WO2024259945A1 - Nitrogen-containing compounds having five-membered ring fused with six-membered ring, preparation method therefor and use thereof - Google Patents

Abstract

Disclosed are nitrogen-containing compounds having a five-membered ring fused with a six-membered ring shown as formula IV, pharmaceutically acceptable salts or isotope compounds thereof, a preparation method therefor and the use thereof. The compounds have good PARG inhibitory activity.

Description

Pentavalent and hexavalent nitrogen-containing compounds, preparation methods and applications thereof

This application claims the priority of Chinese patent application No. 2023107306040 filed on June 19, 2023. This application cites the entire text of the above Chinese patent application.

Technical Field

The invention relates to a pentad and hexaad nitrogen-containing compound, a preparation method and application thereof.

Background Art

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. et al. Emerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation. Nature Communication, 2019, 10, 1182.), including the N-terminal disordered domain, the linker domain, the C-terminal catalytic domain and the ADP-ribose binding domain. The non-conserved disordered domain at the N-terminus is not necessary for in vitro activity. The C-terminal ADP-ribose binding domain is highly conserved with other Macro-domains and together with the catalytic domain forms the minimum structure with complete enzyme activity in vitro (Slade D et al. The structure and catalytic mechanism of a poly(ADP-ribose)glycohydrolase. Nature, 2011, 477: 616-620.).

Poly ADP-ribosylation (PARylation) 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, 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. After DNA damage, many DNA damage response factors recognize PARylation and are recruited to the vicinity of DNA damage sites through PARylation. However, PARylation needs to be digested in time so that DNA damage response factors can directly recognize DNA damage and play a repair function. Otherwise, DNA repair factors will be trapped near DNA damage by PARylation and cannot play a normal repair role. Therefore, 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. In addition, studies have shown (Mincheng Y et al.PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy.Hepatic and Biliary Cancer,2022,S0168-8278(22)00072-1.), high PARG expression is closely related to poor prognosis of liver cancer, and hepatocyte-specific PARG function loss affects tumor occurrence. Therefore, PARG inhibitors have received increasing attention as potential therapeutic methods. There are currently many PARG inhibitors under development, and all are in the preclinical research stage. Therefore, it is of great research significance to develop small molecule drugs that can target and inhibit PARG activity to provide patients with safer and more effective PARG inhibitors.

Summary of the invention

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;

n is 0, 1 or 2; m is 0, 1 or 2; k is 0, 1 or 2;

R ^1-3' is hydrogen or R ^1-3 ;

Each R ^1-3 is independently cyano, deuterium, hydroxyl, amino, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3-1 , C ₁ -C ₆ alkoxy which is 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 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 more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

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 ;

R ^2-3-2 is hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-3-2-1 , C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^2-3-2-2 , C ₁ -C ₆ alkoxy which is unsubstituted or substituted by one or more R ^2-3-2-4 , 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 ^2-3-3 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 ^2-3-2-4 is independently halogen;

Each R ^2-3-2-5 is independently halogen, hydroxy, oxo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl 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 ^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;

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

Each 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.

In a preferred embodiment, the compound shown in Formula IV may be a compound shown in Formula V,

M is N, O or S;

i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time;

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.

In a preferred embodiment, the compound shown in formula IV may be a compound shown in formula VI,

Y, X, W, Z, ring C, ring A, R ^1-3′ , R ^1-3 , R ^2-3 , R ^3-1 , n, m, k, i and j are as defined above.

In a preferred embodiment, 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 ;

m is 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.

In a preferred embodiment, 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.

In a preferred embodiment, the compound represented by formula IV may be a compound represented by formula IX,

U is CH ₂ , NH or O;

p is 0, 1 or 2; q is 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.

In a preferred embodiment, the compound represented by formula IV may be a compound represented by formula X,

R ^G is R ^2-3-2 or

^V1 is CH or N; ^V2 is CH or N; ^V1 and ^V2 are not CH at the same time;

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.

In a preferred embodiment, 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.

In a preferred embodiment, m is 1 or 2.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, each R ^1-3-1 is independently halogen.

In a preferred embodiment, each R ^1-3-2 is independently halogen.

In a preferred embodiment, 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 .

In a preferred embodiment, 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.

In a preferred embodiment, each R ^2-3-4 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, each R ^2-3-7 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, each R ^2-3-9 is independently oxo or C ₁ -C ₆ alkyl.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, each R ^2-3-2-2-1 is independently halogen or hydroxyl.

In a preferred embodiment, each R ^2-3-2-2-2 is independently halogen, deuterium, oxo or hydroxy.

In a preferred embodiment, each R ^2-3-2-2-3 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, each R ^2-3-2-3 is independently hydrogen or

In a preferred embodiment, 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.

In a preferred embodiment, each R ^2-3-2-4 is independently halogen.

In a preferred embodiment, 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.

In a preferred embodiment, each R ^2-3-2-6 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, each R ^3-1 is independently hydroxyl, halogen, C ₁ -C ₆ alkyl substituted by one or more R ^3-1-1 , or

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, each R ^4-1 is independently

In a preferred embodiment, 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.

In a preferred embodiment, R ^4-1-1 is a C ₁ -C ₆ alkyl group.

In a preferred embodiment, each R ^4-1-2 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, each R ^4-2-1 is independently a C ₁ -C ₆ alkyl group.

In a certain embodiment, 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.

In one embodiment, each R ^1-3-1 is independently halogen or deuterium.

In one embodiment, each R ^1-3-1 is independently halogen.

In one embodiment, each R ^2-3 is independently oxo, unsubstituted or substituted by one or more R ^2-3-1 C ₁ -C ₆ alkyl,

In one embodiment, 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.

In one embodiment, each R ^2-3-1 is independently hydroxyl, halogen, C ₁ -C ₆ alkoxyl group which is unsubstituted or substituted by one or more R ^2-3-1-1 , or amino group which is unsubstituted or substituted by one or more R ^2-3-1-3 ; preferably, each R ^2-3-1 is independently hydroxyl, C ₁ -C ₆ alkoxyl group which is unsubstituted or substituted by one or more R ^2-3-1-1 .

In one embodiment, each R ^2-3-1-1 is independently deuterium.

In one embodiment, each R ^2-3-1-3 is independently C ₁ -C ₆ alkyl.

In one embodiment, 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.

In one embodiment, 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 .

In one embodiment, each R ^2-3-2-1 is independently hydroxyl,

In one embodiment, each R ^2-3-2-1-1 is independently C ₁ -C ₆ alkyl.

In a certain embodiment, 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.

In a certain embodiment, 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 .

In one embodiment, each R ^2-3-2-2-2 is independently deuterium.

In one embodiment, each R ^2-3-2-3 is independently hydrogen or

In one embodiment, 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 .

In one embodiment, each R ^2-3-2-3-1-1 is independently C ₁ -C ₆ alkoxy.

In one embodiment, 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.

In one embodiment, 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 .

In one embodiment, each R ^2-3-2-5-1 is independently halogen.

In one embodiment, 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 .

In one embodiment, each R ^2-3-3-1 is independently amino which is unsubstituted or substituted with one or more R ^2-3-3-1-1 .

In one embodiment, each R ^2-3-3-1-1 is independently C ₁ -C ₆ alkyl.

In one embodiment, 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.

In one embodiment, each R ^3-1 is independently a C ₁ -C ₆ alkyl substituted with one or more R ^3-1-1 .

In one embodiment, each R ^3-1-1 is independently halogen.

In a certain embodiment, k is 0; 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.

In one embodiment, ring A is R ^3-1 is -CF ₃ .

In one embodiment, 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.

In one embodiment, R ⁴ is hydrogen, deuterium, halogen, or C ₁ -C ₆ alkyl.

In one embodiment, each R ^4-1 is independently R ^4-1-1 is a C ₁ -C ₆ alkyl group.

In a preferred embodiment,

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.

In a preferred embodiment,

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.

In a preferred embodiment, in ring D, the heteroatom of the 3-6 membered heterocycloalkyl is O, and the number of the heteroatom is 1.

In a preferred embodiment, in ring D, the 3-6-membered heterocycloalkyl group is a 4-membered heterocycloalkyl group.

In a preferred embodiment, 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 .

In a preferred embodiment, 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 .

In a preferred embodiment, each R ^1-3-1 is independently halogen.

In a preferred embodiment, in ring C, 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.

In a preferred embodiment, 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 .

In a preferred embodiment, 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.

In a preferred embodiment, each R ^2-3 is independently oxo, unsubstituted or substituted by one or more R ^2-3-1 C ₁ -C ₆ alkyl,

In a preferred embodiment, 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 .

In a preferred embodiment, 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 .

In a preferred embodiment, 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 .

In a preferred embodiment, 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 .

In a preferred embodiment, each R ^2-3-6 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, each R ^2-3-1-1 is independently halogen or deuterium.

In a preferred embodiment, each R ^2-3-1-1 is independently halogen.

In a preferred embodiment, each R ^2-3-1-1 is independently deuterium.

In a preferred embodiment, each R ^2-3-1-3 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, 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 .

In a preferred embodiment, each R ^2-3-2-2-2 is independently deuterium.

In a preferred embodiment, 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 .

In a preferred embodiment, each R ^2-3-3-1-1 is independently a C ₁ -C ₆ alkyl group.

In a preferred embodiment, in ring A, the heteroatom of the 5-10 membered heteroaryl group is N and/or S, and the number of heteroatoms is 1, 2 or 3.

In a preferred embodiment, each R ^3-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more R ^3-1-1 .

In a preferred embodiment, each R ^3-1-1 is independently halogen or hydroxyl.

In a preferred embodiment, W is N, CH or CR ⁴ .

In a preferred embodiment, R ⁴ is deuterium, halogen, or unsubstituted C ₁ -C ₆ alkyl.

In a preferred embodiment,

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 ;

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.

In a preferred embodiment,

Y is N, X is C,

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 is 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;

m is 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 is 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.

In a preferred embodiment,

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.

In a preferred embodiment,

Y is N, X is C,

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 is 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;

m is 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 is 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.

In a preferred embodiment,

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.

In a preferred embodiment,

Y is N, X is C,

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 is 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;

m is 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 is 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.

In a preferred embodiment, in each R ^1-3 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^1-3 , 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.

In a preferred embodiment, in each R ^1-3 , 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.

In a preferred embodiment, in each R ^1-3 , the C ₂ -C ₆ alkynyl group is For example

In a preferred embodiment, in each R ^1-3-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^1-3-2 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3 , 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.

In a preferred embodiment, in each R ^2-3 , 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

In a preferred embodiment, in each R ^2-3 , 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.

In a preferred embodiment, in each R ^2-3 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

In a preferred embodiment, in each R ^2-3 , 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

In a preferred embodiment, in each R ^2-3-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-1 , 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.

In a preferred embodiment, in each R ^2-3-1 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

In a preferred embodiment, in R ^2-3-2 , 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.

In a preferred embodiment, in R ^2-3-2 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl or cyclobutyl.

In a preferred embodiment, in R ^2-3-2 , 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.

In a preferred embodiment, in R ^2-3-2 , 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

In a preferred embodiment, in R ^2-3-2 , 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.

In a preferred embodiment, in each R ^2-3-3 , 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 or ethyl.

In a preferred embodiment, in each R ^2-3-4 , 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.

In a preferred embodiment, in each R ^2-3-5 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-6 , 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.

In a preferred embodiment, in each R ^2-3-7 , 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.

In a preferred embodiment, in each R ^2-3-8 , 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.

In a preferred embodiment, in each R ^2-3-8 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

In a preferred embodiment, in each R ^2-3-9 , 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.

In a preferred embodiment, in each R ^2-3-1-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-1-2 , 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.

In a preferred embodiment, in each R ^2-3-1-3 , 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.

In a preferred embodiment, in each R ^2-3-2-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-2-1 , 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.

In a preferred embodiment, in each R ^2-3-2-1 , 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.

In a preferred embodiment, in each R ^2-3-2-1-1 , 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.

In a preferred embodiment, in each R ^2-3-2-1-1 , the 6-10 membered aryl group may be phenyl or naphthyl, for example phenyl.

In a preferred embodiment, in each R ^2-3-2-1-2 , 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.

In a preferred embodiment, in each R ^2-3-2-1-3 , 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.

In a preferred embodiment, in each R ^2-3-2-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-2-2 , 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, and may also be methyl.

In a preferred embodiment, in each R ^2-3-2-2 , 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.

In a preferred embodiment, in each R ^2-3-2-2-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-2-2-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-2-2-3 , 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, prim-butyl, sec-butyl or tert-butyl, such as methyl.

In a preferred embodiment, in each R ^2-3-2-3-1 , the 6-10 membered aryl group is phenyl or naphthyl, for example phenyl.

In a preferred embodiment, in each R ^2-3-2-3-1-1 , 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.

In a preferred embodiment, in each R ^2-3-2-4 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-2-5 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-2-5 , 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.

In a preferred embodiment, in each R ^2-3-2-5 , 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.

In a preferred embodiment, in each R ^2-3-2-5-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^2-3-2-6 , 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.

In a preferred embodiment, in each R ^2-3-3-1-1 , 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.

In a preferred embodiment, in each R ^3-1 , 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.

In a preferred embodiment, in each R ^3-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in each R ^3-1-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

In a preferred embodiment, in R ^3-1-2 , 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 or an ethyl group.

In a preferred embodiment, in R ^3-1-2 , the C ₂ -C ₆ alkenyl group may be For example

In a preferred embodiment, in R ⁴ , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

In a preferred embodiment, in R ⁴ , 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.

In a preferred embodiment, in R ⁴ , 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.

In a preferred embodiment, in each R ^4-2 , 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.

In a preferred embodiment, in R ^4-1-1 , 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.

In a preferred embodiment, in each R ^4-1-2 , 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.

In a preferred embodiment, in each R ^4-2-1 , 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.

In one embodiment, Y is N.

In one embodiment, X is C.

In one embodiment, W is N, CH or CR ⁴ , and R ⁴ is chloro, deuterium or methyl.

In one embodiment, Z is CH or N.

In one plan, for

In one embodiment, ring D is

In one embodiment, n is zero.

In one embodiment, R ^1-3' is hydrogen, cyano, methyl,

In one plan, for

In one embodiment, ring C is

In one embodiment, R ^2-3 is hydroxy, oxo, methyl, -CF ₃ ,

In one plan, for

In one embodiment, ring A is

In one embodiment, k is 1.

In one embodiment, R ^3-1 is -CHF ₂ , -CF ₃ ,

In one plan, for In one embodiment, 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 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.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In a preferred embodiment, the PARG-related disease is breast cancer, such as triple-negative breast cancer, and other PARG-related diseases.

Explanation of terms

The term "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. When multiple groups A appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other. For example, "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.

The term "plurality" refers to 2 or more, for example, 2, 3, 4, 5.

The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, 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. When the compound contains a relatively basic functional group, 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).

"-" in a group means that the group is attached to the rest of the molecule through this site. For example, CH3 _- C(=O)- refers to acetyl.

The term "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.

The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, replacing a methylene group with a carbonyl group.

The term "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.

The term "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.

The term "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.

The term "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.

Unless otherwise specified in the present invention, the term "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.

Unless otherwise specified in the present invention, the term "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.

Unless otherwise specified in the present invention, the term "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

Unless otherwise specified in the present invention, the term "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. The 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.

The term "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.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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.

DETAILED DESCRIPTION

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. In addition, 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 chemical reactions and synthesis techniques described herein are carried out in the reagents and corresponding solvents described herein, and the corresponding reaction yields are also affected by the reagents and solvents used. In addition, it should be understood that in the synthetic method described below, all the reaction conditions mentioned, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and reaction feeding order, should be regarded as the operating condition standard of the reaction, which should be easily recognized by those skilled in the art. At the same time, it is also understandable to those skilled in the art in the field of organic synthesis. The functional groups present on each part of the molecule must be compatible with the reagents used and the reaction itself. For such restrictions that some functional groups present on each part of the molecule are incompatible with the reaction conditions, alternative methods must be used, which will be obvious to those skilled in the art. It is obvious that it is necessary to judge to adjust the order of the synthetic steps, or to select a specific synthetic process scheme to obtain the desired compound of the present invention. This is understandable and easily recognized by those skilled in the art in the field of organic synthesis. It should also be recognized that another major consideration for any synthetic route designed in this field is the reasonable selection of protecting groups for protecting the tolerance of reactive functional groups present in the compounds described in the present invention. For details, please refer to the work of Greene and other authorities in the field of chemistry (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

Example

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.

In the examples given herein, the term "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. In some cases, 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.

List of abbreviations

Intermediate 1: 1,8-dichloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl )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

Under nitrogen protection, 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-15% ethyl acetate) to obtain the title compound (yellow solid, 600 mg, yield 75.1%). LC/MS(ESI)(m/z): 385[M+H] ⁺ .

Step 2: 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

Under nitrogen protection, 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-20% ethyl acetate) to obtain the title compound (yellow solid, 500 mg, yield 83.7%). LC/MS(ESI)(m/z): 383[M+H] ⁺ .

Step 3: 2-(6-(Benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

Under nitrogen protection, N,N-diisopropylethylamine (505 mg, 3.91 mmol), Xantphos (151 mg, 0.26 mmol), and Pd 2 (dba) 3 (119 mg, 0.13 mmol) were added to a solution of 2-(6-bromo- ₈ -chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (500 mg, 1.30 mmol) and benzyl mercaptan (0.15 mL, 1.30 mmol) in 1,4-dioxane (5 mL) in sequence. The reaction solution was replaced with nitrogen three times and stirred at 80°C for 3 hours under nitrogen protection. 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-25% ethyl acetate) to give the title compound (yellow solid, 510 mg, yield 91.6%). LC/MS (ESI) (m/z): 427 [M+H] ⁺ .

Step 4: 1,8-Dichloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

Under nitrogen protection, slowly add sulfonyl chloride (13.5 g, 100 mmol) to a solution of 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (7.0 g, 16.4 mmol) in dichloromethane (150 mL). Stir the reaction at 0°C under nitrogen for 60 minutes. After the reaction is complete, slowly add it to an ice-saturated sodium bicarbonate solution, separate the layers, and extract the aqueous phase with dichloromethane. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (yellow solid, 7.0 g, yield 97.5%). LC/MS(ESI)(m/z):437[M+H] ⁺ .

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

Under nitrogen protection, a solution of 1,8-dichloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (7.0 g, 16.0 mmol) in dichloromethane (100 mL) was slowly dripped into 3-methyloxetane-3-amine (2.8 g, 32.0 mmol) and pyridine (3 mL) in dichloromethane (100 mL). The reaction was stirred at 0 ° C for 60 minutes under nitrogen. After the reaction was complete, it was slowly added to ice water, separated, and the aqueous phase was extracted with dichloromethane. The organic phase was 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 obtain the title compound (yellow solid, 4.9 g, yield 62.7%). LC/MS(ESI)(m/z):488[M+H] ⁺ .

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

Under ice bath, 1,8-dichloro-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazolide [1,5-a] Pyridine-6-sulfonamide (4.9 g, 10 mmol) and N,N-diisopropylethylamine (3.9 g, 30 mmol) in dichloromethane (50 mL) were slowly added dropwise with 2-(trimethylsilyl)ethoxymethyl chloride (3.4 g, 20 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was slowly added into water, separated into layers, and the aqueous phase was extracted with dichloromethane. The combined organic phases were 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: 0-25% ethyl acetate) to obtain the title compound (yellow solid, 5.5 g, yield 86.8%). LC/MS (ESI) (m/z): 618 [M+H] ⁺ .

Intermediate 2: 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl )ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide

The synthetic method of intermediate 1 was followed, except that difluoroacetic anhydride was used in place of trifluoroacetic anhydride in step 1 to obtain intermediate 2. LC/MS (ESI) (m/z): 600 [M+H] ⁺ .

Intermediate 3: 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

Step 1: 6-Bromo-8-chloro-N'-(2,2,2-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide

Under nitrogen protection, 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-15% ethyl acetate) to obtain the title compound (yellow solid, 600 mg, yield 75.1%). LC/MS(ESI)(m/z): 385[M+H] ⁺ .

Step 2: 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

Under nitrogen protection, 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-20% ethyl acetate) to obtain the title compound (yellow solid, 500 mg, yield 83.7%). LC/MS(ESI)(m/z): 383[M+H] ⁺ .

Step 3: 2-(6-(Benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

Under nitrogen protection, 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (500 mg, 1.30 mmol) and benzyl mercaptan (0.15mL, 1.30mmol) in 1,4-dioxane (5mL) were added with N,N-diisopropylethylamine (505mg, 3.91mmol), Xantphos (151mg, 0.26mmol), and Pd ₂ (dba) ₃ (119mg, 0.13mmol) in sequence. The reaction solution was replaced with nitrogen three times and stirred at 80°C for 3 hours under nitrogen protection. 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-25% ethyl acetate) to obtain the title compound (yellow solid, 510mg, yield 91.6%). LC/MS (ESI) (m/z): 427 [M+H] ⁺ .

Step 4: 2-(6-(Benzylthio)-1-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

At 0°C, 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-25% ethyl acetate) to obtain the title compound (yellow solid, 550 mg, yield 91.2%). LC/MS(ESI)(m/z): 505[M+H] ⁺ .

Step 5: 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

At 0°C, 1N hydrochloric acid (1.25mL), water (1.25mL) and dichlorohydantoin (643mg, 3.27mmol) were added to a solution of 2-(6-(benzylthio)-1-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (550mg, 1.10mmol) in acetonitrile (5mL) in sequence. The reaction solution was stirred at 0°C for 10 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. The residue was slurried with petroleum ether and dried in vacuo to obtain the title compound (yellow solid, 520mg, yield 99.2%). LC/MS(ESI)(m/z):481[M+H] ⁺ .

Intermediate 4: 1-Bromo-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5-a]pyridine-6-sulfonyl chloride

Referring to the synthesis method of intermediate 3, the difference is that difluoroacetic anhydride is used instead of trifluoroacetic anhydride in step 1 to obtain intermediate 4. LC/MS (ESI) (m/z): 462.7 [M+H] ⁺ .

Intermediate 5: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-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

To a solution of 3-methyloxetane-3-amine (0.017 mL, 0.388 mmol) in pyridine (3 mL) was added dropwise 1-bromo-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5-a]pyridine-6-sulfonyl chloride (90 mg, 0.194 mmol) in DCM (2 mL) at 0 °C. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, water was added, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-50%) to obtain the title compound (yellow solid, 80 mg, yield 80.14%). LC/MS (ESI) (m/z): 514/516 [M+H] ⁺ .

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

At room temperature, 10% Pd/C (20 mg, 0.188 mmol) was added to a solution of 1-bromo-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetane-3-yl)imidazole[1,5]solution-a]pyridine-6-sulfonamide (70 mg, 0.136 mmol) in EtOH (10 mL). The mixture was replaced with hydrogen three times and stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and concentrated to dryness. The residue was used directly in the next step without purification. LC/MS (ESI) (m/z): 436 [M+H] ⁺ .

Intermediate 6: 8-Chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

Referring to the synthesis method of intermediate 5, except that the starting material is intermediate 3, intermediate 6 is obtained. LC/MS (ESI) (m/z): 453.9 [M+H] ⁺ .

Intermediate 7: 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

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. LC/MS (ESI) (m/z): 532 [M+H] ⁺ .

Example 1: (S)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-(methoxymethyl)piperazin-1-yl)-N-(3-methyloxetane -3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

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

Under nitrogen protection, cesium carbonate (1627 mg, 5.01 mmol), Ruphos (156 mg, 0.27 mmol) and Ruphos Pd G3 (139 mg, 0.17 mmol) were added to a solution of 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (1 g, 1.67 mmol) and (S)-2-(methoxymethyl)piperazine-1-carboxylic acid tert-butyl ester (576 mg, 2.50 mmol) in 1,4-dioxane (20 mL) in sequence. The reaction solution was replaced with nitrogen three times and stirred at 80 ° C for 2 hours under nitrogen atmosphere. After the reaction was complete, water was added to the reaction solution and extracted with ethyl acetate twice. The combined organic phases were 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: 0-30% ethyl acetate) to obtain the title compound (yellow solid, 720 mg, yield 54.5%). LC/MS (ESI) (m/z): 794 [M+H]+.

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

Under ice-water bath, trifluoroacetic acid (3 mL) was added to a solution of (S)-4-(1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetane-3-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2-(methoxymethyl)piperazine-1-carboxylic acid tert-butyl ester (720 mg, 0.91 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the 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). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.58(s,1H),8.81(s,1H),7.68(t,J＝53.1Hz,1H),6.82(s,1H),4.62(d,J＝6.0Hz,2H),4.18(d,J＝6.4Hz,2H),3.41-3.39(m,1H), 3.38-3.35(m,4H),3.28(s,3H),3.20-3.11(m,2H),3.06-2.97(m,2H),2.77-2.68(m,1H),1.49(s,3H).LC/MS(ESI)(m/z):564[M+H] ⁺ .

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

Under nitrogen protection, to a solution of 1,8-dichloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (80 mg, 0.13 mmol) in 1,4-dioxane (3 mL) were added (1-methoxycyclopropyl)(piperazine-1-yl)methanone (48 mg, 0.26 mmol), Ruphos (10 mg, 0.02 mmol), Ruphos Pd G3 (14 mg, 0.02 mmol) and cesium carbonate (127 mg, 0.36 mmol) in sequence. The 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

To a solution of 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)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.04 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.7 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 30-95% acetonitrile in H ₂ O and 0.1% TFA) to give the title compound (yellow solid, 13.7 mg, yield 55.0%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.59(s,1H),6.92(s,1H),4.64(d,J＝6.2Hz,2H),4.19(d,J＝6.4Hz,2H),4.13-3.63(m,4H),3.27( s,3H),3.16(s,4H),1.50(s,3H),1.06-1.01(m,2H),0.95-0.90(m,2H).LC/MS(ESI)(m/z):636[M+H] ⁺ .

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

Under nitrogen protection, to a solution of 8-chloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (40 mg, 0.068 mmol) in 1,4-dioxane (3 mL) were added (1-ethylcyclopropyl)(piperazine-1-yl)methanone (18 mg, 0.11 mmol), Ruphos (1 mg, 0.01 mmol), Ruphos Pd G3 (6 mg, 0.005 mmol) and cesium carbonate (45 mg, 0.14 mmol) in sequence. The 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

To a solution of 8-(4-(1-ethylcyclopropane-1-carbonyl)piperazin-1-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.04 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 10-50% acetonitrile in H ₂ O and 0.1% FA) to give the title compound (yellow solid, 6 mg, yield 24%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.58(s,1H),8.74(s,1H),8.13(s,1H),6.76(s,1H),4.64(d,J＝6.2Hz,2H),4.19(d,J＝6.3Hz,2H),3.87-3.76(m,4H),3.33-3.32 (m,4H),2.08-1.96(m,2H),1.57-1.52(m,2H),1.50(s,3H),0.91(t,J＝7.4Hz,3H),0.84-0.82(m,2H).LC/MS(ESI)(m/z):600[M+H] ⁺ .

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

Under nitrogen protection, cesium carbonate (172.7 mg, 0.53 mmol), Ruphos (16.5 mg, 0.035 mmol) and Ruphos Pd G 3 (29.6 mg, 0.035 mmol) were added to a solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[ _1,5 -a]pyridine-6-sulfonamide (100 mg, 0.18 mmol) and (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (56.8 mg, 0.27 mmol) in 1,4-dioxane (2 mL) in sequence. The reaction mixture 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 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%). LC/MS (ESI) (m/z): 744 [M+H] ⁺ _.

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

Add (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetane-3-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)aminosulfonyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.16 mmol), dichloromethane (2 mL), and trifluoroacetic acid (0.6 mL) to the reaction bottle. Stir the reaction solution at room temperature for 30 minutes. After the reaction is complete, adjust the alkalinity with sodium bicarbonate, extract with dichloromethane, wash with saturated brine, dry, and concentrate to obtain the title compound (yellow solid, 70 mg, yield 84.5%). LC/MS(ESI)(m/z):514[M+H] ⁺ _.

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

At room temperature, sodium cyanoborohydride (7.8 mg, 0.20 mmol) and acetic acid (76.3 mg, 0.41 mmol) were added to a solution of 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, 0.14 mmol) and (1-ethoxycyclopropyloxy)trimethylsilane (47.5 mg, 0.27 mmol) in tetrahydrofuran (1 mL). The 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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.86 (s, 1H), 7.73 (s, 1H), 7.00 (t, J=53.6 Hz, 1H), 6.68 (s, 1H), 4.82-4.80 (m, 2H), 4.42-4.39 (m, 2H), 3.43-3.22 (m, 7H), 1.72 (s, 3H), 1.39 (s, 6H), 0.88-0.79 (m, 4H). LC/MS (ESI) (m/z): 554 [M+H] ⁺ _.

Example 11: 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

Step 1: Benzyl (3S,5S)-3,5-dimethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine-1-carboxylate

Under nitrogen protection, potassium carbonate (331 mg, 2.40 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (446 mg, 1.8 mmol) were added to a DMF (5 mL) solution of (3S, 5S)-3,5-dimethylpiperazine-1-carboxylic acid benzyl ester (300 mg, 1.20 mmol) in sequence. The 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 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 obtain the title compound (white solid, 210 mg, yield 46%). LC/MS (ESI) m/z: 377 [M+H] ⁺ .

Step 2: (2S,6S)-2,6-dimethyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine

At room temperature, 10% palladium on carbon (80 mg) was added to ethyl acetate (20 mL) of benzyl (3S, 5S)-3,5-dimethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine-1-carboxylate (210 mg, 0.55 mmol). The reaction mixture was replaced with hydrogen three times and stirred at room temperature for 3 hours under 1 atmosphere of hydrogen. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (colorless oil, 120 mg, yield 88%). LC/MS (ESI) (m/z): 243 [M+H] ⁺ .

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

Under nitrogen protection, to a solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.05 mmol) in dioxane (2 mL) were added (2S,6S)-2,6-dimethyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine (331 mg, 0.08 mmol), cesium carbonate (45 mg, 0.18 mmol), Ruphos (5 mg, 0.01 mmol) and Ruphos Pd G ₃ (5 mg, 0.006 mmol) in sequence. The 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

To a solution of 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-methyloxetane-3-yl)-N((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.03 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) at 0°C. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (yellow solid, 2.43 mg, Yield 5%). ¹ H NMR (400MHz, CD ₃ OD)δ9.89(s,1H),7.91(s,1H),7.34(t,J＝53.5Hz,1H),6.84(d,J＝1.0Hz,1H),4.82–4.77(m,4H),4.35–4.31(m,2H),4.23–4.05(m,2H),3 .98–3.92(m,2H),3.86–3.73(m,2H),3.67–3.61(m,1H),3.54–3.46(m,1H),1.65(s,3H),1.64–1.53(m,6H).LC/MS(ESI)(m/z):558[M+H] ⁺ .

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

Under nitrogen protection, cesium carbonate (45 mg, 0.18 mmol), Ruphos (5 mg, 0.01 mmol) and Ruphos Pd G 3 (5 mg, 0.006 mmol) were added to a solution of methyl (5-(8-chloro-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 (35 mg, 0.06 mmol) and 2S,6S-dimethylmorpholine (9 mg, 0.07 mmol) in 1,4-dioxane (2 mL) in sequence. The 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. The organic phase was 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: 0-80% ethyl acetate) to give the title compound (white solid, 10 mg, yield 95%). LC/MS(ESI)(m/z):537[M+H] ⁺ .

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

To a solution of 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 (10 mg, 0.018 mmol) in methanol (1 mL) at 0°C, tetrahydrofuran (1 mL), water (1 mL) and lithium hydroxide (1 mg, 0.03 mmol) were added. The mixture was stirred at room temperature for 60 minutes. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (white solid, 0.41 mg, yield 5%). ¹ H NMR (400MHz, CD ₃ OD)δ9.82(s,1H),7.77(s,1H),6.68(s,1H),5.18–5.16(m,2H),4.32–4.28(m,4H),3.49–3. 47(m,4H),3.13–3.12(m,2H),1.63(s,3H),1.41–1.39(m,6H).LC/MS(ESI)(m/z):495[M+H] ⁺ .

Example 13: 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

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

Under nitrogen protection, cesium carbonate (45 mg, 0.18 mmol), Ruphos (5 mg, 0.01 mmol) and Ruphos Pd G 3 (5 mg, 0.006 mmol) were added to a solution of methyl (5-(8-chloro-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 (35 mg, 0.06 mmol) and tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate (16 mg, 0.07 mmol) in 1,4-dioxane ( ₂ mL) in sequence. The 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. The organic phase was 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: 0-80% ethyl acetate) to give the title compound (white solid, 20 mg, yield 95%). LC/MS(ESI)(m/z):552[M+H] ⁺ .

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

To a solution of methyl (5-(8-(3-(methoxymethyl)piperazin-1-yl)-6-(N-(3-methyloxetane-3-yl)sulfamoyl)imidazo[1,5-a]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate (20 mg, 0.03 mmol) in methanol (1 mL) at 0°C, tetrahydrofuran (1 mL), water (1 mL), and lithium hydroxide (2 mg, 0.09 mmol) were added. The mixture was stirred at room temperature for 60 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (yellow solid, 0.93 mg, yield 5%). ¹ H NMR (400MHz, CD ₃ OD)δ9.90(s,1H),7.89(s,1H),6.78(s,1H),4.80–4.78(m,2H),4.34–4.30(m,2H),3.94–3.86(m,2H),3.85–3.74(m, 3H),3.70–3.60(m,2H),3.56–3.51(m,2H),3.48(s,3H),3.23–3.15(m,2H),1.65(s,3H).LC/MS(ESI)(m/z):510[M+H] ⁺ .

Example 14: 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-cyanooxetan-3-yl)-2-methylpropane-2-sulfenamide

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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: dichloromethane/methanol, gradient: 0-4% methanol) to obtain the title compound (yellow liquid, 900 mg, yield 78.3%). LC/MS (ESI) (m/z): 203 [M+H] ⁺ .

Step 2: 3-Aminooxetane-3-carbonitrile hydrochloride

At 0°C, slowly add 4M dioxane hydrochloride (1.5mL, 6mmol) solution to a solution of N-(3-cyanooxetane-3-yl)-2-methylpropane-2-sulfenamide (400mg, 2.0mmol) in methanol (3mL). The reaction solution was stirred at 0°C under nitrogen protection for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the title compound (white solid, 266mg, yield 100%), which was used directly in the next step without purification. ¹ H NMR (400MHz, DMSO-d ₆ )δ4.90(d,J＝8.0Hz,2H),4.85(d,J＝7.8Hz,2H).

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

At 0°C, 1-bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (400 mg, 0.86 mmol) was added in batches to a solution of 3-aminooxetane-3-carbonitrile hydrochloride (232 mg, 1.72 mmol) in pyridine (2 mL). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was acidified to pH = 5 with 1N hydrochloric acid and diluted with ethyl acetate. The organic phase was 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: 0-50% ethyl acetate) to give the title compound (yellow solid, 280 mg, yield 61.8%). LC/MS (ESI) (m/z): 525 [M+H] ⁺ .

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

2,4-Dimethoxybenzyl alcohol (64 mg, 0.38 mmol) and cyanomethylene tri-n-butylphosphine (138 mg, 0.57 mmol) were added to a toluene (2 mL) solution of 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 (100 mg, 0.19 mmol). The reaction solution was stirred at 100°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-45% ethyl acetate) to obtain the title compound (yellow solid, 70 mg, yield 54.5%). LC/MS(ESI)(m/z): 675[M+H] ⁺ .

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

Under nitrogen protection, 10% palladium carbon (35 mg) was added to a solution of 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 (70 mg, 0.10 mmol) in ethanol (2 mL). The reaction solution was replaced with nitrogen three times and stirred at room temperature under hydrogen for 6 hours. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-45% ethyl acetate) to obtain the title compound (yellow solid, 30 mg, yield 61.8%). LC/MS(ESI)(m/z):597[M+H] ⁺ .

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

Under nitrogen protection at room temperature, cesium carbonate (33 mg, 0.10 mmol), Ruphos (5 mg, 0.01 mmol) and Ruphos Pd G3 (4 mg, 0.005 mmol) were added to a solution of 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 (30 mg, 0.05 mmol) and 2-methyl-1-(piperazin-1-yl)propan-1-one (16 mg, 0.10 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 90 ° C for 3 hours under nitrogen protection. After the reaction was complete, it was cooled to room temperature, water was added, extracted 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: 0-70% ethyl acetate) to give the title compound (yellow solid, 22 mg, yield 61.4%). LC/MS (ESI) m/z: 717 [M+H] ⁺ .

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

At 0°C, trifluoroacetic acid (1 mL) was slowly added dropwise to a reaction bottle of 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 (22 mg, 0.03 mmol). The reaction solution was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (yellow solid, 2 mg, yield 11.5%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.64(s,1H),8.10(s,1H),7.86-7.47(m,1H),6.66(s,1H),4.87(d,J＝7.4Hz,2H),4.77(d,J＝7.3Hz,2H),3 .80-3.69(m,4H),3.40-3.35(m,4H),2.98-2.90(m,1H),1.04(d,J＝6.7Hz,6H).LC/MS(ESI)(m/z):567[M+H] ⁺ .

Example 15: 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: N-(3-(difluoro(phenylsulfonyl)methyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

Under nitrogen protection at -78°C, lithium bis(trimethylsilyl)amide (11.4 mL, 11.4 mmol, 1 M) was slowly added dropwise to a solution of 2-methyl-N-(oxetane-3-propylidene)propane-2-sulfinamide (1 g, 5.7 mmol) and ((difluoromethyl)sulfonyl)benzene (1.1 g, 5.7 mmol) in tetrahydrofuran (20 mL). After the addition was completed, the reaction mixture was stirred at -78°C to room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with ice water and extracted three times with ethyl acetate. The organic phase was 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: 0-35% ethyl acetate) to obtain the title compound (yellow liquid, 1.4 g, yield 66.8%). LC/MS(ESI)(m/z): 368[M+H] ⁺ .

Step 2: N-(3-(difluoromethyl)oxetan-3-yl)-2-methylpropane-2-sulfenamide

At room temperature, sodium dihydrogen phosphate (5.4 g, 38 mmol) and 20% sodium amalgam (1.1 g, 9.5 mmol) were added to a solution of N-(3-(difluoro(phenylsulfonyl)methyl)oxetane-3-yl)-2-methylpropane-2-sulfinamide (1.4 g, 3.81 mmol) in methanol (20 mL). The reaction solution was stirred under nitrogen protection for 2 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-40% ethyl acetate) to obtain the title compound (yellow liquid, 690 mg, yield 79.7%). LC/MS(ESI)(m/z): 228[M+H] ⁺ .

Step 3: 3-(Difluoromethyl)oxetane-3-amine hydrochloride

At 0°C, slowly add 4M dioxane hydrochloride (0.8mL, 3.2mmol) solution to a solution of N-(3-(difluoromethyl)oxetane-3-yl)-2-methylpropane-2-sulfenamide (400mg, 1.76mmol) in methanol (3.5mL). The reaction solution was stirred at 0°C for 30 minutes under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the title compound (white solid, 281mg, yield 100%), which was used directly in the next step without purification. ¹ H NMR (400MHz, DMSO-d ₆ )δ6.60(t,J＝54.2Hz,1H),4.73(d,J＝8.1Hz,2H),4.67(d,J＝8.0Hz,2H).

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

At 0°C, 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. The organic phase was 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: 0-35% ethyl acetate) to give the title compound (yellow solid, 120 mg, yield 33.7%). LC/MS(ESI)(m/z): 550[M+H] ⁺ .

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

At 0°C, 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. After the reaction was completed, water was added, extracted 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: 0-25% ethyl acetate) to give the title compound (yellow solid, 100 mg, yield 67.4%). LC/MS(ESI)m/z:680[M+H] ⁺ .

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

Under nitrogen protection, 10% palladium carbon (10 mg) was added to a solution of 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 (100 mg, 0.15 mmol) in ethanol (10 mL). The reaction solution was replaced with nitrogen three times and stirred at room temperature under a hydrogen atmosphere for 6 hours. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-25% ethyl acetate) to give the title compound (yellow solid, 70 mg, yield 79.2%). LC/MS(ESI)(m/z):602[M+H] ⁺ .

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

Under nitrogen protection at room temperature, cesium carbonate (76 mg, 0.23 mmol), Ruphos (11 mg, 0.02 mmol) and Ruphos Pd G3 (10 mg, 0.01 mmol) were added to a solution of 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 (70 mg, 0.12 mmol) and 2-methyl-1-(piperazin-1-yl)propan-1-one (36 mg, 0.23 mmol) in 1,4-dioxane (2 mL) at room temperature. The reaction mixture was stirred at 90 ° C for 3 hours under nitrogen protection. After the reaction was complete, it was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was 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, 60 mg, yield 71.5%). LC/MS (ESI) m/z: 722 [M+H] ⁺ .

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

At 0°C, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of 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 (60 mg, 0.08 mmol) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain The title compound (yellow solid, 21 mg, yield 42.7%). ¹ H NMR (400 MHz, CD ₃ OD) δ9.86 (s, 1H), 7.95 (s, 1H), 7.33 (t, J = 53.5 Hz, 1H), 6.78 (d, J = 1.2 Hz, 1H), 6.23 (t, J = 55.6 Hz, 1H), 4.83-4.75 (m, 2H), 4.73-4.64 (m, 2H), 3.94-3.84 (m, 4H), 3.50-3.34 (m, 4H), 3.09-2.95 (m, 1H), 1.15 (d, J = 6.7 Hz, 6H). LC/MS (ESI) (m/z): 592 [M+H] ⁺ .

Example 16: 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

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

At 0°C, N,N-diisopropylethylamine (105 mg, 0.81 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (67 mg, 0.40 mmol) were added to a solution of 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) in N,N-dimethylformamide (2 mL) in sequence. The reaction solution was stirred at room temperature for 1 hour. 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. The residue was purified by slurrying with petroleum ether to obtain the title compound (yellow solid, 143 mg, yield 79.4%). LC/MS(ESI)(m/z): 662[M+H] ⁺ .

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

Under nitrogen protection, 20% palladium hydroxide on carbon (10 mg) was added to a solution of 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 (65 mg, 0.62 mmol) in deuterated methanol (5 mL). The reaction mixture was replaced with nitrogen three times and stirred at 20°C under 1 atmosphere of deuterium for 1 hour. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (yellow solid, 40 mg, yield 69.6%). LC/MS(ESI)(m/z):585[M+H] ⁺ .

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

Under nitrogen protection, 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 (40 mg, 0.068 mmol) and 2-methyl-1-(piperidin-2-yl)-4-nitropropene were added to the mixture. Cesium carbonate (44 mg, 0.13 mmol), Ruphos (6 mg, 0.014 mmol), and Ruphos Pd G3 (11 mg, 0.014 mmol) were added to the solution of 1,4-dioxane (2 mL) in sequence. The reaction solution was replaced with nitrogen three times and stirred at 80 ° C for 30 minutes under nitrogen. 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-70% ethyl acetate) to obtain the title compound (yellow solid, 44 mg, yield 91.6%). LC/MS (ESI) (m/z): 705 [M+H] ⁺ .

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. After the reaction was complete, the 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%). ¹ H NMR (400MHz, CD ₃ OD)δ9.85(s,1H),7.33(t,J＝53.5Hz,1H),6.78(s,1H),4.82-4.79(m,2H),4.78(s,1H),4.66(s,1H),4.47(d,J＝7.1Hz,2H),3. 92-3.86(m,4H),3.44-3.41(m,2H),3.37-3.34(m,2H),3.07-2.99(m,1H),1.15(d,J＝6.7Hz,6H).LC/MS(ESI)(m/z):575[M+H] ⁺ .

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

Under nitrogen protection, 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. After the reaction was completed, it was diluted with ethyl acetate, and the organic phase was 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: 0-35% ethyl acetate) to give the title compound (yellow solid, 12 mg, yield 39.0%). LC/MS(ESI)(m/z):605[M+H] ⁺ .

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

At 0°C, 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-fluoro-N-(3-(fluoromethyl)oxetane-3-yl)-8-(4-isobutyl)- Trifluoroacetic acid (0.2 mL) was slowly added dropwise to a solution of dichloromethane (0.6 mL) of 1,5-a]pyridine-6-sulfonamide (12 mg, 0.02 mmol) and 1,5-d ((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (yellow solid, 1.1 mg, yield 11.2%). ¹ H NMR (400MHz, CD ₃ OD)δ9.89(d,J＝5.4Hz,1H),7.33(t,J＝53.5Hz,1H),4.85-4.82(m,2H),4.79(s,1H),4.67(s,1H),4.51-4.46(m,2 H),3.89-3.77(m,4H),3.50-3.41(m,4H),3.07-2.98(m,1H),1.16(d,J＝6.7Hz,6H).LC/MS(ESI)(m/z):593[M+H] ⁺ .

Example 18: 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

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

Under nitrogen protection at room temperature, 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. After the reaction was completed, the mixture was filtered and the filtrate was purified by preparative HPLC to obtain the title compound (yellow solid, 2 mg, yield 38.7%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.65(d,J＝5.3Hz,1H),8.97(s,1H),7.81-7.53(m,1H),4.71(d,J＝6.3Hz,2H),4.23(d,J＝6.4Hz,2H),3.74-3.6 6(m,4H),3.43-3.39(m,4H),2.97-2.91(m,1H),1.55(s,3H),1.04(d,J＝6.7Hz,6H).LC/MS(ESI)(m/z):575[M+H] ⁺ .

Example 19: 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

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

Under nitrogen protection, 10% palladium on carbon (50 mg) was added to a solution of 1-bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide (180 mg, 0.35 mmol) in deuterated methanol (5 mL). The reaction solution was replaced with nitrogen three times and stirred at room temperature under an atmospheric pressure of deuterium for 6 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (yellow solid, 120 mg, yield 78.55%). LC/MS(ESI)m/z:437/439 [M+H] ⁺ .

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

Under nitrogen protection, cesium carbonate (112 mg, 0.344 mmol), Ruphos (11 mg, 0.024 mmol) and Ruphos Pd G3 (10 mg, 0.012 mmol) were added to a solution 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 (50 mg, 0.114 mmol) and 2-methyl-1-(piperazin-1-yl)propane-1-one (36 mg, 0.23 mmol) in 1,4-dioxane (1 mL) in sequence. The 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61-9.57 (m, 1H), 8.72 (s, 1H), 7.83-7.53 (m, 1H), 6.70 (s, 1H), 4.63 (d, J = 6.2 Hz, 2H), 4.18 (d, J = 6.5 Hz, 2H), 3.84-3.70 (m, 4H), 3.39-3.34 (m, 4H), 2.99-2.91 (m, 1H), 1.50 (s, 3H), 1.05 (d, J = 6.7 Hz, 6H). LC/MS (ESI) m/z: 557 [M+H] ⁺ .

Example 20: 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-1-deuterium

The title compound was obtained by referring to the synthesis method of Example 19 as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.29 (d, J=1.8 Hz, 1H), 7.83-7.49 (m, 1H), 6.71 (s, 1H), 4.69-4.58 (m, 2H), 4.22-4.16 (m, 2H), 3.53-3.43 (m, 2H), 3.36-3.29 (m, 2H), 3.15-3.06 (m, 2H), 1.50 (s, 3H), 1.37-1.16 (m, 6H). LC/MS (ESI) (m/z): 515 [M+H] ⁺ .

Example 21: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-N-(3-methyloxetane-3-yl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide

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

Under nitrogen protection, Pd(dppf)Cl 2 (9 mg, 0.02 mmol) and potassium carbonate (120 mg, 0.69 mmol) were added to a solution of 1-bromo-8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (150 mg, 0.23 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane (0.1 ml, 0.34 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL). The 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

Under nitrogen protection, 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. The 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. The residue was purified by preparative HPLC to give the title compound (yellow solid, 1.5 mg, yield 9.2%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.56(s,1H),8.66(s,1H),7.66(t,J＝53.6Hz,1H),6.73(s,1H),4.62(d,J＝6.2Hz,2H),4.40(s,4H),4.17(d ,J＝6.3Hz,2H),3.01-2.97(m,4H),2.70(s,3H),2.10-1.98(m,4H),1.48(s,3H).LC/MS(ESI)(m/z):541[M+H] ⁺ .

Example 22: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(3-methoxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

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

Under nitrogen protection, cesium carbonate (136 mg, 0.42 mmol), Ruphos (13 mg, 0.02 mmol) and Ruphos Pd G3 (13 mg, 0.01 mmol) were added to a solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methoxy-3-yl)-N-(2-(trimethylsilyl)ethoxy)methyl)imidazole[1,5-a]pyridine-6-sulfonamide (80 mg, 0.14 mmol) and (2R,6R)-2,6-dimethyl-1-piperazinecarboxylic acid tert-butyl ester (38 mg, 0.18 mmol) in 1,4-dioxane (5 mL) in sequence. The 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

At 0°C, trifluoroacetic acid (2 mL) was added to a solution of 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)imidazole[1,5-a]pyridine-6-sulfonamide (100 mg, 0.13 mmol) in dichloromethane (5 mL), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (yellow solid, 37 mg, yield 54%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.62(s,1H),8.96(s,1H),8.74(s,1H),8.01(s,1H),7.68(t,J＝53.1Hz,1H),6.79(s,1H),4.67–4.61(m,2H),4.22–4.17(m,2H),3.9 4–3.85(m,2H),3.53–3.48(m,2H),3.29–3.24(m,2H),1.51(s,3H),1.47–1.44(m,3H),1.43–1.41(m,3H).LC/MS(ESI)(m/z):514[M+H] ⁺ .

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

At 0°C, potassium hydroxide (159 mg, 2.84 mmol) and deuterated iodomethane (613 mg, 4.26 mmol) were added to a solution of 4-benzyl-1-(tert-butyl) 2-(hydroxymethyl) piperazine-1,4-dicarboxylate (500 mg, 1.42 mmol) in DMSO (10 mL) in sequence. The reaction solution was stirred in an ice bath for 2 hours. 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. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-30% ethyl acetate) to obtain the title compound Product (white solid, 320 mg, yield 30%). LC/MS (ESI) (m/z): 368 [M+H] ⁺ .

Step 2: tert-Butyl 2-((methoxy-d ₃ )methyl)piperazine-1-carboxylate

Under nitrogen protection, 10% palladium on carbon (30 mg) was added to a solution of 4-benzyl-1-(tert-butyl)-2-((methoxy-d3)methyl)piperazine-1,4-dicarboxylate (320 mg, 0.87 mmol) in ethyl acetate (20 mL). The reaction solution was replaced with nitrogen three times and stirred for 2 hours under a 15 psi hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (colorless oil, 180 mg, yield 88%). LC/MS (ESI) (m/z): 234 [M+H] ⁺ .

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

Under nitrogen protection, cesium carbonate (97 mg, 0.30 mmol), Ruphos (9 mg, 0.02 mmol) and Ruphos Pd G 3 (9 mg, 0.01 mmol) were added to a solution of 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (60 mg, 0.10 mmol) and tert-butyl 2-((methoxy-d3)methyl)piperazine- ₁ -carboxylate (30 mg, 0.13 mmol) in 1,4-dioxane (8 mL) in sequence. The 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

To a solution of 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)aminosulfonyl)imidazo[1,5-a]pyridin-8-yl)-2-((methoxy-d ₃ )methyl)piperazine-1-carboxylate (30 mg, 0.03 mmol) in dichloromethane (8 mL) was slowly added dropwise trifluoroacetic acid (3 mL) at 0°C. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (yellow solid, 4.8 mg, yield 22%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.64(d,J＝1.1Hz,1H),9.25(s,1H),7.70(t,J＝53.1Hz,1H),6.92(s,1H),4.66-4.61(m,2H),4.21-4.18( m,2H),3.80-3.71(m,1H),3.68-3.47(m,6H),3.09-2.95(m,2H),1.50(s,3H).LC/MS(ESI)(m/z):567[M+H] ⁺ .

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

Under nitrogen protection, 1-aminocyclopropane-1-carboxylic acid methyl ester (154 mg, 1.34 mmol) and sodium triacetoxyborohydride (731 mg, 3.45 mmol) were added to a solution of 4-(tert-butyl) 2-formylpiperazine-1,4-dicarboxylic acid 1-benzyl ester (400 mg, 0.89 mmol) in dichloromethane (6 mL) under nitrogen protection. 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. The organic phase was 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: 0-60% ethyl acetate) to obtain the title compound (yellow oil, 340 mg, yield 66.0%). LC/MS (ESI) m/z: 448 [M+H] ⁺ .

Step 2: 1-Benzyl 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)(methyl)amino)methyl)piperazine-1,4-dicarboxylate

At 0°C, cesium fluoride (346 mg, 2.28 mmol) and iodomethane (162 mg, 1.14 mmol) were added to a solution of 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)amino)methyl)piperazine-1,4-dicarboxylic acid 1-benzyl finger (340 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL) in sequence. The reaction solution was stirred at 80°C for 16 hours. 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-30% ethyl acetate) to obtain the title compound (yellow oil, 140 mg, yield 39.9%). LC/MS(ESI)(m/z):462[M+H] ⁺ .

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

At 0°C, 10% palladium hydroxide on carbon (28 mg) was added to a solution of 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)(methyl)amino)methyl)piperazine-1,4-dicarboxylic acid 1-benzyl (140 mg, 0.30 mmol) in anhydrous methanol (5 mL). The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/dichloromethane, gradient: 0-35% dichloromethane) to give the title compound (yellow solid, 70 mg, yield 78.2%). LC/MS(ESI)(m/z): 296[M+H] ⁺ .

Step 4: 2'-Methylhexahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-a]pyrazino]-4'-one

At room temperature, a solution of 1,4-dioxane solution of hydrochloric acid (1 mL) was added to a solution of tert-butyl 2'-methyl-4'-oxohexahydro-4'H,8'H-pyrro[cyclopropane-1,3'-pyrazino[1,2-a]pyrazine]-8'-carboxylate (70 mg, 0.23 mmol) in methanol (2 mL). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, it was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (yellow oil, 45 mg, yield 97.2%). LC/MS(ESI)m/z:196[M+H] ⁺ .

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

The title compound was prepared by referring to the preparation method of Steps 3-4 of Example 391. ¹ H NMR (400 MHz, CD ₃ OD)δ9.81(s,1H),7.99(s,1H),6.84-6.79(m,1H),4.80-4.71(m,4H),4.34-4.3 0(m,2H),3.87-3.79(m,2H),3.27-3.24(m,1H),3.18-3.11(m,2H),3.00-2.93( m,1H),2.83-2.76(m,1H),2.58(s,3H),1.64(s,3H),1.55-1.50(m,1H),1.32-1 .28(m,1H),1.08-1.02(m,1H),0.96-0.94(m,1H).LC/MS(ESI)(m/z):613[M+H] ⁺ _.

Example 25: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholinyl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

Step 1: (S)-1-((4-methoxybenzyl)amino)propan-2-ol

Under nitrogen protection, p-methoxybenzaldehyde (10.3 mg, 76 mmol) was added to a solution of (S)-1-aminopropan-2-ol (6 g, 80 mmol) in methanol (60 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection, and then sodium borohydride (3.0 g, 80 mmol) was added in batches at zero degrees. 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 then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (white solid, 10 g, yield 64.1%). LC/MS (ESI) m/z: 196 [M + H] ⁺ .

Step 2: ((2R,6S)-4-(4-methoxybenzyl)-6-methylmorpholin-2-yl)methanol

Under nitrogen protection, (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. After the reaction was complete, 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-60% ethyl acetate) to obtain the title compound (yellow oil, 1.8g, yield 22.0%). LC/MS (ESI) m/z: 252[M+H] ⁺ .

Step 3: (2R,6S)-2-(Hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester

To a solution of ((2R,6S)-4-(4-methoxybenzyl)-6-methylmorpholin-2-yl)methanol (900 mg, 3.59 mmol) in anhydrous methanol (10 mL) at 0°C, 10% palladium carbon (90 mg), 10% palladium hydroxide carbon (90 mg) and dicarbonate were added. Tert-butyl ester (1.17 g, 5.38 mmol). The reaction solution was replaced with nitrogen three times and stirred at 60 ° C for 16 hours under 15 psi hydrogen atmosphere. After the reaction was complete, it was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/dichloromethane, gradient: 0-35% dichloromethane) to obtain the title compound (yellow oil, 690 mg, yield 83.3%). LC/MS (ESI) (m/z): 232 [M+H] ⁺ .

Step 4: ((2R,6S)-6-Methylmorpholin-2-yl)methanol hydrochloride

To a solution of (2R,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (400 mg, 0.23 mmol) in 1,4-dioxane (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature under nitrogen protection for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the title compound (yellow oil, 350 mg, yield 91.3%). LC/MS (ESI) m/z: 132 [M+H] ⁺ .

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

The title compound was prepared according to the preparation method of Example 23, Steps 3-4. ¹ H NMR(400MHz,DMSO)δ9.57(s,1H),8.73(s,1H),8.05(s,1H),7.84-7.52(m, 1H),6.70(d,J＝0.9Hz,1H),5.01-4.96(m,1H),4.66-4.61(m,2H),4.20-4.0 9(m,3H),3.96-3.83(m,2H),3.67-3.55(m,2H),3.17-3.13(m,1H),3.01-2. 95(m,1H),1.50(s,3H),1.26(d,J＝6.2Hz,3H).LC/MS(ESI)(m/z):531[M+H] ⁺ _.

Example 26: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-8-((3S,5S)-3,4,5-trimethylpiperazin-1-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

At 0°C, formaldehyde (8 mg, 0.26 mmol), acetic acid (10 mg, 0.17 mmol) and sodium cyanoborohydride (24 mg, 0.39 mmol) were added to a solution of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazine-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide (70 mg, 0.13 mmol) in methanol (2 mL) in sequence. After the addition was completed, the reaction mixture was stirred at 0°C for 20 minutes. After the reaction was completed, water was added to the reaction solution and the mixture was extracted three times with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 50-80% ethyl acetate) and further purified by preparative HPLC to give the title compound (yellow solid, 17 mg, yield 24%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.64(d,J＝2.5Hz,1H),8.77(d,J＝7.6Hz,1H),8.03(d,J＝3.1Hz,1H),7.82(t,J＝53.6Hz,1H),6.79(s,1H),4.70-4.61(m,2H),4.25-4.16( m,2H),3.99-3.92(m,1H),3.86-3.70(m,4H),3.10-3.02(m,1H),2.89(s,3H),1.55-1.47(m,6H),1.41(s,3H).LC/MS(ESI)(m/z):528[M+H] ⁺

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

At 0°C, N,N-diisopropylethylamine (50 mg, 0.39 mmol), acetic acid (10 mg, 0.17 mmol) and HATU (74 mg, 0.19 mmol) were added to a solution of 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) in dichloromethane (2 mL) in sequence. After the addition was complete, the reaction mixture was stirred at 50°C for 1 hour. After the reaction was complete, water was added to the reaction solution and the mixture was extracted three times with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by preparative HPLC to give the title compound (yellow solid, 14 mg, yield 19%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.47(s,1H),8.68(s,1H),8.12(s,1H),7.68(t,J＝53.2Hz,1H),6.38(s,1H),4.68-4.62(m,2H),4.50-4.41(m,1H),4.34-4.26(m,1H ),4.20-4.12(m,4H),3.69-3.59(m,2H),2.09(s,3H),1.52(s,3H),1.38-1.31(m,3H),1.23-1.16(m,3H).LC/MS(ESI)(m/z):556[M+H] ⁺ .

Example 28: 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: (S)-tert-butyl (1-(benzylamino)propan-2-yl)carbamate

Dissolve (S)-(1-oxopropyl-2-yl)carbamic acid tert-butyl ester (5g, 28.9mmol) and benzylamine (3.7g, 34.7mmol) in methanol (50mL). Under ice bath, sodium cyanoborohydride (5.5g, 86.7mmol) and acetic acid (0.327g, 2.89mmol) were added to the reaction mixture in sequence, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride was added to quench under ice bath cooling, extracted 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: 10-30% ethyl acetate) to give the title compound (colorless oil, 5.5 g, yield 72.4%). LC/MS (ESI) m/z: 265 [M+H] ⁺ .

Step 2: tert-Butyl (S)-(1-(N-benzyl-2-chloroacetamido)propan-2-yl)carbamate

(S)-(1-(Benzylamino)propane-2-yl)carbamic acid tert-butyl ester (5.5 g, 20.8 mmol) was mixed with saturated sodium bicarbonate aqueous solution (50 mL) and ethyl acetate (50 mL). 2-Chloroacetyl chloride (4.7 g, 41.6 mmol) was added to the mixture under an ice-water bath and stirred for 2 hours. The organic layer was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were 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: 10-30% ethyl acetate) to give the title compound (colorless oil, 5.4 g, yield 77.7%). LC/MS (ESI) m/z: 341 [M+H] ⁺ .

Step 3: (S)-4-Benzyl-2-methyl-5-oxopiperazine-1-carboxylic acid tert-butyl ester

Mix (S)-(1-(N-benzyl-2-chloroacetamido)propane-2-yl)carbamic acid tert-butyl ester (5.4 g, 15.9 mmol) with tetrahydrofuran (50 mL) and N, N-dimethylformamide (50 mL). Add 60% mass fraction of sodium hydride (1.6 g, 41.3 mmol) slowly in batches under ice-water cooling. After addition, warm the mixture to room temperature and stir for 2 hours. Pour the reaction mixture into a saturated aqueous ammonium chloride solution cooled with ice water and extract with ethyl acetate. Wash the organic phase 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: 10-30% ethyl acetate) to obtain the title compound (colorless oil, 2.4 g, yield 49.7%). LC/MS (ESI) m/z: 305 [M+H] ⁺ .

Step 4: (2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester

(S)-4-benzyl-2-methyl-5-oxopiperazine-1-carboxylic acid tert-butyl ester (1.0 g, 3.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Under a nitrogen atmosphere, 1.0 M lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (4 mL, 4 mmol) was added dropwise to the mixture at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour, and benzyl chloromethyl ether (1.3 g, 8.6 mmol) was added dropwise. After addition, the reaction was stirred at -78 °C for 1 hour. 1N hydrochloric acid (4 mL) was added to the reaction mixture at -20 °C, and extracted with ethyl acetate. The organic phase was 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: 10-30% ethyl acetate) to give the title compound (colorless oil, 800 mg, yield 77.7%). LC/MS(ESI)m/z:425[M+H] ⁺ .

Step 5: tert-Butyl (2R,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methylpiperazine-1-carboxylate

Dissolve (2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (800 mg, 1.9 mmol) in tetrahydrofuran (10 mL). Add 1 M borane/tetrahydrofuran solution (9.5 mL, 9.5 mmol) dropwise to the mixture at 0°C. After addition, heat to 60°C and stir for 6 hours. Quench the reaction mixture with methanol (~10 mL) at 0°C and stir for 1 hour at 60°C. Concentrate under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 10-30% ethyl acetate) to obtain the title compound (colorless oil, 450 mg, yield 57.8%). LC/MS (ESI) m/z: 411 [M+H] ⁺ .

Step 6: (2R,6S)-2-(Hydroxymethyl)-6-methylpiperazine-1-carboxylic acid tert-butyl ester

In an autoclave, 20% mass fraction of palladium hydroxide on carbon (50 mg) was added to a solution of (2R, 6S)-4-benzyl-2-((benzyloxy)methyl)-6-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 488 mmol) in methanol (5 mL), the reaction solution was replaced with hydrogen three times, and the reaction was stirred at room temperature under a 1 MPa hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (white solid, 90 mg, yield 80.4%). LC/MS (ESI) (m/z): 231 [M+H] ⁺ .

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

The title compound was obtained by referring to the preparation method of Steps 3-4 of Example 23. ¹ H NMR (400 MHz, CD ₃ OD) δ9.91 (d, J=1.1 Hz, 1H), 7.35 (t, J=53.5 Hz, 1H), 6.95 (d, J=1.1 Hz, 1H), 4.40-4.32 (m, 2H), 4.07-3.86 (m, 4H), 3.74-3.58 (m, 2H), 3.39-3.32 (m, 2H), 3.26-3.21 (m, 1H), 3.12-2.96 (m, 1H), 1.66 (s, 3H), 1.53 (d, J=4.8 Hz, 3H). LC/MS (ESI) (m/z): 564 [M+H] ⁺ .

Example 29: 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: (2S,6S)-4-benzyl-2-(methoxymethyl)-6-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester

At -78 ° C, slowly add 1.0M bis(trimethylsilyl)amide lithium/tetrahydrofuran solution (2mL, 1.97mmol) to a solution of (S)-4-benzyl-2-methyl-5-oxopiperazine-1-carboxylic acid tert-butyl ester (500mg, 1.64mmol) in anhydrous tetrahydrofuran (5mL) dropwise. After stirring the reaction mixture at -78 ° C for 1 hour, chloromethyl methyl ether (328mg, 4.10mmol) was added dropwise and the reaction was continued to stir for 1 hour. After the reaction was complete, 1N hydrochloric acid (2mL) was added at -20 ° C, extracted with ethyl acetate, the organic phase was 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: 10-30% ethyl acetate) to obtain the title compound (colorless oil, 200mg, yield 34.8%). LC/MS (ESI) m/z: 349[M+H] ⁺ .

Step 2: (2R,6S)-4-benzyl-2-(methoxymethyl)-6-methylpiperazine-1-carboxylic acid tert-butyl ester

At 0°C, slowly drop 1.0M borane/tetrahydrofuran solution (2.9mL, 2.85mmol) into a solution of (2S,6S)-4-benzyl-2-(methoxymethyl)-6-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (200mg, 0.57mmol) in anhydrous tetrahydrofuran (10mL). The reaction solution was stirred at 60°C for 6 hours. After the reaction was complete, methanol (~5mL) was added to the reaction mixture at 0°C to quench it and then the temperature was raised to 60 degrees Celsius and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 10-30% ethyl acetate) to obtain the title compound (colorless oil, 120mg, yield 62.8%). LC/MS (ESI) m/z: 335[M+H] ⁺ .

Step 3: (2R,6S)-2-(methoxymethyl)-6-methylpiperazine-1-carboxylic acid tert-butyl ester

At room temperature, 10% mass fraction of palladium hydroxide on carbon (10 mg) was added to a solution of (2R, 6S)-4-benzyl-2-(methoxymethyl)-6-methylpiperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.36 mmol) in methanol (2 mL). The reaction solution was ventilated three times under nitrogen protection and stirred at room temperature for 1 hour under a hydrogen balloon. After the reaction was completed, the filtrate was filtered on diatomaceous earth and concentrated under reduced pressure to obtain the crude title compound (colorless oil, 85 mg, yield 96.9%), which was used directly in the next step without purification. ¹ H NMR (400MHz, CDCl ₃ )δ3.94-3.89(m,1H),3.85-3.79(m,1H),3.63-3.58(m,1H),3.52-3.47(m,1H),3.37(s,3H),3.35-3.32(m, 1H),3.13-3.10(m,2H),2.75-2.69(m,1H),1.47(s,9H),1.34(d,J＝6.6Hz,3H).LC/MS(ESI)(m/z):245[M+H] ⁺ .

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

The title compound was obtained by referring to the preparation method of Steps 3-4 of Example 23. ¹ H NMR (400 MHz, CD ₃ OD) δ9.90 (d, J=1.7 Hz, 1H), 7.34 (t, J=53.5 Hz, 1H), 6.92 (s, 1H), 4.83-4.79 (m, 2H), 4.34 (d, J=5.9 Hz, 2H), 4.04-3.93 (m, 2H), 3.88-3.82 (m, 1H), 3.75-3.71 (m, 1H), 3.65-3.59 (m, 2H), 3.46 (s, 3H), 3.21-3.13 (m, 2H), 1.65 (s, 3H), 1.49 (d, J=3.7 Hz, 3H). LC/MS (ESI) (m/z): 578 [M+H] ⁺ .

Example 30: 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

The title compound was obtained by referring to the preparation method of Example 29. ¹ H NMR (400MHz, CD ₃ OD)δ9.82(s,1H),7.88(s,1H),7.33(t,J＝53.5Hz,1H),6.79(s,1H),4.79(d, J＝6.0Hz,2H),4.32(d,J＝5.2Hz,2H),3.92-3.85(m,1H),3.83-3.77(m,2H),3 .76-3.71(m,1H),3.64-3.53(m,2H),3.50(s,3H),3.46-3.40(m,1H),3.26-3 .19(m,1H),1.63(s,3H),1.47(d,J＝5.4Hz,3H).LC/MS(ESI)(m/z):544[M+H] ⁺ .

Example 31: 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

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

At 0°C, a solution of 1-bromo-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5-a]pyridine-6-sulfonyl chloride (90 mg, 0.194 mmol) in DCM (2 mL) was added dropwise to a solution of 3-methyloxetane-3-amine (0.017 mL, 0.388 mmol) in pyridine (3 mL). The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, water was added, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-50%) to give the title compound (yellow solid, 80 mg, yield 80.14%). LC/MS (ESI) (m/z): 514/516 [M+H] ⁺ .

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

At room temperature, 10% Pd/C (20 mg, 0.188 mmol) was added to a solution of 1-bromo-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetane-3-yl)imidazole[1,5]solution-a]pyridine-6-sulfonamide (70 mg, 0.136 mmol) in EtOH (10 mL). The mixture was replaced with hydrogen three times and stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and concentrated to dryness. The residue was used directly in the next step without purification. LC/MS (ESI) (m/z): 434/436 [M+H] ⁺ .

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

To a solution of 8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide (35 mg, 0.080 mmol), 2-methyl-1-(piperazine-1-yl)propan-1-one (25 mg, 0.161 mmol) in 1,4-dioxane (1 mL) were added cesium carbonate (26 mg, 0.080 mmol), RuPhos (7 mg, 0.016 mmol), and RuPhos Pd G ₃ (7 mg, 0.008 mmol) in sequence. The reaction solution was replaced with nitrogen three times and stirred at 80° C. under nitrogen protection for 3 hours. After the reaction was complete, it was cooled to room temperature, filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (yellow oil, 5 mg, yield 11.23%). ¹ H NMR (400MHz, DMSO-d6) δ9.59(s,1H),8.72(s,1H),8.08(s,1H)),7.68(t,J＝53.2Hz,1H),6.70(s,1H),4.63(d,J＝6.2Hz,2H),4.18(d,J ＝6.3Hz,2H),3.84–3.68(m,4H),3.41–3.36(m,4H),3.00–2.89(m,1H),1.50(s,3H),1.05(d,J＝6.7Hz,6H).LC/MS(ESI)(m/z):556[M+H] ⁺ .

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.

Example 49: (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

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

At 0°C, DIEA (120 mg, 0.85 mmol) and SEMCl (40 mg, 0.34 mmol) were added in batches to a DMF (2 mL) solution of 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide (80 mg, 0.17 mmol), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, 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, 70 mg, yield 68%). LC/MS (ESI) (m/z): 600 [M+H] ⁺ .

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

Under nitrogen protection, cesium carbonate (100 mg, 0.36 mmol), Ruphos (10 mg, 0.02 mmol) and Ruphos Pd G3 (10 mg, 0.01 mmol) were added to a solution of 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (70 mg, 0.12 mmol) and (R)-2-methyl-1-(2-methylpiperazin-1-yl)propan-1-one (30 mg, 0.17 mmol) in 1,4-dioxane (2 mL) in sequence. The 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%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.62(s,1H),8.77(s,1H),7.87-7.50(m,1H),6.85(s,1H),4.67-4.60(m,2H),4.19(d,J＝6.5Hz ,2H),3.60(d,J＝12.8Hz,1H),3.20- 3.11(m,4H),3.07-3.02(m,1H),2.97-2.85(m,2H),1.50(s,3H),1.40-1.23(m,3H),1.04(d,J＝6.8Hz, 6H).LC/MS(ESI)m/z:604[M+H] ⁺ .

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.

Example 62: (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

Step 1: 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

At 0°C, dilute hydrochloric acid (4mL, 0.5N) was added to a solution of 2-(6-(benzylthio)-1-bromo-8-chloroimidazole[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (300mg, 0.59mmol) in acetonitrile (8mL), and dichlorohydantoin (351mg, 1.78mmol) was added. The reaction solution was stirred at room temperature for 30 minutes and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (yellow solid, 230mg). It was used directly in the next step without purification.

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

At 0°C, 1-bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (230 mg, 0.48 mmol) in dichloromethane (8 mL) was added in batches to a solution of 3-methyloxetane-3-amine (83 mg, 0.95 mmol) in DCM (2 mL) and TFA (145 mg, 1.43 mmol). The reaction solution was stirred at room temperature for 30 minutes. The mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-40% ethyl acetate) to give the title compound (yellow solid, 180 mg, yield 71%). LC/MS(ESI)(m/z): 532[M+H] ⁺ .

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

At 0°C, N,N-diisopropylethylamine (131 mg, 1.01 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (85 mg, 0.51 mmol) were added to a solution of 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) in N,N-dimethylformamide (3 mL) in sequence. The reaction solution was stirred at room temperature for 1 hour. 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. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (yellow solid, 200 mg, yield 89%). LC/MS (ESI) (m/z): 662 [M+H] ⁺ .

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

Under nitrogen protection, 20% palladium hydroxide (100 mg) was added to a solution of 1-bromo-8-chloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (200 mg, 0.30 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL). The reaction solution was replaced with nitrogen three times, and the reaction was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 0-30% ethyl acetate) to give the title compound (yellow solid, 100 mg, yield 57%). LC/MS(ESI)(m/z): 584 [M+H] ⁺ .

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

Under nitrogen protection, cesium carbonate (167 mg, 0.51 mmol), RuPhos (8 mg, 0.02 mmol), and RuPhos Pd G 3 (15 mg, 0.02 mmol) were added to a solution of 8-chloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (100 mg, 0.17 mmol) and (R)-2-methyl-1-(2-methylpiperazin-1-yl)propan-1-one (58 mg, 0.34 mmol) in 1,4-dioxane ( ₃ mL) in sequence. The reaction solution was replaced with nitrogen three times and stirred at 80°C for 10 hours under nitrogen protection. After the reaction was complete, the solution was cooled to room temperature, filtered, and concentrated. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, gradient: 40-80% ethyl acetate) to give the title compound (yellow solid, 100 mg, yield 81%). LC/MS (ESI) (m/z): 718 [M+H] ⁺ .

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

At 0°C, trifluoroacetic acid (0.5 mL) was added to a solution of (R)-8-(4-isobutyryl-3-methylpiperazine-1-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,5-a]pyridine-6-sulfonamide (100 mg, 0.14 mmol) in dichloromethane (1 mL). The reaction solution was stirred at 0°C for 1 hour. After the reaction was complete, the 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). ¹ H NMR(400MHz,DMSO)δ9.55(s,1H),8.74(s,1H),7.99(s,1H),6.72(s,1H), 4.89–4.67(m,1H),4.65-4.61(m,2H),4.47-4.32(m,1H),4.20-4.15(m,2 H),4.12-3.85(m,1H),3.73-3.64(m,2H),3.13-2.87(m,3H),1.52-1.43( m,4H),1.37-1.25(m,2H),1.08-1.00(m,6H).LC/MS(ESI)(m/z):588[M+H] ⁺ .

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

At 0°C, 1N hydrochloric acid (1 mL), water (1 mL) and dichlorohydantoin (887 mg, 4.50 mmol) were added to a solution of 2-(6-(benzylthio)-8-bromoimidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (680 mg, 1.50 mmol) in acetonitrile (4 mL) in sequence. The reaction solution was stirred in an ice bath for 10 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. The residue was purified by slurrying with petroleum ether to obtain the title compound (yellow solid, 640 mg, yield 99.3%). LC/MS(ESI)(m/z):428[M+H] ⁺ .

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

At 0°C, 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (640 mg, 3 mmol) was added to a solution of 3-methyloxetane-3-amine (260 mg, 1.50 mmol) in anhydrous dichloromethane (4 mL) and pyridine (1 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. The residue was purified by column chromatography (eluent: petroleum ether/dichloromethane, gradient: 0-35% dichloromethane) to give the title compound (yellow solid, 600 mg, yield 83.9%). LC/MS(ESI)(m/z):479[M+H] ⁺ .

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

To a solution of 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)imidazo[1,2-a]pyridine-6-sulfonamide (600 mg, 1.25 mmol) in N,N-dimethylformamide (6 mL) was added N,N-diisopropylethylamine (483 mg, 3.75 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (312 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, it was cooled to room temperature, water was added, extracted 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: 0-35% ethyl acetate) to give the title compound (yellow solid, 350 mg, yield 45.9%). LC/MS (ESI) m/z: 610 [M+H] ⁺ . 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

Under nitrogen protection, cesium carbonate (128 mg, 0.39 mmol), Ruphos (12.2 mg, 0.026 mmol) and Ruphos Pd G 3 (21.9 mg, 0.026 mmol) were added to a solution of 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2-a]pyridine-6-sulfonamide (80 mg, 0.13 mmol) and azetidin-1-yl(piperidin-4-yl)methanone (56.1 mg, 0.26 mmol) in 1,4-dioxane ( ₂ mL) in sequence. The reaction mixture was replaced with nitrogen three times and stirred at 80° C. for 4 hours under nitrogen protection. After the reaction is complete, the 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%). LC/MS (ESI) (m/z): 744 [M+H] ⁺ _.

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

To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetane-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)imidazo[1,2-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (40 mg, 0.05 mmol) in dichloromethane (2 mL) at 80°C was added trifluoroacetic acid (0.6 mL). The reaction solution was stirred at room temperature for 30 minutes. After the reaction was complete, the base was adjusted with sodium bicarbonate, extracted with dichloromethane, washed with saturated brine, dried, concentrated, and separated by preparative HPLC (C18, 10-50% acetonitrile in H ₂ O and 0.1% FA) to give the title compound (yellow solid, 6.87 mg, yield 24.9%). ¹ H NMR (400MHz, MeOD) δ9.93(d,J＝1.5Hz,1H),8.45(s,1H),7.35(t,J＝53.5Hz,1H),7.11(d,J＝1.5Hz,1H),4.79(d, J＝6.3Hz,2H),4.32(d,J＝6.6Hz,2H),3.84-3.79(m,4H),3.58-3.53(m,2H),1.64(s,3H),1.46(d,J＝6.5Hz,7H). LC/MS(ESI)(m/z):514[M+H] ⁺ _.

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.

Effect Example

Experimental methods:

1. Biochemical Assay

1) Add 20 nL of different concentrations of compounds to a 384-well plate using Echo 550 (LABCYTE, #550) (final concentrations of compounds: 1000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM, 0.03 nM, 0 nM);

2) Prepare 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);

3) Add reaction buffer I at 10 μL/well into a 384-well plate;

4) Prepare 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);

5) Add reaction buffer II at 10 μL/well into the 384-well plate to start the reaction;

6) Incubate at room temperature for 3 min to react;

7) Place the 384-well plate in the microplate reader and shake for 5 seconds before detecting the signal;

8) Analyze the data using GraphPad software and determine the IC50.

2. Cell Viability Assay

1) Cells were plated in 384-well cell culture plates. HCC1806 (ATCC cell bank, 100 cells/well) and MDA-MB-231 (ATCC cell bank, 120 cells/well) were placed in a 37°C CO ₂ (5%) incubator and incubated for 24 h to allow the cells to fully adhere to the plate;

2) Add culture medium (100 μL/well) containing different concentrations of the test compound (final concentration of the compound is: 30000 nM, 10000 nM, 3000 nM, 1000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0 nM) to the cells and incubate in a CO2 (5%) incubator at 37°C for 7 days;

3) Place the culture plate containing cells at room temperature for 30 minutes to allow the plate and its contents to equilibrate to room temperature;

4) Add CellTiter-Glo (Promega: V9101) reagent equal to the volume of cell culture medium to each well of cells and mix the contents on an orbital shaker for 2 minutes to induce cell lysis;

5) The plate was incubated at room temperature for 10 minutes to allow the signal value to stabilize, and then the luminescence value was detected by a microplate reader (Thermo: VarioskanLUX);

6) Analyze the data using GraphPad software and determine the IC ₅₀ .

Data list:

NT = not tested;

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.

Claims (14)

A compound of 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; n is 0, 1 or 2; m is 0, 1 or 2; k is 0, 1 or 2; R ^1-3' is hydrogen or R ^1-3 ; Each R ^1-3 is independently cyano, deuterium, hydroxyl, amino, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3-1 , C ₁ -C ₆ alkoxy which is 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 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 more of N, O and S, and the number of heteroatoms is 1, 2 or 3; 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 ; R ^2-3-2 is hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-3-2-1 , or C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R ^2-3-2-2 . substituted C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy which is unsubstituted or substituted by one or more R ^2-3-2-4 , 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 ^2-3-3 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 , 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 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 ^2-3-2-4 is independently halogen; Each R ^2-3-2-5 is independently halogen, hydroxy, oxo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl 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 ^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; 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 Each 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 of formula IV, its pharmaceutically acceptable salt or isotope compound according to claim 1, characterized in that the compound of formula IV is a compound of formula V,
M is N, O or S; i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time; 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 in claim 1; Preferably, the compound represented by formula IV is a compound represented by formula VI,
i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time; 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 in claim 1; More preferably, the compound represented by formula IV is a compound represented by formula VII,
^V1 is CH or N; ^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 ; i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time; W, Z, R ^1-3' , R ^1-3 , R ^2-3 , R ^3-1 , n and m are as defined in claim 1; Alternatively, the compound represented by formula IV may be a compound represented by formula VIII,
m is 0, 1 or 2; ^V1 is CH or N; ^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 ; i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time; W, Z, R ^1-3' , R ^1-3 , R ^2-3 , R ^3-1 , n and m are as defined in claim 1; Most preferably, the compound of formula IV is a compound of formula IX,
U is CH ₂ , NH or O; p is 0, 1 or 2; q is 0, 1 or 2; i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time; R ^3-1' is hydrogen or R ^3-1 ; W, Z, R ^1-3' , R ^1-3 , R ^2-3 , R ^3-1 , n and m are as defined in claim 1; Alternatively, the compound represented by formula IV may be a compound represented by formula X,
R ^G is R ^2-3-2 or i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time; R ^3-1' is hydrogen or R ^3-1 ; ^V1 is CH or N; ^V2 is CH or N; ^V1 and ^V2 are not CH at the same time; W, Z, R ^1-3′ , R ^1-3 , R ^2-3 , R ^3-1 , R ^2-3-2 , R ^2-3-3 , n and m are as defined in claim 1. The compound of formula IV, or a pharmaceutically acceptable salt or isotope compound thereof according to claim 1, wherein the compound of formula IV satisfies one or more of the following conditions: (1) In each R ^1-3 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (2) In each R ^1-3 , the C ₁ -C ₆ alkyl group is a C ₁ -C ₄ alkyl group, and may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, and may be a methyl group; (3) In each R ^1-3 , 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; (4) In each R ^1-3 , the C ₂ -C ₆ alkynyl group is For example (5) In each R ^1-3-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (6) In each R ^1-3-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (7) In each R ^2-3 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (8) In each R ^2-3 , the C ₁ -C ₆ alkyl group is a C ₁ -C ₄ alkyl group, which 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 tert-butyl group, and may also be a methyl group, an ethyl group, an isopropyl group or a tert-butyl group; (9) In each R ^2-3 , the heteroatom of the 3-6 membered heterocycloalkyl group is N, O or S, and the number of heteroatoms may be 1 or 2; the heteroatom of the 3-6 membered heterocycloalkyl group may also be O or N, and the number of heteroatoms may also be 1; for example (10) In each R ^2-3 , 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; (11) In each R ^2-3 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl; (12) In each R ^2-3 , 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 (13) In each R ^2-3-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (14) In each R ^2-3-1 , 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 or ethoxy; (15) In each R ^2-3-1 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl; (16) In R ^2-3-2 , 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, isopropyl, Butyl, primary butyl, secondary butyl or tert-butyl, and may also be methyl, ethyl, isopropyl or tert-butyl; (17) In R ^2-3-2 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl or cyclobutyl; (18) In R ^2-3-2 , 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; (19) In R ^2-3-2 , the heteroatom of the 3-6 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of heteroatoms may be 1 or 2; for example (20) In R ^2-3-2 , the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group or a 5- and 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 or 2; the heteroatom of the 5-membered heteroaryl group may be N and/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- and 6-membered heteroaryl group may be O, and the number of heteroatoms is 2; (21) In each R ^2-3-3 , 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, sec-butyl, or tert-butyl, such as methyl or ethyl; (22) In each R ^2-3-4 , 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, sec-butyl, tert-butyl, or may be isopropyl; (23) In each R ^2-3-5 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (24) In each R ^2-3-6 , 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, sec-butyl, or tert-butyl, for example, methyl; (25) In each R ^2-3-7 , 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, sec-butyl, or tert-butyl, for example, methyl; (26) In each R ^2-3-8 , 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, sec-butyl, or tert-butyl, such as methyl or isopropyl; (27) In each R ^2-3-8 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (28) In each R ^2-3-9 , 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, sec-butyl, or tert-butyl, for example, methyl; (29) In each R ^2-3-1-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (30) In each R ^2-3-1-2 , 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, methoxy; (31) In each R ^2-3-1-3 , 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, sec-butyl, or tert-butyl, for example, methyl; (32) In each R ^2-3-2-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (33) In each R ^2-3-2-1 , 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, methoxy; (34) In each R ^2-3-2-1 , 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; (35) In each R ^2-3-2-1-1 , 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, sec-butyl, or tert-butyl, for example, methyl; (36) In each R ^2-3-2-1-1 , the 6-10 membered aryl group is phenyl or naphthyl, for example phenyl; (37) In each R ^2-3-2-1-2 , 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, sec-butyl, or tert-butyl, for example, methyl; (38) In each R ^2-3-2-1-3 , 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, sec-butyl, or tert-butyl, for example, methyl; (39) In each R ^2-3-2-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (40) In each R ^2-3-2-2 , the C ₁ -C ₆ alkyl group is a C ₁ -C ₄ alkyl group, which 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, and may also be a methyl group; (41) In each R ^2-3-2-2 , 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; (42) In each R ^2-3-2-2-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (43) In each R ^2-3-2-2-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (44) In each R ^2-3-2-2-3 , 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, sec-butyl, or tert-butyl, for example, methyl; (45) In each R ^2-3-2-3-1 , the 6-10 membered aryl group is phenyl or naphthyl, for example phenyl; (46) In each R ^2-3-2-3-1-1 , 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, methoxy; (47) In each R ^2-3-2-4 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (48) In each R ^2-3-2-5 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (49) In each R ^2-3-2-5 , 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, methoxy; (50) In each R ^2-3-2-5 , 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, for example, methyl, ethyl, n-propyl or isopropyl; (51) In each R ^2-3-2-5-1 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (52) In each R ^2-3-2-6 , 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, sec-butyl, or tert-butyl, for example, methyl; (53) In each R ^2-3-3-1-1 , 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, sec-butyl, or tert-butyl, for example, methyl; (54) In each R ^3-1 , the C ₁ -C ₆ alkyl group is a C ₁ -C ₄ alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, or a butyl, isobutyl, primary butyl, secondary butyl or tert-butyl, and may also be methyl; (55) In each R ^3-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example, fluorine; (56) In each R ^3-1-1 , the halogen may be fluorine, chlorine, bromine or iodine, for example, fluorine; (57) In R ^3-1-2 , 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 tert-butyl group, or may be a methyl group or an ethyl group; (58) In R ^3-1-2 , the C ₂ -C ₆ alkenyl group may be For example (59) In R ⁴ , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; (60) In R ⁴ , the 5-10 membered heterocycloalkyl is a spiro ring; the spiro ring may be a 4-ring spiro-6 ring, a 4-ring spiro-5 ring or a 4-ring spiro-4 ring, and the heteroatom of the 4-10 membered heterocycloalkyl may be N, and the number of heteroatoms is 1 or 2; (61) In R ⁴ , 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 sec-butyl group, or a tert-butyl group, or may be a methyl group; (62) In each R ^4-2 , the 5-10 membered heteroaryl group is a 5-membered heteroaryl group; the heteroatom of the 5-membered heteroaryl group may be selected from N and/or S, and the number of heteroatoms is 2; (63) In R ^4-1-1 , 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, 1-butyl, sec-butyl or tert-butyl, or may be methyl or isopropyl; (64) In each R ^4-1-2 , 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, sec-butyl, or tert-butyl, or may be methyl; and (65) In each R ^4-2-1 , the C ₁ -C ₆ alkyl group is a C ₁ -C ₄ alkyl group, and may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, prime-butyl, sec-butyl or tert-butyl, and may be methyl. The compound of formula IV, or a pharmaceutically acceptable salt or isotope compound thereof according to claim 1, wherein the compound of formula IV satisfies one or more of the following conditions: (1) Each R ^1-3 is independently cyano, deuterium, hydroxyl, amino, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3-1 , C ₁ -C ₆ alkoxy which is unsubstituted or substituted by one or more R ^1-3-2 , or C ₂ -C ₆ alkynyl; (2) each R ^1-3-1 is independently halogen; (3) each R ^1-3-2 is independently halogen; (4) Each R ^2-3-1 is independently cyano, unsubstituted or C ₃ -C ₆ cycloalkyl substituted by one or more R ^2-3-1-2 ; (5) 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 , or 5-10 membered heteroaryl which is unsubstituted or substituted by one or more R ^2-3-2-6 ; wherein the heteroatom of the 3-6 membered heterocycloalkyl is selected from one or more of N, O and S, and the heteroatom The number of heteroatoms is 1, 2 or 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 heteroatoms is 1, 2 or 3; (6) Each R ^2-3-4 is independently a C ₁ -C ₆ alkyl group; (7) Each R ^2-3-7 is independently a C ₁ -C ₆ alkyl group; (8) Each R ^2-3-9 is independently oxo or C ₁ -C ₆ alkyl; (9) 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 heteroatoms is 1, 2 or 3; (10) 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; (11) 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 ; (12) Each R ^2-3-2-2-1 is independently halogen or hydroxyl; (13) Each R ^2-3-2-2-2 is independently halogen, deuterium, oxo or hydroxy; (14) Each R ^2-3-2-2-3 is independently C ₁ -C ₆ alkyl; (15) Each R ^2-3-2-3 is independently hydrogen or (16) 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; (17) each R ^2-3-2-4 is independently halogen; (18) Each R ^2-3-2-5 is independently halogen, hydroxy, oxo, C ₁ -C ₆ alkoxy, or 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; (19) Each R ^2-3-2-6 is independently C ₁ -C ₆ alkyl; (20) Each R ^3-1 is independently hydroxy, halogen, C ₁ -C ₆ alkyl substituted by one or more R ^3-1-1 , or (21) Each R ^3-1-1 is independently a hydroxyl group; R ^3-1-2 is a C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group; (22) 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; (23) Each R ^4-1 is independently (24) 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; (25) R ^4-1-1 is C ₁ -C ₆ alkyl; (26) Each R ^4-1-2 is independently C ₁ -C ₆ alkyl; (27) Each R ^4-2-1 is independently C ₁ -C ₆ alkyl; Preferably, the compound as shown in formula IV satisfies one or more of the following conditions: (1) Each R ^1-3 is independently cyano, deuterium, hydroxyl, amino, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3-1 , C ₁ -C ₆ alkoxy which is 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; (2) m is 1 or 2; (3) each R ^2-3 is independently a C ₁ -C ₆ alkyl group 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 , 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 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 hydroxy, 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 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 C ₁ -C ₆ alkyl; (4) Each R ^3-1 is independently hydroxy, 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; R ^3-1-2 is a C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group; (5) 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. The compound of formula IV, or a pharmaceutically acceptable salt or isotope compound thereof according to claim 1, wherein the compound of formula IV satisfies one or more of the following conditions: (1) 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 ; (2) Each R ^1-3-1 is independently halogen or deuterium; preferably, each R ^1-3-1 is independently halogen; (3) Each R ^2-3 is independently oxo, unsubstituted or C ₁ -C ₆ alkyl substituted by one or more R ^2-3-1 , Preferably, 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 heteroatoms is 2 or 3; (4) Each R ^2-3-1 is independently hydroxyl, halogen, C ₁ -C ₆ alkoxyl group which is unsubstituted or substituted by one or more R ^2-3-1-1 , or amino group which is unsubstituted or substituted by one or more R ^2-3-1-3 ; preferably, each R ^2-3-1 is independently hydroxyl, C ₁ -C ₆ alkoxyl group ^{which is unsubstituted or substituted by one or more R 2-3-1-1 ;} (5) each R ^2-3-1-1 is independently deuterium; (6) Each R ^2-3-1-3 is independently a C ₁ -C ₆ alkyl group; (7) 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 heteroatom of the 3-6 membered heterocycloalkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatom of the 5-10 membered heteroaryl is N and/or O, and the number of heteroatoms is 1 or 2; preferably, R ^2-3-2 is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^2-3-2-2 ; (8) each R ^2-3-2-1 is independently hydroxyl, (9) Each R ^2-3-2-1-1 is independently a C ₁ -C ₆ alkyl group; (10) Each R ^2-3-2-2 is independently halogen, hydroxyl, 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; preferably, 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 ; (11) each R ^2-3-2-2-2 is independently deuterium; (12) Each R ^2-3-2-3 is independently hydrogen or (13) 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 ; preferably, 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; (14) Each R ^2-3-2-3-1-1 is independently a C ₁ -C ₆ alkoxy group; (15) 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 by one or more R ^2-3-2-5-1 ; (16) each R ^2-3-2-5-1 is independently halogen; (17) Each R ^2-3-3 is independently hydrogen, unsubstituted or C ₁ -C ₆ alkyl substituted by one or more R ^2-3-3-1 ; (18) 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 ; (19) Each R ^2-3-3-1-1 is independently C ₁ -C ₆ alkyl; (20) 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; preferably, k is 0, and 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; or, Ring A is R ^3-1 is -CF ₃ ; (21) each R ^3-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more R ^3-1-1 ; (22) each R ^3-1-1 is independently halogen; (23) 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 heteroatoms is 1 or 2; preferably, R ⁴ is hydrogen, deuterium, halogen, halogen, C ₁ -C ₆ alkyl; and (24) Each R ^4-1 is independently R ^4-1-1 is a C ₁ -C ₆ alkyl group. The compound of formula IV, its pharmaceutically acceptable salt or isotope compound according to claim 1, characterized in that the compound of formula IV is Scheme 1 or Scheme 2: Solution 1: 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, C ₁ -C ₆ alkyl which is unsubstituted or 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 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 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, C ₁ -C ₆ alkyl; Solution 2 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 compound of formula IV, or a pharmaceutically acceptable salt or isotope compound thereof according to claim 1, wherein the compound of formula IV satisfies one or more of the following conditions: (1) In ring D, the heteroatom of the 3-6 membered heterocycloalkyl group is O, and the number of heteroatoms is 1; (2) In ring D, the 3-6 membered heterocycloalkyl is a 4 membered heterocycloalkyl; (3) Each R ^1-3 is independently cyano, unsubstituted or C ₁ -C ₆ alkyl substituted by one or more R ^1-3-1 ; preferably, each R ^1-3 is independently C ₁ -C ₆ alkyl unsubstituted ^or substituted by one or more R ^1-3-1 ; (4) each R ^1-3-1 is independently halogen; (5) In ring C, the heteroatom of the 4-12 membered heterocycloalkyl is N and/or O, and the number of heteroatoms is 1, 2 or 3; (6) 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 ; preferably, each R ^2-3 is independently oxo, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-3-1 , unsubstituted C ₃ -C ₆ cycloalkyl; more preferably, each R ^2-3 is independently oxo, unsubstituted or C ₁ -C ₆ alkyl substituted by one or more R ^2-3-1 , (7) Each R ^2-3-1 is independently hydroxyl, halogen, C ₁ -C ₆ alkoxyl group which is unsubstituted or substituted by one or more R ^2-3-1-1 , or amino group which is unsubstituted or substituted by one or more R ^2-3-1-3 ; preferably, each R ^2-3-1 is independently hydroxyl, C ₁ -C ₆ alkoxyl group ^{which is unsubstituted or substituted by one or more R 2-3-1-1 ;} (8) 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 ; (9) each R ^2-3-3 is independently hydrogen, unsubstituted or C ₁ -C ₆ alkyl substituted by one or more R ^2-3-3-1 ; (10) Each R ^2-3-6 is independently C ₁ -C ₆ alkyl; (11) Each R ^2-3-1-1 is independently halogen or deuterium; preferably, each R ^2-3-1-1 is independently halogen, or, each R ^2-3-1-1 is independently deuterium; (12) Each R ^2-3-1-3 is independently C ₁ -C ₆ alkyl; (13) Each R ^2-3-2-2 is independently an unsubstituted C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group which is unsubstituted or substituted by one or more R ^2-3-2-2-2 ; (14) each R ^2-3-2-2-2 is independently deuterium; (15) 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 ; (16) Each R ^2-3-3-1-1 is independently C ₁ -C ₆ alkyl; (17) In ring A, the heteroatom of the 5-10 membered heteroaryl group is N and/or S, and the number of heteroatoms is 1, 2 or 3; (18) each R ^3-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more R ^3-1-1 ; (19) Each R ^3-1-1 is independently halogen or hydroxyl; (20) W is N, CH or CR ⁴ ; and (21) R ⁴ is deuterium, halogen, or unsubstituted C ₁ -C ₆ alkyl. The compound of formula IV, its pharmaceutically acceptable salt or isotope compound according to claim 1, characterized in that the compound of formula IV is Scheme 3, Scheme 3', Scheme 4, Scheme 4', Scheme 5 or Scheme 5': Solution 3 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 , 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 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 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, C ₁ -C ₆ alkyl; Option 3’ Y is N, X is C, 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 is 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; m is 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 is 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, C ₁ -C ₆ alkyl; Solution 4: 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 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 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, C ₁ -C ₆ alkyl; Option 4’ Y is N, X is C, W is N, CH or CR ⁴ ; Z is CH or N; Ring D is a 3-6 membered heterocycloalkyl group; the heteroatom of the 3-6 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; n is 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; m is 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 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 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 is 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, C ₁ -C ₆ alkyl; Solution 5: 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, C ₁ -C ₆ alkyl; Scheme 5’ Y is N, X is C, 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 is 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; m is 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 is 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 compound of formula IV, or a pharmaceutically acceptable salt or isotope compound thereof according to claim 1, wherein the compound of formula IV satisfies one or more of the following conditions: (1) Y is N; (2) X is C; (3) W is N, CH or CR ⁴ ; preferably, for (4) ^R4 is chlorine, deuterium or methyl; (5) Z is CH or N; (6) Ring D is (7)n is 0; (8) R ^1-3' is hydrogen, cyano, methyl, Preferably, for (9) Ring C is Preferably, for (10) R ^2-3 is hydroxy, oxo, methyl, -CF ₃ , (11) Ring A is Preferably, for (12) k is 1; and (13) R ^3-1 is -CHF ₂ , -CF ₃ , The compound of formula IV, or a pharmaceutically acceptable salt or isotope compound thereof according to claim 1, wherein the compound of formula IV is any of the following compounds:




Any one of the compounds shown below, or a pharmaceutically acceptable salt or isotope compound thereof;
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 any one of claims 1 to 10, any compound as described in claim 11, or a pharmaceutically acceptable salt or isotope compound thereof. A use 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 any one of claims 1 to 10, any compound as described in claim 11, or a pharmaceutically acceptable salt or isotope compound thereof; the PARG-related disease may be breast cancer, such as triple-negative breast cancer. A use 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 any one of claims 1 to 10, any compound as described in claim 11, or a pharmaceutically acceptable salt or isotope compound thereof; and the breast cancer may be triple-negative breast cancer.