WO2023046034A1 - Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et application de celui-ci - Google Patents

Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et application de celui-ci Download PDF

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WO2023046034A1
WO2023046034A1 PCT/CN2022/120655 CN2022120655W WO2023046034A1 WO 2023046034 A1 WO2023046034 A1 WO 2023046034A1 CN 2022120655 W CN2022120655 W CN 2022120655W WO 2023046034 A1 WO2023046034 A1 WO 2023046034A1
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alkyl
independently
substituted
cycloalkyl
membered heteroaryl
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PCT/CN2022/120655
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Chinese (zh)
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李傲
贾达夫·P·K
陈以乐
曹国庆
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明慧医药（杭州）有限公司
明慧医药（上海）有限公司
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Publication of WO2023046034A1 publication Critical patent/WO2023046034A1/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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present invention relates to a nitrogen-containing heterocyclic compound, its preparation method, its intermediate and its application, in particular to a PARP inhibitor, its preparation method, its intermediate, its pharmaceutical composition and its application.
  • PARP Poly ADP-ribose Polymerase
  • PARP1 is responsible for more than 90% of ADP-ribosylation in cells, and is one of the most abundant and widely studied members of the family, and it is generally believed that it plays a key role in the DNA repair pathway It can be activated by DNA single-strand breaks (SSBs) and repair damaged DNA through the process of base excision repair (BER).
  • SSBs DNA single-strand breaks
  • BER base excision repair
  • PARP2 and PARP1 have high protein homology. When PARP1 is deficient, PARP2 can replace PARP1 to achieve DNA damage repair.
  • Synthetic lethality refers to the simultaneous suppression of two non-lethal genes, resulting in cell death. Use this mechanism to find specific mutations in tumors, and then find its "synthetic lethal partner" to specifically kill cancer cells.
  • PARP inhibitors are the first drugs to use the concept of synthetic lethality to achieve clinical success. Healthy cells have multiple mechanisms for DNA strand break repair. But cancer cells sometimes develop mutations that disrupt other types of repair, making them especially sensitive to PARP inhibitors.
  • PARP inhibitors inhibit the repair of DNA single-strand damage by binding to the catalytic site of PARP1 or PARP2, resulting in the accumulation of single-strand damage and triggering DNA double-strand break (DSB, Double strand break).
  • the body repairs DSBs mainly in two ways: Homologous Recombination Repair (HRR) and non-homologous DNA end joining (NHEJ, Non-Homologous End Joining), among which homologous recombination is the main way of DSB repair, And the repair reliability is high.
  • HRR Homologous Recombination Repair
  • NHEJ Non-Homologous End Joining
  • the repair reliability is high.
  • tumor cells deficient in homologous recombination repair such as cancers with mutations in breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2)
  • BRCA1 and BRCA2 breast cancer susceptibility genes 1 and 2
  • PARP inhibitors produce single-agent antitumor activity.
  • PARP inhibitors can also be used in combination with chemotherapy drugs and radiotherapy drugs, so as to achieve the purpose of reducing the dose and improving the efficacy.
  • PARP inhibitors have been reported, among which Olaparib, Rucaparib, Niraparib (MK-4827), Talazoparib (BMN-673), etc. have been successfully marketed, most of which mimic the structure of nicotinamide in the endogenous substrate NAD + , Binding to the nicotinamide binding site or adenosine site in the catalytic domain competitively inhibits the activity of PARP, but it is difficult for existing inhibitors to show selectivity for PARP1 and PARP2 subtypes. Compared with PARP1, although PARP2 plays less than 10% of the role in repairing DNA, studies have shown that PARP2 has an indispensable importance.
  • PARP2 gene has been confirmed to affect the normal function of red blood cells, leading to diseases such as chronic anemia (Cell Death & Differentiation, 2015, 22:1144-1157).
  • Mice knocked out of both PARP1 and PARP2 are already embryonic, which also demonstrates the potential risk of simultaneously inhibiting the activities of PARP1 and PARP2 (Embo Journal, 2003, 22:2255-2263). Therefore, PARP inhibitors that are selective for PARP1 may have improved efficacy and reduced toxicity.
  • PARP inhibitors As the indications of PARP inhibitors continue to expand, the application of PARP inhibitors is also deepening, not only around tumors, but also has certain effects on stroke, myocardial ischemia, inflammation and diabetes. There are still many clinical trials in progress. There is an unmet medical need for effective and safe PARP inhibitors compared to other clinical PARP inhibitors, especially PARP inhibitors that are selective for PARP1.
  • the technical problem to be solved by the present invention is the defects such as poor selectivity of existing PARP inhibitors.
  • the present invention provides a nitrogen-containing heterocyclic compound, its preparation method, its intermediate and its application.
  • the compound of the present invention has strong inhibitory activity on PARP1, especially the selectivity to PARP1/PARP2 has obvious advantages over positive controls Olaparib and AZD5305.
  • the present invention provides a nitrogen-containing heterocyclic compound, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt; wherein, the nitrogen-containing heterocyclic compound is as follows: The nitrogen-containing heterocyclic compound shown in II-a,
  • R 1 is C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or substituted by 1, 2 or 3 R 1-2 substituted C 3-12 cycloalkyl;
  • R 2 is H, C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 2-1 , or substituted by 1, 2 One or three R 2-2 substituted C 3-12 cycloalkyl groups;
  • R 1 and R 2 form a C 6-12 aryl group, a 5-12 membered heteroaryl group, a 3-12 membered heterocycloalkyl group, a C 3-12 cycloalkyl group, one or two Or C 6-12 aryl substituted by 3 R 1-3 , 5-12 membered heteroaryl substituted by 1, 2 or 3 R 1-4 , 1, 2 or 3 R 1 -5 substituted 3-12 membered heterocycloalkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-6 ;
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 2-1 and R 2-2 are independently deuterium, halogen, -COOR 1-1- 3 , cyano, C 3-12 cycloalkyl, C 1-6 alkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-1-4 ;
  • R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl
  • R 1-1-3 is H or C 1-6 alkyl
  • R 1-1-4 are independently halogen or C 1-6 alkyl
  • Y1 is N, CH or C
  • Y2 is N, CH or C
  • W is CH or N
  • X 1 is N, CH or C, when connected to X 1 When it is a double bond, X 1 is C, and R 4a or R 4b does not exist;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, 1, 2 or C 1-6 alkyl substituted by 3 R 3a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 3a-2 ;
  • any two of R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are connected to form C 1-4 alkylene, C 2-4 alkenylene, C 1- 4 heteroalkylene, C 2-4 heteroalkenylene, C 1-4 alkylene substituted by 1, 2 or 3 R 3a- 3, 1, 2 or 3 R 3a- 4 substituted C 2-4 alkenylene, C 1-4 heteroalkylene substituted by 1, 2 or 3 R 3a-5 or substituted by 1, 2 or 3 R 3a-6 C 2-4 heteroalkenylene, the rest are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkane substituted by 1, 2 or 3 R 3a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 3a-2 ;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b is not H;
  • D 1 is 5-12 membered heteroaryl, C 6-12 aryl, 5-12 membered heteroaryl substituted by 1, 2 or 3 R d1-1 , or 1, 2 or 3 A C 6-12 aryl group substituted by R d1-2 ;
  • R L-1 is C 1-6 alkyl, C 3-12 cycloalkyl or deuterated C 1-6 alkyl;
  • R L-2 is C 1-6 alkyl, C 3-12 cycloalkyl or deuterated C 1-6 alkyl;
  • R L-3 are independently halogen, cyano, C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3-1 , R L-3-2 , R L-3-3 and R L-3-4 are independently hydrogen or C 1-6 alkyl;
  • R 11a and R 11b are independently H or deuterium
  • R 12 is H, halogen or C 1-6 alkyl
  • each heteroaryl group is independently one or more heteroatoms independently selected from N, O and S, and the heteroatoms are 1, 2 or 3 heteroaryl groups;
  • the heterocycloalkyl group formed by the above R1 and R2 and the atoms connected to them, is one or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl groups;
  • each heteroalkyl group is independently one or more heteroatoms independently selected from N, O and S A heteroalkyl group with 1, 2 or 3 heteroatoms;
  • each heteroalkylene group is independently a heteroatom independently selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3 heteroalkylene;
  • each The heteroalkenyl group is independently one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • the nitrogen-containing heterocyclic compound shown in formula II-a is a nitrogen-containing heterocyclic compound shown in formula I-a
  • R 1 is C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or substituted by 1, 2 or 3 R 1-2 substituted C 3-12 cycloalkyl;
  • R 2 is H, C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 2-1 , or substituted by 1, 2 One or three R 2-2 substituted C 3-12 cycloalkyl groups;
  • R 1 and R 2 form a C 6-12 aryl group, a 5-12 membered heteroaryl group, a 3-12 membered heterocycloalkyl group, a C 3-12 cycloalkyl group, one or two Or C 6-12 aryl substituted by 3 R 1-3 , 5-12 membered heteroaryl substituted by 1, 2 or 3 R 1-4 , 1, 2 or 3 R 1 -5 substituted 3-12 membered heterocycloalkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-6 ;
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 2-1 and R 2-2 are independently halogen, -COOR 1-1-3 , cyano, C 3-12 cycloalkyl, C 1-6 alkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-1-4 ;
  • R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl
  • R 1-1-3 is H or C 1-6 alkyl
  • R 1-1-4 are independently halogen or C 1-6 alkyl
  • Y 1 is N, CH or C, when connected to Y 1 When it is a double bond, Y 1 is C;
  • X 1 is N, CH or C, when connected to X 1 When it is a double bond, X 1 is C, and R 4a or R 4b does not exist;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, 1, 2 or C 1-6 alkyl substituted by 3 R 3a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 3a-2 ;
  • any two of R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are connected to form C 1-4 alkylene, C 2-4 alkenylene, C 1- 4 heteroalkylene, C 2-4 heteroalkenylene, C 1-4 alkylene substituted by 1, 2 or 3 R 3a- 3, 1, 2 or 3 R 3a- 4 substituted C 2-4 alkenylene, C 1-4 heteroalkylene substituted by 1, 2 or 3 R 3a-5 or substituted by 1, 2 or 3 R 3a-6 C 2-4 heteroalkenylene, the rest are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkane substituted by 1, 2 or 3 R 3a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 3a-2 ;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b is not H;
  • D 1 is 5-12 membered heteroaryl, C 6-12 aryl, 5-12 membered heteroaryl substituted by 1, 2 or 3 R d1-1 , or 1, 2 or 3 A C 6-12 aryl group substituted by R d1-2 ;
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3 are independently halogen, cyano, C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3-1 , R L-3-2 , R L-3-3 and R L-3-4 are independently hydrogen or C 1-6 alkyl;
  • each heteroaryl group is independently one or more heteroatoms independently selected from N, O and S, and the heteroatoms are 1, 2 or 3 heteroaryl groups;
  • the heterocycloalkyl group formed by the above R1 and R2 and the atoms connected to them, is one or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl groups;
  • each heteroalkyl group is independently one or more heteroatoms independently selected from N, O and S A heteroalkyl group with 1, 2 or 3 heteroatoms;
  • each heteroalkylene group is independently a heteroatom independently selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3 heteroalkylene;
  • each The heteroalkenyl group is independently one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • the nitrogen-containing heterocyclic compound shown in formula II-a is a nitrogen-containing heterocyclic compound shown in formula I-E,
  • R 1 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 11a , R 11b , R 12 and D 1 are as described in any scheme of the present invention.
  • the nitrogen-containing heterocyclic compound shown in formula I-E is a nitrogen-containing heterocyclic compound shown in formula I-e,
  • R 1 is C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or substituted by 1, 2 or 3 R 1-2 substituted C 3-12 cycloalkyl;
  • R 1-1 and R 1-2 are independently halogen, -COOR 1-1-3 , cyano, C 3-12 cycloalkyl, C 1-6 alkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-1-4 ;
  • R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl
  • R 1-1-3 is H or C 1-6 alkyl
  • R 1-1-4 are independently halogen or C 1-6 alkyl
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, 1, 2 or C 1-6 alkyl substituted by 3 R 3a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 3a-2 ;
  • any two of R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are connected to form C 1-4 alkylene, C 2-4 alkenylene, C 1- 4 heteroalkylene, C 2-4 heteroalkenylene, C 1-4 alkylene substituted by 1, 2 or 3 R 3a- 3, 1, 2 or 3 R 3a- 4 substituted C 2-4 alkenylene, C 1-4 heteroalkylene substituted by 1, 2 or 3 R 3a-5 or substituted by 1, 2 or 3 R 3a-6 C 2-4 heteroalkenylene, the rest are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkane substituted by 1, 2 or 3 R 3a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 3a-2 ;
  • R 11a and R 11b are independently H or deuterium
  • R 12 is H, halogen or C 1-6 alkyl
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3 are independently halogen, cyano, C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3-1 , R L-3-2 , R L-3-3 and R L-3-4 are independently hydrogen or C 1-6 alkyl;
  • each heteroaryl group is independently one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 heteroaryl groups;
  • each heteroalkyl group is independently one or more heteroatoms independently selected from N, O and S A heteroalkyl group with 1, 2 or 3 heteroatoms;
  • each heteroalkylene group is independently a heteroatom independently selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3 heteroalkylene;
  • each The heteroalkenyl group is independently one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • the present invention provides a nitrogen-containing heterocyclic compound represented by formula II-b, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; wherein,
  • R 1 is C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or substituted by 1, 2 or 3 R 1-2 substituted C 3-12 cycloalkyl;
  • R 2 is H, C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 2-1 , or substituted by 1, 2 One or three R 2-2 substituted C 3-12 cycloalkyl groups;
  • R 1 and R 2 form a C 6-12 aryl group, a 5-12 membered heteroaryl group, a 3-12 membered heterocycloalkyl group, a C 3-12 cycloalkyl group, one or two Or C 6-12 aryl substituted by 3 R 1-3 , 5-12 membered heteroaryl substituted by 1, 2 or 3 R 1-4 , 1, 2 or 3 R 1 -5 substituted 3-12 membered heterocycloalkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-6 ;
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 2-1 and R 2-2 are independently deuterium, halogen, -COOR 1-1- 3 , cyano, C 3-12 cycloalkyl, C 1-6 alkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-1-4 ;
  • R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl
  • R 1-1-3 is H or C 1-6 alkyl
  • R 1-1-4 are independently halogen or C 1-6 alkyl
  • Y1 is N, CH or C
  • Y2 is N, CH or C
  • W is CH or N
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, replaced by 1, 2 or C 1-6 alkyl substituted by 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • any two of R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are connected to form C 1-4 alkylene, C 2-4 alkenylene, C 1- 4 heteroalkylene, C 2-4 heteroalkenylene, C 1-4 alkylene substituted by 1, 2 or 3 R 7a- 3, 1, 2 or 3 R 7a- 4 substituted C 2-4 alkenylene, C 1-4 heteroalkylene substituted by 1, 2 or 3 R 7a-5 or substituted by 1, 2 or 3 R 7a-6 C 2-4 heteroalkenylene, the rest are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkane substituted by 1, 2 or 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • D 2 is 5-12 membered heteroaryl, C 6-12 aryl, 5-12 membered heteroaryl substituted by 1, 2 or 3 R d2-1 or 1, 2 or 3 R d2-2 substituted C 6-12 aryl;
  • R p-1 is independently C 1-6 alkyl, C 3-12 cycloalkyl or deuterated C 1-6 alkyl; and 5-12 substituted by 1, 2 or 3 R d2-1
  • the 5-12 membered heteroaryl in the membered heteroaryl is and R d2-1 is
  • R p-1 is cycloalkyl or deuterated C 1-6 alkyl;
  • R p-2 is C 1-6 alkyl, C 3-12 cycloalkyl or deuterated C 1-6 alkyl;
  • R p-3 is independently F, cyano, C 1-6 alkyl or C 3-12 cycloalkyl
  • R p-3-1 , R p-3-2 , R p-3-3 and R p-3-4 are independently hydrogen or C 1-6 alkyl;
  • R 11a and R 11b are independently H or deuterium
  • R 12 is H, halogen or C 1-6 alkyl
  • each heteroaryl group is independently one or more heteroatoms independently selected from N, O and S, and the heteroatoms are 1, 2 or 3 heteroaryl groups;
  • each heterocycloalkyl group is independently one or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl;
  • each heteroalkyl group is independently one or more heteroatoms independently selected from N, O and S A heteroalkyl group with 1, 2 or 3 heteroatoms;
  • each heteroalkylene group is independently a heteroatom independently selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3 heteroalkylene;
  • each heteroalkenylene group is independently a heteroatom independently selected from A heteroalkenylene group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S.
  • the nitrogen-containing heterocyclic compound shown in formula II-b is a nitrogen-containing heterocyclic compound shown in formula I-b
  • R 1 is C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or substituted by 1, 2 or 3 R 1-2 substituted C 3-12 cycloalkyl;
  • R 2 is H, C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 2-1 , or substituted by 1, 2 One or three R 2-2 substituted C 3-12 cycloalkyl groups;
  • R 1 and R 2 form a C 6-12 aryl group, a 5-12 membered heteroaryl group, a 3-12 membered heterocycloalkyl group, a C 3-12 cycloalkyl group, one or two Or C 6-12 aryl substituted by 3 R 1-3 , 5-12 membered heteroaryl substituted by 1, 2 or 3 R 1-4 , 1, 2 or 3 R 1 -5 substituted 3-12 membered heterocycloalkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-6 ;
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 2-1 and R 2-2 are independently halogen, -COOR 1-1-3 , cyano, C 3-12 cycloalkyl, C 1-6 alkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-1-4 ;
  • R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl
  • R 1-1-3 is H or C 1-6 alkyl
  • R 1-1-4 are independently halogen or C 1-6 alkyl
  • Y 1 is N, CH or C, when connected to Y 1 When it is a double bond, Y 1 is C;
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, replaced by 1, 2 or C 1-6 alkyl substituted by 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • any two of R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are connected to form C 1-4 alkylene, C 2-4 alkenylene, C 1- 4 heteroalkylene, C 2-4 heteroalkenylene, C 1-4 alkylene substituted by 1, 2 or 3 R 7a- 3, 1, 2 or 3 R 7a- 4 substituted C 2-4 alkenylene, C 1-4 heteroalkylene substituted by 1, 2 or 3 R 7a-5 or substituted by 1, 2 or 3 R 7a-6 C 2-4 heteroalkenylene, the rest are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkane substituted by 1, 2 or 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • D 2 is 5-12 membered heteroaryl, C 6-12 aryl, 5-12 membered heteroaryl substituted by 1, 2 or 3 R d2-1 or 1, 2 or 3 R d2-2 substituted C 6-12 aryl;
  • R p-1 is independently C 1-6 alkyl or C 3-12 cycloalkyl; and 5-12 of the 5-12 membered heteroaryl substituted by 1, 2 or 3 R d2-1 Metaheteroaryl is , R p-1 is a cycloalkyl group;
  • R p-2 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R p-3 is independently F, cyano, C 1-6 alkyl or C 3-12 cycloalkyl
  • R p-3-1 , R p-3-2 , R p-3-3 and R p-3-4 are independently hydrogen or C 1-6 alkyl;
  • each heteroaryl group is independently one or more heteroatoms independently selected from N, O and S, and the heteroatoms are 1, 2 or 3 heteroaryl groups;
  • each heterocycloalkyl group is independently one or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl;
  • each heteroalkyl group is independently one or more heteroatoms independently selected from N, O and S A heteroalkyl group with 1, 2 or 3 heteroatoms;
  • each heteroalkylene group is independently a heteroatom independently selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3 heteroalkylene;
  • each heteroalkenylene group is independently a heteroatom independently selected from A heteroalkenylene group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S.
  • the nitrogen-containing heterocyclic compound shown in formula II-b is a nitrogen-containing heterocyclic compound shown in formula I-f,
  • R 1 , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a , R 11b , R 12 , X 2 and D 2 are as defined in any scheme of the present invention. stated.
  • the present invention provides a nitrogen-containing heterocyclic compound represented by formula I-c, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate; wherein,
  • R 3 is C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or substituted by 1, 2 or 3 R 1-2 substituted C 3-12 cycloalkyl;
  • R 4 is H, C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 2-1 , or substituted by 1, 2 One or three R 2-2 substituted C 3-12 cycloalkyl groups;
  • R 3 and R 4 form C 6-12 aryl, 5-12 heteroaryl, 3-12 heterocycloalkyl, C 3-12 cycloalkyl with 1 or 2 Or C 6-12 aryl substituted by 3 R 1-3 , 5-12 membered heteroaryl substituted by 1, 2 or 3 R 1-4 , 1, 2 or 3 R 1 -5 substituted 3-12 membered heterocycloalkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-6 ;
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 2-1 and R 2-2 are independently halogen, -COOR 1-1-3 , cyano, C 3-12 cycloalkyl, C 1-6 alkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-1-4 ;
  • R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl
  • R 1-1-3 is H or C 1-6 alkyl
  • R 1-1-4 are independently halogen or C 1-6 alkyl
  • Y2 is N or CH
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, replaced by 1, 2 or C 1-6 alkyl substituted by 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • any two of R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are connected to form C 1-4 alkylene, C 2-4 alkenylene, C 1- 4 heteroalkylene, C 2-4 heteroalkenylene, C 1-4 alkylene substituted by 1, 2 or 3 R 7a- 3, 1, 2 or 3 R 7a- 4 substituted C 2-4 alkenylene, C 1-4 heteroalkylene substituted by 1, 2 or 3 R 7a-5 or substituted by 1, 2 or 3 R 7a-6 C 2-4 heteroalkenylene, the rest are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkane substituted by 1, 2 or 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • D 3 is 5-12 membered heteroaryl, C 6-12 aryl, 5-12 membered heteroaryl substituted by 1, 2 or 3 R d1-1 , 1, 2 or 3 R d1-2 substituted C 6-12 aryl;
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3 are independently halogen, cyano, C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3-1 , R L-3-2 , R L-3-3 and R L-3-4 are independently hydrogen or C 1-6 alkyl;
  • each heteroaryl group is independently one or more heteroatoms independently selected from N, O and S, and the heteroatoms are 1, 2 or 3 heteroaryl groups;
  • each heterocycloalkyl group is independently one or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl;
  • each heteroalkyl group is independently one or more heteroatoms independently selected from N, O and S A heteroalkyl group with 1, 2 or 3 heteroatoms;
  • each heteroalkylene group is independently a heteroatom independently selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3 heteroalkylene;
  • each heteroalkenylene group is independently a heteroatom independently selected from A heteroalkenylene group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S.
  • the present invention provides a nitrogen-containing heterocyclic compound represented by formula I-d, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate; wherein,
  • R 5 is C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 or substituted by 1, 2 or 3 R 1-2 substituted C 3-12 cycloalkyl; and when R 6 is H, R 5 is C 3-12 cycloalkyl or halogen;
  • R 6 is H, C 1-6 alkyl, C 3-12 cycloalkyl, halogen, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 or 1, 2 Or 3 R 1-2 substituted C 3-12 cycloalkyl;
  • R 5 and R 6 form C 6-12 aryl, 5-12 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkyl, with 1 or 2 Or C 6-12 aryl substituted by 3 R 1-3 , 5-12 membered heteroaryl substituted by 1, 2 or 3 R 1-4 , 1, 2 or 3 R 1 -5 substituted 3-12 membered heterocycloalkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-6 ;
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 2-1 and R 2-2 are independently halogen, -COOR 1-1-3 , cyano, C 3-12 cycloalkyl, C 1-6 alkyl or C 3-12 cycloalkyl substituted by 1, 2 or 3 R 1-1-4 ;
  • R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl
  • R 1-1-3 is H or C 1-6 alkyl
  • R 1-1-4 are independently halogen or C 1-6 alkyl
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, replaced by 1, 2 or C 1-6 alkyl substituted by 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • any two of R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are connected to form C 1-4 alkylene, C 2-4 alkenylene, C 1- 4 heteroalkylene, C 2-4 heteroalkenylene, C 1-4 alkylene substituted by 1, 2 or 3 R 7a- 3, 1, 2 or 3 R 7a- 4 substituted C 2-4 alkenylene, C 1-4 heteroalkylene substituted by 1, 2 or 3 R 7a-5 or substituted by 1, 2 or 3 R 7a-6 C 2-4 heteroalkenylene, the rest are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkane substituted by 1, 2 or 3 R 7a-1 or C 1-6 heteroalkyl substituted by 1, 2 or 3 R 7a-2 ;
  • D 4 is 5-12 membered heteroaryl, C 6-12 aryl, 5-12 membered heteroaryl substituted by 1, 2 or 3 R d1-1 , 1, 2 or 3 R d1-2 substituted C 6-12 aryl;
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3 are independently halogen, cyano, C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-3-1 , R L-3-2 , R L-3-3 and R L-3-4 are independently hydrogen or C 1-6 alkyl;
  • each heteroaryl group is independently one or more heteroatoms independently selected from N, O and S, and the heteroatoms are 1, 2 or 3 heteroaryl groups;
  • each heterocycloalkyl group is independently one or more heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 heterocycloalkyl;
  • each heteroalkyl group is independently one or more heteroatoms independently selected from N, O and S A heteroalkyl group with 1, 2 or 3 heteroatoms;
  • each heteroalkylene group is independently a heteroatom independently selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3 heteroalkylene;
  • each heteroalkenylene group is independently a heteroatom independently selected from A heteroalkenylene group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S.
  • R 1 is independently C 1-6 alkyl or C 3-12 cycloalkyl
  • R 2 is independently H, C 1-6 alkyl or halogen, or, R 1 and R 2 form an atom connected to it C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocycloalkyl.
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently H or C 1-6 alkyl, or, R 3a , R 3b , R Any two of 4a , R 4b , R 5a , R 5b , R 6a and R 6b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently is H or C 1-6 alkyl.
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H or C 1-6 alkyl, or, R 7a , R 7b , R Any two of 8a , R 8b , R 9a , R 9b , R 10a and R 10b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently is H or C 1-6 alkyl.
  • R 3 is independently C 1-6 alkyl or C 3-12 cycloalkyl
  • R 4 is independently H, C 1-6 alkyl or halogen, or, R 3 and R 4 are in combination with
  • the connected atoms form a C 6-12 aryl group, a 5-12 membered heteroaryl group or a 3-12 membered heterocycloalkyl group.
  • R 5 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R 6 is H, C 1-6 alkyl or halogen
  • R 5 is C A 3-12 cycloalkyl group
  • R 5 and R 6 form a C 6-12 aryl group, a 5-12 membered heteroaryl group or a 3-12 membered heterocycloalkyl group.
  • D 1 is 5-12 membered heteroaryl substituted by 1, 2 or 3 R d1-1 or C 6- substituted by 1, 2 or 3 R d1-2 12 aryl.
  • D 3 is 5-12 membered heteroaryl substituted by 1, 2 or 3 R d1-1 or C 6- substituted by 1, 2 or 3 R d1-2 12 aryl.
  • D 4 is 5-12 membered heteroaryl substituted by 1, 2 or 3 R d1-1 or C 6- substituted by 1, 2 or 3 R d1-2 12 aryl.
  • R d1-2 are independently
  • R L-3 is independently C 1-6 alkyl.
  • D 2 is 5-12 membered heteroaryl substituted by 1, 2 or 3 R d2-1 or C 6- substituted by 1, 2 or 3 R d2-2 12 aryl.
  • R d2-2 is independently
  • R p-3 is independently C 1-6 alkyl.
  • R 12 is H or halo.
  • R 1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R 2 is H, C 1-6 alkyl or halogen, or, R 1 and R 2 form a C 6-12 aryl , 5-12 membered heteroaryl or 3-12 membered heterocycloalkyl;
  • Y1 is N, CH or C
  • Y2 is N, CH or C
  • W is CH or N;
  • X1 is N, CH or C, when connected to X1 When it is a double bond, X 1 is C, and R 4a or R 4b does not exist;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently H or C 1-6 alkyl, or, R 3a , R 3b , R 4a , R 4b , R Any two of 5a , R 5b , R 6a and R 6b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently H or C 1- 6 alkyl;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b is not H;
  • D 1 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 R d1-1 or a C 6-12 aryl group substituted by 1, 2 or 3 R d1-2 ;
  • R d1-2 are independently
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl or deuterated C 1-6 alkyl;
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl or deuterated C 1-6 alkyl;
  • R 11a and R 11b are independently H or deuterium
  • R 12 is H or halogen.
  • R 1 is independently C 1-6 alkyl or C 3-12 cycloalkyl
  • R 2 is independently H, C 1-6 alkyl or halogen, or, R 1 and R 2 form a C 6 -12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocycloalkyl;
  • Y1 is N, CH or C
  • Y2 is N, CH or C
  • W is CH or N
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H or C 1-6 alkyl, or, R 7a , R 7b , R 8a , R 8b , R Any two of 9a , R 9b , R 10a and R 10b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently H or C 1- 6 alkyl;
  • D2 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 Rd2-1 or a C6-12 aryl group substituted by 1, 2 or 3 Rd2-2 ;
  • R d2-2 are independently
  • R p-1 is independently C 1-6 alkyl, C 3-12 cycloalkyl or deuterated C 1-6 alkyl; and 5-12 substituted by 1, 2 or 3 R d2-1
  • the 5-12 membered heteroaryl in the membered heteroaryl is and R d2-1 is
  • R p-1 is cycloalkyl or deuterated C 1-6 alkyl;
  • R p-2 is C 1-6 alkyl, C 3-12 cycloalkyl or deuterated C 1-6 alkyl;
  • R 11a and R 11b are independently H or deuterium
  • R 12 is H or halogen.
  • R 1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R 2 is H, C 1-6 alkyl or halogen, or, R 1 and R 2 form a C 6-12 aryl , 5-12 membered heteroaryl or 3-12 membered heterocycloalkyl;
  • Y 1 is N, CH or C, when connected to Y 1 When it is a double bond, Y 1 is C;
  • X 1 is N, CH or C, when connected to X 1 When it is a double bond, X 1 is C, and R 4a or R 4b does not exist;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently H or C 1-6 alkyl, or, R 3a , R 3b , R 4a , R 4b , R Any two of 5a , R 5b , R 6a and R 6b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently H or C 1- 6 alkyl;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b is not H;
  • D 1 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 R d1-1 or a C 6-12 aryl group substituted by 1, 2 or 3 R d1-2 ;
  • R d1-2 are independently
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl.
  • R 1 is independently C 1-6 alkyl or C 3-12 cycloalkyl
  • R 2 is independently H, C 1-6 alkyl or halogen, or, R 1 and R 2 form a C 6 -12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocycloalkyl;
  • Y 1 is N, CH or C, when connected to Y 1 When it is a double bond, Y 1 is C;
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H or C 1-6 alkyl, or, R 7a , R 7b , R 8a , R 8b , R Any two of 9a , R 9b , R 10a and R 10b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently H or C 1- 6 alkyl;
  • D2 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 Rd2-1 or a C6-12 aryl group substituted by 1, 2 or 3 Rd2-2 ;
  • R d2-2 are independently
  • R p-1 is independently C 1-6 alkyl or C 3-12 cycloalkyl; and 5-12 of the 5-12 membered heteroaryl substituted by 1, 2 or 3 R d2-1 Metaheteroaryl is , R p-1 is a cycloalkyl group;
  • R p-2 is C 1-6 alkyl or C 3-12 cycloalkyl.
  • R 3 is independently C 1-6 alkyl or C 3-12 cycloalkyl
  • R 4 is independently H, C 1-6 alkyl or halogen, or, R 3 and R 4 form a C 6 -12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocycloalkyl;
  • Y2 is N or CH
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H or C 1-6 alkyl, or, R 7a , R 7b , R 8a , R 8b , R Any two of 9a , R 9b , R 10a and R 10b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently H or C 1- 6 alkyl;
  • D 3 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 R d1-1 or a C 6-12 aryl group substituted by 1, 2 or 3 R d1-2 ;
  • R d1-2 are independently
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl.
  • R 5 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R 6 is H, C 1-6 alkyl or halogen, and when R 6 is H, R 5 is C 3-12 cycloalkyl , or, R 5 and R 6 form a C 6-12 aryl group, a 5-12 membered heteroaryl group or a 3-12 membered heterocycloalkyl group;
  • X2 is N, CH or C, when connected to X2 When it is a double bond, X 2 is C, and R 8a or R 8b does not exist;
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently H or C 1-6 alkyl, or, R 7a , R 7b , R 8a , R 8b , R Any two of 9a , R 9b , R 10a and R 10b are connected to form C 1-3 alkylene, C 2-3 alkenylene or C 1-3 heteroalkylene, and the rest are independently H or C 1- 6 alkyl;
  • D 4 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 R d1-1 or a C 6-12 aryl group substituted by 1, 2 or 3 R d1-2 ;
  • R d1-2 are independently
  • R L-1 is C 1-6 alkyl or C 3-12 cycloalkyl
  • R L-2 is C 1-6 alkyl or C 3-12 cycloalkyl.
  • R 1 , R 3 or R 5 is C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl or ethyl.
  • R 2 , R 4 or R 6 is C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl or ethyl.
  • R 1 , R 3 or R 5 is C 3-12 cycloalkyl
  • said C 3-12 cycloalkyl is independently C 3-6 cycloalkyl, such as cyclopropyl base, cyclobutyl, cyclopentyl or cyclohexyl, and another example is cyclopropyl.
  • R 2 , R 4 or R 6 is C 3-12 cycloalkyl
  • said C 3-12 cycloalkyl is independently C 3-6 cycloalkyl, such as cyclopropyl base, cyclobutyl, cyclopentyl or cyclohexyl, and another example is cyclopropyl.
  • halogen is independently F, Cl, Br or I, such as F.
  • said C 6 -12Aryl is independently phenyl or naphthyl, for example phenyl.
  • the 12-membered heteroaryl is independently a 5-7 membered heteroaryl, such as pyridyl, and another example is
  • the 3-12 membered heterocycloalkyl is independently 4-7 membered heterocycloalkyl, such as piperidinyl, another example is
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently C 1-6 alkyl
  • said C 1-6 alkyl is independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl.
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are independently C 1-6 alkyl
  • said C 1-6 alkyl is independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl.
  • D 1 , D 3 or D 4 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 R d1-1
  • the heteroatom is N, such as independently pyridyl, imidazolyl, Another example is independently
  • D 1 , D 3 or D 4 is a C 6-12 aryl group substituted by 1, 2 or 3 R d1-2
  • the C 6-12 aryl group is independently Phenyl or naphthyl, for example phenyl.
  • R d1-1 is independently C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl or ethyl.
  • R d1-1 is independently a 5-6 membered heteroaryl group
  • the heteroatom in the heteroaryl group is N
  • the 5-6 membered heteroaryl group is imidazolyl or triazole base
  • R L-1 is independently C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl.
  • R L-1 is independently C 3-12 cycloalkyl
  • said C 3-12 cycloalkyl is independently C 3-6 cycloalkyl, such as cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl, another example is cyclopropyl.
  • R L-2 is independently C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl.
  • D 2 is a 5-12 membered heteroaryl group substituted by 1, 2 or 3 Rd2-1
  • the heteroatom is N
  • pyridyl imidazolyl
  • imidazolyl Another example is
  • R d2-1 is independently C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; another example is methyl or ethyl.
  • R d2-1 is independently a 5-6 membered heteroaryl group
  • the heteroatom in the heteroaryl group is N
  • the 5-6 membered heteroaryl group is imidazolyl or triazole base
  • R p-1 is independently C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl.
  • R p-1 is independently C 3-12 cycloalkyl
  • said C 3-12 cycloalkyl is C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl base, cyclopentyl or cyclohexyl, and another example is cyclopropyl.
  • R p-2 is independently C 1-6 alkyl
  • said C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; for example methyl.
  • halogen is independently F, Cl, Br or I, such as F.
  • the C 1-6 alkyl in the deuterated C 1-6 alkyl is independently methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl; another example of the deuterated C 1-6 alkyl is CD 3 .
  • the C 1-6 alkyl in said deuterated C 1-6 alkyl is independently methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl; another example of the deuterated C 1-6 alkyl is CD 3 .
  • D 1 , D 3 or D 4 are independently preferably
  • D 1 , D 3 or D 4 are independently
  • D2 is
  • D2 is
  • the nitrogen-containing heterocyclic compound shown in formula I-a, I-b, I-c or I-d is shown in formula I-a', I-b', I-c' or I-d' respectively:
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , D 2 , R 3 , R 4 , R 5 and R 6 are as described in the previous scheme.
  • the nitrogen-containing heterocyclic compound shown in formula I-a, I-b, I-c or I-d is selected from any of the following compounds:
  • the invention provides a pharmaceutical composition; the pharmaceutical composition comprises:
  • the present invention provides a nitrogen-containing heterocyclic compound as described in any of the preceding schemes, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt or as described in any of the preceding schemes Application of the pharmaceutical composition in the preparation of PARP inhibitors.
  • said PARP inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly as experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare according to conventional methods in the art Into a kit to provide rapid detection of PARP inhibitory effect.
  • the present invention provides a nitrogen-containing heterocyclic compound as described in any of the preceding schemes, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt or as described in any of the preceding schemes
  • the PARP receptor-related diseases are selected from tumors, stroke, myocardial infarction, inflammation, hypertension, atherosclerosis and diabetes;
  • the tumors are preferably breast cancer, ovarian cancer, prostate cancer, lung cancer, pancreatic cancer cancer, gastric cancer, brain tumor, melanoma, renal cell carcinoma, colorectal cancer, head and neck cancer, bladder cancer, hepatocellular carcinoma or cholangiocarcinoma, etc.
  • the present invention provides a method for treating and/preventing diseases, which comprises administering a therapeutically effective amount of the nitrogen-containing heterocyclic compound, its pharmaceutically acceptable salt, and its solvent as described in any preceding scheme to a patient (such as a human being) compound or a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in any of the previous schemes; the disease is a PARP receptor-related disorder;
  • the PARP receptor-related diseases are selected from tumors, stroke, myocardial infarction, inflammation, hypertension, atherosclerosis and diabetes;
  • the tumors are preferably breast cancer, ovarian cancer, prostate cancer, lung cancer, pancreatic cancer cancer, gastric cancer, brain tumor, melanoma, renal cell carcinoma, colorectal cancer, head and neck cancer, bladder cancer, hepatocellular carcinoma or cholangiocarcinoma, etc.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight-chain or branched-chain alkyl group having the specified number of carbon atoms (eg, C 1-6 ).
  • Alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, etc. .
  • heteroalkyl refers to a straight-chain or branched-chain alkyl parent structure in which a carbon atom at a certain position is replaced by a heteroatom and has a specified number of carbon atoms (such as C 1 to C 6 ), a specified hetero A group with a number of atoms (eg, 1, 2, or 3) and a specified heteroatom type (one or more of N, O, and S).
  • Heteroalkyl includes , but is not limited to , -CH2CH2OCH3 , -CH2CH2SCH3 , -CH2CH2NHCH3 , -OCH2CH2OCH3 , -SCH2CH2OCH3 , and -CH3 COCH 3 (CH 3 ) 2 etc.
  • cycloalkyl refers to a saturated monocyclic, bridged or spirocyclic group consisting only of carbon atoms with a specified number of carbon atoms (eg, C 3 -12 ). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl refers to a group having a specified number of ring atoms (such as 3-12 members), a specified number of heteroatoms (such as 1, 2 or 3), a specified type of heteroatom (N, O, and S A cyclic group of one or more of ), which is a monocyclic ring, a bridged ring or a spiro ring, and each ring is saturated.
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
  • aryl refers to a cyclic group consisting only of carbon atoms with a specified number of carbon atoms (such as C 6 ⁇ 12 ), which is monocyclic or polycyclic, and at least one ring is aromatic (according to Huckell rule).
  • the aryl group is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring.
  • Aryl includes, but is not limited to, phenyl, naphthyl, and the like.
  • heteroaryl refers to a specified number of ring atoms (such as 5-12 members), a specified number of heteroatoms (such as 1, 2 or 3), and a specified type of heteroatom (in N, O, and S).
  • ring atoms such as 5-12 members
  • heteroatoms such as 1, 2 or 3
  • a specified type of heteroatom in N, O, and S.
  • One or more of which is monocyclic or polycyclic, and at least one ring is aromatic (according to Huckel's rule).
  • Heteroaryl groups are linked to other moieties in the molecule through aromatic rings or non-aromatic rings.
  • Heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
  • alkylene refers to a substituent formed by the elimination of two hydrogens of a saturated straight or branched chain alkane.
  • the two hydrogens eliminated can be on the same carbon atom or on different carbon atoms (for example, the two hydrogens eliminated are on the carbon atoms at both ends).
  • C 1 alkylene ie, methylene
  • C 2 alkylene ie, ethylene
  • C 1 alkylene ie, ethylene
  • alkenylene refers to a substituent formed by eliminating two hydrogens from a linear or branched alkene having a specified number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. Wherein the carbon-carbon double bond can be located at any position in the alkenylene group, and the two hydrogens eliminated can be on the same carbon atom or on different carbon atoms (for example, the two hydrogens eliminated are respectively on the carbon atoms at both ends ).
  • -C(CH 3 ) CH-
  • heteroalkylene refers to a substituent of a heteroalkane after elimination of two hydrogens.
  • the two hydrogens eliminated can be on the same atom or on different atoms (eg two atoms with valences at both ends).
  • heteroalkane means that in the parent structure of saturated linear or branched alkanes, the carbon atoms at a certain position are replaced by heteroatoms, and have a specified number of carbon atoms (such as C 1 ⁇ C 6 ), specified The number of heteroatoms (for example, 1, 2 or 3), and the type of heteroatoms specified (one or more of N, O and S).
  • Heteroalkylene includes , but is not limited to -CH2OCH2- and -OCH2OCH2- .
  • heteroalkenylene refers to a substituent of a heteroalkene resulting from the elimination of two hydrogens.
  • the carbon-carbon double bond can be located anywhere in the heteroalkene.
  • heteroalkene refers to the parent structure of linear or branched alkenes containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds.
  • the carbon atoms at a certain position are replaced by heteroatoms, and have a designated carbon
  • the number of atoms such as C 1 to C 6
  • the number of heteroatoms specified such as 1, 2 or 3
  • the type of heteroatoms specified one or more of N, O and S.
  • a "-" at the end of a group means that the group is attached to other fragments in the molecule through this site.
  • linking group is expressed as "absent"
  • the structures on both sides of the linking group are directly linked by a single bond, for example -A-B-C-, when B does not exist, -A-B-C- is -A-C-.
  • fragment means that the structural fragment is connected to other fragments in the molecule through this site.
  • site means cyclohexyl.
  • any variable (such as the group R 1-3 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other.
  • a C 6-12 aryl group substituted by 3 R 1-3 means that the C 6-12 aryl group will be substituted by 3 R 1-3 , and the definitions of the 3 R 1-3 are independent of each other and do not affect each other .
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.
  • solvate refers to a substance formed after crystallization of a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of a pharmaceutically acceptable salt refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term “pharmaceutically acceptable salt” above, and the solvent is stoichiometric or non-stoichiometric.
  • solvent including but not limited to: water, methanol, ethanol etc.
  • Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.
  • therapeutically effective amount refers to the amount of a compound administered to a patient sufficient to effectively treat the disease.
  • the therapeutically effective amount will vary according to the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
  • pharmaceutical excipients refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except for active ingredients. For details, see Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
  • treating refers to any of the following: (1) amelioration of one or more biological manifestations of disease; (2) interference with one or more points in the biological cascade leading to disease; (3) slowing of disease The development of one or more biological manifestations.
  • prevention refers to reducing the risk of developing a disease.
  • patient refers to any animal, preferably a mammal, most preferably a human, who has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is: the compounds of the present invention have strong inhibitory activity on PARP1 at the enzymatic level, especially the selectivity to PARP1/PARP2 has obvious advantages over the positive control Olaparib and AZD5305, and can effectively reduce PARP2-induced blood toxicity.
  • the positive control AZD5305 multiple compounds of the present invention have long half-lives in animals, long action time in animals, and higher blood exposure. Therefore, they have better pharmacokinetic and pharmacodynamic properties, and more High clinical efficacy and good oral bioavailability.
  • Fig. 1 is a tumor volume diagram of Effect Example 5.
  • potassium hexamethyldisilazide (1.0M, 12mL) was added into a three-necked flask, and a solution of 6a (1.99g, 10.00mmol) in tetrahydrofuran (10mL) was added dropwise at -78°C, and kept at -78°C After stirring at low temperature for 30 minutes, a solution of 6b (3.93 g, 11.00 mmol) in tetrahydrofuran (10 mL) was added dropwise, stirring was continued for 30 minutes, and then the mixture was slowly raised to room temperature and stirred for 1 hour.
  • compound 1a (1.50g, 6.94mmol), pinacol bis-boronate (1.94g, 7.64mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium chloride (0.51g, 0.69mmol) and potassium acetate (1.36g, 13.88mmol) were dissolved in anhydrous 1,4-dioxane (30mL), and the mixed system was heated to 80°C and stirred for 2 hours.
  • the crude product 7d (2.90g) from the previous step was dissolved in 1,4-dioxane (50mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (2.50g, 11.20mmol) was added, The mixed system was stirred and reacted at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to remove most of the solvent, and saturated aqueous sodium bicarbonate solution (200mL) was added to the residue, stirred at room temperature for 2 hours and then filtered.
  • compound 6a (10.00g, 50.20mmol) was dissolved in anhydrous tetrahydrofuran (200mL), the mixed system was cooled to -20°C in a dry ice-ethanol bath, and sodium tert-butoxide (5.80g, 65.30 mmol), control the temperature of the reaction system to be less than -5°C, and continue to stir for 0.5 hours between -20°C and -5°C after adding, then cool the mixed system down to -20°C again, and add p-toluenesulfonic anhydride in batches (18.00 g, 57.70 mmol), after the addition, the reaction system was kept at -20°C to -5°C and continued to stir and react for 1 hour.
  • the crude product 7k (720mg) from the previous step was dissolved in methanol (3mL), methylamine-methanol solution (6mL, 42.00mmol, 7M) was added, and the mixed system was stirred and reacted at room temperature for 18 hours.
  • the crude product 15c (380 mg) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added dropwise, and the reaction was stirred at room temperature for half an hour.
  • reaction solution was cooled to room temperature, quenched with water (20mL), the aqueous phase was extracted with ethyl acetate (20mL x 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue.
  • the crude product 16c (300 mg) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added dropwise, and the reaction was stirred at room temperature for half an hour.
  • the reaction solution was concentrated under reduced pressure, the concentrate was dissolved with dichloromethane (20mL), the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted with dichloromethane (20mL x 3), and the organic phases were combined , the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue.
  • the concentrate was diluted with ethyl acetate (30mL), washed with water (20mL x 3) and saturated brine (20mL x 1) successively, and the organic phase was dried over anhydrous sodium sulfate and filtered.
  • compound 17a (0.50g, 2.52mmol) and 1a (0.54g, 2.52mmol), cesium carbonate (1.23g, 3.78mmol), Ruphos-Pd-G3 (0.11g, 0.13mmol) were dissolved in 1, 4-dioxane (20 mL), the temperature of the mixed system was raised to 90° C. for 12 hours. After the reaction was completed, water (20 mL) was added to quench the reaction.
  • the crude product 18c from the previous step was dissolved in methanol (3 mL), added dropwise into methylamine methanol solution (30% w/w, 10 mL), and stirred at room temperature under a nitrogen atmosphere for 2 hours.
  • compound 22a (0.50g, 2.31mmol) and 1-tert-butoxycarbonylpiperazine (0.43g, 2.31mmol), cesium carbonate (1.13g, 3.47mmol), Ruphos-Pd-G3 (90mg, 0.11 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL), and the mixed system was heated to 90° C. for 12 hours. After the reaction was completed, water (10 mL) was added to quench the reaction.
  • compound 22a (0.50g, 2.31mmol) and (S)-1-tert-butoxycarbonyl-2-methylpiperazine (0.46g, 2.31mmol), cesium carbonate (1.13g, 3.47mmol), Ruphos-Pd-G3 (97 mg, 0.12 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL), and the mixed system was heated to 90° C. for 12 hours. After the reaction was completed, water (10 mL) was added to quench the reaction.
  • compound 22a (0.50g, 2.31mmol) and (R)-1-tert-butoxycarbonyl-3-methylpiperazine (0.46g, 2.31mmol), cesium carbonate (1.13g, 3.47mmol), Ruphos-Pd-G3 (97 mg, 0.12 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL), and the mixed system was heated to 90° C. for 12 hours. After the reaction was completed, water (10 mL) was added to quench the reaction.
  • compound 25a (2.00g, 10.93mmol) and 1-tert-butoxycarbonylpiperazine (2.36g, 12.70mmol), cesium carbonate (5.34g, 16.39mmol), Ruphos-Pd-G3 (0.46g, 0.55 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL), and the mixed system was heated to 80° C. for 12 hours. After the reaction was completed, water (20 mL) was added to quench the reaction.
  • Dissolve compound 25b (0.50g, 1.73mmol) in methanol (6mL), add sodium methoxide (9.2mg, 0.17mmol), stir and react at room temperature for 2 hours, after the reaction of raw materials is complete, add 2,2-diethoxyethyl Amine (230mg, 1.73mmol) and glacial acetic acid (188mg, 3.13mmol), the mixed system was heated to 65°C for 0.5 hours, then methanol (1mL) and dilute hydrochloric acid (5N, 2mL) were added, and the reaction was stirred overnight at 65°C.
  • compound 25a (2.81g, 15.30mmol) and (S)-1-tert-butoxycarbonyl-2-methylpiperazine (3.00g, 15.30mmol), cesium carbonate (8.01g, 22.95mmol), Ruphos-Pd-G3 (0.60 g, 0.76 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL), and the mixed system was heated to 80° C. for 12 hours.
  • compound 25a (1.00g, 5.46mmol) and (R)-1-tert-butoxycarbonyl-2-methylpiperazine (1.11g, 5.46mmol), cesium carbonate (2.91g, 8.21mmol), Ruphos-Pd-G3 (229 mg, 0.27 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL), and the mixed system was heated to 80° C. for 12 hours. After the reaction was completed, water (20 mL) was added to quench the reaction.
  • compound 1a (1.00g, 4.62mmol) and 1-tert-butoxycarbonylpiperazine (0.86g, 4.62mmol), cesium carbonate (2.26g, 6.94mmol), Ruphos-Pd-G3 (0.19g, 0.23 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL), and the mixed system was heated to 90° C. for 12 hours. After the reaction was completed, water (20 mL) was added to quench the reaction.
  • V methanol : V dichloromethane 1:10, 300mL
  • reaction solution was cooled to room temperature, filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure to obtain a residue, the residue was diluted with ethyl acetate (500mL), the organic phase was washed with saturated aqueous sodium chloride solution (50mL x 2), washed over anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure to obtain a residue.
  • the reaction solution was filtered to remove insoluble matter, the filter cake was washed with a mixed solvent of water (200 mL), methanol (100 mL) and acetonitrile (100 mL), the combined filtrate was concentrated under reduced pressure to remove the organic phase, and the remaining aqueous phase (about 200 mL) was added with ethyl acetate (50 mL) Wash, discard the organic phase, adjust the pH of the aqueous phase to 3, add ethyl acetate (500 mL) for extraction, dry the organic phase over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the crude product 34b (2.4 g).

Abstract

L'invention concerne un composé hétérocyclique contenant de l'azote, son procédé de préparation, un intermédiaire de celui-ci, et une application de celui-ci. L'invention concerne également des composés hétérocycliques contenant de l'azote représentés par les formules II-a, II-b, I-c ou I-D, leur procédé de préparation, un intermédiaire de ceux-ci, et une application de ceux-ci. Le composé a une forte activité inhibitrice sur PARP1, présente en particulier un avantage significatif dans la sélectivité de PARP1/PARP2 sur les témoins positifs Olaparib et AZD5305, et peut réduire efficacement la toxicité sanguine provoquée par PARP2.
PCT/CN2022/120655 2021-09-22 2022-09-22 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et application de celui-ci WO2023046034A1 (fr)

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WO2023227052A1 (fr) * 2022-05-25 2023-11-30 西藏海思科制药有限公司 Inhibiteur de parp dérivé bicyclique et son utilisation
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WO2024067691A1 (fr) * 2022-09-30 2024-04-04 中国医药研究开发中心有限公司 Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique
WO2024067694A1 (fr) * 2022-09-30 2024-04-04 中国医药研究开发中心有限公司 Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique
WO2024083201A1 (fr) * 2022-10-20 2024-04-25 成都赜灵生物医药科技有限公司 Composé hétérocyclique à cycles condensés et son utilisation
WO2024082654A1 (fr) * 2022-10-20 2024-04-25 上海海和药物研究开发股份有限公司 Composés à activité inhibitrice de parp1 et leurs utilisations
WO2024083218A1 (fr) * 2022-10-20 2024-04-25 成都赜灵生物医药科技有限公司 Composé tétrahydropyridine substitué et son utilisation

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