Macrocyclic compounds containing pyrrolidinone structures

Abstract

Belonging to the field of medicinal chemistry, it relates to macrocyclic compounds containing pyrrolidone structures, specifically compounds of formula I, their stereoisomers or pharmaceutically acceptable salts thereof, their preparation methods, or pharmaceutical compositions thereof, and their use in the preparation of remedies for the treatment or prevention of tumor-related diseases.

Description

Macrocyclic compounds containing pyrrolidone structure

[0001] Citation of Related Applications

[0002] This application claims the benefit of the Chinese invention patent application No. 202311622442.5 filed with the Intellectual Property Office of the People's Republic of China on November 29, 2023, the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0003] The present disclosure belongs to the field of pharmaceutical chemistry and provides a macrocyclic compound containing a pyrrolidone structure, its stereoisomers or pharmaceutically acceptable salts, a preparation method thereof, or a pharmaceutical composition thereof, and use thereof in preparing a drug for treating or preventing tumor-related diseases.

[0004] Background of the Invention

[0005] Robust repair of DNA double-strand breaks (DSBs) is crucial for maintaining genomic stability and cell viability. DSBs can be repaired via one of three major pathways: homologous recombination (HR), nonhomologous end joining (NHEJ), and alternative NHEJ (alt-NHEJ). Microhomology-mediated end joining (MMEJ) is the most well-characterized alt-NHEJ mechanism. MMEJ can function simultaneously with both the HR and NHEJ pathways.

[0006] Unlike normal cells, cancer cells often rely on misregulation of the DNA damage response (DDR) pathway for survival. Aberrant DDR can also sensitize cancer cells to specific types of DNA damage, so defective DDR can be exploited to develop targeted cancer therapies. Crucially, cancer cells with impaired or inactivated HR and NHEJ become hyperdependent on MMEJ-mediated DNA repair.

[0007] PolQ (UniProtKB-075417 (DPOLQ_HUMAN, or Polθ) is a key protein in MMEJ. Therapeutic inactivation of PolQ would disable the cell's ability to execute MMEJ and provide new targeting strategies in a range of defined tumor settings. First, PolQ has been shown to be essential for the survival of HR-deficient (HRD) cells and is upregulated in HRD tumor cell lines. PolQ is largely inhibited in normal tissues but has been shown to be upregulated in matched cancer samples, thus linking elevated expression to disease. Second, its inhibition or blockade confers radiosensitivity to tumor cells. There is a need to provide potent PolQ inhibitors for the potential treatment of cancer. Summary of the Invention

[0008] In one aspect, the present disclosure provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] Ring A and Ring B are independently selected from 3-20 membered rings;

[0011] Every R 1 are independently selected from halogen, -CN, =O or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0012] m is selected from 0, 1, 2, 3, 4 or 5;

[0013] Every R 2 are independently selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NRa R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0014] Or, any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl;

[0015] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0016] Each X is independently selected from -CH2-, -NH-, -O- or -S-;

[0017] k is selected from 0, 1, 2, 3 or 4;

[0018] Every R 4 are independently selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NRa C(O)OR b 、-NR a C(O)NR a R b 、C 3-12 Cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl;

[0019] p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0020] R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0021] R ab Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0022] L is selected from -CONR c -R c1 -、-NR c CO-R c1 -、-SONR c -R c1 -、-NR c SO-R c1 -,-SO2NR c -R c1 -or-NR c SO2-R c1 -;

[0023] R c Selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 3-12 Cycloalkyl, the C1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 3-12 Cycloalkyl is optionally substituted with one or more of the following: deuterium, halogen, CN, OH, SH, NH2, CHO or COOH;

[0024] R c1 Select from bond or C 1-12 Alkylene, the C 1-12 Alkylene is optionally substituted with one or more of the following: halogen, CN, OH, SH, NH2, CHO or COOH;

[0025] L 1 Selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-12 Alkylene, C 1-12 Heteroalkylene, C 1-12 Heteroalkenylene or C 1-12 heteroalkynylene;

[0026] R d Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0027] Or, two R d Together with the atoms to which it is attached, it forms a 3-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl.

[0028] In some embodiments, Ring A and Ring B are each independently selected from a 3-15 membered ring. In some embodiments, Ring A and Ring B are each independently selected from a 3-12 membered ring (eg, an aromatic ring, a partially unsaturated carbocycle, a fully saturated carbocycle, a heteroaromatic ring, or a heterocycle).

[0029] In some embodiments, Ring A and Ring B are each independently selected from C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl.

[0030] In some embodiments, the ring A and ring B are independently selected from phenyl, naphthyl, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heteroaryl, or 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heterocyclyl.

[0031] In some embodiments, the ring A and ring B are independently selected from C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclic group.

[0032] In some embodiments, the ring A and ring B are independently selected from C 6-10 In some embodiments, the rings A and B are independently selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, or 9-membered heteroaryl.

[0033] In some embodiments, the ring A and ring B are each independently selected from phenyl or 5-6 membered heteroaryl.

[0034] In some embodiments, the ring A and ring B are each independently selected from phenyl or 6-membered heteroaryl.

[0035] In some embodiments, when the ring A or ring B is selected from heteroaryl, the ring heteroatom is a nitrogen, oxygen or sulfur atom.

[0036] In some embodiments, the ring A and ring B are each independently selected from phenyl or pyridinyl.

[0037] In some embodiments, Ring A is selected from phenyl. In some embodiments, Ring B is selected from 5-6 membered heteroaryl. In some embodiments, Ring B is selected from 6 membered heteroaryl. In some embodiments, Ring B is selected from pyridinyl.

[0038] In some embodiments, each R 1 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a Rb 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0039] R' is selected from halogen, CN, =O, or the following groups optionally substituted with one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl.

[0040] In some embodiments, each R 1 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a Rb 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0041] In some embodiments, each R 1 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 aryl or 5-8 membered heteroaryl.

[0042] In some embodiments, each R1 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0043] In some embodiments, each R 1 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0044] In some embodiments, each R 1 are independently selected from halogen, -CN, =O, OH, NH2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NHC 1-4Alkyl, -N(C 1-4 alkyl) 2, or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl.

[0045] In some embodiments, each R 1 are independently selected from halogen, -CN, =O, OH, NH2, or C optionally substituted with one or more R' 1-4 alkyl.

[0046] In some embodiments, each R 1 are independently selected from halogen, -CN, =O, OH, NH2, or the following groups optionally substituted with one or more R': methyl, ethyl, n-propyl or isopropyl.

[0047] In some embodiments, each R 1 Each is independently selected from F, Cl, Br, I, CN, =O, OH, NH2, or the following groups optionally substituted with one or more halogens: methyl, ethyl, propyl or isopropyl.

[0048] In some embodiments, each R 1 are independently selected from F, Cl, Br, I, CN, OH, NH2, or methyl optionally substituted by one or more fluorines.

[0049] In some embodiments, each R 1 are independently selected from C optionally substituted by one or more halogens 1-6 alkyl.

[0050] In some embodiments, each R 1 are independently selected from C optionally substituted by one or more halogens 1-4 alkyl.

[0051] In some embodiments, each R 1 are independently selected from C optionally substituted with one or more F, Cl or Br 1-3 alkyl.

[0052] In some embodiments, each R 1 are each independently selected from methyl optionally substituted with one or more F. In some embodiments, R 1 Selected from trifluoromethyl.

[0053] In some embodiments, R' is selected from halogen, -CN, =O, or the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0054] In some embodiments, R' is selected from halogen, -CN, =O, or the following groups optionally substituted with one or more substituents: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 aryl or 5-8 membered heteroaryl.

[0055] In some embodiments, R' is selected from halogen, -CN, =O, or the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0056] In some embodiments, R' is selected from halogen, -CN, =O, OH, NH2, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0057] In some embodiments, R' is selected from halogen, -CN, =O, OH, NH2, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl or -N(C 1-3 Alkyl)2.

[0058] In some embodiments, R' is selected from halogen, -CN, =O, OH, NH2, or C optionally substituted with one or more halogen, -CN, =O, OH, NH2. 1-3 alkyl.

[0059] In some embodiments, R' is selected from halogen, -CN, OH, NH2 or C 1-3 alkyl.

[0060] In some embodiments, R' is selected from F, Cl, Br, I, -CN, OH, or NH2.

[0061] In some embodiments, R' is selected from F, Cl, Br, or I. In some embodiments, R' is selected from F. In some embodiments, m is selected from 0, 1, 2, 3, or 4.

[0062] In some embodiments, m is selected from 0, 1, 2, or 3.

[0063] In some embodiments, m is selected from 0, 1 or 2.

[0064] In some embodiments, m is selected from 1.

[0065] In some embodiments, m is selected from 0.

[0066] In some embodiments, each R 2 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl,

[0067] Or, any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, -CN, -OH, -SH, -NH2, -CHO, -COOH, -OC 1-12 Alkyl, -SC 1-12Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl;

[0068] R" is selected from halogen, -CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl.

[0069] In some embodiments, each R 2 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0070] In some embodiments, each R 2 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0071] In some embodiments, each R 2 are independently selected from halogen, -CN, =O, -OH, NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C1-6 alkyl)2, or C optionally substituted by one or more R" 1-6 alkyl.

[0072] In some embodiments, each R 2 Each independently selected from F, Cl, Br, I, -CN, =O, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 alkyl)2, or C optionally substituted by one or more R" 1-3 alkyl.

[0073] In some embodiments, as described herein, wherein any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, -CN, -OH, -SH, -NH2, -CHO, -COOH, -OC 1-10 Alkyl, -SC 1-10 Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl.

[0074] In some embodiments, as described herein, wherein any two R 2 In the 3-10 membered ring formed together with the atoms to which they are attached, the 3-10 membered ring is selected from a 3-6 membered ring; alternatively, the 3-10 membered ring is selected from a 3-, 4-, 5- or 6-membered ring; alternatively, the 3-10 membered ring is selected from a 3-10 membered alkane ring or a 3-10 membered heteroalkane ring; alternatively, the 3-10 membered ring is selected from a 3-6 membered alkane ring or a 3-6 membered heteroalkane ring; alternatively, the 3-10 membered ring is selected from a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring.

[0075] In some embodiments, as described herein, wherein any two R 2 Together with the atoms to which they are attached, they form a 3-6 membered ring, which is optionally substituted with one or more of the following groups: halogen, -CN, -OH, -SH, -NH2, -CHO, -COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0076] In some embodiments, each R 2 Each independently selected from F, Cl, Br, I, CN, =O, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2.

[0077] In some embodiments, each R 2 Each is independently selected from F, Cl, Br, I, CN, ═O, OH or NH 2 .

[0078] In some embodiments, each R 2 are independently selected from =O or -OR a .

[0079] In some embodiments, each R 2 are independently selected from =O or OH.

[0080] In some embodiments, R" is selected from halogen, CN, =0, or the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0081] In some embodiments, R" is selected from halogen, CN, =0, or the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0082] In some embodiments, R" is selected from halogen, CN, =0, or the following groups optionally substituted with one or more substituents: C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 1-3 Heteroalkyl, -OR a 、-SR a or -NR a R b .

[0083] In some embodiments, in some embodiments, R" is selected from F, Cl, Br, I, -CN, -OH, -NH2, =O or C 1-3 alkyl.

[0084] In some embodiments, R" is selected from F, Cl, Br, I, -CN, -OH, -NH2, or =0.

[0085] In some embodiments, n is selected from 0, 1, 2, 3, 4, or 5.

[0086] In some embodiments, n is selected from 0, 1, 2, 3, or 4. In some embodiments, n is selected from 0, 1, 2, or 3.

[0087] In some embodiments, n is selected from 0, 1, or 2.

[0088] In some embodiments, n is selected from 2, 3, or 4.

[0089] In some embodiments, n is selected from 4.

[0090] In some embodiments, n is selected from 3.

[0091] In some embodiments, n is selected from 2.

[0092] In some embodiments, each X is independently selected from -CH2- or -NH-.

[0093] In some embodiments, each X is independently selected from -O- or -S-.

[0094] In some embodiments, X is selected from -CH2-.

[0095] In some embodiments, X is selected from -NH-.

[0096] In some embodiments, k is selected from 0, 1, 2, or 3.

[0097] In some embodiments, k is selected from 0, 1 or 2.

[0098] In some embodiments, k is selected from 0 or 1.

[0099] In some embodiments, k is selected from 0. In some embodiments, k is selected from 1.

[0100] In some embodiments, each R 4 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or optionally one or more R"' of the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclic group,

[0101] R'' is selected from halogen, -CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl.

[0102] In some embodiments, each R 4 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NRa R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or optionally one or more R"' of the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

[0103] In some embodiments, each R 4 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group.

[0104] In some embodiments, each R 4 are independently selected from halogen, CN, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-3 Alkyl, C 2-4Alkenyl, C 2-4 Alkynyl, or C 3-6 Cycloalkyl.

[0105] In some embodiments, each R 4 are independently selected from F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 Alkyl, the C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 The alkyl group is optionally substituted with one or more of the following: F, Cl, Br, I, or 6-membered heterocycloalkyl.

[0106] In some embodiments, each R 4 Each is independently selected from F, Cl, methyl, ethynyl, cyclopropyl or -NHCH2CH3 alkyl, wherein the methyl, ethynyl, cyclopropyl or -NHCH2CH3 alkyl is optionally substituted with one or more F or 6-membered heterocycloalkyl (e.g. piperazinyl).

[0107] In some embodiments, each R 4 are independently selected from F, Cl, CH3, CF3, ethynyl, cyclopropyl or

[0108] In other embodiments, each R 4 are independently selected from halogen, CN, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-3 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl.

[0109] In other embodiments, each R 4 are independently selected from F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkynyl or -NHC 1-3 Alkyl, the C 1-3 Alkyl, C 2-3 Alkynyl or -NHC 1-3 The alkyl group is optionally substituted with one or more of the following: F, Cl, Br, I, or 6-membered heterocycloalkyl.

[0110] In other embodiments, each R4 Each is independently selected from F, Cl, methyl, ethynyl or -NHCH2CH3 alkyl, wherein the methyl, ethynyl or -NHCH2CH3 alkyl is optionally substituted with one or more F or 6-membered heterocycloalkyl (eg piperazinyl).

[0111] In other embodiments, each R 4 Each independently selected from F, Cl, CH3, CF3, ethynyl or

[0112] In some embodiments, R'' is selected from halogen, -CN, =O, or the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0113] In some embodiments, R'' is selected from halogen, -CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0114] In some embodiments, R'' is selected from halogen, -CN, =O, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Heteroalkyl, -OR a 、-SR a or -NR a R b .

[0115] In some embodiments, R'' is selected from halogen, -CN, OH, NH2 or C 1-3 alkyl.

[0116] In some embodiments, R'' is selected from F, Cl, Br, CN, OH, or NH2. In some embodiments, R'' is selected from F, Cl, Br, or I. In some embodiments, R'' is selected from F.

[0117] In some embodiments, p is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0118] In some embodiments, p is selected from 0, 1, 2, 3, 4, or 5.

[0119] In some embodiments, p is selected from 0, 1, 2, 3, or 4.

[0120] In some embodiments, p is selected from 0. In some embodiments, p is selected from 1. In some embodiments, p is selected from 2. In some embodiments, p is selected from 3. In some embodiments, p is selected from 4.

[0121] In some embodiments, R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0122] In some embodiments, R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0123] In some embodiments, R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group.

[0124] In some embodiments, R a and R bare independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl.

[0125] In some embodiments, R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted C 1-3 alkyl.

[0126] In some embodiments, R a and R b are independently selected from hydrogen, or C optionally substituted by one or more 5-6 membered heterocycloalkyl 1-3 alkyl.

[0127] In some embodiments, R a and R b Each is independently selected from hydrogen, or ethyl optionally substituted by one or more 6-membered heterocycloalkyl groups (eg piperazinyl).

[0128] In some embodiments, R a and R b are independently selected from hydrogen or

[0129] In some embodiments, R ab Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-10 Alkyl, -SC 1-10 Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0130] In some embodiments, R ab Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0131] In some embodiments, R ab Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0132] In some embodiments, R ab Selected from halogen, CN, OH, SH, NH2, C 1-3 Alkyl, C 3-6 In some embodiments, R ab Selected from C 3-6 In some embodiments, R ab is selected from 6-membered heterocyclic groups.

[0133] In some embodiments, R ab Selected from piperazinyl.

[0134] In some embodiments, L is selected from -CONR c -R c1 -、-NR c CO-R c1 -、-SONR c -R c1 -or-NR c SO-R c1 -.

[0135] In some embodiments, L is selected from -CONR c -R c1 -or-NR c CO-R c1 -. In some embodiments, L is selected from -CON(CD3)-. In some embodiments, L is selected from -CONR c -R c1 -* or -NR c CO-R c1 -*, wherein * indicates that the bond at this position is connected to ring A.

[0136] In some embodiments, R cSelected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-10 Cycloalkyl, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-10 The cycloalkyl group is optionally substituted with one or more of the following: deuterium, halogen, -CN, -OH, -SH, -NH2, -CHO, or -COOH.

[0137] In some embodiments, R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 The cycloalkyl group is optionally substituted with one or more of the following: deuterium, halogen, CN, OH, SH, NH2, CHO, or COOH.

[0138] In some embodiments, R c Selected from hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following: deuterium, halogen, CN, OH, SH, or NH2.

[0139] In some embodiments, R c is selected from hydrogen or methyl, said methyl being optionally substituted with one or more of the following groups: deuterium, F, Cl, Br, I.

[0140] In some embodiments, R c is selected from hydrogen or methyl, said methyl being optionally substituted with 1-3 deuteriums.

[0141] In some embodiments, R c is selected from hydrogen, methyl or -CD3.

[0142] In some embodiments, R c1 Select from bond or C 1-10 Alkylene, the C 1-10 The alkylene group is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, or COOH.

[0143] In some embodiments, R c1 Select from bond or C 1-6 Alkylene, the C 1-6The alkylene group is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, or COOH.

[0144] In some embodiments, R c1 Select from bond or C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more of the following groups: F, Cl, Br, I, CN, OH, SH, NH2, CHO, or COOH.

[0145] In some embodiments, R c1 Select from keys.

[0146] In some embodiments, L 1 Selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-10 Alkylene, C 1-10 Heteroalkylene, C 1-10 Heteroalkenylene or C 1-10 Heteroalkynylene.

[0147] In some embodiments, L 1 Selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-6 Alkylene, C 1-6 Heteroalkylene, C 1-6 Heteroalkenylene or C 1-6 Heteroalkynylene.

[0148] In some embodiments, L 1 Selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-4 Alkylene or C 1-4 In some embodiments, L 1 The heteroatom in the heteroalkylene group is selected from N or O; optionally, the number of heteroatoms is selected from 1, 2 or 3.

[0149] In some embodiments, L 1 Selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-3 Alkylene or C 1-3 Heteroalkylene.

[0150] In some embodiments, L 1 Selected from optionally one or more R dSubstituted groups: methylene, ethylene, propylene, isopropylene, -OCH2-*, -CH2O-*, -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-*, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -NHCH2-*, -CH2NH-*, -NHCH2CH2-*, -CH2CH2NH-*, -NHCH2CH2CH2-*, -CH2CH2CH2NH-*, -NHCH2NH-, -NHCH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -CH2OCH2-, -CH2OCH2CH2*-, -CH2CH2OCH2-* , -CH2OCH2O-*, -OCH2OCH2-*, -OCH2OCH2CH2-*, -CH2OCH2OCH2-, -CH2OCH2CH2O-*, -CH2CH2OCH2O-*, -CH2NHCH2-, -CH2NHCH2CH2-*, -CH2CH2NHCH2-*, -CH2NHCH2NH-*, -NHCH2NHCH2-*, -NHCH2NHCH2CH2-*, -CH2NHCH2NHCH2-, -CH2NHCH2CH2NH-*, -CH2CH2NHCH2NH-*, *-OCH2CH2CH2CH2- or -OCH2CH2CH2CH2-*, where * represents that the bond at this position is connected to the ring B portion.

[0151] In some embodiments, L 1 Selected from optionally one or more R d The following substituted groups: methylene, ethylene, propylene, isopropylene, -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-*, -OCH2CH2O-, -NHCH2CH2-*, -CH2CH2NH-*, -NHCH2CH2CH2-*, -CH2CH2CH2NH-*, -NHCH2CH2NH-, *-OCH2CH2CH2CH2- or -OCH2CH2CH2CH2-*, wherein * indicates that the bond at this position is connected to the ring B portion.

[0152] In some embodiments, L 1 Selected from optionally one or more R dThe following substituted groups: -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-*, -OCH2CH2O-, -NHCH2CH2-*, *-NHCH2CH2-, *-OCH2CH2CH2CH2- or -OCH2CH2CH2CH2-*, wherein * indicates that the bond at this position is connected to the ring B portion.

[0153] In some embodiments, L 1 Selected from -OCH2CH2-*, -OCH2CH2CH2-*, -OCH2CH2O-, -N(CH3)CH2CH2-* or -OCH2CH2CH2CH2-*, wherein * indicates that the bond at this position is connected to the ring B portion.

[0154] In other embodiments, L 1 Selected from optionally one or more R d Substituted groups: methylene, ethylene, propylene, isopropylene, -OCH2-*, -CH2O-*, -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-*, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -NHCH2-*, -CH2NH-*, -NHCH2CH2-*, -CH2CH2NH-*, -NHCH2CH2CH2-*, -CH2CH2CH2NH-*, -NHCH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2NH-, -CH2OCH2-, -CH2OCH2CH 2*-, -CH2CH2OCH2-*, -CH2OCH2O-*, -OCH2OCH2CH2-*, -CH2OCH2OCH2-, -CH2OCH2CH2O-*, -CH2CH2OCH2O-*, -CH2NHCH2-, -CH2NHCH2CH2-*, -CH2CH2NHCH2-*, -CH2NHCH2NH-*, -NHCH2NHCH2-*, -NHCH2NHCH2CH2-*, -CH2NHCH2NHCH2-, -CH2NHCH2CH2NH-* or -CH2CH2NHCH2NH-*, wherein * indicates that the bond at this position is connected to the ring B portion.

[0155] In other embodiments, L 1 Selected from optionally one or more R dThe following substituted groups: methylene, ethylene, propylene, isopropylene, -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-*, -OCH2CH2O-, -NHCH2CH2-*, -CH2CH2NH-*, -NHCH2CH2CH2-*, -CH2CH2CH2NH-* or -NHCH2CH2NH-, wherein * indicates that the bond at this position is connected to the ring B portion.

[0156] In other embodiments, L 1 Selected from optionally one or more R d The following groups substituted: -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-* or -OCH2CH2O-, wherein * indicates that the bond at this position is connected to the ring B portion. In other embodiments, L 1 Selected from -OCH2CH2-*, -OCH2CH2CH2-* or -OCH2CH2O-, wherein * indicates that the bond at this position is connected to the ring B portion.

[0157] In some embodiments, R d Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-10 Alkyl, -SC 1-10 Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group.

[0158] In some embodiments, R d Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group.

[0159] In some embodiments, R d Selected from halogen, CN, OH, NH2, C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0160] In some embodiments, R d Selected from halogen, CN, OH, SH, NH2 or C 1-3 In some embodiments, R d is selected from halogen, CN, OH, SH, NH2 or methyl.

[0161] In some embodiments, as described herein, wherein the two R d The atoms to which it is attached form a 3-10 membered ring, wherein the 3-10 membered ring is selected from a 3-6 membered ring; alternatively, the 3-10 membered ring is selected from a 3-, 4-, 5- or 6-membered ring; alternatively, the 3-10 membered ring is selected from a 3-10 membered alkane ring or a 3-10 membered heteroalkane ring; alternatively, the 3-10 membered ring is selected from a 3-6 membered alkane ring or a 3-6 membered heteroalkane ring; alternatively, the 3-10 membered ring is selected from a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring.

[0162] In some embodiments, as described herein, wherein the two R d The atoms to which it is attached form a 3-8 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-10 Alkyl, -SC 1-10 Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl.

[0163] In some embodiments, as described herein, wherein the two R d The atoms to which it is attached form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0164] In some embodiments, as described herein, wherein the two R d The atoms to which it is attached form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3Alkyl, -N(C 1-3 Alkyl)2 or C 1-3 alkyl.

[0165] In some embodiments, as described herein, wherein the two R d The atoms to which it is attached form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, NH2 or C 1-3 alkyl.

[0166] In some embodiments, the moiety Selected from Or, the structural part Selected from wherein q is selected from 0, 1, 2, 3 or 4.

[0167] In some embodiments, q is selected from 0, 1, 2, or 3; or q is selected from 1 or 2.

[0168] In some embodiments, the moiety Selected from where R 2a and R 2b are independently selected from hydrogen, halogen, -CN, =O, or the following groups optionally substituted with one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR aR b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0169] Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl.

[0170] In some embodiments, the moiety Selected from

[0171] In some embodiments, the moiety Selected from

[0172] In some embodiments, the moiety Selected from

[0173] In some embodiments, as described herein, wherein the R 2a and R 2b In the 3-10 membered ring formed together with the atoms to which they are attached, the 3-10 membered ring is selected from a 3-6 membered ring; alternatively, the 3-10 membered ring is selected from a 3-, 4-, 5- or 6-membered ring; alternatively, the 3-10 membered ring is selected from a 3-10 membered alkane ring or a 3-10 membered heteroalkane ring; alternatively, the 3-10 membered ring is selected from a 3-6 membered alkane ring or a 3-6 membered heteroalkane ring; alternatively, the 3-10 membered ring is selected from a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring.

[0174] In some embodiments, R 2a and R 2b are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-12 Alkyl, C 2-12 Alkenyl, C2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl,

[0175] Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl;

[0176] R" is selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl.

[0177] In some embodiments, R 2a and R 2b are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl,

[0178] Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-10 Alkyl, -SC 1-10Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl.

[0179] In some embodiments, R 2a and R 2b are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl,

[0180] Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 3-6 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0181] In some embodiments, R 2a and R 2b are independently selected from halogen, CN, OH, NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, or C optionally substituted by one or more R" 1-6 alkyl.

[0182] In some embodiments, R 2a and R 2b Each independently selected from F, Cl, Br, I, CN, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3alkyl)2, or C optionally substituted by one or more R" 1-3 alkyl.

[0183] In some embodiments, R 2a and R 2b Each independently selected from F, Cl, Br, I, CN, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2.

[0184] In some embodiments, R 2a and R 2b Each is independently selected from F, Cl, Br, I, CN, OH or NH2.

[0185] In some embodiments, R 2a and R 2b are independently selected from -OR a .

[0186] In some embodiments, R 2a and R 2b Selected from OH.

[0187] In some embodiments, R" is selected from halogen, CN, =0, or the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0188] In some embodiments, R" is selected from halogen, CN, =0, or the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -OR a 、-SR a 、-NR a R b 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0189] In some embodiments, R" is selected from halogen, CN, =0, or the following groups optionally substituted with one or more substituents: C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Heteroalkyl, -OR a 、-SR a or -NR a R b .

[0190] In some embodiments, R" is selected from F, Cl, Br, I, CN, OH, NH2, =O, or C 1-3 alkyl.

[0191] In some embodiments, R" is selected from F, Cl, Br, I, CN, OH, NH2, or =0.

[0192] In some embodiments, the moiety Selected from wherein q is selected from 0, 1 or 2; or q is selected from 0 or 1.

[0193] In some embodiments, the moiety Selected from wherein q is selected from 0, 1 or 2; or q is selected from 0 or 1.

[0194] In some embodiments, the moiety Selected from

[0195] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0196] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula II or a pharmaceutically acceptable salt thereof:

[0197] m、R 2 ,n,k,X,L 1 、R c and p is as defined in this disclosure;

[0198] X a 、X b 、X c 、Xd 、X e 、X f 、X h 、X j 、X k and X n are independently selected from CH or N;

[0199] Every R 1a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, R' is as defined in the present disclosure;

[0200] Or any two adjacent R 1a Together with the atoms to which it is attached, it forms a 5-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-6 alkyl;

[0201] R a and R b is as defined in this disclosure;

[0202] Every R 4a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a SO2R b 、、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R"': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl, R'' is as defined in the present disclosure;

[0203] Or any two adjacent R 4a Together with the atoms to which it is attached, it forms a 5-10 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-6 alkyl.

[0204] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from Or, the structural part Selected from Or, the structural part Selected from

[0205] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0206] In some embodiments, X a 、X b 、X c 、X d and X e Optionally one or two of X are selected from N, and the others are selected from CH. In some embodiments, X a 、X b 、X c 、X d and X e One of the is selected from N and the others are selected from CH. In some embodiments, X a 、X b 、X c 、X d and X e One of the is selected from N and the others are selected from CH. In some embodiments, X e Selected from N, X a 、X b 、X c and X d Selected from CH.

[0207] In some embodiments, the R 1a Substitution occurs at X b On, and X b Selected from CH.

[0208] In some embodiments, X f 、X h 、X j 、X k Optionally one or two of X are selected from N, and the others are selected from CH. In some embodiments, X f 、X h 、X j 、X k Optionally one of X is selected from N and the others are selected from CH. In some embodiments, X f 、X h 、X j and X k Selected from CH.

[0209] In some embodiments, each R 1a are independently selected from halogen, CN, =O, -OR a 、-SRa 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0210] In some embodiments, each R 1a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2Rb 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 aryl or 5-8 membered heteroaryl.

[0211] In some embodiments, each R 1a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl.

[0212] In some embodiments, each R 1a are independently selected from halogen, CN, =O, -ORa 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0213] In some embodiments, each R 1a are independently selected from halogen, CN, OH, NH2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2, or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl.

[0214] In some embodiments, each R 1a are independently selected from halogen, CN, OH, NH2, or C optionally substituted with one or more R' 1-4 alkyl.

[0215] In some embodiments, each R 1a are independently selected from halogen, CN, OH, NH2, or the following groups optionally substituted with one or more R': methyl, ethyl, n-propyl or isopropyl.

[0216] In some embodiments, each R 1a are independently selected from F, Cl, Br, I, CN, OH, NH2, or the following groups optionally substituted with one or more halogens: methyl, ethyl, propyl or isopropyl.

[0217] In some embodiments, each R 1a are independently selected from F, Cl, Br, I, CN, OH, NH2, or methyl optionally substituted by one or more fluorines.

[0218] In some embodiments, each R 1a are independently selected from C optionally substituted by one or more halogens 1-6 alkyl.

[0219] In some embodiments, each R 1a are independently selected from C optionally substituted by one or more halogens 1-4 alkyl.

[0220] In some embodiments, each R 1a are independently selected from C optionally substituted with one or more F, Cl or Br 1-3 alkyl.

[0221] In some embodiments, each R 1a are each independently selected from methyl optionally substituted with one or more F. In some embodiments, each R 1a are independently selected from CF3.

[0222] In some embodiments, R' is as defined in the disclosure.

[0223] In some embodiments, as described herein, wherein any two adjacent R 1a Together with the atoms to which it is attached, it forms a 5-8 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-3 alkyl.

[0224] In some embodiments, as described herein, wherein any two adjacent R 1a Together with the atoms to which it is attached, it forms a 5-6 membered ring.

[0225] In some embodiments, each R 4a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group.

[0226] In some embodiments, each R 4a are independently selected from halogen, CN, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 Cycloalkyl.

[0227] In some embodiments, each R 4aare independently selected from F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 Alkyl, the C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 The alkyl group is optionally substituted with one or more of the following: F, Cl, Br, I, or 6-membered heterocycloalkyl.

[0228] In some embodiments, each R 4a Each is independently selected from F, Cl, methyl, ethynyl, cyclopropyl or -NHCH2CH3, wherein the methyl, ethynyl, cyclopropyl or -NHCH2CH3 is optionally substituted with one or more F or piperazinyl.

[0229] In some embodiments, each R 4a are independently selected from F, Cl, CH3, CF3, ethynyl, cyclopropyl or

[0230] In some embodiments, each R 4a are independently selected from halogen, CN, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-3 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl.

[0231] In some embodiments, each R 4a are independently selected from F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkynyl or -NHC 1-3 Alkyl, the C 1-3 Alkyl, C 2-3 Alkynyl or -NHC 1-3 The alkyl group is optionally substituted with one or more of the following: F, Cl, Br, I, or 6-membered heterocycloalkyl.

[0232] In some embodiments, each R 4a Each is independently selected from F, Cl, methyl, ethynyl or -NHCH2CH3, wherein the methyl, ethynyl or -NHCH2CH3 is optionally substituted with one or more F or piperazinyl.

[0233] In some embodiments, each R4a Each independently selected from F, Cl, CH3, CF3, ethynyl or

[0234] In some embodiments, as described herein, wherein any two adjacent R 4a Together with the atoms to which it is attached, it forms a 5-8 membered ring, which is optionally substituted with one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-3 alkyl.

[0235] In some embodiments, as described herein, wherein any two adjacent R 4a Together with the atoms to which it is attached, it forms a 5-6 membered ring.

[0236] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula III or a pharmaceutically acceptable salt thereof,

[0237] Among them, R 1a ,m,R 2 ,q,k,X,L 1 、R c 、R 4a ,p,X a 、X b 、X c 、X e 、X f 、X h 、X j and X k The definition of is as described in this disclosure.

[0238] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0239] In some embodiments, the heteroalkyl, heteroaryl, heterocyclyl or heterocycloalkyl groups disclosed herein, wherein the heteroatoms are selected from B, NH, N, O, P or S; in some specific embodiments, the number of the heteroatoms is selected from 1, 2, 3, 4 or 5; in some specific embodiments, the number of the heteroatoms is selected from 1, 2 or 3.

[0240] In some embodiments, the “one or more” described in the present disclosure is selected from 1, 2, 3, 4 or 5; in some specific embodiments, the number of the heteroatoms is selected from 1, 2 or 3.

[0241] In another aspect, the present disclosure provides the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0242] In another aspect, the present disclosure provides the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0243] On the other hand, the present disclosure also provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0244] On the other hand, the present disclosure also provides a method for treating or preventing a disease, comprising administering a therapeutically or preventively effective amount of the above-mentioned compound of the present disclosure, its stereoisomers, its pharmaceutically acceptable salts, or pharmaceutical compositions thereof to a mammal, preferably a human, in need of such treatment.

[0245] On the other hand, the present disclosure also provides the use of the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating or preventing a disease.

[0246] On the other hand, the present disclosure also provides the use of the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, or its pharmaceutical composition in treating or preventing diseases.

[0247] On the other hand, the present disclosure also provides the above-mentioned compound of the present disclosure, its stereoisomers, its pharmaceutically acceptable salts, or pharmaceutical compositions thereof for treating or preventing diseases.

[0248] In some embodiments, the disease is selected from cancer.

[0249] In some embodiments, the disease is selected from a Pol Q-related disease (eg, cancer).

[0250] In some embodiments, the disease is selected from Pol Q-related cancers.

[0251] Technical Effects

[0252] The compounds disclosed herein have good in vitro and in vivo inhibitory activity related to Pol Q (eg, Pol Q in vitro enzyme inhibitory activity) and metabolic stability (eg, liver microsome metabolic stability and in vivo pharmacokinetic parameters).

[0253] definition

[0254] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0255] When a covalent bond in certain structural units or groups in the present disclosure is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group as long as it does not violate the valence bond connection rules.

[0256] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0257] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0258] The "substituents" described herein include, but are not limited to, the terms "alkyl", "alkoxy", "alkylthio", "cycloalkyloxy", "heteroalkyl", "alkenyl", "alkynyl", "cycloalkenyl", "cycloalkyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocyclyl", "aryl", "heteroaryl", "alkylene", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituents" include -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloalkyl group, a halo-cycloalkyl group, an alkenyl group, a halo-alkenyl group, a cycloalkenyl group, a halo-cycloalkenyl group, an alkynyl group, a halo-alkynyl group, a cycloalkynyl group, a halo-cycloalkynyl group, a heteroalkyl group, a halo-heteroalkyl group, an alkoxy group, an alkylthio group, an aryl group, an aryloxy group, an arylthio group, an aralkyl group, an arylalkoxy group, an arylalkylthio group, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroaralkyl group, a heteroarylalkoxy group, a heteroarylalkylthio group, a heterocyclyl group, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., which are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0259] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0260] In some embodiments herein, the substituent is selected from hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0261] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0262] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0263] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually AZ.

[0264] When a substituent's bond crosses two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, the bonds on either side of Ring A may be bonded to any two different atoms on Ring A.

[0265] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0266] The term "alkyl" refers to a group of the formula C n H 2n+1 The hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The alkyl group may be straight or branched, for example, it may be "C 1-12 Alkyl" or "C 1-6 Alkyl" etc. For example, the term "C 1-12 "Alkyl" refers to an alkyl group containing 1 to 12 carbon atoms, including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12and any combination of these. 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. For another example, the term "C 1-3 The term "alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

[0267] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms, for example, "C 2-12 Alkenyl" or "C 2-6 Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0268] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms, for example, "C 2-12 Alkynyl" or "C 2-6 Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), and the like.

[0269] The term "alkoxy" refers to an -O-alkyl group.

[0270] The term "alkylthio" refers to an -S-alkyl group.

[0271] The term "cycloalkoxy" refers to an -O-cycloalkyl group.

[0272] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, and the like. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl.

[0273] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring having at least one double bond and which can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0274] The term "cycloalkynyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and has at least one triple bond and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5- to 8-membered ring.

[0275] The term "carbocycle" refers to a ring in which the ring atoms do not involve heteroatoms and are all composed of carbon atoms, including aromatic rings, partially unsaturated carbocycles, fully saturated carbocycles (i.e., cycloalkyl groups), and the like.

[0276] Term " heterocyclic radical " refers to fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can be with monocycle, bridged ring, and ring or spirocyclic non-aromatic ring.Unless otherwise indicated, the heterocycle is generally 3 to 10 rings (such as 3 yuan, 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan), 4 to 8 yuan rings, 5 to 8 yuan rings or 5 to 6 yuan rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron.The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N- methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H- pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0277] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are independently replaced by the same or different heteroatoms. 1-12 Heteroalkyl" or "C 1-6 Unless otherwise indicated, the heteroalkyl group contains 1, 2 or 3 heteroatom groups, non-limiting examples of which include O, S, N or NH. For example, the term "C 1-6 "Heteroalkyl" refers to a heteroalkyl group containing from 1 to 6 carbon atoms and from 1 to 3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal), including the position that connects the alkyl group to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatoms are not adjacent to each other. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, and the like.

[0278] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (including fused) or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10-membered ring, a 3 to 7-membered ring, a 4 to 8-membered ring, a 5 to 8-membered ring or a 5 to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0279] The term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group or "aromatic ring" can have 6-20 carbon atoms, 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0280] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryl groups have single 5 to 8 rings (e.g., 5, 6, 7, or 8 members), or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms (e.g., 6, 7, 8, 9, or 10 ring atoms). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, pyridopyrrolyl, etc.

[0281] The term "alkylene" refers to a divalent group formed by removing a hydrogen from any position of an alkyl group, for example, the term "C 1-6 "Alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C 1-4"Alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-. The terms "heteroalkylene", "cycloalkylene", "heterocycloalkylene", "arylene" and "heteroarylene" are defined similarly and refer to a divalent group formed by removing one hydrogen at any position of "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl" and "heteroaryl", respectively.

[0282] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0283] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0284] Structural part It indicates that the ring system is a 6-membered aromatic ring or a heteroaromatic ring system, specifically a benzene ring or a pyridine ring.

[0285] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.

[0286] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0287] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0288] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0289] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0290] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0291] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0292] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0293] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0294] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0295] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0296] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0297] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 For example, it should be understood that compounds wherein one or more hydrogen atoms in the compounds of Formula I of the present disclosure are replaced with deuterium atoms are still within the scope of the compounds of Formula I of the present disclosure.

[0298] Certain isotopically-labeled compounds of the present disclosure (e.g., those labeled with 3H and 14C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0299] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of this disclosure.

[0300] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0301] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0302] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0303] The therapeutic dose of the disclosed compounds may be determined, for example, based on the specific use of the treatment, the manner in which the compound is administered, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is from about 0.001 mg / kg to about 1000 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0304] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0305] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0306] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as the amino groups in the present disclosure). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0307] In some embodiments, the compounds of the present disclosure can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0308] Route 1:

[0309] Route 2:

[0310] Route 3:

[0311] Among them, R 1 、R 1a ,m,R 2 ,q,k,X,L 1 、R c 、R 4a 、R 4 ,p,X a 、X b 、X c 、X e 、X f 、X h 、X j and X k The definition of is as described in this disclosure; According to the known technology in the art, With L 1Y is selected from a leaving group, including but not limited to F, Cl, Br, I, OTf, B(OH)2; Z is selected from H or a protecting group, including but not limited to THP; Pro represents a protecting group including but not limited to THP or Bn.

[0312] In some embodiments, the Z and L 1 The O, N or S atoms are directly connected; preferably, the Z and L 1 The O atoms are directly connected.

[0313] This disclosure uses the following abbreviations:

[0314] t-BuOK represents potassium tert-butoxide; DMEDA represents N,N'-dimethylethylenediamine; CD3I represents deuterated iodomethane; MeI represents iodomethane; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; Xantphos represents 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; T3P / DMF represents a solution of 1-propylphosphonic cyclic anhydride in N,N-dimethylformamide; DMF represents N,N-dimethylformamide; Bn represents benzyl; and THP represents tetrahydropyranyl.

[0315] For the sake of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0316] Example 1: Compound 1

[0317] 1) Preparation method of compound 1-a:

[0318] (3aS,4S,6aS)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxylic acid (1 g), benzyl bromide (935 mg), triethylamine (1 g), and acetone (30 mL) were added to a reaction flask and reacted at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, 20 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 1-a (760 mg). ESI-MS: m / z = 292.2 [M+H] + .

[0319] 2) Preparation method of compound 1-b:

[0320] DMF (20 mL) was added to the reaction flask and stirred in an ice bath for 5 minutes. NaH (834 mg) was slowly added. After stirring for 5 minutes, diethyl malonate (3.7 g) was added dropwise. After stirring for 10 minutes, 2,6-dichloro-4-trifluoromethylpyridine (2 g) was slowly added. After the addition was complete, the reaction mixture was heated to 70°C and stirred for 5 hours. The reaction solution was cooled to room temperature and 40 mL of saturated ammonium chloride solution was added. The mixture was extracted twice with 40 mL of ethyl acetate. The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1-b (2.2 g), which was used directly in the next step. ESI-MS: m / z = 340.02 [M+H] + .

[0321] 3) Preparation method of compound 1-c:

[0322] 1-b (2.2 g) and anhydrous methanol (20 mL) were added to a reaction flask and stirred in an ice bath for 5 minutes. Sodium methoxide (1 g) was slowly added and stirred at room temperature for 1 hour. The reaction mixture was then heated to 45°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 1-c (1.5 g). ESI-MS: m / z = 253.91 [M+H] + .

[0323] 4) Preparation method of compound 1-d:

[0324] 1-c (500 mg) was dissolved in phosphorus trichloride (5 mL), replaced with nitrogen three times, and heated to 80°C for 6 hours. Dilute with dichloromethane, adjust the pH to ≥ 7 with saturated sodium bicarbonate solution in an ice bath, and extract with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography to obtain 1-d (300 mg). ESI-MS: m / z = 299.8 [M+H] + .

[0325] 5) Preparation method of compound 1-e:

[0326] 1-d (190 mg) was dissolved in anhydrous methanol (10 mL), sodium borohydride (72 mg) was added under ice-cooling conditions, and the mixture was stirred at room temperature overnight. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 1-e (120 mg). ESI-MS: m / z = 269.82 [M+H] + .

[0327] 6) Preparation method of compound 1-f:

[0328] 1-e (150 mg) and toluene (5 mL) were added to a reaction flask, followed by t-BuOK (187 mg) at 0°C. The mixture was reacted in an ice bath for 30 minutes, followed by 4-fluoro-3-nitrotoluene (86 mg). The reaction was allowed to react at room temperature for 2-3 hours. The mixture was quenched with 10 mL of water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to yield compound 1-f (65 mg). ESI-MS: m / z = 406.95 [M+H] + .

[0329] 7) Preparation method of compound 1-g:

[0330] Compound 1-f (65 mg), 1-a (47 mg), cuprous iodide (6 mg), DMEDA (3 mg), potassium carbonate (67 mg), and dioxane (5 mL) were added to a reaction flask and stirred at 60°C under nitrogen for 4 hours. The reaction solution was filtered, and the filtrate was washed with 10 mL of ethyl acetate and 10 mL of water. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield 1-g (70 mg). ESI-MS: m / z = 616.28 [M+H] + .

[0331] 8) Preparation method of compound 1-h:

[0332] 1-g (70 mg) and anhydrous methanol (5 mL) were added to a reaction flask, and Pd / C (50 mg) was added. The reaction was allowed to proceed overnight at room temperature under hydrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-h (56 mg). ESI-MS: m / z = 496.14 [M+H] + .

[0333] 9) Preparation method of compound 1-i:

[0334] 1-h (56 mg), EDCI (65 mg), and pyridine (5 mL) were added to a reaction flask and allowed to react overnight at room temperature. After quenching with 10 mL of water, the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-i (54 mg). ESI-MS: m / z = 478.14 [M+H] + .

[0335] 10) Preparation method of compound 1:

[0336] 1-i (20 mg) and HCl / 1,4-dioxane (5 mL) were added to a reaction flask and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by HPLC to obtain compound 1 (4 mg).

[0337] ESI-MS: m / z = 438.09 [M+H] + .

[0338] 1 H NMR (500MHz, DMSO) δ8.74(s,1H),7.44(s,1H),6.62(d,J=1.4Hz,1H),6.19(dd,J=8 .2,2.2Hz,1H),6.11–6.02(m,2H),4.87(d,J=8.2Hz,1H),4.40(d,J=5.0Hz,1H),3. 84(ddd,J=8.6,7.1,3.4Hz,1H), 3.68(ddd,J=22.2,9.1,5.3Hz,2H), 2.86(td,J=8. 2,2.8Hz,1H),2.46–2.39(m,1H),2.30(ddd,J=12.1,7.7,3.8Hz,1H),1.41(s,3H).

[0339] Example 2: Compound 2

[0340] 1) Preparation method of compound 2-a:

[0341] 1-i (50 mg), CD3I (45 mg), cesium carbonate (102 mg), and DMF (5 mL) were added to a reaction flask and reacted at room temperature for 2 hours. After quenching with 10 mL of water, the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 2-a (50 mg). ESI-MS: m / z = 495.18 [M+H] + .

[0342] 2) Preparation method of compound 2:

[0343] Referring to Example 1, step 10) the preparation method of compound 1, compound 2 (3 mg) was obtained.

[0344] ESI-MS: m / z = 455.15 [M+H] + .

[0345] 1H NMR(500MHz,CD3CN)δ8.20(s,1H),7.08(d,J=1.4Hz,1H),7.04(d,J=8.2Hz,2H),6.92(d,J=8.0Hz,1H),5.01(d,J=7.2Hz,1H),4.30– 4.24(m,2H),4.14(t,J=6.8Hz,1H),3.84(d,J=6.3Hz,1H),3.02(dt,J=15.9,5.9Hz,1H),2.84(dt,J=15.9,4.4Hz,1H),2.13(s,3H).

[0346] Example 3: Compound 3

[0347] 1) Preparation method of compound 3-a:

[0348] 1-i (36 mg), MeI (11 mg), cesium carbonate (74 mg), and DMF (5 mL) were added to a reaction flask and reacted at room temperature for 2 hours. After quenching with 10 mL of water, the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 3-a (37 mg). ESI-MS: m / z = 492.15 [M+H] + .

[0349] 2) Preparation method of compound 3:

[0350] Referring to Example 1, step 10) the preparation method of compound 1, 1-i was replaced by 3-a to obtain compound 3 (2.8 mg).

[0351] ESI-MS: m / z = 452.11 [M+H] + .

[0352] 1 H NMR (500MHz, DMSO) δ7.48 (s, 1H), 6.64 (d, J = 1.4Hz, 1H), 6.43–6.37 (m, 3H), 4. 68(d,J=5.8Hz,1H),4.53(d,J=10.3Hz,1H),4.25(s,1H),3.76–3.67(m,1H),3 .57(dd,J=10.0,6.7Hz,1H),3.49(q,J=6.5Hz,1H),3.28(dd,J=10.2,6.5Hz,1 H),2.43–2.35(m,1H),2.31(dd,J=15.2,6.9Hz,1H),2.22(s,3H),1.49(s,3H).

[0353] Example 4: Compound 4

[0354] 1) Preparation method of compound 4-a:

[0355] 1-e (50 mg) and toluene (5 mL) were added to a reaction flask, cooled to 0°C, potassium tert-butoxide (62 mg) was added and the reaction was continued for 30 minutes. 2-Fluoro-5-chloronitrobenzene (29 mg) was added and the reaction was continued for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Compound 4-a (50 mg) was obtained by HPLC purification. ESI-MS: m / z = 424.90 [M+H] + .

[0356] 2) Preparation method of compound 4-b:

[0357] Compound 4-a (40 mg), 10% Pt / C (5 mg), and anhydrous methanol (3 mL) were added to a reaction flask and stirred at room temperature under hydrogen protection for 8 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain compound 4-b (26 mg). ESI-MS: m / z = 394.95 [M+H] + .

[0358] 3) Preparation method of compound 4-c:

[0359] Compound 4-b (51 mg), compound 4-f (26 mg), and EDCI (4 mL) were added to a reaction flask and stirred at room temperature for 8 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain compound 4-c (38 mg). ESI-MS: m / z = 577.95 [M+H] + .

[0360] 4) Preparation method of compound 4-d:

[0361] Referring to the reaction conditions of step 7) of Example 1, compound 4-c was used to replace 1-f and 1-a to obtain compound 4-d (30 mg). ESI-MS: m / z=498.09 [M+H] + .

[0362] 5) Preparation method of compound 4-e:

[0363] Referring to step 1 of Example 2, compound 4-d was used to replace 1-i to obtain compound 4-e (20 mg). ESI-MS: m / z=515.10 [M+H] + .

[0364] 6) Preparation method of compound 4:

[0365] With reference to Example 1, step 10), 1-i was replaced with compound 4-e to give compound 4 (10 mg).

[0366] ESI-MS: m / z = 475.11 [M+H] + .

[0367] Example 5: Compound 5

[0368] 1) Preparation method of compound 5-a:

[0369] Compound 1-e (60 mg) and 5-chloro-2,4-difluoronitrobenzene (42 mg) were added to dichloromethane (2 mL). A 1M KHMDS tetrahydrofuran solution (0.22 mL) was added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 hours. 10 mL of saturated aqueous ammonium chloride was added to the reaction solution, which was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to yield 5-a (42 mg). ESI-MS: m / z = 442.9 [M+H] + .

[0370] 2) Preparation method of compound 5-b:

[0371] Referring to step 8 of Example 1, compound 5-a was used to replace compound 1-g to obtain 5-b (18 mg). ESI-MS: m / z=412.9 [M+H] + .

[0372] 3) Preparation method of compound 5-c:

[0373] Compound 5-b (18 mg), compound 4-f (10 mg), and T3P (50% w / w, DMF solution) (159 mg) were added to pyridine (1 mL). The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure until no liquid flowed out. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to obtain 5-c (22 mg). ESI-MS: m / z = 595.9 [M+H] + .

[0374] 4) Preparation method of compound 5-d:

[0375] Referring to Example 1, step 7), 1-f and 1-a were replaced with compound 5-c to obtain 5-d (18 mg). ESI-MS: m / z = 516.0 [M+H] + .

[0376] 5) Preparation method of compound 5-e:

[0377] Referring to step 1 of Example 2, 1-i was replaced with compound 5-d to obtain 5-e (20 mg). ESI-MS: m / z=533.0 [M+H] + .

[0378] 6) Preparation method of compound 5:

[0379] With reference to Example 1, step 10), compound 1-i was replaced with compound 5-e to obtain compound 5 (5 mg).

[0380] ESI-MS: m / z = 493.03 [M+H] + .

[0381] 1 H NMR(500MHz, Methanol-d4)δ8.41(s,1H),7.62(d,J=7.9Hz,1H),7.35–7.27(m,2H),5.17(d,J =6.7Hz,1H),4.71–4.63(m,1H),4.42–4.35(m,2H),4.21(d,J=6.5Hz,1H),3.29–3.22(m,2H).

[0382] Example 6: Compound 6

[0383] 1) Preparation method of compound 6-a:

[0384] DMF (5 mL) was added to the reaction flask. NaH (160 mg) was slowly added while stirring on an ice bath. After stirring for 5 minutes, 2-(tetrahydro-2H-pyran-2-oxy)ethanol (292 mg) was added. After stirring for 15 minutes, 2,6-dichloro-4-(trifluoromethyl)pyridine (432 mg) was added. After reacting at room temperature for 3 hours, a saturated ammonium chloride solution (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-a (400 mg). ESI-MS: m / z = 325.90 [M+H] + .

[0385] 2) Preparation method of compound 6-b:

[0386] Compound 6-a (400 mg) and HCl / 1,4-dioxane (5 mL) were added to a reaction flask and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain compound 6-b (300 mg). ESI-MS: m / z = 242.11 [M+H] + .

[0387] 3) Preparation method of compound 6-c:

[0388] Compound 6-b (300 mg) and toluene (10 ml) were added to a reaction flask. Potassium tert-butoxide (138 mg) was added while stirring in an ice bath. After stirring for 15 minutes, 5-chloro-2,4-difluoronitrobenzene (240 mg) was added. After the addition was complete, the mixture was warmed to room temperature and reacted for 1 hour. Saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain compound 6-c (300 mg). ESI-MS: m / z = 414.98 [M+H] + .

[0389] 4) Preparation method of compound 6-d:

[0390] Compound 6-c (300 mg), Pd / C (30 mg) and anhydrous methanol were added to a reaction flask and reacted under hydrogen protection for 8 hours. The mixture was filtered and the filtrate was concentrated to dryness to obtain compound 6-d (150 mg). ESI-MS: m / z = 385.02 [M+H] + .

[0391] 5) Preparation method of compound 6-e:

[0392] Referring to step 3 of Example 5), compound 5-b was replaced with compound 6-d and purified by column chromatography to give compound 6-e (75 mg). ESI-MS: m / z=568.04 [M+H] + .

[0393] 6) Preparation method of compound 6-f:

[0394] Compound 6-e (75 mg), Pd2(dba)3 (8 mg), Xantphos (5 mg), cesium carbonate (200 mg), and dioxane (5 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 100°C and stirred for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain compound 6-f (30 mg). ESI-MS: m / z = 532.00 [M+H] + .

[0395] 7) Preparation method of compound 6-g:

[0396] Referring to step 1 of Example 2, compound 6-f was used to replace 1-i to obtain 6-g (55 mg). ESI-MS: m / z=549.07 [M+H]+.

[0397] 8) Preparation method of compound 6:

[0398] Refer to Example 1, step 10), replacing 1-i with compound 6-g. After completion of the reaction, the reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 6 (8 mg).

[0399] ESI-MS: m / z = 509.04 [M+H] + .

[0400] 1 H NMR (500MHz, CDCl3) δ8.37(s,1H),7.86(d,J=7.9Hz,1H),6.82(d,J=10.2Hz,1H),6.75(s,1H),5.27(d,J=7.4Hz,1H),4.89(ddd,J=13.2,7.1 ,1.7Hz,1H),4.62(ddd,J=13.9,4.3,1.6Hz,1H),4.47(ddd,J=14.0,7.2,1.8Hz,2H),4.34(d,J=17.1Hz,1H),4.26–4.19(m,2H),3.40(s,1H).

[0401] Example 7: Compound 7

[0402] 1) Preparation method of compound 7-a:

[0403] Compound 1-e (400 mg) and toluene (10 mL) were added to a reaction flask, cooled in an ice bath, and potassium tert-butoxide (448 mg) was added. After stirring for 15 minutes, 4-bromo-1-fluoro-2-nitrobenzene (570 mg) was added and the mixture was allowed to warm to room temperature for 6 hours. Saturated ammonium chloride solution (20 mL) was added and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain compound 7-a (450 mg). ESI-MS: m / z = 468.86 [M+H] + .

[0404] 2) Preparation method of compound 7-b:

[0405] Referring to step 8 of Example 1, 1-g was replaced with compound 7-a to obtain compound 7-b (300 mg). ESI-MS: m / z=438.89 [M+H] + .

[0406] 3) Preparation method of compound 7-c:

[0407] Referring to step 3 of Example 5), compound 7-b was used to replace 5-b to obtain compound 7-c (150 mg). ESI-MS: m / z=622.20 [M+H] + .

[0408] 4) Preparation method of compound 7-d:

[0409] Referring to step 7 of Example 1, 1-f and 1-a were replaced with compound 7-c to obtain compound 7-d (65 mg). ESI-MS: m / z=542.06 [M+H] + .

[0410] 5) Preparation method of compound 7-e:

[0411] Referring to step 1 of Example 2, 1-i was replaced with compound 7-d to obtain 7-e (60 mg). ESI-MS: m / z=559.06 [M+H] + .

[0412] 6) Preparation method of compound 7-f:

[0413] Compound 7-e (60 mg), triisopropylsilylene (150 mg), tetrakistriphenylphosphine palladium (40 mg), cuprous iodide (10 mg), N,N-diisopropylethylamine (100 mg), and toluene (5 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 110°C and stirred for 6 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain compound 7-f (60 mg). ESI-MS: m / z = 661.46 [M+H] + .

[0414] 7) Preparation method of compound 7-g:

[0415] Compound 7-f (60 mg) was added to dichloromethane (5 mL) and stirred in an ice bath. Boron trichloride (40 mg) was slowly added. After addition, the mixture was naturally warmed to room temperature and stirred for 3 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7-g (30 mg). ESI-MS: m / z = 621.32 [M+H] + .

[0416] 8) Preparation method of compound 7:

[0417] Compound 7-g (30 mg) and 1M tetrabutylammonium fluoride solution in tetrahydrofuran (5 mL) were added to a reaction flask and stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to obtain compound 7 (15 mg).

[0418] ESI-MS: m / z = 465.16 [M+H] + .

[0419] 1 H NMR (500MHz, CDCl3) δ8.53(s,1H),7.63(d,J=2.1Hz,1H),7.53(d,J=2.1Hz,1H),7.11(s,1H),7.06(s,1H),5.25(d ,J=7.3Hz,1H),4.55(m,1H),4.47(m,1H),4.37(t,J=6.8Hz,1H),4.22(d,J=6.4Hz,1H),3.46(s,1H),3.08(m,2H).

[0420] Example 8: Compound 8

[0421] 1) Preparation method of compound 8-a:

[0422] With reference to step 1 of Example 7, 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,4-difluoro-2-nitrobenzene to obtain compound 8-a.

[0423] 2) Preparation method of compound 8-b:

[0424] With reference to Example 4, step 2), 4-a was replaced with compound 8-a to obtain compound 8-b.

[0425] 3) Preparation method of compound 8-c:

[0426] With reference to step 3 of Example 5), 5-b was replaced with compound 8-b to obtain compound 8-c.

[0427] 4) Preparation method of compound 8-d:

[0428] With reference to Example 5, step 4), 5-c was replaced with compound 8-c to give compound 8-d.

[0429] 5) Preparation method of compound 8-e:

[0430] With reference to Example 5, step 5), 5-d was replaced with compound 8-d to give compound 8-e.

[0431] 6) Preparation method of compound 8:

[0432] Refer to Example 5, step 6), replace 5-e with compound 8-e to obtain compound 8.

[0433] ESI-MS: m / z = 459.08 [M+H] + .

[0434] Example 9: Compound 9

[0435] 1) Preparation method of compound 9-a:

[0436] With reference to Example 7, step 1), 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1-fluoro-2-nitrobenzene to obtain compound 9-a.

[0437] 2) Preparation method of compound 9-b:

[0438] With reference to Example 4, step 2), 4-a was replaced with compound 9-a to give compound 9-b.

[0439] 3) Preparation method of compound 9-c:

[0440] With reference to step 3 of Example 5), 5-b was replaced with compound 9-b to give compound 9-c.

[0441] 4) Preparation method of compound 9-d:

[0442] With reference to step 4 of Example 5), 5-c was replaced with compound 9-c to give compound 9-d.

[0443] 5) Preparation method of compound 9-e:

[0444] With reference to Example 5, step 5), 5-d was replaced with compound 9-d to give compound 9-e.

[0445] 6) Preparation method of compound 9:

[0446] With reference to Example 5, step 6), 5-e was replaced with compound 9-e to obtain compound 9.

[0447] ESI-MS: m / z = 441.24 [M+H] + .

[0448] 1H NMR (500MHz, CDCl3) δ8.57(s,1H),7.52–7.36(m,2H),7.19–6.96(m,3H),5.33(d,J=7.3Hz,1H),5.20(d,J=11.3Hz,1H),4.53(d d,J=6.2,4.2Hz,2H),4.30(q,J=6.7Hz,1H),4.20(d,J=7.9Hz,1H),3.27(dt,J=15.6,5.9Hz,2H),3.05(dt,J=15.6,4.3Hz,1H).

[0449] Example 10: Compound 10

[0450] 1) Preparation method of compound 10-a:

[0451] With reference to step 1 of Example 7, 4-bromo-1-fluoro-2-nitrobenzene was replaced with 2,4-difluoro-1-nitrobenzene to obtain compound 10-a.

[0452] 2) Preparation method of compound 10-b:

[0453] With reference to Example 4, step 2), 4-a was replaced with compound 10-a to obtain compound 10-b.

[0454] 3) Preparation method of compound 10-c:

[0455] With reference to step 3 of Example 5), 5-b was replaced with compound 10-b to obtain compound 10-c.

[0456] 4) Preparation method of compound 10-d:

[0457] With reference to step 4 of Example 5), 5-c was replaced with compound 10-c to obtain compound 10-d.

[0458] 5) Preparation method of compound 10-e:

[0459] With reference to Example 5, step 5), 5-d was replaced with compound 10-d to obtain compound 10-e.

[0460] 6) Preparation method of compound 10:

[0461] With reference to Example 5, step 6), 5-e was replaced by compound 10-e to obtain compound 10.

[0462] ESI-MS: m / z = 459.05 [M+H] + .

[0463] Example 11: Compound 11

[0464] 1) Preparation method of compound 11-a:

[0465] With reference to Example 7, step 1), 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,2-difluoro-3-nitrobenzene to obtain compound 11-a.

[0466] 2) Preparation method of compound 11-b:

[0467] With reference to Example 4, step 2), 4-a was replaced with compound 11-a to obtain compound 11-b.

[0468] 3) Preparation method of compound 11-c:

[0469] With reference to Example 5, step 3), 5-b was replaced with compound 11-b to obtain compound 11-c.

[0470] 4) Preparation method of compound 11-d:

[0471] With reference to step 4 of Example 5), 5-c was replaced with compound 11-c to obtain compound 11-d.

[0472] 5) Preparation method of compound 11-e:

[0473] With reference to Example 5, step 5), 5-d was replaced with compound 11-d to obtain compound 11-e.

[0474] 6) Preparation method of compound 11:

[0475] With reference to Example 5, step 6), 5-e was replaced with compound 11-e to obtain compound 11.

[0476] ESI-MS: m / z = 459.08 [M+H] + .

[0477] 1 H NMR(500MHz,MeOD)δ8.40(s,1H),7.37–7.28(m,3H),7.16(td,J=8.2,5.4Hz,1H),5.10(d,J=6.3Hz,1H),4.99(dtd,J=10.4,5.2,1.8 Hz,1H),4.43(t,J=6.3Hz,1H),4.38–4.31(m,1H),4.25(d,J=6.4Hz,1H),3.37(dd,J=17.8,9.7Hz,1H),3.19(dd,J=17.7,5.2Hz,1H).

[0478] Example 12: Compound 12

[0479] 1) Preparation method of compound 12-a:

[0480] With reference to Example 7, step 1), 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,2,3,4,5-pentafluoro-6-nitrobenzene to obtain compound 12-a.

[0481] 2) Preparation method of compound 12-b:

[0482] With reference to Example 4, step 2), 4-a was replaced with compound 12-a to obtain compound 12-b.

[0483] 3) Preparation method of compound 12-c:

[0484] With reference to Example 5, step 3), 5-b was replaced with compound 12-b to obtain compound 12-c.

[0485] 4) Preparation method of compound 12-d:

[0486] With reference to Example 5, step 4), 5-c was replaced with compound 12-c to obtain compound 12-d.

[0487] 5) Preparation method of compound 12-e:

[0488] With reference to Example 5, step 5), 5-d was replaced with compound 12-d to give compound 12-e.

[0489] 6) Preparation method of compound 12:

[0490] Refer to Example 5, step 6), replace 5-e with compound 12-e to obtain compound 12.

[0491] ESI-MS: m / z = 513.20 [M+H] + .

[0492] 1 H NMR(500MHz, CDCl3)δ8.47(s,1H),7.17(s,1H),5.54(m,1H),4.91(m,1H),4.7 3(m,1H),4.38(s,1H),3.99(s,2H),3.43–3.26(m,2H),3.21(d,J=15.2Hz,1H).

[0493] Example 13: Compound 13

[0494] 1) Preparation method of compound 13-a:

[0495] With reference to Example 7, step 1), 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,2,4-trifluoro-5-nitrobenzene to obtain compound 13-a.

[0496] 2) Preparation method of compound 13-b:

[0497] With reference to Example 4, step 2), 4-a was replaced with compound 13-a to obtain compound 13-b.

[0498] 3) Preparation method of compound 13-c:

[0499] With reference to Example 5, step 3), 5-b was replaced with compound 13-b to obtain compound 13-c.

[0500] 4) Preparation method of compound 13-d:

[0501] With reference to Example 5, step 4), 5-c was replaced with compound 13-c to obtain compound 13-d.

[0502] 5) Preparation method of compound 13-e:

[0503] With reference to Example 5, step 5), 5-d was replaced with compound 13-d to obtain compound 13-e.

[0504] 6) Preparation method of compound 13:

[0505] Refer to Example 5, step 6), replace 5-e with compound 13-e to obtain compound 13.

[0506] ESI-MS: m / z = 477.03 [M+H] + .

[0507] 1 H NMR(500MHz,MeOD)δ8.41(s,1H),7.45(dd,J=10.4,8.5Hz,1H),7.34–7.27(m,2H),5.17(d,J=6.7Hz,1H),4.65(ddd,J=10.3,5 .5,3.4Hz,1H),4.40(t,J=6.6Hz,1H),4.35(ddd,J=10.6,7.3,3.6Hz,1H),4.21(d,J=6.4Hz,1H),3.26(dt,J=5.7,3.5Hz,2H).

[0508] Example 14: Compound 14

[0509] 1) Preparation method of compound 14-a:

[0510] With reference to step 1 of Example 7), 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,2,4,5-tetrafluoro-3-nitrobenzene to obtain compound 14-a.

[0511] 2) Preparation method of compound 14-b:

[0512] With reference to Example 4, step 2), 4-a was replaced with compound 14-a to obtain compound 14-b.

[0513] 3) Preparation method of compound 14-c:

[0514] With reference to Example 5, step 3), 5-b was replaced with compound 14-b to obtain compound 14-c.

[0515] 4) Preparation method of compound 14-d:

[0516] With reference to Example 5, step 4), 5-c was replaced with compound 14-c to obtain compound 14-d.

[0517] 5) Preparation method of compound 14-e:

[0518] With reference to Example 5, step 5), 5-d was replaced with compound 14-d to obtain compound 14-e.

[0519] 6) Preparation method of compound 14:

[0520] With reference to Example 5, step 6), 5-e was replaced with compound 14-e to obtain compound 14.

[0521] ESI-MS: m / z = 495.23 [M+H] + .

[0522] 1 H NMR(500MHz, CDCl3)δ8.48(s,1H),7.21–7.07(m,2H),5.02(dd,J=5.1,1.0Hz,1H),4.95–4.83(m,1H),4.53(d,J=5.3Hz,1H),4.49– 4.36(m,1H),4.29(d,J=7.4Hz,1H),3.80(d,J=9.6Hz,1H),3.63(d,J=6.0Hz,1H),3.32(dd,J=17.4,9.1Hz,1H),3.18–3.04(m,1H).

[0523] Example 15: Compound 15

[0524] 1) Preparation method of compound 15-a:

[0525] With reference to step 1 of Example 7, 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,3-difluoro-2-nitrobenzene to obtain compound 15-a.

[0526] 2) Preparation method of compound 15-b:

[0527] With reference to Example 4, step 2), 4-a was replaced with compound 15-a to obtain compound 15-b.

[0528] 3) Preparation method of compound 15-c:

[0529] With reference to step 3 of Example 5), 5-b was replaced with compound 15-b to obtain compound 15-c.

[0530] 4) Preparation method of compound 15-d:

[0531] With reference to Example 5, step 4), 5-c was replaced with compound 15-c to obtain compound 15-d.

[0532] 5) Preparation method of compound 15-e:

[0533] With reference to Example 5, step 5), 5-d was replaced with compound 15-d to obtain compound 15-e.

[0534] 6) Preparation method of compound 15:

[0535] Refer to Example 5, step 6), replace 5-e with compound 15-e to obtain compound 15.

[0536] ESI-MS: m / z = 459.23 [M+H] + .

[0537] 1 H NMR(500MHz,MeOD)δ8.42(s,1H),7.32(s,1H),7.26(td,J=8.4,6.3Hz,1H),6.81–6.74(m,2H),5.79(d,J=5.2 Hz,1H),4.87(t,J=5.5Hz,2H),4.58(p,J=3.5Hz,2H),3.79(ddd,J=11.1,8.8,1.9Hz,1H),3.30–3.23(m,1H).

[0538] Example 16: Compound 16

[0539] 1) Preparation method of compound 16-a:

[0540] With reference to step 1 of Example 7, 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,2,5-trifluoro-3-nitrobenzene to obtain compound 16-a.

[0541] 2) Preparation method of compound 16-b:

[0542] With reference to Example 4, step 2), 4-a was replaced with compound 16-a to obtain compound 16-b.

[0543] 3) Preparation method of compound 16-c:

[0544] With reference to Example 5, step 3), 5-b was replaced with compound 16-b to obtain compound 16-c.

[0545] 4) Preparation method of compound 16-d:

[0546] With reference to Example 5, step 4), 5-c was replaced with compound 16-c to obtain compound 16-d.

[0547] 5) Preparation method of compound 16-e:

[0548] With reference to Example 5, step 5), 5-d was replaced with compound 16-d to give compound 16-e.

[0549] 6) Preparation method of compound 16:

[0550] Refer to Example 5, step 6), replace 5-e with compound 16-e to obtain compound 16.

[0551] ESI-MS: m / z = 477.19 [M+H] + .

[0552] Example 17: Compound 17

[0553] 1) Preparation method of compound 17-a:

[0554] With reference to Example 7, step 1), 4-bromo-1-fluoro-2-nitrobenzene was replaced with 4-fluoro-3-nitrobenzotrifluoride to obtain compound 17-a.

[0555] 2) Preparation method of compound 17-b:

[0556] With reference to Example 4, step 2), 4-a was replaced with compound 17-a to give compound 17-b.

[0557] 3) Preparation method of compound 17-c:

[0558] With reference to step 3 of Example 5), 5-b was replaced with compound 17-b to obtain compound 17-c.

[0559] 4) Preparation method of compound 17-d:

[0560] With reference to Example 5, step 4), 5-c was replaced with compound 17-c to obtain compound 17-d.

[0561] 5) Preparation method of compound 17-e:

[0562] With reference to Example 5, step 5), 5-d was replaced with compound 17-d to give compound 17-e.

[0563] 6) Preparation method of compound 17:

[0564] With reference to Example 5, step 6), 5-e was replaced with compound 17-e to obtain compound 17.

[0565] ESI-MS: m / z = 509.04 [M+H] + .

[0566] Example 18: Compound 18

[0567] 1) Preparation method of compound 18-a:

[0568] With reference to Example 7, step 1), 4-bromo-1-fluoro-2-nitrobenzene was replaced with 1,2,3,4-tetrafluoro-5-nitrobenzene to obtain compound 18-a.

[0569] 2) Preparation method of compound 18-b:

[0570] With reference to Example 4, step 2), 4-a was replaced with compound 18-a to obtain compound 18-b.

[0571] 3) Preparation method of compound 18-c:

[0572] With reference to Example 5, step 3), 5-b was replaced with compound 18-b to obtain compound 18-c.

[0573] 4) Preparation method of compound 18-d:

[0574] With reference to Example 5, step 4), 5-c was replaced with compound 18-c to give compound 18-d.

[0575] 5) Preparation method of compound 18-e:

[0576] With reference to Example 5, step 5), 5-d was replaced with compound 18-d to give compound 18-e.

[0577] 6) Preparation method of compound 18:

[0578] With reference to Example 5, step 6), 5-e was replaced by compound 18-e to obtain compound 18.

[0579] ESI-MS: m / z = 495.19 [M+H] + .

[0580] Example 19: Compound 19

[0581] 1) Preparation method of compound 19-a:

[0582] Compound 1-d (300 mg) was added to tetrahydrofuran (10 mL) and water (3 mL), and lithium hydroxide monohydrate (211 mg) was added. The mixture was stirred at room temperature for 30 minutes. The pH of the system was adjusted to approximately 4 with a 2M aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain compound 19-a (280 mg). ESI-MS: m / z = 283.94 [M+H] + .

[0583] 2) Preparation method of compound 19-b:

[0584] Compound 19-a (280 mg), ammonium chloride (105 mg), 1-hydroxybenzotriazole (200 mg), EDCI (283 mg), triethylamine (300 mg), and DMF (15 mL) were added to a reaction flask and stirred at room temperature overnight. 15 mL of water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, slurried with a mixed solvent of petroleum ether and ethyl acetate, filtered, and the filter cake was dried to obtain compound 19-b (120 mg). ESI-MS: m / z = 282.97 [M+H] + .

[0585] 3) Preparation method of compound 19-c:

[0586] Compound 19-b (90 mg) was added to tetrahydrofuran (10 mL), and a 1 M borane tetrahydrofuran solution (3 mL) was added. The mixture was heated to 80°C and stirred for 4 hours. After slowly adding a 1:1 mixed solvent of tetrahydrofuran and water to quench the reaction, a 2 M aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with dichloromethane, and the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 19-c (85 mg). ESI-MS: m / z = 268.94 [M+H] + .

[0587] 4) Preparation method of compound 19-d:

[0588] Compound 19-c (85 mg), 5-chloro-2,4-difluoronitrobenzene (60 mg), N,N-diisopropylethylamine (81 mg), and DMF (5 mL) were added to a reaction flask and heated to 60°C with stirring for 2 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 19-d (70 mg) was purified by column chromatography. ESI-MS: m / z = 442.00 [M+H] + .

[0589] 5) Preparation method of compound 19-e:

[0590] Compound 19-d (70 mg), potassium carbonate (88 mg), and DMF (5 mL) were added to a reaction flask, followed by iodomethane (92 mg) and allowed to react at room temperature for 2 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 19-e (80 mg). ESI-MS: m / z = 456.05 [M+H] + .

[0591] 6) Preparation method of compound 19-f:

[0592] With reference to Example 4, step 2), 4-a was replaced with compound 19-e to obtain compound 19-f.

[0593] 7) Preparation method of compound 19-g:

[0594] With reference to Example 5, step 3), 5-b was replaced with compound 19-f to obtain compound 19-g.

[0595] 8) Preparation method of compound 19-h:

[0596] With reference to Example 5, step 4), 5-c was replaced with compound 19-g to obtain compound 19-h.

[0597] 9) Preparation method of compound 19-i:

[0598] With reference to Example 5, step 5), 5-d was replaced with compound 19-h to obtain compound 19-i.

[0599] 10) Preparation method of compound 19:

[0600] With reference to Example 5, step 6), 5-e was replaced by compound 19-i to obtain compound 19.

[0601] ESI-MS: m / z = 506.16 [M+H] + .

[0602] Example 20: Compound 20

[0603] 1) Preparation method of compound 20-a:

[0604] 3-(Trimethylsilyl)propargyl alcohol (6.1 g) and cesium fluoride (1.45 g) were added to DMF (50 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and 2,6-dibromo-4-trifluoromethylpyridine (14.5 g), cuprous iodide (905.9 mg), bis(triphenylphosphine)palladium(II) dichloride (1.67 g), and triethylamine (60 mL) were added to the filtrate. The atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for 1 hour. 80 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield 20-a (6.8 g). ESI-MS: m / z = 279.90 [M+H] + .

[0605] 2) Preparation method of compound 20-b:

[0606] 20-a (6.8 g), platinum dioxide (551.8 mg), triethylamine (5 mL), and ethanol (60 mL) were added to a reaction flask, replaced with hydrogen, and stirred at room temperature for 8 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain compound 20-b (14.6 g). ESI-MS: m / z = 283.96 [M+H] + .

[0607] 3) Preparation method of compound 20-c:

[0608] With reference to step 1 of Example 7), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 5-chloro-2,4-difluoronitrobenzene to obtain compound 20-c.

[0609] 4) Preparation method of compound 20-d:

[0610] With reference to Example 4, step 2), 4-a was replaced with compound 20-c to obtain compound 20-d.

[0611] 5) Preparation method of compound 20-e:

[0612] With reference to Example 5, step 3), 5-b was replaced with compound 20-d to obtain compound 20-e.

[0613] 6) Preparation method of compound 20-f:

[0614] With reference to Example 5, step 4), 5-c was replaced with compound 20-e to obtain compound 20-f.

[0615] 7) Preparation method of compound 20-g:

[0616] With reference to Example 5, step 5), 5-d was replaced with compound 20-f to obtain compound 20-g.

[0617] 8) Preparation method of compound 20:

[0618] With reference to Example 5, step 6), 5-e was replaced by compound 20-g to obtain compound 20.

[0619] ESI-MS: m / z = 507.18 [M+H] + .

[0620] 1 H NMR(500MHz,MeOD)δ8.40(s,1H),7.66(d,J=8.0Hz,1H),7.36(d,J=10.7Hz,1H),7.31(d, J=1.4Hz,1H),4.70(d,J=5.6Hz,1H),4.48(ddd,J=8.5,4.9,2.5Hz,1H),4.28(d,J=6.3Hz, 1H),4.23(t,J=5.9Hz,1H),3.89(ddd,J=12.1,9.0,3.2Hz,1H),3.17(td,J=12.9,4.1Hz,1 H),2.94(dt,J=13.3,4.3Hz,1H),2.39(ddq,J=14.2,11.9,4.7Hz,1H),1.98–1.90(m,1H).

[0621] Example 21: Compound 21

[0622] 1) Preparation method of compound 21-a:

[0623] With reference to Example 7, step 1), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 4-fluoro-3-nitrotoluene to obtain compound 21-a.

[0624] 2) Preparation method of compound 21-b:

[0625] With reference to Example 4, step 2), 4-a was replaced with compound 21-a to obtain compound 21-b.

[0626] 3) Preparation method of compound 21-c:

[0627] With reference to Example 5, step 3), 5-b was replaced with compound 21-b to obtain compound 21-c.

[0628] 4) Preparation method of compound 21-d:

[0629] With reference to Example 5, step 4), 5-c was replaced with compound 21-c to obtain compound 21-d.

[0630] 5) Preparation method of compound 21-e:

[0631] With reference to Example 5, step 5), 5-d was replaced with compound 21-d to obtain compound 21-e.

[0632] 6) Preparation method of compound 21:

[0633] With reference to Example 5, step 6), 5-e was replaced with compound 21-e to obtain compound 21.

[0634] ESI-MS: m / z = 469.19 [M+H] + .

[0635] 1 H NMR (500MHz, MeOD) δ8.41(s,1H),7.32–7.22(m,4H),4.68(d,J=4.1Hz,1H),4.46–4.42(m,1H),4.26(d,J=3.7Hz,2H),3.86(d dd,J=12.1,8.9,3.2Hz,1H),3.20(td,J=13.0,4.0Hz,1H),2.91(dt,J=13.2,4.3Hz,1H),2.36(s,4H),1.88(d,J=11.9Hz,1H).

[0636] Example 22: Compound 22

[0637] 1) Preparation method of compound 22-a:

[0638] With reference to step 1 of Example 7), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 2,5-difluoronitrobenzene to obtain compound 22-a.

[0639] 2) Preparation method of compound 22-b:

[0640] With reference to Example 4, step 2), 4-a was replaced with compound 22-a to obtain compound 22-b.

[0641] 3) Preparation method of compound 22-c:

[0642] With reference to Example 5, step 3), 5-b was replaced with compound 22-b to obtain compound 22-c.

[0643] 4) Preparation method of compound 22-d:

[0644] With reference to Example 5, step 4), 5-c was replaced with compound 22-c to obtain compound 22-d.

[0645] 5) Preparation method of compound 22-e:

[0646] With reference to Example 5, step 5), 5-d was replaced with compound 22-d to give compound 22-e.

[0647] 6) Preparation method of compound 22:

[0648] With reference to Example 5, step 6), 5-e was replaced by compound 22-e to obtain compound 22.

[0649] ESI-MS: m / z = 473.20 [M+H] + .

[0650] 1 H NMR(500MHz,MeOD)δ8.43(s,1H),7.46–7.38(m,1H),7.38–7.30(m,2H),7.28–7.20(m,1H),4.7 4(d,J=5.0Hz,1H),4.38–4.21(m,2H),3.96–3.83(m,2H),3.00–2.86(m,2H),2.55–2.30(m,2H).

[0651] Example 23: Compound 23

[0652] 1) Preparation method of compound 23-a:

[0653] With reference to Example 7, step 1), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 2,4-difluoronitrobenzene to obtain compound 23-a.

[0654] 2) Preparation method of compound 23-b:

[0655] With reference to Example 4, step 2), 4-a was replaced with compound 23-a to obtain compound 23-b.

[0656] 3) Preparation method of compound 23-c:

[0657] With reference to Example 5, step 3), 5-b was replaced with compound 23-b to obtain compound 23-c.

[0658] 4) Preparation method of compound 23-d:

[0659] With reference to Example 5, step 4), 5-c was replaced with compound 23-c to obtain compound 23-d.

[0660] 5) Preparation method of compound 23-e:

[0661] With reference to Example 5, step 5), 5-d was replaced with compound 23-d to give compound 23-e.

[0662] 6) Preparation method of compound 23:

[0663] With reference to Example 5, step 6), 5-e was replaced by compound 23-e to obtain compound 23.

[0664] ESI-MS: m / z = 473.19 [M+H] + .

[0665] 1 H NMR(500MHz,MeOD)δ8.41(d,J=19.0Hz,1H),7.50(dd,J=8.7,6.2Hz,1H),7.33(d,J=22.7Hz,1 H),7.17(dd,J=10.4,2.8Hz,1H),6.88(qd,J=8.6,2.8Hz,1H),4.67(d,J=4.7Hz,1H),4.48(td ,J=7.4,3.3Hz,1H),4.24(d,J=5.3Hz,2H),3.89(ddd,J=12.2,9.1,3.2Hz,1H),3.19(td,J=12 .9,4.0Hz,1H),2.94(dt,J=13.5,4.4Hz,1H),2.38(tq,J=9.1,4.7Hz,1H),2.06–1.78(m,1H).

[0666] Example 24: Compound 24

[0667] 1) Preparation method of compound 24-a:

[0668] With reference to Example 7, step 1), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 2,3-difluoronitrobenzene to obtain compound 24-a.

[0669] 2) Preparation method of compound 24-b:

[0670] With reference to Example 4, step 2), 4-a was replaced with compound 24-a to give compound 24-b.

[0671] 3) Preparation method of compound 24-c:

[0672] With reference to Example 5, step 3), 5-b was replaced with compound 24-b to obtain compound 24-c.

[0673] 4) Preparation method of compound 24-d:

[0674] With reference to Example 5, step 4), 5-c was replaced with compound 24-c to obtain compound 24-d.

[0675] 5) Preparation method of compound 24-e:

[0676] With reference to Example 5, step 5), 5-d was replaced with compound 24-d to give compound 24-e.

[0677] 6) Preparation method of compound 24:

[0678] With reference to Example 5, step 6), 5-e was replaced with compound 24-e to obtain compound 24.

[0679] ESI-MS: m / z = 473.24 [M+H] + .

[0680] Example 25: Compound 25

[0681] 1) Preparation method of compound 25-a:

[0682] With reference to Example 7, step 1), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 4-fluoro-3-nitrobenzotrifluoride to obtain compound 25-a.

[0683] 2) Preparation method of compound 25-b:

[0684] With reference to Example 4, step 2), 4-a was replaced with compound 25-a to obtain compound 25-b.

[0685] 3) Preparation method of compound 25-c:

[0686] With reference to Example 5, step 3), 5-b was replaced with compound 25-b to obtain compound 25-c.

[0687] 4) Preparation method of compound 25-d:

[0688] With reference to step 4 of Example 5), 5-c was replaced with compound 25-c to obtain compound 25-d.

[0689] 5) Preparation method of compound 25-e:

[0690] With reference to Example 5, step 5), 5-d was replaced with compound 25-d to obtain compound 25-e.

[0691] 6) Preparation method of compound 25:

[0692] Refer to Example 5, step 6), replace 5-e with compound 25-e to obtain compound 25.

[0693] ESI-MS: m / z = 523.16 [M+H] + .

[0694] 1 H NMR(500MHz,MeOD)δ8.38(s,1H),7.87(d,J=2.4Hz,1H),7.77(dd,J=8.8,2.4Hz,1H),7 .53(d,J=8.7Hz,1H),7.31(s,1H),4.64(d,J=5.5Hz,1H),4.59(ddd,J=8.7,5.1,3.1Hz, 1H),4.25(d,J=6.3Hz,1H),4.17(t,J=5.9Hz,1H),3.95(ddd,J=11.9,9.2,3.2Hz,1H), 3.24–3.18(m,1H),2.97(dt,J=13.4,4.4Hz,1H),2.45–2.36(m,1H),2.02–1.95(m,1H).

[0695] Example 26: Compound 26

[0696] 1) Preparation method of compound 26-a:

[0697] With reference to Example 7, step 1), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 5-chloro-2-fluoronitrobenzene to obtain compound 26-a.

[0698] 2) Preparation method of compound 26-b:

[0699] With reference to Example 4, step 2), 4-a was replaced with compound 26-a to obtain compound 26-b.

[0700] 3) Preparation method of compound 26-c:

[0701] With reference to Example 5, step 3), 5-b was replaced with compound 26-b to give compound 26-c.

[0702] 4) Preparation method of compound 26-d:

[0703] With reference to Example 5, step 4), 5-c was replaced with compound 26-c to obtain compound 26-d.

[0704] 5) Preparation method of compound 26-e:

[0705] With reference to Example 5, step 5), 5-d was replaced with compound 26-d to give compound 26-e.

[0706] 6) Preparation method of compound 26:

[0707] Refer to Example 5, step 6), replace 5-e with compound 26-e to obtain compound 26.

[0708] ESI-MS: m / z = 489.3 [M+H] + .

[0709] 1 H NMR(500MHz,CD3CN)δ8.27(s,1H),7.58(d,J=2.7Hz,1H),7.45(dd,J=8.9,2.7Hz,1H),7.37–7.31 (m,2H),4.66(d,J=6.1Hz,1H),4.46(ddd,J=8.5,5.2,2.7Hz,1H),4.27(t,J=6.1Hz,1H),4.15(d, J=6.1Hz,1H),3.85(dt,J=8.8,4.2Hz,1H),3.75(ddd,J=12.2,9.1,3.4Hz,2H),3.14(td,J=12.9, 4.2Hz,1H),2.94(dt,J=13.2,4.4Hz,1H),2.35(ddt,J=14.7,7.1,4.8Hz,1H),1.95–1.89(m,1H).

[0710] Example 27: Compound 27

[0711] 1) Preparation method of compound 27-a:

[0712] With reference to Example 7, step 1), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 2,3,5-trifluoronitrobenzene to obtain compound 27-a.

[0713] 2) Preparation method of compound 27-b:

[0714] With reference to Example 4, step 2), 4-a was replaced with compound 27-a to obtain compound 27-b.

[0715] 3) Preparation method of compound 27-c:

[0716] With reference to Example 5, step 3), 5-b was replaced with compound 27-b to obtain compound 27-c.

[0717] 4) Preparation method of compound 27-d:

[0718] With reference to Example 5, step 4), 5-c was replaced with compound 27-c to obtain compound 27-d.

[0719] 5) Preparation method of compound 27-e:

[0720] With reference to Example 5, step 5), 5-d was replaced with compound 27-d to give compound 27-e.

[0721] 6) Preparation method of compound 27:

[0722] With reference to Example 5, step 6), 5-e was replaced by compound 27-e to obtain compound 27.

[0723] ESI-MS: m / z = 491.20 [M+H] + .

[0724] Example 28: Compound 28

[0725] 1) Preparation method of compound 28-a:

[0726] With reference to Example 7, step 1), 1-e was replaced by 20-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 4-cyclopropyl-1-fluoro-2-nitrobenzene to obtain compound 28-a.

[0727] 2) Preparation method of compound 28-b:

[0728] With reference to Example 4, step 2), 4-a was replaced with compound 28-a to obtain compound 28-b.

[0729] 3) Preparation method of compound 28-c:

[0730] With reference to Example 5, step 3), 5-b was replaced with compound 28-b to obtain compound 28-c.

[0731] 4) Preparation method of compound 28-d:

[0732] With reference to Example 5, step 4), 5-c was replaced with compound 28-c to give compound 28-d.

[0733] 5) Preparation method of compound 28-e:

[0734] With reference to Example 5, step 5), 5-d was replaced with compound 28-d to give compound 28-e.

[0735] 6) Preparation method of compound 28:

[0736] With reference to Example 5, step 6), 5-e was replaced with compound 28-e to obtain compound 28.

[0737] ESI-MS: m / z = 495.25 [M+H] + .

[0738] 1 H NMR(500MHz,MeOD)δ8.33(s,1H),7.24–7.20(m,1H),7.19–7.15(m,1H),7.14–7.07(m,2H),4.59(d,J=5.3Hz,1H),4.42–4.30(m,1H),4.23–4.1 4(m,2H),3.83–3.71(m,1H),3.18–3.07(m,1H),2.89–2.76(m,1H),2.38 –2.20(m,1H),1.93–1.83(m,2H),0.96–0.88(m,2H),0.67–0.59(m,2H).

[0739] Example 29: Compound 29

[0740] 1) Preparation method of compound 29-a:

[0741] 2,6-Dibromo-4-trifluoromethylpyridine (300 mg), 3-butyn-1-ol (55 mg), cuprous iodide (19 mg), bis(triphenylphosphine)palladium(II) dichloride (69 mg), and triethylamine (200 mg) were added to THF (10 mL), the atmosphere was replaced with nitrogen, and the reaction was stirred at 60°C for 1.5 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 29-a (290 mg). ESI-MS: m / z = 293.98 [M+H] + .

[0742] 2) Preparation method of compound 29-b:

[0743] With reference to Example 20, step 2), 20-a was replaced with 29-a to give compound 29-b.

[0744] 3) Preparation method of compound 29-c:

[0745] With reference to Example 7, step 1), 1-e was replaced by 29-b, and 4-bromo-1-fluoro-2-nitrobenzene was replaced by 5-chloro-2,4-difluoronitrobenzene to obtain compound 29-c.

[0746] 4) Preparation method of compound 29-d:

[0747] With reference to Example 4, step 2), 4-a was replaced with compound 29-c to obtain compound 29-d.

[0748] 5) Preparation method of compound 29-e:

[0749] With reference to Example 5, step 3), 5-b was replaced with compound 29-d to obtain compound 29-e.

[0750] 6) Preparation method of compound 29-f:

[0751] With reference to Example 5, step 4), 5-c was replaced with compound 29-e to obtain compound 29-f.

[0752] 7) Preparation method of compound 29-g:

[0753] With reference to Example 5, step 5), 5-d was replaced with compound 29-f to obtain compound 29-g.

[0754] 8) Preparation method of compound 29:

[0755] With reference to Example 5, step 6), 5-e was replaced with compound 29-g to obtain compound 29.

[0756] ESI-MS: m / z = 521.12 [M+H] + .

[0757] 1 H NMR(500MHz,MeOD)δ8.35(s,1H),7.75(d,J=7.9Hz,1H),7.23–7.18(m,2H),5.04(d,J=5.1Hz,1H),4.35–4.22(m,4H),2.82(ddd, J=10.5,8.6,6.4Hz,1H),2.70(ddd,J=13.4,8.9,4.2Hz,1H),2.18–2.09(m,1H),2.02(tp,J=11.2,5.5Hz,1H),1.92–1.81(m,2H).

[0758] Experimental Example 1: Determination of POLQ protein inhibitory activity

[0759] 6 μL of PolQ protein solution (4 nM concentration) was added to the assay wells. Different compounds dissolved in DMSO were added to the assay wells using a nanoliter pipette to a final concentration of 2000 nM to 0.488 nM. Two replicate wells were used, and a control was also set up. 100 nM PolQ substrate and 40 μM dNTP were mixed and added to the assay wells at 6 μL per well. The above system was incubated for 60 minutes. PicoGreen dye (manufacturer: Thermo) was diluted 1:80 with stop buffer and added to the assay wells at 8 μL per well. After reacting at room temperature for 90 minutes, the assay was performed using a PerkinElmer Envision multi-function microplate reader (excitation 485 nm, emission 520 nm). IC was calculated using a four-parameter fit. 50 The results are shown in Table 1.

[0760] Table 1. POLQ protein inhibitory activity

[0761] The test results show that the compound of the present application has POLQ protein inhibitory activity.

[0762] Test Example 2: In vitro liver microstructure stability evaluation

[0763] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared. The supernatant was diluted and used for LC / MS / MS analysis.

[0764] The test results of the test compound showed that the compound of the present application exhibited good metabolic stability in liver microsomes.

[0765] Test Example 3: In vivo pharmacokinetics

[0766] ICR mice weighing 18-22 g were randomly divided into groups after acclimation for 3-5 days and were injected intravenously with 1 mg / kg or orally with 10 mg / kg of the test compound solution.

[0767] Blood was collected from the eye socket at time points 0, 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, and 24 h after intravenous injection to prepare plasma samples.

[0768] Blood was collected from the eye sockets at 0, 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, and 24 h after gavage, and plasma samples were prepared.

[0769] 30 μL of plasma sample and standard curve were aspirated and added to an acetonitrile solution containing an internal standard for protein precipitation. The supernatant was diluted and used for LC / MS / MS analysis. A non-compartmental model was used for fitting.

[0770] The test results of the test compound showed that the compound of the present application exhibited good in vivo metabolic kinetics (AUC, Tmax, Cmax and bioavailability).

Claims

1. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Ring A and Ring B are independently selected from 3-20 membered rings; Every R 1 are independently selected from halogen, -CN, =O or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; m is selected from 0, 1, 2, 3, 4 or 5; Every R 2 are independently selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Or, any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl; n is selected from 0, 1, 2, 3, 4, 5 or 6; Each X is independently selected from -CH2-, -NH-, -O- or -S-; k is selected from 0, 1, 2, 3 or 4; Every R 4 are independently selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , C 3-12 Cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl; p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; R ab Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; L is selected from -CONR c -R c1 -、-NR c CO-R c1 -、-SONR c -R c1 -、-NR c SO-R c1 -、-SO2NR c -R c1 -or-NR c SO2-R c1 -; R c Selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 3-12 Cycloalkyl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 3-12 Cycloalkyl is optionally substituted with one or more of the following: deuterium, halogen, CN, OH, SH, NH2, CHO or COOH; R c1 Select from key or C 1-12 Alkylene, the C 1-12 The alkylene group is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO or COOH; L 1 is selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-12 Alkylene, C 1-12 Heteroalkylene, C 1-12 Heteroalkenylene or C 1-12 heteroalkynylene; R d Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; Or, two R d Together with the atoms to which it is attached, it forms a 3-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A and Ring B are independently selected from 3-15 membered rings; Alternatively, Ring A and Ring B are independently selected from 3-12 membered rings; Alternatively, Ring A and Ring B are independently selected from C 6-12 Aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl; Alternatively, the ring A and the ring B are independently selected from C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl; Alternatively, the ring A and the ring B are independently selected from phenyl or 5-6 membered heteroaryl; Alternatively, the ring A and the ring B are independently selected from phenyl or 6-membered heteroaryl; Alternatively, when the ring A or ring B is selected from a heteroaryl group, the ring heteroatom is a nitrogen, oxygen or sulfur atom; Alternatively, the ring A and the ring B are independently selected from phenyl or pyridyl; Alternatively, the ring A is selected from phenyl; Alternatively, the ring B is selected from pyridyl.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; R' is selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Or, each R 1 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl; Or, each R 1 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Or, each R 1 are independently selected from halogen, -CN, =O, OH, NH2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2, or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl; Or, each R 1 are independently selected from halogen, -CN, =O, OH, NH2, or the following groups optionally substituted by one or more R': methyl, ethyl, n-propyl or isopropyl; Or, each R 1 are independently selected from C optionally substituted by one or more halogen 1-6 alkyl; Or, each R 1 are each independently selected from methyl optionally substituted with one or more F; Or, R 1 Selected from trifluoromethyl; Optionally, R' is selected from halogen, -CN, =O, or the following groups optionally substituted by one or more substituents: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, R' is selected from halogen, -CN, =O, OH, NH2, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Alternatively, R' is selected from halogen, -CN, =O, OH, NH2, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl or -N(C 1-3 Alkyl)2; Alternatively, R' is selected from halogen, -CN, =O, OH, NH2, or C optionally substituted with one or more halogen, -CN, =O, OH, NH2 1-3 alkyl; Alternatively, R' is selected from F, Cl, Br or I; Alternatively, R' is selected from F.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, Or, any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, -CN, -OH, -SH, -NH2, -CHO, -COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl; R" is selected from halogen, -CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Or, each R 2 are independently selected from halogen, -CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl; Or, each R 2 Each independently selected from F, Cl, Br, I, -CN, =O, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 alkyl)2, or C optionally substituted by one or more R" 1-3 alkyl; Optionally, any two R 2 Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, -CN, -OH, -SH, -NH2, -CHO, -COOH, -OC 1-10 Alkyl, -SC 1-10 Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl; Or, any two R 2 In the 3-10 membered ring formed together with the atoms to which they are attached, the 3-10 membered ring is selected from a 3-6 membered ring; or, the 3-10 membered ring is selected from a 3-membered, 4-membered, 5-membered or 6-membered ring; or, the 3-10 membered ring is selected from a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring; Or, any two R 2 Together with the atoms to which they are attached, they form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, -CN, -OH, -SH, -NH2, -CHO, -COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Or, each R 2 Each independently selected from F, Cl, Br, I, CN, =O, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2; Or, each R 2 Each independently selected from F, Cl, Br, I, CN, =O, OH or NH2; Or, each R 2 Each independently selected from =O or OH; Optionally, R" is selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, R" is selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl; Alternatively, R" is selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Heteroalkyl, -OR a 、-SR a or -NR a R b ; Alternatively, R" is selected from F, Cl, Br, I, -CN, -OH, -NH2, =O or C 1-3 alkyl; Alternatively, R" is selected from F, Cl, Br, I, -CN, -OH, -NH2 or =O.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each X is independently selected from -CH2- or -NH-; or, each X is independently selected from -O- or -S-; or, X is selected from -CH2-; or, X is selected from -NH-.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or optionally one or more R"' of the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclic group, R'' is selected from halogen, -CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Or, each R 4 are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group; Or, each R 4 are independently selected from halogen, CN, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 Cycloalkyl; Or, each R 4 are independently selected from F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 Alkyl, the C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 Alkyl is optionally substituted with one or more of the following: F, Cl, Br, I or 6-membered heterocycloalkyl; Or, each R 4 Each independently selected from F, Cl, CH3, CF3, ethynyl, cyclopropyl or Optionally, R'' is selected from halogen, -CN, =O, or the following groups optionally substituted by one or more substituents: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, R'' is selected from halogen, -CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl; Alternatively, R'' is selected from halogen, -CN, =O, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Heteroalkyl, -OR a 、-SR a or -NR a R b ; Alternatively, R'' is selected from halogen, -CN, OH, NH2 or C 1-3 alkyl; Alternatively, R'' is selected from F.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Or, R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; Or, R a and R b are independently selected from hydrogen, or optionally replaced by one or more R ab Substituted C 1-3 alkyl; Or, R a and R b are independently selected from hydrogen, or C optionally substituted by one or more 5-6 membered heterocycloalkyl 1-3 alkyl; Or, R a and R b are independently selected from hydrogen or Optionally, R ab Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-10 Alkyl, -SC 1-10 Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Or, R ab Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl; Or, R ab Selected from C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; Or, R ab is selected from a 6-membered heterocyclic group; Or, R ab Selected from piperazinyl.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -CONR c -R c1 -、-NR c CO-R c1 -、-SONR c -R c1 -or-NR c SO-R c1 -; Alternatively, L is selected from -CONR c -R c1 -* or -NR c CO-R c1 -*, where * indicates that the bond at this position is connected to ring A; Optionally, R c Selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-10 Cycloalkyl, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-10 Cycloalkyl is optionally substituted with one or more of the following: deuterium, halogen, -CN, -OH, -SH, -NH2, -CHO or -COOH; Or, R c Selected from hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following: deuterium, halogen, CN, OH, SH or NH2; Or, R c is selected from hydrogen or methyl, the methyl group being optionally substituted by 1 to 3 deuteriums; Or, R c is selected from hydrogen, methyl or -CD3; Optionally, R c1 Select from key or C 1-10 Alkylene, the C 1-10 The alkylene group is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO or COOH; Or, R c1 Select from key or C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more of the following groups: F, Cl, Br, I, CN, OH, SH, NH2, CHO or COOH; Or, R c1 Select from keys.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, L 1 is selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-10 Alkylene, C 1-10 Heteroalkylene, C 1-10 Heteroalkenylene or C 1-10 heteroalkynylene; Or, L 1 is selected from a bond, or optionally one or more R d Substituted with the following groups: C 1-3 Alkylene or C 1-3 heteroalkylene; Or, L 1 Selected from optionally one or more R d Substituted: methylene, ethylene, propylene, isopropylene, -OCH2-*, -CH2O-*, -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-*, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -NHCH2-*, -CH2NH-*, -NHCH2CH2-*, -CH2CH2NH-*, -NHCH2CH2CH2-*, -CH2CH2CH2NH-*, -NHCH2NH-, -NHCH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -CH2OCH2-, -CH2OCH2CH2*-, -CH2CH2OCH2-* , -CH2OCH2O-*, -OCH2OCH2-*, -OCH2OCH2CH2-*, -CH2OCH2OCH2-, -CH2OCH2CH2O-*, -CH2CH2OCH2O-*, -CH2NHCH2-, -CH2NHCH2CH2-*, -CH2CH2NHCH2-*, -CH2NHCH2NH-*, -NHCH2NHCH2-*, -NHCH2NHCH2-*, -NHCH2NHCH2CH2-*, -CH2NHCH2NHCH2-, -CH2NHCH2CH2NH-*, -CH2CH2NHCH2-*, -CH2NHCH2NHCH2-, -CH2NHCH2CH2NH-*, -CH2CH2NHCH2NH-*, *-OCH2CH2CH2CH2- or -OCH2CH2CH2CH2-*, wherein * indicates that the bond at this position is connected to the ring B portion; Or, L 1 Selected from optionally one or more R d The following groups substituted: -OCH2CH2-*, -CH2CH2O-*, -OCH2CH2CH2-*, -CH2CH2CH2O-*, -OCH2CH2O-, -NHCH2CH2-*, *-NHCH2CH2-, *-OCH2CH2CH2CH2- or -OCH2CH2CH2CH2-*, wherein * indicates that the bond at this position is connected to the ring B portion; Or, L 1 Selected from -OCH2CH2-*, -OCH2CH2CH2-*, -OCH2CH2O-, -N(CH3)CH2CH2-* or -OCH2CH2CH2CH2-*, wherein * indicates that the bond at this position is connected to the ring B portion; Optionally, R d Selected from halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-10 Alkyl, -SC 1-10 Alkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; Or, R d Selected from halogen, CN, OH, NH2, C 1-3 Alkyl or C 3-6 Cycloalkyl; Or, R d Selected from halogen, CN, OH, SH, NH2 or C 1-3 alkyl; Or, R d is selected from halogen, CN, OH, SH, NH2 or methyl; Optionally, the two R d The atoms connected thereto together form a 3-10 membered ring, wherein the 3-10 membered ring is selected from a 3-6 membered ring; or, the 3-10 membered ring is selected from a 3-, 4-, 5- or 6-membered ring; or, the 3-10 membered ring is selected from a 3-10 membered alkyl ring or a 3-10 membered heteroalkyl ring; or, the 3-10 membered ring is selected from a 3-6 membered alkyl ring or a 3-6 membered heteroalkyl ring; or, the 3-10 membered ring is selected from a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring; Alternatively, the two R d The atoms to which it is attached form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Alternatively, the two R d The atoms to which it is attached form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 or C 1-3 alkyl; Alternatively, the two R d The atoms to which it is attached form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, NH2 or C 1-3 alkyl.

10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural part Selected from Or, the structural part Selected from wherein q is selected from 0, 1, 2, 3 or 4; Alternatively, q is selected from 0, 1, 2 or 3; or q is selected from 1 or 2; Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from 11. The compound according to claim 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently selected from hydrogen, halogen, -CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Optionally, R 2a and R 2b Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl; Alternatively, as described in the present disclosure, wherein the R 2a and R 2b In the 3-10 membered ring formed together with the atoms to which they are attached, the 3-10 membered ring is selected from a 3-6 membered ring; or, the 3-10 membered ring is selected from a 3-, 4-, 5- or 6-membered ring; or, the 3-10 membered ring is selected from a 3-10 membered alkyl ring or a 3-10 membered heteroalkyl ring; or, the 3-10 membered ring is selected from a 3-6 membered alkyl ring or a 3-6 membered heteroalkyl ring; or, the 3-10 membered ring is selected from a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring; Or, R 2a and R 2b are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 3-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl; R" is selected from halogen, CN, =O, or the following groups optionally substituted by one or more substituents: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Heteroalkyl, -OR a 、-SR a 、-NR a R b , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Or, R 2a and R 2b are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or the following groups optionally substituted by one or more R": C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-6 membered heteroaryl, Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 3-6 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Or, R 2a and R 2b Each independently selected from F, Cl, Br, I, CN, OH, NH2, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2; Or, R 2a and R 2b Each independently selected from F, Cl, Br, I, CN, OH or NH2; Or, R 2a and R 2b Each independently selected from -OR a ; Or, R 2a and R 2b Selected from OH.

12. The compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, 3 or 4; optionally, n is selected from 0, 1, 2, 3, 4 or 5; optionally, k is selected from 0, 1, 2 or 3; optionally, p is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; Alternatively, m is selected from 0, 1, 2, or 3; Alternatively, m is selected from 0, 1 or 2; Alternatively, m is selected from 1; Alternatively, m is selected from 0; Alternatively, n is selected from 0, 1, 2, 3 or 4; Alternatively, n is selected from 0, 1, 2 or 3; Alternatively, n is selected from 0, 1 or 2; Alternatively, n is selected from 2, 3 or 4; Alternatively, n is selected from 4; Alternatively, n is selected from 3; Alternatively, n is selected from 2; Alternatively, k is selected from 0, 1 or 2; Alternatively, k is selected from 0 or 1; Alternatively, k is selected from 0; Alternatively, k is selected from 1; Alternatively, p is selected from 0, 1, 2, 3, 4 or 5; Alternatively, p is selected from 0, 1, 2, 3 or 4; Alternatively, p is selected from 0; Alternatively, p is selected from 1; Alternatively, p is selected from 2; alternatively, p is selected from 3; alternatively, p is selected from 4.

13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the compound of formula II or a pharmaceutically acceptable salt thereof: X a , X b , X c , X d , X e , X f , X h , X j , X k and X n are independently selected from CH or N; Every R 1a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, Or any two adjacent R 1a Together with the atoms to which it is attached, it forms a 5-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-6 alkyl; Every R 4a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a S02R b 、、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R"': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclic group, Or any two adjacent R 4a Together with the atoms to which it is attached, it forms a 5-10 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-6 alkyl; Or, X a , X b , X c , X d and X e Optionally, one or two of X are selected from N, and the others are selected from CH; or, X a , X b , X c , X d and X e One of them is selected from N, and the other is selected from CH; or, X a , X b , X c , X d and X e One of them is selected from N, and the other is selected from CH; or, X e Select from N, X a , X b , X c and X d is selected from CH; or, said R 1a Substitution occurs at X b On, and X b is selected from CH; or, X f , X h , X j and X k Selected from CH; Or, each R 1a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a ,-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a S02R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b , or the following groups optionally substituted by one or more R': C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl; Or, each R 1a are independently selected from halogen, CN, OH, NH2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2, or the following groups optionally substituted by one or more R': C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl; Or, each R 1a Each is independently selected from F, Cl, Br, I, CN, OH, NH2, or a methyl group optionally substituted with one or more fluorine groups; Or, each R 1a are independently selected from C optionally substituted with one or more F, Cl or Br 1-3 alkyl; Or, each R 1a are each independently selected from methyl optionally substituted with one or more F; Or, each R 1a Each independently selected from CF3; Or, any two adjacent R 1a Together with the atoms to which it is attached, it forms a 5-8 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-3 alkyl; Or, any two adjacent R 1a Together with the atoms to which it is attached, it forms a 5-6 membered ring; Or, each R 4a are independently selected from halogen, CN, =O, -OR a 、-SR a 、-NR a R b , or optionally one or more R"' of the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group; Or, each R 4a are independently selected from F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 Alkyl, the C 1-3 Alkyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl or -NHC 1-3 Alkyl is optionally substituted with one or more of the following: F, Cl, Br, I or 6-membered heterocycloalkyl; Or, each R 4a Each is independently selected from F, Cl, methyl, ethynyl, cyclopropyl or -NHCH2CH3, wherein the methyl, ethynyl, cyclopropyl or -NHCH2CH3 is optionally substituted with one or more F or piperazinyl; Or, each R 4a Each independently selected from F, Cl, CH3, CF3, ethynyl, cyclopropyl or Or, any two adjacent R 4a Together with the atoms to which it is attached, it forms a 5-8 membered ring, which is optionally substituted by one or more of the following groups: halogen, CN, =O, OH, NH2 or C 1-3 alkyl; Or, any two adjacent R 4a Together with the atoms to which it is attached, it forms a 5-6 membered ring.

14. The compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula III or a pharmaceutically acceptable salt thereof, 15. The following compound, its stereoisomer or its pharmaceutically acceptable salt: Alternatively, the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15, its stereoisomer or a pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable excipient.

17. Use of the compound according to any one of claims 1 to 15, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing or treating cancer.

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