WO2022089406A1 - Composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation - Google Patents

Composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation 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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English (en)
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/zh
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/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

L'invention concerne un composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation. L'invention concerne un composé hétérocyclique condensé contenant de l'azote tel que représenté dans la formule I, un stéréoisomère, un tautomère, ou un sel pharmaceutiquement acceptable de celui-ci, qui peut être utilisé pour préparer un médicament pour Le traitement de maladies ou d'états liés à une activité de SHP2 anormale, notamment le cancer, etc.
PCT/CN2021/126331 2020-10-26 2021-10-26 Composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation WO2022089406A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023230205A1 (fr) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1153516A (zh) * 1994-07-15 1997-07-02 武田药品工业株式会社 三环化合物、它们的制备及其用途
CN1176785A (zh) * 1996-09-02 1998-03-25 武田药品工业株式会社 三环化合物、其制备方法和应用
WO1998029136A1 (fr) * 1996-12-27 1998-07-09 Takeda Chemical Industries, Ltd. Compose tricyclique stabilise
WO1998047901A1 (fr) * 1997-04-18 1998-10-29 Takeda Chemical Industries, Ltd. Procede de production de composes tricycliques et de leurs intermediaires
JP2002201193A (ja) * 2000-10-25 2002-07-16 Takeda Chem Ind Ltd 三環性化合物、その製造法および剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1153516A (zh) * 1994-07-15 1997-07-02 武田药品工业株式会社 三环化合物、它们的制备及其用途
CN1176785A (zh) * 1996-09-02 1998-03-25 武田药品工业株式会社 三环化合物、其制备方法和应用
WO1998029136A1 (fr) * 1996-12-27 1998-07-09 Takeda Chemical Industries, Ltd. Compose tricyclique stabilise
WO1998047901A1 (fr) * 1997-04-18 1998-10-29 Takeda Chemical Industries, Ltd. Procede de production de composes tricycliques et de leurs intermediaires
JP2002201193A (ja) * 2000-10-25 2002-07-16 Takeda Chem Ind Ltd 三環性化合物、その製造法および剤

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023230205A1 (fr) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations

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