 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.43 (d, J= 8.5Hz, 1H), 7.33(d, J＝7.8Hz, 1H), 6.43(d, J＝8.4Hz, 1H), 6.37(s, 2H), 5.54(d, J＝5.4Hz, 1H), 4.50 (s, 1H), 4.07(s, 1H), 3.82(s, 1H), 3.74(d, J=18.0Hz, 1H), 3.56(s, 1H), 3.00(s, 7H), 2.70(d, J = 16.4Hz, 1H), 2.41 (s, 2H), 1.92–1.77 (m, 2H), 1.64 (s, 1H), 1.39 (s, 1H) ppm; LCMS: [M+H] + = 546.2
实施例101(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 101 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000414
Figure PCTCN2021126331-appb-000414
1H NMR(400MHz,DMSO-d 6)δ8.59(s,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.34(d,J＝7.8Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.48(s,1H),4.09(s,1H),4.03(s,1H),3.71(s,2H),2.88(d,J＝15.3Hz,1H),2.80(s,1H),2.68–2.61(m,3H),2.02(d,J＝45.5Hz,2H),1.77(s,4H)ppm；LCMS:[M+H] +＝522.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.34 (d, J= 7.8Hz, 1H), 6.38(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.48(s, 1H), 4.09(s, 1H), 4.03(s, 1H), 3.71(s, 2H), 2.88(d, J＝15.3Hz, 1H), 2.80(s, 1H), 2.68–2.61(m, 3H), 2.02(d, J＝45.5Hz, 2H), 1.77(s, 4H)ppm ; LCMS: [M+H] + =522.2
实施例102(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 102 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000415
Figure PCTCN2021126331-appb-000415
1H NMR(400MHz,DMSO-d 6)δ9.02(s,1H),8.61(s,1H),8.10(d,J＝7.8Hz,1H),7.51(d,J＝5.4Hz,1H),7.35(d,J＝7.8Hz,1H),6.39(s,2H),5.53(d,J＝5.4Hz,1H),4.45(d,J＝31.2Hz,1H),4.09(s,2H),3.72(d,J＝36.5Hz,2H),2.97(d,J＝15.1Hz,1H),2.86(d,J＝15.6Hz,1H),1.98(s,2H),1.79(s,4H)ppm；LCMS:[M+H] +＝509.0 1 H NMR (400MHz, DMSO-d 6 ) δ 9.02 (s, 1H), 8.61 (s, 1H), 8.10 (d, J=7.8Hz, 1H), 7.51 (d, J=5.4Hz, 1H) ,7.35(d,J＝7.8Hz,1H),6.39(s,2H),5.53(d,J＝5.4Hz,1H),4.45(d,J＝31.2Hz,1H),4.09(s,2H) ,3.72(d,J＝36.5Hz,2H),2.97(d,J＝15.1Hz,1H),2.86(d,J＝15.6Hz,1H),1.98(s,2H),1.79(s,4H) ppm; LCMS: [M+H] + =509.0
实施例103(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-N2-甲基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-2,5-二胺Example 103 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-N2-methyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]-2,5-diamine
Figure PCTCN2021126331-appb-000416
Figure PCTCN2021126331-appb-000416
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.34–7.29(m,2H),6.36(s,2H),6.29(d,J＝5.0Hz,1H),6.24(d,J＝8.3Hz,1H),5.54(d,J＝5.4Hz,1H),4.49(s,1H),4.06(s,1H),3.78(s,1H),3.57(s,2H),2.75(d,J＝4.8Hz,3H),1.87(d,J＝20.6Hz,4H),1.64(s,2H),1.47(s,2H)ppm；LCMS:[M+H] +＝532.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.08 (d, J=7.8Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.34-7.29 (m, 2H), 6.36(s, 2H), 6.29(d, J=5.0Hz, 1H), 6.24(d, J=8.3Hz, 1H), 5.54(d, J=5.4Hz, 1H), 4.49(s, 1H), 4.06(s, 1H), 3.78(s, 1H), 3.57(s, 2H), 2.75(d, J=4.8Hz, 3H), 1.87(d, J=20.6Hz, 4H), 1.64( s, 2H), 1.47 (s, 2H) ppm; LCMS: [M+H] + =532.1
实施例104(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-甲基-2,6-二氢-4H-螺[环戊二烯并[c]吡唑-5,4'-哌啶]-4-胺Example 104 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-methyl-2,6-dihydro-4H-spiro[cyclopentadieno[c]pyrazol-5,4'-piperidin]-4-amine
Figure PCTCN2021126331-appb-000417
Figure PCTCN2021126331-appb-000417
1H NMR(400MHz,DMSO-d 6)δ8.56(d,J＝8.5Hz,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.37(s,1H),7.32(d,J＝7.8Hz,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.52–4.27(m,1H),4.04(s,1H),3.77(d,J＝4.5Hz,5H),3.61(d,J＝15.6Hz,1H),2.78(d,J＝15.3Hz,1H),2.58(d,J＝15.3Hz,1H),1.80(d,J＝97.3Hz,6H)ppm；LCMS:[M+H] +＝506.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (d, J=8.5 Hz, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.37 (s, 1H), 7.32(d, J=7.8Hz, 1H), 6.37(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.52–4.27(m, 1H), 4.04(s, 1H), 3.77(d, J＝4.5Hz, 5H), 3.61(d, J＝15.6Hz, 1H), 2.78(d, J＝15.3Hz, 1H), 2.58(d, J＝15.3Hz, 1H) ,1.80(d,J=97.3Hz,6H)ppm; LCMS:[M+H] + =506.1
实施例105(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-7-胺Example 105(S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000418
Figure PCTCN2021126331-appb-000418
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.49(s,1H),8.38(d,J＝4.9Hz,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.27(d,J＝4.8Hz,1H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.49(s,1H),4.05(d,J＝22.8Hz,2H),3.78–3.67(m,1H),3.55(s,1H),3.18(d,J＝16.6Hz,1H),2.76(d,J＝16.5Hz,1H),2.12(s,2H),1.88(d,J＝22.4Hz,3H),1.26(s,1H)ppm；LCMS:[M+H] +＝503.0 1 H NMR (400MHz, DMSO-d 6 )δ8.56(s,1H),8.49(s,1H),8.38(d,J=4.9Hz,1H),8.09(d,J=7.8Hz,1H) ,7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.27(d,J＝4.8Hz,1H),6.38(s,2H),5.54(d,J＝ 5.4Hz, 1H), 4.49(s, 1H), 4.05(d, J=22.8Hz, 2H), 3.78–3.67(m, 1H), 3.55(s, 1H), 3.18(d, J=16.6Hz, 1H), 2.76(d, J=16.5Hz, 1H), 2.12(s, 2H), 1.88(d, J=22.4Hz, 3H), 1.26(s, 1H) ppm; LCMS: [M+H] + =503.0
实施例106(S)-1-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-N-(甲基-d3)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺Example 106(S)-1-Amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno [cd]Inden-2-yl)-N-(methyl-d3)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carboxamide
Figure PCTCN2021126331-appb-000419
Figure PCTCN2021126331-appb-000419
1H NMR(400MHz,DMSO-d 6)δ8.82(s,2H),8.66(d,J＝24.8Hz,1H),8.53(s,1H),8.27–8.01(m,2H),7.86(d,J＝7.9Hz,1H),7.59(s,1H),7.40(s,1H),5.72(d,J＝6.0Hz,1H),4.93–4.34(m,3H),4.19(s,1H),3.77(s,2H),3.16–3.06(m,2H),2.16–1.55(m,5H),1.24(d,J＝3.6Hz,1H)ppm；LCMS:[M+H] +＝562.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.82(s, 2H), 8.66(d, J=24.8Hz, 1H), 8.53(s, 1H), 8.27-8.01(m, 2H), 7.86( d, J＝7.9Hz, 1H), 7.59(s, 1H), 7.40(s, 1H), 5.72(d, J＝6.0Hz, 1H), 4.93–4.34(m, 3H), 4.19(s, 1H) ), 3.77 (s, 2H), 3.16–3.06 (m, 2H), 2.16–1.55 (m, 5H), 1.24 (d, J=3.6Hz, 1H) ppm; LCMS: [M+H] + =562.1
实施例107(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-(吖丁啶-1-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 107 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-(azetidin-1-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000420
Figure PCTCN2021126331-appb-000420
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.43(d,J＝8.2Hz,1H),7.32(d,J＝7.8Hz,1H),6.36(s,2H),6.14(d,J＝8.2Hz,1H),5.54(d,J＝5.4Hz,1H),4.50(s,1H),4.17–4.01(m,1H),3.89(t,J＝7.3Hz,4H),3.81(s,1H),3.71(s,1H),3.55(s,2H),3.00(d,J＝16.4Hz,1H),2.68(d,J＝16.4Hz,1H),2.28(q,J＝7.3Hz,2H),1.93–1.54(m,4H),1.47–1.32(m,1H)ppm；LCMS:[M+H] +＝558.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.43 (d, J= 8.2Hz, 1H), 7.32(d, J＝7.8Hz, 1H), 6.36(s, 2H), 6.14(d, J＝8.2Hz, 1H), 5.54(d, J＝5.4Hz, 1H), 4.50 (s,1H),4.17–4.01(m,1H),3.89(t,J=7.3Hz,4H),3.81(s,1H),3.71(s,1H),3.55(s,2H),3.00( d, J=16.4Hz, 1H), 2.68 (d, J=16.4Hz, 1H), 2.28 (q, J=7.3Hz, 2H), 1.93–1.54 (m, 4H), 1.47–1.32 (m, 1H) )ppm; LCMS: [M+H] + =558.1
实施例108(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-6,8-二氢螺[环戊二烯并[e][1,2,4]三唑并[4,3-a]吡啶-7,4'-哌啶]-6-胺Example 108 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-6,8-dihydrospiro[cyclopentadieno[e][1,2,4]triazolo[4,3-a]pyridine-7,4'-piperidine]- 6-amine
Figure PCTCN2021126331-appb-000421
Figure PCTCN2021126331-appb-000421
1H NMR(400MHz,DMSO-d 6)δ9.20(s,1H),8.60(s,1H),8.10(d,J＝7.8Hz,1H),7.70(d,J＝9.3Hz,1H),7.51(d,J＝5.4Hz,1H),7.47(d,J＝9.3Hz,1H),7.35(d,J＝7.8Hz,1H),6.38(s,2H),5.55(d,J＝5.4Hz,1H),4.51(s,2H),4.13(s,2H),4.01(s,1H),3.77(s,4H),2.00(d,J＝7.5Hz,2H)ppm；LCMS:[M+H] +＝543.1 1 H NMR (400MHz, DMSO-d 6 ) δ 9.20(s, 1H), 8.60(s, 1H), 8.10(d, J=7.8Hz, 1H), 7.70(d, J=9.3Hz, 1H) ,7.51(d,J＝5.4Hz,1H),7.47(d,J＝9.3Hz,1H),7.35(d,J＝7.8Hz,1H),6.38(s,2H),5.55(d,J＝ 5.4Hz, 1H), 4.51(s, 2H), 4.13(s, 2H), 4.01(s, 1H), 3.77(s, 4H), 2.00(d, J=7.5Hz, 2H) ppm; LCMS: [ M+H] + = 543.1
实施例109(S)-1'-(5-((3-氯-2-(甲基氨基)吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 109 (S)-1'-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno [cd]inden-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000422
Figure PCTCN2021126331-appb-000422
1H NMR(400MHz,DMSO-d 6)δ8.59(s,1H),8.11(d,J＝7.8Hz,1H),7.60(d,J＝5.5Hz,1H),7.49(d,J＝6.9Hz,1H),7.36(d,J＝7.9Hz,1H),7.34–7.30(m,3H),6.66–6.62(m,1H),5.53(d,J＝5.4Hz,1H),4.57(s,1H),4.28(s,1H),4.12(s,1H),3.75(s,1H),3.54(s,1H),3.25(d,J＝16.1Hz,1H),2.98(d,J＝16.7Hz,1H),2.84(d,J＝4.6Hz,3H),1.80(d,J＝74.7Hz,6H)ppm；LCMS:[M+H] +＝516.1. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.11 (d, J=7.8Hz, 1H), 7.60 (d, J=5.5Hz, 1H), 7.49 (d, J= 6.9Hz, 1H), 7.36 (d, J=7.9Hz, 1H), 7.34–7.30 (m, 3H), 6.66–6.62 (m, 1H), 5.53 (d, J=5.4Hz, 1H), 4.57 ( s, 1H), 4.28(s, 1H), 4.12(s, 1H), 3.75(s, 1H), 3.54(s, 1H), 3.25(d, J＝16.1Hz, 1H), 2.98(d, J =16.7Hz,1H),2.84(d,J=4.6Hz,3H),1.80(d,J=74.7Hz,6H)ppm; LCMS:[M+H] + =516.1.
实施例110(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-(3-氟氮杂环丁烷-1-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 110 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-(3-fluoroazetidin-1-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidine]- 5-amine
Figure PCTCN2021126331-appb-000423
Figure PCTCN2021126331-appb-000423
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.09(d,J＝7.8Hz,1H),7.49(dd,J＝12.0,6.8Hz,2H),7.33(d,J＝7.8Hz,1H),6.37(s,2H),6.26(d,J＝8.2Hz,1H),5.55(dd,J＝8.3,4.3Hz,2H),5.42(s,1H),4.50(s,1H),4.23(dd,J＝13.1,7.9Hz,2H),4.07(s,1H),4.00–3.91(m,2H),3.83(s,1H),3.70(d,J＝27.9Hz,2H),3.55(s,2H),1.90(s,3H),1.66(s,2H)ppm；LCMS:[M+H] +＝576.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.49 (dd, J=12.0, 6.8Hz, 2H), 7.33 (d, J=7.8Hz, 1H), 6.37(s, 2H), 6.26(d, J=8.2Hz, 1H), 5.55(dd, J=8.3, 4.3Hz, 2H), 5.42(s, 1H), 4.50( s, 1H), 4.23(dd, J=13.1, 7.9Hz, 2H), 4.07(s, 1H), 4.00–3.91(m, 2H), 3.83(s, 1H), 3.70(d, J=27.9Hz , 2H), 3.55(s, 2H), 1.90(s, 3H), 1.66(s, 2H) ppm; LCMS: [M+H] + =576.1
实施例111(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-甲基-4,6-二氢螺[环戊[d]噻唑-5,4'-哌啶]-4-胺Example 111 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-methyl-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-4-amine
Figure PCTCN2021126331-appb-000424
Figure PCTCN2021126331-appb-000424
1H NMR(400MHz,DMSO-d 6)δ8.58(s,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.8Hz,1H),6.37(s,2H),5.54(d,J＝5.4Hz,1H),4.28(s,2H),4.05(s,2H),3.82(d,J＝11.9Hz,4H),2.03(s,2H),1.75(s,4H)ppm；LCMS:[M+H] +＝523.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.33 (d, J= 7.8Hz, 1H), 6.37(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.28(s, 2H), 4.05(s, 2H), 3.82(d, J=11.9Hz, 4H) , 2.03(s, 2H), 1.75(s, 4H) ppm; LCMS: [M+H] + =523.1
实施例112(S)-N-(4-((2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)环戊二烯并[cd]茚-5-基)硫代)-3-氯吡啶-2-基)-N-甲基甲磺酰胺Example 112 (S)-N-(4-((2-(1-Amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)cyclopentadieno [cd]Inden-5-yl)thio)-3-chloropyridin-2-yl)-N-methylmethanesulfonamide
Figure PCTCN2021126331-appb-000425
Figure PCTCN2021126331-appb-000425
1H NMR(400MHz,DMSO-d 6)δ8.58(s,1H),8.16(d,J＝7.8Hz,1H),8.03(d,J＝5.4Hz,1H),7.37(d,J＝7.8Hz,2H),7.23(dd,J＝8.3,4.9Hz,3H),6.45(d,J＝5.3Hz,1H),4.55(s,2H),4.08(d,J＝28.8Hz,3H),3.72(s,2H),3.56(s,2H),3.24(s,3H),3.18(s,3H),1.88–1.79(m,2H)ppm；LCMS:[M+H] +＝594.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.03 (d, J=5.4 Hz, 1H), 7.37 (d, J= 7.8Hz, 2H), 7.23 (dd, J=8.3, 4.9Hz, 3H), 6.45 (d, J=5.3Hz, 1H), 4.55 (s, 2H), 4.08 (d, J=28.8Hz, 3H) , 3.72(s, 2H), 3.56(s, 2H), 3.24(s, 3H), 3.18(s, 3H), 1.88–1.79(m, 2H) ppm; LCMS: [M+H] + = 594.1
实施例113(S)-N-(4-((2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)环戊基[cd]茚-5-基)硫代)-3-氯吡啶-2-基)-N-甲磺酰胺Example 113 (S)-N-(4-((2-(1-amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)cyclopentyl[cd ]Inden-5-yl)thio)-3-chloropyridin-2-yl)-N-methanesulfonamide
Figure PCTCN2021126331-appb-000426
Figure PCTCN2021126331-appb-000426
1H NMR(400MHz,DMSO-d 6)δ8.59(s,1H),8.10(d,J＝7.8Hz,1H),7.57(d,J＝5.4Hz,1H),7.46(d,J＝7.0Hz,1H),7.42–7.22(m,5H),5.60(d,J＝5.4Hz,1H),4.57(s,1H),4.30(s,1H),4.13(s,1H),3.74(s,1H),3.54(s,1H),3.24(d,J＝16.2Hz,3H),2.98(s,4H),1.76(d,J＝99.0Hz,4H)ppm；LCMS:[M+H] +＝580.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.46 (d, J= 7.0Hz, 1H), 7.42–7.22(m, 5H), 5.60(d, J=5.4Hz, 1H), 4.57(s, 1H), 4.30(s, 1H), 4.13(s, 1H), 3.74( s, 1H), 3.54 (s, 1H), 3.24 (d, J=16.2Hz, 3H), 2.98 (s, 4H), 1.76 (d, J=99.0Hz, 4H) ppm; LCMS: [M+H ] + = 580.1
实施例114(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-环丙基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 114 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000427
Figure PCTCN2021126331-appb-000427
1H NMR(400MHz,DMSO-d 6)δ8.58(s,1H),8.11(d,J＝7.8Hz,1H),7.73(d,J＝7.9Hz,1H),7.51(d,J＝5.4Hz,1H),7.37(d,J＝7.8Hz,1H),7.20(d,J＝7.9Hz,1H),6.38(d,J＝6.7Hz,2H),5.53(d,J＝5.4Hz,1H),4.28(s,1H),4.14(s,1H),3.75(s,1H),3.54(s,1H),3.19(d,J＝16.8Hz,1H),3.02(d,J＝16.5Hz,1H),2.11(td,J＝8.2,4.2Hz,1H),1.78(d,J＝62.5Hz,5H),0.95(dd,J＝15.6,6.1Hz,5H)ppm；LCMS:[M+H] +＝543.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58 (s, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.51 (d, J= 5.4Hz, 1H), 7.37 (d, J=7.8Hz, 1H), 7.20 (d, J=7.9Hz, 1H), 6.38 (d, J=6.7Hz, 2H), 5.53 (d, J=5.4Hz) ,1H),4.28(s,1H),4.14(s,1H),3.75(s,1H),3.54(s,1H),3.19(d,J＝16.8Hz,1H),3.02(d,J＝ 16.5Hz, 1H), 2.11 (td, J=8.2, 4.2Hz, 1H), 1.78 (d, J=62.5Hz, 5H), 0.95 (dd, J=15.6, 6.1Hz, 5H) ppm; LCMS: [ M+H] + = 543.2
实施例115(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-N2,N2-二甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-2,6-二胺Example 115(S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-N2,N2-dimethyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-2,6-diamine
Figure PCTCN2021126331-appb-000428
Figure PCTCN2021126331-appb-000428
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.08(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.33(d,J＝7.9Hz,1H),6.36(s,2H),5.54(dd,J＝5.4,1.6Hz,1H),5.14(d,J＝7.3Hz,1H),4.66(d,J＝7.0Hz,1H),4.24(s,1H),4.01(s,2H),3.85(s,2H),3.75(s,2H),3.28(s,1H),3.03(d,J＝7.8Hz,6H),2.65(d,J＝15.0Hz,1H),2.58(s,1H)ppm；LCMS:[M+H] +＝552.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 7.33 (d, J= 7.9Hz, 1H), 6.36 (s, 2H), 5.54 (dd, J=5.4, 1.6Hz, 1H), 5.14 (d, J=7.3Hz, 1H), 4.66 (d, J=7.0Hz, 1H) ,4.24(s,1H),4.01(s,2H),3.85(s,2H),3.75(s,2H),3.28(s,1H),3.03(d,J＝7.8Hz,6H),2.65( d, J=15.0Hz, 1H), 2.58 (s, 1H)ppm; LCMS: [M+H] + =552.0
实施例116(S)-1'-(7-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-3-基)-2-(3-氟吖丁啶-1-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 116(S)-1'-(7-((2-Amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -3-yl)-2-(3-fluoroazetidin-1-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidine]-6- amine
Figure PCTCN2021126331-appb-000429
Figure PCTCN2021126331-appb-000429
1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.12(d,J＝7.9Hz,1H),7.53(d,J＝5.4Hz,1H),7.37(d,J＝7.8Hz,1H),6.41(s,2H),5.63(s,1H),5.55(d,J＝5.4Hz,1H),5.49(s,1H),4.49(s,1H),4.34(ddd,J＝21.2,10.1,5.8Hz,3H),4.10(dd,J＝22.8,10.1Hz,3H),3.99(s,1H),3.81(s,2H),2.73(d,J＝9.1Hz,1H),1.85(d,J＝59.8Hz,6H)ppm；LCMS:[M+H] +＝582.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.63 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.53 (d, J=5.4 Hz, 1H), 7.37 (d, J= 7.8Hz, 1H), 6.41(s, 2H), 5.63(s, 1H), 5.55(d, J=5.4Hz, 1H), 5.49(s, 1H), 4.49(s, 1H), 4.34(ddd, J=21.2, 10.1, 5.8Hz, 3H), 4.10(dd, J=22.8, 10.1Hz, 3H), 3.99(s, 1H), 3.81(s, 2H), 2.73(d, J=9.1Hz, 1H) ), 1.85 (d, J=59.8Hz, 6H) ppm; LCMS: [M+H] + =582.1
实施例117(S)-2-(6-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-2-基)丙烷-2-醇Example 117(S)-2-(6-amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopenta Dieno[cd]inden-2-yl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-2-yl)propan-2-ol
Figure PCTCN2021126331-appb-000430
Figure PCTCN2021126331-appb-000430
1H NMR(400MHz,DMSO-d 6)δ8.63–8.51(m,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.34(d,J＝7.8Hz,1H),6.37(s,2H),5.88(s,1H),5.54(d,J＝5.4Hz,1H),4.43(d,J＝35.6Hz,1H),4.08(s,1H),3.98(s,1H),3.66(d,J＝54.2Hz,3H),2.88(d,J＝15.6Hz,1H),2.75(d,J＝15.4Hz,1H),1.98(s,2H),1.75(s,3H),1.49(s,6H)ppm；LCMS:[M+H] +＝567.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.63-8.51 (m, 1H), 8.09 (d, J=7.8Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 6.37(s, 2H), 5.88(s, 1H), 5.54(d, J=5.4Hz, 1H), 4.43(d, J=35.6Hz, 1H), 4.08(s, 1H), 3.98(s, 1H), 3.66(d, J=54.2Hz, 3H), 2.88(d, J=15.6Hz, 1H), 2.75(d, J=15.4Hz, 1H), 1.98(s, 2H), 1.75 (s, 3H), 1.49 (s, 6H) ppm; LCMS: [M+H] + =567.0
实施例118(S)-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-(二氟甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 118 (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopentadieno[cd]indene -2-yl)-2-(difluoromethyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000431
Figure PCTCN2021126331-appb-000431
1H NMR(400MHz,DMSO-d 6)δ8.59(s,1H),8.09(d,J＝7.8Hz,1H),7.50(d,J＝5.4Hz,1H),7.47–7.11(m,2H),6.38(s,2H),5.54(d,J＝5.4Hz,1H),4.46(s,1H),4.12(s,2H),3.76(s,2H),3.00(d,J＝15.6Hz,1H),2.86(d,J＝15.5Hz,1H),2.53(s,2H),1.99(s,1H),1.78(s,3H)ppm；LCMS:[M+H] +＝559.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.50 (d, J=5.4Hz, 1H), 7.47-7.11 (m, 2H), 6.38(s, 2H), 5.54(d, J=5.4Hz, 1H), 4.46(s, 1H), 4.12(s, 2H), 3.76(s, 2H), 3.00(d, J=15.6 Hz, 1H), 2.86(d, J=15.5Hz, 1H), 2.53(s, 2H), 1.99(s, 1H), 1.78(s, 3H) ppm; LCMS: [M+H] + =559.0
实施例119(S)-2-(5-氨基-1'-(5-((2-氨基-3-氯吡啶-4-基)硫代)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-2-基)Example 119 (S)-2-(5-amino-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)-1,2a1,4-triazacyclopenta Dieno[cd]inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidin]-2-yl)
Figure PCTCN2021126331-appb-000432
Figure PCTCN2021126331-appb-000432
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.09(d,J＝7.8Hz,1H),7.64(d,J＝7.9Hz,1H),7.50(d,J＝5.4Hz,1H),7.46(d,J＝7.8Hz,1H),7.33(d,J＝7.8Hz,1H),6.37(s,2H),5.55(d,J＝5.4Hz,1H),5.17(s,1H),4.52(s,1H),4.07(d,J＝16.2Hz,1H),3.93(s,1H),3.75(dt,J＝30.1,11.6Hz,1H),3.54(dd,J＝17.0,5.8Hz,1H),3.17(d,J＝16.4Hz,2H),2.83(d,J＝16.4Hz,1H),1.88(s,3H),1.71(dt,J＝23.2,8.7Hz,1H),1.44(d,J＝2.6Hz,6H),1.23(s,1H)ppm；LCMS:[M+H] +＝561.0 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.50 (d, J= 5.4Hz, 1H), 7.46 (d, J=7.8Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 6.37 (s, 2H), 5.55 (d, J=5.4Hz, 1H), 5.17 (s, 1H), 4.52(s, 1H), 4.07(d, J=16.2Hz, 1H), 3.93(s, 1H), 3.75(dt, J=30.1, 11.6Hz, 1H), 3.54(dd, J=17.0, 5.8Hz, 1H), 3.17 (d, J=16.4Hz, 2H), 2.83 (d, J=16.4Hz, 1H), 1.88 (s, 3H), 1.71 (dt, J=23.2, 8.7 Hz, 1H), 1.44 (d, J=2.6Hz, 6H), 1.23 (s, 1H) ppm; LCMS: [M+H] + =561.0
采用实施例30相同的制备方法，使用实施例29得到的中间体C1、螺环胺中间体A1-A57以及硼酸中间体C3-C6或商业化硼酸制备如下化合物：Using the same preparation method of Example 30, using the intermediate C1 obtained in Example 29, the spirocyclic amine intermediate A1-A57 and the boronic acid intermediate C3-C6 or commercial boronic acid to prepare the following compounds:
实施例120(S)-1'-(5-(2-甲基吡啶-3-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 120(S)-1'-(5-(2-methylpyridin-3-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-1 ,3-Dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000433
Figure PCTCN2021126331-appb-000433
1H NMR(400MHz,DMSO-d 6)δ8.51–8.46(m,2H),7.80(dd,J＝7.7,3.1Hz,2H),7.35–7.31(m,1H),7.29(d,J＝7.7Hz,1H),7.25(d,J＝5.9Hz,1H),7.17–7.10(m,3H),4.43(s,1H),4.05(s,1H),3.84(s,1H),3.40(s,2H),3.08(s,1H),2.65(d,J＝15.6Hz,1H),2.44(s,3H),1.92–1.50(m,5H),1.17(s,1H)ppm；LCMS:[M+H] +＝435.3 1 H NMR (400MHz, DMSO-d 6 ) δ 8.51-8.46 (m, 2H), 7.80 (dd, J=7.7, 3.1 Hz, 2H), 7.35-7.31 (m, 1H), 7.29 (d, J =7.7Hz,1H),7.25(d,J=5.9Hz,1H),7.17–7.10(m,3H),4.43(s,1H),4.05(s,1H),3.84(s,1H),3.40 (s,2H), 3.08(s,1H), 2.65(d,J=15.6Hz,1H), 2.44(s,3H), 1.92–1.50(m,5H), 1.17(s,1H)ppm; LCMS :[M+H] + =435.3
实施例121(S)-1'-(5-(3-氨基-2-氯苯基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 121 (S)-1'-(5-(3-amino-2-chlorophenyl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-1 ,3-Dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000434
Figure PCTCN2021126331-appb-000434
1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝15.3Hz,2H),8.31(d,J＝4.8Hz,1H),7.90(d,J＝7.8Hz,1H),7.21(dd,J＝10.4,6.4Hz,2H),6.67(d,J＝7.9Hz,1H),6.51(d,J＝8.2Hz,1H),5.69(d,J＝7.7Hz,1H),5.43(s,2H),4.42(s,2H),3.95(s,2H),3.62–3.58(m,1H),3.11(d,J＝16.9Hz,1H),2.69(d,J＝16.4Hz,1H),1.69(d,J＝77.8Hz,5H),1.27(s,1H)ppm；LCMS:[M+H] +＝502.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (d, J=15.3 Hz, 2H), 8.31 (d, J=4.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.21 (dd,J＝10.4,6.4Hz,2H),6.67(d,J＝7.9Hz,1H),6.51(d,J＝8.2Hz,1H),5.69(d,J＝7.7Hz,1H),5.43 (s, 2H), 4.42 (s, 2H), 3.95 (s, 2H), 3.62–3.58 (m, 1H), 3.11 (d, J=16.9Hz, 1H), 2.69 (d, J=16.4Hz, 1H), 1.69 (d, J=77.8Hz, 5H), 1.27 (s, 1H) ppm; LCMS: [M+H] + =502.1
实施例122(S)-1'-(5-(2,3-二氯苯基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-7-胺Example 122 (S)-1'-(5-(2,3-dichlorophenyl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-5, 7-Dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000435
Figure PCTCN2021126331-appb-000435
1H NMR(400MHz,DMSO-d 6)δ8.49(s,1H),8.43(s,1H),8.32(d,J＝4.6Hz,1H),7.86(d,J＝7.8Hz,1H),7.70(dd,J＝8.0,1.6Hz,1H),7.59–7.56(m,1H),7.46(t,J＝7.9Hz,1H),7.29(d,J＝7.8Hz,1H),7.21(d,J＝4.6Hz,1H),4.43(s,2H),3.98(s,3H),3.10(s,1H),2.74(s,1H),1.80(s,4H),1.61(s,2H)ppm；LCMS:[M+H] +＝489.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.49(s, 1H), 8.43(s, 1H), 8.32(d, J=4.6Hz, 1H), 7.86(d, J=7.8Hz, 1H) ,7.70(dd,J＝8.0,1.6Hz,1H),7.59–7.56(m,1H),7.46(t,J＝7.9Hz,1H),7.29(d,J＝7.8Hz,1H),7.21( d, J＝4.6Hz, 1H), 4.43(s, 2H), 3.98(s, 3H), 3.10(s, 1H), 2.74(s, 1H), 1.80(s, 4H), 1.61(s, 2H) )ppm; LCMS: [M+H] + =489.1
实施例123(S)-1'-(5-(2-(三氟甲基)吡啶-3-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺 [茚-2,4'-哌啶]-1-胺Example 123 (S)-1'-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,2a1,4-triazacyclopentadieno[cd]indene-2- base)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000436
Figure PCTCN2021126331-appb-000436
1H NMR(400MHz,DMSO-d 6)δ8.87(d,J＝4.7Hz,1H),8.55(s,1H),8.18(d,J＝6.8Hz,1H),7.88(dd,J＝7.9,4.7Hz,1H),7.82(d,J＝7.7Hz,1H),7.39–7.30(m,2H),7.25–7.16(m,3H),4.52(s,2H),4.09(s,2H),3.93(s,1H),3.60(d,J＝71.1Hz,3H),2.02–1.62(m,5H)ppm；LCMS:[M+H] +＝489.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (d, J=4.7 Hz, 1H), 8.55 (s, 1H), 8.18 (d, J=6.8 Hz, 1H), 7.88 (dd, J= 7.9, 4.7Hz, 1H), 7.82 (d, J=7.7Hz, 1H), 7.39–7.30 (m, 2H), 7.25–7.16 (m, 3H), 4.52 (s, 2H), 4.09 (s, 2H) ), 3.93 (s, 1H), 3.60 (d, J=71.1Hz, 3H), 2.02–1.62 (m, 5H) ppm; LCMS: [M+H] + = 489.1
实施例124(S)-1-氨基-1'-(5-(2-甲基吡啶-3-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲腈Example 124(S)-1-Amino-1'-(5-(2-methylpyridin-3-yl)-1,2a1,4-triazacyclopentadieno[cd]indene-2- base)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-carbonitrile
Figure PCTCN2021126331-appb-000437
Figure PCTCN2021126331-appb-000437
1H NMR(400MHz,DMSO-d 6)δ8.61–8.49(m,2H),7.87(d,J＝7.7Hz,2H),7.70(s,1H),7.66(d,J＝7.7Hz,1H),7.43(d,J＝7.7Hz,1H),7.41–7.32(m,2H),4.69–4.32(m,1H),4.24–4.03(m,1H),3.95(s,1H),3.82–3.53(m,2H),3.27(d,J＝14.4Hz,1H),2.80(d,J＝14.4Hz,1H),2.49(s,3H),1.96–1.64(m,4H)ppm；LCMS:[M+H] +＝460.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.61-8.49 (m, 2H), 7.87 (d, J=7.7Hz, 2H), 7.70 (s, 1H), 7.66 (d, J=7.7Hz, 1H), 7.43(d, J=7.7Hz, 1H), 7.41–7.32 (m, 2H), 4.69–4.32 (m, 1H), 4.24–4.03 (m, 1H), 3.95 (s, 1H), 3.82 –3.53(m,2H),3.27(d,J=14.4Hz,1H),2.80(d,J=14.4Hz,1H),2.49(s,3H),1.96–1.64(m,4H)ppm; LCMS :[M+H] + = 460.1
实施例125(S)-1'-(5-((6aS,8R)-8-氟-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]噁嗪-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 125(S)-1'-(5-((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1 ,2-d][1,4]oxazin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-5,7-dihydrospiro[ Cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000438
Figure PCTCN2021126331-appb-000438
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.34(d,J＝5.1Hz,1H),8.27(d,J＝7.9Hz,1H),7.81(d,J＝5.3Hz,1H),7.67(d,J＝7.5Hz,1H),7.34(t,J＝5.7Hz,2H),7.20(dd,J＝7.5,5.0Hz,1H),5.51(d,J＝52.9Hz,1H),4.60(dd,J＝10.4,3.8Hz,1H),3.98(d,J＝9.0Hz,2H),3.94–3.72(m,3H),3.48(t,J＝10.0Hz,1H),3.21(d,J＝16.4Hz,1H),2.84(d,J＝16.4Hz,1H),2.37(s,2H),1.91(s,6H),1.29(s,1H)ppm；LCMS:[M+H] +＝537.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.81 (d, J= 5.3Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 7.34 (t, J=5.7Hz, 2H), 7.20 (dd, J=7.5, 5.0Hz, 1H), 5.51 (d, J= 52.9Hz, 1H), 4.60(dd, J=10.4, 3.8Hz, 1H), 3.98(d, J=9.0Hz, 2H), 3.94–3.72(m, 3H), 3.48(t, J=10.0Hz, 1H), 3.21(d, J=16.4Hz, 1H), 2.84(d, J=16.4Hz, 1H), 2.37(s, 2H), 1.91(s, 6H), 1.29(s, 1H) ppm; LCMS :[M+H] + =537.2
实施例126(S)-1'-(5-((S)-6a,7,8,9-四氢-6H-吡啶并[3,2-b]吡咯并[1,2-d][1,4]噁嗪-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 126(S)-1'-(5-((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][ 1,4]oxazin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[ b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000439
Figure PCTCN2021126331-appb-000439
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.34(d,J＝4.5Hz,1H),8.25(d,J＝7.9Hz,1H),7.79(d,J＝5.3Hz,1H),7.67(d,J＝7.3Hz,1H),7.33(d,J＝7.9Hz,1H),7.26(d,J＝5.3Hz,1H),7.20(dd,J＝7.4,5.1Hz,1H),4.54(dd,J＝10.4,3.6Hz,2H),4.15–4.07(m,1H),3.97(s,1H),3.70(ddd,J＝26.4,13.3,7.1Hz,4H),2.09(ddd,J＝32.1,12.7,6.0Hz,3H),2.00–1.84(m,4H),1.79–1.44(m,4H),1.38–1.17(m, 3H)ppm；LCMS:[M+H] +＝519.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.34 (d, J=4.5Hz, 1H), 8.25 (d, J=7.9Hz, 1H), 7.79 (d, J= 5.3Hz, 1H), 7.67 (d, J=7.3Hz, 1H), 7.33 (d, J=7.9Hz, 1H), 7.26 (d, J=5.3Hz, 1H), 7.20 (dd, J=7.4, 5.1Hz, 1H), 4.54 (dd, J=10.4, 3.6Hz, 2H), 4.15–4.07 (m, 1H), 3.97 (s, 1H), 3.70 (ddd, J=26.4, 13.3, 7.1Hz, 4H ), 2.09 (ddd, J=32.1, 12.7, 6.0 Hz, 3H), 2.00–1.84 (m, 4H), 1.79–1.44 (m, 4H), 1.38–1.17 (m, 3H) ppm; LCMS: [M +H] + = 519.2
实施例127(S)-1'-(5-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 127 (S)-1'-(5-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000440
Figure PCTCN2021126331-appb-000440
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.00(d,J＝5.0Hz,1H),7.94(d,J＝7.8Hz,1H),7.34(dd,J＝10.5,6.8Hz,2H),7.20(dt,J＝9.0,3.2Hz,3H),6.84(d,J＝5.0Hz,1H),6.45(s,2H),4.51(s,1H),4.10(s,2H),3.92(s,1H),3.51(s,4H),1.94–1.66(m,5H)ppm；LCMS:[M+H] +＝470.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.34 (dd, J= 10.5, 6.8Hz, 2H), 7.20(dt, J=9.0, 3.2Hz, 3H), 6.84(d, J=5.0Hz, 1H), 6.45(s, 2H), 4.51(s, 1H), 4.10( s, 2H), 3.92 (s, 1H), 3.51 (s, 4H), 1.94–1.66 (m, 5H) ppm; LCMS: [M+H] + = 470.1
实施例128(S)-1'-(5-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 128 (S)-1'-(5-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000441
Figure PCTCN2021126331-appb-000441
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.34(d,J＝4.2Hz,1H),8.01(d,J＝5.0Hz,1H),7.95(d,J＝7.8Hz,1H),7.67(d,J＝7.3Hz,1H),7.35(d,J＝7.8Hz,1H),7.19(dd,J＝7.5,5.0Hz,1H),6.84(d,J＝5.0Hz,1H),6.45(s,2H),4.52(s,2H),4.08(d,J＝37.4Hz,2H),3.96(s,1H),3.69(s,2H),3.53(s,2H),1.91(s,2H),1.71(s,2H)ppm；LCMS:[M+H] +＝471.1 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.34 (d, J=4.2 Hz, 1H), 8.01 (d, J=5.0 Hz, 1H), 7.95 (d, J= 7.8Hz, 1H), 7.67 (d, J=7.3Hz, 1H), 7.35 (d, J=7.8Hz, 1H), 7.19 (dd, J=7.5, 5.0Hz, 1H), 6.84 (d, J= 5.0Hz, 1H), 6.45(s, 2H), 4.52(s, 2H), 4.08(d, J=37.4Hz, 2H), 3.96(s, 1H), 3.69(s, 2H), 3.53(s, 2H), 1.91 (s, 2H), 1.71 (s, 2H) ppm; LCMS: [M+H] + =471.1
实施例129(S)-1'-(5-(4-氯-2-甲基-2H-吲唑-5-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺Example 129 (S)-1'-(5-(4-Chloro-2-methyl-2H-indazol-5-yl)-1,2a1,4-triazacyclopentadieno[cd] inden-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-amine
Figure PCTCN2021126331-appb-000442
Figure PCTCN2021126331-appb-000442
1H NMR(400MHz,DMSO-d 6)δ8.58(d,J＝5.8Hz,2H),7.99(d,J＝7.8Hz,1H),7.75–7.69(m,1H),7.58(d,J＝8.8Hz,1H),7.44–7.37(m,2H),7.26(dq,J＝7.4,2.1Hz,3H),4.53(s,1H),4.25(d,J＝5.7Hz,4H),4.13(s,1H),3.55(s,2H),3.22(d,J＝15.9Hz,1H),2.87(d,J＝15.8Hz,1H),1.89(d,J＝40.9Hz,2H),1.69(s,1H),1.43(s,1H)ppm；LCMS:[M+H] +＝508.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58(d, J=5.8Hz, 2H), 7.99(d, J=7.8Hz, 1H), 7.75-7.69(m, 1H), 7.58(d, J=8.8Hz, 1H), 7.44–7.37(m, 2H), 7.26(dq, J=7.4, 2.1Hz, 3H), 4.53(s, 1H), 4.25(d, J=5.7Hz, 4H), 4.13(s, 1H), 3.55(s, 2H), 3.22(d, J=15.9Hz, 1H), 2.87(d, J=15.8Hz, 1H), 1.89(d, J=40.9Hz, 2H), 1.69 (s, 1H), 1.43 (s, 1H) ppm; LCMS: [M+H] + =508.2
实施例130(S)-1'-(5-(4-氯-2-甲基-2H-吲唑-5-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-1-甲基-4,6-二氢-1H-螺[环戊二烯并[c]吡唑-5,4'-哌啶]-4-胺Example 130 (S)-1'-(5-(4-Chloro-2-methyl-2H-indazol-5-yl)-1,2a1,4-triazacyclopentadieno[cd] Inden-2-yl)-1-methyl-4,6-dihydro-1H-spiro[cyclopentadieno[c]pyrazol-5,4'-piperidin]-4-amine
Figure PCTCN2021126331-appb-000443
Figure PCTCN2021126331-appb-000443
1H NMR(400MHz,DMSO-d 6)δ8.58(d,J＝7.3Hz,2H),7.99(d,J＝7.8Hz,1H),7.71(dd,J＝8.8,0.9Hz,1H),7.58(d,J＝8.8Hz,1H),7.38(d,J＝7.8Hz,1H),7.17(s,1H),4.36(s,1H),4.25(s,3H),4.08(s,1H),3.77(s,1H),3.71(s,5H),2.83–2.70(m,2H),1.94(s,1H),1.73(s,3H)ppm；LCMS:[M+H] +＝ 512.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58 (d, J=7.3Hz, 2H), 7.99 (d, J=7.8Hz, 1H), 7.71 (dd, J=8.8, 0.9Hz, 1H) ,7.58(d,J=8.8Hz,1H),7.38(d,J=7.8Hz,1H),7.17(s,1H),4.36(s,1H),4.25(s,3H),4.08(s, 1H), 3.77(s, 1H), 3.71(s, 5H), 2.83–2.70(m, 2H), 1.94(s, 1H), 1.73(s, 3H) ppm; LCMS: [M+H] + = 512.2
实施例131(S)-1'-(7-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-3-基)-2-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 131 (S)-1'-(7-(2-Amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-3-yl )-2-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000444
Figure PCTCN2021126331-appb-000444
1H NMR(400MHz,DMSO-d 6)δ8.52(s,1H),7.94(d,J＝5.0Hz,1H),7.88(d,J＝7.8Hz,1H),7.30(d,J＝7.8Hz,1H),6.78(d,J＝5.0Hz,1H),6.37(s,2H),4.35(s,1H),3.99(s,2H),3.68(s,2H),2.82(d,J＝15.7Hz,1H),2.74(d,J＝15.5Hz,1H),2.58(s,3H),1.84(s,6H)ppm；LCMS:[M+H] +＝491.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.52 (s, 1H), 7.94 (d, J=5.0 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.30 (d, J= 7.8Hz, 1H), 6.78(d, J=5.0Hz, 1H), 6.37(s, 2H), 4.35(s, 1H), 3.99(s, 2H), 3.68(s, 2H), 2.82(d, J=15.7Hz, 1H), 2.74 (d, J=15.5Hz, 1H), 2.58 (s, 3H), 1.84 (s, 6H) ppm; LCMS: [M+H] + =491.0
实施例132(S)-1'-(5-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-环丙基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 132 (S)-1'-(5-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-2-cyclopropyl-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000445
Figure PCTCN2021126331-appb-000445
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.01(d,J＝5.0Hz,1H),7.94(d,J＝7.8Hz,1H),7.53(d,J＝7.7Hz,1H),7.35(d,J＝7.9Hz,1H),7.09(d,J＝7.8Hz,1H),6.84(d,J＝5.0Hz,1H),6.45(s,2H),4.51(s,1H),4.09(s,1H),3.92(s,1H),3.69(s,1H),3.51(s,3H),3.11(d,J＝16.4Hz,1H),2.78(d,J＝16.4Hz,1H),2.12–2.01(m,1H),1.85(s,2H),1.66(s,1H),0.90(d,J＝8.2Hz,4H)ppm；LCMS:[M+H] +＝511.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.01 (d, J=5.0 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.53 (d, J= 7.7Hz, 1H), 7.35(d, J=7.9Hz, 1H), 7.09(d, J=7.8Hz, 1H), 6.84(d, J=5.0Hz, 1H), 6.45(s, 2H), 4.51 (s, 1H), 4.09(s, 1H), 3.92(s, 1H), 3.69(s, 1H), 3.51(s, 3H), 3.11(d, J=16.4Hz, 1H), 2.78(d, J=16.4Hz, 1H), 2.12–2.01 (m, 1H), 1.85 (s, 2H), 1.66 (s, 1H), 0.90 (d, J=8.2Hz, 4H) ppm; LCMS: [M+H ] + = 511.0
实施例133(S)-1'-(5-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-2-甲基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺Example 133 (S)-1'-(5-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-2-yl )-2-methyl-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-5-amine
Figure PCTCN2021126331-appb-000446
Figure PCTCN2021126331-appb-000446
1H NMR(400MHz,DMSO-d 6)δ8.65(d,J＝4.8Hz,3H),8.05–7.99(m,2H),7.93(d,J＝7.9Hz,1H),7.41(d,J＝7.9Hz,1H),7.24(s,1H),6.92(d,J＝5.3Hz,1H),6.81(s,1H),4.54(s,1H),4.44(s,1H),3.73(s,2H),3.20–3.10(m,2H),2.70–2.56(m,1H),2.49(s,3H),2.04–1.83(m,3H),1.70(s,2H),1.23(s,1H)ppm；LCMS:[M+H] +＝485.0 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (d, J=4.8 Hz, 3H), 8.05-7.99 (m, 2H), 7.93 (d, J=7.9 Hz, 1H), 7.41 (d, J=7.9Hz, 1H), 7.24(s, 1H), 6.92(d, J=5.3Hz, 1H), 6.81(s, 1H), 4.54(s, 1H), 4.44(s, 1H), 3.73( s, 2H), 3.20–3.10 (m, 2H), 2.70–2.56 (m, 1H), 2.49 (s, 3H), 2.04–1.83 (m, 3H), 1.70 (s, 2H), 1.23 (s, 1H) ppm; LCMS: [M+H] + =485.0
实施例134(S)-2-(5-氨基-1'-(5-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-2-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-2-基)丙烷-2-醇Example 134 (S)-2-(5-Amino-1'-(5-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[ cd]Inden-2-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4'-piperidin]-2-yl)propan-2-ol
Figure PCTCN2021126331-appb-000447
Figure PCTCN2021126331-appb-000447
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.00(d,J＝5.0Hz,1H),7.93(d,J＝7.9Hz,1H),7.64 (d,J＝7.9Hz,1H),7.46(d,J＝7.8Hz,1H),7.34(d,J＝7.8Hz,1H),6.84(d,J＝5.0Hz,1H),6.43(s,2H),5.17(s,1H),4.51(s,1H),4.08(s,1H),3.92(s,1H),3.60(d,J＝62.0Hz,3H),3.16(dd,J＝16.4,7.0Hz,2H),2.82(dd,J＝16.4,5.8Hz,1H),1.87(q,J＝20.7,17.4Hz,3H),1.68(s,1H),1.43(d,J＝2.7Hz,6H)ppm；LCMS:[M+H] +＝529.0 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.64 (d, J= 7.9Hz, 1H), 7.46 (d, J=7.8Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 6.84 (d, J=5.0Hz, 1H), 6.43 (s, 2H), 5.17 (s,1H),4.51(s,1H),4.08(s,1H),3.92(s,1H),3.60(d,J=62.0Hz,3H),3.16(dd,J=16.4,7.0Hz, 2H), 2.82(dd, J＝16.4, 5.8Hz, 1H), 1.87(q, J＝20.7, 17.4Hz, 3H), 1.68(s, 1H), 1.43(d, J＝2.7Hz, 6H)ppm ; LCMS: [M+H] + =529.0
实施例135(S)-1'-(7-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-3-基)-2-((二甲氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 135 (S)-1'-(7-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-3-yl )-2-((dimethylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000448
Figure PCTCN2021126331-appb-000448
1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.01(d,J＝5.0Hz,1H),7.96(d,J＝7.8Hz,1H),7.38(d,J＝7.8Hz,1H),6.85(d,J＝5.0Hz,1H),6.45(s,2H),4.22–4.01(m,2H),3.85–3.64(m,4H),3.01–2.80(m,2H),2.28(s,6H),2.04–1.94(m,2H),1.85–1.69(m,2H),1.24(s,3H)ppm；LCMS:[M+H] +＝533.7 1 H NMR (400MHz, DMSO-d 6 )δ8.60(s, 1H), 8.01(d, J=5.0Hz, 1H), 7.96(d, J=7.8Hz, 1H), 7.38(d, J= 7.8Hz, 1H), 6.85(d, J=5.0Hz, 1H), 6.45(s, 2H), 4.22-4.01(m, 2H), 3.85-3.64(m, 4H), 3.01-2.80(m, 2H) ), 2.28 (s, 6H), 2.04–1.94 (m, 2H), 1.85–1.69 (m, 2H), 1.24 (s, 3H) ppm; LCMS: [M+H] + = 533.7
实施例136(S)-6-氨基-1'-(7-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-3-基)-N-甲基-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-2-甲酰胺Example 136 (S)-6-amino-1'-(7-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]indene -3-yl)-N-methyl-4,6-dihydrospiro[cyclopentadieno[d]thiazole-5,4'-piperidine]-2-carboxamide
Figure PCTCN2021126331-appb-000449
Figure PCTCN2021126331-appb-000449
1H NMR(400MHz,DMSO-d 6)δ8.81(q,J＝4.7Hz,1H),8.61(s,1H),8.01(d,J＝5.0Hz,1H),7.96(d,J＝7.8Hz,1H),7.38(d,J＝7.8Hz,1H),6.85(d,J＝5.0Hz,1H),6.46(s,2H),4.75–3.67(m,7H),3.10–2.89(m,3H),2.79(d,J＝4.8Hz,3H),2.14–1.58(m,5H)ppm；LCMS:[M+H] +＝533.7 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (q, J=4.7 Hz, 1H), 8.61 (s, 1H), 8.01 (d, J=5.0 Hz, 1H), 7.96 (d, J= 7.8Hz, 1H), 7.38 (d, J=7.8Hz, 1H), 6.85 (d, J=5.0Hz, 1H), 6.46 (s, 2H), 4.75–3.67 (m, 7H), 3.10–2.89 ( m, 3H), 2.79 (d, J=4.8Hz, 3H), 2.14–1.58 (m, 5H) ppm; LCMS: [M+H] + =533.7
实施例137(S)-1'-(7-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-3-基)-3-甲基-5,7-二氢螺[环戊二烯并[c]吡啶-6,4'-哌啶]-7-胺Example 137 (S)-1'-(7-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-3-yl )-3-methyl-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4'-piperidin]-7-amine
Figure PCTCN2021126331-appb-000450
Figure PCTCN2021126331-appb-000450
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.36(s,1H),8.01(s,1H),7.95(d,J＝7.7Hz,1H),7.35(d,J＝7.8Hz,1H),7.14(s,1H),6.84(d,J＝5.0Hz,1H),6.44(s,2H),4.68–4.33(m,2H),4.28–3.90(m,3H),3.13(d,J＝16.6Hz,1H),2.75(d,J＝16.6Hz,1H),2.44(s,3H),2.05–1.10(m,4H)ppm；LCMS:[M+H] +＝485.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56(s, 1H), 8.36(s, 1H), 8.01(s, 1H), 7.95(d, J=7.7Hz, 1H), 7.35(d, J=7.8Hz, 1H), 7.14(s, 1H), 6.84(d, J=5.0Hz, 1H), 6.44(s, 2H), 4.68-4.33(m, 2H), 4.28-3.90(m, 3H) ), 3.13(d, J=16.6Hz, 1H), 2.75(d, J=16.6Hz, 1H), 2.44(s, 3H), 2.05–1.10(m, 4H) ppm; LCMS: [M+H] + = 485.2
实施例138(S)-1'-(7-(2-氨基-3-氯吡啶-4-基)-1,2a1,4-三氮杂环戊二烯并[cd]茚-3-基)-2-((甲基氨基)甲基)-4,6-二氢螺[环戊二烯并[d]噻唑-5,4'-哌啶]-6-胺Example 138 (S)-1'-(7-(2-amino-3-chloropyridin-4-yl)-1,2a1,4-triazacyclopentadieno[cd]inden-3-yl )-2-((methylamino)methyl)-4,6-dihydrospiro[cyclopentadieno[d]thiazol-5,4'-piperidin]-6-amine
Figure PCTCN2021126331-appb-000451
Figure PCTCN2021126331-appb-000451
1H NMR(400MHz,DMSO-d 6)δ8.62(s,1H),8.01(d,J＝5.0Hz,1H),7.97(d,J＝7.8Hz,1H),7.40(d,J＝7.8Hz,1H),6.84(d,J＝4.9Hz,1H),6.46(s,2H),4.76–4.07(m,4H),4.06–3.95(m,3H),3.08–2.88(m,2H),2.40(s,3H),2.12–1.57(m,4H)ppm；LCMS:[M+H] +＝520.2 1 H NMR (400MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 8.01 (d, J=5.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.40 (d, J= 7.8Hz, 1H), 6.84 (d, J=4.9Hz, 1H), 6.46 (s, 2H), 4.76–4.07 (m, 4H), 4.06–3.95 (m, 3H), 3.08–2.88 (m, 2H) ), 2.40 (s, 3H), 2.12–1.57 (m, 4H) ppm; LCMS: [M+H] + = 520.2
测试实施例1-3药理相关实施例Test Examples 1-3 Pharmacologically related examples
测试实施例1：SHP2酶活性抑制实验Test Example 1: SHP2 Enzyme Activity Inhibition Experiment
化合物粉末溶于DMSO中制成母液。实验时，化合物存贮液用DMSO进行3-倍梯度稀释，同一化合物设置10个不同的测试浓度。取1μL各浓度点的化合物至检测板(Corning,Costar 3915)孔内,每个浓度点设置2个平行重复。所用蛋白为第76位氨基酸突变的活性蛋白SHP2 E76A,所用底物为DiFMUP(Invitrogen,E12020)。SHP2 E76A蛋白和底物分别用缓冲液(0.1M NaAc(pH 7.2)，0.02％Tween20,0.1％BSA,1mM EDTA,5mM DTT)稀释至1.2nM和20μM。向检测孔中加入50μL酶溶液，随之再加入50μL底物。在Spectra max i3(Molecular Devices)仪器上，每隔1分钟记录(Ex 358nm/Em455nm)一次荧光信号，以此算出产物的积累速率以表征酶活性。用GraphPad Prism 5进行非线性回归分析，通过Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))方程拟合出酶活性随化合物浓度变化的曲线。求得各化合物的IC 50值。 Compound powders were dissolved in DMSO to make mother liquors. During the experiment, compound stock solutions were serially diluted 3-fold with DMSO, and 10 different test concentrations were set for the same compound. Take 1 μL of the compound at each concentration point to the well of the detection plate (Corning, Costar 3915), and set 2 parallel replicates for each concentration point. The protein used was the active protein SHP2 E76A mutated at the 76th amino acid, and the substrate used was DiFMUP (Invitrogen, E12020). SHP2 E76A protein and substrate were diluted to 1.2 nM and 20 μM with buffer (0.1 M NaAc (pH 7.2), 0.02% Tween20, 0.1% BSA, 1 mM EDTA, 5 mM DTT), respectively. 50 μL of enzyme solution was added to the assay wells, followed by 50 μL of substrate. On a Spectra max i3 (Molecular Devices) instrument, the fluorescence signal was recorded (Ex 358 nm/Em 455 nm) every 1 minute, and the product accumulation rate was calculated to characterize the enzymatic activity. Nonlinear regression analysis was performed with GraphPad Prism 5, and the curve of enzyme activity as a function of compound concentration was fitted by the equation Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope)). The IC50 value of each compound was obtained.
结果result
下表显示了本发明部分化合物的IC 50值。 The table below shows IC50 values for some compounds of the present invention.
Figure PCTCN2021126331-appb-000452
Figure PCTCN2021126331-appb-000452
Figure PCTCN2021126331-appb-000453
Figure PCTCN2021126331-appb-000453
Figure PCTCN2021126331-appb-000454
Figure PCTCN2021126331-appb-000454
Figure PCTCN2021126331-appb-000455
Figure PCTCN2021126331-appb-000455
Figure PCTCN2021126331-appb-000456
Figure PCTCN2021126331-appb-000456
Figure PCTCN2021126331-appb-000457
Figure PCTCN2021126331-appb-000457
Figure PCTCN2021126331-appb-000458
Figure PCTCN2021126331-appb-000458
Figure PCTCN2021126331-appb-000459
Figure PCTCN2021126331-appb-000459
测试实施例2：磷酸化蛋白激酶(p-ERK)细胞实验Test Example 2: Phosphorylated Protein Kinase (p-ERK) Cell Experiment
通过AlphaLISA方法检测化合物抑制细胞内蛋白激酶(ERK)的磷酸化水平。The compounds inhibited the phosphorylation level of intracellular protein kinase (ERK) by AlphaLISA method.
第一步化合物处理细胞。待测化合物先用100％DMSO进行3-倍稀释，共设置9个不同的浓度梯度；接着以每孔40000个细胞密度接种Kyse520细胞到96孔板，每孔体积100μL；随后每孔分别加入3μL的DMSO(10％，用全培养基稀释)或者不同浓度的待测化合物，每个浓度设置2个重复，DMSO的终浓度控制在0.3％。The first step compound treats the cells. The compounds to be tested were first diluted 3-fold with 100% DMSO, and a total of 9 different concentration gradients were set; then Kyse520 cells were seeded into a 96-well plate at a density of 40,000 cells per well, and the volume of each well was 100 μL; then 3 μL were added to each well. DMSO (10%, diluted with complete medium) or different concentrations of the test compounds, each concentration was set to 2 replicates, and the final concentration of DMSO was controlled at 0.3%.
第二步裂解细胞。细胞处理2小时之后，除去培养基，磷酸缓冲盐溶液洗涤细胞3次，每孔加入50μl新鲜配置的裂解缓冲液，震荡并室温放置10分钟。The second step lyses the cells. After the cells were treated for 2 hours, the medium was removed, the cells were washed three times with phosphate buffered saline, 50 μl of freshly prepared lysis buffer was added to each well, shaken and left at room temperature for 10 minutes.
第三步
Figure PCTCN2021126331-appb-000460
Ultra TM p-ERK 1/2(Thr202/Tyr204)试剂盒(Perkin Elmer,ALSU-PERK-A10K))检测磷酸化的细胞外信号调节激酶(p-ERK)。取10μl的上述裂解液至384孔板(Perkin Elmer,6005350)，根据产品说明书检测样品的细胞外信号调节激酶的磷酸化水平。使用Spectra max i3(Molecular Devices)上的AlphaScreen检测器读取信号。抑制百分率(％)通过以下公式计算获得： third step
Figure PCTCN2021126331-appb-000460
Ultra ™ p-ERK 1/2 (Thr202/Tyr204) kit (Perkin Elmer, ALSU-PERK-A10K)) detects phosphorylated extracellular signal-regulated kinase (p-ERK). Take 10 μl of the above lysate to a 384-well plate (Perkin Elmer, 6005350), and detect the phosphorylation level of extracellular signal-regulated kinase in the sample according to the product instructions. Signals were read using an AlphaScreen detector on a Spectra max i3 (Molecular Devices). The percent inhibition (%) was calculated by the following formula:
抑制百分率(％)＝(1-化合物处理细胞的p-ERK信号/DMSO处理细胞的p-ERK信号)*100Inhibition percentage (%)=(1-p-ERK signal of compound-treated cells/p-ERK signal of DMSO-treated cells)*100
结果显示了本发明部分化合物具有较好的IC 50值。 The results show that some compounds of the present invention have better IC 50 values.
Figure PCTCN2021126331-appb-000461
Figure PCTCN2021126331-appb-000461
Figure PCTCN2021126331-appb-000462
Figure PCTCN2021126331-appb-000462
Figure PCTCN2021126331-appb-000463
Figure PCTCN2021126331-appb-000463
Figure PCTCN2021126331-appb-000464
Figure PCTCN2021126331-appb-000464
Figure PCTCN2021126331-appb-000465
Figure PCTCN2021126331-appb-000465
Figure PCTCN2021126331-appb-000466
Figure PCTCN2021126331-appb-000466
Figure PCTCN2021126331-appb-000467
Figure PCTCN2021126331-appb-000467
Figure PCTCN2021126331-appb-000468
Figure PCTCN2021126331-appb-000468
测试实施例3：MV4-11细胞增殖实验Test Example 3: MV4-11 Cell Proliferation Experiment
悬浮于培养基(RPMI-1640，含10％FBS和1％Penicillin-Streptomycin,Gibco)中的MV4-11细胞以3000个细胞(97μL/孔)接种到96孔板上。细胞立即用待测化合物进行处理，化合物浓度分别为10MV4-11 cells suspended in medium (RPMI-1640 with 10% FBS and 1% Penicillin-Streptomycin, Gibco) were seeded at 3000 cells (97 μL/well) on a 96-well plate. Cells were immediately treated with test compounds at concentrations of 10
.0，3.33，1.11，0.37，0.12，0.041，0.013，0.00457，0.001524μΜ。5天后，每孔加入40μL的CellTiter-Glo试剂(Promega,ZG7572)，室温避光放置10分钟。通过Spectra max i3(Molecular Devices)检测荧光信号。处理细胞的相对生长率与DMSO对照进行比较。.0, 3.33, 1.11, 0.37, 0.12, 0.041, 0.013, 0.00457, 0.001524 μM. After 5 days, 40 μL of CellTiter-Glo reagent (Promega, ZG7572) was added to each well, and it was placed at room temperature for 10 minutes in the dark. Fluorescence signal was detected by Spectra max i3 (Molecular Devices). Relative growth rates of treated cells were compared to DMSO controls.
结果显示了本发明部分化合物具有较好的IC 50值。 The results show that some compounds of the present invention have better IC 50 values.
Figure PCTCN2021126331-appb-000469
Figure PCTCN2021126331-appb-000469
Figure PCTCN2021126331-appb-000470
Figure PCTCN2021126331-appb-000470
Figure PCTCN2021126331-appb-000471
Figure PCTCN2021126331-appb-000471
Figure PCTCN2021126331-appb-000472
Figure PCTCN2021126331-appb-000472
Figure PCTCN2021126331-appb-000473
Figure PCTCN2021126331-appb-000473
Figure PCTCN2021126331-appb-000474
Figure PCTCN2021126331-appb-000474
Figure PCTCN2021126331-appb-000475
Figure PCTCN2021126331-appb-000475
Figure PCTCN2021126331-appb-000476
Figure PCTCN2021126331-appb-000476
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (16)

  1. 一种如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；其特征在于，A nitrogen-containing fused heterocyclic compound as shown in formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt; it is characterized in that,
    Figure PCTCN2021126331-appb-100001
    Figure PCTCN2021126331-appb-100001
    其中，R 1为
    Figure PCTCN2021126331-appb-100002
    where R1 is
    Figure PCTCN2021126331-appb-100002
    其中，L 1为连接键、-O-或-S-； Wherein, L 1 is a connecting bond, -O- or -S-;
    环D为连接键、C 4-C 8环烷基、5-6元单环杂环基、8-10元双环杂环基、C 6-C 10芳基、5-10元杂芳基、5-10元杂环基并苯基、5-10元杂环基并5-6元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S和P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O和S； Ring D is a connecting bond, C 4 -C 8 cycloalkyl, 5-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, 5-10-membered heterocyclyl acyl group, 5-10-membered heterocyclyl group and 5-6 membered heteroaryl group; in the heterocyclyl group, it contains 1-3 heteroatoms selected from the following group: N, O, S and P; in the heteroaryl group, 1-3 heteroatoms are selected from the group consisting of N, O and S;
    n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
    R 1a独立地为卤素、氰基、羟基、C 1-C 6烷基、C 1-C 6烷基-O-、C 3-C 8环烷基、3-8元杂环基、-C(＝O)OR 1a2、-NHC(＝O)R 1a2、-NR 1a3R 1a5、5-10元杂芳基、被一个或多个R 1a1取代的C 3-C 8环烷基、被一个或多个R 1a4取代的3-8元杂环基、或者，被一个或多个R a取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； R 1a is independently halogen, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, -C (=O)OR 1a2 , -NHC(=O)R 1a2 , -NR 1a3 R 1a5 , 5-10 membered heteroaryl, C 3 -C 8 cycloalkyl substituted by one or more R 1a1 , by one 3-8-membered heterocyclic group substituted by or more R 1a4 , or, substituted by one or more R a : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-; when the substituent is When more than one, the same or different; the heterocyclic group contains 1-3 heteroatoms selected from the following group: N, O, S or P; the heteroaryl group contains 1-3 heteroatoms a heteroatom selected from the group consisting of N, O or S;
    R 1a1和R 1a4独立地为卤素、C 1-C 4烷基或氧代； R 1a1 and R 1a4 are independently halogen, C 1 -C 4 alkyl or oxo;
    R 1a2、R 1a3和R 1a5独立地为氢、C 1-C 4烷基、取代或未取代的烯基、酰胺、C 3-C 12单或多杂环、5-6元的芳基、5-6元杂芳基、被一个或多个卤素取代的5-6元芳基或被一个或多个卤素取代的5-6元杂芳基或
    Figure PCTCN2021126331-appb-100003
    所述的单或多杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S；     R 1a2 , R 1a3 and R 1a5 are independently hydrogen, C 1 -C 4 alkyl, substituted or unsubstituted alkenyl, amide, C 3 -C 12 mono- or polyheterocycle, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered aryl substituted with one or more halogens or 5-6 membered heteroaryl substituted with one or more halogens or
    Figure PCTCN2021126331-appb-100003
    In the described single or polyheterocyclic group, 1-3 heteroatoms selected from the following group are included: N, O, S or P; in the described heteroaryl group, 1-3 heteroatoms selected from the following group are included. Heteroatom: N, O or S;
    R a独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
    R c为H或C 1-C 4烷基； R c is H or C 1 -C 4 alkyl;
    X 1为CR 3，X 2为CR 3；或，X 1为N，X 2为CR 3；或，X 1为CR 3，X 2为N； X 1 is CR 3 , and X 2 is CR 3 ; or, X 1 is N, and X 2 is CR 3 ; or, X 1 is CR 3 , and X 2 is N;
    R 3独立地为氢、卤素、氨基、硝基、三氟甲基、C 3-C 8的环烷基、乙烯基或C 1-C 4烷基； R 3 is independently hydrogen, halogen, amino, nitro, trifluoromethyl, C 3 -C 8 cycloalkyl, vinyl or C 1 -C 4 alkyl;
    R 4独立地为氢、卤素、C 1-C 4烷基、氨基、硝基、三氟甲基、C 1-C 4含有羟基或氨基或卤素取代的烷基； R 4 is independently hydrogen, halogen, C 1 -C 4 alkyl, amino, nitro, trifluoromethyl, C 1 -C 4 containing hydroxy or amino or halogen substituted alkyl;
    R 2为
    Figure PCTCN2021126331-appb-100004
     R2 is
    Figure PCTCN2021126331-appb-100004
    o1、o2独立地为0、1或2；且o1+o2小于等于3；o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
    R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b独立地为氢、卤素、C 1-C 4烷基； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen, halogen, C 1 -C 4 alkyl;
    Y＝N或C；Y=N or C;
    当Y＝N时，R 7独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基取代的C 1-C 4烷基、氨基取代的3-12元环烷基；R 8不存在； When Y=N, R 7 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino substituted C 1 -C 4 alkyl, amino substituted 3-12 membered cycloalkyl; R 8 is absent;
    当Y＝C时，R 7、R 8独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基、C 1-C 4烷基取代氨基、C 1-C 4烷基-O-取代氨基-； When Y=C, R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino, C 1 -C 4 alkyl substituted amino, C 1 - C 4 alkyl-O-substituted amino-;
    或者，当Y＝C时，R 7和R 8与Y一起形成：
    Figure PCTCN2021126331-appb-100005
    Alternatively, when Y=C, R7 and R8 together with Y form:
    Figure PCTCN2021126331-appb-100005
    p、q独立地为0、1或2；且p+q小于等于3；p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
    R 9a、R 9b、R 10a、R 10b独立地为氢、氘、卤素、氨基、-NHR 9-1、C 1-C 4烷基； R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, halogen, amino, -NHR 9-1 , C 1 -C 4 alkyl;
    R 9-1为C 1-C 4烷基； R 9-1 is C 1 -C 4 alkyl;
    W为连接键、-C(R w) 2-、-O-、-S-或-NR w-； W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
    R w独立地为氢或C 1-C 4烷基； R w is independently hydrogen or C 1 -C 4 alkyl;
    环H独立地为不存在或为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O、或S； Ring H is independently absent or C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heteroaryl group; in the heterocyclic group, Contains 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, contains 1-3 heteroatoms selected from the following group: N, O, or S;
    当环H不存在时，Z 1为CR z1aR z1b或者O，Z 2为CR z2aR z2b或者O； When ring H does not exist, Z 1 is CR z1a R z1b or O, and Z 2 is CR z2a R z2b or O;
    当环H为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂环芳基时，Z 1为CR z1a或者N，Z 2为CR z2a或者N，
    Figure PCTCN2021126331-appb-100006
    为单键；或者Z 1为C且Z 2为C，
    Figure PCTCN2021126331-appb-100007
    为双键；     When ring H is C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heterocyclic aryl group, Z 1 is CR z1a or N, and Z 2 is CR z2a or N,
    Figure PCTCN2021126331-appb-100006
    is a single bond; or Z 1 is C and Z 2 is C,
    Figure PCTCN2021126331-appb-100007
    is a double bond;
    R z1a、R z1b、R z2a、R z2b独立地为氢原子、卤素、C 1-C 4烷基； R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
    r独立地为0、1、2、3或4；r is independently 0, 1, 2, 3, or 4;
    R 11独立地为卤素、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-，硝基、C 3-C 8的环烷基、3-7元杂环基、-(CH 2) iNR 11-1R 11-2、-C(＝O)N(R 11-3R 11-3)、
    Figure PCTCN2021126331-appb-100008
    被一个羟基取代的C 1-C 6烷基、未取代或被1-4个R b取代的C 6-C 10芳基、含有1-3个杂原子的5-6元的芳杂基，或者，被一个或 多个R b取代的：C 1-C 6烷基、C 1-C 6烷基-O-、或者，被一个或多个R 11-7取代的3-7元杂环基；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述5-6元的芳杂基中，选自1-3个选自下组的杂原子：N、O、S或P；     R 11 is independently halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, nitro, C 3 -C 8 cycloalkyl, 3-7 membered heterocycle group, -(CH 2 ) i NR 11-1 R 11-2 , -C(=O)N(R 11-3 R 11-3 ),
    Figure PCTCN2021126331-appb-100008
    C 1 -C 6 alkyl substituted with one hydroxyl group, C 6 -C 10 aryl group unsubstituted or substituted with 1-4 R b , 5-6 membered heteroaryl group containing 1-3 heteroatoms, Alternatively, substituted with one or more R b : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, or, 3-7 membered heterocycle substituted with one or more R 11-7 base; when there are multiple substituents, they are the same or different; the heterocyclic group contains 1-3 heteroatoms selected from the following group: N, O, S or P; the 5-6 membered In the heteroaryl group, 1-3 heteroatoms are selected from the following group: N, O, S or P;
    R 11-1和R 11-2独立地为H或C 1-C 4烷基； R 11-1 and R 11-2 are independently H or C 1 -C 4 alkyl;
    R 11-3独立地为H、C 1-C 4烷基或CD 3； R 11-3 is independently H, C 1 -C 4 alkyl or CD 3 ;
    R 11-4独立地为H或C 1-C 4烷基； R 11-4 is independently H or C 1 -C 4 alkyl;
    R 11-5和R 11-6独立地为H或C 1-C 4烷基； R 11-5 and R 11-6 are independently H or C 1 -C 4 alkyl;
    R 11-7独立地为卤素或氨基； R 11-7 is independently halogen or amino;
    i独立地为0、1、2、3或4；i is independently 0, 1, 2, 3, or 4;
    R b独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-。 R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
  2. 如权利要求1所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；其特征在于，The nitrogen-containing fused heterocyclic compound represented by formula I as claimed in claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt; it is characterized in that,
    Figure PCTCN2021126331-appb-100009
    为：
    Figure PCTCN2021126331-appb-100009
    for:
    Figure PCTCN2021126331-appb-100010
    Figure PCTCN2021126331-appb-100010
    其中，n1、n2和n3独立地为0、1、2、3或4，且n1+n2等于0、1、2、3、4、5或6；n1+n2+n3等于0、1、2、3、4、5或6；where n1, n2, and n3 are independently 0, 1, 2, 3, or 4, and n1+n2 equals 0, 1, 2, 3, 4, 5, or 6; n1+n2+n3 equals 0, 1, 2 , 3, 4, 5 or 6;
    环E为含有1至3个N原子的6元杂芳基；环F为含有1至4个N、S、O杂原子的5元杂芳基；G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms; Ring F is a 5-membered heteroaryl containing 1 to 4 N, S, O heteroatoms; G is independently C, C(=O) , N, S or O heteroatoms or groups; G' is independently a linkage, C, C(=O), N, S or O atoms or groups;
    例如，为
    Figure PCTCN2021126331-appb-100011
    n为0、1、2、3、4或5；R 1a独立地为卤素、C 1-C 6烷基、氨基；     For example, for
    Figure PCTCN2021126331-appb-100011
    n is 0, 1, 2, 3, 4 or 5; R 1a is independently halogen, C 1 -C 6 alkyl, amino;
    较佳地，为
    Figure PCTCN2021126331-appb-100012
    更佳地
    Figure PCTCN2021126331-appb-100013
    Preferably, for
    Figure PCTCN2021126331-appb-100012
    better
    Figure PCTCN2021126331-appb-100013
    和/或，L 1为-S-或-O-，又例如-S-， And/or, L 1 is -S- or -O-, for example -S-,
    和/或，R 1a独立地为卤素、氨基、C 1-C 6烷基、3-8元杂环烷基、-NHC(＝O)R 1a2、-NHR 1a3、5-10元杂芳基、被一个或多个R 1a4取代的3-8元杂环烷基或被一个或多个R a取代的：C 1-C 6烷基；例如卤素、氨基； and/or, R 1a is independently halogen, amino, C 1 -C 6 alkyl, 3-8 membered heterocycloalkyl, -NHC(=O)R 1a2 , -NHR 1a3 , 5-10 membered heteroaryl , 3-8-membered heterocycloalkyl substituted by one or more R 1a4 or substituted by one or more R a : C 1 -C 6 alkyl; such as halogen, amino;
    和/或，环D为连接键、C 6-C 10芳基、5-10元杂芳基或5-10元杂环基并5-6元杂芳基； And/or, Ring D is a bond, C 6 -C 10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl and 5-6 membered heteroaryl;
    和/或，R 3独立地为氢； and/or, R is independently hydrogen;
    和/或，R 4独立地为氢； and/or, R4 is independently hydrogen ;
    和/或，X 1为CR 3，X 2为CR 3； and/or, X 1 is CR 3 and X 2 is CR 3 ;
    和/或，n为0、1或2个；and/or, n is 0, 1 or 2;
    和/或，R 1a2独立地为5-6元芳基或被一个或多个卤素取代的5-6元芳基； and/or, R 1a2 is independently a 5-6 membered aryl group or a 5-6 membered aryl group substituted with one or more halogens;
    和/或，R 1a3和R 1a5独立地为H、C 1-C 4烷基、5-6元杂芳基或
    Figure PCTCN2021126331-appb-100014
    and/or, R 1a3 and R 1a5 are independently H, C 1 -C 4 alkyl, 5-6 membered heteroaryl or
    Figure PCTCN2021126331-appb-100014
    和/或，R 1a4独立地为氧代； and/or, R 1a4 is independently oxo;
    和/或，R a独立地为卤素； and/or, R is independently halogen ;
    和/或，o1为0或1；and/or, o1 is 0 or 1;
    和/或，o2为0或1；and/or, o2 is 0 or 1;
    和/或，p为1或2；and/or, p is 1 or 2;
    和/或，q为0或1；and/or, q is 0 or 1;
    和/或，R 9a和R 9b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基； And/or, among R 9a and R 9b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group;
    和/或，R 10a和R 10b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基； And/or, in R 10a and R 10b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group;
    和/或，W独立地为连接键、-C(R w) 2-、-O-、或-NR w-； and/or, W is independently a linkage, -C( Rw ) 2- , -O-, or -NRw- ;
    和/或，环H为苯基或5-6元杂芳基；例如苯基；And/or, Ring H is phenyl or 5-6 membered heteroaryl; for example, phenyl;
    和/或，环H不存在时，Z 1为CR z1aR z1b，Z 2为O；或者，Z 1为O，Z 2为CR z2aR z2b； And/or, when ring H does not exist, Z 1 is CR z1a R z1b , and Z 2 is O; or, Z 1 is O, and Z 2 is CR z2a R z2b ;
    和/或，R z1a和R z1b中，或者，R z2a和R z2b中，一个为氢，另一个为氢或C 1-C 4烷基； and/or, in R z1a and R z1b , or, in R z2a and R z2b , one is hydrogen and the other is hydrogen or C 1 -C 4 alkyl;
    和/或，r独立地为0或1；例如0；and/or, r is independently 0 or 1; eg, 0;
    和/或，R 11独立地为卤素、氰基、C 1-C 6烷基、C 1-C 6烷基-O-、C 3-C 8的环烷基、3-7元杂环基、- (CH 2) qNR 11-1R 11-2、-C(＝O)N(R 11-3R 11-3)、
    Figure PCTCN2021126331-appb-100015
    被一个羟基取代的C 1-C 6烷基、C 6-C 10芳基、被一个或多个R b取代的C 1-C 6烷基、被一个或多个R 11-7取代的3-7元杂环基；     And/or, R 11 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, 3-7 membered heterocyclyl , -(CH 2 ) q NR 11-1 R 11-2 , -C(=O)N(R 11-3 R 11-3 ),
    Figure PCTCN2021126331-appb-100015
    C 1 -C 6 alkyl substituted with one hydroxy, C 6 -C 10 aryl, C 1 -C 6 alkyl substituted with one or more R b , 3 substituted with one or more R 11-7 -7-membered heterocyclyl;
    和/或，R 2为
    Figure PCTCN2021126331-appb-100016
    Y＝C，R 7和R 8与Y一起形成：
    Figure PCTCN2021126331-appb-100017
    and/or, R2 is
    Figure PCTCN2021126331-appb-100016
    Y=C, R7 and R8 together with Y form:
    Figure PCTCN2021126331-appb-100017
    和/或，
    Figure PCTCN2021126331-appb-100018
    为
    Figure PCTCN2021126331-appb-100019
    p’为0或1；q为0、1或2；且p’+q小于等于2；例如W为连接键；再例如W为连接键，p’为0，q为1；     and / or,
    Figure PCTCN2021126331-appb-100018
    for
    Figure PCTCN2021126331-appb-100019
    p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2; for example, W is a connecting bond; for example, W is a connecting bond, p' is 0, and q is 1;
    和/或，
    Figure PCTCN2021126331-appb-100020
    为
    Figure PCTCN2021126331-appb-100021
    其中，p’为0；q为0；W为-NR w-；     and / or,
    Figure PCTCN2021126331-appb-100020
    for
    Figure PCTCN2021126331-appb-100021
    Among them, p' is 0; q is 0; W is -NR w -;
    和/或，
    Figure PCTCN2021126331-appb-100022
    为
    Figure PCTCN2021126331-appb-100023
    其中，p’为0；q为0；W为-O-；即
    Figure PCTCN2021126331-appb-100024
    and / or,
    Figure PCTCN2021126331-appb-100022
    for
    Figure PCTCN2021126331-appb-100023
    Among them, p' is 0; q is 0; W is -O-; namely
    Figure PCTCN2021126331-appb-100024
  3. 如权利要求1所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；其特征在于，The nitrogen-containing fused heterocyclic compound represented by formula I as claimed in claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt; it is characterized in that,
    当环D为5-10元杂芳基时，所述的5-10元杂芳基为含有1至3个N原子的6元杂芳基；例如吡啶，又例如
    Figure PCTCN2021126331-appb-100025
    When Ring D is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 6-membered heteroaryl group containing 1 to 3 N atoms; for example, pyridine, or for example
    Figure PCTCN2021126331-appb-100025
    和/或，当环D为5-10元杂芳基时，所述5-10元杂芳基为含有1至3个N原子的9-10元杂芳基， 例如为苯并吡唑基、苯并吡啶基，又例如为
    Figure PCTCN2021126331-appb-100026
    And/or, when Ring D is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 9-10-membered heteroaryl group containing 1 to 3 N atoms, such as benzopyrazolyl , benzopyridyl, another example is
    Figure PCTCN2021126331-appb-100026
    和/或，当环D为C 6-C 10芳基时，所述的C 6-C 10芳基为苯基或萘基；例如苯基或
    Figure PCTCN2021126331-appb-100027
    And/or, when ring D is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is phenyl or naphthyl; for example, phenyl or
    Figure PCTCN2021126331-appb-100027
    和/或，当环D为5-10元杂环基并5-6元杂芳基时，所述的5-10元杂环基并5-6元杂芳基为
    Figure PCTCN2021126331-appb-100028
    环E为含有1至3个N原子的6元杂芳基；G独立地为C、C(＝O)、N、S或O原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；例如，
    Figure PCTCN2021126331-appb-100029
    Figure PCTCN2021126331-appb-100030
    And/or, when Ring D is a 5-10-membered heterocyclic group and a 5-6-membered heteroaryl group, the 5-10-membered heterocyclic group and the 5-6-membered heteroaryl group are
    Figure PCTCN2021126331-appb-100028
    Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms; G is independently a C, C(=O), N, S or O atom or group; G' is independently a linkage, C, C (=O), N, S or O atom or group; for example,
    Figure PCTCN2021126331-appb-100029
    Figure PCTCN2021126331-appb-100030
    和/或，当R 1a独立地为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟； and/or, when R 1a is independently halogen, said halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine;
    和/或，当R 1a独立地为C 1-C 6烷基时，所述的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基； And/or, when R 1a is independently C 1 -C 6 alkyl, said C 1 -C 6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl;
    和/或，当R 1a独立地为3-8元杂环基时，所述3-8元杂环基独立地为3-5元杂环烷基，例如吡咯烷基，又例如为
    Figure PCTCN2021126331-appb-100031
    And/or, when R 1a is independently a 3-8-membered heterocyclic group, the 3-8-membered heterocyclic group is independently a 3-5-membered heterocycloalkyl, such as pyrrolidinyl, and another example is
    Figure PCTCN2021126331-appb-100031
    和/或，当R 1a独立地为被一个或多个R 1a4取代的3-8元杂环基时，所述被一个或多个R 1a4取代的3-8元杂环基为被一个或多个R 1a4取代的3-5元杂环烷基；例如为
    Figure PCTCN2021126331-appb-100032
    And/or, when R 1a is independently a 3-8 membered heterocyclyl substituted by one or more R 1a4 , the 3-8 membered heterocyclyl substituted by one or more R 1a4 is a 3-8 membered heterocyclyl substituted by one or more R 1a4 Multiple R 1a4 substituted 3-5 membered heterocycloalkyl; for example
    Figure PCTCN2021126331-appb-100032
    和/或，当R 1a独立地为-NHC(＝O)R 1a2时，所述-NHC(＝O)R 1a2独立地为
    Figure PCTCN2021126331-appb-100033
    Figure PCTCN2021126331-appb-100034
    and/or, when R 1a is independently -NHC(=O)R 1a2 , said -NHC(=O)R 1a2 is independently
    Figure PCTCN2021126331-appb-100033
    Figure PCTCN2021126331-appb-100034
    和/或，当R 1a独立地为-NR 1a3R 1a5时，所述-NR 1a3R 1a5为-NH 2、-NHCH 3、
    Figure PCTCN2021126331-appb-100035
    Figure PCTCN2021126331-appb-100036
    And/or, when R 1a is independently -NR 1a3 R 1a5 , the -NR 1a3 R 1a5 is -NH 2 , -NHCH 3 ,
    Figure PCTCN2021126331-appb-100035
    Figure PCTCN2021126331-appb-100036
    和/或，当R 1a独立地为5-10元杂芳基时，所述5-10元杂芳基独立地为吡嗪基、噁唑基或苯并噁唑基，例如为
    Figure PCTCN2021126331-appb-100037
    And/or, when R 1a is independently a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is independently pyrazinyl, oxazolyl or benzoxazolyl, such as
    Figure PCTCN2021126331-appb-100037
    和/或，当R 1a独立地为被一个或多个R a取代的C 1-C 6烷基时，所述被一个或多个R a取代的C 1-C 6烷基为-CF 3； and/or, when R 1a is independently C 1 -C 6 alkyl substituted with one or more R a, the C 1 -C 6 alkyl substituted with one or more R a is -CF 3 ;
    和/或，当R 1a1、R 1a4、R 1a2、R 1a3或R 1a5独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如为甲基或乙基； And/or, when R 1a1 , R 1a4 , R 1a2 , R 1a3 or R 1a5 are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl;
    和/或，当R 1a2、R 1a3和R 1a5独立地为5-6元的芳基时，所述5-6元的芳基为苯基； And/or, when R 1a2 , R 1a3 and R 1a5 are independently a 5-6 membered aryl group, the 5-6 membered aryl group is a phenyl group;
    和/或，当R 1a2、R 1a3和R 1a5独立地为5-6元杂芳基，所述5-6元杂芳基为
    Figure PCTCN2021126331-appb-100038
    and/or, when R 1a2 , R 1a3 and R 1a5 are independently 5-6 membered heteroaryl, the 5-6 membered heteroaryl is
    Figure PCTCN2021126331-appb-100038
    和/或，当R 1a2、R 1a3和R 1a5独立地为被一个或多个卤素取代的5-6元芳基，所述一个或多个卤素取代的5-6元芳基为
    Figure PCTCN2021126331-appb-100039
    and/or, when R 1a2 , R 1a3 and R 1a5 are independently 5-6 membered aryl substituted with one or more halogens, the one or more halogen substituted 5-6 membered aryls are
    Figure PCTCN2021126331-appb-100039
    和/或，当R 1a2、R 1a3和R 1a5独立地为
    Figure PCTCN2021126331-appb-100040
    时，所述
    Figure PCTCN2021126331-appb-100041
    为
    Figure PCTCN2021126331-appb-100042
    and/or, when R 1a2 , R 1a3 and R 1a5 are independently
    Figure PCTCN2021126331-appb-100040
    when, the
    Figure PCTCN2021126331-appb-100041
    for
    Figure PCTCN2021126331-appb-100042
    和/或，当R a独立地为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟； and/or, when Ra is independently halogen, said halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine;
    和/或，当R c独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如为甲基或乙基； And/or, when R c is independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl butyl, sec- or tert-butyl, for example methyl or ethyl;
    和/或，当环D为苯基或6元杂芳基时，R 1a独立地位于环D与L 1连接键的邻位、间位及对位， 例如当n为2时，位于相邻的邻位和对位； And/or, when Ring D is a phenyl or 6-membered heteroaryl group, R 1a is independently located at the ortho, meta and para positions of the bond between Ring D and L 1 , for example, when n is 2, it is located adjacent to ortho and para;
    和/或，n独立地为0、1、2；例如1或2；and/or, n is independently 0, 1, 2; eg, 1 or 2;
    和/或，当R 9a和R 9b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when R 9a and R 9b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl;
    和/或，当R 9a-1为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when R 9a-1 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl group, sec-butyl or tert-butyl; for example methyl;
    和/或，当R 10a和R 10b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when R 10a and R 10b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl;
    和/或，当R w为C 1-C 4烷基时，所述的C 1～C 4烷基例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基； And/or, when R w is C 1 -C 4 alkyl, said C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl;
    和/或，当环H独立地为5-6元杂芳基时，所述的5-6元杂芳基为1-2个N原子的6元杂芳基、1-3个选自N、O及S原子的5元杂芳基；所述的6元杂芳基可为吡啶基、吡嗪基，所述的5元杂芳基可为噻唑基；所述的6元杂芳基例如
    Figure PCTCN2021126331-appb-100043
    所述的5元杂芳基例如
    Figure PCTCN2021126331-appb-100044
    a表示稠合位置；     And/or, when Ring H is independently a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is a 6-membered heteroaryl group with 1-2 N atoms, 1-3 members selected from N , 5-membered heteroaryl of O and S atoms; the 6-membered heteroaryl can be pyridyl, pyrazinyl, the 5-membered heteroaryl can be thiazolyl; the 6-membered heteroaryl E.g
    Figure PCTCN2021126331-appb-100043
    The 5-membered heteroaryl group such as
    Figure PCTCN2021126331-appb-100044
    a represents the fused position;
    和/或，当环H为C 6-C 10芳基时，所述C 6-C 10芳基为苯基或萘基，例如苯基； and/or, when ring H is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is phenyl or naphthyl, such as phenyl;
    和/或，当R z1a、R z1b、R z2a、R z2b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基； And/or, when R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl;
    和/或，R 11独立地为卤素，所述的卤素为氯、氟；例如氯； And/or, R 11 is independently halogen, and the halogen is chlorine, fluorine; for example chlorine;
    和/或，当R 11独立地为C 1-C 6烷基时，所述的C 1-C 6烷基独立地为C 1～C 4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；再例如甲基； And/or, when R 11 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl;
    和/或，当R 11独立地为C 1-C 6烷基-O-时，所述的C 1-C 6烷基-O-独立地为C 1-C 4烷基-O-，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基；再例如甲氧基； And/or, when R 11 is independently C 1 -C 6 alkyl-O-, said C 1 -C 6 alkyl-O- is independently C 1 -C 4 alkyl-O-, for example Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; another example is methoxy;
    和/或，当R 11独立地为C 3-C 8的环烷基时，所述C 3-C 8的环烷基为C 3-C 5的环烷基，例如为环丙基、环丁基或环戊基； And/or, when R 11 is independently a C 3 -C 8 cycloalkyl group, the C 3 -C 8 cycloalkyl group is a C 3 -C 5 cycloalkyl group, such as cyclopropyl, cycloalkyl Butyl or cyclopentyl;
    和/或，当R 11独立地为3-7元杂环基时，所述3-7元杂环基为所述3-7元杂环烷基，例如
    Figure PCTCN2021126331-appb-100045
    and/or, when R 11 is independently a 3-7 membered heterocyclyl, the 3-7 membered heterocyclyl is the 3-7 membered heterocycloalkyl, eg
    Figure PCTCN2021126331-appb-100045
    和/或，当R 11独立地为-(CH 2) qNR 11-1R 11-2时，所述-(CH 2) qNR 11-1R 11-2为
    Figure PCTCN2021126331-appb-100046
    And/or, when R 11 is independently -(CH 2 ) q NR 11-1 R 11-2 , the -(CH 2 ) q NR 11-1 R 11-2 is
    Figure PCTCN2021126331-appb-100046
    和/或，当R 11独立地为-C(＝O)N(R 11-3R 11-3)时，所述-C(＝O)N(R 11-3R 11-3)为
    Figure PCTCN2021126331-appb-100047
    Figure PCTCN2021126331-appb-100048
    and/or, when R 11 is independently -C(=O)N(R 11-3 R 11-3 ), the -C(=O)N(R 11-3 R 11-3 ) is
    Figure PCTCN2021126331-appb-100047
    Figure PCTCN2021126331-appb-100048
    和/或，当R 11独立地为
    Figure PCTCN2021126331-appb-100049
    时，所述
    Figure PCTCN2021126331-appb-100050
    为
    Figure PCTCN2021126331-appb-100051
    and/or, when R 11 is independently
    Figure PCTCN2021126331-appb-100049
    when, the
    Figure PCTCN2021126331-appb-100050
    for
    Figure PCTCN2021126331-appb-100051
    和/或，当R 11独立地为
    Figure PCTCN2021126331-appb-100052
    时，所述
    Figure PCTCN2021126331-appb-100053
    为
    Figure PCTCN2021126331-appb-100054
    and/or, when R 11 is independently
    Figure PCTCN2021126331-appb-100052
    when, the
    Figure PCTCN2021126331-appb-100053
    for
    Figure PCTCN2021126331-appb-100054
    和/或，当R 11独立地为被一个羟基取代的C 1-C 6烷基，所述被一个羟基取代的C 1-C 6烷基中C 1-C 6烷基独立地为C 1～C 4烷基；例如
    Figure PCTCN2021126331-appb-100055
    And/or, when R 11 is independently C 1 -C 6 alkyl substituted with one hydroxy group, the C 1 -C 6 alkyl group in the C 1 -C 6 alkyl substituted with one hydroxy group is independently C 1 ~C 4 alkyl; for example
    Figure PCTCN2021126331-appb-100055
    和/或，当R 11独立地为未取代或被1-4个R b取代的C 6-C 10芳基时，所述C 6-C 10芳基为苯基； and/or, when R 11 is independently a C 6 -C 10 aryl group that is unsubstituted or substituted with 1-4 R b , the C 6 -C 10 aryl group is phenyl;
    和/或，当所述R 11-1和R 11-2独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when said R 11-1 and R 11-2 are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl;
    和/或，当所述R 11-3和R 11-4独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when said R 11-3 and R 11-4 are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl;
    和/或，当所述R 11-5和R 11-6独立地为C 1-C 4烷基时，所述C 1-C 4烷基独立地为例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when said R 11-5 and R 11-6 are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl is independently, for example, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl;
    和/或，当R 11-7独立地为卤素，所述的卤素为氟、氯或溴；例如氟或氯。 And/or, when R 11-7 is independently halogen, said halogen is fluorine, chlorine or bromine; eg, fluorine or chlorine.
  4. 如权利要求1所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；其特征在于，The nitrogen-containing fused heterocyclic compound represented by formula I as claimed in claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt; it is characterized in that,
    Figure PCTCN2021126331-appb-100056
    为
    Figure PCTCN2021126331-appb-100057
    Figure PCTCN2021126331-appb-100058
    Figure PCTCN2021126331-appb-100056
    for
    Figure PCTCN2021126331-appb-100057
    Figure PCTCN2021126331-appb-100058
    Figure PCTCN2021126331-appb-100059
    Figure PCTCN2021126331-appb-100060
    例如
    Figure PCTCN2021126331-appb-100061
    又例如
    Figure PCTCN2021126331-appb-100062
    Figure PCTCN2021126331-appb-100059
    Figure PCTCN2021126331-appb-100060
    E.g
    Figure PCTCN2021126331-appb-100061
    Another example
    Figure PCTCN2021126331-appb-100062
    和/或，R 1为
    Figure PCTCN2021126331-appb-100063
    Figure PCTCN2021126331-appb-100064
    and/or, R1 is
    Figure PCTCN2021126331-appb-100063
    Figure PCTCN2021126331-appb-100064
    和/或，
    Figure PCTCN2021126331-appb-100065
    为
    Figure PCTCN2021126331-appb-100066
    Figure PCTCN2021126331-appb-100067
    and / or,
    Figure PCTCN2021126331-appb-100065
    for
    Figure PCTCN2021126331-appb-100066
    Figure PCTCN2021126331-appb-100067
    Figure PCTCN2021126331-appb-100068
    Figure PCTCN2021126331-appb-100069
    例如
    Figure PCTCN2021126331-appb-100070
    Figure PCTCN2021126331-appb-100071
    表示对映体，即为S构型和R构型的混合物；
    Figure PCTCN2021126331-appb-100068
    Figure PCTCN2021126331-appb-100069
    E.g
    Figure PCTCN2021126331-appb-100070
    Figure PCTCN2021126331-appb-100071
    Represents an enantiomer, that is, a mixture of S configuration and R configuration;
    和/或，R 2为
    Figure PCTCN2021126331-appb-100072
    Figure PCTCN2021126331-appb-100073
    and/or, R2 is
    Figure PCTCN2021126331-appb-100072
    Figure PCTCN2021126331-appb-100073
    Figure PCTCN2021126331-appb-100074
    Figure PCTCN2021126331-appb-100074
    Figure PCTCN2021126331-appb-100075
    Figure PCTCN2021126331-appb-100076
    表示对映体，即为S构型和R构型的混合物。
    Figure PCTCN2021126331-appb-100075
    Figure PCTCN2021126331-appb-100076
    Indicates the enantiomer, which is a mixture of the S and R configurations.
  5. 如权利要求1所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；其特征在于，所述的如式I所示的含氮稠杂环类化合物中；其为以下方案1、方案2、方案3、方案4或方案5；The nitrogen-containing fused heterocyclic compound represented by formula I as claimed in claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt; Among the nitrogen-containing fused heterocyclic compounds shown in formula I; it is the following scheme 1, scheme 2, scheme 3, scheme 4 or scheme 5;
    方案1、所述的如式I所示的含氮稠杂环类化合物中：Scheme 1, in the nitrogen-containing fused heterocyclic compound shown in formula I:
    R 1为
    Figure PCTCN2021126331-appb-100077
     R1 is
    Figure PCTCN2021126331-appb-100077
    其中，L 1为连接键或-S-； Wherein, L 1 is a connecting key or -S-;
    环D为连接键、C 6-C 10芳基、5-10元杂芳基、5-10元杂环基并5-6元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S和P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O和S； Ring D is a connecting bond, a C 6 -C 10 aryl group, a 5-10-membered heteroaryl group, a 5-10-membered heterocyclic group, and a 5-6-membered heteroaryl group; among the heterocyclic groups, 1-3 a heteroatom selected from the following group: N, O, S and P; the heteroaryl group contains 1-3 heteroatoms selected from the following group: N, O and S;
    n为0、1或2；n is 0, 1 or 2;
    R 1a独立地为卤素、C 1-C 6烷基、3-8元杂环基、-C(＝O)OR 1a2、-NHC(＝O)R 1a2、-NR 1a3R 1a5、5-10元 杂芳基、被一个或多个R 1a4取代的3-8元杂环基、或者，被一个或多个R a取代的：C 1-C 6烷基；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； R 1a is independently halogen, C 1 -C 6 alkyl, 3-8 membered heterocyclyl, -C(=O)OR 1a2 , -NHC(=O)R 1a2 , -NR 1a3 R 1a5 , 5-10 Membered heteroaryl, 3-8 membered heterocyclyl substituted by one or more R 1a4 , or, substituted by one or more R a : C 1 -C 6 alkyl; when there are multiple substituents, The same or different; the heterocyclic group contains 1-3 heteroatoms selected from the following group: N, O, S or P; the heteroaryl group contains 1-3 heteroatoms selected from the following group heteroatom: N, O or S;
    R 1a4独立地为氧代(＝O)； R 1a4 is independently oxo (=O);
    R 1a2、R 1a3和R 1a5独立地为氢、5-6元的芳基、5-6元杂芳基、被一个或多个卤素取代的5-6元芳基或
    Figure PCTCN2021126331-appb-100078
    所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S；     R 1a2 , R 1a3 and R 1a5 are independently hydrogen, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered aryl substituted with one or more halogens, or
    Figure PCTCN2021126331-appb-100078
    In the described heteroaryl group, contains 1-3 heteroatoms selected from the following group: N, O or S;
    R a独立地为卤素； Ra is independently halogen;
    R c为H或C 1-C 4烷基； R c is H or C 1 -C 4 alkyl;
    X 1为CR 3，X 2为CR 3； X 1 is CR 3 , X 2 is CR 3 ;
    R 3独立地为氢、卤素、氨基或C 1-C 4烷基； R 3 is independently hydrogen, halogen, amino or C 1 -C 4 alkyl;
    R 4独立地为氢、卤素、氨基或C 1-C 4烷基； R 4 is independently hydrogen, halogen, amino, or C 1 -C 4 alkyl;
    R 2为
    Figure PCTCN2021126331-appb-100079
     R2 is
    Figure PCTCN2021126331-appb-100079
    o1、o2独立地为0、1或2；且o1+o2小于等于3；o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
    R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b独立地为氢； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen;
    Y＝N或C；Y=N or C;
    当Y＝C时，R 7和R 8与Y一起形成：
    Figure PCTCN2021126331-appb-100080
    When Y=C, R7 and R8 together with Y form:
    Figure PCTCN2021126331-appb-100080
    p、q独立地为0、1或2；且p+q小于等于3；p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
    R 9a、R 9b、R 10a、R 10b独立地为氢、氘、氨基或-NHR 9-1； R 9a , R 9b , R 10a , R 10b are independently hydrogen, deuterium, amino, or -NHR 9-1 ;
    R 9-1为C 1-C 4烷基； R 9-1 is C 1 -C 4 alkyl;
    W为连接键、-C(R w) 2-、-O-、-S-或-NR w-； W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
    R w独立地为氢或C 1-C 4烷基； R w is independently hydrogen or C 1 -C 4 alkyl;
    环H独立地为不存在或为C 6-C 10芳基、5-10元杂芳基；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O或S； Ring H is independently absent or a C 6 -C 10 aryl group, a 5-10 membered heteroaryl group; the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S;
    当环H不存在时，Z 1为CR z1aR z1b或者O，Z 2为CR z2aR z2b或者O； When ring H does not exist, Z 1 is CR z1a R z1b or O, and Z 2 is CR z2a R z2b or O;
    当环H为C 6-C 10芳基、5-10元杂芳基时，Z 1为C且Z 2为C，
    Figure PCTCN2021126331-appb-100081
    为双键；     When ring H is C 6 -C 10 aryl, 5-10 membered heteroaryl, Z 1 is C and Z 2 is C,
    Figure PCTCN2021126331-appb-100081
    is a double bond;
    R z1a、R z1b、R z2a、R z2b独立地为氢原子、卤素、C 1-C 4烷基； R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
    r独立地为0、1、2、3或4；r is independently 0, 1, 2, 3, or 4;
    R 11独立地为卤素、氰基、C 1-C 6烷基、C 1-C 6烷基-O-，C 3-C 8的环烷基、3-7元杂环基、-(CH 2) iNR 11- 1R 11-2、-C(＝O)N(R 11-3R 11-3)、
    Figure PCTCN2021126331-appb-100082
    被一个羟基取代的C 1-C 6烷基、未取代或被1-4个R b取代的C 6-C 10芳基，或者，被一个或多个R b取代的：C 1-C 6烷基、或者，被一个或多个R 11- 7取代的3-7元杂环基；当取代基为多个时，相同或不同；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述5-6元的芳杂基中，选自1-3个选自下组的杂原子：N、O、S或P；     R 11 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, 3-7 membered heterocyclyl, -(CH 2 ) i NR 11-1 R 11-2 , -C( = O)N(R 11-3 R 11-3 ),
    Figure PCTCN2021126331-appb-100082
    C 1 -C 6 alkyl substituted with one hydroxy, C 6 -C 10 aryl unsubstituted or substituted with 1-4 R b , or, substituted with one or more R b : C 1 -C 6 Alkyl, or 3-7 -membered heterocyclic group substituted by one or more R 11-7 ; when there are multiple substituents, they are the same or different; among the heterocyclic groups, 1-3 optional groups are included A heteroatom from the following group: N, O, S or P; in the 5-6-membered aromatic hetero group, 1-3 heteroatoms are selected from the following group: N, O, S or P;
    R 11-1和R 11-2独立地为H或C 1-C 4烷基； R 11-1 and R 11-2 are independently H or C 1 -C 4 alkyl;
    R 11-3独立地为H、C 1-C 4烷基或CD 3； R 11-3 is independently H, C 1 -C 4 alkyl or CD 3 ;
    R 11-4独立地为H或C 1-C 4烷基； R 11-4 is independently H or C 1 -C 4 alkyl;
    R 11-5和R 11-6独立地为H或C 1-C 4烷基； R 11-5 and R 11-6 are independently H or C 1 -C 4 alkyl;
    R 11-7独立地为卤素或氨基； R 11-7 is independently halogen or amino;
    i独立地为0、1、2、3或4；i is independently 0, 1, 2, 3, or 4;
    R b独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
    方案2、Scenario 2,
    所述的式I所示的含氮稠杂环类化合物为式为式I-2所示；The nitrogen-containing fused heterocyclic compound shown in the formula I is shown in the formula I-2;
    Figure PCTCN2021126331-appb-100083
    Figure PCTCN2021126331-appb-100083
    其中，L 1独立为连接键或S； Wherein, L 1 is independently a connecting key or S;
    n独立地为0、1、2、3、4、5或6；n is independently 0, 1, 2, 3, 4, 5, or 6;
    环D独立地为苯基、5-6元杂芳基或5-10元杂环基并5-6元杂芳基；Ring D is independently phenyl, 5-6 membered heteroaryl, or 5-10 membered heterocyclyl and 5-6 membered heteroaryl;
    R 1a独立地为卤素、C 1-C 6烷基、C 1-C 6烷基-O-、氨基、氰基、羟基，或者，被一个或多个R a取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同； R 1a is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, amino, cyano, hydroxy, or, substituted with one or more R a : C 1 -C 6 Alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different;
    R a独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
    环H选自苯基、5-6元杂芳基；Ring H is selected from phenyl, 5-6 membered heteroaryl;
    R 11独立地为选自氢原子、卤素、硝基、氰基、C 1-C 6烷基、C 1-C 6烷氧基； R 11 is independently selected from hydrogen atom, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
    r独立地选自0、1和2；r is independently selected from 0, 1 and 2;
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；The carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
    方案3、Option 3,
    Figure PCTCN2021126331-appb-100084
    为
    Figure PCTCN2021126331-appb-100085
    G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；
    Figure PCTCN2021126331-appb-100084
    for
    Figure PCTCN2021126331-appb-100085
    G is independently a C, C(=O), N, S or O heteroatom or group; G' is independently a linkage, C, C(=O), N, S or O atom or group;
    R 1a独立地为卤素、氨基或C 1-C 6烷基； R 1a is independently halogen, amino or C 1 -C 6 alkyl;
    n独立地为0、1、2或3；n is independently 0, 1, 2, or 3;
    环E为含有1至3个N原子的6元杂芳基；G独立地为C、C(＝O)、N、S或O原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；Ring E is a 6-membered heteroaryl group containing 1 to 3 N atoms; G is independently a C, C(=O), N, S or O atom or group; G' is independently a linkage, C, C (=O), N, S or O atom or group;
    L 1为连接键、-O-或-S-； L 1 is a connection key, -O- or -S-;
    X 1为CR 3，X 2为CR 3；或，X 1为N，X 2为CR 3； X 1 is CR 3 and X 2 is CR 3 ; or, X 1 is N and X 2 is CR 3 ;
    R 3和R 4独立地为氢； R3 and R4 are independently hydrogen ;
    R 2为
    Figure PCTCN2021126331-appb-100086
    Y＝C，R 7和R 8与Y一起形成：
    Figure PCTCN2021126331-appb-100087
     R2 is
    Figure PCTCN2021126331-appb-100086
    Y=C, R7 and R8 together with Y form:
    Figure PCTCN2021126331-appb-100087
    o1、o2独立地为0、1或2；o1, o2 are independently 0, 1 or 2;
    R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a和R 6b独立地为氢； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently hydrogen;
    q独立地为0、1或2；p’为0或1；q is independently 0, 1 or 2; p' is 0 or 1;
    R 9a、R 9b、R 10a和R 10b独立地为氢原子、氨基或C 1-C 4烷基； R 9a , R 9b , R 10a and R 10b are independently a hydrogen atom, an amino group or a C 1 -C 4 alkyl group;
    W独立地为连接键、-C(R w) 2-； W is independently a connecting bond, -C(R w ) 2 -;
    环H独立地为不存在或者苯基或5-6元杂芳基；Ring H is independently absent or phenyl or 5-6 membered heteroaryl;
    当环H不存在时，Z 1为CR z1aR z1b，Z 2为O，或者Z 1为O，Z 2为CR z2aR z2b； When ring H does not exist, Z 1 is CR z1a R z1b and Z 2 is O, or Z 1 is O and Z 2 is CR z2a R z2b ;
    R z1a、R z1b、R z2a、R z2b独立地为氢原子或C 1-C 4烷基；
    Figure PCTCN2021126331-appb-100088
    为单键；     R z1a , R z1b , R z2a , R z2b are independently a hydrogen atom or a C 1 -C 4 alkyl group;
    Figure PCTCN2021126331-appb-100088
    is a single key;
    当环H为苯基或5-6元杂芳基时；Z 1和Z 2独立地为C，
    Figure PCTCN2021126331-appb-100089
    为双键；     When ring H is phenyl or 5-6 membered heteroaryl; Z 1 and Z 2 are independently C,
    Figure PCTCN2021126331-appb-100089
    is a double bond;
    R 11独立地为氢原子、卤素、C 1-C 6的烷基； R 11 is independently a hydrogen atom, a halogen, a C 1 -C 6 alkyl group;
    r独立地为0、或2；r is independently 0, or 2;
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；The carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
    方案4、Option 4,
    L 1为连接键、-O-或-S-； L 1 is a connection key, -O- or -S-;
    Figure PCTCN2021126331-appb-100090
    为
    Figure PCTCN2021126331-appb-100091
    G独立地为C、C(＝O)、 N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；
    Figure PCTCN2021126331-appb-100090
    for
    Figure PCTCN2021126331-appb-100091
    G is independently a C, C(=O), N, S or O heteroatom or group; G' is independently a bond, C, C(=O), N, S or O atom or group;
    R 1a独立地为卤素、C 1-C 6烷基、氨基； R 1a is independently halogen, C 1 -C 6 alkyl, amino;
    环E为含有1至3个N原子的6元杂芳基；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms;
    n独立地为1或2；n is independently 1 or 2;
    X 1为CR 3，X 2为CR 3；R 3独立地为氢；R 4独立地为氢； X 1 is CR 3 , X 2 is CR 3 ; R 3 is independently hydrogen; R 4 is independently hydrogen;
    R 2为
    Figure PCTCN2021126331-appb-100092
     R2 is
    Figure PCTCN2021126331-appb-100092
    环H独立地为苯基或5-10元杂环芳基；Ring H is independently phenyl or 5-10 membered heterocyclic aryl;
    p’为0，q为1；或p’为1，q为0；p' is 0 and q is 1; or p' is 1 and q is 0;
    R 9a为氢原子或C 1-C 4烷基； R 9a is a hydrogen atom or a C 1 -C 4 alkyl group;
    r独立地为0或1；r is independently 0 or 1;
    R 11独立地为C 1-C 4烷基； R 11 is independently C 1 -C 4 alkyl;
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；The carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
    方案5、Option 5.
    L 1为连接键、-S-； L 1 is the connection key, -S-;
    Figure PCTCN2021126331-appb-100093
    为
    Figure PCTCN2021126331-appb-100094
    G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；
    Figure PCTCN2021126331-appb-100093
    for
    Figure PCTCN2021126331-appb-100094
    G is independently a C, C(=O), N, S or O heteroatom or group; G' is independently a linkage, C, C(=O), N, S or O atom or group;
    R 1a独立地为卤素、C 1-C 6烷基、氨基； R 1a is independently halogen, C 1 -C 6 alkyl, amino;
    环E为含有1至3个N原子的6元杂芳基；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms;
    n独立地为1或2；n is independently 1 or 2;
    X 1为CR 3，X 2为CR 3；R 3独立地为氢；R 4独立地为氢； X 1 is CR 3 , X 2 is CR 3 ; R 3 is independently hydrogen; R 4 is independently hydrogen;
    R 2为
    Figure PCTCN2021126331-appb-100095
     R2 is
    Figure PCTCN2021126331-appb-100095
    环H独立地为苯基或5-10元杂环芳基；Ring H is independently phenyl or 5-10 membered heterocyclic aryl;
    p’为0，q为1；p' is 0, q is 1;
    r独立地为0；r is independently 0;
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  6. 如权利要求1所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药 学上可接受的盐；其特征在于，The nitrogen-containing fused heterocyclic compound shown in formula I as claimed in claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt; It is characterized in that,
    Figure PCTCN2021126331-appb-100096
    Figure PCTCN2021126331-appb-100096
    其中，R 1为
    Figure PCTCN2021126331-appb-100097
    where R1 is
    Figure PCTCN2021126331-appb-100097
    其中，L 1为连接键、-O-或-S-； Wherein, L 1 is a connecting bond, -O- or -S-;
    环D为C 4-C 8环烷基、5-6元单环杂环基、8-10元双环杂环基、C 6-C 10芳基、5-10元杂芳基、5-10元杂环基并苯基、5-10元杂环基并5-6元杂芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O、或S； Ring D is C 4 -C 8 cycloalkyl, 5-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl acyl group, 5-10 membered heterocyclyl group and 5-6 membered heteroaryl group; the heterocyclyl group contains 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, it contains 1-3 heteroatoms selected from the group consisting of N, O, or S;
    n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
    R 1a独立地为卤素、氨基、氰基、羟基、C 1-C 6烷基、C 1-C 6烷基-O-、C 3-C 8环烷基、-C(＝O)OR 1a2、-NHC(＝O)R 1a2、被一个或多个R 1a1取代的C 3-C 8环烷基，或者，被一个或多个R a取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同； R 1a is independently halogen, amino, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 3 -C 8 cycloalkyl, -C(=O)OR 1a2 , -NHC(=O)R 1a2 , C 3 -C 8 cycloalkyl substituted with one or more R 1a1 , or, substituted with one or more R a : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different;
    R 1a1独立的为卤素或C 1-C 4烷基； R 1a1 is independently halogen or C 1 -C 4 alkyl;
    R 1a2独立的为氢、C 1-C 4烷基、取代或未取代的烯基、酰胺、C 3-C 12单或多杂环；5-6元的芳基或杂芳基； R 1a2 is independently hydrogen, C 1 -C 4 alkyl, substituted or unsubstituted alkenyl, amide, C 3 -C 12 single or polyheterocycle; 5-6 membered aryl or heteroaryl;
    R a独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-； R a is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-;
    X 1为CR 3，X 2为CR 3；或，X 1为N，X 2为CR 3；或，X 1为CR 3，X 2为N； X 1 is CR 3 , and X 2 is CR 3 ; or, X 1 is N, and X 2 is CR 3 ; or, X 1 is CR 3 , and X 2 is N;
    R 3独立地为氢、卤素、氨基、硝基、三氟甲基、C 3-C 8的环烷基、乙烯基或C 1-C 4烷基； R 3 is independently hydrogen, halogen, amino, nitro, trifluoromethyl, C 3 -C 8 cycloalkyl, vinyl or C 1 -C 4 alkyl;
    R 4独立地为氢、卤素、C 1-C 4烷基、氨基、硝基、三氟甲基、C 1-C 4含有羟基或氨基或卤素取代的烷基； R 4 is independently hydrogen, halogen, C 1 -C 4 alkyl, amino, nitro, trifluoromethyl, C 1 -C 4 containing hydroxy or amino or halogen substituted alkyl;
    R 2为
    Figure PCTCN2021126331-appb-100098
     R2 is
    Figure PCTCN2021126331-appb-100098
    o1、o2独立地为0、1或2；且o1+o2小于等于3；o1 and o2 are independently 0, 1 or 2; and o1+o2 is less than or equal to 3;
    R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b独立地为氢、卤素、C 1-C 4烷基； R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently hydrogen, halogen, C 1 -C 4 alkyl;
    当Y＝N时，R 7独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基取代的C 1-C 4烷基、氨基取代的3-12元环烷基；R 8不存在； When Y=N, R 7 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino substituted C 1 -C 4 alkyl, amino substituted 3-12 membered cycloalkyl; R 8 is absent;
    当Y＝C时，R 7、R 8独立地为氢、C 1-C 4烷基、C 1-C 4烷基-O-、氨基、C 1-C 4烷基取代氨基、C 1-C 4 烷基-O-取代氨基-； When Y=C, R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-, amino, C 1 -C 4 alkyl substituted amino, C 1 - C 4 alkyl-O-substituted amino-;
    或者当Y＝C时，R 7和R 8与Y一起形成：
    Figure PCTCN2021126331-appb-100099
    Or when Y=C, R7 and R8 together with Y form:
    Figure PCTCN2021126331-appb-100099
    p、q独立地为0、1或2；且p+q小于等于3；p, q are independently 0, 1 or 2; and p+q is less than or equal to 3;
    R 9a、R 9b、R 10a、R 10b独立地为氢、卤素、氨基、C 1-C 4烷基； R 9a , R 9b , R 10a , R 10b are independently hydrogen, halogen, amino, C 1 -C 4 alkyl;
    W为连接键、-C(R w) 2-、-O-、-S-或-NR w-； W is a connecting bond, -C(R w ) 2 -, -O-, -S- or -NR w -;
    R w独立地为氢、C 1-C 4烷基； R w is independently hydrogen, C 1 -C 4 alkyl;
    环H独立地为不存在或为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂环芳基；所述的杂环基中，包含1-3个选自下组的杂原子：N、O、S或P；所述的杂芳基中，包含1-3个选自下组的杂原子：N、O、或S； Ring H is independently absent or C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl, 5-10-membered heterocyclic aryl; among the heterocyclic groups , containing 1-3 heteroatoms selected from the following group: N, O, S or P; in the heteroaryl group, containing 1-3 heteroatoms selected from the following group: N, O, or S;
    当环H不存在时，Z 1为CR z1aR z1b或者O，Z 2为CR z2aR z2b或者O； When ring H does not exist, Z 1 is CR z1a R z1b or O, and Z 2 is CR z2a R z2b or O;
    当环H为C 4-C 8环烷基、5-10元杂环基、C 6-C 10芳基、5-10元杂环芳基时，Z 1为CR z1a或者N，Z 2为CR z2a或者N，
    Figure PCTCN2021126331-appb-100100
    为单键；或者Z 1为C且Z 2为C，
    Figure PCTCN2021126331-appb-100101
    为双键；     When ring H is C 4 -C 8 cycloalkyl, 5-10-membered heterocyclic group, C 6 -C 10 -membered aryl group, 5-10-membered heterocyclic aryl group, Z 1 is CR z1a or N, and Z 2 is CR z2a or N,
    Figure PCTCN2021126331-appb-100100
    is a single bond; or Z 1 is C and Z 2 is C,
    Figure PCTCN2021126331-appb-100101
    is a double bond;
    R z1a、R z1b、R z2a、R z2b独立地为氢原子、卤素、C 1-C 4烷基； R z1a , R z1b , R z2a , R z2b are independently hydrogen atom, halogen, C 1 -C 4 alkyl;
    r独立地为0、1、2、3或和4；r is independently 0, 1, 2, 3 or and 4;
    R 11独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-，硝基、C 3-C 8的环烷基、未取代或1-4个R b取代的芳基、含有1-3杂原子的5-6元的芳杂基，或者，被一个或多个R b取代的：C 1-C 6烷基、C 1-C 6烷基-O-；当取代基为多个时，相同或不同；所述5-6元的芳杂基中，选自1-3个选自下组的杂原子：N、O、S或P； R 11 is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, nitro, C 3 -C 8 cycloalkyl, unsubstituted or 1 -Aryl substituted with 4 R b , 5-6 membered heteroaryl group containing 1-3 heteroatoms, or, substituted with one or more R b : C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-; when there are multiple substituents, the same or different; in the 5-6-membered aromatic hetero group, 1-3 heteroatoms are selected from the following group: N, O, S or P;
    R b独立地为卤素、氨基、羟基、氰基、C 1-C 6烷基、C 1-C 6烷基-O-。 R b is independently halogen, amino, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-.
  7. 如权利要求6所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    Figure PCTCN2021126331-appb-100102
    为     The nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt as claimed in claim 6, characterized in that,
    Figure PCTCN2021126331-appb-100102
    for
    Figure PCTCN2021126331-appb-100103
    Figure PCTCN2021126331-appb-100103
    其中，n1和n2独立地为0、1、2、3或4，且n1+n2等于0、1、2、3、4、5或6；wherein n1 and n2 are independently 0, 1, 2, 3, or 4, and n1+n2 is equal to 0, 1, 2, 3, 4, 5, or 6;
    环E为含有1至3个N原子的6元杂芳基；环F为含有1至4个N、S、O杂原子的5元杂芳基；G独立地为C、C(＝O)、N、S或O杂原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；Ring E is a 6-membered heteroaryl containing 1 to 3 N atoms; Ring F is a 5-membered heteroaryl containing 1 to 4 N, S, O heteroatoms; G is independently C, C(=O) , N, S or O heteroatoms or groups; G' is independently a linkage, C, C(=O), N, S or O atoms or groups;
    和/或，L 1为-S-或-O-； and/or, L 1 is -S- or -O-;
    和/或，R 1a独立地为卤素、C 1-C 6烷基、氨基； and/or, R 1a is independently halogen, C 1 -C 6 alkyl, amino;
    和/或，R 3独立地为氢； and/or, R is independently hydrogen;
    和/或，R 4独立地为氢； and/or, R4 is independently hydrogen ;
    和/或，X 1为CR 3，X 2为CR 3； and/or, X 1 is CR 3 and X 2 is CR 3 ;
    和/或，R 3a、R 3b、R 4a、R 4b独立地为氢； and/or, R 3a , R 3b , R 4a , R 4b are independently hydrogen;
    和/或，R 5a、R 5b、R 6a和R 6b独立地为氢或C 1-C 6烷基； and/or, R 5a , R 5b , R 6a and R 6b are independently hydrogen or C 1 -C 6 alkyl;
    和/或，o1为1；and/or, o1 is 1;
    和/或，o2为1；and/or, o2 is 1;
    和/或，p为1或2；and/or, p is 1 or 2;
    和/或，q独立地为1；and/or, q is independently 1;
    和/或，R 9a和R 9b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基； And/or, among R 9a and R 9b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group;
    和/或，R 10a和R 10b中，一个为氢原子或C 1-C 4烷基，另一个为氢原子、C 1-C 4烷基或氨基； And/or, in R 10a and R 10b , one is a hydrogen atom or a C 1 -C 4 alkyl group, and the other is a hydrogen atom, a C 1 -C 4 alkyl group or an amino group;
    和/或，W独立地为连接键或-C(R w) 2-； and/or, W is independently a connecting bond or -C(R w ) 2 -;
    和/或，环H独立地为不存在或环H为苯基或5-6元杂芳基；and/or, Ring H is independently absent or Ring H is phenyl or 5-6 membered heteroaryl;
    和/或，当环H不存在时，Z 1为CR z1aR z1b，Z 2为O；或者，Z 1为O，Z 2为CR z2aR z2b； And/or, when ring H does not exist, Z 1 is CR z1a R z1b , and Z 2 is O; or, Z 1 is O, and Z 2 is CR z2a R z2b ;
    和/或，R z1a和R z1b中，或者，R z2a和R z2b中，一个为氢，另一个为氢或C 1-C 4烷基； and/or, in R z1a and R z1b , or, in R z2a and R z2b , one is hydrogen and the other is hydrogen or C 1 -C 4 alkyl;
    和/或，r独立地为0或1；and/or, r is independently 0 or 1;
    和/或，R 11独立地为氢原子、卤素、或C 1-C 6烷基； and/or, R 11 is independently a hydrogen atom, halogen, or C 1 -C 6 alkyl;
    和/或，R 2为
    Figure PCTCN2021126331-appb-100104
    Y＝C，R 7和R 8与Y一起形成：
    Figure PCTCN2021126331-appb-100105
    and/or, R2 is
    Figure PCTCN2021126331-appb-100104
    Y=C, R7 and R8 together with Y form:
    Figure PCTCN2021126331-appb-100105
    和/或，
    Figure PCTCN2021126331-appb-100106
    为
    Figure PCTCN2021126331-appb-100107
    p’为0或1；q为0、1或2；且p’+q小于等于2。     and / or,
    Figure PCTCN2021126331-appb-100106
    for
    Figure PCTCN2021126331-appb-100107
    p' is 0 or 1; q is 0, 1, or 2; and p'+q is less than or equal to 2.
  8. 如权利要求7所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，The nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt as claimed in claim 7, characterized in that,
    环D为C 6-C 10芳基、5-10元杂芳基、或5-10元杂环基并5-6元杂芳基； Ring D is C 6 -C 10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl and 5-6 membered heteroaryl;
    和/或，L 1为-S-； and/or, L 1 is -S-;
    和/或，R 2为
    Figure PCTCN2021126331-appb-100108
    环H为不存在或为苯基或5-6元杂芳基；p’为0或1；q为0、1或2；且p’+q小于等于2；例如，当环H为不存在时，R 2为
    Figure PCTCN2021126331-appb-100109
    q为1或2；例如
    Figure PCTCN2021126331-appb-100110
    当环H为苯基或5-6元杂芳基时，R 2为
    Figure PCTCN2021126331-appb-100111
    and/or, R2 is
    Figure PCTCN2021126331-appb-100108
    Ring H is absent or is phenyl or 5-6 membered heteroaryl; p' is 0 or 1; q is 0, 1 or 2; and p'+q is less than or equal to 2; for example, when Ring H is absent , R 2 is
    Figure PCTCN2021126331-appb-100109
    q is 1 or 2; for example
    Figure PCTCN2021126331-appb-100110
    When ring H is phenyl or 5-6 membered heteroaryl, R 2 is
    Figure PCTCN2021126331-appb-100111
    和/或，R 9a和R 9b独立地为氢； and/or, R 9a and R 9b are independently hydrogen;
    和/或，R 10a和R 10b独立地为氢； and/or, R 10a and R 10b are independently hydrogen;
    和/或，R z1a、R z1b、R z2a、R z2b独立地为氢原子； and/or, R z1a , R z1b , R z2a , R z2b are independently hydrogen atoms;
    和/或，r独立地为0。and/or, r is independently zero.
  9. 如权利要求6所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，The nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt as claimed in claim 6, characterized in that,
    当环D为5-10元杂芳基时，所述的5-10元杂芳基为含有1至3个N原子的6元杂芳基；例如吡啶，又例如
    Figure PCTCN2021126331-appb-100112
    When Ring D is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 6-membered heteroaryl group containing 1 to 3 N atoms; for example, pyridine, or for example
    Figure PCTCN2021126331-appb-100112
    和/或，当环D为C 6-C 10芳基时，所述的C 6-C 10芳基为苯基或萘基；例如苯基； And/or, when Ring D is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is a phenyl group or a naphthyl group; for example, a phenyl group;
    和/或，当环D为5-10元杂环基并5-6元杂芳基时，所述的5-10元杂环基并5-6元杂芳基为
    Figure PCTCN2021126331-appb-100113
    G独立地为C、C(＝O)、N、S或O原子或基团；G’独立地为连接键、C、C(＝O)、N、S或O原子或基团；例如，
    Figure PCTCN2021126331-appb-100114
    And/or, when Ring D is a 5-10-membered heterocyclic group and a 5-6-membered heteroaryl group, the 5-10-membered heterocyclic group and the 5-6-membered heteroaryl group are
    Figure PCTCN2021126331-appb-100113
    G is independently a C, C(=O), N, S or O atom or group; G' is independently a bond, C, C(=O), N, S or O atom or group; for example,
    Figure PCTCN2021126331-appb-100114
    和/或，当R 1a独立地为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟； and/or, when R 1a is independently halogen, said halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine;
    和/或，当R 1a独立地为C 1-C 6烷基时，所述的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基； And/or, when R 1a is independently C 1 -C 6 alkyl, said C 1 -C 6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl;
    和/或，当环D为苯基或6元杂芳基时，R 1a独立地位于环D与L 1连接键的邻位、间位及对位，例如当n为2时，位于相邻的邻位和对位； And/or, when Ring D is a phenyl or 6-membered heteroaryl group, R 1a is independently located in the ortho, meta and para positions of the bond between Ring D and L 1 , for example, when n is 2, in the adjacent ortho and para;
    和/或，n独立地为0、1、2；例如1或2；and/or, n is independently 0, 1, 2; eg, 1 or 2;
    和/或，当R 9a和R 9b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when R 9a and R 9b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl;
    和/或，当R 10a和R 10b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基； And/or, when R 10a and R 10b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl;
    和/或，当环H独立地为5-6元杂芳基时，所述的5-6元杂芳基为1-2个N原子的6元杂芳基、1-3个选自N、O及S原子的5元杂芳基；所述的6元杂芳基可为吡啶基、吡嗪基，所述的5元杂芳基可为噻唑基；所述的6元杂芳基例如
    Figure PCTCN2021126331-appb-100115
    所述的5元杂芳基例如
    Figure PCTCN2021126331-appb-100116
    a表示稠合位置；     And/or, when Ring H is independently a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is a 6-membered heteroaryl group with 1-2 N atoms, 1-3 members selected from N , 5-membered heteroaryl of O and S atoms; the 6-membered heteroaryl can be pyridyl, pyrazinyl, the 5-membered heteroaryl can be thiazolyl; the 6-membered heteroaryl E.g
    Figure PCTCN2021126331-appb-100115
    The 5-membered heteroaryl group such as
    Figure PCTCN2021126331-appb-100116
    a represents the fused position;
    和/或，当R z1a、R z1b、R z2a、R z2b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基； And/or, when R z1a , R z1b , R z2a and R z2b are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl;
    和/或，R 11独立地为卤素，所述的卤素为氯、氟；例如氯。 And/or, R 11 is independently halogen, said halogen being chlorine, fluorine; eg chlorine.
  10. 如权利要求6所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，The nitrogen-containing fused heterocyclic compound represented by formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt as claimed in claim 6, characterized in that,
    Figure PCTCN2021126331-appb-100117
    为
    Figure PCTCN2021126331-appb-100118
    例如
    Figure PCTCN2021126331-appb-100119
    又例如
    Figure PCTCN2021126331-appb-100120
    Figure PCTCN2021126331-appb-100117
    for
    Figure PCTCN2021126331-appb-100118
    E.g
    Figure PCTCN2021126331-appb-100119
    Another example
    Figure PCTCN2021126331-appb-100120
    和/或，R 2为
    Figure PCTCN2021126331-appb-100121
    and/or, R2 is
    Figure PCTCN2021126331-appb-100121
    和/或，
    Figure PCTCN2021126331-appb-100122
    为
    Figure PCTCN2021126331-appb-100123
    Figure PCTCN2021126331-appb-100124
    例如
    Figure PCTCN2021126331-appb-100125
    表示对映体。     and / or,
    Figure PCTCN2021126331-appb-100122
    for
    Figure PCTCN2021126331-appb-100123
    Figure PCTCN2021126331-appb-100124
    E.g
    Figure PCTCN2021126331-appb-100125
    represents the enantiomer.
  11. 如权利要求1所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐；其特征在于，所述的式I所示的含氮稠杂环类化合物为如下化合物；The nitrogen-containing fused heterocyclic compound represented by formula I as claimed in claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt; characterized in that said formula The nitrogen-containing fused heterocyclic compounds shown in I are the following compounds;
    Figure PCTCN2021126331-appb-100126
    Figure PCTCN2021126331-appb-100126
    Figure PCTCN2021126331-appb-100127
    Figure PCTCN2021126331-appb-100127
    Figure PCTCN2021126331-appb-100128
    Figure PCTCN2021126331-appb-100128
    Figure PCTCN2021126331-appb-100129
    Figure PCTCN2021126331-appb-100129
    Figure PCTCN2021126331-appb-100130
    Figure PCTCN2021126331-appb-100130
    Figure PCTCN2021126331-appb-100131
    Figure PCTCN2021126331-appb-100131
    Figure PCTCN2021126331-appb-100132
    Figure PCTCN2021126331-appb-100132
  12. 如权利要求1-11中任一项所述的如式I所示的含氮稠杂环类化合物的制备方法，其特征在于，其为如下方案1、方案2、方案3、方案4；The preparation method of the nitrogen-containing fused heterocyclic compound represented by formula I according to any one of claims 1-11, characterized in that, it is the following scheme 1, scheme 2, scheme 3, scheme 4;
    方案1、当式I化合物为通式I’所示化合物时，其包括如下步骤：在酸性条件下，将如式II’所示的化合物进行脱除保护基反应，得到如式I’所示的化合物即可；Scheme 1. When the compound of formula I is a compound represented by general formula I', it includes the following steps: under acidic conditions, the compound represented by formula II' is subjected to a deprotection reaction to obtain a compound represented by formula I' The compound can be;
    Figure PCTCN2021126331-appb-100133
    Figure PCTCN2021126331-appb-100133
    其中，Pg选自保护基Boc、Ac、S(＝O) tBu；环H、R 1、X 1、X 2、R 4、W、Z 1、Z 2、o1、o2、p’、q、r、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b、R 9a、R 9b、R 10a、R 10b、R 11、*和
    Figure PCTCN2021126331-appb-100134
    的定义如权利要求1-11中任一项所述；     wherein, Pg is selected from protecting groups Boc, Ac, S(=O) t Bu; ring H, R 1 , X 1 , X 2 , R 4 , W, Z 1 , Z 2 , o1 , o2 , p′, q , r, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 9a , R 9b , R 10a , R 10b , R 11 , * and
    Figure PCTCN2021126331-appb-100134
    is defined as described in any one of claims 1-11;
    方案2、当式I化合物为通式I-a所示化合物或者通式I-b所示化合物时，其包括如下步骤：Scheme 2. When the compound of formula I is a compound represented by general formula I-a or a compound represented by general formula I-b, it comprises the following steps:
    Figure PCTCN2021126331-appb-100135
    Figure PCTCN2021126331-appb-100135
    式I-1与式I-2所示硼酸进行偶联反应后得到式I-a、或者，式I-1与式I-3所示硫醇或硫钠进行偶联反应后得到式I-b；Formula I-1 and the boronic acid shown in formula I-2 are subjected to coupling reaction to obtain formula I-a, or, formula I-1 is subjected to coupling reaction with thiol or sodium sulfide shown in formula I-3 to obtain formula I-b;
    其中，W 1代表卤素或磺酰基，优选Br、I、或磺酰基；R为H或C 1-C 4烷基；X 1、X 2、环D、n、R 4、R 1a和R 2的定义如权利要求1-11中任一项所述； Wherein, W 1 represents halogen or sulfonyl, preferably Br, I, or sulfonyl; R is H or C 1 -C 4 alkyl; X 1 , X 2 , ring D, n, R 4 , R 1a and R 2 is defined as described in any one of claims 1-11;
    方案3、当式I化合物为通式III化合物时：Scheme 3. When the compound of formula I is a compound of general formula III:
    Figure PCTCN2021126331-appb-100136
    Figure PCTCN2021126331-appb-100136
    中间体III-1在碱性条件下被中间体胺III-2取代得到中间体化合物III-3，然后中间体III-3在与硼酸、硫醇或硫钠进行偶联反应后得到式III；Intermediate III-1 is substituted by intermediate amine III-2 under basic conditions to obtain intermediate compound III-3, and then intermediate III-3 is subjected to coupling reaction with boronic acid, thiol or sodium sulfide to obtain formula III;
    其中，W 1和W 2代表卤素或磺酰基，优选氯、Br、I或磺酰基；X 1、X 2、Y、L 1、环D、o1、n、R 5a、R 5b、R 6a、R 6b、R 7、R 8的定义如权利要求1-11中任一项所述； Wherein, W 1 and W 2 represent halogen or sulfonyl, preferably chlorine, Br, I or sulfonyl; X 1 , X 2 , Y, L 1 , ring D, o1 , n, R 5a , R 5b , R 6a , The definitions of R 6b , R 7 and R 8 are as described in any one of claims 1-11;
    方案4、当式I化合物为
    Figure PCTCN2021126331-appb-100137
    Figure PCTCN2021126331-appb-100138
    时，其包括如下步骤：     Scheme 4. When the compound of formula I is
    Figure PCTCN2021126331-appb-100137
    Figure PCTCN2021126331-appb-100138
    , it includes the following steps:
    将中间体C1和胺在碱性条件下，在合适的溶剂和反应温度下得到V-1-a1；V-1-a1 is obtained by subjecting intermediate C1 and amine under basic conditions, under suitable solvent and reaction temperature;
    将V-1-a1在碱性条件下，在催化剂存在下与I-2通过偶联反应得到V-1-a2，然后在酸性条件下脱去保护基Pg，得到V-1-a即可；V-1-a1 is coupled with I-2 under alkaline conditions to obtain V-1-a2, and then the protective group Pg is removed under acidic conditions to obtain V-1-a. ;
    或者，将V-1-a1与式I-3所示化合物在碱性条件下，在催化剂存在下通过偶联得到V-1-b2；然后在酸性条件下脱去保护基Pg，得到V-1-b即可；Alternatively, V-1-b2 can be obtained by coupling V-1-a1 with the compound represented by formula I-3 in the presence of a catalyst under basic conditions; and then removing the protecting group Pg under acidic conditions to obtain V- 1-b can be;
    Figure PCTCN2021126331-appb-100139
    Figure PCTCN2021126331-appb-100139
    其中，Pg为N保护基，优选Boc、Ac、S(＝O)tBu；W 1和W 2代表卤素或磺酰基，优选氯、Br、I或磺酰基；R为H或C 1-C 4烷基；环D、环H、n、r、R 1a和R 11的定义如权利要求1-11中任一项所述。 Wherein, Pg is an N protecting group, preferably Boc, Ac, S(=O)tBu; W 1 and W 2 represent halogen or sulfonyl, preferably chlorine, Br, I or sulfonyl; R is H or C 1 -C 4 Alkyl; Ring D, Ring H, n, r, R 1a and R 11 are as defined in any one of claims 1-11.
  13. 一种如式II’、III-3所示的化合物，A compound shown in formula II', III-3,
    Figure PCTCN2021126331-appb-100140
    Figure PCTCN2021126331-appb-100140
    其中，Pg选自保护基Boc、Ac、S(＝O) tBu；环H、R 1、X 1、X 2、R 4、W、W 1、Z 1、Z 2、o1、o2、p’、q、r、R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 6a、R 6b、R 9a、R 9b、R 10a、R 10b、R 11、R 7、R 8、*和
    Figure PCTCN2021126331-appb-100141
    的定义如权利要求1-11中任一项所述；     wherein, Pg is selected from protecting groups Boc, Ac, S(=O) t Bu; ring H, R 1 , X 1 , X 2 , R 4 , W, W 1 , Z 1 , Z 2 , o1 , o2 , p ', q, r, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 9a , R 9b , R 10a , R 10b , R 11 , R 7 , R 8 ,*and
    Figure PCTCN2021126331-appb-100141
    is defined as described in any one of claims 1-11;
    例如，如式II’所示的化合物选自如下化合物：For example, the compound of formula II' is selected from the following compounds:
    Figure PCTCN2021126331-appb-100142
    Figure PCTCN2021126331-appb-100142
    Figure PCTCN2021126331-appb-100143
    Figure PCTCN2021126331-appb-100143
  14. 一种
    Figure PCTCN2021126331-appb-100144
    C1的合成方法，其包括如下步骤：     A sort of
    Figure PCTCN2021126331-appb-100144
    The synthetic method of C1, it comprises the steps:
    将2-氯氨基嘧啶类化合物C1-0与关环试剂在溶剂中室温或加热的条件下得到C1-1中间体；将C1-1中间体与氨的水溶液或醇溶液室温或加热的条件下得到C1-2中间体；将C1-2在碱性条件下室温或加热得C1-3；将C1-3转化成C1；The C1-1 intermediate is obtained by combining 2-chloroaminopyrimidine compound C1-0 with a ring-closing reagent in a solvent at room temperature or under heating conditions; the C1-1 intermediate and an aqueous or alcoholic solution of ammonia are obtained at room temperature or under heating conditions Obtain C1-2 intermediate; C1-2 is obtained under basic conditions at room temperature or heated to C1-3; C1-3 is converted into C1;
    Figure PCTCN2021126331-appb-100145
    Figure PCTCN2021126331-appb-100145
    其中，W 1、W 2定义权利要求12所述。 Wherein, W 1 and W 2 define what is described in claim 12 .
  15. 一种药物组合物，其包含如权利要求1-11中任一项所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐、以及药学上可接受的辅料。A pharmaceutical composition comprising the nitrogen-containing condensed heterocyclic compound shown in formula I as described in any one of claims 1-11, its stereoisomer, its tautomer or its pharmacy acceptable salts, and pharmaceutically acceptable excipients.
  16. 一种如权利要求1-11中任一项所述的如式I所示的含氮稠杂环类化合物、其立体异构体、其互变异构体或其药学上可接受的盐或如权利要求15所述的药物组合物用于制备药物方面的用途；所述药物可为治疗与SHP2活性异常相关疾病或病症的药物；所述疾病或病症包括但不局限于包括努南综合症、豹综合症、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤 或成胶质细胞瘤。A nitrogen-containing fused heterocyclic compound shown in formula I as described in any one of claims 1-11, its stereoisomer, its tautomer or its pharmaceutically acceptable salt or Use of the pharmaceutical composition as claimed in claim 15 for the preparation of a medicament; the medicament can be a medicament for treating a disease or condition related to abnormal SHP2 activity; the disease or condition includes but is not limited to including Noonan syndrome , Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck , gastric cancer, anaplastic large cell lymphoma or glioblastoma.
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