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

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

Penta- and hexa-membered nitrogen-containing compounds, preparation methods and applications thereof

[0001] This application claims the benefit of Chinese Patent Application No. 2023107306040, filed on June 19, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention relates to a five-membered and six-membered nitrogen-containing compound, a preparation method and application thereof. Background Art

[0003] PARG is the first poly(ADP-ribose) hydrolase to be 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 an N-terminal disordered domain, a linker domain, a C-terminal catalytic domain, and an ADP-ribose binding domain. The non-conserved disordered domain at the N-terminus is not required for in vitro activity, while 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 enzymatic activity in vitro (Slade D et al. The structure and catalytic mechanism of a poly(ADP-ribose)glycohydrolase. Nature, 2011, 477: 616-620.).

[0004] 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, abbreviated as PAR, is composed of adenosine diphosphate-ribose units, with NAD +PARylation is a donor, formed by the catalysis of poly (ADP-ribose) polymerases (PARPs), and can be rapidly degraded by poly (ribosyl) hydrolases. Following DNA damage, many DNA damage response factors recognize PARylation and are recruited to the site of DNA damage through PARylation. However, PARylation needs to be digested promptly so that DNA damage response factors can directly recognize DNA damage and perform repair functions. Otherwise, DNA repair factors will be trapped near DNA damage by PARylation and unable to perform repair functions normally. Therefore, as a direct downstream step of PARylation in DNA repair, inhibiting this process will affect PARylation-dependent DNA damage repair and selectively kill tumor cells with DNA repair defects.

[0005] 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 affect 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).

[0006] PARG has been shown to be associated with a variety of diseases. 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.) that high PARG expression is closely associated with poor prognosis in liver cancer, and hepatocyte-specific PARG functional loss affects tumorigenesis. Therefore, PARG inhibitors have received increasing attention as potential therapeutic approaches. There are many PARG inhibitors currently 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 and provide patients with safer and more effective PARG inhibitors.

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the relatively simple structure of PARG inhibitory compounds in the prior art. To this end, 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.

[0009] The first aspect of the present invention provides a compound as shown in Formula IV, or a pharmaceutically acceptable salt or isotope compound thereof;

[0010] Y is C or N, X is C or N,

[0011] W is N, CH, O, or NR 4 or CR 4 ;

[0012] Z is CH, O or N;

[0013] 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;

[0014] 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;

[0015] Ring A is a 5-10 membered heteroaryl group; 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;

[0016] n is 0, 1 or 2; m is 0, 1 or 2; k is 0, 1 or 2;

[0017] R 1-3’ is hydrogen or R 1-3 ;

[0018] Each R 1-3 are independently cyano, deuterium, hydroxyl, amino, halogen, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-3-2 Substituted C1-C6 alkoxy or C2-C6 alkynyl; each R 1-3-1 are independently halogen; each R 1-3-2 are independently halogen;

[0019] Each R 2-3 are independently cyano, oxo, hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-4 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-5 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-6 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-7 Substituted amino groups, unsubstituted or replaced by one or more R 2-3-9 substituted 5-10 membered heteroaryl; 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; 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;

[0020] Each R 2-3-1 are independently hydroxy, cyano, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-1-3 substituted amino groups;

[0021] R2-3-2 is hydrogen, unsubstituted or replaced by one or more R 2-3-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-2-4 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-5 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-2-6 substituted 5-10 membered heteroaryl; 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; 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;

[0022] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0023] Each R 2-3-4 are independently C1-C6 alkyl or oxo;

[0024] Each R 2-3-5 are independently halogen or deuterium;

[0025] Each R 2-3-6 are independently C1-C6 alkyl;

[0026] Each R 2-3-7 are independently C1-C6 alkyl;

[0027] Each R 2-3-8 are independently C1-C6 alkyl or C3-C6 cycloalkyl;

[0028] Each R 2-3-9 are independently C1-C6 alkyl;

[0029] Each R 2-3-1-1 are independently halogen or deuterium;

[0030] Each R 2-3-1-2 are independently C1-C6 alkoxy;

[0031] Each R 2-3-1-3 are independently C1-C6 alkyl;

[0032] Each R 2-3-2-1 are independently halogen, carboxyl, hydroxy, oxo, C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-1-2 Substituted amino, unsubstituted or replaced by one or more R2-3-2-1-3 Substituted 5-10 membered heteroaryl; 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;

[0033] Each R 2-3-2-1-1 are independently C1-C6 alkyl or 6-10 membered aryl;

[0034] Each R 2-3-2-1-2 are independently C1-C6 alkyl;

[0035] Each R 2-3-2-1-3 are independently C1-C6 alkyl;

[0036] Each R 2-3-2-2 are independently halogen, hydroxy, unsubstituted or substituted with one or more R 2-3-2-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-2-3 substituted amino groups;

[0037] Each R 2-3-2-2-1 are independently halogen or hydroxy;

[0038] Each R 2-3-2-2-2 are independently carboxyl, halogen, deuterium, oxo or hydroxy;

[0039] Each R 2-3-2-2-3 are independently C1-C6 alkyl;

[0040] Each R 2-3-2-3 are independently hydrogen or Each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1- 1 substituted 6-10 membered aryl; each R 2-3-2-3-1-1 are independently C1-C6 alkoxy;

[0041] Each R 2-3-2-4 are independently halogen;

[0042] Each R 2-3-2-5 are independently halogen, hydroxy, oxo, C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-3-2-5-1 Substituted C1-C6 alkyl; each R 2-3-2-5-1 are independently halogen;

[0043] Each R 2-3-2-6 are independently C1-C6 alkyl;

[0044] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R2-3-3-1-1 Substituted amino; each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0045] Each R 3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 3-1-1 Substituted C1-C6 alkyl or

[0046] Each R 3-1-1 are independently halogen or hydroxy; R 3-1-2 is a C1-C6 alkyl group or a C2-C6 alkenyl group;

[0047] R 4 is hydrogen, deuterium, halogen, cyano, unsubstituted or replaced by one or more R 4-1 substituted 5-10 membered heterocycloalkyl or unsubstituted or substituted by one or more R 4-2 Substituted C1-C6 alkyl; the heteroatoms of the 5-10 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0048] Each R 4-1 Independently

[0049] Each R 4-2 are independently unsubstituted or substituted with one or more R 4-2-1 Substituted 5-10 membered heteroaryl; 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;

[0050] R 4-1-1 is a C1-C6 alkyl group; each R 4-1-2 are independently C1-C6 alkyl; each R 4-2-1 are independently C1-C6 alkyl.

[0051] In a preferred embodiment, the compound shown in Formula IV may be a compound shown in Formula V,

[0052] M is N, O or S;

[0053] i is 0, 1 or 2; j is 0, 1 or 2; i and j are not 0 at the same time;

[0054] 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 defined as above.

[0055] In a preferred embodiment, the compound shown in Formula IV may be a compound shown in Formula VI,

[0056] 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 defined as above.

[0057] In a preferred embodiment, the compound shown in Formula IV may be a compound shown in Formula VII,

[0058] V 1 is CH, N or O; V 2 is CH, N or O; V 1 and V 2 Not at the same time CH;

[0059] R 3-1’ is hydrogen or R 3-1 ;

[0060] R V 1 is absent, hydrogen or R 2-3 ; R V 2 is absent, hydrogen or R 2-3 ;

[0061] m is 0, 1, or 2;

[0062] W, Z, R 1-3’ 、R 1-3 、R 2-3 、R 3-1 , n, m, i and j are defined as above.

[0063] In a preferred embodiment, the compound shown in Formula IV may be a compound shown in Formula VIII,

[0064] W, Z, R V 1 、R V 2 、R 1-3’ 、R 1-3 、R 2-3 、R 3-1’ , n, m, i and j are defined as above.

[0065] In a preferred embodiment, the compound shown in Formula IV may be a compound shown in Formula IX,

[0066] U is CH2, NH or O;

[0067] p is 0, 1 or 2; q is 0, 1 or 2;

[0068] W, Z, R 1-3’ 、R 1-3 、R 2-3 、R 3-1’ , n, m, i and j are defined as above.

[0069] In a preferred embodiment, the compound represented by formula IV may be a compound represented by formula X,

[0070] R G R 2-3-2 or

[0071] V 1 CH or N; V 2 CH or N; V 1 and V 2 Not at the same time CH;

[0072] 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 defined as above.

[0073] In a preferred embodiment, each R 1-3 are independently cyano, deuterium, hydroxyl, amino, halogen, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-3-2 Substituted C1-C6 alkoxy or C2-C6 alkynyl; each R 1-3-1 are independently halogen; each R 1-3-2 are independently halogen.

[0074] In a preferred embodiment, m is 1 or 2.

[0075] In a preferred embodiment, each R 2-3 Independently by one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-4 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-7 Substituted amino, unsubstituted or replaced by one or more R 2-3-9substituted 5-10 membered heteroaryl; 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; 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;

[0076] Each R 2-3-1 is independently cyano, unsubstituted or substituted with one or more R 2-3-1-2 substituted C3-C6 cycloalkyl;

[0077] R 2-3-2 is hydrogen or, is replaced by one or more R 2-3-2-1 Substituted C1-C6 alkyl, one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-2-5 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2- 3-2-6 substituted 5-10 membered heteroaryl; 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; 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;

[0078] Each R 2-3-4 are independently C1-C6 alkyl;

[0079] Each R 2-3-7 are independently C1-C6 alkyl;

[0080] Each R 2-3-9 are independently oxo or C1-C6 alkyl;

[0081] Each R 2-3-1-2 are independently C1-C6 alkoxy; each R 2-3-2-1 are independently hydroxy, oxo, unsubstituted or replaced by one or more R 2-3-2-1-3 Substituted 5-10 membered heteroaryl; 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;

[0082] Each R 2-3-2-1-1 are independently C1-C6 alkyl or 6-10 membered aryl; each R 2-3-2-1-2 are independently C1-C6 alkyl; each R 2-3-2- 1-3 are independently C1-C6 alkyl;

[0083] Each R 2-3-2-2are independently halogen, hydroxy, unsubstituted or substituted with one or more R 2-3-2-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-2-3 substituted amino groups;

[0084] Each R 2-3-2-2-1 are independently halogen or hydroxy;

[0085] Each R 2-3-2-2-2 are independently halogen, deuterium, oxo or hydroxy;

[0086] Each R 2-3-2-2-3 are independently C1-C6 alkyl;

[0087] Each R 2-3-2-3 are independently hydrogen or Each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1- 1 substituted 6-10 membered aryl; each R 2-3-2-3-1-1 are independently C1-C6 alkoxy;

[0088] Each R 2-3-2-4 are independently halogen;

[0089] Each R 2-3-2-5 independently halogen, hydroxy, oxo, C1-C6 alkoxy, 2-3-2-5-1 Substituted C1-C6 alkyl; each R 2-3-2-5-1 are independently halogen;

[0090] Each R 2-3-2-6 are independently C1-C6 alkyl.

[0091] In a preferred embodiment, each R 3-1 are independently hydroxy, halogen, 3-1-1 Substituted C1-C6 alkyl or

[0092] Each R 3-1-1 are independently hydroxyl; R 3-1-2 It is a C1-C6 alkyl group or a C2-C6 alkenyl group.

[0093] In a preferred embodiment, R 4 is deuterium, cyano, unsubstituted or replaced by one or more R 4-1 substituted 5-10 membered heterocycloalkyl, or one or more R 4-2Substituted C1-C6 alkyl; the heteroatoms of the 5-10 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0094] Each R 4-1 Independently

[0095] Each R 4-2 are independently unsubstituted or substituted with one or more R 4-2-1 Substituted 5-10 membered heteroaryl; 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;

[0096] R 4-1-1 is a C1-C6 alkyl group; each R 4-1-2 are independently C1-C6 alkyl; each R 4-2-1 are independently C1-C6 alkyl.

[0097] In a preferred embodiment, each R 1-3 are independently cyano, deuterium, hydroxyl, amino, halogen, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-3-2 Substituted C1-C6 alkoxy or C2-C6 alkynyl.

[0098] In a preferred embodiment, each R 1-3-1 are independently halogen.

[0099] In a preferred embodiment, each R 1-3-2 are independently halogen.

[0100] In a preferred embodiment, each R 2-3-1 is independently cyano, unsubstituted or substituted with one or more R 2-3-1-2 Substituted C3-C6 cycloalkyl.

[0101] In a preferred embodiment, R 2-3-2 is hydrogen or, is replaced by one or more R 2-3-2-1 Substituted C1-C6 alkyl, one or more R 2-3-2- 2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-2-5 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-2-6substituted 5-10 membered heteroaryl; 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; 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.

[0102] In a preferred embodiment, each R 2-3-4 are independently C1-C6 alkyl.

[0103] In a preferred embodiment, each R 2-3-7 are independently C1-C6 alkyl.

[0104] In a preferred embodiment, each R 2-3-9 are independently oxo or C1-C6 alkyl.

[0105] In a preferred embodiment, each R 2-3-1-2 are independently C1-C6 alkoxy; each R 2-3-2-1 are independently hydroxy, oxo, unsubstituted or replaced by one or more R 2-3-2-1-3 Substituted 5-10 membered heteroaryl; 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.

[0106] In a preferred embodiment, each R 2-3-2-1-1 are independently C1-C6 alkyl or 6-10 membered aryl; each R 2-3-2-1-2 are independently C1-C6 alkyl; each R 2-3-2-1-3 are independently C1-C6 alkyl.

[0107] In a preferred embodiment, each R 2-3-2-2 are independently halogen, hydroxy, unsubstituted or substituted with one or more R 2-3-2-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-2-3 Substituted amino groups.

[0108] In a preferred embodiment, each R 2-3-2-2-1 are independently halogen or hydroxy.

[0109] In a preferred embodiment, each R 2-3-2-2-2 are independently halogen, deuterium, oxo or hydroxy.

[0110] In a preferred embodiment, each R 2-3-2-2-3 are independently C1-C6 alkyl.

[0111] In a preferred embodiment, each R2-3-2-3 are independently hydrogen or

[0112] In a preferred embodiment, each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1-1 substituted 6-10 membered aryl; each R 2-3-2-3-1-1 are independently C1-C6 alkoxy.

[0113] In a preferred embodiment, each R 2-3-2-4 are independently halogen.

[0114] In a preferred embodiment, each R 2-3-2-5 independently halogen, hydroxy, oxo, C1-C6 alkoxy, 2-3- 2-5-1 Substituted C1-C6 alkyl; each R 2-3-2-5-1 are independently halogen.

[0115] In a preferred embodiment, each R 2-3-2-6 are independently C1-C6 alkyl.

[0116] In a preferred embodiment, each R 3-1 are independently hydroxy, halogen, 3-1-1 Substituted C1-C6 alkyl or

[0117] In a preferred embodiment, each R 3-1-1 are independently hydroxyl; R 3-1-2 It is a C1-C6 alkyl group or a C2-C6 alkenyl group.

[0118] In a preferred embodiment, R 4 is deuterium, cyano, unsubstituted or replaced by one or more R 4-1 substituted 5-10 membered heterocycloalkyl, or one or more R 4-2 Substituted C1-C6 alkyl; the heteroatoms of the 5-10 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0119] In a preferred embodiment, each R 4-1 Independently

[0120] In a preferred embodiment, each R 4-2 are independently unsubstituted or substituted with one or more R 4-2-1 Substituted 5-10 membered heteroaryl; 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.

[0121] In a preferred embodiment, R 4-1-1 It is a C1-C6 alkyl group.

[0122] In a preferred embodiment, each R 4-1-2 are independently C1-C6 alkyl.

[0123] In a preferred embodiment, each R 4-2-1 are independently C1-C6 alkyl.

[0124] In a certain scheme, each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, C2-C6 alkynyl.

[0125] In a certain scheme, each R 1-3-1 are independently halogen and deuterium.

[0126] In a certain scheme, each R 1-3-1 are independently halogen.

[0127] In a certain scheme, each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0128] In a certain scheme, each R 2-3 Independently 5-10 membered heteroaryl; the heteroatoms of the 5-10 membered heteroaryl are N and / or O, and the number of heteroatoms is 2 or 3.

[0129] In a certain scheme, each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 substituted amino; preferably, each R 2-3-1 are independently hydroxy, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy.

[0130] In a certain scheme, each R 2-3-1-1 independently deuterium.

[0131] In a certain scheme, each R 2-3-1-3 are independently C1-C6 alkyl.

[0132] In one scenario, R 2-3-2 For one or more R 2-3-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-2-5 a substituted 3-6 membered heterocycloalkyl group or a 5-10 membered heteroaryl 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; the heteroatoms of the 5-10 membered heteroaryl group are N and / or O, and the number of heteroatoms is 1 or 2.

[0133] In one scenario, R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl.

[0134] In a certain scheme, each R 2-3-2-1 are independently hydroxyl,

[0135] In a certain scheme, each R 2-3-2-1-1 are independently C1-C6 alkyl.

[0136] In a certain scheme, each R 2-3-2-2 are independently halogen, hydroxy, C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, amino.

[0137] In a certain scheme, each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy.

[0138] In a certain scheme, each R 2-3-2-2-2 independently deuterium.

[0139] In a certain scheme, each R 2-3-2-3 are independently hydrogen or

[0140] In a certain scheme, each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1-1 Substituted 6-10 membered aryl.

[0141] In a certain scheme, each R 2-3-2-3-1-1 are independently C1-C6 alkoxy.

[0142] In a certain scheme, each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1-1 substituted 6-10 membered aryl; each R 2-3-2-3-1-1 are independently C1-C6 alkoxy.

[0143] In a certain scheme, each R2-3-2-5 are independently halogen, C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-3-2-5-1 Substituted C1-C6 alkyl.

[0144] In a certain scheme, each R 2-3-2-5-1 are independently halogen.

[0145] In a certain scheme, each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl.

[0146] In a certain scheme, each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups.

[0147] In a certain scheme, each R 2-3-3-1-1 are independently C1-C6 alkyl.

[0148] 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.

[0149] In a certain scheme, each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl.

[0150] In a certain scheme, each R 3-1-1 are independently halogen.

[0151] In one 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.

[0152] In one embodiment, ring A is R 3-1 It is -CF3.

[0153] In one scenario, R 4 is deuterium, cyano, unsubstituted or replaced by one or more R 4-1 Substituted 5-10 membered heterocycloalkyl; 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 or 2.

[0154] In one scenario, R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0155] In a certain scheme, each R 4-1 Independently R 4-1-1 It is a C1-C6 alkyl group.

[0156] In a preferred embodiment,

[0157] Each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, C2-C6 alkynyl;

[0158] Each R 1-3-1 are independently halogen, deuterium;

[0159] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0160] Each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 substituted amino groups;

[0161] Each R 2-3-1-1 independently for deuterium;

[0162] Each R 2-3-1-3 are independently C1-C6 alkyl;

[0163] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0164] Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0165] Each R 2-3-2-2-2 independently for deuterium;

[0166] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0167] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0168] Each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0169] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0170] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0171] Each R 3-1-1 are independently halogen;

[0172] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0173] In a preferred embodiment,

[0174] Each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, C2-C6 alkynyl;

[0175] Each R 1-3-1 are independently halogen;

[0176] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0177] Each R 2-3-1 are independently hydroxy, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy;

[0178] Each R 2-3-1-1 independently for deuterium;

[0179] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0180] Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0181] Each R 2-3-2-2-2 independently for deuterium;

[0182] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0183] Each R 2-3-3-1are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0184] Each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0185] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0186] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0187] Each R 3-1-1 are independently halogen;

[0188] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0189] In a preferred embodiment, in ring D, the heteroatom of the 3-6 membered heterocycloalkyl group is O, and the number of heteroatoms is 1.

[0190] In a preferred embodiment, in ring D, the 3-6 membered heterocycloalkyl group is a 4 membered heterocycloalkyl group.

[0191] In a preferred embodiment, each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl.

[0192] In a preferred embodiment, each R 1-3 are independently unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl.

[0193] In a preferred embodiment, each R 1-3-1 are independently halogen.

[0194] 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 heteroatoms is 1, 2 or 3.

[0195] In a preferred embodiment, each R 2-3 are independently oxo, hydroxy, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-6 Substituted C3-C6 cycloalkyl.

[0196] In a preferred embodiment, each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1Substituted C1-C6 alkyl, Unsubstituted C3-C6 cycloalkyl.

[0197] In a preferred embodiment, each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0198] In a preferred embodiment, each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 Substituted amino groups.

[0199] In a preferred embodiment, each R 2-3-1 are independently hydroxy, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy.

[0200] In a preferred embodiment, R 2-3-2 is an unsubstituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl.

[0201] In a preferred embodiment, each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl.

[0202] In a preferred embodiment, each R 2-3-6 are independently C1-C6 alkyl.

[0203] In a preferred embodiment, each R 2-3-1-1 are independently halogen or deuterium.

[0204] In a preferred embodiment, each R 2-3-1-1 are independently halogen.

[0205] In a preferred embodiment, each R 2-3-1-1 independently deuterium.

[0206] In a preferred embodiment, each R 2-3-1-3 are independently C1-C6 alkyl.

[0207] In a preferred embodiment, each R 2-3-2-2 are independently unsubstituted C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy.

[0208] In a preferred embodiment, each R2-3-2-2-2 independently deuterium.

[0209] In a preferred embodiment, each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups.

[0210] In a preferred embodiment, each R 2-3-3-1-1 are independently C1-C6 alkyl.

[0211] 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.

[0212] In a preferred embodiment, each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl.

[0213] In a preferred embodiment, each R 3-1-1 are independently halogen or hydroxy.

[0214] In a preferred embodiment, W is N, CH or CR 4 .

[0215] In a preferred embodiment, R 4 is deuterium, halogen, or unsubstituted C1-C6 alkyl.

[0216] In a preferred embodiment,

[0217] Each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl;

[0218] Each R 1-3-1 are independently halogen;

[0219] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0220] Each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 substituted amino groups;

[0221] Each R 2-3-1-1 independently for deuterium;

[0222] Each R 2-3-1-3are independently C1-C6 alkyl;

[0223] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0224] Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0225] Each R 2-3-2-2-2 independently for deuterium;

[0226] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0227] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0228] Each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0229] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0230] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0231] Each R 3-1-1 are independently halogen;

[0232] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0233] In a preferred embodiment,

[0234] Y is N, X is C,

[0235] W is N, CH or CR 4 ;

[0236] Z is CH or N;

[0237] 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;

[0238] n is 0;

[0239] R 1-3’ R1-3 ;

[0240] R 1-3 is cyano, unsubstituted or replaced by one or more R 1-3-1 Substituted C1-C6 alkyl;

[0241] Each R 1-3-1 are independently halogen;

[0242] 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;

[0243] m is 0, 1, or 2;

[0244] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0245] Each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 substituted amino groups;

[0246] Each R 2-3-1-1 independently for deuterium;

[0247] Each R 2-3-1-3 are independently C1-C6 alkyl;

[0248] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0249] Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0250] Each R 2-3-2-2-2 independently for deuterium;

[0251] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0252] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0253] Each R2-3-3-1-1 are independently C1-C6 alkyl;

[0254] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0255] k is 1;

[0256] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0257] Each R 3-1-1 are independently halogen;

[0258] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0259] In a preferred embodiment,

[0260] Each R 1-3 are independently unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl;

[0261] Each R 1-3-1 are independently halogen;

[0262] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl;

[0263] Each R 2-3-1 are independently hydroxy, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy;

[0264] Each R 2-3-1-1 independently for deuterium;

[0265] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0266] Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0267] Each R 2-3-2-2-2 independently for deuterium;

[0268] Each R 2-3-3are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0269] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0270] Each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0271] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0272] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0273] Each R 3-1-1 are independently halogen;

[0274] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0275] In a preferred embodiment,

[0276] Y is N, X is C,

[0277] W is N, CH or CR 4 ;

[0278] Z is CH or N;

[0279] 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;

[0280] n is 0;

[0281] R 1-3’ R 1-3 ;

[0282] R 1-3 is unsubstituted or replaced by one or more R 1-3-1 Substituted C1-C6 alkyl;

[0283] Each R 1-3-1 are independently halogen;

[0284] 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;

[0285] m is 0, 1, or 2;

[0286] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl;

[0287] Each R 2-3-1 are independently hydroxy, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy;

[0288] Each R 2-3-1-1 independently for deuterium;

[0289] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0290] Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0291] Each R 2-3-2-2-2 independently for deuterium;

[0292] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0293] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0294] Each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0295] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0296] k is 1;

[0297] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0298] Each R 3-1-1 are independently halogen;

[0299] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0300] In a preferred embodiment,

[0301] Each R 1-3 are independently unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl;

[0302] Each R 1-3-1 are independently halogen;

[0303] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0304] Each R 2-3-1 are independently hydroxy, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy;

[0305] Each R 2-3-1-1 independently for deuterium;

[0306] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0307] Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0308] Each R 2-3-2-2-2 independently for deuterium;

[0309] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0310] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0311] Each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0312] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0313] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0314] Each R 3-1-1 are independently halogen;

[0315] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0316] In a preferred embodiment,

[0317] Y is N, X is C,

[0318] W is N, CH or CR 4 ;

[0319] Z is CH or N;

[0320] 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;

[0321] n is 0;

[0322] R 1-3’ R 1-3 ;

[0323] R 1-3 is unsubstituted or replaced by one or more R 1-3-1 Substituted C1-C6 alkyl;

[0324] Each R 1-3-1 are independently halogen;

[0325] 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;

[0326] m is 0, 1, or 2;

[0327] Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl,

[0328] Each R 2-3-1 are independently hydroxy, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy;

[0329] Each R 2-3-1-1 independently for deuterium;

[0330] R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted by one or more R 2-3-2-2 substituted C3-C6 cycloalkyl;

[0331] Each R 2-3-2-2are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy;

[0332] Each R 2-3-2-2-2 independently for deuterium;

[0333] Each R 2-3-3 are independently hydrogen, unsubstituted or replaced by one or more R 2-3-3-1 Substituted C1-C6 alkyl;

[0334] Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 substituted amino groups;

[0335] Each R 2-3-3-1-1 are independently C1-C6 alkyl;

[0336] Ring A is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are N and / or S, and the number of heteroatoms is 3;

[0337] k is 1;

[0338] Each R 3-1 Independently by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0339] Each R 3-1-1 are independently halogen;

[0340] R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0341] In a preferred embodiment, each R 1-3 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0342] In a preferred embodiment, each R 1-3 In the embodiment, the C1-C6 alkyl group may be a C1-C4 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 1-butyl group, a 2-butyl group or a t-butyl group, or may be a methyl group.

[0343] In a preferred embodiment, each R 1-3 In the embodiment, the C1-C6 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, and may be a methoxy group or an ethoxy group.

[0344] In a preferred embodiment, each R 1-3 wherein the C2-C6 alkynyl group is For example

[0345] In a preferred embodiment, each R 1-3-1 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0346] In a preferred embodiment, each R 1-3-2 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0347] In a preferred embodiment, each R 2-3 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0348] In a preferred embodiment, each R 2-3 In the embodiment, the C1-C6 alkyl group is a C1-C4 alkyl group, which can be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, and can also be a methyl group, an ethyl group, an isopropyl group or a tert-butyl group.

[0349] In a preferred embodiment, each R 2-3 In the 3-6 membered heterocycloalkyl group, the heteroatom may be 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

[0350] In a preferred embodiment, each R 2-3 In the embodiment, the C1-C6 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.

[0351] In a preferred embodiment, each R 2-3 wherein the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group.

[0352] In a preferred embodiment, each R 2-3 In the embodiment, the 5-10 membered heteroaryl group is a 5-membered heteroaryl group or a 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, 2 or 3. The heteroatoms 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

[0353] In a preferred embodiment, each R 2-3-1 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0354] In a preferred embodiment, each R 2-3-1In the embodiment, the C1-C6 alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, methoxy or ethoxy.

[0355] In a preferred embodiment, each R 2-3-1 wherein the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group.

[0356] In a preferred embodiment, R 2-3-2 In the embodiment, the C1-C6 alkyl group is a C1-C4 alkyl group, which can be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, and can also be a methyl group, an ethyl group, an isopropyl group or a tert-butyl group.

[0357] In a preferred embodiment, R 2-3-2 wherein the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group or a cyclobutyl group.

[0358] In a preferred embodiment, R 2-3-2 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, isopropoxy.

[0359] In a preferred embodiment, R 2-3-2 In the 3-6 membered heterocycloalkyl group, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms may be 1 or 2; for example

[0360] In a preferred embodiment, R 2-3-2 In the embodiment, 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- and 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.

[0361] In a preferred embodiment, each R 2-3-3 wherein the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a 1-butyl group, a 2-butyl group or a t-butyl group, for example, a methyl group or an ethyl group.

[0362] In a preferred embodiment, each R 2-3-4In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a 1-butyl group, a 2-butyl group or a t-butyl group, or may be an isopropyl group.

[0363] In a preferred embodiment, each R 2-3-5 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0364] In a preferred embodiment, each R 2-3-6 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0365] In a preferred embodiment, each R 2-3-7 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0366] In a preferred embodiment, each R 2-3-8 wherein the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group or an isopropyl group.

[0367] In a preferred embodiment, each R 2-3-8 wherein the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group.

[0368] In a preferred embodiment, each R 2-3-9 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0369] In a preferred embodiment, each R 2-3-1-1 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0370] In a preferred embodiment, each R 2-3-1-2 In the embodiment, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, methoxy.

[0371] In a preferred embodiment, each R 2-3-1-3 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0372] In a preferred embodiment, each R 2-3-2-1 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0373] In a preferred embodiment, each R 2-3-2-1 In the embodiment, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, methoxy.

[0374] In a preferred embodiment, each R 2-3-2-1 wherein 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.

[0375] In a preferred embodiment, each R 2-3-2-1-1 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0376] In a preferred embodiment, each R 2-3-2-1-1 In the embodiment, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, for example, a phenyl group.

[0377] In a preferred embodiment, each R 2-3-2-1-2 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0378] In a preferred embodiment, each R 2-3-2-1-3 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0379] In a preferred embodiment, each R 2-3-2-2 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0380] In a preferred embodiment, each R 2-3-2-2 In the embodiment, the C1-C6 alkyl group is a C1-C4 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 1-butyl group, a 2-butyl group or a t-butyl group, and may also be a methyl group.

[0381] In a preferred embodiment, each R 2-3-2-2 In the embodiment, the C1-C6 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, and may be a methoxy group, an ethoxy group or a n-propoxy group.

[0382] In a preferred embodiment, each R 2-3-2-2-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0383] In a preferred embodiment, each R 2-3-2-2-2 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0384] In a preferred embodiment, each R 2-3-2-2-3 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0385] In a preferred embodiment, each R 2-3-2-3-1 wherein the 6-10 membered aryl group is a phenyl group or a naphthyl group, for example, a phenyl group.

[0386] In a preferred embodiment, each R 2-3-2-3-1-1 In the embodiment, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, methoxy.

[0387] In a preferred embodiment, each R 2-3-2-4 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0388] In a preferred embodiment, each R 2-3-2-5 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0389] In a preferred embodiment, each R 2-3-2-5 In the embodiment, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, methoxy.

[0390] In a preferred embodiment, each R 2-3-2-5 wherein the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a 1-butyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group, an ethyl group, an n-propyl group or an isopropyl group.

[0391] In a preferred embodiment, each R 2-3-2-5-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0392] In a preferred embodiment, each R 2-3-2-6 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0393] In a preferred embodiment, each R 2-3-3-1-1 In the embodiment, the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group.

[0394] In a preferred embodiment, each R 3-1 In the embodiment, the C1-C6 alkyl group may be a C1-C4 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 1-butyl group, a 2-butyl group or a t-butyl group, or may be a methyl group.

[0395] In a preferred embodiment, each R 3-1 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0396] In a preferred embodiment, each R 3-1-1 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0397] In a preferred embodiment, R 3-1-2 In the embodiment, the C1-C6 alkyl group may be a C1-C4 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 1-butyl group, a 2-butyl group or a t-butyl group, or may be a methyl group or an ethyl group.

[0398] In a preferred embodiment, R 3-1-2 In the embodiment, the C2-C6 alkenyl group may be For example

[0399] In a preferred embodiment, R 4 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0400] In a preferred embodiment, R 4 In the embodiment, 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, or a 4-ring spiro-4 ring. The heteroatom of the 4-10 membered heterocycloalkyl group may be N, and the number of heteroatoms may be 1 or 2.

[0401] In a preferred embodiment, R 4 In the embodiment, the C1-C6 alkyl group may be a C1-C4 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 1-butyl group, a 2-butyl group or a t-butyl group, or may be a methyl group.

[0402] In a preferred embodiment, each R 4-2 wherein 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.

[0403] In a preferred embodiment, R 4-1-1 In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group or an isopropyl group.

[0404] In a preferred embodiment, each R 4-1-2 In the embodiment, the C1-C6 alkyl group may be a C1-C4 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 1-butyl group, a 2-butyl group or a t-butyl group, or may be a methyl group.

[0405] In a preferred embodiment, each R 4-2-1 In the embodiment, the C1-C6 alkyl group may be a C1-C4 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 1-butyl group, a 2-butyl group or a t-butyl group, or may be a methyl group.

[0406] In one embodiment, Y is N.

[0407] In one embodiment, X is C.

[0408] In one embodiment, W is N, CH or CR 4 , R 4 is chlorine, deuterium or methyl.

[0409] In one embodiment, Z is CH or N.

[0410] In one plan, for

[0411] In one embodiment, ring D is

[0412] In one embodiment, n is 0.

[0413] In one scenario, R 1-3’ For hydrogen, cyano, methyl,

[0414] In one plan, for

[0415] In one embodiment, ring C is

[0416] In one scenario, R 2-3 For hydroxyl, oxo, methyl, -CF3,

[0417] In one plan, for

[0418] In one embodiment, ring A is

[0419] In one embodiment, k is 1.

[0420] In one scenario, R 3-1 -CHF2, -CF3,

[0421] In one plan, for In one embodiment, the compound represented by formula IV is any of the following compounds:

[0422] The second aspect of the present invention provides any one of the following compounds, or a pharmaceutically acceptable salt or isotope compound thereof;

[0423] 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.

[0424] The present invention also provides a substance Z for use as a drug; the substance Z is the compound 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.

[0425] 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.

[0426] The present invention also provides 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 of 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.

[0427] In a preferred embodiment, the PARG-related disease is breast cancer, such as triple-negative breast cancer, and other PARG-related diseases.

[0428] The present invention also provides 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 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.

[0429] In a preferred embodiment, the breast cancer is triple-negative breast cancer.

[0430] The present invention also provides a method for treating and / or preventing PARG-related diseases, which comprises 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.

[0431] In a preferred embodiment, the PARG-related disease is breast cancer, such as triple-negative breast cancer, and other PARG-related diseases.

[0432] 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.

[0433] In a preferred embodiment, the PARG-related disease is breast cancer, such as triple-negative breast cancer, and other PARG-related diseases.

[0434] Explanation of terms

[0435] The term "a group B which is unsubstituted or substituted by multiple groups A" means that one or more hydrogen atoms in 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 C6-C8 substituted by 3 halogens" 10 "Aryl" refers to C6~C 10 The aryl group may be substituted by three halogens, the definitions of which are independent of each other and do not affect each other, including but not limited to: wait.

[0436] A double bond or a single bond.

[0437] The term "plurality" refers to 2 or more, such as 2, 3, 4, 5.

[0438] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0439] 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, and ammonium salts. 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, and methanesulfonates. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0440] "-" in a group means that the group is attached to the rest of the molecule through that site. For example, CH3-C(=O)- means acetyl.

[0441] The term "halogen" refers to fluorine, chlorine, bromine or iodine. 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 generally multiple substitutions occur on one carbon atom.

[0442] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, a carbonyl replacing a methylene group.

[0443] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0444] The term "alkoxy" refers to a group R X -O-, R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0445] The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2 to C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond. Alkenyl groups include but are not limited to: vinyl, wait.

[0446] The term "alkynyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C2 to C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 Triple bond. Alkynyl includes but is not limited to: ethynyl, wait.

[0447] Unless otherwise specified in the present invention, the term "cycloalkyl" refers to a group having a specified number of carbon atoms (e.g., C3 to C 10 ) is a cyclic, saturated, monovalent hydrocarbon group, which is monocyclic or polycyclic (e.g., 2 or 3, bridged, spiro, and fused rings), with two or more carbon atoms shared between the monocyclic rings. Monocyclic rings include, but are 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 includes but is not limited to: wait.

[0448] Unless otherwise specified in the present invention, the term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6 to C 10 ) cyclic, unsaturated monovalent hydrocarbon group, which is monocyclic or polycyclic (for example, 2 or 3), in the case of polycyclic, the monocyclics share two atoms and one bond, and (at least one ring / each ring) has aromaticity. The aryl group is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring. Aryl groups include but are not limited to: phenyl, naphthyl, wait.

[0449] Unless otherwise specified herein, the term "heterocycloalkyl" refers to a monocyclic, bridged, spirocyclic, or fused ring having a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). The heterocycloalkyl group may be saturated or unsaturated. The (monocyclic) heterocycloalkyl group is attached to the rest of the molecule via a carbon atom or a heteroatom. Monocyclic heterocycloalkyl groups include, but are not limited to: Spirocyclic heterocycloalkyl groups include but are not limited to: etc. Bridged heterocycloalkyl groups include but are not limited to: Etc. Cycloheterocycloalkyl includes Unsaturated heterocycloalkyl refers to the presence of carbon-carbon double bonds or carbon-carbon triple bonds in the heterocycloalkyl group, for example

[0450] 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., 5-10 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 monocyclic or polycyclic, with two atoms and one bond shared between the monocyclic 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.

[0451] 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 is replaced by an atom of a lower mass number than occurs naturally - a hydrogen atom in a compound is replaced by deuterium, or a C is replaced by 13 C replacement.

[0452] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0453] The reagents and raw materials used in the present invention are commercially available.

[0454] The positive improvement effect of the present invention is that the compound of the present invention has good PARG inhibitory activity. DETAILED DESCRIPTION

[0455] All compounds of the present invention can be synthesized by different methods by those skilled in the art of organic chemistry. The following describes general synthetic schemes for preparing the compounds of the present invention. These schemes are general and are not meant to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. 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 compound or compounds. The preparation and examples described below provide examples of the preparation of the compounds of the present invention by the methods described in the general schemes. The preparation of compounds containing chiral center embodiments can be performed by techniques known to 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.

[0456] The chemical reactions and synthetic techniques described herein are performed in the reagents and corresponding solvents described herein, and the corresponding reaction yields will also be affected by the reagents and solvents used. Furthermore, it should be understood that in the synthetic methods described below, all reaction conditions mentioned, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and reaction feed sequence, should be considered standard operating conditions for the reaction, as readily recognized by those skilled in the art. This is also understood by those skilled in the art of organic synthesis. The functional groups present on various parts of the molecule must be compatible with the reagents used and the reaction itself. Limitations such as incompatibility of some functional groups on various parts of the molecule with the reaction conditions necessitate alternative methods, as will be readily apparent to those skilled in the art. The need to adjust the order of synthetic steps or select a specific synthetic process scheme to obtain the desired compounds of the present invention is readily apparent to those skilled in the art of organic synthesis. It should also be recognized that another key consideration in any synthetic route designed in this field is the tolerance of the appropriate protecting groups used to protect the reactive functional groups present in the compounds described herein. For details, please refer to the work of Greene et al., an authority in the field of chemistry (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0457] Example

[0458] 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 rather to illustrate how to prepare the relevant compounds. The starting materials and reagents used in these examples, when not prepared by the procedures described herein, are generally commercially available or reported in the relevant chemical literature, or can be prepared by using the procedures described in the chemical literature.

[0459] In the examples given herein, the term "drying and concentrating" generally refers to adding anhydrous sodium sulfate or magnesium sulfate drying solution to an organic solvent, followed by filtration and removal of the solvent from the filtrate (usually performed under reduced pressure and at a temperature suitable for the stability of the prepared compound). 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 silica gel column and eluting in a specified solvent or solvent mixture. In some cases, the final product is quickly purified by preparative thin layer chromatography using a 20cm x 20cm x 0.5mm or 20cm x 20cm x 1mm silica gel plate in an appropriate solvent system. Preparative high performance liquid chromatography (HPLC) is performed using a reversed-phase column (Waters Sunfire C18, Waters Xbridge C18, or similar) of a size appropriate to the amount of compound being separated. Elution is typically performed using a gradient of methanol or acetonitrile added to the aqueous phase, with the eluent containing 0.05% or 0.1% formic acid, trifluoroacetic acid, or 10 mM ammonium acetate, at an elution rate that matches the size of the reversed-phase column used and the resolution of the preparation being prepared.

[0460] List of abbreviations

[0461] 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

[0462] Step 1: 6-Bromo-8-chloro-N'-(2,2,2-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide

[0463] Under nitrogen, 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 mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water was added and the mixture 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: 0-15% ethyl acetate) to obtain the title compound (yellow solid, 600 mg, 75.1% yield). LC / MS (ESI) (m / z): 385 [M+H] + .

[0464] Step 2: 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

[0465] Under nitrogen, 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 mixture was stirred at 110°C for 4 hours. After the reaction was complete, sodium bicarbonate 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: 0-20% ethyl acetate) to yield the title compound (yellow solid, 500 mg, 83.7% yield). LC / MS (ESI) (m / z): 383 [M+H] + .

[0466] Step 3: 2-(6-(Benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

[0467] Under nitrogen, 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) were added N,N-diisopropylethylamine (505 mg, 3.91 mmol), Xantphos (151 mg, 0.26 mmol), and Pd2(dba)3 (119 mg, 0.13 mmol). The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 3 hours. After the reaction was complete, 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: 0-25% ethyl acetate) to give the title compound (yellow solid, 510 mg, 91.6% yield). LC / MS (ESI) (m / z): 427 [M+H] + .

[0468] Step 4: 1,8-Dichloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

[0469] Under nitrogen, sulfonyl chloride (13.5 g, 100 mmol) was slowly added dropwise 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). The reaction was stirred at 0°C under nitrogen for 60 minutes. After the reaction was complete, the mixture was slowly added to an ice-cold saturated sodium bicarbonate solution. The layers were separated 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 to give the title compound (yellow solid, 7.0 g, 97.5% yield). LC / MS (ESI) (m / z): 437 [M+H] + .

[0470] Step 5: 1,8-Dichloro-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0471] Under nitrogen, 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 added dropwise to a solution of 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 under nitrogen for 60 minutes. After the reaction was complete, the mixture was slowly added to ice water, the layers were 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 yield the title compound (yellow solid, 4.9 g, 62.7% yield). LC / MS (ESI) (m / z): 488 [M+H] + .

[0472] Step 6: 1,8-Dichloro-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

[0473] To a solution of 1,8-dichloro-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide (4.9 g, 10 mmol) and N,N-diisopropylethylamine (3.9 g, 30 mmol) in dichloromethane (50 mL) was slowly added dropwise 2-(trimethylsilyl)ethoxymethyl chloride (3.4 g, 20 mmol) under ice. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, water was slowly added, the layers were separated, 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 afford the title compound as a yellow solid, 5.5 g, 86.8% yield. LC / MS (ESI) (m / z): 618 [M+H] + .

[0474] 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

[0475] Refer to the synthesis method of intermediate 1, except that difluoroacetic anhydride is used instead of trifluoroacetic anhydride in step 1 to obtain intermediate 2. LC / MS (ESI) (m / z): 600 [M+H] + .

[0476] Intermediate 3: 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

[0477] Step 1: 6-Bromo-8-chloro-N'-(2,2,2-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide

[0478] Under nitrogen, 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 mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water was added and the mixture 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: 0-15% ethyl acetate) to obtain the title compound (yellow solid, 600 mg, 75.1% yield). LC / MS (ESI) (m / z): 385 [M+H]+ .

[0479] Step 2: 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

[0480] Under nitrogen, 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 mixture was stirred at 110°C for 4 hours. After the reaction was complete, sodium bicarbonate 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: 0-20% ethyl acetate) to yield the title compound (yellow solid, 500 mg, 83.7% yield). LC / MS (ESI) (m / z): 383 [M+H] + .

[0481] Step 3: 2-(6-(Benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

[0482] Under nitrogen, 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) were added N,N-diisopropylethylamine (505 mg, 3.91 mmol), Xantphos (151 mg, 0.26 mmol), and Pd2(dba)3 (119 mg, 0.13 mmol). The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 3 hours. After the reaction was complete, 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: 0-25% ethyl acetate) to give the title compound (yellow solid, 510 mg, 91.6% yield). LC / MS (ESI) (m / z): 427 [M+H] + .

[0483] Step 4: 2-(6-(Benzylthio)-1-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole

[0484] 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) at 0°C was added NBS (213 mg, 1.20 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, 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: 0-25% ethyl acetate) to afford the title compound as a yellow solid, 550 mg, 91.2% yield. LC / MS (ESI) (m / z): 505 [M+H] + .

[0485] Step 5: 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

[0486] To a solution of 2-(6-(benzylthio)-1-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (550 mg, 1.10 mmol) in acetonitrile (5 mL) were added 1N hydrochloric acid (1.25 mL), water (1.25 mL), and dichlorohydantoin (643 mg, 3.27 mmol) in sequence at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. After the reaction was complete, water was added and the mixture 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 slurried with petroleum ether and dried in vacuo to give the title compound as a yellow solid (520 mg, 99.2% yield). LC / MS (ESI) (m / z): 481 [M+H] + .

[0487] Intermediate 4: 1-bromo-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5-a]pyridine-6-sulfonyl chloride

[0488] Refer to the synthesis method of intermediate 3, except 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] + .

[0489] 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

[0490] 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

[0491] To a solution of 3-methyloxetane-3-amine (0.017 mL, 0.388 mmol) in pyridine (3 mL) was added dropwise 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) at 0°C. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, water was added, the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50%) to afford the title compound (yellow solid, 80 mg, 80.14% yield). LC / MS (ESI) (m / z): 514 / 516 [M+H] + .

[0492] 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

[0493] 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)imidazol[1,5]-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] + .

[0494] 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

[0495] 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] + .

[0496] 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

[0497] Refer to the synthesis method of intermediate 5 step 1, except that the starting material is 3-fluoromethyloxetane-3-amine to obtain intermediate 7. LC / MS (ESI) (m / z): 532 [M+H] + .

[0498] 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

[0499] Step 1: (S)-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-(methoxymethyl)piperazine-1-carboxylate

[0500] Under nitrogen, 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)-tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate (576 mg, 2.50 mmol) in 1,4-dioxane (20 mL) were added cesium carbonate (1627 mg, 5.01 mmol), Ruphos (156 mg, 0.27 mmol), and Ruphos Pd G3 (139 mg, 0.17 mmol). The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 2 hours. After the reaction was complete, water was added and the mixture was extracted twice 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: 0-30% ethyl acetate) to yield the title compound (yellow solid, 720 mg, 54.5% yield). LC / MS (ESI) (m / z): 794 [M+H].

[0501] Step 2: (S)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-(methoxymethyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0502] Under ice-water bath, trifluoroacetic acid (3 mL) was added to a solution of (S)-tert-butyl 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-carboxylate (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 added dropwise to a 5% aqueous sodium bicarbonate 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 H2O and 0.1% FA) to give the title compound (yellow solid, 278 mg, 54.4% yield). 1 H NMR (400MHz, DMSO-d6) 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] + .

[0503] The following examples are prepared with reference to the preparation method of Example 1. Starting from appropriate starting materials, the crude product was synthesized according to a similar route. The crude product was subjected to reverse phase HPLC and freeze-dried to obtain the title compound.

[0504] 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

[0505] 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

[0506] Under nitrogen, 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)(piperazin-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). The reaction mixture was stirred at 80°C under nitrogen for 3 hours. After completion of the reaction, the reaction mixture 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] + .

[0507] 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

[0508] To a solution of 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 (30 mg, 0.04 mmol) in dichloromethane (2 mL) at 0°C was added trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 30-95% acetonitrile in H2O and 0.1% TFA) to afford the title compound as a yellow solid, 13.7 mg, 55.0% yield. 1H NMR (400MHz, DMSO-d6) 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] + .

[0509] 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

[0510] Step 1: 8-(4-(1-ethylcyclopropane-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

[0511] Under nitrogen, 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)(piperazin-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). The reaction mixture was stirred at 80°C under nitrogen for 3 hours. After completion of the reaction, the reaction mixture 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] + .

[0512] Step 2: 8-(4-(1-ethylcyclopropane-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

[0513] 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) at 0°C was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 10-50% acetonitrile in H2O and 0.1% FA) to afford the title compound as a yellow solid, 6 mg, 24% yield. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0514] The following examples are prepared with reference to the preparation method of Example 6. Starting from appropriate starting materials, the crude product was synthesized according to a similar route. The crude product was prepared by reverse phase HPLC and freeze-dried to obtain the title compound.

[0515] 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

[0516] Step 1: (2S,6S)-tert-butyl 4-(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)-2,6-dimethylpiperazine-1-carboxylate

[0517] Under nitrogen protection, to a solution of 8-chloro-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 (100 mg, 0.18 mmol) and tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (56.8 mg, 0.27 mmol) in 1,4-dioxane (2 mL) were added cesium carbonate (172.7 mg, 0.53 mmol), Ruphos (16.5 mg, 0.035 mmol), and Ruphos Pd G3 (29.6 mg, 0.035 mmol) in sequence. The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen protection for 2 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate, washed sequentially with water and 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 yield the title compound (yellow solid, 120 mg, 91.4% yield). LC / MS (ESI) (m / z): 744 [M+H] + .

[0518] Step 2: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0519] To the reaction flask was added tert-butyl (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-carboxylate (120 mg, 0.16 mmol), dichloromethane (2 mL), and 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, and concentrated to give the title compound (yellow solid, 70 mg, 84.5% yield). LC / MS (ESI) (m / z): 514 [M+H] + .

[0520] Step 3: 8-((3S,5S)-4-cyclopropyl-3,5-dimethylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0521] To a solution of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetan-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) was added sodium cyanoborohydride (7.8 mg, 0.20 mmol) and acetic acid (76.3 mg, 0.41 mmol) at room temperature. The reaction mixture was stirred at 60°C under nitrogen for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 10-50% acetonitrile in H2O and 0.1% FA) to give the title compound (yellow solid, 1.54 mg, 2.0% yield). 1 H NMR (400MHz, CDCl3) δ9.86 (s, 1H), 7.73 (s, 1H), 7.00 (t, J = 53.6Hz, 1H), 6.68 (s, 1H), 4.82-4.80 (m, 2H), 4.4 2-4.39(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] + .

[0522] 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

[0523] Step 1: Benzyl (3S,5S)-3,5-dimethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine-1-carboxylate

[0524] Under nitrogen protection, potassium carbonate (331 mg, 2.40 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (446 mg, 1.8 mmol) were added sequentially to a solution of benzyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (300 mg, 1.20 mmol) in DMF (5 mL). The reaction solution was purged with nitrogen three times and stirred at 80°C under nitrogen protection for 3 hours. 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, 46% yield). LC / MS (ESI) m / z: 377 [M+H] + .

[0525] Step 2: (2S,6S)-2,6-Dimethyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine

[0526] To a solution of benzyl (3S,5S)-3,5-dimethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine-1-carboxylate (210 mg, 0.55 mmol) in ethyl acetate (20 mL) was added 10% palladium on carbon (80 mg) at room temperature. The reaction mixture was purged with hydrogen three times and stirred at room temperature under 1 atmosphere of hydrogen for 3 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford the title compound as a colorless oil (120 mg, 88% yield). LC / MS (ESI) (m / z): 243 [M+H] + .

[0527] 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

[0528] 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 G3 (5 mg, 0.006 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, 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 yield the title compound (yellow solid, 30 mg, 69% yield). LC / MS (ESI) m / z: 772 [M+H] + .

[0529] Step 4: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0530] 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-methyloxetan-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 as a yellow solid, 2.43 mg, 5% yield.1 H NMR (400MHz, CD3OD) 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] + .

[0531] 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

[0532] 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

[0533] Under nitrogen protection, to a solution of methyl (5-(8-chloro-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 (35 mg, 0.06 mmol) and 2S,6S-dimethylmorpholine (9 mg, 0.07 mmol) in 1,4-dioxane (2 mL) were added cesium carbonate (45 mg, 0.18 mmol), Ruphos (5 mg, 0.01 mmol), and Ruphos Pd G3 (5 mg, 0.006 mmol) in sequence. The reaction solution was purged with nitrogen three times and stirred at 80°C under nitrogen protection for 5 hours. 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] + .

[0534] 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

[0535] To a solution of 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 (13 mg, 0.01 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) sequentially at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, water was added and the mixture 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: 0-80% ethyl acetate) to give the title compound as a white solid, 10 mg, 95% yield. LC / MS (ESI) (m / z): 537 [M+H] + .

[0536] Step 3: 8-((2S.6S)-2,6-dimethylmorpholinyl)-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0537] 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 was added tetrahydrofuran (1 mL), water (1 mL), and lithium hydroxide (1 mg, 0.03 mmol). 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 as a white solid, 0.41 mg, 5% yield. 1 H NMR(400MHz,CD3OD)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] + .

[0538] 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

[0539] 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

[0540] Under nitrogen protection, to a solution of methyl (5-(8-chloro-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 (35 mg, 0.06 mmol) and tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate (16 mg, 0.07 mmol) in 1,4-dioxane (2 mL) were added cesium carbonate (45 mg, 0.18 mmol), Ruphos (5 mg, 0.01 mmol), and Ruphos Pd G3 (5 mg, 0.006 mmol) in sequence. The reaction solution was purged with nitrogen three times and stirred at 80°C under nitrogen protection for 2 hours. 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] + .

[0541] 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

[0542] 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) was added trifluoroacetic acid (1 mL) sequentially at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, water was added and the mixture 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: 0-80% ethyl acetate) to give the title compound as a white solid, 20 mg, 95% yield. LC / MS(ESI)(m / z):552[M+H] + .

[0543] Step 3: 3-(5-(Hydroxymethyl)-1,3,4-thiadiazol-2-yl)-8-(3-(methoxymethyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0544] To a solution of 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 (20 mg, 0.03 mmol) in methanol (1 mL) at 0°C were added tetrahydrofuran (1 mL), water (1 mL), and lithium hydroxide (2 mg, 0.09 mmol). 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 as a yellow solid, 0.93 mg, 5% yield. 1 H NMR(400MHz,CD3OD)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] + .

[0545] 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

[0546] Step 1: N-(3-cyanooxetan-3-yl)-2-methylpropane-2-sulfenamide

[0547] To a solution of 2-methyl-N-(oxetane-3-ylidene)propane-2-sulfenamide (1 g, 5.7 mmol) in dichloromethane (20 mL) was added tetraethyl titanate (1.3 g, 5.7 mmol). After the addition was complete, the reaction mixture was stirred for 10 minutes. Trimethylsilyl cyanide (1.5 mL, 11.4 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was poured into saturated brine and filtered. 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 isolated by column chromatography (eluent: dichloromethane / methanol, gradient: 0-4% methanol) to yield the title compound (yellow liquid, 900 mg, 78.3% yield). LC / MS (ESI) (m / z): 203 [M+H] + .

[0548] Step 2: 3-Aminooxetane-3-carbonitrile hydrochloride

[0549] To a solution of N-(3-cyanooxetan-3-yl)-2-methylpropane-2-sulfenamide (400 mg, 2.0 mmol) in methanol (3 mL) was slowly added dropwise a 4 M solution of dioxane hydrochloride (1.5 mL, 6 mmol) at 0°C. The reaction mixture was stirred at 0°C under nitrogen for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the title compound (white solid, 266 mg, 100% yield), which was used directly in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ4.90 (d, J = 8.0 Hz, 2H), 4.85 (d, J = 7.8 Hz, 2H).

[0550] Step 3: 1-Bromo-8-chloro-N-(3-cyanooxetan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0551] To a solution of 3-aminooxetane-3-carbonitrile hydrochloride (232 mg, 1.72 mmol) in pyridine (2 mL) was added portionwise 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) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture 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 isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to afford the title compound (yellow solid, 280 mg, 61.8% yield). LC / MS (ESI) (m / z): 525 [M+H] + .

[0552] 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

[0553] To a solution of 1-bromo-8-chloro-N-(3-cyanooxetan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide (100 mg, 0.19 mmol) in toluene (2 mL) were added 2,4-dimethoxybenzyl alcohol (64 mg, 0.38 mmol) and cyanomethylenetri-n-butylphosphine (138 mg, 0.57 mmol). The reaction mixture was stirred at 100°C under nitrogen for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-45% ethyl acetate) to afford the title compound (yellow solid, 70 mg, 54.5% yield). LC / MS (ESI) (m / z): 675 [M+H] + .

[0554] Step 5: 8-chloro-N-(3-cyanooxetan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyridine-6-sulfonamide

[0555] Under nitrogen protection, 10% palladium on 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 purged with nitrogen three times and stirred at room temperature under hydrogen for 6 hours. After completion, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-45% ethyl acetate) to obtain the title compound (yellow solid, 30 mg, 61.8% yield). LC / MS (ESI) (m / z): 597 [M+H] + .

[0556] Step 6: N-(3-cyanooxetan-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

[0557] To a solution of 8-chloro-N-(3-cyanooxetane-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) was added cesium carbonate (33 mg, 0.10 mmol), Ruphos (5 mg, 0.01 mmol), and Ruphos Pd G3 (4 mg, 0.005 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 90°C under nitrogen for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, added with water, 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] + .

[0558] Step 7: N-(3-cyanooxetan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0559] To a reaction flask containing N-(3-cyanooxetan-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) was slowly added trifluoroacetic acid (1 mL) dropwise at 0°C. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to afford the title compound (yellow solid, 2 mg, 11.5% yield). 1 H NMR (400MHz, DMSO-d6) 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] + .

[0560] 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

[0561] Step 1: N-(3-(difluoro(phenylsulfonyl)methyl)oxetan-3-yl)-2-methylpropane-2-sulfenamide

[0562] To a solution of 2-methyl-N-(oxetane-3-yl)propane-2-sulfenamide (1 g, 5.7 mmol) and ((difluoromethyl)sulfonyl)benzene (1.1 g, 5.7 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise lithium bistrimethylsilylamide (11.4 mL, 11.4 mmol, 1 M) at -78°C under nitrogen. After the addition was complete, the reaction mixture was stirred at -78°C to room temperature for 3 hours. After completion, the reaction mixture 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 isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-35% ethyl acetate) to afford the title compound (yellow liquid, 1.4 g, 66.8% yield). LC / MS (ESI) (m / z): 368 [M+H] + .

[0563] Step 2: N-(3-(difluoromethyl)oxetan-3-yl)-2-methylpropane-2-sulfenamide

[0564] To a solution of N-(3-(difluoro(phenylsulfonyl)methyl)oxetane-3-yl)-2-methylpropane-2-sulfenamide (1.4 g, 3.81 mmol) in methanol (20 mL) was added disodium hydrogen phosphate (5.4 g, 38 mmol) and 20% sodium amalgam (1.1 g, 9.5 mmol) at room temperature. The reaction mixture was stirred under nitrogen for 2 hours. After completion of the reaction, 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 afford the title compound (yellow liquid, 690 mg, 79.7% yield). LC / MS (ESI) (m / z): 228 [M+H] + .

[0565] Step 3: 3-(Difluoromethyl)oxetane-3-amine hydrochloride

[0566] To a solution of N-(3-(difluoromethyl)oxetane-3-yl)-2-methylpropane-2-sulfenamide (400 mg, 1.76 mmol) in methanol (3.5 mL) was slowly added dropwise a 4M solution of dioxane hydrochloride (0.8 mL, 3.2 mmol) at 0°C. The reaction mixture was stirred at 0°C under nitrogen for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the title compound (white solid, 281 mg, 100% yield), which was used directly in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ6.60 (t, J = 54.2Hz, 1H), 4.73 (d, J = 8.1Hz, 2H), 4.67 (d, J = 8.0Hz, 2H).

[0567] 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

[0568] To a solution of 3-(difluoromethyl)oxetane-3-amine hydrochloride (206 mg, 1.29 mmol) in pyridine (5 mL) was added portionwise 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) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture 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 isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-35% ethyl acetate) to afford the title compound (yellow solid, 120 mg, 33.7% yield). LC / MS (ESI) (m / z): 550 [M+H] + .

[0569] 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

[0570] To a 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) in DMF (2 mL) at 0°C was added N,N-diisopropylethylamine (84 mg, 0.64 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (73 mg, 0.44 mmol). The reaction mixture was stirred at 0°C under nitrogen for 0.5 hours. After completion, water was added, the mixture was 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 afford the title compound as a yellow solid, 100 mg, 67.4% yield. LC / MS(ESI)m / z:680[M+H] + .

[0571] 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

[0572] Under nitrogen protection, 10% palladium 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-(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 purged with nitrogen three times and stirred at room temperature under a hydrogen atmosphere for 6 hours. After completion, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-25% ethyl acetate) to obtain the title compound (yellow solid, 70 mg, 79.2% yield). LC / MS (ESI) (m / z): 602 [M+H] + .

[0573] 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

[0574] 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 under nitrogen was added cesium carbonate (76 mg, 0.23 mmol), Ruphos (11 mg, 0.02 mmol), and Ruphos Pd G3 (10 mg, 0.01 mmol). The reaction mixture was stirred at 90°C under nitrogen for 3 hours. After completion of the reaction, the mixture 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] + .

[0575] 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

[0576] 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) was slowly added dropwise trifluoroacetic acid (1 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture 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 yield the title compound (yellow solid, 21 mg, 42.7% yield). 1 H NMR (400MHz, CD3OD) δ9.86 (s, 1H), 7.95 (s, 1H), 7.33 (t, J = 53.5Hz, 1H), 6.78 (d, J = 1.2Hz, 1H), 6.23 (t, J = 55.6Hz, 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=6.7Hz,6H).LC / MS(ESI)(m / z):592[M+H] + .

[0577] 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

[0578] 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

[0579] 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) at 0°C were added N,N-diisopropylethylamine (105 mg, 0.81 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (67 mg, 0.40 mmol) in sequence. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, 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 slurrying with petroleum ether to obtain the title compound (yellow solid, 143 mg, 79.4% yield). LC / MS (ESI) (m / z): 662 [M+H] + .

[0580] 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

[0581] Under nitrogen protection, 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) was added 20% palladium hydroxide on carbon (10 mg). The reaction mixture was purged 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 give the title compound (yellow solid, 40 mg, 69.6% yield). LC / MS (ESI) (m / z): 585 [M+H] + .

[0582] 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

[0583] Under nitrogen, to a solution of 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), 2-methyl-1-(piperazin-1-yl)propan-1-one (21 mg, 0.13 mmol), and 1,4-dioxane (2 mL) were added cesium carbonate (44 mg, 0.13 mmol), Ruphos (6 mg, 0.014 mmol), and Ruphos Pd G3 (11 mg, 0.014 mmol) in sequence. The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 30 minutes. After the reaction was complete, 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: 0-70% ethyl acetate) to yield the title compound (yellow solid, 44 mg, 91.6% yield). LC / MS (ESI) (m / z): 705 [M+H] + .

[0584] 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

[0585] 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) was added trifluoroacetic acid (0.2 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction mixture was added dropwise to an ice-cold 5% aqueous sodium bicarbonate 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 H2O and 0.1% formic acid) to give the title compound (yellow solid, 3 mg, 24.5% yield). 1H NMR (400MHz, CD3OD) 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] + .

[0586] 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

[0587] 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

[0588] Under nitrogen, 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) was added N-fluorobisbenzenesulfonamide (16 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction 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 isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-35% ethyl acetate) to afford the title compound as a yellow solid, 12 mg, 39.0% yield. LC / MS (ESI) (m / z): 605 [M+H] + .

[0589] 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

[0590] To a solution of 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 (12 mg, 0.02 mmol) in dichloromethane (0.6 mL) was slowly added dropwise trifluoroacetic acid (0.2 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound as a yellow solid, 1.1 mg, 11.2% yield. 1 H NMR (400MHz, CD3OD) 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,2H),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] + .

[0591] 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

[0592] 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

[0593] 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) at room temperature under nitrogen was added N-fluorobisbenzenesulfonamide (5.7 mg, 0.018 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was purified by preparative HPLC to yield the title compound (yellow solid, 2 mg, 38.7% yield). 1H NMR (400MHz, DMSO-d6) 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) ,3.74-3.66(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] + .

[0594] 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

[0595] 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

[0596] Under nitrogen protection, 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) was added 10% palladium on carbon (50 mg). The reaction solution was purged with nitrogen three times and stirred at room temperature under an atmosphere of deuterium for 6 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (yellow solid, 120 mg, yield 78.55%). LC / MS (ESI) m / z: 437 / 439 [M+H] + .

[0597] 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

[0598] Under nitrogen, to a solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide-1-deuterium (50 mg, 0.114 mmol) and 2-methyl-1-(piperazin-1-yl)propan-1-one (36 mg, 0.23 mmol) in 1,4-dioxane (1 mL) were added cesium carbonate (112 mg, 0.344 mmol), Ruphos (11 mg, 0.024 mmol), and Ruphos Pd G3 (10 mg, 0.012 mmol). The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed sequentially with water and saturated brine, 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 (400MHz, DMSO-d6) δ9.61-9.57(m,1H),8.72(s,1H),7.83-7.53(m,1H),6.70(s,1H),4.63(d,J=6.2Hz,2H),4.18(d,J=6.5H z,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=6.7Hz,6H).LC / MS(ESI)m / z:557[M+H] + .

[0599] 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

[0600] The title compound was obtained by referring to the synthesis method of Example 19 as a light yellow solid. 1 H NMR(400MHz, DMSO-d6)δ9.57(s,1H),8.29(d,J=1.8Hz,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]+ .

[0601] 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

[0602] 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

[0603] Under nitrogen, to a solution of 1-bromo-8-chloro-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 (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) was added Pd(dppf)Cl2 (9 mg, 0.02 mmol) and potassium carbonate (120 mg, 0.69 mmol). The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and extracted three times with ethyl acetate. 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 afford the title compound (yellow solid, 50 mg, 37.3% yield). LC / MS (ESI) (m / z): 580 [M+H] + .

[0604] 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

[0605] Under nitrogen, to a solution of 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 (50 mg, 0.09 mmol) and 2-oxa-7-azaspiro[3.5]nonane (15 mg, 0.09 mmol) in 1,4-dioxane (2 mL) were added Ruphos (4 mg, 0.01 mmol), Ruphos Pd G3 (4 mg, 0.01 mmol), and cesium carbonate (75 mg, 0.27 mmol). The reaction mixture was stirred at 80°C under nitrogen for 3 hours. After completion of the reaction, the reaction mixture 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] + .

[0606] 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

[0607] To a solution of 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 (20 mg, 0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to yield the title compound (yellow solid, 1.5 mg, 9.2% yield). 1 H NMR (400MHz, DMSO-d6) 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,4 H),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]+ .

[0608] 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

[0609] Step 1: 8-((3R,5R)-tert-butyl 3,5-dimethylpiperazine-4-carboxylate-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

[0610] Under nitrogen, 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)imidazo[1,5-a]pyridine-6-sulfonamide (80 mg, 0.14 mmol) and tert-butyl (2R,6R)-2,6-dimethyl-1-piperazinecarboxylate (38 mg, 0.18 mmol) in 1,4-dioxane (5 mL) were added cesium carbonate (136 mg, 0.42 mmol), Ruphos (13 mg, 0.02 mmol), and Ruphos Pd G3 (13 mg, 0.01 mmol) in sequence. The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 5 hours. After completion of the reaction, the mixture 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, 96% yield). LC / MS (ESI) (m / z): 744 [M+H] + .

[0611] 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

[0612] To a solution of tert-butyl 8-((3R,5R)-3,5-dimethylpiperazine-4-carboxylate-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 (100 mg, 0.13 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture 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 yield the title compound (yellow solid, 37 mg, 54% yield). 1 H NMR(400MHz, DMSO-d6)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),3.94–3.85(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] + .

[0613] Example 23: 1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-((methoxy-d3)methyl)piperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0614] Step 1: 4-Benzyl-1-(tert-butyl)-2-((methoxy-d3)methyl)piperazine-1,4-dicarboxylate

[0615] To a solution of 4-benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (500 mg, 1.42 mmol) in DMSO (10 mL) at 0°C were added potassium hydroxide (159 mg, 2.84 mmol) and deuterated iodomethane (613 mg, 4.26 mmol) in sequence. The reaction mixture was stirred in an ice bath for 2 hours. After the reaction was complete, water was added and the mixture 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 isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to yield the title compound (white solid, 320 mg, 30% yield). LC / MS (ESI) (m / z): 368 [M+H] + .

[0616] Step 2: tert-Butyl 2-((methoxy-d3)methyl)piperazine-1-carboxylate

[0617] Under nitrogen, 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 mixture was purged with nitrogen three times and stirred under a 15 psi hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (colorless oil, 180 mg, 88% yield). LC / MS (ESI) (m / z): 234 [M+H] + .

[0618] 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-d3)methyl)piperazine-1-carboxylate

[0619] Under nitrogen protection, 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) were added cesium carbonate (97 mg, 0.30 mmol), Ruphos (9 mg, 0.02 mmol), and Ruphos Pd G3 (9 mg, 0.01 mmol) in sequence. The reaction solution was purged with nitrogen three times and stirred at 80°C under nitrogen protection for 2 hours. 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: 0-30% ethyl acetate) to yield the title compound (yellow solid, 30 mg, 37% yield). LC / MS (ESI) m / z: 797 [M+H] + .

[0620] Step 4: 1-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(3-((methoxy-d3)methyl)piperazin-1-yl)-N-(3-methyloxetane-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0621] 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-d3)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 as a yellow solid, 4.8 mg, 22% yield. 1H NMR (400MHz, DMSO-d6) 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] + .

[0622] 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

[0623] Step 1: 1-Benzyl 4-(tert-Butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)amino)methyl)piperazine-1,4-dicarboxylate

[0624] Under nitrogen, to a solution of 1-benzyl 4-(tert-butyl)-2-formylpiperazine-1,4-dicarboxylate (400 mg, 0.89 mmol) in dichloromethane (6 mL) were added methyl 1-aminocyclopropane-1-carboxylate (154 mg, 1.34 mmol) and sodium triacetoxyborohydride (731 mg, 3.45 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, 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: 0-60% ethyl acetate) to afford the title compound as a yellow oil (340 mg, 66.0% yield). LC / MS (ESI) m / z: 448 [M+H] + .

[0625] Step 2: 1-Benzyl 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)(methyl)amino)methyl)piperazine-1,4-dicarboxylate

[0626] To a solution of 1-benzylidene 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)amino)methyl)piperazine-1,4-dicarboxylate (340 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL) at 0°C were added cesium fluoride (346 mg, 2.28 mmol) and iodomethane (162 mg, 1.14 mmol) in sequence. The reaction mixture was stirred at 80°C for 16 hours. After the reaction was complete, 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: 0-30% ethyl acetate) to afford the title compound as a yellow oil (140 mg, 39.9% yield). LC / MS (ESI) (m / z): 462 [M+H] + .

[0627] Step 3: tert-Butyl 2'-methyl-4'-oxohexahydro-4'H,8'H-pyrrolidone-1,3'-pyrazino[1,2-a]pyrazine]-8'-carboxylate

[0628] To a solution of 1-benzyl 4-(tert-butyl)-2-(((1-(methoxycarbonyl)cyclopropyl)(methyl)amino)methyl)piperazine-1,4-dicarboxylate (140 mg, 0.30 mmol) in anhydrous methanol (5 mL) at 0°C was added 10% palladium hydroxide on carbon (28 mg). The reaction mixture 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, 78.2% yield). LC / MS (ESI) (m / z): 296 [M+H] + .

[0629] Step 4: 2'-Methylhexahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-a]pyrazino]-4'-one

[0630] To a solution of tert-butyl 2'-methyl-4'-oxohexahydro-4'H,8'H-pyridine-1,3'-pyrazino[1,2-a]pyrazine]-8'-carboxylate (70 mg, 0.23 mmol) in methanol (2 mL) was added a solution of hydrochloric acid in 1,4-dioxane (1 mL) at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (yellow oil, 45 mg, 97.2% yield). LC / MS (ESI) m / z: 196 [M+H] + .

[0631] Step 5-6: 8-(2'-methyl-4'-oxohexahydro-4'H,8'H-spiro[cyclopropane-1,3'-pyrazino[1,2-a]pyrazino]-8'-yl)-N-(3-methyloxetane-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0632] The title compound was prepared according to the preparation method of Example 391, Steps 3-4. 1 H NMR(400MHz,CD3OD)δ9.81(s,1H),7.99(s,1H),6.84-6.79(m,1H),4.80-4.71(m,4 H),4.34-4.30(m,2H),3.87-3.79(m,2H),3.27-3.24(m,1H),3.18-3.11(m,2H),3.0 0-2.93(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] + .

[0633] 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

[0634] Step 1: (S)-1-((4-methoxybenzyl)amino)propan-2-ol

[0635] Under nitrogen, p-anisaldehyde (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 under nitrogen for 1 hour, followed by the addition of sodium borohydride (3.0 g, 80 mmol) in portions at zero degrees Celsius. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction solution, followed by extraction 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, 64.1% yield). LC / MS (ESI) m / z: 196 [M+H] + .

[0636] Step 2: ((2R,6S)-4-(4-methoxybenzyl)-6-methylmorpholin-2-yl)methanol

[0637] Under nitrogen, to a solution of (S)-1-((4-methoxybenzyl)amino)propan-2-ol (8 g, 41.03 mmol) in toluene (60 mL) were added (S)-2-(chloromethyl)oxirane (3 g, 32.61 mmol) and lithium perchlorate (3.5 g, 32.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 18 hours. A 30% solution of sodium methoxide in methanol (25 mL) was added. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added, and the mixture was 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 afford the title compound as a yellow oil (1.8 g, 22.0% yield). LC / MS (ESI) m / z: 252 [M+H] + .

[0638] Step 3: tert-Butyl (2R,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate

[0639] 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 were added 10% palladium on carbon (90 mg), 10% palladium hydroxide on carbon (90 mg), and di-tert-butyl dicarbonate (1.17 g, 5.38 mmol). The reaction mixture was purged with nitrogen three times and stirred at 60°C under a 15 psi hydrogen atmosphere for 16 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / dichloromethane, gradient: 0-35% dichloromethane) to afford the title compound as a yellow oil (690 mg, 83.3% yield). LC / MS (ESI) (m / z): 232 [M+H] + .

[0640] Step 4: ((2R,6S)-6-Methylmorpholin-2-yl)methanol hydrochloride

[0641] To a solution of tert-butyl (2R,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (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 for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the title compound (yellow oil, 350 mg, 91.3% yield). LC / MS (ESI) m / z: 132 [M+H]+ .

[0642] 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

[0643] The title compound was obtained by referring 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] + .

[0644] 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

[0645] 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

[0646] 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 methanol (2 mL) at 0°C were added formaldehyde (8 mg, 0.26 mmol), acetic acid (10 mg, 0.17 mmol), and sodium cyanoborohydride (24 mg, 0.39 mmol). After the addition was complete, the reaction mixture was stirred at 0°C for 20 minutes. 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 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, 24% yield). 1 H NMR (400MHz, DMSO-d6) 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] +

[0647] 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

[0648] Step 1: 8-((3S,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0649] 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) at 0°C were added N,N-diisopropylethylamine (50 mg, 0.39 mmol), acetic acid (10 mg, 0.17 mmol), and HATU (74 mg, 0.19 mmol) in sequence. After the additions were complete, the reaction mixture was stirred at 50°C for 1 hour. After completion of the reaction, 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 yield the title compound (yellow solid, 14 mg, 19% yield). 1 H NMR(400MHz, DMSO-d6)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] + .

[0650] 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

[0651] Step 1: tert-Butyl (S)-(1-(Benzylamino)propan-2-yl)carbamate

[0652] Dissolve tert-butyl (S)-(1-oxopropan-2-yl)carbamate (5 g, 28.9 mmol) and benzylamine (3.7 g, 34.7 mmol) in methanol (50 mL). Add sodium cyanoborohydride (5.5 g, 86.7 mmol) and acetic acid (0.327 g, 2.89 mmol) sequentially to the reaction mixture under ice-cooling, and stir at room temperature for 16 hours. After the reaction is complete, saturated ammonium chloride is added to quench the reaction mixture under ice-cooling. The mixture is extracted 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: 10-30% ethyl acetate) to yield the title compound (colorless oil, 5.5 g, 72.4% yield). LC / MS (ESI) m / z: 265 [M+H] + .

[0653] Step 2: tert-Butyl (S)-(1-(N-benzyl-2-chloroacetamido)propan-2-yl)carbamate

[0654] Mix tert-butyl (S)-(1-(benzylamino)propan-2-yl)carbamate (5.5 g, 20.8 mmol) with saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). Add 2-chloroacetyl chloride (4.7 g, 41.6 mmol) to the mixture under ice-water bath, and stir for 2 hours. The organic layer is separated, the aqueous phase is extracted with ethyl acetate, and the combined organic phases are 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: 10-30% ethyl acetate) to obtain the title compound (colorless oil, 5.4 g, 77.7% yield). LC / MS (ESI) m / z: 341 [M+H] + .

[0655] Step 3: (S)-tert-Butyl 4-benzyl-2-methyl-5-oxopiperazine-1-carboxylate

[0656] Mix tert-butyl (S)-(1-(N-benzyl-2-chloroacetamido)propan-2-yl)carbamate (5.4 g, 15.9 mmol) with tetrahydrofuran (50 mL) and N,N-dimethylformamide (50 mL). Add 60% by mass sodium hydride (1.6 g, 41.3 mmol) slowly in portions under ice-water cooling. After addition, warm the mixture to room temperature and stir for 2 hours. Pour the reaction mixture into an ice-water-cooled saturated aqueous ammonium chloride solution and extract with ethyl acetate. The organic phase is 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: 10-30% ethyl acetate) to yield the title compound (colorless oil, 2.4 g, 49.7% yield). LC / MS (ESI) m / z: 305 [M+H] + .

[0657] Step 4: tert-Butyl (2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylate

[0658] (S)-tert-Butyl 4-benzyl-2-methyl-5-oxopiperazine-1-carboxylate (1.0 g, 3.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Under a nitrogen atmosphere, a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (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 the addition, the reaction mixture was stirred at -78°C for 1 hour. 1N hydrochloric acid (4 mL) was added to the reaction mixture at -20°C, 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: 10-30% ethyl acetate) to obtain the title compound (colorless oil, 800 mg, 77.7% yield). LC / MS(ESI)m / z:425[M+H] + .

[0659] Step 5: tert-Butyl (2R,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methylpiperazine-1-carboxylate

[0660] Tert-butyl (2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylate (800 mg, 1.9 mmol) was dissolved in tetrahydrofuran (10 mL). A 1 M borane / tetrahydrofuran solution (9.5 mL, 9.5 mmol) was added dropwise to the mixture at 0°C. After addition, the temperature was raised to 60°C and the reaction was stirred for 6 hours. The reaction mixture was quenched by the addition of methanol (~10 mL) at 0°C and stirred at 60°C 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 afford the title compound as a colorless oil (450 mg, 57.8% yield). LC / MS (ESI) m / z: 411 [M+H] + .

[0661] Step 6: tert-Butyl (2R,6S)-2-(hydroxymethyl)-6-methylpiperazine-1-carboxylate

[0662] In an autoclave, 20% mass fraction of palladium hydroxide on carbon (50 mg) was added to a solution of tert-butyl (2R,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methylpiperazine-1-carboxylate (200 mg, 488 mmol) in methanol (5 mL). The reaction solution was replaced with hydrogen three times and stirred at room temperature under a 1 MPa hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (white solid, 90 mg, 80.4% yield). LC / MS (ESI) (m / z): 231 [M+H] + .

[0663] 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-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0664] The title compound was obtained by referring to the preparation method of Example 23, Steps 3-4. 1 H NMR (400MHz, CD3OD) δ9.91(d,J=1.1Hz,1H),7.35(t,J=53.5Hz,1H),6.95(d,J=1.1Hz,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=4.8Hz,3H).LC / MS(ESI)(m / z):564[M+H]+ .

[0665] 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

[0666] Step 1: (2S,6S)-4-benzyl-2-(methoxymethyl)-6-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester

[0667] To a solution of (S)-tert-butyl 4-benzyl-2-methyl-5-oxopiperazine-1-carboxylate (500 mg, 1.64 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2 mL, 1.97 mmol) at -78°C. The reaction mixture was stirred at -78°C for 1 hour, and then chloromethyl methyl ether (328 mg, 4.10 mmol) was added dropwise and the reaction was continued with stirring for 1 hour. After the reaction was complete, 1N hydrochloric acid (2 mL) was added at -20°C, 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: 10-30% ethyl acetate) to afford the title compound as a colorless oil (200 mg, 34.8% yield). LC / MS (ESI) m / z: 349 [M+H] + .

[0668] Step 2: tert-Butyl (2R,6S)-4-benzyl-2-(methoxymethyl)-6-methylpiperazine-1-carboxylate

[0669] To a solution of tert-butyl (2S,6S)-4-benzyl-2-(methoxymethyl)-6-methyl-3-oxopiperazine-1-carboxylate (200 mg, 0.57 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise a 1.0 M borane / tetrahydrofuran solution (2.9 mL, 2.85 mmol) at 0°C. The reaction mixture was stirred at 60°C for 6 hours. After completion of the reaction, the reaction mixture was quenched by the addition of methanol (~5 mL) at 0°C, then heated to 60°C 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 afford the title compound as a colorless oil (120 mg, 62.8% yield). LC / MS (ESI) m / z: 335 [M+H] + .

[0670] Step 3: tert-Butyl (2R,6S)-2-(methoxymethyl)-6-methylpiperazine-1-carboxylate

[0671] To a solution of tert-butyl (2R,6S)-4-benzyl-2-(methoxymethyl)-6-methylpiperazine-1-carboxylate (120 mg, 0.36 mmol) in methanol (2 mL) was added 10% palladium hydroxide on carbon (10 mg) at room temperature. The reaction solution was purged three times under nitrogen and stirred at room temperature under a hydrogen balloon for 1 hour. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford the crude title compound (colorless oil, 85 mg, 96.9% yield), which was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) 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] + .

[0672] 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-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0673] The title compound was obtained by referring to the preparation method of Example 23, Steps 3-4. 1 H NMR (400MHz, CD3OD) δ9.90 (d, J = 1.7Hz, 1H), 7.34 (t, J = 53.5Hz, 1H), 6.92 (s, 1H), 4.83-4.79 (m, 2H), 4.34 (d, J = 5.9Hz, 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),3.21-3.1 3(m,2H),1.65(s,3H),1.49(d,J=3.7Hz,3H).LC / MS(ESI)(m / z):578[M+H] + .

[0674] 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

[0675] The title compound was obtained by referring to the preparation method of Example 29. 1 H NMR (400MHz, CD3OD) 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] + .

[0676] 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

[0677] 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

[0678] To a solution of 3-methyloxetane-3-amine (0.017 mL, 0.388 mmol) in pyridine (3 mL) was added dropwise 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) at 0°C. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, water was added, the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50%) to afford the title compound (yellow solid, 80 mg, 80.14% yield). LC / MS (ESI) (m / z): 514 / 516 [M+H] + .

[0679] 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

[0680] 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)imidazol[1,5]-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] + .

[0681] Step 3: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0682] 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) and 2-methyl-1-(piperazin-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 G3 (7 mg, 0.008 mmol). The reaction solution was purged with nitrogen three times and stirred at 80°C under nitrogen for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (yellow oil, 5 mg, 11.23% yield). 1H 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] + .

[0683] The following examples are prepared with reference to the preparation method of Example 43, starting from appropriate starting materials, and synthesizing the target compounds according to similar routes.

[0684] 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

[0685] 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

[0686] To a 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) in DMF (2 mL) was added portionwise DIEA (120 mg, 0.85 mmol) and SEMCl (40 mg, 0.34 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-100% ethyl acetate) to afford the title compound (yellow solid, 70 mg, 68% yield). LC / MS (ESI) (m / z): 600 [M+H] + .

[0687] 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

[0688] Under nitrogen protection, 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) were added cesium carbonate (100 mg, 0.36 mmol), Ruphos (10 mg, 0.02 mmol), and Ruphos Pd G3 (10 mg, 0.01 mmol) in sequence. The reaction mixture was purged with nitrogen three times and stirred at 90°C under nitrogen protection for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and 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: 0-70% ethyl acetate) to yield the title compound (yellow solid, 40 mg, 45% yield). LC / MS (ESI) m / z: 734 [M+H] + .

[0689] Step 3: (R)-1-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0690] To a solution of (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 (40 mg, 0.05 mmol) in dichloromethane (1 mL) was slowly added dropwise trifluoroacetic acid (0.5 mL) at 0°C. The reaction mixture was stirred at 30°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to yield the title compound (yellow solid, 11 mg, 36% yield).

[0691] 1H NMR (400MHz, DMSO-d6) 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,3 H),1.40-1.23(m,3H),1.04(d,J=6.8Hz,6H).LC / MS(ESI)m / z:604[M+H] + .

[0692] The following examples are prepared with reference to the preparation method of Example 49. Starting from appropriate starting materials, the crude product was synthesized according to a similar route. The crude product was prepared by reverse phase HPLC and freeze-dried to obtain the title compound.

[0693] 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

[0694] Step 1: 1-Bromo-8-chloro-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride

[0695] To a solution of 2-(6-(benzylthio)-1-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (300 mg, 0.59 mmol) in acetonitrile (8 mL) was added dilute hydrochloric acid (4 mL, 0.5 N) at 0°C. Dichlorohydantoin (351 mg, 1.78 mmol) was then added. The reaction mixture 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 yield the title compound as a yellow solid, 230 mg. This was used directly in the next step without purification.

[0696] 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

[0697] To a solution of 3-methyloxetane-3-amine (83 mg, 0.95 mmol) in DCM (2 mL) and TFA (145 mg, 1.43 mmol) at 0°C was added portionwise a solution of 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). The reaction mixture was stirred at room temperature for 30 minutes and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-40% ethyl acetate) to afford the title compound (yellow solid, 180 mg, 71% yield). LC / MS (ESI) (m / z): 532 [M+H] + .

[0698] 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

[0699] To a solution of 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 (180 mg, 0.34 mmol) in N,N-dimethylformamide (3 mL) at 0°C were added N,N-diisopropylethylamine (131 mg, 1.01 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (85 mg, 0.51 mmol) in sequence. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, 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: 0-15% ethyl acetate) to afford the title compound as a yellow solid, 200 mg, 89% yield. LC / MS (ESI) (m / z): 662 [M+H] + .

[0700] 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

[0701] Under nitrogen, 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 purged with nitrogen three times and stirred at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was isolated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to afford the title compound as a yellow solid (100 mg, 57% yield). LC / MS (ESI) (m / z): 584 [M+H] + .

[0702] 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

[0703] 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 (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) were added cesium carbonate (167 mg, 0.51 mmol), RuPhos (8 mg, 0.02 mmol), and RuPhos Pd G3 (15 mg, 0.02 mmol) in sequence. The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen protection for 10 hours. After the reaction was complete, the mixture 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, 81% yield). LC / MS (ESI) (m / z): 718 [M+H] + .

[0704] Step 6: (R)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide

[0705] To a solution of (R)-8-(4-isobutyryl-3-methylpiperazin-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) at 0°C was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction mixture was added dropwise to an ice-cooled 5% aqueous sodium bicarbonate 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 H2O 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] + .

[0706] The following examples are prepared with reference to the preparation method of Example 62. Starting from appropriate starting materials, the crude product was synthesized along a similar route. The crude product was prepared by reverse phase HPLC and freeze-dried to obtain the title compound.

[0707] 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

[0708] Step 1: 8-Bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride

[0709] 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) at 0°C were added 1N hydrochloric acid (1 mL), water (1 mL), and dichlorohydantoin (887 mg, 4.50 mmol) in sequence. The reaction mixture was stirred in an ice bath for 10 minutes. After the reaction was complete, water was added and the mixture 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 slurrying with petroleum ether to obtain the title compound (yellow solid, 640 mg, 99.3% yield). LC / MS (ESI) (m / z): 428 [M+H] + .

[0710] Step 2: 8-Bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)imidazo[1,2-a]pyridine-6-sulfonamide

[0711] To a solution of 3-methyloxetane-3-amine (260 mg, 1.50 mmol) in anhydrous dichloromethane (4 mL) and pyridine (1 mL) at 0°C was added 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (640 mg, 3 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water was added and the mixture 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 / dichloromethane, gradient: 0-35% dichloromethane) to give the title compound (yellow solid, 600 mg, 83.9% yield). LC / MS (ESI) (m / z): 479 [M+H] + .

[0712] Step 3: 8-Bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2-a]pyridine-6-sulfonamide

[0713] To a solution of 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-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 under nitrogen for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The mixture 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: 0-35% ethyl acetate) to afford the title compound as a yellow solid, 350 mg, 45.9% yield. 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

[0714] Under nitrogen protection, to a solution of 8-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-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) were added cesium carbonate (128 mg, 0.39 mmol), Ruphos (12.2 mg, 0.026 mmol), and Ruphos Pd G3 (21.9 mg, 0.026 mmol) in sequence. The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen protection for 4 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate, washed sequentially with water and 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: 0-40% ethyl acetate) to yield the title compound (yellow solid, 40 mg, 59.4% yield). LC / MS (ESI) (m / z): 744 [M+H] + .

[0715] Step 5: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,2-a]pyridine-6-sulfonamide

[0716] To a solution of (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 (40 mg, 0.05 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.6 mL) at 80°C. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was made alkaline with sodium bicarbonate, extracted with dichloromethane, washed with saturated brine, dried, concentrated, and isolated by preparative HPLC (C18, 10-50% acetonitrile in H2O and 0.1% FA) to afford the title compound as a yellow solid (6.87 mg, 24.9% yield). 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] + .

[0717] The following examples are prepared with reference to the preparation method of Example 75. Starting from appropriate starting materials, the crude product is synthesized according to a similar route. The crude product is prepared by reverse phase HPLC and freeze-dried to obtain the title compound.

[0718] Effect embodiment

[0719] Experimental methods:

[0720] 1. Biochemical Assay

[0721] 1) Add 20 nL of compound at different concentrations to a 384-well plate using Echo 550 (LABCYTE, #550) (final compound concentrations: 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);

[0722] 2) Prepare reaction buffer I: 50 mM 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), 5 mM KCl, 66.2 μM TFMU-ADPr (fluorescein-4-trifluoromethylumbelliferyl-ADP ribose);

[0723] 3) Add reaction buffer I at 10 μL / well to a 384-well plate;

[0724] 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);

[0725] 5) Add 10 μL / well of reaction buffer II to the 384-well plate to start the reaction;

[0726] 6) Incubate at room temperature for 3 minutes to react;

[0727] 7) Place the 384-well plate in a microplate reader and shake for 5 seconds before detecting the signal.

[0728] 8) Analyze the data using GraphPad software and determine the IC50.

[0729] 2. Cell Viability Assay

[0730] 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, 5% CO2 incubator and incubated for 24 h to allow the cells to fully adhere.

[0731] 2) Culture medium (100 μL / well) containing different concentrations of the test compound (final concentrations of the compound: 30,000 nM, 10,000 nM, 3,000 nM, 1,000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0 nM) was added to the cells and incubated in a 37°C CO2 (5%) incubator for 7 days;

[0732] 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;

[0733] 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;

[0734] 5) Incubate the plate at room temperature for 10 minutes to allow the signal to stabilize, then use a microplate reader (Thermo: Varioskan LUX) to detect and record the luminescence value;

[0735] 6) Analyze the data using GraphPad software and determine the IC 50 .

[0736] Data list:

[0737] NT = not tested;

[0738] 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 in inhibiting the proliferation of the two cell types.

Claims

1. 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 are independently cyano, deuterium, hydroxyl, amino, halogen, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-3-2 Substituted C1-C6 alkoxy or C2-C6 alkynyl; each R 1-3-1 are independently halogen; each R 1-3-2 are independently halogen; Each R 2-3 are independently cyano, oxo, hydroxyl, halogen, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-4 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-5 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-6 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-7 Substituted amino groups, unsubstituted or substituted with one or more R 2-3-9 substituted 5-10 membered heteroaryl; 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 are independently hydroxy, cyano, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 2-3-1-3 Substituted amino groups; R 2-3-2 is hydrogen, unsubstituted or replaced by one or more R 2-3-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2 Pick Substituted C3-C6 cycloalkyl, unsubstituted or substituted with one or more R 2-3-2-4 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-5 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-2-6 substituted 5-10 membered heteroaryl; 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 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-4 are independently C1-C6 alkyl or oxo; Each R 2-3-5 are independently halogen or deuterium; Each R 2-3-6 are independently C1-C6 alkyl; Each R 2-3-7 are independently C1-C6 alkyl; Each R 2-3-8 are independently C1-C6 alkyl or C3-C6 cycloalkyl; Each R 2-3-9 are independently C1-C6 alkyl; Each R 2-3-1-1 are independently halogen or deuterium; Each R 2-3-1-2 are independently C1-C6 alkoxy; Each R 2-3-1-3 are independently C1-C6 alkyl; Each R 2-3-2-1 are independently halogen, carboxyl, hydroxyl, oxo, C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-3-2-1-2 Substituted amino, unsubstituted or replaced by one or more R 2-3-2-1-3 Substituted 5-10 membered heteroaryl; 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 are independently C1-C6 alkyl or 6-10 membered aryl; Each R 2-3-2-1-2 are independently C1-C6 alkyl; Each R 2-3-2-1-3 are independently C1-C6 alkyl; Each R 2-3-2-2 are independently halogen, hydroxy, unsubstituted or substituted with one or more R 2-3-2-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-2-3 Substituted amino groups; Each R 2-3-2-2-1 are independently halogen or hydroxy; Each R 2-3-2-2-2 are independently carboxyl, halogen, deuterium, oxo or hydroxy; Each R 2-3-2-2-3 are independently C1-C6 alkyl; Each R 2-3-2-3 are independently hydrogen or Each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1- 1 Substituted 6-10 membered aryl; each R 2-3-2-3-1-1 are independently C1-C6 alkoxy; Each R 2-3-2-4 are independently halogen; Each R 2-3-2-5 are independently halogen, hydroxy, oxo, C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-3-2-5-1 Substituted C1-C6 alkyl; each R 2-3-2-5-1 are independently halogen; Each R 2-3-2-6 are independently C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino group; each R 2-3-3-1-1 are independently C1-C6 alkyl; Each R 3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 3-1-1 Substituted C1-C6 alkyl or Each R 3-1-1 are independently halogen or hydroxy; R 3-1-2 is C1-C6 alkyl or C2-C6 alkenyl; R 4 is hydrogen, deuterium, halogen, cyano, unsubstituted or replaced by one or more R 4-1 substituted 5-10 membered heterocycloalkyl or unsubstituted or with one or more R 4-2 Substituted C1-C6 alkyl; 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 Independently Each R 4-2 are independently unsubstituted or substituted with one or more R 4-2-1 Substituted 5-10 membered heteroaryl; 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; R 4-1-1 is a C1-C6 alkyl group; each R 4-1-2 are independently C1-C6 alkyl; each R 4-2-1 are independently C1-C6 alkyl.

2. The compound of formula IV according to claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound shown in formula IV is 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 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, V 1 CH or N; V 2 CH, N or O; V 1 and V 2 Not at the same time CH; 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; V 1 CH or N; V 2 CH, N or O; V 1 and V 2 Not at the same time CH; 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 CH2, 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 For 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 ; V 1 CH or N; V 2 CH or N; V 1 and V 2 Not at the same time CH; 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.

3. The compound of formula IV as claimed in claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound as shown in formula IV satisfies one or more of the following conditions: (1) Each R 1-3 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (2) Each R 1-3 In the above, the C1-C6 alkyl group is a C1-C4 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 be a methyl group; (3) Each R 1-3 In the above, the C1-C6 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) Each R 1-3 In the above, the C2-C6 alkynyl group is For example (5) Each R 1-3-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (6) Each R 1-3-2 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (7) Each R 2-3 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (8) Each R 2-3 In the above, the C1-C6 alkyl group is a C1-C4 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 pri-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group, an isopropyl group or a tert-butyl group; (9) Each R 2-3 In the above, the heteroatom of the 3-6 membered heterocycloalkyl is N, O or S, and the number of heteroatoms can be 1 or 2; the heteroatom of the 3-6 membered heterocycloalkyl can also be O or N, and the number of heteroatoms can also be 1; for example (10) Each R 2-3 In the above, the C1-C6 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) Each R 2-3 wherein the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (12) Each R 2-3 In the above, 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) Each R 2-3-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (14) Each R 2-3-1 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy or ethoxy; (15) Each R 2-3-1 wherein the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (16)R 2-3-2 wherein the C1-C6 alkyl group is a C1-C4 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, Butyl, primary butyl, secondary butyl or tert-butyl, and may also be methyl, ethyl, isopropyl or tert-butyl; (17)R 2-3-2 wherein the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl or cyclobutyl; (18)R 2-3-2 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, for example, isopropoxy; (19)R 2-3-2 In the above, the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms may be 1 or 2; for example (20)R 2-3-2 wherein the 5-10 membered heteroaryl is a 5- or 6-membered heteroaryl or a 5- and 6-membered heteroaryl; the heteroatom of the 5-10 membered heteroaryl is N and / or O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-membered heteroaryl may be N and / or O, and the number of heteroatoms is 2; the heteroatom of the 6-membered heteroaryl may be N, and the number of heteroatoms is 1; the heteroatom of the 5- and 6-membered heteroaryl may be O, and the number of heteroatoms is 2; (21) Each R 2-3-3 wherein the C1-C6 alkyl group is a C1-C4 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 pri-butyl group, a sec-butyl group or a tert-butyl group, such as a methyl group or an ethyl group; (22) Each R 2-3-4 In the above, the C1-C6 alkyl group is a C1-C4 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, or an isopropyl group; (23) Each R 2-3-5 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (24) Each R 2-3-6 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (25) Each R 2-3-7 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (26) Each R 2-3-8 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group or an isopropyl group; (27) Each R 2-3-8 wherein the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (28) Each R 2-3-9 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (29) Each R 2-3-1-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (30) Each R 2-3-1-2 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy; (31) Each R 2-3-1-3 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (32) Each R 2-3-2-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (33) Each R 2-3-2-1 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy; (34) Each R 2-3-2-1 In the above, 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) Each R 2-3-2-1-1 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (36) Each R 2-3-2-1-1 wherein the 6-10 membered aryl group is phenyl or naphthyl, for example phenyl; (37) Each R 2-3-2-1-2 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (38) Each R 2-3-2-1-3 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (39) Each R 2-3-2-2 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (40) Each R 2-3-2-2 In the above, the C1-C6 alkyl group is a C1-C4 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 pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group; (41) Each R 2-3-2-2 In the above, the C1-C6 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) Each R 2-3-2-2-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (43) Each R 2-3-2-2-2 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (44) Each R 2-3-2-2-3 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (45) Each R 2-3-2-3-1 wherein the 6-10 membered aryl group is phenyl or naphthyl, for example phenyl; (46) Each R 2-3-2-3-1-1 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy; (47) Each R 2-3-2-4 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (48) Each R 2-3-2-5 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (49) Each R 2-3-2-5 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, such as methoxy; (50) Each R 2-3-2-5 wherein the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group, an ethyl group, an n-propyl group or an isopropyl group; (51) Each R 2-3-2-5-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (52) Each R 2-3-2-6 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (53) Each R 2-3-3-1-1 wherein the C1-C6 alkyl group is a C1-C4 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, for example, a methyl group; (54) Each R 3-1 In the embodiment, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, butyl, isobutyl, primary butyl, secondary butyl or tert-butyl, and may also be methyl; (55) Each R 3-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine; (56) Each R 3-1-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine; (57)R 3-1-2 In the above, the C1-C6 alkyl group may be a C1-C4 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; (58)R 3-1-2 In the above, the C2-C6 alkenyl group may be For example (59)R 4 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; (60)R 4 wherein 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)R 4 In the above, the C1-C6 alkyl group may be a C1-C4 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; (62) Each R 4-2 wherein 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)R 4-1-1 In the above, the C1-C6 alkyl group is a C1-C4 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, or a methyl group or an isopropyl group; (64) Each R 4-1-2 wherein the C1-C6 alkyl group is a C1-C4 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 priming-butyl group, a sec-butyl group or a tert-butyl group, and may be a methyl group; and (65) Each R 4-2-1 In the above, the C1-C6 alkyl group is a C1-C4 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 prim-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group.

4. The compound of formula IV as claimed in claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound as shown in formula IV satisfies one or more of the following conditions: (1) Each R 1-3 are independently cyano, deuterium, hydroxyl, amino, halogen, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-3-2 Substituted C1-C6 alkoxy or C2-C6 alkynyl; (2) Each R 1-3-1 are independently halogen; (3) Each R 1-3-2 are independently halogen; (4) Each R 2-3-1 is independently cyano, unsubstituted or substituted with one or more R 2-3-1-2 Substituted C3-C6 cycloalkyl; (5)R 2-3-2 is hydrogen or, is replaced by one or more R 2-3-2-1 Substituted C1-C6 alkyl, one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl, unsubstituted or substituted with one or more R 2-3-2-5 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-2-6 substituted 5-10 membered heteroaryl; the heteroatom of the 3-6 membered heterocycloalkyl is selected from one or more of N, O and S, 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 are independently C1-C6 alkyl; (7) Each R 2-3-7 are independently C1-C6 alkyl; (8) Each R 2-3-9 are independently oxo or C1-C6 alkyl; (9) Each R 2-3-1-2 are independently C1-C6 alkoxy; each R 2-3-2-1 are independently hydroxy, oxo, unsubstituted or substituted with one or more R 2-3-2-1-3 Substituted 5-10 membered heteroaryl; 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; (10) Each R 2-3-2-1-1 are independently C1-C6 alkyl or 6-10 membered aryl; each R 2-3-2-1-2 are independently C1-C6 alkyl; each R 2-3-2-1-3 are independently C1-C6 alkyl; (11) Each R 2-3-2-2 are independently halogen, hydroxy, unsubstituted or substituted with one or more R 2-3-2-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-2-3 Substituted amino groups; (12) Each R 2-3-2-2-1 are independently halogen or hydroxy; (13) Each R 2-3-2-2-2 are independently halogen, deuterium, oxo or hydroxy; (14) Each R 2-3-2-2-3 are independently C1-C6 alkyl; (15) Each R 2-3-2-3 are independently hydrogen or (16) Each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1-1 Substituted 6-10 membered aryl; each R 2-3-2-3-1- 1 are independently C1-C6 alkoxy; (17) Each R 2-3-2-4 are independently halogen; (18) Each R 2-3-2-5 are independently halogen, hydroxy, oxo, C1-C6 alkoxy, 2-3-2-5-1 Substituted C1-C6 alkyl; each R 2-3-2-5-1 are independently halogen; (19) Each R 2-3-2-6 are independently C1-C6 alkyl; (20) Each R 3-1 are independently hydroxy, halogen, 3-1-1 Substituted C1-C6 alkyl or (21) Each R 3-1-1 are independently hydroxyl groups; R 3-1-2 is C1-C6 alkyl or C2-C6 alkenyl; (22)R 4 is deuterium, cyano, unsubstituted or replaced by one or more R 4-1 substituted 5-10 membered heterocycloalkyl, or one or more R 4- 2 Substituted C1-C6 alkyl; 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; (23) Each R 4-1 Independently (24) Each R 4-2 are independently unsubstituted or substituted with one or more R 4-2-1 Substituted 5-10 membered heteroaryl; 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; (25)R 4-1-1 is a C1-C6 alkyl group; (26) Each R 4-1-2 are independently C1-C6 alkyl; (27) Each R 4-2-1 are independently C1-C6 alkyl; Preferably, the compound as shown in Formula IV satisfies one or more of the following conditions: (1) Each R 1-3 are independently cyano, deuterium, hydroxyl, amino, halogen, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-3-2 Substituted C1-C6 alkoxy or C2-C6 alkynyl; each R 1-3-1 are independently halogen; each R 1-3-2 are independently halogen; (2) m is 1 or 2; (3) Each R 2-3 Independently for one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-4 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-3-7 Substituted amino, unsubstituted or replaced by one or more R 2-3-9 substituted 5-10 membered heteroaryl; 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, unsubstituted or substituted with one or more R 2-3-1-2 Substituted C3-C6 cycloalkyl; R 2-3-2 is hydrogen or, is replaced by one or more R 2-3-2-1 Substituted C1-C6 alkyl, one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl, unsubstituted or substituted with one or more R 2-3-2-5 substituted 3-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2- 3-2-6 substituted 5-10 membered heteroaryl; 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 are independently C1-C6 alkyl; Each R 2-3-7 are independently C1-C6 alkyl; Each R 2-3-9 are independently oxo or C1-C6 alkyl; Each R 2-3-1-2 are independently C1-C6 alkoxy; each R 2-3-2-1 are independently hydroxy, oxo, unsubstituted or substituted with one or more R 2-3-2-1-3 Substituted 5-10 membered heteroaryl; 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 are independently C1-C6 alkyl or 6-10 membered aryl; each R 2-3-2-1-2 are independently C1-C6 alkyl; each R 2-3-2- 1-3 are independently C1-C6 alkyl; Each R 2-3-2-2 are independently halogen, hydroxy, unsubstituted or substituted with one or more R 2-3-2-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-2-2-3 Substituted amino groups; Each R 2-3-2-2-1 are independently halogen or hydroxy; Each R 2-3-2-2-2 are independently halogen, deuterium, oxo or hydroxy; Each R 2-3-2-2-3 are independently C1-C6 alkyl; Each R 2-3-2-3 are independently hydrogen or Each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1- 1 Substituted 6-10 membered aryl; each R 2-3-2-3-1-1 are independently C1-C6 alkoxy; Each R 2-3-2-4 are independently halogen; Each R 2-3-2-5 are independently halogen, hydroxy, oxo, C1-C6 alkoxy, 2-3-2-5-1 Substituted C1-C6 alkyl; each R 2-3-2-5-1 are independently halogen; Each R 2-3-2-6 are independently C1-C6 alkyl; (4) Each R 3-1 are independently hydroxy, halogen, 3-1-1 Substituted C1-C6 alkyl or Each R 3-1-1 are independently hydroxyl groups; R 3-1-2 is C1-C6 alkyl or C2-C6 alkenyl; (5)R 4 is deuterium, cyano, unsubstituted or replaced by one or more R 4-1 substituted 5-10 membered heterocycloalkyl, or one or more R 4-2 Substituted C1-C6 alkyl; 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 Independently Each R 4-2 are independently unsubstituted or substituted with one or more R 4-2-1 Substituted 5-10 membered heteroaryl; 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; R 4-1-1 is a C1-C6 alkyl group; each R 4-1-2 are independently C1-C6 alkyl; each R 4-2-1 are independently C1-C6 alkyl.

5. The compound of formula IV as claimed in claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound as shown in formula IV satisfies one or more of the following conditions: (1) Each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, C2-C6 alkynyl; (2) Each R 1-3-1 are independently halogen or deuterium; preferably, each R 1-3-1 are independently halogen; (3) Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Preferably, each R 2-3 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 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 substituted amino; preferably, each R 2-3-1 are independently hydroxyl, unsubstituted or substituted with one or more R 2- 3-1-1 Substituted C1-C6 alkoxy; (5) Each R 2-3-1-1 independently for deuterium; (6) Each R 2-3-1-3 are independently C1-C6 alkyl; (7)R 2-3-2 For one or more R 2-3-2-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl, unsubstituted or substituted with one or more R 2-3-2-5 substituted 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl; 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 C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; (8) Each R 2-3-2-1 are independently hydroxyl groups, (9) Each R 2-3-2-1-1 are independently C1-C6 alkyl; (10) Each R 2-3-2-2 are independently halogen, hydroxy, C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy, amino; preferably, each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; (11) Each R 2-3-2-2-2 independently for deuterium; (12) Each R 2-3-2-3 are independently hydrogen or (13) Each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1-1 substituted 6-10 membered aryl; preferably, each R 2-3-2-3-1 are independently unsubstituted or substituted with one or more R 2-3-2-3-1-1 Substituted 6-10 membered aryl, each R 2-3-2-3-1-1 are independently C1-C6 alkoxy; (14) Each R 2-3-2-3-1-1 are independently C1-C6 alkoxy; (15) Each R 2-3-2-5 are independently halogen, C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-3-2-5-1 Substituted C1-C6 alkyl; (16) Each R 2-3-2-5-1 are independently halogen; (17) Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; (18) Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; (19) Each R 2-3-3-1-1 are independently C1-C6 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 -CF3; (21) Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; (22) Each R 3-1-1 are independently halogen; (23)R 4 is deuterium, cyano, unsubstituted or replaced by one or more R 4-1 substituted 5-10 membered heterocycloalkyl; 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 or 2; preferably, R 4 Hydrogen, deuterium, halogen halogen, C1-C6 alkyl; and (24) Each R 4-1 Independently R 4-1-1 It is a C1-C6 alkyl group.

6. The compound of formula IV according to claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound shown in Formula IV is Scheme 1 or Scheme 2: Solution 1: Each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, C2-C6 alkynyl; Each R 1-3-1 independently halogen, deuterium; Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 Substituted amino groups; Each R 2-3-1-1 independently for deuterium; Each R 2-3-1-3 are independently C1-C6 alkyl; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl; Solution 2 Each R 1-3 is independently cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl, C2-C6 alkynyl; Each R 1-3-1 are independently halogen; Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Each R 2-3-1 are independently hydroxyl, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy; Each R 2-3-1-1 independently for deuterium; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

7. The compound of formula IV according to claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound as shown in 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 substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; preferably, each R 1- 3 are independently unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; (4) Each R 1-3-1 are 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 are independently oxo, hydroxy, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-6 substituted C3-C6 cycloalkyl; preferably, each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl; more preferably, each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, (7) Each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 substituted amino; preferably, each R 2-3-1 are independently hydroxyl, unsubstituted or substituted with one or more R 2- 3-1-1 Substituted C1-C6 alkoxy; (8)R 2-3-2 is unsubstituted C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; (9) Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; (10) Each R 2-3-6 are independently C1-C6 alkyl; (11) Each R 2-3-1-1 are independently halogen or deuterium; preferably, each R 2-3-1-1 is independently halogen, or, each R 2-3-1-1 independently for deuterium; (12) Each R 2-3-1-3 are independently C1-C6 alkyl; (13) Each R 2-3-2-2 are independently unsubstituted C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; (14) Each R 2-3-2-2-2 independently for deuterium; (15) Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; (16) Each R 2-3-3-1-1 are independently C1-C6 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 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; (19) Each R 3-1-1 are independently halogen or hydroxy; (20)W is N, CH or CR 4 ;and (21)R 4 It is deuterium, halogen, or unsubstituted C1-C6 alkyl.

8. The compound of formula IV as claimed in claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound shown in 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 substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; Each R 1-3-1 are independently halogen; Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 Substituted amino groups; Each R 2-3-1-1 independently for deuterium; Each R 2-3-1-3 are independently C1-C6 alkyl; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl; Scheme 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’ For R 1-3 ; R 1-3 is cyano, unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; Each R 1-3-1 are 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 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Each R 2-3-1 are independently hydroxy, halogen, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 2-3-1-3 Substituted amino groups; Each R 2-3-1-1 independently for deuterium; Each R 2-3-1-3 are independently C1-C6 alkyl; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; k is 1; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl; Solution 4: Each R 1-3 are independently unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; Each R 1-3-1 are independently halogen; Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Unsubstituted C3-C6 cycloalkyl; Each R 2-3-1 are independently hydroxyl, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy; Each R 2-3-1-1 independently for deuterium; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl; Scheme 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’ For R 1-3 ; R 1-3 is unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; Each R 1-3-1 are 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 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Unsubstituted C3-C6 cycloalkyl; Each R 2-3-1 are independently hydroxyl, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy; Each R 2-3-1-1 independently for deuterium; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; k is 1; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl; Solution 5: Each R 1-3 are independently unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; Each R 1-3-1 are independently halogen; Each R 2-3 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Each R 2-3-1 are independently hydroxyl, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy; Each R 2-3-1-1 independently for deuterium; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 is hydrogen, deuterium, halogen, C1-C6 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’ For R 1-3 ; R 1-3 is unsubstituted or substituted with one or more R 1-3-1 Substituted C1-C6 alkyl; Each R 1-3-1 are 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 are independently oxo, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, Each R 2-3-1 are independently hydroxyl, unsubstituted or substituted with one or more R 2-3-1-1 Substituted C1-C6 alkoxy; Each R 2-3-1-1 independently for deuterium; R 2-3-2 is C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2 Substituted C3-C6 cycloalkyl; Each R 2-3-2-2 are independently C1-C6 alkyl, unsubstituted or substituted with one or more R 2-3-2-2-2 Substituted C1-C6 alkoxy; Each R 2-3-2-2-2 independently for deuterium; Each R 2-3-3 are independently hydrogen, unsubstituted or substituted with one or more R 2-3-3-1 Substituted C1-C6 alkyl; Each R 2-3-3-1 are independently unsubstituted or substituted with one or more R 2-3-3-1-1 Substituted amino groups; Each R 2-3-3-1-1 are independently C1-C6 alkyl; Ring A is a 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N and / or S, and the number of heteroatoms is 3; k is 1; Each R 3-1 Independently for one or more R 3-1-1 Substituted C1-C6 alkyl; Each R 3-1-1 are independently halogen; R 4 It is hydrogen, deuterium, halogen, or C1-C6 alkyl.

9. The compound of formula IV according to claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound as shown in 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)R 4 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 Hydroxyl, oxo, methyl, -CF3, (11) Ring A is Preferably, for (12) k is 1; and (13)R 3-1 -CHF2, -CF3, 10. The compound of formula IV according to claim 1, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound shown in formula IV is any of the following compounds:

11. Any one of the compounds shown below, or a pharmaceutically acceptable salt or isotope compound thereof; 12. A pharmaceutical composition comprising a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound of 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.

13. 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.

14. 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; the breast cancer may be triple-negative breast cancer.

Images