WO2024259945A1 - Composés azotés ayant un cycle à cinq chaînons fusionné à un cycle à six chaînons, leur procédé de préparation et leur utilisation - Google Patents

Composés azotés ayant un cycle à cinq chaînons fusionné à un cycle à six chaînons, leur procédé de préparation et leur utilisation Download PDF

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WO2024259945A1
WO2024259945A1 PCT/CN2023/142929 CN2023142929W WO2024259945A1 WO 2024259945 A1 WO2024259945 A1 WO 2024259945A1 CN 2023142929 W CN2023142929 W CN 2023142929W WO 2024259945 A1 WO2024259945 A1 WO 2024259945A1
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independently
group
substituted
alkyl
unsubstituted
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贺虎
葛崇勋
刘颂
施松
崔亚琦
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Hangzhou Synrx Therapeutics Biomedical Technology Co Ltd
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Hangzhou Synrx Therapeutics Biomedical Technology Co Ltd
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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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention relates to a pentad and hexaad nitrogen-containing compound, a preparation method and application thereof.
  • PARG is the first poly(ADP-ribose) hydrolase identified and encoded by a single gene (Mirella et al. Human poly(ADP-ribose) glycohydrolase is expressed in alternative splice variants yielding isoforms that localize to different cell compartments. Experimental Cell Research, 2004, 297(2):521-532.), which can hydrolyze the O-glycosidic bonds between ADP-ribose subunits. PARG is composed of four domains (Meyer B et al. Clustered DNA damage induces pan-nuclear H2AX phosphorylation mediated by ATM and DNA-PK. Nucleic Acids Res, 2003, 41: 6109-6118.; O’Sullivan J.
  • Poly ADP-ribosylation is a unique post-translational modification that plays an important role in maintaining genome stability in different signaling pathways, especially in DNA damage repair.
  • Poly ADP-ribose referred to as PAR
  • PAR is composed of adenosine diphosphate-ribose units, with NAD + as the donor, catalyzed by poly ADP-ribose polymerase (PARPs), and can be rapidly degraded by polyribosyl hydrolases.
  • PARPs poly ADP-ribose polymerase
  • PARylation needs to be digested in time so that DNA damage response factors can directly recognize DNA damage and play a repair function.
  • dePARylation is a direct downstream step of PARylation in DNA repair. Inhibition of this process will affect PARylation-dependent DNA damage repair and selectively kill tumor cells with DNA repair defects.
  • PARG as the most important poly (ADP-ribose) hydrolase, plays a role in about 90% of PAR in cells (Laetitia D et al. Poly (ADP-ribose) glycohydrolase (PARG) and its therapeutic potential. Front Biosci, 2009, 14 (5): 1619-1626.), and plays a role in multiple cellular processes such as DNA damage repair, DNA replication, chromatin regulation, transcription and cell apoptosis.
  • the imbalance of intracellular PAR levels caused by abnormal PARG function will have a significant impact on It affects the transformation and invasion of cancer cells (Rack JD et al. Macrodomain: structure, function, evolution, and catalytic activities. Annu Rev Biochem. 2016, 85: 431-454; Marques M et al. Oncogenic activity of poly (ADP-ribose) glycohydrolase. Oncogene, 2019, 38: 2177-2191).
  • PARG has been shown to be associated with a variety of diseases, and data show that (Maud M et al, Oncogenic activity of poly(ADP-ribose) glycohydrolase.Oncogene,2019,38:2177-2191.), PARG elevation is associated with poor prognosis in HER2+ patients, PARG and HER2 synergistically promote the growth of breast cancer cells, and inhibition of PARG significantly affects the growth and migration of breast cancer.
  • the technical problem to be solved by the present invention is to overcome the relatively simple structure of PARG inhibitor compounds in the prior art, and for this purpose, the present invention provides a five-membered and six-membered nitrogen-containing compound, a preparation method and application thereof.
  • the compound of the present invention has good PARG inhibitory activity.
  • the first aspect of the present invention provides a compound as shown in Formula IV, or a pharmaceutically acceptable salt or isotope compound thereof;
  • Y is C or N
  • X is C or N
  • W is N, CH, O, NR 4 or CR 4 ;
  • Z is CH, O or N
  • Ring D is a 3-6 membered heterocycloalkyl group; the heteroatoms of the 3-6 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Ring C is a 4-12 membered heterocycloalkyl group; the heteroatoms of the 4-12 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Ring A is a 5-10 membered heteroaryl group; the heteroatom of the 5-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • R 1-3' is hydrogen or R 1-3 ;
  • Each R 2-3 is independently cyano, oxo, hydroxyl, halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-1 , 3-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 2-3-4 , C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-5 , C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 2-3-6 , amino which is unsubstituted or substituted by one or more R 2-3-7 , 5-10 membered heteroaryl which is unsubstituted or substituted by one or more R 2-3-9 ; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5-10 membered heteroaryl are selected from one or
  • Each R 2-3-1 is independently hydroxy, cyano, halogen, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 , C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 2-3-1-2 , or amino which is unsubstituted or substituted by one or more R 2-3-1-3 ;
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-4 is independently C 1 -C 6 alkyl or oxo
  • Each R 2-3-5 is independently halogen or deuterium
  • Each R 2-3-6 is independently C 1 -C 6 alkyl
  • Each R 2-3-7 is independently C 1 -C 6 alkyl
  • Each R 2-3-8 is independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • Each R 2-3-9 is independently C 1 -C 6 alkyl
  • Each R 2-3-1-1 is independently halogen or deuterium
  • Each R 2-3-1-2 is independently a C 1 -C 6 alkoxy group
  • Each R 2-3-1-3 is independently C 1 -C 6 alkyl
  • Each R 2-3-2-1 is independently halogen, carboxyl, hydroxyl, oxo, C 1 -C 6 alkoxy, Amino which is unsubstituted or substituted by one or more R 2-3-2-1-2 , or 5-10 membered heteroaryl which is unsubstituted or substituted by one or more R 2-3-2-1-3 ; the heteroatom of the 5-10 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 2-3-2-1-1 is independently a C 1 -C 6 alkyl group or a 6-10 membered aryl group;
  • Each R 2-3-2-1-2 is independently C 1 -C 6 alkyl
  • Each R 2-3-2-1-3 is independently C 1 -C 6 alkyl
  • Each R 2-3-2-2 is independently halogen, hydroxy, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-2-2-1 , or unsubstituted or C 1 -C 6 alkoxy substituted by one or more R 2-3-2-2-2 , amino unsubstituted or substituted by one or more R 2-3-2-2-3 ;
  • Each R 2-3-2-2-1 is independently halogen or hydroxy
  • Each R 2-3-2-2-2 is independently carboxy, halogen, deuterium, oxo or hydroxy;
  • Each R 2-3-2-2-3 is independently a C 1 -C 6 alkyl group
  • Each R 2-3-2-3 is independently hydrogen or Each R 2-3-2-3-1 is independently a 6-10 membered aryl group which is unsubstituted or substituted by one or more R 2-3-2-3-1-1 ; each R 2-3-2-3-1-1 is independently a C 1 -C 6 alkoxy group;
  • Each R 2-3-2-5 is independently halogen, hydroxy, oxo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-2-5-1 ; each R 2-3-2-5-1 is independently halogen;
  • Each R 2-3-2-6 is independently C 1 -C 6 alkyl
  • Each R 3-1 is independently hydroxy, halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 3-1-1 , or
  • R 3-1-1 is independently halogen or hydroxyl
  • R 3-1-2 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl
  • R 4 is hydrogen, deuterium, halogen, cyano, 5-10 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 4-1 , or C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 4-2 ;
  • the heteroatom of the 5-10 membered heterocycloalkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 4-1 is independently
  • Each R 4-2 is independently a 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more R 4-2-1 ;
  • the heteroatom of the 5-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • R 4-1-1 is a C 1 -C 6 alkyl group; each R 4-1-2 is independently a C 1 -C 6 alkyl group; each R 4-2-1 is independently a C 1 -C 6 alkyl group.
  • the compound shown in Formula IV may be a compound shown in Formula V,
  • M is N, O or S
  • Y, X, W, Z, ring C, ring A, R 1-3′ , R 1-3 , R 2-3 , R 3-1 , n, m and k are as defined above.
  • the compound shown in formula IV may be a compound shown in formula VI,
  • the compound shown in Formula IV may be a compound shown in Formula VII,
  • V1 is CH, N or O
  • V2 is CH, N or O
  • V1 and V2 are not CH at the same time
  • R 3-1' is hydrogen or R 3-1 ;
  • R V 1 is absent, hydrogen or R 2-3 ;
  • R V 2 is absent, hydrogen or R 2-3 ;
  • n 0, 1 or 2;
  • W, Z, R 1-3' , R 1-3 , R 2-3 , R 3-1 , n, m, i and j are as defined above.
  • the compound represented by formula IV may be a compound represented by formula VIII,
  • W, Z, RV1 , RV2 , R1-3 ' , R1-3 , R2-3 , R3-1' , n, m, i and j are as defined above.
  • the compound represented by formula IV may be a compound represented by formula IX,
  • U is CH 2 , NH or O
  • W, Z, R 1-3′ , R 1-3 , R 2-3 , R 3-1′ , n, m, i and j are as defined above.
  • the compound represented by formula IV may be a compound represented by formula X,
  • R G is R 2-3-2 or
  • W, Z, R 1-3' , R 1-3 , R 2-3 , R 3-1' , R 2-3-2 , R 2-3-3 , n, m, i and j are as defined above.
  • each R 1-3 is independently cyano, deuterium, hydroxyl, amino, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-3-1 , C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-3-2 , or C 2 -C 6 alkynyl; each R 1-3-1 is independently halogen; and each R 1-3-2 is independently halogen.
  • m is 1 or 2.
  • each R 2-3 is independently a C 1 -C 6 alkyl substituted by one or more R 2-3-1 , 3-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 2-3-4 , amino which is unsubstituted or substituted by one or more R 2-3-7 , A 5-10 membered heteroaryl substituted by one or more R 2-3-9 ;
  • the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • the heteroatoms of the 5-10 membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 2-3-1 is independently cyano, or C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 2-3-1-2 ;
  • R 2-3-2 is hydrogen or C 1 -C 6 alkyl substituted by one or more R 2-3-2-1 , C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 , 3-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 2-3-2-5 , 5-10 membered heteroaryl which is unsubstituted or substituted by one or more R 2-3-2-6 ; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5-10 membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 2-3-4 is independently C 1 -C 6 alkyl
  • Each R 2-3-7 is independently C 1 -C 6 alkyl
  • Each R 2-3-9 is independently oxo or C 1 -C 6 alkyl
  • Each R 2-3-1-2 is independently C 1 -C 6 alkoxy; each R 2-3-2-1 is independently hydroxyl, oxo, A 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more R 2-3-2-1-3 ; wherein the heteroatom of the 5-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
  • Each R 2-3-2-1-1 is independently a C 1 -C 6 alkyl group or a 6-10 membered aryl group; each R 2-3-2-1-2 is independently a C 1 -C 6 alkyl group; each R 2-3-2-1-3 is independently a C 1 -C 6 alkyl group;
  • Each R 2-3-2-2 is independently halogen, hydroxy, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-2-2-1 , C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-2-2-2 , or amino which is unsubstituted or substituted by one or more R 2-3-2-2-3 ;
  • Each R 2-3-2-2-1 is independently halogen or hydroxy
  • Each R 2-3-2-2-2 is independently halogen, deuterium, oxo or hydroxy
  • Each R 2-3-2-2-3 is independently a C 1 -C 6 alkyl group
  • Each R 2-3-2-3 is independently hydrogen or Each R 2-3-2-3-1 is independently a 6-10 membered aryl group which is unsubstituted or substituted by one or more R 2-3-2-3-1-1 ; each R 2-3-2-3-1-1 is independently a C 1 -C 6 alkoxy group;
  • Each R 2-3-2-4 is independently halogen
  • Each R 2-3-2-5 is independently halogen, hydroxy, oxo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl substituted with one or more R 2-3-2-5-1 ; each R 2-3-2-5-1 is independently halogen;
  • Each R 2-3-2-6 is independently a C 1 -C 6 alkyl group.
  • each R 3-1 is independently hydroxyl, halogen, C 1 -C 6 alkyl substituted by one or more R 3-1-1 , or
  • Each R 3-1-1 is independently a hydroxyl group; and R 3-1-2 is a C 1 -C 6 alkyl group or a C 2 -C 6 alkenyl group.
  • R 4 is deuterium, cyano, a 5-10 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R 4-1 , or a C 1 -C 6 alkyl group which is substituted by one or more R 4-2 ;
  • the heteroatom of the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 4-1 is independently
  • Each R 4-2 is independently a 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more R 4-2-1 ;
  • the heteroatom of the 5-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • R 4-1-1 is a C 1 -C 6 alkyl group; each R 4-1-2 is independently a C 1 -C 6 alkyl group; each R 4-2-1 is independently a C 1 -C 6 alkyl group.
  • each R 1-3 is independently cyano, deuterium, hydroxyl, amino, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-3-1 , C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-3-2 , or C 2 -C 6 alkynyl.
  • each R 1-3-1 is independently halogen.
  • each R 1-3-2 is independently halogen.
  • each R 2-3-1 is independently cyano, or C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 2-3-1-2 .
  • R 2-3-2 is hydrogen or C 1 -C 6 alkyl substituted by one or more R 2-3-2-1 , C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 , 3-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 2-3-2-5 , 5-10 membered heteroaryl which is unsubstituted or substituted by one or more R 2-3-2-6 ; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1 , 2 or 3; the heteroatoms of the 5-10 membered heteroaryl are selected from one or more of N, O and S , and the number of heteroatoms is 1, 2 or 3.
  • each R 2-3-4 is independently a C 1 -C 6 alkyl group.
  • each R 2-3-7 is independently a C 1 -C 6 alkyl group.
  • each R 2-3-9 is independently oxo or C 1 -C 6 alkyl.
  • each R 2-3-1-2 is independently C 1 -C 6 alkoxy; each R 2-3-2-1 is independently hydroxyl, oxo, A 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more R 2-3-2-1-3 ; the heteroatoms of the 5-10 membered heteroaryl group are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3.
  • each R 2-3-2-1-1 is independently a C 1 -C 6 alkyl group or a 6-10 membered aryl group; each R 2-3-2-1-2 is independently a C 1 -C 6 alkyl group; and each R 2-3-2-1-3 is independently a C 1 -C 6 alkyl group.
  • each R 2-3-2-2 is independently halogen, hydroxyl, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-2-2-1 , C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-2-2-2 , or C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-2-2-3 .
  • Substituted amino group is independently halogen, hydroxyl, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-2-2-1 , C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-2-2-2 , or C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-2-2-3 .
  • each R 2-3-2-2-1 is independently halogen or hydroxyl.
  • each R 2-3-2-2-2 is independently halogen, deuterium, oxo or hydroxy.
  • each R 2-3-2-2-3 is independently a C 1 -C 6 alkyl group.
  • each R 2-3-2-3 is independently hydrogen or
  • each R 2-3-2-3-1 is independently a 6-10 membered aryl group which is unsubstituted or substituted by one or more R 2-3-2-3-1-1 ; and each R 2-3-2-3-1-1 is independently a C 1 -C 6 alkoxy group.
  • each R 2-3-2-4 is independently halogen.
  • each R 2-3-2-5 is independently halogen, hydroxy, oxo, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl substituted by one or more R 2-3- 2-5-1 ; each R 2-3-2-5-1 is independently halogen.
  • each R 2-3-2-6 is independently a C 1 -C 6 alkyl group.
  • each R 3-1-1 is independently a hydroxyl group; and R 3-1-2 is a C 1 -C 6 alkyl group or a C 2 -C 6 alkenyl group.
  • R 4 is deuterium, cyano, a 5-10 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R 4-1 , or a C 1 -C 6 alkyl group which is substituted by one or more R 4-2 ; the heteroatom of the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3.
  • each R 4-1 is independently
  • each R 4-2 is independently a 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more R 4-2-1 ; the heteroatoms of the 5-10 membered heteroaryl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • R 4-1-1 is a C 1 -C 6 alkyl group.
  • each R 4-1-2 is independently a C 1 -C 6 alkyl group.
  • each R 4-2-1 is independently a C 1 -C 6 alkyl group.
  • each R 1-3 is independently cyano, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 1-3-1 , or C 2 -C 6 alkynyl.
  • each R 1-3-1 is independently halogen or deuterium.
  • each R 1-3-1 is independently halogen.
  • each R 2-3 is independently oxo, unsubstituted or substituted by one or more R 2-3-1 C 1 -C 6 alkyl,
  • each R 2-3 is independently 5-10 membered heteroaryl; the heteroatom of the 5-10 membered heteroaryl is N and/or O, and the number of the heteroatoms is 2 or 3.
  • each R 2-3-1-1 is independently deuterium.
  • each R 2-3-1-3 is independently C 1 -C 6 alkyl.
  • R 2-3-2 is C 1 -C 6 alkyl substituted by one or more R 2-3-2-1 , C 3 -C 6 cycloalkyl unsubstituted or substituted by one or more R 2-3-2-2 , 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl which is unsubstituted or substituted by one or more R 2-3-2-5 ;
  • the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • the heteroatoms of the 5-10 membered heteroaryl are N and/or O, and the number of heteroatoms is 1 or 2.
  • R 2-3-2 is C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl which is unsubstituted or substituted with one or more R 2-3-2-2 .
  • each R 2-3-2-1 is independently hydroxyl
  • each R 2-3-2-1-1 is independently C 1 -C 6 alkyl.
  • each R 2-3-2-2 is independently halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-2-2-2 , or amino.
  • each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 .
  • each R 2-3-2-2-2 is independently deuterium.
  • each R 2-3-2-3 is independently hydrogen or
  • each R 2-3-2-3-1 is independently a 6-10 membered aryl group which is unsubstituted or substituted with one or more R 2-3-2-3-1-1 .
  • each R 2-3-2-3-1-1 is independently C 1 -C 6 alkoxy.
  • each R 2-3-2-3-1 is independently a 6-10 membered aryl group which is unsubstituted or substituted with one or more R 2-3-2-3-1-1 ; and each R 2-3-2-3-1-1 is independently a C 1 -C 6 alkoxy group.
  • each R 2-3-2-5 is independently halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-2-5-1 .
  • each R 2-3-3-1 is independently amino which is unsubstituted or substituted with one or more R 2-3-3-1-1 .
  • each R 2-3-3-1-1 is independently C 1 -C 6 alkyl.
  • ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3.
  • each R 3-1 is independently a C 1 -C 6 alkyl substituted with one or more R 3-1-1 .
  • each R 3-1-1 is independently halogen.
  • ring A is R 3-1 is -CF 3 .
  • R 4 is deuterium, cyano, or a 5-10 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R 4-1 ; the heteroatom of the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatoms is 1 or 2.
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • each R 4-1 is independently R 4-1-1 is a C 1 -C 6 alkyl group.
  • Each R 1-3 is independently cyano, C 1 -C 6 alkyl, or C 2 -C 6 alkynyl which is unsubstituted or substituted by one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen or deuterium
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 ,
  • Each R 2-3-1 is independently hydroxy, halogen, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 , or amino which is unsubstituted or substituted by one or more R 2-3-1-3 ;
  • each R 2-3-1-1 is independently deuterium
  • Each R 2-3-1-3 is independently C 1 -C 6 alkyl
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • Each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group
  • Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3;
  • Each R 3-1 is independently a C 1 -C 6 alkyl group substituted with one or more R 3-1-1 ;
  • Each R 3-1-1 is independently halogen
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • Each R 1-3 is independently cyano, C 1 -C 6 alkyl, or C 2 -C 6 alkynyl which is unsubstituted or substituted by one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 ,
  • Each R 2-3-1 is independently hydroxy, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 ;
  • each R 2-3-1-1 is independently deuterium
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • Each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group
  • Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3;
  • Each R 3-1 is independently a C 1 -C 6 alkyl group substituted with one or more R 3-1-1 ;
  • Each R 3-1-1 is independently halogen
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • the heteroatom of the 3-6 membered heterocycloalkyl is O, and the number of the heteroatom is 1.
  • the 3-6-membered heterocycloalkyl group is a 4-membered heterocycloalkyl group.
  • each R 1-3 is independently cyano, or C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 1-3-1 .
  • each R 1-3 is independently a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-3-1 .
  • each R 1-3-1 is independently halogen.
  • the heteroatom of the 4-12 membered heterocycloalkyl group is N and/or O, and the number of the heteroatoms is 1, 2 or 3.
  • each R 2-3 is independently oxo, hydroxyl, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-1 , C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 2-3-6 .
  • each R 2-3 is independently oxo, unsubstituted or substituted by one or more R 2-3-1 C 1 -C 6 alkyl, Unsubstituted C 3 -C 6 cycloalkyl.
  • each R 2-3 is independently oxo, unsubstituted or substituted by one or more R 2-3-1 C 1 -C 6 alkyl,
  • each R 2-3-1 is independently hydroxy, halogen, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 , or amino which is unsubstituted or substituted by one or more R 2-3-1-3 .
  • each R 2-3-1 is independently hydroxyl, or C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 .
  • R 2-3-2 is unsubstituted C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 2-3-2-2 .
  • each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-3-1 .
  • each R 2-3-6 is independently a C 1 -C 6 alkyl group.
  • each R 2-3-1-1 is independently halogen or deuterium.
  • each R 2-3-1-1 is independently halogen.
  • each R 2-3-1-1 is independently deuterium.
  • each R 2-3-1-3 is independently a C 1 -C 6 alkyl group.
  • each R 2-3-2-2 is independently an unsubstituted C 1 -C 6 alkyl group, or an unsubstituted C 1 -C 6 alkoxy group which is or is substituted with one or more R 2-3-2-2-2 .
  • each R 2-3-2-2-2 is independently deuterium.
  • each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted by one or more R 2-3-3-1-1 .
  • each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group.
  • the heteroatom of the 5-10 membered heteroaryl group is N and/or S, and the number of heteroatoms is 1, 2 or 3.
  • each R 3-1 is independently a C 1 -C 6 alkyl group substituted by one or more R 3-1-1 .
  • each R 3-1-1 is independently halogen or hydroxyl.
  • W is N, CH or CR 4 .
  • R 4 is deuterium, halogen, or unsubstituted C 1 -C 6 alkyl.
  • Each R 1-3 is independently cyano, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 ,
  • Each R 2-3-1 is independently hydroxy, halogen, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 , amino which is unsubstituted or substituted by one or more R 2-3-1-3 ;
  • each R 2-3-1-1 is independently deuterium
  • Each R 2-3-1-3 is independently C 1 -C 6 alkyl
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently amino which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • W is N, CH or CR 4 ;
  • Z is CH or N
  • Ring D is a 3-6 membered heterocycloalkyl group; the heteroatoms of the 3-6 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • n 0;
  • R 1-3′ is R 1-3 ;
  • R 1-3 is cyano, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen
  • Ring C is a 4-12 membered heterocycloalkyl group; the heteroatoms of the 4-12 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • n 0, 1 or 2;
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 ,
  • Each R 2-3-1 is independently hydroxy, halogen, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 , or amino which is unsubstituted or substituted by one or more R 2-3-1-3 ;
  • each R 2-3-1-1 is independently deuterium
  • Each R 2-3-1-3 is independently C 1 -C 6 alkyl
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • Each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group
  • Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3;
  • k 1;
  • Each R 3-1 is independently a C 1 -C 6 alkyl group substituted with one or more R 3-1-1 ;
  • Each R 3-1-1 is independently halogen
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • Each R 1-3 is independently a C 1 -C 6 alkyl group which is unsubstituted or substituted with one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 , unsubstituted C 3 -C 6 cycloalkyl;
  • Each R 2-3-1 is independently hydroxy, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 ;
  • each R 2-3-1-1 is independently deuterium
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • Each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group
  • Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3;
  • Each R 3-1 is independently a C 1 -C 6 alkyl group substituted with one or more R 3-1-1 ;
  • Each R 3-1-1 is independently halogen
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • W is N, CH or CR 4 ;
  • Z is CH or N
  • Ring D is a 3-6 membered heterocycloalkyl group; the heteroatoms of the 3-6 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • n 0;
  • R 1-3′ is R 1-3 ;
  • R 1-3 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen
  • Ring C is a 4-12 membered heterocycloalkyl group; the heteroatoms of the 4-12 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • n 0, 1 or 2;
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 , unsubstituted C 3 -C 6 cycloalkyl;
  • Each R 2-3-1 is independently hydroxy, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 ;
  • each R 2-3-1-1 is independently deuterium
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • Each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group
  • Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3;
  • k 1;
  • Each R 3-1 is independently a C 1 -C 6 alkyl group substituted with one or more R 3-1-1 ;
  • Each R 3-1-1 is independently halogen
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • Each R 1-3 is independently a C 1 -C 6 alkyl group which is unsubstituted or substituted with one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 ,
  • Each R 2-3-1 is independently hydroxy, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 ;
  • each R 2-3-1-1 is independently deuterium
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • Each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group
  • Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3;
  • Each R 3-1 is independently a C 1 -C 6 alkyl group substituted with one or more R 3-1-1 ;
  • Each R 3-1-1 is independently halogen
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • W is N, CH or CR 4 ;
  • Z is CH or N
  • Ring D is a 3-6 membered heterocycloalkyl group; the heteroatoms of the 3-6 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • n 0;
  • R 1-3′ is R 1-3 ;
  • R 1-3 is C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 1-3-1 ;
  • Each R 1-3-1 is independently halogen
  • Ring C is a 4-12 membered heterocycloalkyl group; the heteroatoms of the 4-12 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • n 0, 1 or 2;
  • Each R 2-3 is independently oxo, unsubstituted or C 1 -C 6 alkyl substituted by one or more R 2-3-1 ,
  • Each R 2-3-1 is independently hydroxy, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 2-3-1-1 ;
  • each R 2-3-1-1 is independently deuterium
  • R 2-3-2 is C 1 -C 6 alkyl, unsubstituted or C 3 -C 6 cycloalkyl substituted by one or more R 2-3-2-2 ;
  • Each R 2-3-2-2 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more R 2-3-2-2-2 ;
  • each R 2-3-2-2-2 is independently deuterium
  • Each R 2-3-3 is independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 2-3-3-1 ;
  • Each R 2-3-3-1 is independently an amino group which is unsubstituted or substituted with one or more R 2-3-3-1-1 ;
  • Each R 2-3-3-1-1 is independently a C 1 -C 6 alkyl group
  • Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 3;
  • k 1;
  • Each R 3-1 is independently a C 1 -C 6 alkyl group substituted with one or more R 3-1-1 ;
  • Each R 3-1-1 is independently halogen
  • R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, and may be methoxy or ethoxy.
  • the C 2 -C 6 alkynyl group is For example
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, which can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, and can also be methyl, ethyl, isopropyl or tert-butyl.
  • the heteroatom of the 3-6 membered heterocycloalkyl group may be N, O or S, and the number of heteroatoms may be The number of heteroatoms in the 3-6 membered heterocycloalkyl group may be 1 or 2; the heteroatoms in the 3-6 membered heterocycloalkyl group may also be O or N, and the number of heteroatoms may also be 1; for example
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, and may be methoxy, ethoxy or isopropoxy.
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.
  • the 5-10 membered heteroaryl group is a 5-membered heteroaryl group or a 6-membered heteroaryl group.
  • the heteroatom of the 5-10 membered heteroaryl group is N and/or O, and the number of heteroatoms is 1, 2 or 3.
  • the heteroatom of the 5-membered heteroaryl group may be N and/or O, and the number of heteroatoms is 2 or 3, for example
  • the heteroatom of the 6-membered heteroaryl group may be N, and the number of heteroatoms may be 1 or 2, for example
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy or ethoxy.
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.
  • the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, which can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, and can also be methyl, ethyl, isopropyl or tert-butyl.
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl or cyclobutyl.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, isopropoxy.
  • the heteroatom of the 3-6 membered heterocycloalkyl is selected from one or more of N, O and S, and the number of heteroatoms may be 1 or 2; for example
  • the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group or a 5- and 6-membered heteroaryl group.
  • the heteroatoms of the 5-10 membered heteroaryl group are N and/or O, and the number of heteroatoms is 1 or 2.
  • the heteroatoms of the 5-membered heteroaryl group may be N and/or O. or O, and the number of heteroatoms is 2.
  • the heteroatom of the 6-membered heteroaryl group may be N, and the number of heteroatoms is 1.
  • the heteroatom of the 5-membered and 6-membered heteroaryl group may be O, and the number of heteroatoms is 2.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl or ethyl.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be an isopropyl group.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl or isopropyl.
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.
  • the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy.
  • the 5-10 membered heteroaryl group is a 5-membered heteroaryl group.
  • the heteroatom of the 5-membered heteroaryl group may be N, and the number of heteroatoms is 3.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the 6-10 membered aryl group may be phenyl or naphthyl, for example phenyl.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, and may also be methyl.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, and may be methoxy, ethoxy or n-propoxy.
  • the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
  • the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prim-butyl, sec-butyl or tert-butyl, such as methyl.
  • the 6-10 membered aryl group is phenyl or naphthyl, for example phenyl.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy.
  • the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
  • the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, first-butoxy, second-butoxy or tert-butoxy, such as methoxy.
  • the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, for example, methyl, ethyl, n-propyl or isopropyl.
  • the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, such as methyl.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group or an ethyl group.
  • the C 2 -C 6 alkenyl group may be
  • the C 2 -C 6 alkenyl group may be
  • the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.
  • the 5-10 membered heterocycloalkyl group may be a spiro ring.
  • the spiro ring may be a 4-ring spiro 6-ring, a 4-ring spiro 5-ring, a
  • the heteroatom of the 4-10 membered heterocycloalkyl group may be N, and the number of the heteroatoms is 1 or 2.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.
  • the 5-10-membered heteroaryl group is a 5-membered heteroaryl group.
  • the heteroatom of the 5-membered heteroaryl group can be selected from N and/or S, and the number of heteroatoms is 2.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a primary butyl group, a secondary butyl group or a tertiary butyl group, or may be a methyl group or an isopropyl group.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.
  • Y is N.
  • X is C.
  • W is N, CH or CR 4
  • R 4 is chloro, deuterium or methyl.
  • Z is CH or N.
  • ring D is
  • n is zero.
  • R 1-3' is hydrogen, cyano, methyl
  • ring C is
  • R 2-3 is hydroxy, oxo, methyl, -CF 3 ,
  • ring A is
  • k is 1.
  • R 3-1 is -CHF 2 , -CF 3 ,
  • the compound shown in formula IV is any of the following compounds:
  • the second aspect of the present invention provides any one of the following compounds, or a pharmaceutically acceptable salt or isotope compound thereof;
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound as shown in formula IV as described in the first aspect of the present invention, any compound as described in the second aspect of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.
  • the present invention also provides a substance Z for use as a drug; the substance Z is a compound as shown in formula IV as described in the first aspect of the present invention, any compound as described in the second aspect of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.
  • the present invention also provides a substance Z for treating breast cancer, wherein the substance Z is a compound as shown in formula IV as described in the first aspect of the present invention, any compound as described in the second aspect of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.
  • the present invention also provides an application of a substance Z in the preparation of a PARG inhibitor and a drug for treating and/or preventing PARG-related diseases, wherein the substance Z is a compound as shown in formula IV as described in the first aspect of the present invention, any compound as described in the second aspect of the present invention, Its pharmaceutically acceptable salt or isotope compound.
  • the PARG-related disease is breast cancer, such as triple-negative breast cancer, and other PARG-related diseases.
  • the present invention also provides an application of a substance Z in the preparation of a drug for treating and/or preventing breast cancer, wherein the substance Z is a compound as shown in formula IV as described in the first aspect of the present invention, any compound as described in the second aspect of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.
  • the breast cancer is triple-negative breast cancer.
  • the present invention also provides a method for treating and/or preventing PARG-related diseases, comprising administering to a patient an effective amount of substance Z, wherein substance Z is a compound as shown in formula IV as described in the first aspect of the present invention, any compound as described in the second aspect of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.
  • the PARG-related disease is breast cancer, such as triple-negative breast cancer, and other PARG-related diseases.
  • the present invention also provides a substance Z for treating and/or preventing PARG-related diseases, wherein the substance Z is a compound as shown in formula IV as described in the first aspect of the present invention, any compound as described in the second aspect of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.
  • the PARG-related disease is breast cancer, such as triple-negative breast cancer, and other PARG-related diseases.
  • a group B which is unsubstituted or substituted by multiple groups A means that one or more hydrogen atoms in the group B are independently replaced by a group A or B is unsubstituted.
  • groups A appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other.
  • a C 6 ⁇ C 10 aryl group substituted by 3 halogens means that a C 6 ⁇ C 10 aryl group is substituted by 3 halogens, and the definitions of the 3 halogens are independent of each other and do not affect each other, including but not limited to: wait.
  • a double bond or a single bond is
  • plurality refers to 2 or more, for example, 2, 3, 4, 5.
  • pharmaceutically acceptable means relatively non-toxic, safe, and suitable for use by patients.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting 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.
  • an acid addition salt can be obtained by contacting 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, formates, methanesulfonates, and the like. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • the halogen substitution in the present invention includes, but is not limited to, substitution by one halogen, substitution by two halogens, substitution by three halogens, and usually multiple substitutions occur on one carbon atom.
  • alkyl refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 1 to C 6 ).
  • Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • alkoxy refers to the group R X -O-, where R X is defined as the term “alkyl”. Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • alkenyl refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 2 to C 6 ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 double bonds.
  • Alkenyl groups include, but are not limited to, vinyl, wait.
  • alkynyl refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 2 to C 6 ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 triple bonds.
  • Alkynyl groups include, but are not limited to, ethynyl, wait.
  • cycloalkyl refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 3 to C 10 ), which is a single ring or multiple rings (e.g., 2 or 3, bridged rings, spiro rings, and fused rings), with two or more carbon atoms shared between the single rings.
  • the single ring includes, but is not limited to: etc.
  • Bridged ring cycloalkyl groups include but are not limited to: Spirocyclic cycloalkyl groups include, but are not limited to: Etc.
  • Cycloalkyl groups include but are not limited to: wait.
  • aryl refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 6 to C 10 ), which is a single ring or multiple rings (e.g., 2 or 3). When it is a multiple ring, the single rings share two atoms and a bond, and (at least one ring/each ring) has aromaticity.
  • Aryl includes but is not limited to: phenyl, naphthyl, wait.
  • heterocycloalkyl refers to a monocyclic, bridged, spirocyclic, or fused ring having a specified number of ring atoms (e.g., 3 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S).
  • the heterocycloalkyl may be saturated or unsaturated. (Monocyclic) heterocycloalkyl is connected to the rest of the molecule via a carbon atom or a heteroatom.
  • Monocyclic heterocycloalkyl includes, but is not limited to: Spirocyclic heterocycloalkyl groups include but are not limited to: etc.
  • Bridged heterocycloalkyl groups include but are not limited to: Etc.
  • Cyclic heterocycloalkyl includes Unsaturated heterocycloalkyl means that there is a carbon-carbon double bond or a carbon-carbon triple bond in the heterocycloalkyl group, for example
  • heteroaryl refers to a cyclic, unsaturated, monovalent group with a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is a single ring or multiple rings, with two atoms and a bond shared between the single rings, and at least one ring having aromatic properties.
  • heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties.
  • Heteroaryl groups include, but are not limited to: wait.
  • isotopic compound refers to a compound in which one or more atoms have an isotopic abundance that differs from its natural abundance. For example, one or more atoms in a compound has been replaced by an atom with a lower mass number than is found in nature - a hydrogen atom in a compound The atom is replaced by deuterium, or C is replaced by 13 C.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive improvement effect of the present invention is that the compound of the present invention has good PARG inhibitory activity.
  • All compounds of the present invention can be synthesized by different methods by those skilled in the art of organic chemistry.
  • the following describes a general synthetic scheme for preparing the compounds of the present invention. These schemes are general, but are not meant to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein.
  • the different methods for preparing the compounds of the present invention will be apparent to those skilled in the art.
  • the various steps in the synthesis can be performed in an alternating order to obtain the desired one or more compounds.
  • the preparation and examples described below give examples of the preparation of the compounds of the present invention by the methods described in the general scheme.
  • the preparation of compounds containing chiral center embodiments can be performed by techniques mastered by those skilled in the art. For example, chiral compounds can be prepared by chiral separation of racemic products by HPLC; alternatively, the example compounds can be prepared by known methods to obtain chiral compounds.
  • the preparation of the compounds and the intermediates used in the preparation of the compounds can be prepared using the procedures shown in the following examples and related procedures.
  • the methods and conditions used in these examples and the actual compounds prepared in these examples are not meant to be limiting, but are meant to illustrate how to prepare the related compounds.
  • the starting materials and reagents used in these examples, when not prepared by the procedures described herein, are generally available on the market, or reported in the relevant chemical literature, or can be prepared by using the procedures described in the chemical literature.
  • drying and concentrating generally refers to the addition of anhydrous sodium sulfate or magnesium sulfate drying solution to an organic solvent, followed by filtration and removal of the solvent from the filtrate (generally performed under reduced pressure and at a temperature appropriate to the stability of the compound being prepared).
  • Column chromatography is generally performed using conventional column chromatography or flash column chromatography for column separation and purification, or using a medium pressure chromatograph (Biotage Isola One) pre-packed with silica gel columns and eluted in a specified solvent or solvent mixture.
  • the final product is rapidly purified by preparative thin layer chromatography using 20cm x 20cm x 0.5mm or 20cm x 20cm x 1mm silica gel plates in an appropriate solvent system.
  • Preparative high performance liquid chromatography HPLC is performed using a reverse phase column (Waters Sunfire C18, Waters Xbridge C18 or similar reverse phase column) of a size appropriate to the amount of compound to be separated, typically using a gradient of methanol or acetonitrile concentration added to the aqueous phase, with the eluent containing 0.05% or 0.1% formic acid, trifluoroacetic acid or 10 mM ammonium acetate, with an elution rate matching the size of the reverse phase column used and the resolution of the preparation.
  • a reverse phase column Waters Sunfire C18, Waters Xbridge C18 or similar reverse phase column
  • Step 1 6-Bromo-8-chloro-N'-(2,2,2-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide
  • trifluoroacetic anhydride (435 mg, 2.07 mmol) was added to a solution of 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carbohydrazide (600 mg, 2.07 mmol) in dichloromethane (6 mL). The reaction solution was stirred at room temperature for 30 minutes. After the reaction was complete, water was added and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole
  • Lawesson's reagent (692 mg, 1.71 mmol) was added to a solution of 6-bromo-8-chloro-N'-(2,2,2-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide (600 mg, 1.56 mmol) in anhydrous toluene (6 mL).
  • the reaction solution was stirred at 110°C for 4 hours. After the reaction was complete, sodium bicarbonate was added and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • N,N-diisopropylethylamine 505 mg, 3.91 mmol
  • Xantphos 151 mg, 0.26 mmol
  • Pd 2 (dba) 3 119 mg, 0.13 mmol
  • 2-(6-bromo- 8 -chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole 500 mg, 1.30 mmol
  • benzyl mercaptan 0.15 mL, 1.30 mmol
  • 1,4-dioxane 5 mL
  • Step 4 1,8-Dichloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride
  • Step 5 1,8-dichloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyrrolidone Pyridine-6-sulfonamide
  • Step 6 1,8-dichloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylmethoxy)-1,3,4-thiadiazol-2-yl)- Silyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 6-Bromo-8-chloro-N'-(2,2,2-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide
  • trifluoroacetic anhydride (435 mg, 2.07 mmol) was added to a solution of 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carbohydrazide (600 mg, 2.07 mmol) in dichloromethane (6 mL). The reaction solution was stirred at room temperature for 30 minutes. After the reaction was complete, water was added and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole
  • Lawesson's reagent (692 mg, 1.71 mmol) was added to a solution of 6-bromo-8-chloro-N'-(2,2,2-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide (600 mg, 1.56 mmol) in anhydrous toluene (6 mL).
  • the reaction solution was stirred at 110°C for 4 hours. After the reaction was complete, sodium bicarbonate was added and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 2-(6-(Benzylthio)-1-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole
  • NBS NBS (213 mg, 1.20 mmol) was added to a solution of 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (510 mg, 1.20 mmol) in N,N-dimethylformamide (5 mL).
  • the reaction solution was stirred at room temperature for 30 minutes. After the reaction was complete, water was added and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 5 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride
  • Step 1 1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 2 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • step 1 of intermediate 5 Referring to the synthesis method of step 1 of intermediate 5, except that the starting material is 3-fluoromethyloxetane-3-amine, intermediate 7 is obtained.
  • Step 1 (S)-4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetane-3-yl)-N-(2-(trimethyl)- tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate
  • Step 2 (S)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-(methoxymethyl)piperazin-1-yl)-N-(3-methyloxazol-2-yl)- Cyclobutane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was slowly dripped into a 5% sodium bicarbonate aqueous solution cooled in an ice-water bath, and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 10-50% acetonitrile in H 2 O and 0.1% FA) to give the title compound (yellow solid, 278 mg, 54.4% yield).
  • Example 2 The following examples are prepared by referring to the preparation method of Example 1, starting from appropriate starting materials, and synthesizing the crude product according to a similar route .
  • the crude product is prepared by reverse phase HPLC and freeze-dried to obtain the title compound.
  • Example 5 1-Chloro-8-(4-(1-methoxycyclopropane-1-carbonyl)piperazin-1-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl )-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 1-chloro-8-(4-(1-methoxycyclopropane-1-carbonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was stirred at 80°C under nitrogen protection for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-100% ethyl acetate) to give the title compound (yellow solid, 30 mg, yield 30.2%). LC/MS (ESI) (m/z): 766 [M+H] + .
  • Step 2 1-chloro-8-(4-(1-methoxycyclopropane-1-carbonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 6 8-(4-(1-ethylcyclopropane-1-carbonyl)piperazin-1-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4 -thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 8-(4-(1-ethylcyclopropane-1-carbonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4- Thiadiazole-2-yl)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was stirred at 80°C under nitrogen protection for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-80% ethyl acetate) to give the title compound (yellow solid, 30 mg, yield 60%). LC/MS (ESI) (m/z): 730 [M+H] + .
  • Step 2 8-(4-(1-ethylcyclopropane-1-carbonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4- Thiadiazole-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 6 The following examples are prepared with reference to the preparation method of Example 6. Starting from appropriate starting materials, the crude product is synthesized along a similar route . The crude product is prepared by reverse phase HPLC and freeze-dried to obtain the title compound.
  • Example 10 8-((3S,5S)-4-cyclopropyl-3,5-dimethylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3 - methyloxetane- 3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetane-3-yl)-N-(2-(trimethyl)- tert-butyl silyl)ethoxy)methyl)aminosulfonyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
  • reaction mixture was replaced with nitrogen three times and stirred at 80° C. for 2 hours under nitrogen protection.
  • reaction solution is diluted with ethyl acetate, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue is purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-35% ethyl acetate) to obtain the title compound (yellow solid, 120 mg, yield 91.4%).
  • Step 2 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetane -3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 3 8-((3S,5S)-4-cyclopropyl-3,5-dimethylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyl Oxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was stirred at 60°C under nitrogen protection for 4 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 10-50% acetonitrile in H 2 O and 0.1% FA) to give the title compound (yellow solid, 1.54 mg, yield 2.0%).
  • Step 1 Benzyl (3S,5S)-3,5-dimethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine-1-carboxylate
  • Step 3 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethyl-4-(2-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was replaced with nitrogen three times and reacted with stirring at 80° C. for 3 hours under nitrogen protection. After the reaction is complete, the reaction solution is cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-45% ethyl acetate) to obtain the title compound (yellow solid, 30 mg, yield 69%). LC/MS (ESI) m/z: 772 [M+H] + .
  • Step 4 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 12 8-((2S,6S)-2,6-dimethylmorpholinyl)-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 Methyl (5-(8-((2S,6S)-2,6-dimethylmorpholinyl)-6-(N-(3-methyloxetan-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo[1,5-a]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate
  • reaction solution was replaced with nitrogen three times and stirred at 80°C for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-45% ethyl acetate) to give the title compound (white solid, 30 mg, yield 74%). LC/MS (ESI) m/z: 667 [M+H] + .
  • Step 2 Methyl (5-(8-((2S,6S)-2,6-dimethylmorpholinyl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)imidazo[1,5-a]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate
  • Trifluoroacetic acid (1 mL) was added to a solution of methyl (5-(8-((2S,6S)-2,6-dimethylmorpholinyl)-6-(N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo[1,5-a]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate (13 mg, 0.01 mmol) in dichloromethane (3 mL) at 0°C. The reaction solution was stirred at 0°C for 1 hour. After the reaction was complete, water was added and extracted with dichloromethane.
  • Step 3 8-((2S.6S)-2,6-dimethylmorpholinyl)-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 Methyl (5-(8-(2-(methoxymethyl)piperazine-1-carboxylate)-6-(N-(3-methyloxetan-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo[1,5-a]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate
  • reaction solution was replaced with nitrogen three times and stirred at 80°C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-45% ethyl acetate) to give the title compound (white solid, 30 mg, yield 64%). LC/MS (ESI) m/z: 782 [M+H] + .
  • Step 2 Methyl (5-(8-(3-(methoxymethyl)piperazin-1-yl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)imidazo[1,5-a]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate
  • Trifluoroacetic acid (1 mL) was added to a solution of methyl (5-(8-(2-(methoxymethyl)piperazine-1-carboxylate tert-butyl)-6-(N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo[1,5-a]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate (30 mg, 0.03 mmol) in dichloromethane (3 mL) at 0°C. The reaction solution was stirred at 0°C for 1 hour. After the reaction was complete, water was added and extracted with dichloromethane.
  • Step 3 3-(5-(Hydroxymethyl)-1,3,4-thiadiazol-2-yl)-8-(3-(methoxymethyl)piperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Tetraethyl titanate (1.3 g, 5.7 mmol) was added to a solution of 2-methyl-N-(oxetane-3-ylidene)propane-2-sulfenamide (1 g, 5.7 mmol) in dichloromethane (20 mL). After the addition was completed, the reaction mixture was stirred for 10 minutes. Trimethylsilyl cyanide (1.5 mL, 11.4 mmol) was continued to be added to the above reaction solution. The reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into saturated brine, filtered, and the filtrate was extracted three times with dichloromethane.
  • Step 3 1-Bromo-8-chloro-N-(3-cyanoxetane-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 4 1-Bromo-8-chloro-N-(3-cyanoxetane-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 5 8-Chloro-N-(3-cyanoxetane-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 6 N-(3-cyanoxetane-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2,4-dimethoxybenzyl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 7 N-(3-cyanooxetane-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 N-(3-(difluoro(phenylsulfonyl)methyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide
  • Step 4 1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(difluoromethyl)oxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • 3-(difluoromethyl)oxetane-3-amine hydrochloride (206 mg, 1.29 mmol) in pyridine (5 mL) was separated into 1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (300 mg, 0.65 mmol) was added in batches, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was acidified to pH ⁇ 5 with 1N hydrochloric acid and extracted with ethyl acetate.
  • Step 5 1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(difluoromethyl)oxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • N,N-diisopropylethylamine (84 mg, 0.64 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (73 mg, 0.44 mmol) were added to a DMF (2 mL) solution of 1-bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(difluoromethyl)oxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide (120 mg, 0.22 mmol) at 0°C.
  • the reaction solution was stirred at 0°C for 0.5 hours under nitrogen protection.
  • Step 6 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(difluoromethyl)oxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 7 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(difluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 8 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(difluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • N,N-diisopropylethylamine 105 mg, 0.81 mmol
  • 2-(trimethylsilyl)ethoxymethyl chloride 67 mg, 0.40 mmol
  • 1-bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide 145 mg, 0.27 mmol
  • N,N-dimethylformamide 2 mL
  • Step 2 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • Step 3 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • Step 4 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • Trifluoroacetic acid (0.2 mL) was added to a solution of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium (15 mg, 0.02 mmol) in dichloromethane (0.6 mL) at 0°C. The reaction solution was stirred at 0°C for 1 hour.
  • reaction solution was dropped into an ice-cooled 5% sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 10-50% acetonitrile in H 2 O and 0.1% formic acid) to give the title compound (yellow solid, 3 mg, yield 24.5%).
  • Example 17 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-fluoro-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • Step 1 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-fluoro-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • N-fluorobisbenzenesulfonamide (16 mg, 0.05 mmol) was added to a solution of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium (30 mg, 0.04 mmol) in acetonitrile (0.7 mL). The reaction solution was stirred at room temperature for 1 hour.
  • Step 2 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-fluoro-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • Step 1 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-fluoro-8-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • N-fluorobisbenzenesulfonamide (5.7 mg, 0.018 mmol) was added to a solution of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium (5 mg, 0.009 mmol) in N,N-dimethylformamide (0.5 mL). The reaction solution was stirred at room temperature for 16 hours.
  • Step 1 Preparation of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • Step 2 Preparation of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium
  • reaction solution was replaced with nitrogen three times and stirred at 80°C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (yellow solid, 18.2 mg, yield 28.7%).
  • Step 1 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-N-(3-methyloxetan-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was replaced with nitrogen three times and stirred at 80°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-100% ethyl acetate) to give the title compound (yellow solid, 50 mg, yield 37.3%). LC/MS (ESI) (m/z): 580 [M+H] + .
  • Step 2 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-N-(3-methyloxetan-3-yl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Ruphos (4 mg, 0.01 mmol), Ruphos Pd G 3 (4 mg, 0.01 mmol), and cesium carbonate (75 mg, 0.27 mmol) were added to a solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (50 mg, 0.09 mmol) and 2-oxa-7-azaspiro[3.5]nonane (15 mg, 0.09 mmol) in 1,4-dioxane ( 2 mL) under nitrogen protection.
  • reaction solution was stirred at 80° C. under nitrogen protection for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-100% ethyl acetate) to give the title compound (yellow solid, 20 mg, yield 33%). LC/MS (ESI) (m/z): 671 [M+H] + .
  • Step 3 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-N-(3-methyloxetan-3-yl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Trifluoroacetic acid (1 mL) was added to a solution of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-N-(3-methyloxetane-3-yl)-8-(2-oxa-7-azaspiro[3.5]non-7-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 0.03 mmol) in dichloromethane (1 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure.
  • Step 1 8-((3R,5R)-3,5-dimethylpiperazine-4-carboxylic acid tert-butyl ester-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3- methoxy-3-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was replaced with nitrogen three times and stirred at 80°C for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (yellow solid, 100 mg, yield 96%). LC/MS (ESI) (m/z): 744 [M+H] + .
  • Step 2 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(3-methoxy-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 23 1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-((methoxy-d 3 )methyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 4-Benzyl-1-(tert-butyl)-2-((methoxy-d 3 )methyl)piperazine-1,4-dicarboxylate
  • Step 2 tert-Butyl 2-((methoxy-d 3 )methyl)piperazine-1-carboxylate
  • Step 3 tert-butyl 4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-((methoxy-d 3 )methyl)piperazine-1-carboxylate
  • reaction solution was replaced with nitrogen three times and stirred at 80°C for 2 hours under nitrogen protection. After the reaction is complete, the reaction solution is cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-30% ethyl acetate) to obtain the title compound (yellow solid, 30 mg, yield 37%). LC/MS (ESI) m/z: 797 [M+H] + .
  • Step 4 1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-((methoxy-d 3 )methyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 24 8-(2'-methyl-4'-oxohexahydro-4'H,8'H-spiro[cyclopropane-1,3'-pyrazino[1,2-a]pyrazine]-8'-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 1-Benzyl 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)amino)methyl)piperazine-1,4-dicarboxylate
  • 1-aminocyclopropane-1-carboxylic acid methyl ester 154 mg, 1.34 mmol
  • sodium triacetoxyborohydride 731 mg, 3.45 mmol
  • the reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to the reaction solution and extracted with ethyl acetate.
  • Step 2 1-Benzyl 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)(methyl)amino)methyl)piperazine-1,4-dicarboxylate
  • Step 3 2'-methyl-4'-oxohexahydro-4'H,8'H-pyrro[cyclopropane-1,3'-pyrazino[1,2-a]pyrazine]-8'-carboxylic acid tert-butyl ester
  • Step 4 2'-Methylhexahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-a]pyrazino]-4'-one
  • Step 5-6 8-(2'-methyl-4'-oxohexahydro-4'H,8'H-spiro[cyclopropane-1,3'-pyrazine[1,2-a]pyrazine]-8'-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • (S)-2-(chloromethyl)oxirane (3g, 32.61mmol) and lithium perchlorate (3.5g, 32.6mmol) were added to a toluene (60mL) solution of (S)-1-((4-methoxybenzyl)amino)propan-2-ol (8g, 41.03mmol).
  • the reaction mixture was stirred at room temperature for 18 hours under nitrogen protection.
  • a 30% sodium methoxide methanol solution (25mL) was added.
  • a saturated aqueous solution of ammonium chloride was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 5-6 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholinyl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-8-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 27 8-((3S,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 8-((3S,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • N,N-diisopropylethylamine 50 mg, 0.39 mmol
  • acetic acid 10 mg, 0.17 mmol
  • HATU 74 mg, 0.19 mmol
  • 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide 70 mg, 0.13 mmol
  • dichloromethane 2 mL
  • Step 2 tert-Butyl (S)-(1-(N-benzyl-2-chloroacetamido)propan-2-yl)carbamate
  • Step 3 (S)-4-Benzyl-2-methyl-5-oxopiperazine-1-carboxylic acid tert-butyl ester
  • Step 4 (2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester
  • Step 7-8 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3R,5S)-3-(hydroxymethyl)-5-methylpiperazin-1-yl)-N-(3- methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 (2S,6S)-4-benzyl-2-(methoxymethyl)-6-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester
  • Step 4-5 1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3R,5S)-3-(methoxymethyl)-5-methylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 1-Bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 2 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 3 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 43 The following examples are prepared by referring to the preparation method of Example 43, starting from appropriate starting materials, and synthesizing the target compounds according to a similar route.
  • Step 1 1,8-Dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 2 (R)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was replaced with nitrogen three times and stirred at 90 ° C for 3 hours under nitrogen protection. After the reaction is complete, cool to room temperature, dilute the reaction solution with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-70% ethyl acetate) The title compound was obtained after purification (yellow solid, 40 mg, yield 45%). LC/MS (ESI) m/z: 734 [M+H] + .
  • Step 3 (R)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Trifluoroacetic acid (0.5 mL) was slowly added dropwise to (R)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (40 mg, 0.05 mmol) in dichloromethane (1 mL) at 0°C. The reaction solution was stirred at 30°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (yellow solid, 11 mg, yield 36%).
  • Example 49 The following examples are prepared with reference to the preparation method of Example 49, starting from appropriate starting materials, and synthesizing the crude product according to a similar route.
  • the crude product is prepared by reverse phase HPLC and freeze-dried to obtain the title compound.
  • Step 1 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride
  • Step 2 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 3 1-Bromo-8-chloro-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • N,N-diisopropylethylamine 131 mg, 1.01 mmol
  • 2-(trimethylsilyl)ethoxymethyl chloride 85 mg, 0.51 mmol
  • 1-bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide 180 mg, 0.34 mmol
  • N,N-dimethylformamide 3 mL
  • Step 4 8-Chloro-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 5 (R)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 6 (R)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • reaction solution was dropped into a 5% sodium bicarbonate aqueous solution cooled in an ice bath and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 10-50% acetonitrile in H 2 O and 0.1% FA) to give the title compound (yellow solid, 50 mg, 61% yield).
  • Example 62 The following examples are prepared with reference to the preparation method of Example 62, starting from appropriate starting materials, and synthesizing the crude product along a similar route.
  • the crude product is prepared by reverse phase HPLC and freeze-dried to obtain the title compound.
  • Example 75 3-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetane- 3-yl)imidazo[1,2-a]pyridine-6-sulfonamide
  • Step 1 8-Bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride
  • Step 2 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,2-a]pyridine-6-yl Sulfonamide
  • Step 3 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilane) (1,2-a)pyridine-6-sulfonamide
  • Step 4 (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo [1,2-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
  • reaction mixture was replaced with nitrogen three times and stirred at 80° C. for 4 hours under nitrogen protection.
  • reaction solution is diluted with ethyl acetate, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue is purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-40% ethyl acetate) to obtain the title compound (yellow solid, 40 mg, yield 59.4%).
  • Step 5 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetane alkyl-3-yl)imidazo[1,2-a]pyridine-6-sulfonamide
  • Example 75 The following examples are prepared with reference to the preparation method of Example 75, starting from appropriate starting materials, and synthesized in a similar route to obtain a crude product, which is prepared by reverse phase HPLC and freeze-dried to obtain the title compound.
  • reaction buffer I 50mM Tris (2-amino-2-hydroxymethyl-1,3-propanediol, Sigma, #T1503) PH 7.4, 0.015% Triton X-100 (4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Sigma, #T8787), 0.1% BSA (bovine serum albumin, Sigma, #A1933), 5mM KCl, 66.2uM TFMU-ADPr (fluorescein-4-trifluoromethylumbelliferyl-ADP ribose);
  • reaction buffer I 10 ⁇ L/well into a 384-well plate
  • reaction buffer II 50 mM Tris PH 7.4, 0.015% Triton X-100, 0.1% BSA, 5 mM KCl, 4 nM PARG (poly ADP-ribose hydrolase);
  • reaction buffer II 10 ⁇ L/well into the 384-well plate to start the reaction
  • HCC1806 ATCC cell bank, 100 cells/well
  • MDA-MB-231 ATCC cell bank, 120 cells/well
  • the test showed that the example compounds of the present application had a strong inhibitory effect on the proliferation of HCC1806 cells, and a weak inhibitory effect on the proliferation of MDA-MB-231 cells, indicating that the example compounds of the present application had good selectivity for the inhibitory effect on the proliferation of the two types of cells.

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Abstract

L'invention concerne des composés azotés ayant un cycle à cinq chaînons fusionné avec un cycle à six chaînons, représentés par la formule IV, des sels pharmaceutiquement acceptables ou des composés isotopiques de ceux-ci, leur procédé de préparation et leur utilisation. Les composés ont une bonne activité inhibitrice vis-à-vis de PARG.
PCT/CN2023/142929 2023-06-19 2023-12-28 Composés azotés ayant un cycle à cinq chaînons fusionné à un cycle à six chaînons, leur procédé de préparation et leur utilisation Ceased WO2024259945A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025133396A1 (fr) * 2023-12-22 2025-06-26 Forx Therapeutics Ag Nouveaux inhibiteurs de parg bicyclo hétéroaryles

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103936757A (zh) * 2013-01-18 2014-07-23 上海昀怡健康管理咨询有限公司 五元并六元杂环化合物、其制备方法、药物组合物和应用
CN111867581A (zh) * 2018-01-29 2020-10-30 默克专利股份有限公司 Gcn2抑制剂及其用途
WO2022123272A1 (fr) * 2020-12-11 2022-06-16 AdoRx Therapeutics Limited Antagonistes du récepteur a2a de l'adénosine
WO2023057389A1 (fr) * 2021-10-04 2023-04-13 Forx Therapeutics Ag Composés inhibiteurs de parg
WO2024002284A1 (fr) * 2022-06-29 2024-01-04 杭州圣域生物医药科技有限公司 Composé contenant de l'azote à cinq chaînons et à six chaînons, et intermédiaire, procédé de préparation et utilisation associée

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103936757A (zh) * 2013-01-18 2014-07-23 上海昀怡健康管理咨询有限公司 五元并六元杂环化合物、其制备方法、药物组合物和应用
CN111867581A (zh) * 2018-01-29 2020-10-30 默克专利股份有限公司 Gcn2抑制剂及其用途
WO2022123272A1 (fr) * 2020-12-11 2022-06-16 AdoRx Therapeutics Limited Antagonistes du récepteur a2a de l'adénosine
WO2023057389A1 (fr) * 2021-10-04 2023-04-13 Forx Therapeutics Ag Composés inhibiteurs de parg
WO2024002284A1 (fr) * 2022-06-29 2024-01-04 杭州圣域生物医药科技有限公司 Composé contenant de l'azote à cinq chaînons et à six chaînons, et intermédiaire, procédé de préparation et utilisation associée

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025133396A1 (fr) * 2023-12-22 2025-06-26 Forx Therapeutics Ag Nouveaux inhibiteurs de parg bicyclo hétéroaryles

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