PRMT5 inhibitor as well as preparation method and application thereof

Abstract

The invention provides a PRMT5 inhibitor as well as a preparation method and application thereof. Specifically disclosed are a compound represented by formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and an application thereof in the preparation of drugs for treating and / or preventing cancers, which can be MTAP-related / mediated cancers. # imgabs0 #

Description

A PRMT5 inhibitor, its preparation method and application

[0001] This application claims priority to Chinese Patent Application No. 2022109224322 filed on August 2, 2022, Chinese Patent Application No. 2022113131424 filed on October 25, 2022, Chinese Patent Application No. 2022116357441 filed on December 19, 2022, Chinese Patent Application No. 202310233629X filed on March 10, 2023, and Chinese Patent Application No. 202310918224X filed on July 24, 2023. The entire text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] The present invention relates to a PRMT5 inhibitor, a preparation method and application thereof. Background Art

[0003] Protein arginine N-methyltransferases (PRMTs) are responsible for the methylation of the guanidino group of arginine. The guanidino group of arginine has two terminal nitrogen atoms that can undergo monomethylation or dimethylation. PRMTs can transfer the methyl group from S-adenosylmethionine (SAM) to the guanidino nitrogen atom of the protein arginine side chain to generate methylated arginine. PRMTs regulate arginine methylation in three different forms: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) methylation. PRMTs mainly include 9 subtypes, and the enzymes are further divided into type I or type II based on the type of dimethylation. Type I PRMTs catalyze monomethylation or asymmetric dimethylation, while type II enzymes catalyze symmetric dimethylation.

[0004] Protein arginine N-methyltransferase 5 (PRMT5) is a type II arginine methyltransferase responsible for symmetrical dimethylation of arginine residues on histones and non-histone proteins, thereby regulating many life processes in mammalian cells. PRMT5 is overexpressed in many types of cancer, including lymphoma, lung cancer, breast cancer, colorectal cancer, leukemia, glioblastoma, prostate cancer, and ovarian cancer, and is associated with the progression and poor prognosis of most cancers. PRMT5 can also inhibit the transcription of several tumor suppressor genes, including tumorigenicity suppressor 7, non-metastatic gene 23, retinoblastoma family, and programmed cell death 4. Therefore, PRMT5 is a potential target for cancer treatment.

[0005] Methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene that is frequently deleted in many human tumors, including 53% of glioblastomas and 26% of pancreatic cancers. It is the most frequently mutated gene in cancer. Furthermore, MTAP is often co-deleted with the common tumor suppressor gene CDKN2A, with this co-deletion occurring in 9% to 15% of tumors.

[0006] Synthetic lethality refers to a phenomenon in which simultaneous mutations in two genes lead to cell death, whereas mutations in either gene alone do not cause cell death. Studies have shown that PRMT5 and MTAP form a synthetic lethal pair, and that inhibition of PRMT5 can lead to synthetic lethality in MTAP-deficient tumor cells. MTAP is involved in the metabolism of methylthioadenosine (MTA). In cancer cells with MTAP gene deletion, MTA accumulates and binds to PRMT5, forming a PRMT5-MTA complex. Therefore, PRMT5 inhibitors may be a highly selective treatment for patients with MTAP deficiency or low expression.

[0007] MRTX1719, developed by Mirati Therapeutics, is a novel PRMT5 inhibitor that selectively inhibits PRMT5 bound to MTA. Its structure is as follows:

[0008] Although the above-mentioned new PRMT5 inhibitors have entered the clinical trial stage and replaced certain progress in this field, they have not yet been approved for treatment. Therefore, there is still a need to continue to develop new PRMT5 inhibitors targeting the PRMT5-MTA complex. This new PRMT5-specific small molecule inhibitor may bring new chemotherapy for cancer.

[0009] Summary of the Invention

[0010] The technical problem to be solved by the present invention is to overcome the single structure of PRMT5 inhibitors in the prior art and provide a novel PRMT5 inhibitor, its preparation method and use. The PRMT5 inhibitor provided by the present invention has good inhibitory activity or selectivity against human colon cancer cells with stable MTAP protein knockout (HCT-116-MTAP-KO-1A2), and can inhibit the proliferation of tumor cells.

[0011] The present invention provides a compound as shown in Formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof,

[0012] Among them, X 1 and X 2 Each independently CR 5 or N;

[0013] Each R5 are independently deuterium, hydrogen, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 alkoxy;

[0014] R 1 is a 3-8 membered cycloalkyl group, which is occupied by one or more R 1a Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 1b Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 1c Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 1d substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 1b The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0015] R 1a 、R 1b 、R 1c and R 1d are independently deuterium, hydroxyl, halogen, cyano, -N(R 6 )2、C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3 to 8-membered cycloalkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3- to 8-membered cycloalkyl in a 3- to 8-membered cycloalkyl group, -Z 1c -C 6-10 C in aromatic groups 6-10Aryl, -Z 1d -5-10 membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1- a Substituted; the 4 to 10 membered heterocyclic group, -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0016] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)-, (halogenated C 1-6 alkyl) 2N-C(=O)-, -NH2 or -OH; the number of heteroatoms in the 4- to 10-membered heterocyclic group and the 4- to 10-membered heterocyclic group substituted with halogen is independently 1, 2 or 3, and the heteroatoms are independently selected from N, O and S;

[0017] When X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2d Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2d The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0018] Or, when X 1 and X 2 are each independently CH, and R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1- a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different;

[0019] When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 For hydrogen, cyano, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2l The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0020] R 2a、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m and R 2n are independently deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -N(R 6 ) 2, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or 5-10 membered heteroaryl; the number of heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0021] R 3 and R 4 are independently deuterium, hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2)m-OP(=O)(OR 3c )2;

[0022] R 3a and R 3b are each independently deuterium, hydrogen or C 1-20 alkyl;

[0023] Each R 3c are independently deuterium, hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or C 6-10 Aryl; the number of heteroatoms in the 4- to 10-membered heterocyclic group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0024] R 4a is deuterium, H or a 3- to 8-membered cycloalkyl group;

[0025] m is an integer from 0 to 10;

[0026] Y, Z 1a 、Z 1b 、Z 1c 、Z 1d 、Z1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0027] L, U 1a and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0028] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0029] In the present invention, the terms "deuterated", "halogenated" and "halogen-substituted" refer to the replacement of one or more hydrogen atoms by a specific substituent. For example, "deuterated" refers to the replacement of one or more hydrogen atoms by deuterium.

[0030] In certain preferred embodiments of the present invention, certain groups in the compound of Formula I, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof are defined as follows. Unmentioned groups are the same as those described in any embodiment of the present application (referred to as "certain preferred embodiments of the present invention").

[0031] Among them, X 1 and X 2 Each independently CR 5 or N;

[0032] Each R 5 are independently deuterium, hydrogen, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 alkoxy;

[0033] R 1 is a 3-8 membered cycloalkyl group, which is occupied by one or more R 1a Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 1b Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 1c Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 1d substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 1b The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 1dThe number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0034] R 1a 、R 1b 、R 1c and R 1d are independently deuterium, hydroxyl, halogen, cyano, -N(R 6 )2、C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3 to 8-membered cycloalkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3- to 8-membered cycloalkyl in a 3- to 8-membered cycloalkyl group, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1- a Substituted; the 4 to 10 membered heterocyclic group, -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0035] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e-Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group, C 1-6 Alkyl-C(=O)-O-, C1-6alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)- or (halogenated C 1-6 alkyl)2N-C(=O)-;

[0036] When X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2d Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2d The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0037] Or, when X 1 and X 2 are each independently CH, and R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1- a Replaced When there are multiple substituents, they may be the same or different;

[0038] When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 For hydrogen, cyano, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2kSubstituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2l The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0039] R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m and R 2n are independently deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -N(R 6 ) 2, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or 5-10 membered heteroaryl; the number of heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0040] R 3 and R 4 are independently deuterium, hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2)m-OP(=O)(OR 3c )2;

[0041] R 3a and R 3b are each independently deuterium, hydrogen or C 1-20 alkyl;

[0042] Each R3c are independently deuterium, hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or C 6-10 Aryl; the number of heteroatoms in the 4- to 10-membered heterocyclic group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0043] R 4a is deuterium, H or a 3- to 8-membered cycloalkyl group;

[0044] m is an integer from 0 to 10;

[0045] Y, Z 1a 、Z 1b 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0046] L, U 1a and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0047] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0048] In certain preferred embodiments of the present invention, certain groups in the compound of Formula I, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof are defined as follows. Unmentioned groups are the same as those described in any embodiment of the present application (referred to as "certain preferred embodiments of the present invention").

[0049] Among them, X 1 and X 2 Each independently CR 5 or N;

[0050] Each R 5 are independently deuterium, hydrogen, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 alkoxy;

[0051] R 1 is a 3-8 membered cycloalkyl group, which is occupied by one or more R1a Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 1b Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 1c Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 1d substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 1b The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0052] R 1a 、R 1b 、R 1c and R 1d are independently deuterium, hydroxyl, halogen, cyano, -N(R 6 )2、C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3 to 8-membered cycloalkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3- to 8-membered cycloalkyl in a 3- to 8-membered cycloalkyl group, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1- a Substituted; the 4 to 10 membered heterocyclic group, -Z1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0053] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0054] When X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2d Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2d The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0055] Or, when X 1 and X 2 are each independently CH, and R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0056] When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 For hydrogen, cyano, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2lThe 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0057] R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m and R 2n are independently deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -N(R 6 ) 2, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or 5-10 membered heteroaryl; the number of heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0058] R 3 and R 4 are independently deuterium, hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2)m-OP(=O)(OR 3c )2;

[0059] R 3a and R 3b are each independently deuterium, hydrogen or C 1-20 alkyl;

[0060] Each R 3c are independently deuterium, hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or C 6-10 Aryl; the number of heteroatoms in the 4- to 10-membered heterocyclic group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0061] R 4a is deuterium, H or a 3- to 8-membered cycloalkyl group;

[0062] m is an integer from 0 to 10;

[0063] Y, Z 1a 、Z 1b 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0064] L, U 1a and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0065] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0066] In certain preferred embodiments of the present invention, certain groups in the compound of Formula I, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof are defined as follows. Unmentioned groups are the same as those described in any embodiment of the present application (referred to as "certain preferred embodiments of the present invention").

[0067] Among them, X 1 and X 2 Each independently CR 5 or N;

[0068] Each R 5 are independently deuterium, hydrogen, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 alkoxy;

[0069] R 1 is a 3-8 membered cycloalkyl group, which is occupied by one or more R 1a Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 1b Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 1c Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 1d substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R1b Substituted 4- to 10-membered heterocyclic groups, 5- to 10-membered heteroaryl groups, and groups replaced by one or more R 1d The number of heteroatoms in the substituted 5- to 10-membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0070] R 1a 、R 1b 、R 1c and R 1d are independently deuterium, hydroxyl, halogen, cyano, -N(R 6 )2、C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3 to 8-membered cycloalkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl; said C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3- to 8-membered cycloalkyl in a 3- to 8-membered cycloalkyl group, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a Substituted; the 4 to 10 membered heterocyclic group and -Z 1d - the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0071] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0072] When X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2d Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2d The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0073] When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 For hydrogen, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2l The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0074] R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m and R 2n are independently deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -N(R 6 ) 2, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or 5-10 membered heteroaryl; the number of heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0075] R 3 and R 4 are independently deuterium, hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2)m-OP(=O)(OR 3c)2;

[0076] R 3a and R 3b are each independently deuterium, hydrogen or C 1-20 alkyl;

[0077] Each R 3c are independently deuterium, hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or C 6-10 Aryl; the number of heteroatoms in the 4- to 10-membered heterocyclic group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0078] R 4a is deuterium, H or a 3- to 8-membered cycloalkyl group;

[0079] m is an integer from 0 to 10;

[0080] Y, Z 1a 、Z 1b 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0081] L, U 1a and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0082] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0083] In certain embodiments of the present invention, the compound of formula I is not:

[0084] In certain embodiments of the present invention, the compound of formula I is not:

[0085] In certain preferred embodiments of the present invention, when X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c Substituted 3-8 membered cycloalkyl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0086] When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 Halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2l The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0087] Or, when X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 Alkoxy, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is hydrogen;

[0088] Alternatively, the compound shown in formula I is

[0089] In certain preferred embodiments of the present invention, when X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C2-6 alkynyl, 3-8 membered cycloalkyl, substituted by one or more R 2c Substituted 3-8 membered cycloalkyl, C 6-10 Aryl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0090] When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 Halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2l The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0091] Or, when X 1 CR5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 Alkoxy, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is hydrogen;

[0092] Alternatively, the compound shown in formula I is

[0093] In certain preferred embodiments of the present invention, each R 1-a are independently halogen-substituted 4- to 10-membered heterocyclic groups, -NH2 or -OH.

[0094] In certain preferred embodiments of the present invention, each R 1-a Deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)- or (halogenated C 1-6 alkyl)2N-C(=O)-.

[0095] In certain preferred embodiments of the present invention, when X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 It is a cyano group.

[0096] In certain preferred embodiments of the present invention, when X 1 and X 2 are each independently CH, and R 2 H, C 1-6 When alkyl or deuterated C1-6 alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different;

[0097] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, C1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)-, (halogenated C 1-6 alkyl)2N-C(=O)-, -NH2 or -OH;

[0098] Z 1a 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0099] U 1b independently a chemical bond or C 1-3 alkylene;

[0100] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0101] In certain preferred embodiments of the present invention, when X 1 and X 2 are each independently CH, and R 2 H, C 1-6 When alkyl or deuterated C1-6 alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different;

[0102] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group, C 1-6 Alkyl-C(=O)-O-, C 1- 6-alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)- or (halogenated C 1-6 alkyl)2N-C(=O)-;

[0103] Z 1a 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0104] U 1b independently a chemical bond or C 1-3 alkylene;

[0105] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0106] In certain preferred embodiments of the present invention, when X 1 and X 2 are each independently CH, and R 2 H, C 1-6 When alkyl or deuterated C1-6 alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different;

[0107] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0108] Z 1a 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0109] U 1b independently a chemical bond or C 1-3 alkylene;

[0110] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0111] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c and R 1d Each independently -Z 1d -11 to 20 membered heteroaryl, said -Z 1d -11 to 20 membered heteroaryl groups are optionally substituted with one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0112] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group, C 1-6 Alkyl-C(=O)-O-, C 1- 6-alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)- or (halogenated C 1-6 alkyl)2N-C(=O)-;

[0113] Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0114] U 1b independently a chemical bond or C 1-3 alkylene;

[0115] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0116] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c and R 1d Each independently -Z 1d -11 to 20 membered heteroaryl, said -Z 1d -11 to 20 membered heteroaryl groups are optionally substituted with one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0117] Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0118] Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-;

[0119] U 1b independently a chemical bond or C 1-3 alkylene;

[0120] Each R 6 are independently hydrogen or C 1-6 alkyl.

[0121] In certain preferred embodiments of the present invention, R 1-a In the -Z 1f -U 1b The 3- to 8-membered cycloalkyl group in the 3- to 8-membered cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl, for example, cyclopropyl.

[0122] In certain preferred embodiments of the present invention, R 2 wherein the 3- to 8-membered cycloalkyl group is replaced by one or more R 2c The 3- to 8-membered cycloalkyl in the substituted 3- to 8-membered cycloalkyl and the 3- to 8-membered cycloalkyl in the substituted 3- to 8-membered cycloalkyl 2k The 3- to 8-membered cycloalkyl groups in the substituted 3- to 8-membered cycloalkyl groups are independently cyclopropyl, cyclobutyl, or cyclopentyl, for example, cyclopropyl.

[0123] In certain preferred embodiments of the present invention, R 2b In the above, the 3- to 8-membered cycloalkyl groups are each independently cyclopropyl, cyclobutyl, or cyclopentyl, for example, cyclopropyl.

[0124] In certain preferred embodiments of the present invention, R 2j In the above, the 3- to 8-membered cycloalkyl groups are each independently cyclopropyl, cyclobutyl, or cyclopentyl, for example, cyclopropyl.

[0125] In certain preferred embodiments of the present invention, R 4a In the embodiment, the 3- to 8-membered cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl, for example, cyclopropyl.

[0126] In certain preferred embodiments of the present invention, R 1 、R 1a 、R 1b 、R1c 、R 1d 、R 2a 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2k 、R 2l 、R 2m 、R 2n and R 3c wherein the 3- to 8-membered cycloalkyl group is replaced by one or more R 1a 3- to 8-membered cycloalkyl in substituted 3- to 8-membered cycloalkyl, and -Z 1b -U 1a The 3- to 8-membered cycloalkyl group in the 3- to 8-membered cycloalkyl group is independently cyclopropyl, cyclobutyl, or cyclopentyl, for example, cyclopropyl.

[0127] In certain preferred embodiments of the present invention, R 1 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m 、R 2n and R 3c In the embodiment, the 4-10 membered heterocyclic group is replaced by one or more R 1b The 4- to 10-membered heterocyclic group in the substituted 4- to 10-membered heterocyclic group is replaced by one or more R 2d substituted 4- to 10-membered heterocyclic group, and one or more R 2l The substituted 4- to 10-membered heterocyclic group is independently a 4- to 6-membered heterocyclic group, such as piperidinyl, piperazinyl or pyrrolidinyl.

[0128] In the present invention means that the corresponding group passes through the Connect with other fragments and groups in the compound.

[0129] In certain preferred embodiments of the present invention, R 1-aIn the embodiment, the 4-10 membered heterocyclic group is a 4-6 membered heterocyclic group, such as oxetane, piperidinyl, piperazinyl or pyrrolidinyl, and another example is oxetane

[0130] In certain preferred embodiments of the present invention, R 1-a In the 4- to 10-membered heterocyclic group and the 4- to 10-membered heterocyclic group substituted by halogen, the 4- to 10-membered heterocyclic group is a 4- to 6-membered heterocyclic group, such as oxetane, azetidinyl, piperidinyl, piperazinyl or pyrrolidinyl, and another example is oxetane Azetidine or pyrrolidin

[0131] In certain preferred embodiments of the present invention, R 1d In the -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl is independently phenyl or naphthyl.

[0132] In certain preferred embodiments of the present invention, R 1 、R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 and R 3c In the C 6-10 Aryl, one or more R 1c Substituted C 6-10 C in aromatic groups 6-10 Aryl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, one or more R 2e Substituted C 6-10 C in aromatic groups 6-10 Aryl, and one or more R 2m Substituted C 6-10 C in aromatic groups 6-10 Aryl is independently phenyl or naphthyl.

[0133] In certain preferred embodiments of the present invention, R 1 wherein the 5- to 10-membered heteroaryl group and the one or more R 1d The 5- to 10-membered heteroaryl groups in the substituted 5- to 10-membered heteroaryl groups are independently 5- to 6-membered monoheteroaryl groups or 8- to 10-membered fused heteroaryl groups. The 5- to 6-membered monoheteroaryl groups can independently be pyrazole or triazole, for example

[0134] In certain preferred embodiments of the present invention, R 1 wherein the 5- to 10-membered heteroaryl group and the one or more R 1d The 5- to 10-membered heteroaryl groups in the substituted 5- to 10-membered heteroaryl groups are independently 5- to 6-membered monoheteroaryl groups or 8- to 10-membered fused heteroaryl groups. The 5- to 6-membered monoheteroaryl groups can be independently pyrazolyl or imidazolyl, for example

[0135] In certain preferred embodiments of the present invention, R 1 wherein the 5- to 10-membered heteroaryl group and the one or more R 1d The 5- to 10-membered heteroaryl groups in the substituted 5- to 10-membered heteroaryl groups are independently 5- to 6-membered monoheteroaryl groups or 8- to 10-membered fused heteroaryl groups. The 5- to 6-membered monoheteroaryl groups can independently be pyrazolyl, imidazolyl or triazolyl groups, for example

[0136] In certain preferred embodiments of the present invention, R 1 wherein the 5- to 10-membered heteroaryl group and the one or more R 1d The 5- to 10-membered heteroaryl group in the substituted 5- to 10-membered heteroaryl group may independently have 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from nitrogen.

[0137] In certain preferred embodiments of the present invention, R 2 wherein the 5- to 10-membered heteroaryl group is replaced by one or more R 2f The 5- to 10-membered heteroaryl in the substituted 5- to 10-membered heteroaryl, and the ... 2n The 5- to 10-membered heteroaryl groups in the substituted 5- to 10-membered heteroaryl groups are independently 5- to 6-membered monoheteroaryl groups or 8- to 10-membered fused heteroaryl groups. The 5- to 6-membered monoheteroaryl groups can independently be pyrazole or triazole, for example

[0138] In certain preferred embodiments of the present invention, R 2 wherein the 5- to 10-membered heteroaryl group is replaced by one or more R 2f The 5- to 10-membered heteroaryl in the substituted 5- to 10-membered heteroaryl, and the ... 2n The 5- to 10-membered heteroaryl group in the substituted 5- to 10-membered heteroaryl group may independently have 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from nitrogen.

[0139] In certain preferred embodiments of the present invention, R 2aIn the embodiment, the 5- to 10-membered heteroaryl group is independently a 5- to 6-membered single heteroaryl group or an 8- to 10-membered fused heteroaryl group. The 5- to 6-membered single heteroaryl group can be independently a pyrazole or a triazole, for example

[0140] In certain preferred embodiments of the present invention, R 2a In the embodiment of the present invention, the 5- to 10-membered heteroaryl group may independently have 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from nitrogen.

[0141] In certain preferred embodiments of the present invention, R 2i In the above, the 5- to 10-membered heteroaryl group is independently a 5- to 6-membered single heteroaryl group or an 8- to 10-membered fused heteroaryl group. The 5- to 6-membered single heteroaryl group can be independently pyrazole or triazole, for example

[0142] In certain preferred embodiments of the present invention, R 2i In the embodiment of the present invention, the 5- to 10-membered heteroaryl group may independently have 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from nitrogen.

[0143] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c 、R 1d 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2j 、R 2k 、R 2l 、R 2m and R 2n wherein the 5- to 10-membered heteroaryl and -Z 1d The 5- to 10-membered heteroaryl group in the 5- to 10-membered heteroaryl group is independently a 5- to 6-membered single heteroaryl group or an 8- to 10-membered condensed heteroaryl group. The 5- to 6-membered single heteroaryl group may independently be pyrazole or triazole, for example

[0144] In certain preferred embodiments of the present invention, R 1 、R 1a 、R 1b 、R 1c 、R 1d 、R 2b 、R 2c 、R 2d 、R2e 、R 2f 、R 2g 、R 2h 、R 2j 、R 2k 、R 2l 、R 2m and R 2n wherein the 5- to 10-membered heteroaryl and -Z 1d The 5- to 10-membered heteroaryl group in the 5- to 10-membered heteroaryl group may independently have 2 or 3 heteroatoms, wherein the heteroatoms may be independently selected from nitrogen.

[0145] In certain preferred embodiments of the present invention, R 1d In the -Z 1d - The 5- to 10-membered heteroaryl groups in the 5- to 10-membered heteroaryl groups are independently 5- to 6-membered single heteroaryl groups or 8- to 10-membered fused heteroaryl groups. The 8- to 10-membered fused heteroaryl groups are independently

[0146] In certain preferred embodiments of the present invention, R 1d In the -Z 1d The 5- to 10-membered heteroaryl group in the 5- to 10-membered heteroaryl group independently has 1, 2, or 3 heteroatoms, which are independently selected from nitrogen and oxygen.

[0147] In certain preferred embodiments of the present invention, R 1d In the -Z 1d The 11-20 membered heteroaryl in the -11-20 membered heteroaryl is independently an 11-16 membered heteroaryl, such as a 12-membered heteroaryl, a 13-membered heteroaryl or a 15-membered heteroaryl, and for example

[0148] In certain preferred embodiments of the present invention, R 1d In the -Z 1d The 11-20 membered heteroaryl in the -11-20 membered heteroaryl is independently an 11-16 membered heteroaryl, such as a 12-membered heteroaryl, a 13-membered heteroaryl, a 14-membered heteroaryl or a 15-membered heteroaryl, and for example

[0149] In certain preferred embodiments of the present invention, R 1d In the -Z 1d The 11-20 membered heteroaryl in the -11-20 membered heteroaryl is independently an 11-16 membered heteroaryl, such as a 12-membered heteroaryl, a 13-membered heteroaryl, a 14-membered heteroaryl or a 15-membered heteroaryl, and for example

[0150] In certain preferred embodiments of the present invention, R 1d In the -Z 1d The 11- to 20-membered heteroaryl group in the 11- to 20-membered heteroaryl group independently has 2, 3, or 4 heteroatoms, which are independently selected from nitrogen and oxygen.

[0151] In certain preferred embodiments of the present invention, R 1-a wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0152] In certain preferred embodiments of the present invention, R 1-a In the halogen-substituted 4- to 10-membered heterocyclic group, the halogen is independently fluorine, chlorine, bromine or iodine, for example, fluorine.

[0153] In certain preferred embodiments of the present invention, R 2 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0154] In certain preferred embodiments of the present invention, R 2c wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0155] In certain preferred embodiments of the present invention, R 2g wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0156] In certain preferred embodiments of the present invention, R 2k wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0157] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c 、R 1d 、R 2a 、R 2b 、R 2d 、R 2e 、R 2f 、R 2h 、R 2i 、R 2j 、R 2l 、R 2m 、R 2n and R 5 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0158] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c 、R1d and R 1-a In the C 1-6 Hydroxyalkyl is independently C1-4 hydroxyalkyl, for example -CH2OH, -CH2CH2OH, -CH(CH3)OH or -CH(CH3)CH2OH.

[0159] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c 、R 1d 、R 1-a 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m 、、R 2n and R 5 In the C 1-6 Alkoxy, one or more R 2h Substituted C 1- 6 Alkoxy, halogenated C 1-6 C in the alkoxy group 1-6 Alkoxy and deuterated C 1-6 C in the alkoxy group 1-6 Alkoxy is independently methoxy, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -O(CH2)3CH3, -OCH2CH(CH3)2, -OCHCH3CH2CH3 or -OC(CH3)3, for example, methoxy, ethoxy or -OCH2CH(CH3)2.

[0160] In certain preferred embodiments of the present invention, R 2 In the C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 C in alkenyl 2-6 Alkenyl, and one or more R 2i Substituted C 2-6 C in alkenyl 2-6 Alkenyl is independently C 2-4 Alkenyl groups, such as vinyl,

[0161] In certain preferred embodiments of the present invention, R3c In the C 2-6 Alkenyl is independently C 2-4 Alkenyl groups, such as vinyl,

[0162] In certain preferred embodiments of the present invention, R 2 In the C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 C in the alkynyl group 2-6 Alkynyl, and one or more R 2j Substituted C 2-6 C in the alkynyl group 2-6 Alkynyl is independently C 2-4 Alkynyl groups, such as ethynyl,

[0163] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c 、R 1d and R 3c In the C 2-6 Alkynyl is independently C 2-4 Alkynyl groups, such as ethynyl,

[0164] In certain preferred embodiments of the present invention, R 1d In the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0165] In certain preferred embodiments of the present invention, R 2 In the C 1-6 Alkyl, and one or more R 2g Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl.

[0166] In certain preferred embodiments of the present invention, R 2b In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0167] In certain preferred embodiments of the present invention, R 2j In the C 1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0168] In certain preferred embodiments of the present invention, R 1a 、R 1b 、R 1c 、R 1-a 、R 2a 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2k 、R 2l 、R 2m 、R 2n 、R 3 、R 4 、R 3c 、R 5 and R 6 In the C 1-6 Alkyl, -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl and -C(=O)-C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0169] In certain preferred embodiments of the present invention, R 1-a In the C 1-6 Alkyl, deuterated C 1-6 C in the alkyl group 1-6 Alkyl, C 1-6 C in alkyl-C(=O)- 1-6 Alkyl, C 1-6 C in alkyl-SO2- 1-6 Alkyl, C 1-6 C in alkyl-OC(=O)- 1-6 Alkyl, halogenated C 1- C in 6-alkyl-OC(=O)- 1-6 Alkyl, deuterated C 1-6 C in alkyl-OC(=O)- 1-6 Alkyl, C 1-6 C in alkyl-C(=O)-O- 1-6 Alkyl, C 1-6 C in alkyl-NH-C(=O)- 1-6 Alkyl, (C 1-6 C in alkyl)2N-C(=O)-1-6 Alkyl, deuterated C 1-6 C in alkyl-NH-C(=O)- 1-6 Alkyl, halogenated C 1-6 C in alkyl-NH-C(=O)- 1-6 Alkyl, (deuterated C 1-6 C in alkyl)2N-C(=O)- 1-6 Alkyl and (halogenated C 1-6 C in alkyl)2N-C(=O)- 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl.

[0170] In certain preferred embodiments of the present invention, R 1-a In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl.

[0171] In certain preferred embodiments of the present invention, R 1-a and R 3c wherein the halogenated C 1-6 Alkyl and -Z 1e -Halogenated C 1-6 Halogenated C in alkyl 1-6 Alkyl is independently halogenated C 1-4 Alkyl groups, such as -CF3, -CHF2 or -CH2CF3.

[0172] In certain preferred embodiments of the present invention, R 1-a In the -Z 1e -Halogenated C 1-6 Halogenated C in alkyl 1-6 Alkyl is independently halogenated C 1-4 Alkyl, such as -CF3, -CHF2, -CH2CHF2 or -CH2CF3.

[0173] In certain preferred embodiments of the present invention, R 2 wherein the halogenated C 1-6 Alkoxy is preferably halogenated C 1-4 Alkoxy, such as -OCF3,

[0174] In certain preferred embodiments of the present invention, R 2 In the above, the deuterated C 1-6 The alkoxy group is preferably a deuterated C 1-4 Alkoxy, for example -OCD3 or -OCD2CD3.

[0175] In certain preferred embodiments of the present invention, R 3a and R 3b In the C 1-20 The alkyl groups are independently C 1-6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl.

[0176] In certain preferred embodiments of the present invention, in L, the C 1-3 Alkylene is preferably methylene, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-, for example methylene.

[0177] In certain preferred embodiments of the present invention, U 1a In the C 1-3 Alkylene is preferably methylene, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-, for example methylene.

[0178] In certain preferred embodiments of the present invention, U 1b In the C 1-3 Alkylene is preferably methylene, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-, for example methylene.

[0179] In certain preferred embodiments of the present invention, R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl.

[0180] In certain preferred embodiments of the present invention, each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a replace.

[0181] In certain preferred embodiments of the present invention, each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5-10 membered heteroaryl in 5-10 membered heteroaryl, or -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace.

[0182] In certain preferred embodiments of the present invention, each R 1-a are independently deuterium, cyano, halogen, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3- to 8-membered cycloalkyl group.

[0183] In certain preferred embodiments of the present invention, each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3- to 8-membered cycloalkyl group.

[0184] In certain preferred embodiments of the present invention, each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)- or a 4- to 10-membered heterocyclic group.

[0185] In certain preferred embodiments of the present invention, each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)- or a 4- to 10-membered heterocyclic group.

[0186] In certain preferred embodiments of the present invention, each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, -NH2 or -OH.

[0187] In certain preferred embodiments of the present invention, when X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2- 6-membered alkynyl, 3-8-membered cycloalkyl, one or more R 2c substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl.

[0188] In certain preferred embodiments of the present invention, when X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl.

[0189] In certain preferred embodiments of the present invention, when X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2 For hydrogen, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl.

[0190] In certain preferred embodiments of the present invention, when X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2 Halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2- 6 alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, C 6-10 Aryl, one or more R 2m Substituted C6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl;

[0191] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For hydrogen.

[0192] In certain preferred embodiments of the present invention, R 2a 、R 2b 、R 2c 、R 2f 、R 2g 、R 2i 、R 2j 、R 2k 、R 2m and R 2n are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 )2, 3-8 membered cycloalkyl or 5-10 membered heteroaryl.

[0193] In certain preferred embodiments of the present invention, R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2.

[0194] In certain preferred embodiments of the present invention, R 3a and R 3b are each independently hydrogen or C 1-6 alkyl.

[0195] In certain preferred embodiments of the present invention, each R 3c are independently hydrogen.

[0196] In certain preferred embodiments of the present invention, R 4a It is H or a 3- to 8-membered cycloalkyl group.

[0197] In certain preferred embodiments of the present invention, m is 1, 2 or 3.

[0198] In certain preferred embodiments of the present invention, each R 5 are independently hydrogen, halogen or -N(R 6 )2.

[0199] In certain preferred embodiments of the present invention, Y, Z 1a 、Z 1c 、Z1d 、Z 1e and Z 1f Each is independently a chemical bond, -O- or -S-.

[0200] In certain preferred embodiments of the present invention, Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-,R 6 For H.

[0201] In certain preferred embodiments of the present invention, Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -S-, R 6 For H.

[0202] In certain preferred embodiments of the present invention, Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O-, -S- or -C(=O)-, R 6 For H.

[0203] In certain preferred embodiments of the present invention, L and U 1b Each independently a chemical bond or C 1-3 Alkylene.

[0204] In certain preferred embodiments of the present invention, each R 6 are independently hydrogen.

[0205] In certain preferred embodiments of the present invention, the compound represented by Formula I, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by Formula Ia, Formula Ib, or Formula Ic, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,

[0206] Among them, R 1 、R 2 、R 3 、R 4 、R 4a , Y and L are defined as above.

[0207] In certain preferred embodiments of the present invention, the compound represented by Formula I, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by Formula Ia', Formula Ib', or Formula Ic', its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,

[0208] Among them, R 1d’ -Z 1a -C 1-6 Alkyl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 The alkyl group is optionally replaced by one or more R 1-a replace;

[0209] Ring B is

[0210] (1) In formula Ia', when R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c Substituted 3-8 membered cycloalkyl, C 6-10 Aryl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f In the case of a substituted 5- to 10-membered heteroaryl group,

[0211] R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace;

[0212] (2) In Formula Ia', R 2 H, C 1-6Alkyl or deuterated C 1-6 When alkyl, R 1d for By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0213] (3) In formulas Ib' and Ic', R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, substituted by one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n When substituted 5-10 membered heteroaryl, or Y is -NR 6 -, R 6 is H, L is a chemical bond, R 2 When it is hydrogen,

[0214] R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace;

[0215] Z 1a 、Z 1c and Z 1d Each is independently a chemical bond;

[0216] R 1-a 、R 2a 、R 2b 、R 2c 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m 、R 2n 、R 3 、R 4 、R 4a , Y and L are defined as above.

[0217] In certain preferred embodiments of the present invention, the compound represented by Formula I, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by Formula Ia', Formula Ib', or Formula Ic', its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,

[0218] Among them, R 1d’ -Z 1a -C 1-6 Alkyl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 The alkyl group is optionally replaced by one or more R 1-a replace;

[0219] Ring B is

[0220] (1) In formula Ia', when R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c Substituted 3-8 membered cycloalkyl, C 6-10 Aryl, one or more R 2e Substituted C 6-10Aryl, 5-10 membered heteroaryl, or one or more R 2f In the case of a substituted 5- to 10-membered heteroaryl group,

[0221] R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace;

[0222] (2) In Formula Ia', R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1d for By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0223] (3) In formulas Ib' and Ic', R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n When substituted 5-10 membered heteroaryl, or Y is -NR 6 -, R 6 is H, L is a chemical bond, R 2 When it is hydrogen,

[0224] R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace;

[0225] Z 1a 、Z 1c and Z 1d Each is independently a chemical bond;

[0226] R 1-a 、R 2a 、R 2b 、R 2c 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m 、R 2n 、R 3 、R 4 、R 4a , Y and L are defined as above.

[0227] In certain preferred embodiments of the present invention, the compound represented by Formula I, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by Formula Ia', Formula Ib', or Formula Ic', its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,

[0228] Among them, R 1d’ -Z 1a -C 1-6 Alkyl, wherein the -Z1a -C 1-6 C in the alkyl group 1-6 The alkyl group is optionally replaced by one or more R 1-a replace;

[0229] Ring B is

[0230] (1) In formula Ia', when R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c Substituted 3-8 membered cycloalkyl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f In the case of a substituted 5- to 10-membered heteroaryl group,

[0231] R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace;

[0232] (2) In Formula Ia', R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1d for By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0233] (3) In formulas Ib' and Ic', R2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n When substituted 5-10 membered heteroaryl, or Y is -NR 6 -, R 6 is H, L is a chemical bond, R 2 When it is hydrogen,

[0234] R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace;

[0235] Z 1a 、Z 1c and Z 1d Each is independently a chemical bond;

[0236] R 1-a 、R 2a 、R 2b 、R 2c 、R 2e 、R 2f 、R 2g 、R 2h 、R2i 、R 2j 、R 2k 、R 2l 、R 2m 、R 2n 、R 3 、R 4 、R 4a , Y and L are defined as above.

[0237] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula II-a, Formula II-b or Formula II-c, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0238] Among them, Y, L, R 1d and R 2 The definition of is as mentioned above.

[0239] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula II-a, Formula II-b, Formula II-c, Formula II-d, Formula II-e or Formula II-f, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0240] Among them, Y, L, R 1d and R 2 The definition of is as mentioned above.

[0241] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0242] R 1 is a 5- to 10-membered heteroaryl group, supported by one or more R 1d substituted 5- to 10-membered heteroaryl;

[0243] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a replace;

[0244] Each R 1-a are independently deuterium, cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0245] R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl;

[0246] R 2a 、R 2b 、R 2c and R 2f are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3-8 membered cycloalkyl or 5-10 membered heteroaryl;

[0247] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0248] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0249] Each R 3c are independently hydrogen;

[0250] m is 1, 2, or 3;

[0251] R 4a is H or a 3- to 8-membered cycloalkyl group;

[0252] Each R 6 independently H;

[0253] Y, Z 1a 、Z 1c 、Z 1d and Z 1f Each is independently a chemical bond or -O-;

[0254] L and U 1b For chemical bonds or C 1-3 Alkylene.

[0255] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0256] R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0257] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0258] Each R 1-a are independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0259] R 2 Halogenated C 1-6 Alkoxy, deuterated C1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0260] Or, when R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0261] R 2a 、R 2b 、R 2c and R 2f are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0262] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0263] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0264] Each R 3c are independently hydrogen;

[0265] m is 1, 2, or 3;

[0266] R 4a is H or a 3- to 8-membered cycloalkyl group;

[0267] Y, Z 1a 、Z 1c 、Z 1d and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-;

[0268] Each R 6 independently H;

[0269] L and U 1b For chemical bonds or C 1-3 Alkylene.

[0270] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0271] R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0272] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a Substitution; said -Z1d - the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0273] Each R 1-a are independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-NH-C(=O)- or 4- to 10-membered heterocyclic group;

[0274] R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2c substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0275] Or, when R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-aReplaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0276] R 2a 、R 2b 、R 2c and R 2f are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0277] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0278] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0279] Each R 3c are independently hydrogen;

[0280] m is 1, 2, or 3;

[0281] R 4a is H or a 3- to 8-membered cycloalkyl group;

[0282] Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-;

[0283] Each R 6 independently H;

[0284] L and U 1b For chemical bonds or C 1-3 Alkylene.

[0285] In certain preferred embodiments of the present invention, X 1 and X2 Each independently is CH;

[0286] R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0287] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0288] Each R 1-a are independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-NH-C(=O)- or 4- to 10-membered heterocyclic group;

[0289] R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0290] Or, when R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0291] R 2a 、R 2b 、R 2c and R 2f are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0292] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0293] R 3a and R3b are each independently hydrogen or C 1-6 alkyl;

[0294] Each R 3c are independently hydrogen;

[0295] m is 1, 2, or 3;

[0296] R 4a is H or a 3- to 8-membered cycloalkyl group;

[0297] Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-;

[0298] Each R 6 independently H;

[0299] L and U 1b For chemical bonds or C 1-3 Alkylene.

[0300] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0301] R 1 is a 5- to 10-membered heteroaryl group, supported by one or more R 1d substituted 5- to 10-membered heteroaryl;

[0302] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a replace;

[0303] Each R 1-a are independently deuterium, cyano, halogen or -Z1f -U 1b -3 to 8-membered cycloalkyl;

[0304] R 2 For hydrogen, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl;

[0305] R 2g 、R 2i 、R 2j 、R 2k and R 2n are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3-8 membered cycloalkyl or 5-10 membered heteroaryl;

[0306] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0307] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0308] Each R 3c are independently hydrogen;

[0309] m is 1, 2, or 3;

[0310] R 4a is hydrogen or a 3- to 8-membered cycloalkyl group;

[0311] Each R 5 are independently H, halogen or -N(R 6 )2;

[0312] Each R 6 independently H;

[0313] Y, Z 1a 、Z 1c 、Z 1d and Z 1f Each is independently a chemical bond or -O-;

[0314] L and U 1b Each independently a chemical bond or C 1-3 Alkylene.

[0315] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0316] R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0317] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0318] Each R 1-aare independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0319] R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0320] R 2g 、R 2i 、R 2j 、R 2k and R 2n are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0321] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0322] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0323] Each R 3c are independently hydrogen;

[0324] m is 1, 2, or 3;

[0325] R 4a is hydrogen or a 3- to 8-membered cycloalkyl group;

[0326] Each R 5 are independently H, halogen or -N(R 6 )2;

[0327] Y, Z 1a 、Z 1c 、Z 1e 、Z 1d and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-;

[0328] Each R 6 independently H;

[0329] L and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0330] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0331] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0332] R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0333] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0334] Each R 1-a are independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)- or 4- to 10-membered heterocyclic group;

[0335] R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2nThe number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0336] R 2g 、R 2i 、R 2j 、R 2k and R 2n are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0337] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0338] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0339] Each R 3c are independently hydrogen;

[0340] m is 1, 2, or 3;

[0341] R 4a is hydrogen or a 3- to 8-membered cycloalkyl group;

[0342] Each R 5 are independently H, halogen or -N(R 6 )2;

[0343] Y, Z 1a 、Z 1c 、Z 1e 、Z 1d and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-;

[0344] Each R 6 independently H;

[0345] L and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0346] Alternatively, Y is -NR6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0347] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0348] R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0349] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0350] Each R 1-a are independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, -NH2 or -OH;

[0351] R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0352] R 2g 、R 2i 、R 2j 、R 2k and R 2n are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0353] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0354] R 3a and R3b are each independently hydrogen or C 1-6 alkyl;

[0355] Each R 3c are independently hydrogen;

[0356] m is 1, 2, or 3;

[0357] R 4a is hydrogen or a 3- to 8-membered cycloalkyl group;

[0358] Each R 5 are independently H, halogen or -N(R 6 )2;

[0359] Y, Z 1a 、Z 1c 、Z 1e 、Z 1d and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-;

[0360] Each R 6 independently H;

[0361] L and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0362] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0363] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0364] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0365] Each R 1d Independently -Z 1a -C 1-6 Alkyl or -Z 1c -C 6-10 Aryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl and -Z1c -C 6-10 C in aromatic groups 6-10 Each aryl group is optionally substituted by one or more R 1-a replace;

[0366] Each R 1-a are independently cyano, halogen, C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0367] R 2 Halogenated C 1-6 Alkoxy, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c a substituted 3- to 8-membered cycloalkyl or 5- to 10-membered heteroaryl group; the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and each heteroatom is independently selected from N, O, and S; when there are multiple substituents, they may be the same or different;

[0368] Or, when R 2 H or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0369] R 2a 、R 2b and R 2c are each independently halogen, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0370] R 3 and R 4 Each independently is hydrogen or -(CH2)m-OP(=O)(OR 3c )2;

[0371] Each R 3c are independently hydrogen;

[0372] m is 1;

[0373] R 4a is H;

[0374] Y, Z 1a 、Z 1c and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-;

[0375] Each R 6 independently H;

[0376] L and U 1b For chemical bonds or C 1-3 Alkylene.

[0377] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0378] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0379] Each R 1d Independently -Z 1a -C 1-6 Alkyl or -Z 1c -C 6-10 Aryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl and -Z 1c -C 6-10 C in aromatic groups 6-10 Each aryl group is optionally substituted by one or more R 1-a replace;

[0380] Each R 1-a are independently cyano, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0381] R2 Halogenated C 1-6 Alkoxy, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c a substituted 3- to 8-membered cycloalkyl or 5- to 10-membered heteroaryl group; the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and each heteroatom is independently selected from N, O, and S; when there are multiple substituents, they may be the same or different;

[0382] Or, when R 2 H or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0383] R 2a 、R 2b and R 2c are each independently halogen, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0384] R 3 and R 4 Each independently is hydrogen or -(CH2)m-OP(=O)(OR 3c )2;

[0385] Each R 3c are independently hydrogen;

[0386] m is 1;

[0387] R 4a is H;

[0388] Y, Z 1a 、Z 1c 、Z 1e and Z 1fEach independently represents a chemical bond, -NR 6 -or-O-;

[0389] Each R 6 independently H;

[0390] L and U 1b For chemical bonds or C 1-3 Alkylene.

[0391] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0392] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0393] Each R 1d Independently -Z 1a -C 1-6 Alkyl or -Z 1c -C 6-10 Aryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl and -Z 1c -C 6-10 C in aromatic groups 6-10 Each aryl group is optionally substituted by one or more R 1-a replace;

[0394] Each R 1-a are independently cyano, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0395] R 2 Halogenated C 1-6 Alkoxy, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2ca substituted 3- to 8-membered cycloalkyl or 5- to 10-membered heteroaryl group; the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and each heteroatom is independently selected from N, O, and S; when there are multiple substituents, they may be the same or different;

[0396] Or, when R 2 H or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0397] R 2a 、R 2b and R 2c are each independently halogen, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S;

[0398] R 3 and R 4 Each independently is hydrogen or -(CH2)m-OP(=O)(OR 3c )2;

[0399] Each R 3c are independently hydrogen;

[0400] m is 1;

[0401] R 4a is H;

[0402] Y, Z 1a 、Z 1c 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-;

[0403] Each R 6 independently H;

[0404] L and U 1b For chemical bonds or C 1-3 Alkylene.

[0405] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0406] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0407] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0408] Each R 1-a are independently deuterium, cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0409] R 2 For halogen, cyano, C 1-6 Alkyl, one or more R2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl or one or more R 2k substituted 3- to 8-membered cycloalkyl;

[0410] R 2g 、R 2j , and R 2k are independently deuterium, halogen, C 1-6 Alkyl or -N(R 6 )2;

[0411] R 3 and R 4 are each independently hydrogen or -C(=O)-O-CH(R 3a )-OC(O)-R 3b ;

[0412] R 3a and R 3b Each independently is C 1-6 alkyl;

[0413] R 4a is hydrogen or a 3- to 8-membered cycloalkyl group;

[0414] Each R 5 independently H;

[0415] Y, Z 1a 、Z 1c 、Z 1d and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-;

[0416] Each R 6 independently H;

[0417] L and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0418] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0419] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2CR 5 ;

[0420] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0421] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0422] Each R 1-a are independently deuterium, cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-NH-C(=O)- or 4- to 10-membered heterocyclic group;

[0423] R 2 For halogen, cyano, C1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl or one or more R 2k substituted 3- to 8-membered cycloalkyl;

[0424] R 2g 、R 2j , and R 2k are independently deuterium, halogen, C 1-6 Alkyl or -N(R 6 )2;

[0425] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0426] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0427] Each R 3c are independently hydrogen;

[0428] R 4a is hydrogen or a 3- to 8-membered cycloalkyl group;

[0429] Each R 5 independently H;

[0430] Y, Z 1a 、Z 1c 、Z 1d 、 Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-;

[0431] Each R 6 independently H;

[0432] L and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0433] Alternatively, Y is -NR 6 -, R 6When H and L are chemical bonds, R 2 For H.

[0434] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0435] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0436] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0437] Each R 1-a are independently deuterium, cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-NH-C(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, -NH2 or -OH;

[0438] R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl or one or more R 2k substituted 3- to 8-membered cycloalkyl;

[0439] R 2g 、R 2j , and R 2k are independently deuterium, halogen, C 1-6 Alkyl or -N(R 6 )2;

[0440] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0441] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0442] Each R 3c are independently hydrogen;

[0443] R 4a is hydrogen or a 3- to 8-membered cycloalkyl group;

[0444] Each R 5 independently H;

[0445] Y, Z 1a 、Z 1c 、Z 1d 、 Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-;

[0446] Each R 6 independently H;

[0447] L and U 1b Each independently a chemical bond or C 1-3 alkylene;

[0448] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0449] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0450] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0451] When R 2 H or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0452] Each R 1-a are independently cyano, halogen or C 1-6 alkyl;

[0453] R 3 and R 4 are each independently hydrogen;

[0454] R 4a is H;

[0455] Y and Z 1a Each independently is a chemical bond or -NR 6 -;

[0456] R 6 is H;

[0457] L is a chemical bond.

[0458] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0459] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0460] When R 2 H or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0461] Each R 1-a are independently cyano, halogen, C 1-6 Alkyl or -Z 1e -Halogenated C 1-6 alkyl;

[0462] R 3 and R 4 are each independently hydrogen;

[0463] R 4a is H;

[0464] Y, Z 1a and Z 1e Each independently is a chemical bond or -NR 6 -;

[0465] R 6 is H;

[0466] L is a chemical bond.

[0467] In certain preferred embodiments of the present invention, X 1 and X 2 Each independently is CH;

[0468] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0469] When R 2 When H, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced or by one or more R 1-a Replaced

[0470] Each R 1-a are independently cyano, halogen or C 1-6 alkyl;

[0471] R 3 and R 4 are each independently hydrogen;

[0472] R 4a is H;

[0473] Y and Z 1a Each is independently a chemical bond;

[0474] L is a chemical bond.

[0475] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0476] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1dThe number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0477] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0478] Each R 1-a are independently cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl;

[0479] R 2 For cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3- to 8-membered cycloalkyl; when there are multiple substituents, they may be the same or different;

[0480] R 2g are independently deuterium or halogen;

[0481] R 3 and R 4 are each independently hydrogen;

[0482] R 4a is hydrogen;

[0483] Each R 5 independently H;

[0484] Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-;

[0485] R 6 is H;

[0486] L and U 1b Each is independently a chemical bond;

[0487] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0488] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0489] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0490] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0491] Each R 1-a are independently deuterium, cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)- or 4- to 10-membered heterocyclic group;

[0492] R 2 For cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3- to 8-membered cycloalkyl; when there are multiple substituents, they may be the same or different;

[0493] R 2g are independently deuterium or halogen;

[0494] R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2;

[0495] R 3a and R 3b are each independently hydrogen or C 1-6 alkyl;

[0496] Each R 3c are independently hydrogen;

[0497] R 4a is hydrogen;

[0498] Each R 5 independently H;

[0499] Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-;

[0500] R 6 is H;

[0501] L and U 1b Each is independently a chemical bond;

[0502] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0503] In certain preferred embodiments of the present invention, X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ;

[0504] R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different.

[0505] Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d- the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different;

[0506] Each R 1-a are independently cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3- to 8-membered cycloalkyl, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, -NH2 or -OH;

[0507] R 2 For one or more R 2g Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0508] R 2g independently for deuterium;

[0509] R 3 and R 4 are each independently hydrogen;

[0510] R 4a is hydrogen;

[0511] Each R 5 independently H;

[0512] Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-;

[0513] R 6 is H;

[0514] L and U 1b Each is independently a chemical bond.

[0515] In certain preferred embodiments of the present invention, each R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0516] In certain preferred embodiments of the present invention, each R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0517] In certain preferred embodiments of the present invention, each R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced

[0518] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula III-a, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0519] Among them, each R 1-a are independently deuterium, cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 Halogenated C 1-6 Alkoxy; R 3 and R4 are each independently hydrogen; R 4a is H; Y is a chemical bond; Z 1f -O-; L and U 1b are independently chemical bonds; n is 2, 3, 4 or 5;

[0520] For example, each R 1-a are independently cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 Halogenated C 1-6 Alkoxy; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond; Z 1f -O-; L and U 1b are independently chemical bonds; n is 4.

[0521] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula III-b, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0522] Among them, each R 1-a Independently C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 H, C 1-6 Alkyl or deuterated C 1-6 Alkyl; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond or --NR 6 -, where R 6 H; Z 1e and Z 1f are independently chemical bonds; L and U 1b independently a chemical bond;

[0523] For example, each R 1-a Independently C 1-6 Alkyl; R 2 H; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond; L is a chemical bond.

[0524] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula III-c, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0525] Among them, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently deuterium, cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond;

[0526] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H;

[0527] For example, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond;

[0528] Alternatively, Y is -NR 6 -, where R 6 When H and L are chemical bonds, R 2 For H.

[0529] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula III-d, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0530] Among them, R 1d for By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, or one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently chemical bonds; L and U 1b independently a chemical bond;

[0531] For example, R 1d For one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently cyano, oxo, halogen, C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1f is a chemical bond; L and U 1b are independently chemical bonds.

[0532] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula III-d, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0533] Among them, R 1d for By one or more R 1-a Replaced or by one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)- or 4-10 membered heterocyclic group; R 2 C 1-6 Alkyl, or one or more R 2g Substituted C 1-6 Alkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b independently a chemical bond;

[0534] For example, R 1d for By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)- or 4-10 membered heterocyclic group; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b independently a chemical bond;

[0535] For example, R 1d For one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8 membered cycloalkyl or C 1-6 Alkyl-OC(=O)-; R2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b are independently chemical bonds.

[0536] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula III-c, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0537] Among them, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently deuterium, cyano, halogen, 4- to 10-membered heterocyclic group, halogen-substituted 4- to 10-membered heterocyclic group, or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond;

[0538] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H;

[0539] For example, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently cyano, halogen, 4- to 10-membered heterocyclic group, halogen-substituted 4- to 10-membered heterocyclic group, or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond;

[0540] Alternatively, Y is -NR 6 -, where R 6 When H and L are chemical bonds, R 2 For H.

[0541] In certain preferred embodiments of the present invention, the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound as shown in Formula III-d, its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

[0542] Among them, R 1d for By one or more R 1-a Replaced or by one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group or -OH; R 2 C 1-6 Alkyl, or one or more R 2g Substituted C 1-6 Alkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b independently a chemical bond;

[0543] For example, R 1d for By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6Alkyl-OC(=O)-, 4-10 membered heterocyclic group or -OH; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b independently a chemical bond;

[0544] For example, R 1d For one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, C 1-6 Alkyl-OC(=O)- or C 1-6 Alkyl-SO2-; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b are independently chemical bonds.

[0545] In certain preferred embodiments of the present invention, the compound shown in Formula I is a compound shown in Formula III-e-1 or Formula III-e-2,

[0546] Among them, each R1-a are independently cyano, halogen, -Z 1f -U 1b -3- to 8-membered cycloalkyl, 4- to 10-membered heterocyclic group, or halogen-substituted 4- to 10-membered heterocyclic group; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1f -O-; L and U 1b are independently chemical bonds; n is 4.

[0547] In certain preferred embodiments of the present invention, the compound shown in Formula I is a compound shown in Formula III-f-1 or Formula III-f-2,

[0548] in, Indicates a single bond or a double bond;

[0549] when When representing a double bond, W is CR 1-a ;when When it represents a single bond, W is C=O, CH2 or NR 1-a ;

[0550] Each R 1-a Independently C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is -NR 6 -, where R 6 H; Z 1e and Z 1f are independently chemical bonds; L and U 1b independently a chemical bond;

[0551] For example, each R 1-a Independently C 1-6 Alkyl or -Z1e -Halogenated C 1-6 Alkyl; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1e and L are independently a chemical bond.

[0552] In certain preferred embodiments of the present invention, X 1 and X 2 are each independently CH or N.

[0553] In certain preferred embodiments of the present invention, R 1 for

[0554] In certain preferred embodiments of the present invention, R 1 for

[0555] In certain preferred embodiments of the present invention, R 1 for

[0556] In certain preferred embodiments of the present invention, R 1 for

[0557] In certain preferred embodiments of the present invention, when X 1 and X 2 When each is independently CH, R 2 for

[0558] In certain preferred embodiments of the present invention, when X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2For H, F, Cl, -CF3, -CH2CF3, -CD3,

[0559] In certain preferred embodiments of the present invention, when X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2 For F, Cl, -CF3, -CH2CF3, -CD3, Triazole (e.g. ), pyrazolyl (e.g. ), -CH3, cyano, -CH2CHF2, -CH2CD3, -CD2CD3 or -CD2CH3;

[0560] Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 For H.

[0561] In certain preferred embodiments of the present invention, R 3 For H,

[0562] In certain preferred embodiments of the present invention, R 4 H or

[0563] In certain preferred embodiments of the present invention, R 4a H or

[0564] In certain preferred embodiments of the present invention, Y is a chemical bond or -O-.

[0565] In certain preferred embodiments of the present invention, Y is a chemical bond, -NR 6 - or -O-, where R 6 For H.

[0566] In certain preferred embodiments of the present invention, L is a chemical bond or C 1-3 Alkylene.

[0567] In certain preferred embodiments of the present invention, each R 5 are independently H.

[0568] In certain preferred embodiments of the present invention, the compound as shown in Formula I is selected from any of the following structures:

[0569] The present invention also provides a pharmaceutical composition comprising the compound as described above as shown in Formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts, and at least one pharmaceutical excipient.

[0570] The selection of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and can generally be fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. conventional in the art.

[0571] The present invention also provides the use of the compound represented by Formula I, its stereoisomers, its tautomers, or pharmaceutically acceptable salts, or the pharmaceutical composition described above, in the preparation of a PRMT5 inhibitor, such as a PRMT5·MTA inhibitor. In such applications, the PRMT5 inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, for example, as a standard or control sample for comparison, or prepared according to conventional methods in the art to provide a kit for rapid detection of the effect of inhibiting PRMT5.

[0572] In the present invention, PRMT5·MTA refers to a complex formed by the binding of MTA (methylthioadenosine) and PRMT5 (protein arginine N-methyltransferase 5) in cancer cells lacking the MTAP (methylthioadenosine phosphorylase) gene.

[0573] The present invention also provides the use of the compound as shown in Formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition as described above in the preparation of drugs, for example, in the preparation of drugs for treating and / or preventing cancer. The cancer may be an MTAP-related / mediated cancer, preferably, the MTAP-related / mediated cancer is head and neck cancer (such as thyroid cancer, meningeal cancer, intracranial metastasis or glioblastoma), respiratory system cancer (such as lung cancer or nasopharyngeal cancer), digestive system cancer (esophageal cancer, gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, rectal cancer or colon cancer), urinary system cancer (such as kidney cancer, bladder cancer, prostate cancer or testicular cancer), bone cancer, gynecological cancer (such as breast cancer, endometrial cancer, cervical cancer or ovarian cancer), blood system cancer (such as leukemia, lymphoma or myeloma) or other types of cancer (such as melanoma or skin cancer), more preferably lymphoma, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, leukemia, glioblastoma, prostate cancer or ovarian cancer.

[0574] The present invention also provides the use of the compound of Formula I, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described above, in the preparation of a medicament, for example, in the preparation of a medicament for treating and / or preventing a disease associated with or mediated by MTAP. The disease may be cancer. The cancer may be head and neck cancer (e.g., thyroid cancer, meningeal cancer, intracranial metastasis or glioblastoma), respiratory cancer (e.g., lung cancer or nasopharyngeal cancer), digestive system cancer (esophageal cancer, gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, rectal cancer or colon cancer), urinary system cancer (e.g., kidney cancer, bladder cancer, prostate cancer or testicular cancer), bone cancer, gynecological cancer (e.g., breast cancer, endometrial cancer, cervical cancer or ovarian cancer), blood system cancer (e.g., leukemia, lymphoma or myeloma) or other types of cancer (e.g., melanoma or skin cancer), preferably lymphoma, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, leukemia, glioblastoma, prostate cancer or ovarian cancer.

[0575] The present application provides a method for treating and / or preventing cancer, the method comprising administering a therapeutically effective amount of a substance X to a subject in need thereof; the substance X is a compound as shown in Formula I as described above, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. The cancer may be head and neck cancer (e.g., thyroid cancer, meningeal cancer, intracranial metastasis, or glioblastoma), respiratory cancer (e.g., lung cancer or nasopharyngeal cancer), digestive cancer (esophageal cancer, gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, rectal cancer, or colon cancer), urinary cancer (e.g., kidney cancer, bladder cancer, prostate cancer, or testicular cancer), bone cancer, gynecological cancer (e.g., breast cancer, endometrial cancer, cervical cancer, or ovarian cancer), hematological cancer (e.g., leukemia, lymphoma, or myeloma), or other types of cancer (e.g., melanoma or skin cancer), preferably lymphoma, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, leukemia, glioblastoma, prostate cancer, or ovarian cancer.

[0576] The present application provides a method for treating and / or preventing a disease associated with or mediated by MTAP, comprising administering to a subject in need thereof a therapeutically effective amount of a substance Y; the substance Y being a compound as described above as represented by Formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. The disease may be cancer. The cancer may be head and neck cancer (e.g., thyroid cancer, meningeal cancer, intracranial metastasis or glioblastoma), respiratory system cancer (e.g., lung cancer or nasopharyngeal cancer), digestive system cancer (esophageal cancer, gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, rectal cancer or colon cancer), urinary system cancer (e.g., kidney cancer, bladder cancer, prostate cancer or testicular cancer), bone cancer, gynecological cancer (e.g., breast cancer, endometrial cancer, cervical cancer or ovarian cancer), blood system cancer (e.g., leukemia, lymphoma or myeloma) or other types of cancer (e.g., melanoma or skin cancer), preferably lymphoma, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, leukemia, glioblastoma, prostate cancer or ovarian cancer.

[0577] The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition described above can be a therapeutically effective amount.

[0578] The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition described above can be administered to a subject by any suitable route, preferably orally or by injection (intravenous, intramuscular, subcutaneous and coronary).

[0579] The present invention also provides a method for preparing the compound of Formula I as described above, wherein the method comprises the following Scheme 1, Scheme 2 or Scheme 3:

[0580] Scheme 1: When the compound represented by Formula I is the compound represented by Formula II-a, starting from raw material 1a, intermediate 1b is obtained through substitution reaction; intermediate 1b is brominated and ring-closed to obtain intermediate 1d; 1d is then reacted with N,N-dimethylformamide dimethyl acetal to obtain intermediate 1e; 1e is reacted with hydrazine hydrate to obtain intermediate 1f; 1f is then chlorinated and substituted with phthalimide to obtain intermediate 1h; intermediate 1h is reacted with the corresponding borate compound through Suzuki coupling reaction to obtain intermediate 1i; or intermediate 1h is converted into borate intermediate 1j, which is then reacted with the corresponding iodide to obtain intermediate 1i; intermediate 1i is subjected to hydrazinolysis to obtain compound II-a;

[0581] Scheme 2, when the compound represented by formula I is the compound represented by formula II-a, starting from raw material 2a (prepared according to the method described in patent US20210078994A1), the iodide intermediate 2b is obtained by Sandmeyer reaction, and the intermediate 2b is then reduced to an alcohol by ester reduction, chlorination, and phthalamide substitution to obtain intermediate 2e; intermediate 2e is subjected to hydrazinolysis and then protected with tert-butyl carbonate to obtain intermediate 2g; intermediate 2g is subjected to a two-step coupling reaction and removal of the tert-butyloxycarbonyl protecting group to obtain compound II-a;

[0582] Scheme 3: When the compound represented by Formula I is the compound represented by Formula II-b, the raw material 3a is subjected to hydrogen extraction and halogen migration with a strong base lithium diisopropylamide and then treated with carbon dioxide to obtain a carboxylic acid intermediate 3b, which is then esterified to obtain an intermediate 3c; 3c is subjected to a Stille coupling reaction to obtain an intermediate 3e; 3e is reacted with N-bromosuccinimide to obtain an intermediate 3f; 3f is substituted with potassium acetate or dimethylamine to obtain an intermediate 3g-1 or 3g-2; 3g-1 or 3g-2 is reacted with hydrazine hydrate and ring-closed to obtain an intermediate 3i-1 or 3i-2; 3i-1 or 3i-2 is reacted with a corresponding borate compound through a Suzuki coupling reaction to obtain an intermediate 3j-1 or 3j-2; 3j-1 or 3j-2 is then subjected to chlorination, phthalimide substitution, and hydrazinolysis to obtain compound II-b;

[0583] Wherein, W is Cl or Br; Y, L, R 1d and R 2 The definition of is as mentioned above.

[0584] The present invention also provides a compound as shown below,

[0585] Definition of terms

[0586] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0587] As used herein, the compounds of Formula I of the present invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound comprises enantiomers. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of Formula I contains more than one chiral center, diastereomers may exist. The present invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.

[0588] The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds described in the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as meso-, racemic-, and equal mixtures of atropisomers, or single enantiomers, single diastereomers, or mixtures thereof, or single atropisomers or mixtures thereof.

[0589] The term "tautomer" refers to functional isomers that result from the rapid shift of an atom between two positions in a molecule.

[0590] When the compounds described herein contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.

[0591] The compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is intended to cover any isotopically labeled (or "radiolabeled") variant of the compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt. Such a variant can be a compound as shown in Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. The radionuclide used will depend on the specific application of the radiolabeled variant. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C is often useful. For radiographic applications, 11 C or 18 F is often useful.

[0592] Certain isotopic variants of the compounds of the invention, particularly those into which one or more radioactive isotopes have been incorporated, can be useful, for example, in studying the mechanism of action or the distribution of the active ingredient in the body; because of the relative ease of preparation and detectability, isotopic variants labeled with 3 H or 14 Compounds containing a C isotope are particularly suitable for this purpose. Furthermore, the incorporation of an isotope, such as deuterium, can provide particular therapeutic benefits due to improved metabolic stability of the compound, for example, by extending the half-life in vivo or reducing the required effective dose; thus, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention in some cases. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, such as those described below and in the working examples, by using corresponding isotopically modified specific reagents and / or starting compounds.

[0593] As used herein, a "pharmaceutical composition" refers to a formulation comprising a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0594] In this application, "pharmaceutically acceptable" refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0595] The term "pharmaceutical excipient" or "pharmaceutically acceptable carrier" refers to the excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations in addition to the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the drug, or to promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0596] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0597] When used as a medicine, the compound as shown in Formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof can be administered in any form of a pharmaceutical composition. These compositions can be applied in various ways, depending on the local or systemic treatment and the area to be treated. Administration can be topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal or intranasal), oral (solid and liquid preparations) or parenteral administration form. Examples of solid oral preparations include but are not limited to powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include but are not limited to suspensions, emulsions, elixirs and solutions. Examples of topical preparations include but are not limited to emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial administration, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or may be administered by continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, and the like may be necessary or desirable. Pharmaceutical compositions comprising the present invention may also be in the form of controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres).

[0598] The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0599] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0600] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0601] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0602] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, the chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0603] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0604] In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.

[0605] Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, a C1-C4 alkyl or a C 1-4 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3 or 4 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0606] As used herein, numerical ranges defined in substituents, such as 0 to 10, 1-6, 1-3, etc., indicate integers within the range, such as 1-6 represents 1, 2, 3, 4, 5, 6.

[0607] The term "optionally with one or more R 1‐a "Replaced" means not replaced by R 1‐a substituted and replaced by one or more R 1‐a Replace the two cases. For example, "the -Z 1a -C 1‐6 C in the alkyl group 1‐6 The alkyl group is optionally replaced by one or more R 1‐a "Substitution" means -Z1a -C 1‐6 Alkyl and -Z 1a -(by one or more R 1‐a Replaced)C 1‐6 alkyl.

[0608] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0609] The term "substituted with" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced with a substituent, as long as the valence of the particular atom is normal and the compound after the substitution is stable.

[0610] In general, the term "substituted" or "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Furthermore, when a group is substituted with one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at every substitutable position of the substituted group. When more than one position in a given structure is substituted by one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0611] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group types and ranges. The term "C x -C y Alkyl" or "C x-y "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, the term "C1-C6 alkyl" or "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently; "C 1-4 The term "alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl (i.e., propyl, including n-propyl and isopropyl), and C4 alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0612] As used herein, the terms "moiety," "moiety," "chemical moiety," "group," and "chemical group" refer to specific segments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0613] When a substituent is listed without indicating the atom via which it is bonded in a chemical formula (including but not specifically mentioned compounds), such substituent may be bonded via any atom thereof. Combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0614] When any variable (such as R 1-a ) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R 1-a group substituted, that is, the group may be replaced by up to 3 R 1-a Substitution, where a position R 1-a Definition and other positions R 1-a In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0615] When a group is listed without specifying that it has a substituent, such group is only meant to be unsubstituted. For example, when "C 1-6 When "alkyl" is not limited to "substituted or unsubstituted", it only refers to "C 1-6 Alkyl" itself or "unsubstituted C 1-6 alkyl".

[0616] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", it should be understood that the "alkyl" represents a linking alkylene group.

[0617] In some specific structures, when an alkyl group is explicitly indicated as a linking group, the alkyl group represents a linking alkylene group, for example, the group "halo-C 1-6 C in "alkyl-" 1-6 Alkyl should be understood as C 1-6 Alkylene.

[0618] The term "halogen" refers to fluorine, chlorine, bromine or iodine, in particular to F, Cl or Br.

[0619] In this application, the term "alkyl" as a group or part of another group (for example, in a group such as a haloalkyl group, a deuterated alkyl group, etc.) refers to a saturated aliphatic hydrocarbon group including branched and straight chains having the specified number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, and most preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, wherein propyl is a C3 alkyl group (including isomers such as n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers such as n-butyl, sec-butyl, isobutyl or tert-butyl); butyl); pentyl is a C5 alkyl group (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); hexyl is a C6 alkyl group (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, decyl, and the like.

[0620] In this application, the term "alkylene" as a group or part of another group means a saturated divalent hydrocarbon group derived from a saturated straight-chain or branched hydrocarbon by removing two hydrogen atoms; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl is as described above. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2-, -CH2CH(CH3)- or -C(CH3)2-}, and the like.

[0621] In this application, the term "alkoxy" as a group or part of another group refers to -O-alkyl, and alkyl is as defined above.

[0622] In this application, the term "hydroxyalkyl" as a group or part of another group refers to HO-alkyl-, where alkyl is as defined above.

[0623] In the present application, the term "alkenyl" as a group or part of another group refers to a straight-chain or branched hydrocarbon group having at least one double bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, for example, including but not limited to vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1,4-dienyl, etc.

[0624] In this application, the term "alkynyl" as a group or part of another group refers to a straight or branched hydrocarbon group having at least one triple bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, for example, including but not limited to ethynyl, 1-propynyl, n-propargyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl or pent-1,4-diynyl, etc.

[0625] In this application, the term "cycloalkyl" as a group or part of another group means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) carbocyclic substituent, which can be connected to the rest of the molecule by a single bond through any suitable carbon atom; such as a 3-15 membered cycloalkyl having 3 to 15 carbon atoms, preferably a 3-12 membered cycloalkyl having 3 to 12 carbon atoms, more preferably a 3-8 membered cycloalkyl having 3 to 8 carbon atoms, and most preferably a 3-6 membered cycloalkyl having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.

[0626] In the present application, the term "heterocyclyl" as a group or part of another group refers to a stable saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged, fused or spirocyclic) non-aromatic cyclic group consisting of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S; preferably a 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, more preferably a 3-10 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, and most preferably a 3-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S. When it is a bicyclic, tricyclic or higher ring cycloheterocyclic group, it may also include the formation of a cycloheterocyclic group (condensed ring) with a cycloalkyl, aryl or heteroaryl group as defined herein, provided that the heterocyclyl group is connected to the rest of the molecule by a single bond via any suitable atom in the saturated or partially unsaturated heterocycle. When it is a bicyclic, tricyclic or higher ring spirocyclic heterocyclyl group, it may also include the formation of a spirocyclic group with a cycloalkyl group as defined herein, provided that the heterocyclyl group is connected to the rest of the molecule by a single bond via any suitable atom in the saturated or partially unsaturated heterocycle. In a certain embodiment of the present invention, heterocyclic groups include "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkyl" refers to a cyclic group consisting of a stable saturated monocyclic or polycyclic ring (e.g., a bicyclic, tricyclic or more cyclic bridged ring, a cyclic (condensed ring) or a spirocyclic system) of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S, and a non-aromatic cyclic group consisting of a stable partially unsaturated monocyclic or polycyclic ring (e.g., a bicyclic, tricyclic or more cyclic bridged ring, a cyclic (condensed ring) or a spirocyclic system) of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S. For example, the 3-10 membered heterocyclic group includes a 3-10 membered heterocycloalkyl or a 3-10 membered heterocycloalkenyl. In some embodiments, "heterocycloalkyl" is a 3 to 7 membered monocyclic heterocycloalkyl, a 4 to 8 membered heterocycloalkyl, a 4 to 8 membered heterocycloalkyl or a 5 to 10 membered spirocyclic heterocycloalkyl. Exemplary 3-membered heterocycloalkyl groups include, but are not limited to, aziridine, oxiranyl, and thiirane, or stereoisomers thereof; exemplary 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl (e.g. ), propylene oxide, oxetane (e.g. ), thietanyl, or isomers and stereoisomers thereof; exemplary 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl (For example ), or isomers and stereoisomers thereof. Exemplary 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, cyclopentylsulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof. Exemplary 7-membered heterocycloalkyl groups include, but are not limited to, or isomers and stereoisomers thereof. Exemplary 8-membered heterocycloalkyl groups include, but are not limited to, or isomers and stereoisomers thereof.

[0627] In this application, the term "aryl" as a group or part of another group refers to an aromatic group consisting of a conjugated hydrocarbon ring system of carbon atoms that satisfies the 4n+2 rule, with each ring having aromaticity. In one embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6 to 10) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl.

[0628] In the present application, the term "heteroaryl" as a group or part of another group means a conjugated ring system radical having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specified in the specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or higher ring system. When it is a bicyclic, tricyclic or higher ring fused ring, it can also include a cycloalkyl or heterocyclyl group as defined herein, provided that the heteroaryl group is connected to the rest of the molecule by a single bond through an atom on the aromatic ring. Preferably, the 5- to 10-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S, or the 11- to 20-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S, more preferably the 5- to 6-membered heteroaryl group, the 8- to 10-membered heteroaryl group, the 12-membered heteroaryl group, the 13-membered heteroaryl group, the 14-membered heteroaryl group or the 15-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl (e.g., ), thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl Pyrimidinyl Pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl furyl, pyrrolyl, triazolyl (e.g. ), tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, naphthiazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl or benzisoxazolyl. Examples of heteroaryl groups include, but are not limited to

[0629] The "-" at the end or both ends of a group means that the group is connected to other fragments in the molecule through this site.

[0630] It is to be understood that as used herein, the singular forms, such as "a," "an," and the like, include plural referents unless otherwise specified.

[0631] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0632] Unless otherwise stated, the present invention adopts conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operating steps and conditions in the art.

[0633] Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some instances, standard techniques were used for chemical syntheses and chemical analyses.

[0634] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can independently represent the same or different specific groups. More specifically, the term "independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0635] Those skilled in the art will understand that according to the conventions used in the art, the structural formulas used in this application to describe groups means that the corresponding group passes through the Connect with other fragments and groups in the compound.

[0636] Unless otherwise specified, all technical and scientific terms used herein have the standard meanings in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0637] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0638] The reagents and raw materials used in the present invention are commercially available.

[0639] The positive progress of the present invention is that: the present invention provides a class of PRMT5 inhibitors, which have good inhibitory activity or selectivity against human colon cancer stably knocked-out MTAP protein cells (HCT-116-MTAP-KO-1A2) and can inhibit the proliferation of tumor cells. DETAILED DESCRIPTION

[0640] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0641] The following examples illustrate the present invention in more detail, but do not limit the present invention in any way.

[0642] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). Nuclear magnetic resonance chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard. Mass spectrometry measurements were performed using an Agilent 1260-6125B single quadrupole liquid chromatography-mass spectrometer employing an electrospray ionization (ESI) source.

[0643] For the opposite silica gel column chromatography, a Biotage Selekt flash preparative chromatograph and a Biotage BK-SIL silica gel prepacked column or an Agela Claricep Flash silica gel prepacked column of appropriate specifications were used.

[0644] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of which is 0.15mm-0.20mm, and the specification of which is 0.4mm-0.5mm for preparative thin layer chromatography.

[0645] Preparative high-performance liquid chromatography (HPLC) was performed using a Waters AutoPurification LC system equipped with an ACQUITY QDa mass spectrometer. A SunFire C18 5μm 19x250mm OBD preparative column was used as the preparative column. Compounds were eluted using a gradient of water (containing 0.1% formic acid)-acetonitrile as the mobile phase.

[0646] The Chinese and English abbreviations are as follows:

[0647] Boc: tert-butyloxycarbonyl; SEM: (trimethylsilyl)ethoxymethyl; THP: tetrahydropyranyl; TIPS: triisopropylsilyl; CDCl3: deuterated chloroform; DMSO: dimethyl sulfoxide; -Bpin:

[0648] Example 1

[0649] 2-(4-(4-(Aminomethyl)-1-oxo-8-(2,2,2-trifluoroethoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 1)

[0650] Step 1: Methyl 4-bromo-2-methyl-6-(2,2,2-trifluoroethoxy)benzoate

[0651] Methyl 4-bromo-2-fluoro-6-methylbenzoate (247 mg, 1.0 mmol) and trifluoroethanol (200 mg, 2.0 mmol) were dissolved in dimethyl sulfoxide (5 mL). Cesium carbonate (652 mg, 2.0 mmol) was added and stirred at 80°C for 18 hours. The mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (236 mg, yield 72.1%). ESI-MS m / z: 326.9 [M+1] + .

[0652] Step 2: Methyl 4-bromo-2-(bromomethyl)-6-(2,2,2-trifluoroethoxy)benzoate

[0653] Methyl 4-bromo-2-methyl-6-(2,2,2-trifluoroethoxy)benzoate (2610 mg, 8.0 mmol) was dissolved in carbon tetrachloride (30 mL). Benzoyl peroxide (258 mg, 0.8 mmol, 75%) and N-bromosuccinimide (1570 mg, 8.8 mmol) were added and stirred at 80°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a light yellow oil (3060 mg, yield 94.7%). ESI-MS m / z: 404.9 [M+1] + .

[0654] Step 3: 5-Bromo-7-(2,2,2-trifluoroethoxy)isobenzofuran-1(3H)-one

[0655] Methyl 4-bromo-2-(bromomethyl)-6-(2,2,2-trifluoroethoxy)benzoate (3060 mg, 7.57 mmol) was dissolved in a mixture of 1,4-dioxane (30 mL) and water (10 mL) and stirred at 100°C for 8 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to afford the product as a pale yellow oil (1600 mg, yield 68.2%). ESI-MS m / z: 310.9 [M+1] + . 1 H NMR (400MHz, CDCl3): δ7.35(s,1H),7.19(s,1H),5.33-5.19(m,2H),4.74-4.57(m,2H).

[0656] Step 4: 5-Bromo-3-((dimethylamino)methylene)-7-(2,2,2-trifluoroethoxy)isobenzofuran-1(3H)-one

[0657] 5-Bromo-7-(2,2,2-trifluoroethoxy)isobenzofuran-1(3H)-one (1240 mg, 4.0 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (3065 mg, 25.76 mmol), and potassium tert-butoxide (45 mg, 0.4 mmol, 75%) was added. The reaction was stirred at 110°C for 12 hours. The mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a white solid (930 mg, yield 63.7%). ESI-MS m / z: 365.9 [M+1] + .

[0658] Step 5: 6-Bromo-4-((dimethylamino)methyl)-8-(2,2,2-trifluoroethoxy)phthalazin-1(2H)-one

[0659] 5-Bromo-3-((dimethylamino)methylene)-7-(2,2,2-trifluoroethoxy)isobenzofuran-1(3H)-one (930 mg, 2.54 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrate (318 mg, 5.08 mmol, 85%) was added. The reaction was stirred at 70°C for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a white solid (630 mg, yield 65.4%). ESI-MS m / z: 380.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),7.98(d,J=1.6Hz,1H),7.65(d,J=1.5Hz,1H),4.91(q,J=8.8Hz,2H),3.56(s,2H),2.17(s,6H).

[0660] Step 6: 6-Bromo-4-(chloromethyl)-8-(2,2,2-trifluoroethoxy)phthalazin-1(2H)-one

[0661] 6-Bromo-4-((dimethylamino)methyl)-8-(2,2,2-trifluoroethoxy)phthalazin-1(2H)-one (630 mg, 1.66 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. Isobutyl chloroformate (272 mg, 2.0 mmol) was added dropwise under an argon atmosphere. The temperature was naturally returned to 25°C and stirred for 6 hours. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic phase was washed three times with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to afford the product as a white solid (500 mg, 81.4% yield). ESI-MS m / z: 370.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),7.89(d,J=1.5Hz,1H),7.72(d,J=1.4Hz,1H),5.02(s,2H),4.95(q,J=8.8Hz,2H).

[0662] Step 7: 2-((7-bromo-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione

[0663] Potassium phthalimide (412 mg, 2.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and slowly added dropwise to a solution of 6-bromo-4-(chloromethyl)-8-(2,2,2-trifluoroethoxy)phthalazin-1(2H)-one (550 mg, 1.48 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 15°C for 0.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to afford the product as a white solid (420 mg, 59.1% yield). ESI-MS m / z: 482.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.32 (s, 1H), 8.01 (d, J = 1.5Hz, 1H), 7.97-7.92 (m, 2H) ,7.92-7.87(m,2H),7.74(d,J=1.3Hz,1H),5.11(s,2H),4.94(q,J=8.8Hz,2H).

[0664] Step 8: (4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-8-(2,2,2-trifluoroethoxy)-1,2-dihydrophthalazin-6-yl)boronic acid

[0665] 2-((7-bromo-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (73 mg, 0.15 mmol), bipyralidoboronic acid (77 mg, 0.3 mmol), potassium acetate (45 mg, 0.45 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (11 mg, 0.015 mmol), and dioxane (5 mL) were added to a reaction flask and stirred at 100°C under an argon atmosphere for 13 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was directly used in the next step to obtain a yellow oil (67 mg, 99% yield). ESI-MS m / z: 448 [M+1] + .

[0666] Step 9: 4-chloro-6-cyclopropyloxy-2-(4-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-8-(2,2,2-trifluoroethoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile

[0667] (4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-8-(2,2,2-trifluoroethoxy)-1,2-dihydrophthalazin-6-yl)boric acid (67 mg, 0.15 mmol), 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (72 mg, 0.195 mmol, prepared according to the method in patent US20210078994A1), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (10 mg, 0.015 mmol), sodium bicarbonate (38 mg, 0.45 mmol), dioxane (4 mL), and water (1 mL) were added to the reaction flask and stirred at 80 ° C under argon atmosphere for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a brown solid (40 mg, yield 38.8%). ESI-MS m / z: 693.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.41(s,1H),8.03(d,J=6.0Hz,1H),7.99-7.93(m,2H),7.93-7.87(m,2H),7.57 (s,1H),7.02(s,1H),4.95(q,J=9.0Hz,2H),4.69(q,J=9.0Hz,2H),4.19-4.12(m,1H),3.81(s,3H),0.97-0.76(m,4H).

[0668] Step 10: 2-(4-(4-(Aminomethyl)-1-oxo-8-(2,2,2-trifluoroethoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0669] 4-Chloro-6-cyclopropyloxy-2-(4-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-8-(2,2,2-trifluoroethoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (40 mg, 0.06 mmol) was dissolved in ethanol (4 mL), and hydrazine hydrate (19.5 mg, 0.33 mmol, 85%) was added. The reaction was stirred at 25°C for 20 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography to obtain the product as a white solid (7 mg, yield 21.2%). ESI-MS m / z: 563.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),8.38(s,1H),8.03(d,J=6.1Hz,1H),7.40(d,J=0.9Hz,1H), 7.18(s,1H),4.83-4.66(m,2H),4.24-4.16(m,1H),3.85(s,2H),3.80(s,3H),0.95-0.76(m,4H).

[0670] Example 2

[0671] 2-(4-(4-(aminomethyl)-8-((1-fluorocyclopropyl)methoxy)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 2)

[0672] Step 1: 4-Chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-1H-pyrazol-5-yl)benzonitrile

[0673] Under argon protection, 4-chloro-6-cyclopropyloxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (11 g, 26.4 mmol, the synthesis reference of this intermediate is Journal of Medicinal Chemistry, 2022, vol. 65, (3) p. 1749–1766) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.9 g, 42.2 mmol) were dissolved in tetrahydrofuran (100 mL), cooled to 0°C, and isopropylmagnesium chloride (31.7 mL, 1 M) was added dropwise. The mixture was stirred at 0°C for 3 hours, and saturated ammonium chloride (20 mL) was added to quench the reaction. The product was extracted with ethyl acetate (100 mL x 2), washed with water, and purified by column chromatography (petroleum ether: ethyl acetate: 4:1) to obtain the product as a yellow liquid (8.4 g, yield 76%). ESI-MS m / z: 418.1, 420.1[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=6.0Hz,1H),7.75(s,1H),3.74(s,3H),3.60(t,J =5.1Hz,1H),1.15(d,J=2.1Hz,12H),0.92(d,J=2.1Hz,2H),0.79(t,J=1.5Hz,2H).

[0674] Step 2: Methyl 4-bromo-2-((1-fluorocyclopropyl)methoxy)-6-methylbenzoate

[0675] Sodium hydride (1.07 g, 26.72 mmol, 60% purity) was dissolved in N,N-dimethylformamide (20 mL). Under an argon atmosphere, (1-fluorocyclopropyl)methanol (1.2 g, 13.36 mmol) was added at 0°C. The mixture was stirred at 15°C for 30 minutes. Methyl 4-bromo-2-hydroxy-6-methylbenzoate (2.2 g, 8.91 mmol) was then added and stirred at 15°C for 2 hours. The reaction was quenched by the slow addition of ice water (10 mL) at 0°C. The reaction solution was then poured into ice water (200 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain a clear oil (1.7 g, yield: 60%). ESI-MS m / z: 317.0, 319.0[M+1] + . 1H NMR (400MHz, CDCl3) δ7.01 (d, J= 1.7Hz,1H),6.94(d,J=1.6Hz,1H),4.26(s,1H),4.21(s,1H),3.89(s,3H),2.27(s,3H),1.20–1.09(m,2H),0.83–0.75(m,2H).

[0676] Step 3: Methyl 4-bromo-2-(bromomethyl)-6-((1-fluorocyclopropyl)methoxy)benzoate

[0677] Methyl 4-bromo-2-((1-fluorocyclopropyl)methoxy)-6-methylbenzoate (1.5 g, 4.73 mmol) was dissolved in carbon tetrachloride (20 mL). Dibenzoyl peroxide (200 mg, 0.83 mmol) and N-bromosuccinimide (1.5 g, 8.43 mmol) were added and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude yellow solid (2.1 g). The crude product was used directly in the next step. ESI-MS m / z: 418.9 [M+1] + .

[0678] Step 4: 5-Bromo-7-((1-fluorocyclopropyl)methoxy)isobenzofuran-1(3H)-one

[0679] Methyl 4-bromo-2-(bromomethyl)-6-((1-fluorocyclopropyl)methoxy)benzoate (2.1 g, 5.33 mmol) was dissolved in 1,4-dioxane (21 mL), and water (7 mL) was added. The reaction was stirred at 100°C for 16 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain a light yellow solid (540 mg, yield: 34%). ESI-MS m / z: 300.9, 302.9 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.22(d,J=1.2Hz,1H),7.19(d,J=1.2Hz,1H),5.20(s,2H),4.48(d,J=19.4Hz,2H),1.27–1.17(m,2H),0.96–0.89(m,2H).

[0680] Step 5: 5-Bromo-3-((dimethylamino)methylene)-7-((1-fluorocyclopropyl)methoxy)isobenzofuran-1(3H)-one

[0681] 5-Bromo-7-((1-fluorocyclopropyl)methoxy)isobenzofuran-1(3H)-one (540 mg, 1.8 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (10 mL) and stirred at 120°C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to afford a yellow oil (620 mg, yield: 97%). ESI-MS m / z: 356.0, 358.0 [M+1] + .

[0682] Step 6: 6-Bromo-4-((dimethylamino)methyl)-8-((1-fluorocyclopropyl)methoxy)phthalazin-1(2H)-one

[0683] 5-Bromo-3-((dimethylamino)methylene)-7-((1-fluorocyclopropyl)methoxy)isobenzofuran-1(3H)-one (140 mg, 0.393 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (50 mg, 0.786 mmol, 85% purity) was added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was directly concentrated under reduced pressure to obtain a crude product, which was then slurried with ethyl acetate (10 mL) to obtain a white solid (75 mg, yield: 52%). ESI-MS m / z: 370.0, 372.0 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.72 (s, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 4.46 (d, J = 18.3 Hz, 2H), 3.58 (s, 2H), 2.31 (s, 6H), 1.27–1.17 (m, 2H), 1.02–0.94 (m, 2H). Step 7: 6-Bromo-4-(chloromethyl)-8-((1-fluorocyclopropyl)methoxy)phthalazin-1(2H)-one

[0684] 6-Bromo-4-((dimethylamino)methyl)-8-((1-fluorocyclopropyl)methoxy)phthalazin-1(2H)-one (400 mg, 1.08 mmol) was dissolved in tetrahydrofuran (10 mL). Isobutyl chloroformate (176 mg, 1.28 mmol) was added to the mixture at 0-5°C under an argon atmosphere. The mixture was stirred at 15°C for 16 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography (dichloromethane / methanol = 10:1) to give a yellow solid (368 mg, yield: 94%). ESI-MS m / z: 363.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.54(s,1H),7.77(d,J=1.6Hz,1H),7.63(d,J=1.7Hz, 1H),5.00(s,2H),4.52(d,J=20.9Hz,2H),1.17–1.09(m,2H),0.95–0.90(m,2H).

[0685] Step 8: 2-((7-Bromo-5-((1-fluorocyclopropyl)methoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindole-1,3-dione

[0686] Potassium phthalimide (345 mg, 1.86 mmol) was dissolved in N,N-dimethylformamide (15 mL). A solution of 6-bromo-4-(chloromethyl)-8-((1-fluorocyclopropyl)methoxy)phthalazin-1(2H)-one (368 mg, 1.02 mmol) in N,N-dimethylformamide (5 mL) was slowly added and stirred at 15°C for 20 minutes. The reaction mixture was poured into ice water (200 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to afford a light yellow solid (450 mg, yield: 94%). ESI-MS m / z: 472.0, 474.0 [M+1] + . 1 H NMR(400MHz, CDCl3) δ9.53(s,1H),7.91(dd,J=5.4,3.0Hz,2H),7.77(dd,J=5.5,3.0Hz,2H),7.65(d,J=1.6 Hz,1H),7.46(d,J=1.6Hz,1H),5.07(s,2H),4.46(d,J=18.1Hz,2H),1.22–1.15(m,2H),0.98–0.94(m,2H).

[0687] Step 9: 4-chloro-6-cyclopropyloxy-2-(4-(4-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-fluorocyclopropyl)methoxy)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile

[0688] 2-((7-Bromo-5-((1-fluorocyclopropyl)methoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindole-1,3-dione (80 mg, 0.17 mmol) and 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzonitrile (102 mg, 0.17 mmol, 70% purity) were dissolved in 1,4-dioxane (5 mL), potassium carbonate (70 mg, 0.51 mmol), water (1 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.02 mmol) were added, and the reaction was stirred at 80 °C for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (dichloromethane / methanol = 10:1) to obtain a yellow solid (130 mg). ESI-MS m / z: 683.1 [M+1] + .

[0689] Step 10: 2-(4-(4-(aminomethyl)-8-((1-fluorocyclopropyl)methoxy)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0690] 4-Chloro-6-cyclopropyloxy-2-(4-(4-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-fluorocyclopropyl)methoxy)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (130 mg, 0.19 mmol) was dissolved in ethanol (5 mL) and hydrazine hydrate (34 mg, 0.57 mmol, 85% purity). The reaction was stirred at 50°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by preparative liquid phase separation to obtain a white solid (5 mg). ESI-MS m / z: 553.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.35(s,1H),8.03(d,J=6.0Hz,1H),7.29(s,1H),7.15(s,1H),4.30(d,J=20.8Hz,2H),4 .18(tq,J=7.5,4.6,3.7Hz,1H),3.78(s,3H),3.74(s,2H),1.10–1.04(m,2H),0.86(td,J=7.8,5.3Hz,4H),0.83–0.78(m,2H).

[0691] Example 3

[0692] 2-(4-(8-((1H-1,2,4-triazol-3-yl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 3)

[0693] Step 1: 5-Bromo-7-((2-(trimethylsilyl)ethoxy)methoxy)isobenzofuran-1(3H)-one

[0694] 5-Bromo-7-hydroxyisobenzofuran-1(3H)-one (840 mg, 3.65 mmol) was dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (1.41 g, 10.93 mmol) was added, followed by 2-(trimethylsilyl)ethoxymethyl chloride (915 mg, 5.48 mmol). The mixture was stirred at 15°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a white solid (1.3 g, yield: 100%). ESI-MS m / z: 381.0, 383.0 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ7.41(d,J=1.3Hz,1H),7.23(d,J=1.3Hz,1H),5.40(s,2H),5.21(s,2H),3.85–3.79(m,2H),0.99–0.92(m,2H),0.00(s,9H).

[0695] Step 2: 5-Bromo-3-((dimethylamino)methylene)-7-((2-(trimethylsilyl)ethoxy)methoxy)isobenzofuran-1(3H)-one

[0696] 5-Bromo-7-((2-(trimethylsilyl)ethoxy)methoxy)isobenzofuran-1(3H)-one (1.4 g, 3.89 mmol) was dissolved in tert-butoxybis(dimethylamino)methane (5 mL) and stirred at 120°C under an argon atmosphere for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to afford a yellow solid (1.6 g, yield: 100%). ESI-MS m / z: 414.0, 416.0 [M+1] + .

[0697] Step 3: 6-Bromo-4-((dimethylamino)methyl)-8-((2-(trimethylsilyl)ethoxy)methoxy)phthalazin-1(2H)-one

[0698] 5-Bromo-3-((dimethylamino)methylene)-7-((2-(trimethylsilyl)ethoxy)methoxy)isobenzofuran-1(3H)-one (1.6 g, 3.87 mmol) was dissolved in ethanol (20 mL), and hydrazine hydrate (455 mg, 7.73 mmol) was added. The mixture was stirred at 80°C under an argon atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a white solid (850 mg, yield: 51%). ESI-MS m / z: 428.1, 430.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ9.83 (s, 1H), 7.89 (d, J = 1.7Hz, 1H), 7.64 (d, J = 1.7Hz, 1H), 5.43 (s,2H),3.88–3.82(m,2H),3.61(s,2H),2.33(s,6H),1.01–0.93(m,2H),0.00(s,9H).

[0699] Step 4: 6-Bromo-4-(chloromethyl)-8-((2-(trimethylsilyl)ethoxy)methoxy)phthalazin-1(2H)-one

[0700] 6-Bromo-4-((dimethylamino)methyl)-8-((2-(trimethylsilyl)ethoxy)methoxy)phthalazin-1(2H)-one (650 mg, 1.52 mmol) was dissolved in tetrahydrofuran (10 mL), and potassium carbonate (313 mg, 2.27 mmol) was added. Isobutyl chloroformate (311 mg, 2.27 mmol) was added at -70 to -60°C, and the mixture was stirred at 15°C for 3 hours. The reaction mixture was filtered directly, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a yellow solid (230 mg, yield: 36%). ESI-MS m / z: 442.9 [M+Na] + .

[0701] Step 5: 2-((7-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindole-1,3-dione

[0702] Potassium phthalimide (218 mg, 1.18 mmol) was dissolved in N,N-dimethylformamide (5 mL). A solution of 6-bromo-4-(chloromethyl)-8-((2-(trimethylsilyl)ethoxy)methoxy)phthalazin-1(2H)-one (330 mg, 0.78 mmol) in N,N-dimethylformamide (2 mL) was slowly added and stirred at 15°C for 30 minutes. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to afford a white solid (450 mg, yield: 94%). ESI-MS m / z: 552.0, 554.0 [M+1] + .

[0703] Step 6: tert-Butyl 6-bromo-4-((1,3-dioxoisoindol-2-yl)methyl)-1-oxo-8-((2-(trimethylsilyl)ethoxy)methoxy)phthalazine-2(1H)-carboxylate

[0704] 2-((7-Bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindole-1,3-dione (300 mg, 0.57 mmol) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (185 mg, 0.85 mmol) and dimethylaminopyridine (7 mg, 0.06 mmol) were added. The mixture was stirred at 15°C for 1 hour. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a white solid (330 mg, yield: 93%). ESI-MS m / z: 472.0, 474.0 [M-158] + .

[0705] Step 7: tert-Butyl 6-bromo-4-((1,3-dioxoisoindol-2-yl)methyl)-8-hydroxy-1-oxophthalazine-2(1H)-carboxylate

[0706] Tert-butyl 6-bromo-4-((1,3-dioxoisoindol-2-yl)methyl)-1-oxo-8-((2-(trimethylsilyl)ethoxy)methoxy)phthalazine-2(1H)-carboxylate (200 mg, 0.32 mmol) was dissolved in methanol (10 mL), and p-toluenesulfonic acid monohydrate (120 mg, 0.63 mmol) was added. The mixture was stirred at 15°C for 1 hour. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to afford a white solid (140 mg, yield: 94%). ESI-MS m / z: 521.9, 524.0 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ12.13(s,1H),7.92(tt,J=5.2,2.5Hz,2H),7.78(dd,J=5.5,3.0Hz,2H),7.44–7.38(m,2H),5.09(s,2H),1.25(s,9H).

[0707] Step 8: tert-Butyl 6-bromo-4-((1,3-dioxoisoindol-2-yl)methyl)-1-oxo-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)methoxy)phthalazine-2(1H)-carboxylate

[0708] Tert-butyl 6-bromo-4-((1,3-dioxoisoindol-2-yl)methyl)-8-hydroxy-1-oxophthalazine-2(1H)-carboxylate (140 mg, 0.28 mmol) and 3-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (140 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cesium carbonate (137 mg, 0.42 mmol) was added and stirred at 80°C for 7 hours. The reaction mixture was cooled to room temperature, poured into ice water (100 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (dichloromethane / methanol = 10:1) to obtain a light yellow solid (120 mg, yield: 65%). ESI-MS m / z: 665.1, 667.1[M+1] + .

[0709] Step 9: tert-Butyl 6-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-((1,3-dioxoisoindol-2-yl)methyl)-1-oxo-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)methoxy)phthalazine-2(1H)-carboxylate

[0710] Tert-butyl 6-bromo-4-((1,3-dioxoisoindol-2-yl)methyl)-1-oxo-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)methoxy)phthalazine-2(1H)-carboxylate (120 mg, 0.18 mmol) and 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzonitrile (129 mg, 0.22 mmol, 70% purity) was dissolved in 1,4-dioxane (10 mL), and potassium carbonate (75 mg, 0.54 mmol), water (2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.02 mmol) were added. The reaction was stirred at 80°C for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (ethyl acetate 100%) to obtain a yellow solid (140 mg, yield: 89%). ESI-MS m / z: 867.2 [M+1] + .

[0711] Step 10: tert-Butyl 4-(aminomethyl)-6-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)methoxy)phthalazine-2(1H)-carboxylate

[0712] Tert-butyl 6-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-((1,3-dioxoisoindol-2-yl)methyl)-1-oxo-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)methoxy)phthalazine-2(1H)-carboxylate (140 mg, 0.16 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrate (28 mg, 0.48 mmol, 85% purity) was added and the reaction was stirred at 15°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude yellow solid (150 mg). The crude product was directly used in the next step. ESI-MS m / z: 646.2 [M-100]+ .

[0713] Step 11: 2-(4-(8-((1H-1,2,4-triazol-3-yl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0714] Tert-butyl 4-(aminomethyl)-6-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)methoxy)phthalazine-2(1H)-carboxylate (150 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The reaction was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was separated by preparative liquid phase to obtain a white solid (25 mg, yield: 22%). ESI-MS m / z: 562.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 12.51(s,1H),8.38(s,1H),8.36(s,1H),7.96(d,J=6.0Hz,1H),7.37(d,J=1.4Hz,1H),7.22(d,J=1.4Hz ,1H),4.98(s,2H),4.22(d,J=2.9Hz,2H),4.15(tt,J=6.2,3.0Hz,1H),3.79(s,3H),0.95–0.76(m,4H).

[0715] Example 4

[0716] 2-(4-(4-(Aminomethyl)-8-(difluoromethoxy)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 4)

[0717] Step 1: Methyl 4-bromo-2-hydroxy-6-methylbenzoate

[0718] Methyl 4-bromo-2-methoxy-6-methylbenzoate (5.27 g, 20.3 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0°C under an argon atmosphere. A dichloromethane solution of boron tribromide (30.5 mL, 30.5 mmol, 1.0 M) was added dropwise. The mixture was stirred at 0°C for 0.5 h. The reaction solution was poured into ice water and extracted with dichloromethane. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, volume ratio) to obtain the product as a white solid (3.8 g, yield 76.3%). ESI-MS m / z: 244.9 [M+1] + .

[0719] Step 2: Methyl 4-bromo-2-(difluoromethoxy)-6-methylbenzoate

[0720] Methyl 4-bromo-2-hydroxy-6-methylbenzoate (6.28 mg, 25.6 mmol) was dissolved in N,N-dimethylformamide (120 mL), and potassium carbonate (7.07 g, 51.3 mmol) and ethyl bromodifluoroacetate (7.8 g, 38.4 mmol) were added. The mixture was stirred at 80°C for 18 hours, then cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1, volume ratio) to obtain the product as a white solid (1.5 g, yield 19.8%). ESI-MS m / z: 294.9 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.27 (s, 1H), 7.22 (s, 1H), 6.46 (t, J = 73.5Hz, 1H), 3.92 (s, 3H), 2.33 (s, 3H).

[0721] Step 3: Methyl 4-bromo-2-(bromomethyl)-6-(difluoromethoxy)benzoate

[0722] Methyl 4-bromo-2-(difluoromethoxy)-6-methylbenzoate (1.5 g, 5.08 mmol) was dissolved in carbon tetrachloride (20 mL), and benzoyl peroxide (164 mg, 0.51 mmol, 75%) and N-bromosuccinimide (905 mg, 5.08 mmol) were added. The mixture was stirred at 80°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, volume ratio) to obtain the product as a light yellow oil (1.8 g, yield 94.7%). ESI-MS m / z: 372.9 [M+1] +.

[0723] Step 4: 5-Bromo-7-(difluoromethoxy)isobenzofuran-1(3H)-one

[0724] Methyl 4-bromo-2-(bromomethyl)-6-(difluoromethoxy)benzoate (1.8 g, 4.81 mmol) was dissolved in a mixture of 1,4-dioxane (30 mL) and water (10 mL). The mixture was stirred at 100°C for 24 hours, cooled to room temperature, added with water, and extracted with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a white solid (900 mg, yield 67.2%). ESI-MS m / z: 278.9 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.51(d,J=1.2Hz,1H),7.47(s,1H),6.90(t,J=72.9Hz,1H),5.28(s,2H).

[0725] Step 5: 5-Bromo-7-(difluoromethoxy)-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one

[0726] 5-Bromo-7-(difluoromethoxy)isobenzofuran-1(3H)-one (900 mg, 3.23 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (15 mL), and potassium tert-butoxide (36.2 mg, 0.32 mmol) was added. The mixture was stirred at 110°C for 3 hours, then cooled to room temperature, added with water, and extracted with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, volume ratio) to obtain the product as a yellow solid (670 mg, yield 62.2%). ESI-MS m / z: 334.0 [M+1] + .

[0727] Step 6: 6-Bromo-8-(difluoromethoxy)-4-(dimethylamino)methyl)phthalazin-1(2H)-one

[0728] 5-Bromo-7-(difluoromethoxy)-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one (670 mg, 2.00 mmol) was dissolved in ethanol (30 mL), and hydrazine hydrate (235 mg, 4.00 mmol, 85%) was added. The mixture was stirred under reflux for 24 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, volume ratio) to obtain the product as a yellow solid (420 mg, yield 60.2%). ESI-MS m / z: 348.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),8.26(d,J=1.8Hz,1H),7.77(d,J=1.8Hz,1H),7.21(t,J=74.5Hz,1H),3.60(s,2H),2.19(s,6H).

[0729] Step 7: 6-Bromo-4-(chloromethyl)-8-(difluoromethoxy)phthalazin-1(2H)-one

[0730] 6-Bromo-8-(difluoromethoxy)-4-(dimethylamino)methyl)phthalazin-1(2H)-one (420 mg, 1.21 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C, and isobutyl chloroformate (198 mg, 1.45 mmol) was added dropwise under an argon atmosphere. The mixture was allowed to return to room temperature and stirred for 18 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a white solid (240 mg, yield 58.6%). ESI-MS m / z: 338.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.20(d,J=1.8Hz,1H),7.84(d,J=1.7Hz,1H),7.24(t,J=74.3Hz,1H),5.07(s,2H).

[0731] Step 8: 2-((7-bromo-5-(difluoromethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione

[0732] Potassium phthalimide (81.5 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (2 mL). A solution of 6-bromo-4-(chloromethyl)-8-(difluoromethoxy)phthalazin-1(2H)-one (100 mg, 0.29 mmol) dissolved in N,N-dimethylformamide (2 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to afford the product as a white solid (87 mg, 65.6% yield). ESI-MS m / z: 450.0 [M+1] + .

[0733] Step 9: (8-(Difluoromethoxy)-4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)boronic acid

[0734] 2-((7-Bromo-5-(difluoromethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (93 mg, 0.21 mmol), pinacol diboron (104.9 mg, 0.41 mmol), and potassium acetate (60.7 mg, 0.62 mmol) were dissolved in dioxane (5 mL). 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (15.1 mg, 0.021 mmol) was added under an argon atmosphere. The mixture was stirred at 100°C for 17 hours. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product as a brown oil. ESI-MS m / z: 416.1 [M+1] + .

[0735] Step 10: 4-chloro-6-cyclopropyloxy-2-(4-(8-(difluoromethoxy)-4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile

[0736] (8-(Difluoromethoxy)-4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)boronic acid (85.8 mg, 0.21 mmol), 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (76.2 mg, 0.21 mmol), and sodium bicarbonate (53 mg, 0.62 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (1 mL). 1,1'-di-tert-butylphosphinoferrocenepalladium dichloride (13.7 mg, 0.021 mmol) was added under argon atmosphere, and the reaction was stirred at 80°C for 2.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, volume ratio) to obtain the product as a brown oil (136 mg, yield 100%). ESI-MS m / z: 661.1 [M+1] + .

[0737] Step 11: 2-(4-(4-(Aminomethyl)-8-(difluoromethoxy)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0738] (4-Chloro-6-cyclopropyloxy-2-(4-(8-(difluoromethoxy)-4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (136 mg, 0.21 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (37 mg, 0.63 mmol, 85%) was added. The mixture was stirred at 50°C for 4 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and then analyzed by preparative high performance liquid chromatography to obtain the product as a white solid (9 mg, yield 8.2%). ESI-MS m / z: 531.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.04(d,J=6.0Hz,1H),7.87(s,1H),7.19(t,J=74.3Hz,1H) ,6.60(d,J=1.9Hz,1H),4.20(m,1H),3.93(s,2H),3.79(s,3H),0.92(m,2H),0.87–0.73(m,2H).

[0739] Example 5

[0740] 2-(4-(8-((1-aminocyclopropyl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 5a)

[0741] 2-(4-(8-((1-aminocyclopropyl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 5b)

[0742] Step 1: Methyl 4-bromo-2-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methoxy)-6-methylbenzoate

[0743] Methyl 4-bromo-2-fluoro-6-methylbenzoate (1.0 g, 4.05 mmol) and tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (1.14 g, 6.07 mmol) were dissolved in tetrahydrofuran (10 mL) and cooled to 0°C under an argon atmosphere. Sodium hydride (648 mg, 16.19 mmol, 60%) was added and stirred at 0°C for 1.0 hour. The mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed three times with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (1.43 g, yield 85.1%). ESI-MS m / z: 436.1; 438.1 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ6.98(s,1H),6.90(s,1H),5.14(s,1H),4.02(s,2H),3.90(s,3H),2.26(s,3H),1.41(s,9H),0.85(dt,J=7.3,2.2Hz,4H).

[0744] Step 2: Methyl 2-((1-(di-tert-butyloxycarbonyl)amino)cyclopropyl)methoxy)-4-bromo-6-methylbenzoate

[0745] Methyl 4-bromo-2-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methoxy)-6-methylbenzoate (200 mg, 0.48 mmol) was dissolved in tetrahydrofuran (4 mL), and 4-dimethylaminopyridine (88.5 mg, 0.72 mmol) and di-tert-butyl dicarbonate (158.0 mg, 0.72 mmol) were added. The reaction was stirred under reflux for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (204 mg, yield 82.2%). ESI-MS m / z: 536.1; 538.1 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ6.97(s,1H),6.93(s,1H),4.19(s,2H),3.87(s,3H),2.24(s,3H),1.50(s,18H),1.06–0.87(m,4H).

[0746] Step 3: Methyl 2-(1-(di-tert-butyloxycarbonyl)amino)cyclopropyl)methoxy)-4-bromo-6-(bromomethyl)benzoate

[0747] Methyl 2-((1-(di-tert-butyloxycarbonyl)amino)cyclopropyl)methoxy)-4-bromo-6-methylbenzoate (193 mg, 0.38 mmol) was dissolved in carbon tetrachloride (4 mL). Benzoyl peroxide (12 mg, 0.038 mmol, 75%) and N-bromosuccinimide (100 mg, 0.56 mmol) were added. The mixture was stirred at 80°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a light yellow oil (167 mg, yield 75.0%). ESI-MS m / z: 391.9; 393.9; 395.9 [M-2Boc+1] + . 1 H NMR (400MHz, CDCl3) δ7.17(d,J=1.7Hz,1H),7.06(d,J=1.7Hz,1H),4.43(s,2H),4.20(d,J=2.4Hz,2H),3.92(s,3H),1.50(s,18H),1.06–0.94(m,4H)

[0748] Step 4: 7-((1-aminocyclopropyl)methoxy)-5-bromoisobenzofuran-1(3H)-one

[0749] Methyl 2-(1-(di-tert-butyloxycarbonyl)amino)cyclopropyl)methoxy)-4-bromo-6-(bromomethyl)benzoate (158 mg, 0.27 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (0.5 mL). The mixture was stirred at 100°C for 24 hours, cooled to room temperature, and concentrated under reduced pressure to give the crude product (80 mg, 100% yield). ESI-MS m / z: 298.0; 300 [M+1] + .

[0750] Step 5: tert-Butyl(1-((6-bromo-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)cyclopropyl(tert-butyloxycarbonyl)carbamate

[0751] 7-((1-Aminocyclopropyl)methoxy)-5-bromoisobenzofuran-1(3H)-one (80 mg, 0.27 mmol) was dissolved in tetrahydrofuran (4 mL), and triethylamine (80.8 mg, 0.80 mmol), 4-dimethylaminopyridine (97.6 mg, 0.80 mmol), and di-tert-butyl dicarbonate (174.0 mg, 0.80 mmol) were added. The reaction was stirred under reflux for 2 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a yellow oil (40 mg, yield 29.7%). ESI-MS m / z: 520.1; 522.0 [M+Na] + .

[0752] Step 6: tert-Butyl(1-((6-bromo-1-((dimethylamino)methylene)-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)cyclopropyl)(tert-butyloxycarbonyl)carbamate

[0753] Tert-butyl (1-((6-bromo-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)cyclopropyl (tert-butoxycarbonyl) carbamate (250 mg, 0.50 mmol) was dissolved in tert-butoxybis(dimethylamino)methane (5 mL). The reaction was stirred at 120°C for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a yellow solid (160 mg, yield 57.8%). ESI-MS m / z: 575.1; 577.1 [M+1] + .

[0754] Step 7: tert-Butyl(1-((7-bromo-1-((dimethylamino)methyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)methyl)cyclopropyl(tert-butyloxycarbonyl)carbamate

[0755] Tert-butyl (1-((6-bromo-1-((dimethylamino)methylene)-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)cyclopropyl)(tert-butoxycarbonyl)carbamate (170 mg, 0.31 mmol) was dissolved in ethanol (3 mL), and hydrazine hydrate (36 mg, 0.62 mmol, 85%) was added. The reaction was stirred at reflux for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a white solid (160 mg, 91.0% yield). ESI-MS m / z: 567.2; 569.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),7.84(d,J=1.7Hz,1H),7.61(d,J=1.7Hz ,1H),4.34(s,2H),3.53(s,2H),2.16(s,6H),1.41(s,18H),0.96–0.76(m,4H).

[0756] Step 8: tert-Butyl(1-((7-bromo-1-(chloromethyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)methyl)cyclopropyl)(tert-butyloxycarbonyl)carbamate

[0757] Tert-butyl (1-((7-bromo-1-((dimethylamino)methyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)methyl)cyclopropyl (tert-butoxycarbonyl)carbamate (160 mg, 0.28 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to 0°C. Isobutyl chloroformate (46.2 mg, 0.34 mmol) was added dropwise under an argon atmosphere. The mixture was allowed to return to room temperature and stirred for 6 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to afford the product as a white solid (95 mg, 60.7% yield). ESI-MS m / z: 358.0; 360.0 [M-2Boc+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),7.74(d,J=1.6Hz,1H),7.69(d,J=1.7Hz,1H),4.99(s,2H),4.37(s,2H),1.41(s,18H),0.96–0.76(m,4H).

[0758] Step 9: tert-Butyl(1-((7-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)methyl)cyclopropyl(tert-butyloxycarbonyl)carbamate

[0759] Potassium phthalimide (47.2 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL). A solution of tert-butyl (1-((7-bromo-1-(chloromethyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)methyl)cyclopropyl)(tert-butoxycarbonyl)carbamate (95 mg, 0.17 mmol) dissolved in N,N-dimethylformamide (2 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to afford the product as a white solid (110 mg, 96.6% yield). ESI-MS m / z: 669.1; 671.1 [M+1] + .

[0760] Step 10: tert-Butyl(tert-butyloxycarbonyl)(1-((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)cyclopropyl)carbamate

[0761] Tert-butyl (1-((7-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)methyl)cyclopropyl(tert-butoxycarbonyl)carbamate (110 mg, 0.16 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1H-pyrazol-5-yl)benzonitrile (124.9 mg, 0.21 mmol), and potassium carbonate (86.6 mg, 0.63 mmol) were dissolved in dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (15.3 mg, 0.021 mmol) was added under argon atmosphere, and the reaction was stirred at 80°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a brown solid (110 mg, yield 78.1%). ESI-MS m / z: 780.2; 782.2 [M-Boc+1] + .

[0762] Step 11: 2-(4-(8-((1-aminocyclopropyl)methoxy)-4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0763] Tert-butyl(tert-butyloxycarbonyl)(1-((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydrophthalazin-5-yl)oxy)cyclopropyl)carbamate (110 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 hour. Saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to give the product as a brown solid (75 mg, 91.9% yield). ESI-MS m / z: 680.2; 682.2 [M+1] + .

[0764] Step 12: 2-(4-(8-((1-aminocyclopropyl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (5a) and 2-(4-(8-((1-aminocyclopropyl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile (5b)

[0765] (2-(4-(8-((1-aminocyclopropyl)methoxy)-4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (75 mg, 0.11 mmol) was dissolved in ethanol (4 mL), and hydrazine hydrate (19.5 mg, 0.33 mmol, 85% ), stirred at 30°C for 20 hours. Cooled to room temperature, concentrated under reduced pressure, and then analyzed by preparative high-performance liquid chromatography to obtain the product 2-(4-(8-((1-aminocyclopropyl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 5a) as a white solid (4 mg, yield 6.6%). ESI-MS m / z: 550.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 8.03 (d, J = 6.1Hz, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 4. 19(td,J=6.0,3.1Hz,1H),3.80(s,2H),3.78(s,3H),3.72(s,2H),0.95–0.88(m,2H),0.86 –0.76 (m, 2H), 0.53 (m, 2H), 0.51 (m, 2H). The dechlorinated product (2-(4-(8-((1-aminocyclopropyl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 5b)) was obtained as a white solid (2 mg, 3.5% yield). ESI-MS m / z: 516.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.91(d,J=8.9Hz,1H),7.81(d,J=4.2Hz,1H),7.18(d,J=1.5Hz,1H),7.03 (d,J=1.6Hz,1H),4.17–4.09(m,1H),3.75(d,J=3.7Hz,5H),3.71(s,2H),0.94–0.74(m,4H),0.57–0.45(m,4H).

[0766] Example 6

[0767] 2-(4-(8-(1H-pyrazol-3-yl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 6)

[0768] Step 1: Methyl 4-bromo-2-methoxy-6-methylbenzoate

[0769] Methyl 4-bromo-2-fluoro-6-methylbenzoate (10.0 g, 40.5 mmol) was dissolved in N,N-dimethylformamide (80 mL), and a methanol solution of sodium methoxide (14.6 g, 81.0 mmol, 30%) was added. The mixture was stirred at 70°C for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed three times with water and saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain the product as a light yellow oil (10.0 g, yield 94.8%). ESI-MS m / z: 258.9 [M+1] + .

[0770] Step 2: Methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate

[0771] Methyl 4-bromo-2-methoxy-6-methylbenzoate (8.95 g, 34.5 mmol) was dissolved in carbon tetrachloride (180 mL), and benzoyl peroxide (1.12 g, 3.45 mmol, 75%) and N-bromosuccinimide (6.76 g, 38.0 mmol) were added. The mixture was stirred at 80°C for 6 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, volume ratio) to obtain the product as a white solid (10.8 g, yield 92.6%). ESI-MS m / z: 336.8 [M+1] + .

[0772] Step 3: 5-Bromo-7-methoxyisobenzofuran-1(3H)-one

[0773] Methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate (10.8 g, 32.0 mmol) was dissolved in a mixture of 1,4-dioxane (150 mL) and water (50 mL). The mixture was stirred at 100°C for 14 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a white solid (6.0 g, yield 77.3%). ESI-MS m / z: 242.9 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.43(q,J=1.1Hz,1H),7.33(d,J=1.3Hz,1H),5.28(s,2H),3.93(s,3H).

[0774] Step 4: 5-Bromo-7-hydroxyisobenzofuran-1(3H)-one

[0775] 5-Bromo-7-methoxyisobenzofuran-1(3H)-one (6.0 g, 24.7 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0°C under an argon atmosphere. A dichloromethane solution of boron tribromide (74.1 mL, 74.1 mmol, 1.0 M) was added dropwise. The mixture was stirred at 0°C for 0.5 hours. The reaction solution was poured into ice water and extracted with dichloromethane. The organic phase was washed three times with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product as a light yellow solid (5.4 g, 95.5% yield). ESI-MS m / z: 228.9 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ7.24(d,J=1.3Hz,1H),7.06(d,J=1.4Hz,1H),5.24(s,2H).

[0776] Step 5: 5-Bromo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)isobenzofuran-1(3H)-one

[0777] 5-Bromo-7-hydroxyisobenzofuran-1(3H)-one (1.0 g, 4.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.8 g, 13.1 mmol) was added, and the mixture was stirred at 70°C for 15 minutes. Sodium iodide (327 mg, 2.2 mmol) was added, and a solution of 3-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (876 mg, 4.4 mmol) dissolved in N,N-dimethylformamide (5 mL) was added dropwise. The mixture was stirred at 70°C for 1 hour, then cooled to room temperature, added with water, and extracted with ethyl acetate. The organic phase was washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product as a colorless oil (1.2 g, 70.0% yield). ESI-MS m / z: 393.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.89(d,J=2.4Hz,1H),7.53(d,J=1.3Hz,1H),7.43(d,J=1.2Hz, 1H),6.42(d,J=2.4Hz,1H),5.40(dd,J=9.9,2.4Hz,1H),5.27(s,2H),5.24(s,2H),3.99– 3.84(m,1H),3.65–3.58(m,1H),2.00–1.41(m,6H).

[0778] Step 6: 5-Bromo-3-(dimethylamino)methylene)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)isobenzofuran-1(3H)-one

[0779] 5-Bromo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)isobenzofuran-1(3H)-one (1.2 g, 3.05 mmol) was dissolved in tert-butoxybis(dimethylamino)methane (15 mL). The mixture was stirred at 120°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product as a yellow solid (910 mg, yield 66.5%). ESI-MS m / z: 448.0; 450.0 [M+1] + .

[0780] Step 7: 6-Bromo-4-(dimethylamino)methyl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)phthalazin-1(2H)-one

[0781] 5-Bromo-3-(dimethylamino)methylene)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)isobenzofuran-1(3H)-one (200 mg, 0.45 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (52.5 mg, 0.90 mmol, 85%) was added. The mixture was stirred at reflux for 17 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a light yellow solid (150 mg, yield 72.7%). ESI-MS m / z: 462.1; 464.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.30(s,1H),7.87(d,J=2.4Hz,1H),7.84(d,J=1.7Hz,1H),7.69(d,J=1.7Hz,1H),6.48(d,J=2.4Hz,1H),5.39( dd,J=9.9,2.4Hz,1H),5.23(s,2H),3.95–3.86(m,1H),3.61(ddd,J=13.8,7.2,5.0Hz,1H),3.53(s,2H),2.16(s,6H),2.00–1.47(m,6H).

[0782] Step 8: 6-Bromo-4-(chloromethyl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)phthalazin-1(2H)-one

[0783] 6-Bromo-4-(dimethylamino)methyl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)phthalazin-1(2H)-one (150 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0°C. Isobutyl chloroformate (53.2 mg, 0.39 mmol) was added dropwise under an argon atmosphere. The mixture was allowed to return to room temperature and stirred for 6 hours. Saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed three times with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, volume ratio) to afford the product as a white solid (85 mg, 57.7% yield). ESI-MS m / z: 453.0; 455.0 [M+1] + .

[0784] Step 9: 2-(7-Bromo-4-oxo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindole-1,3-dione

[0785] Potassium phthalimide (49.0 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (1 mL). A solution of 6-bromo-4-(chloromethyl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)phthalazin-1(2H)-one (80 mg, 0.18 mmol) dissolved in N,N-dimethylformamide (1 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, volume ratio) to afford the product as a white solid (90 mg, 90.4% yield). ESI-MS m / z: 564.0; 566.0 [M+1] + .

[0786] Step 10: 4-chloro-6-cyclopropyloxy-2-(4-(4-(1,3-dioxoisooctyl-2-yl)methyl)-1-oxo-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile

[0787] 2-(7-Bromo-4-oxo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindole-1,3-dione (100 mg, 0.18 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazol-5-yl)benzonitrile (92.6 mg, 0.18 mmol), and potassium carbonate (73.4 mg, 0.53 mmol) were dissolved in dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (13.0 mg, 0.018 mmol) was added under argon atmosphere, and the reaction was stirred at 80°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a yellow solid (30 mg, yield 21.8%). ESI-MS m / z: 775.2.

[0788] Step 11: 2-(4-(Aminomethyl)-1-oxo-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0789] 4-Chloro-6-cyclopropyloxy-2-(4-(4-(1,3-dioxoisooctyl-2-yl)methyl)-1-oxo-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (30 mg, 0.039 mmol) was dissolved in ethanol (4 mL). Hydrazine hydrate (6.8 mg, 0.12 mmol, 85%) was added and stirred at 25°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product as a yellow oil (25 mg, 100% yield). ESI-MS m / z: 645.2 [M+1] + .

[0790] Step 12: 2-(4-(8-(1H-pyrazol-3-yl)methoxy)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0791] 2-(4-(Aminomethyl)-1-oxo-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (25 mg, 0.039 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added dropwise and stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure and analyzed by preparative high-performance liquid chromatography to obtain the product as a white solid (4 mg, 18.4% yield). ESI-MS m / z: 561.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),12.49(s,1H),8.37(d,J=1.4Hz,1H),7.99(d,J=6.0Hz,1H),7.67(s,1H), 7.30(s,1H),7.12(s,1H),6.28(s,1H),4.90(s,2H),4.21(s,2H),4.17(m,1H),3.79(s,3H),0.99–0.67(m,4H).

[0792] Example 7

[0793] 2-(4-(4-(Aminomethyl)-8-(cyclopropylethynyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 7)

[0794] Step 1: 7-Bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid methyl ester

[0795] 5-Amino-7-bromo-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid methyl ester (600 mg, 2.0 mmol) (prepared according to the method described in patent US20210078994A1), acetonitrile (20 mL), and toluenesulfonic acid (1.38 g, 8 mmol) were added to the reaction flask, cooled to 0 ° C, and an aqueous solution of sodium nitrite (345 mg, 5 mmol) was added. After stirring for ten minutes, an aqueous solution of potassium iodide (996 mg, 6.0 mmol) was slowly added, and then the temperature was raised to 20 ° C and stirred for 1.0 hour. The reaction was quenched with sodium thiosulfate solution, the acetonitrile was removed, filtered, washed with water, and washed with ethanol to obtain the product as a white solid (636 mg, yield 77.9%). ESI-MS m / z: 408.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.73(d,J=1.9Hz,1H),8.60(d,J=1.9Hz,1H),3.90(s,3H).

[0796] Step 2: 6-Bromo-4-(hydroxymethyl)-8-iodophthalazin-1(2H)-one

[0797] Methyl 7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-1-carboxylate (64 mg, 0.15 mmol) and ethanol (10 mL) were added to a reaction flask, cooled to 0°C, and sodium borohydride (11.4 mg, 0.3 mmol) and calcium chloride (20 mg, 0.18 mmol) were added. The reaction was stirred at 20°C for 1 hour. The reaction was quenched with aqueous ammonium chloride, the ethanol was removed, and the mixture was filtered, washed with water, and then washed with ethanol to obtain the product as a white solid (35 mg, 61.4% yield). ESI-MS m / z: 380.8 [M+1] + .

[0798] Step 3: 6-Bromo-4-(chloromethyl)-8-iodophthalazin-1(2H)-one

[0799] 6-Bromo-4-(hydroxymethyl)-8-iodophthalazin-1(2H)-one (210 mg, 0.55 mmol) and thionyl chloride (5 mL) were added to a reaction flask and stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure to obtain the product as a yellow solid (218 mg, 99% yield). ESI-MS m / z: 398.8 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.60(d,J=1.8Hz,1H),8.27(d,J=1.8Hz,2H),5.01(s,2H).

[0800] Step 4: 4-(Aminomethyl)-6-bromo-8-iodophthalazin-1(2H)-one

[0801] 6-Bromo-4-(chloromethyl)-8-iodophthalazin-1(2H)-one (120 mg, 0.3 mmol) and 7.0 M ammonia methanol solution (15 mL) were added to a reaction flask. The reaction was stirred at 20°C for 2 hours and then concentrated under reduced pressure to obtain a crude product (110 mg, 99% yield). ESI-MS m / z: 379.8 [M+1] + .

[0802] Step 5: tert-Butyl ((7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0803] 4-(Aminomethyl)-6-bromo-8-iodophthalazin-1(2H)-one (110 mg, 0.3 mmol), dichloromethane (5 mL), triethylamine (90 mg, 0.9 mmol), and di-tert-butyl dicarbonate (131 mg, 0.6 mmol) were stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a white solid (41 mg, yield 28.6%). ESI-MS m / z: 479.8 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),11.34(s,1H),8.56(d,J=1.7Hz,1H),8.23(s,1H),4.35(d,J=6.0Hz,2H),1.36(s,9H).

[0804] Step 6: tert-Butyl ((7-bromo-5-(cyclopropylethynyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0805] Tert-butyl ((7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (40 mg, 0.085 mmol), cyclopropylacetylene (33 mg, 0.51 mmol), triethylamine (0.3 mL), cuprous iodide (1.7 mg, 0.0085 mmol), bistriphenylphosphine palladium chloride (6.1 mg, 0.0085 mmol), and tetrahydrofuran (5 mL) were added to a reaction flask and stirred at 20°C for 1 hour. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the product as a yellow solid (35 mg, 99% yield). ESI-MS m / z: 418.1 [M+1] + .

[0806] Step 7: tert-Butyl ((7-(5-(3-chloro-6-methylcyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-5-(cyclopropylethynyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0807] Tert-butyl ((7-bromo-5-(cyclopropylethynyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (42 mg, 0.1 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzonitrile (48 mg, 0.1 mmol), potassium carbonate (42 mg, 0.3 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (7.3 mg, 0.01 mmol), dioxane (4 mL), and water (1 mL) were added to a reaction flask and stirred at 80°C under argon atmosphere for 3 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and directly used in the next step (62 mg, 99% yield). ESI-MS m / z: 629.2[M+1] + .

[0808] Step 8: 2-(4-(4-(aminomethyl)-8-(cyclopropylethynyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0809] Tert-butyl ((7-(5-(3-chloro-6-methylcyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-5-(cyclopropylethynyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (62 mg, 0.1 mmol), dichloromethane (2.5 mL), and trifluoroacetic acid (2.5 mL) were added to a reaction flask and stirred at 20°C for 1 hour. The reactants were directly concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to obtain the product as a white solid (25 mg, 48.1% yield). ESI-MS m / z: 529.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),8.30(s,1H),8.03(d,J=6.1Hz,1H),7.53(s,1H),7.16(s ,1H),4.55-4.38(m,2H),4.24-4.16(m,1H),3.80(s,3H),2.04-1.94(m,1H),1.05-0.76(m,8H).

[0810] Example 8

[0811] (E)-2-(4-(8-(2-(1H-pyrazol-3-yl)vinyl)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 8)

[0812] Step 1: tert-Butyl (E)-((7-bromo-4-oxo-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)vinyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0813] Tert-butyl ((7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (24 mg, 0.05 mmol), (E)-1-(tetrahydro-2H-pyran-2-yl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1H-pyrazole (15 mg, 0.05 mmol), potassium carbonate (21 mg, 0.15 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloride (3.7 mg, 0.005 mmol), dioxane (2 mL), and water (0.5 mL) were added to a reaction flask and stirred at 80°C under argon atmosphere for 2 hours. The product was cooled to room temperature, concentrated under reduced pressure, and directly reacted in the next step (26 mg, 99% yield). ESI-MS m / z: 530.1 [M+1]+ .

[0814] Step 2: Tert-butyl (E)-((7-(5-(3-chloro-6-methylcyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)vinyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0815] Tert-butyl (E)-((7-bromo-4-oxo-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)vinyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (26 mg, 0.05 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzonitrile (24 mg, 0.05 mmol), potassium carbonate (21 mg, 0.15 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (3.7 mg, 0.005 mmol), dioxane (4 mL), and water (1 mL) were added to a reaction flask and stirred at 85°C under argon atmosphere for 3 hours. The reaction mixture was directly concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the product as a yellow solid (16 mg, yield 43.2%). ESI-MS m / z: 741.3 [M+1] + .

[0816] Step 3: (E)-2-(4-(8-(2-(1H-pyrazol-3-yl)vinyl)-4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0817] Tert-butyl (E)-((7-(5-(3-chloro-6-methylcyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)vinyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (16 mg, 0.02 mmol), dichloromethane (2.5 mL), and trifluoroacetic acid (2.5 mL) were added to the reaction flask and stirred at 20°C for 1 hour. The reactants were directly concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to obtain the product as a white solid (5 mg, 45.5% yield). ESI-MS m / z: 557.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.55-8.43(m,1H),8.07(d,J=6.1Hz,1H),7.81-7.70(m,1H),7.52-7.45(m,1H),7.39 -7.34(m,1H),7.24-7.12(m,2H),6.48-6.42(m,1H),6.42-6.34(m,1H),4.45-4.32(m,3H),3.83(s,3H),0.96-0.77(m,4H).

[0818] Example 9

[0819] 2-(4-(4-(Aminomethyl)-8-ethynyl-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compounds 9, 9a, and 9b)

[0820] Step 1: tert-Butyl ((7-bromo-4-oxo-5-((triisopropylsilyl)ethynyl)-3,4-dihydrophthalen-1-yl)methyl)carbamate

[0821] To a solution of tert-butyl (((7-bromo-5-iodo-4-oxo-3,4-dihydrophthalen-1-yl)methyl)carbamate (55 mg, 0.1146 mmol), palladium acetate (1.29 mg, 0.0057 mmol), triphenylphosphine (3.01 mg, 0.01146 mmol) and cuprous iodide (1 mg, 0.0053 mmol) in tetrahydrofuran (5 mL) and diisopropylethylamine (5 mL) was added ethynyltriisopropylsilane. A solution of 22.98 mg, 0.126 mmol) in tetrahydrofuran (1 mL) was added, and the reaction system was stirred at room temperature under argon protection for 1 hour. After the reaction was completed, a saturated sodium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-11%, volume ratio) to obtain a yellow oily product (49 mg, 80%). ESI-MS m / z: 534.1 [M+H] +

[0822] Step 2: tert-Butyl((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-5-((triisopropylsilyl))ethynyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0823] Under argon protection, tert-butyl ((7-bromo-4-oxo-5-((triisopropylsilyl)ethynyl)-3,4-dihydrophthalen-1-yl)methyl)carbamate (48 mg, 0.0898 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzonitrile (45 mg, 0. To a solution of 1,1'-bis(diphenylphosphinoferrocenepalladium) (108 mmol) and potassium carbonate (24.82 mg, 0.180 mmol) in dioxane (10 mL) and water (1 mL) was added 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (32.85 mg, 0.045 mmol). The reaction solution was stirred at 90°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%, volume ratio) to obtain the product as a red oil (25 mg, 37.35% yield).

[0824] Step 3: tert-Butyl ((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-5-ethynyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0825] To a solution of tert-butyl ((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-5-((triisopropylsilyl)ethynyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (25 mg, 0.03359 mmol) in tetrahydrofuran (4 mL) at 0°C was added tetrabutylammonium fluoride solution in tetrahydrofuran (67 μL, 0.0672 mmol, 1 M). The reaction mixture was stirred for 15 minutes. After completion of the reaction, saturated sodium chloride solution (20 mL) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated sodium chloride (60 mL*2) and concentrated under reduced pressure to yield the product as a yellow oil (25 mg, crude product). ESI-MS m / z: 589.1 [M+H] + .

[0826] Step 4: 2-(4-(4-(Aminomethyl)-8-ethynyl-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0827] To a solution of tert-butyl ((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-5-ethynyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (25 mg, 0.0424 mmol) in dichloromethane (5 mL) at 0°C was added trifluoroacetic acid (0.5 mL), and the reaction solution was stirred at room temperature for 0.5 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to afford compound 9a (3 mg, yield 14.46%) and compound 9b (8 mg, yield 38.55%), 9a and 9b being atropisomers.

[0828] The characterization data of compound 9a and compound 9b are as follows:

[0829] ESI-MS m / z:489.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),8.40(s,1H),8.06(d,J=6.0Hz,1H),7.68(d,J=1.7Hz, 1H),7.52(d,J=1.6Hz,1H),4.34–4.16(m,3H),3.80(s,3H),1.24(s,1H),0.95–0.72(m,4H).

[0830] ESI-MS m / z:489.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.01(d,J=6.0Hz,1H),7.58(s,1H),7.50(d,J=5.8Hz,1H),7.3 3(s,1H),4.53–4.33(m,2H),4.19(m,1H),3.79(s,3H),1.24(s,1H),0.92(m,2H),0.87–0.78(m,2H).

[0831] Example 10

[0832] 2-(4-(1-(Aminomethyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 10)

[0833] Step 1: 6-Bromo-2-fluoro-3-iodopyridine

[0834] 2-Bromo-6-fluoropyridine (4.2 g, 23.8 mmol) was dissolved in tetrahydrofuran (42 mL) and, under argon, lithium diisopropylamide (13.1 mL, 26.2 mmol, 2N in n-heptane) was added dropwise at -78°C and stirred for 1.0 hour. A solution of iodine (6.0 g, 23.8 mmol) in tetrahydrofuran was added dropwise at -78°C and stirred for 1.5 hours. Saturated sodium sulfite solution was added at -78°C, followed by ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to afford the product as a white solid (5.98 g, 83% yield). ESI-MS m / z: 301.8 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.98 (t, J = 8.0 Hz, 1H), 7.18 (dd, J = 7.9, 1.3 Hz, 1H).

[0835] Step 2: 6-Bromo-2-fluoro-4-iodonicotinic acid

[0836] 6-Bromo-2-fluoro-3-iodopyridine (5.98 g, 19.8 mmol) was dissolved in tetrahydrofuran (60 mL) and, under argon, lithium diisopropylamide (10.9 mL, 21.8 mmol, 2N in n-heptane) was added dropwise at -78°C. The reaction mixture was stirred for 1.0 hour. Dry carbon dioxide was then introduced into the reaction mixture at -78°C and stirred for 1.5 hours. The reaction mixture was allowed to return to room temperature naturally, and concentrated hydrochloric acid (3.6 mL) and water (6.0 mL) were added, followed by dichloromethane. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to afford the product as a white solid (3.42 g, 49% yield). ESI-MS m / z: 345.8 [M+1] + .

[0837] Step 3: Methyl 6-bromo-2-fluoro-4-iodonicotinate

[0838] 6-Bromo-2-fluoro-4-iodonicotinic acid (3.42 g, 9.9 mmol), iodomethane (2.1 g, 7.3 mmol), and potassium carbonate (2.05 g, 14.8 mmol) were dissolved in N,N-dimethylacetamide (35 mL) under argon and stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to obtain the product as a white solid (2.5 g, 70% yield). ESI-MS m / z: 359.8 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.94 (s, 1H), 3.99 (s, 3H).

[0839] Step 4: Methyl 6-bromo-4-(1-ethoxyvinyl)-2-fluoronicotinate

[0840] Methyl 6-bromo-2-fluoro-4-iodonicotinate (6.1 g, 17.0 mmol), tributyl(1-ethoxyethylene)tin (6.1 g, 17.0 mmol), tetrakistriphenylphosphine palladium (1.96 g, 1.70 mmol), and bistriphenylphosphine palladium dichloride (1.2 g, 1.70 mmol) were dissolved in dioxane (100 mL) and stirred at 105°C under argon for 24 hours. The reaction mixture was cooled to room temperature, potassium fluoride was added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the product as a yellow oil (3.51 g, 68% yield). ESI-MS m / z: 303.9 [M+1] + .

[0841] Step 5: Methyl 6-bromo-4-(1-ethoxyvinyl)-2-(2,2,2-trifluoroethoxy)nicotinate

[0842] Methyl 6-bromo-4-(1-ethoxyvinyl)-2-fluoronicotinate (1.5 g, 4.95 mmol), trifluoroethanol (544 mg, 5.44 mmol), and potassium tert-butoxide (5.4 mL, 5.44 mmol, 1 N in tetrahydrofuran) were dissolved in tetrahydrofuran (20 mL) and stirred at 0°C for 1 hour. The reaction was diluted with water, and ethyl acetate was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the product as a colorless oil (1.85 g, 97% yield). ESI-MS m / z: 384.0 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.30 (s, 1H), 4.75 (t, J = 8.3Hz, 2H), 4.64 (d, J = 3.4Hz, 1H), 4.42(d,J=3.4Hz,1H),3.88(s,3H),3.83(t,J=7.0Hz,2H),1.34(t,J=7.0Hz,3H).

[0843] Step 6: Methyl 6-bromo-4-(2-bromoacetyl)-2-(2,2,2-trifluoroethoxy)nicotinate

[0844] Methyl 6-bromo-4-(1-ethoxyvinyl)-2-(2,2,2-trifluoroethoxy)nicotinate (1.0 g, 2.61 mmol), N-bromosuccinimide (464 mg, 2.61 mmol), and water (5 mL) were dissolved in tetrahydrofuran (10 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate, and water was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain a white solid (960 mg, 85% yield). ESI-MS m / z: 433.8 [M+1] + .

[0845] Step 7: 4-(2-acetoxyacetyl)-6-bromo-2-(2,2,2-trifluoroethoxy)nicotinate

[0846] Methyl 6-bromo-4-(2-bromoacetyl)-2-(2,2,2-trifluoroethoxy)nicotinate (1.6 g, 3.69 mmol), acetic acid (332 mg, 5.54 mmol), and potassium acetate (1.08 g, 11.07 mmol) were dissolved in acetonitrile (16 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, water was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product (crude product). ESI-MS m / z: 413.9 [M+1] + .

[0847] Step 8: 2-(6-bromo-3-(hydrazinecarbonyl)-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)-2-oxoethyl acetate

[0848] Methyl 4-(2-acetoxyacetyl)-6-bromo-2-(2,2,2-trifluoroethoxy)nicotinate (crude product) and hydrazine hydrate (184 mg, 3.69 mmol, 85%) were dissolved in trifluoroethanol (30 mL) and reacted at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and water was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the product (1.06 g, 70% yield for two steps). ESI-MS m / z: 413.9 [M+1] + .

[0849] Step 9: 6-Bromo-4-(2-hydroxyacetyl)-2-(2,2,2-trifluoroethoxy)nicotinamide

[0850] 2-(6-Bromo-3-(hydrazinecarbonyl)-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)-2-oxoethyl acetate (1.06 g, 2.56 mmol), lithium hydroxide monohydrate (161 mg, 3.84 mmol), and water (1 mL) were dissolved in tetrahydrofuran (10 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, water was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the product (896 mg, 94% yield). ESI-MS m / z: 371.9 [M+1] + .

[0851] Step 10: 7-Bromo-1-(hydroxymethyl)-5-(2,2,2-trifluoroethoxy)pyridin[3,4-d]pyridazin-4(3H)-one

[0852] 6-Bromo-4-(2-hydroxyacetyl)-2-(2,2,2-trifluoroethoxy)nicotinamide (896 mg, 2.41 mmol) was dissolved in trifluoroethanol (10 mL) and stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the product (296 mg, 34% yield). ESI-MS m / z: 353.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),7.83(s,1H),5.57(t,J=5.8Hz,1H),5.13(q,J=8.9Hz,2H),4.61(d,J=5.9Hz,2H).

[0853] Step 11: 4-Chloro-6-cyclopropyloxy-3-fluoro-2-(4-(1-(hydroxymethyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)benzonitrile

[0854] 7-Bromo-1-(hydroxymethyl)-5-(2,2,2-trifluoroethoxy)pyridin[3,4-d]pyridazin-4(3H)-one (60 mg, 0.17 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazol-5-yl)benzonitrile (106 mg, 0.25 mmol), potassium carbonate (70 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (12 mg, 0.017 mmol) and water (0.5 mL) were dissolved in dioxane (5 mL) and stirred under argon protection at 80°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and water was added to separate the organic phase. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol = 30:1) to obtain the product (22.1 mg, 23% yield). ESI-MS m / z: 565.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.51(s,1H),7.97(d,J=6.0Hz,1H),7.81(s,1H),5.50(t,J=6.1Hz,1H),4 .64(d,J=4.7Hz,2H),4.36–4.25(m,2H),4.19–4.11(m,1H),3.76(s,3H),0.97–0.90(m,2H),0.86–0.77(m,2H).

[0855] Step 12: 4-Chloro-2-(4-(1-(chloromethyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile

[0856] 4-Chloro-6-cyclopropyloxy-3-fluoro-2-(4-(1-(hydroxymethyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)benzonitrile (15 mg, 0.026 mmol) was dissolved in thionyl chloride (2 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the product (13.2 mg, 85% yield). ESI-MS m / z: 583.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),8.60(s,1H),7.98(d,J=6.0Hz,1H),7.78(s,1H),5.02(d,J=1 .2Hz,2H),4.39–4.28(m,2H),4.18–4.11(m,1H),3.76(s,3H),0.96–0.91(m,2H),0.85–0.76(m,2H).

[0857] Step 13: 4-chloro-6-cyclopropyloxy-2-(4-(1-(1,3-dioxoisoindole-2-yl)methyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile

[0858] 4-Chloro-2-(4-(1-(chloromethyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile (13.2 mg, 0.022 mmol) was dissolved in N'N-dimethylformamide (2 mL) under argon. Potassium phthalimide (6.3 mg, 0.034 mmol) was added at 0°C and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the product (12.8 mg, 84% yield). ESI-MS m / z: 694.1[M+1] + .

[0859] Step 14: 2-(4-(1-(aminomethyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0860] 4-Chloro-6-cyclopropyloxy-2-(4-(1-(1,3-dioxoindole-2-yl)methyl)-4-oxo-5-(2,2,2-trifluoroethoxy)-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (12.8 mg, 0.0184 mmol) and hydrazine hydrate (9.2 mg, 0.184 mmol) were dissolved in trifluoroethanol (3 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain the product (5.8 mg, 55% yield). ESI-MS m / z: 564.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.28(s,1H),7.97(d,J=6.0Hz,1H),7.84(s,1H),4.27–4. 20(m,2H),4.17–4.11(m,1H),4.05(s,2H),3.75(s,3H),0.96–0.90(m,2H),0.85–0.76(m,2H).

[0861] Example 11

[0862] 2-(4-(5-((1-aminocyclopropyl)methoxy)-1-(aminomethyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 11)

[0863] Step 1: 6-Chloro-2-fluoro-3-iodopyridine

[0864] Under argon at -70°C, lithium diisopropylamide (41.82 mL, 83.65 mmol) was added to a solution of 2-chloro-6-fluoropyridine (10 g, 76.04 mmol) in tetrahydrofuran (100 mL). The reaction mixture was stirred for 2 hours, followed by the addition of a solution of iodine (21.23 g, 83.65 mmol) in tetrahydrofuran (100 mL). The reaction mixture was stirred at -70°C for 1 hour. After completion, saturated sodium sulfite (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL x 3), the organic phase dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether = 100%, volume ratio) to afford the product as a white solid (16 g, yield 81.76%). ESI-MS m / z: 257.8 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.09 (t, J = 8.0 Hz, 1H), 7.03 (dd, J = 7.9, 1.2 Hz, 1H).

[0865] Step 2: 6-Chloro-2-fluoro-4-iodonicotinic acid

[0866] Under argon protection and at -70°C to -60°C, lithium diisopropylamide (29.96 mL, 59.94 mmol) was added to a solution of 6-chloro-2-fluoro-3-iodopyridine (14 g, 54.74 mmol) in tetrahydrofuran (20 mL). The reaction solution was stirred for 2 hours. The reaction system was purged with a carbon dioxide balloon and stirred for another 5 hours. After the reaction was complete, water (100 mL) was added to the reaction solution, and the reaction system was extracted with ethyl acetate (50 mL). The aqueous phase was adjusted to pH 6-7 with dilute hydrochloric acid (2 M) and then extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated to obtain a red solid product (16 g, crude product). ESI-MS m / z: 301.9 [M+1] + .

[0867] Step 3: Methyl 6-chloro-2-fluoro-4-iodonicotinate

[0868] To a solution of 6-chloro-2-fluoro-4-iodonicotinic acid (1.4 g, 4.64 mmol) and potassium carbonate (0.963 g, 6.97 mmol) in N,N-dimethylformamide (15 mL) at 0°C was added iodomethane (433 μL, 6.97 mmol). The reaction mixture was stirred for 3 hours. After completion of the reaction, water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-2%, volume ratio) to afford the product as a yellow solid (1.12 g, yield 76.45%). ESI-MS m / z: 315.9 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),3.99(s,3H).

[0869] Step 4: Methyl 6-chloro-4-(1-ethoxyvinyl)-2-fluoronicotinate

[0870] Under argon, a reaction mixture of methyl 6-chloro-2-fluoro-4-iodonicotinate (5 g, 15.873 mmol), tetrakistriphenylphosphine palladium (917 mg, 0.7936 mmol), bis(triphenylphosphine)palladium chloride (557.02 mg, 0.7936 mmol), and tributyl(1-ethoxyethylene)tin (5.732 g, 15.873 mmol) was stirred at 110°C for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-3%, volume ratio) to afford the product as a colorless oil (3.4 g, 82.62% yield). ESI-MS m / z: 260.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.35 (s, 1H), 4.68 (d, J = 3.5Hz, 1H), 4.47 (d, J = 3.5Hz, 1H), 3.91 (s, 3H), 3.86 (q, J = 7.0Hz, 2H), 1.35 (t, J = 7.0Hz, 3H).

[0871] Step 5: Methyl 2-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methoxy)-6-chloro-4-(1-ethoxyvinyl)nicotinate

[0872] To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (867.5 mg, 4.633 mmol) and sodium hydride (463 mg, 11.58 mmol) in N,N-dimethylformamide (15 mL) was added methyl 6-chloro-4-(1-ethoxyvinyl)-2-fluoronicotinate (1 g, 3.861 mmol) at 0°C. The reaction mixture was stirred for 0.5 hours. After completion, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-11%, v / v) to afford the product as a colorless oil (1.55 g, 94.28% yield). ESI-MS m / z: 449.1 [M+Na] +

[0873] Step 6: Methyl 4-(2-bromoacetyl)-2-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methoxy)-6-chloronicotinate

[0874] To a solution of methyl 2-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methoxy)-6-chloro-4-(1-ethoxyvinyl)nicotinate (1 g, 2.343 mmol) in tetrahydrofuran (30 mL) and water (10 mL) at 0°C was added a solution of N-bromosuccinimide (0.417 g, 2.343 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred for 0.5 hours. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-17%, v / v) to afford the product as a white solid (1.1 g, 98.3% yield). ESI-MS m / z: 499.0 [M+Na] + Step 7: tert-Butyl (1-(((6-chloro-4-(dimethylglycyl)-3-(formylhydrazide)pyridin-2-yl)oxy)methyl)cyclopropyl)carbamate

[0875] To a solution of methyl 4-(2-bromoacetyl)-2-((1-(tert-butoxycarbonyl)amino)cyclopropyl)methoxy)-6-chloronicotinate (500 mg, 1.0482 mmol) in tetrahydrofuran (5 mL) at 0°C was added a solution of dimethylamine in tetrahydrofuran (1.048 mL, 2.096 mmol). The reaction mixture was stirred for 0.5 hours, and then a solution of hydrazine hydrate (60 μL, 1.0482 mmol) was added. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-4%, volume ratio) to afford the product as a light red solid (246 mg, 53.19% yield). ESI-MS m / z: 442.1 [M+Na] +

[0876] Step 8: tert-Butyl(1-(((7-chloro-1-((dimethylamino)methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate

[0877] A solution of tert-butyl (1-(((6-chloro-4-(dimethylglycyl)-3-(formylhydrazide)pyridin-2-yl)oxy)methyl)cyclopropyl)carbamate (246 mg, 0.5567 mmol) in toluene (10 mL) was stirred at 70°C for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%, volume ratio) to afford the product as a light red solid (180 mg, 76.16% yield). ESI-MS m / z: 424.1 [M+H] + .

[0878] Step 9: tert-Butyl (1-(((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-((dimethylamino))methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate

[0879] Under argon protection, to a solution of tert-butyl (1-(((7-chloro-1-((dimethylamino)methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate (240 mg, 0.566 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzonitrile (473.3 mg, 1.132 mmol) and potassium carbonate (156.5 mg, 1.132 mmol) in dioxane (10 mL) and water (1 mL) was added 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (207.13 mg, 0.566 mmol). The reaction mixture was stirred at 90°C for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%, volume ratio) to obtain a yellow solid product (220 mg, 57.2% yield). ESI-MS m / z: 679.2 [M+H] + .

[0880] Step 10: tert-Butyl (1-(((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-(chloromethyl))-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate

[0881] To a solution of tert-butyl (1-(((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-((dimethylamino))methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate (100 mg, 0.1472 mmol) in tetrahydrofuran (10 mL) at 0°C under argon was slowly added isobutyl chloroformate (24.13 mg, 0.1767 mmol). The reaction system was stirred for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (methanol / dichloromethane = 0-5%, volume ratio) to obtain the product as a yellow oil (63 mg, yield 63.83%). ESI-MS m / z: 692.1 [M+Na] + . 1H NMR (400MHz, CDCl3) δ10.34(s,1H),8.15(s,1H),7.68(d,J=5.8Hz,1H),7.34(s,1H),5.69(s,1H),4. 79–4.62(m,2H),4.28(s,1H),3.79(s,3H),3.65(m,2H),1.40(s,9H),0.93(m,4H),0.84–0.80(m,4H).

[0882] Step 11: tert-Butyl (1-(((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate

[0883] To a solution of potassium phthalimide (19.14 mg, 0.1033 mmol) in N,N-dimethylformamide (2 mL) was added a solution of tert-butyl (1-(((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-(chloromethyl))-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate (63 mg, 0.094 mmol) in N,N-dimethylformamide (3 mL) at 0°C. The reaction system was stirred for 0.5 hours. After completion of the reaction, saturated sodium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (methanol / dichloromethane = 0-5%, volume ratio) to obtain the product as a yellow oil (100 mg, crude product). ESI-MS m / z: 781.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.59(s,1H),7.97(dd,J=5.5,3.1Hz,2H),7.93–7.89(m,2H),7.86(s,1H),6. 99(s,1H),5.16(s,2H),4.28(s,1H),3.76(s,3H),3.64–3.45(m,2H),1.34(s,9H),0.99–0.79(m,4H),0.68(m,4H).

[0884] Step 12: 2-(4-(5-((1-aminocyclopropyl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0885] To a solution of tert-butyl (1-(((7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)oxy)methyl)cyclopropyl)carbamate (100 mg, crude) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL*3). The organic phase was concentrated under reduced pressure to give the product as a yellow oil (50 mg, crude). ESI-MS m / z: 681.1 [M+H] + .

[0886] Step 13: 2-(4-(5-((1-aminocyclopropyl)methoxy)-1-(aminomethyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0887] To a solution of 2-(4-(5-((1-aminocyclopropyl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (50 mg, 0.0735 mmol) in ethanol (5 mL) was added hydrazine hydrate (28.5 μL, 0.5882 mmol). The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product as a white solid (10 mg, 24.72% yield). ESI-MS m / z: 551.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.48(s,1H),8.59(s,1H),7.99(d,J=5.9Hz,1H),7.72(s,1H),4.19(m,1H) ,4.04(s,2H),3.73(s,3H),3.38(s,2H),0.94(m,2H),0.88–0.78(m,2H),0.53(m,2H),0.39(m,2H).

[0888] Example 12

[0889] 2-(4-(1-(aminomethyl)-5-(2-fluoro-2-methylpropyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 12)

[0890] Step 1: Methyl 6-chloro-4-(1-ethoxyvinyl)-2-(2-fluoro-2-methylpropoxy)nicotinate

[0891] 2-Fluoro-2-methyl-1-propanol (221 mg, 2.4 mmol) and N,N-dimethylformamide (3 mL) were added to a reaction flask, cooled to 0°C under argon atmosphere, and sodium hydride (160 mg, 4.0 mmol, 60%) was added. The reaction was stirred at 0°C for 1.0 hour. A solution of methyl 6-chloro-4-(1-ethoxyvinyl)-2-fluoronicotinate (520 g, 2.0 mmol) in N,N-dimethylformamide (5 mL) was added, and the reaction was stirred at 0°C for another 1.0 hour. The reaction was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to afford the product as a white solid (556 mg, 83.7% yield). ESI-MS m / z: 332.1 [M+1] + .

[0892] Step 2: 4-(2-bromoacetyl)-6-chloro-2-(2-fluoro-2-methylpropoxy)nicotinate

[0893] Methyl 6-chloro-4-(1-ethoxyvinyl)-2-(2-fluoro-2-methylpropoxy)nicotinate (390 mg, 1.17 mmol), tetrahydrofuran (6 mL), and water (2 mL) were added to a reaction flask, cooled to 0°C, and N-bromosuccinimide (209 mg, 1.17 mmol) was added. The reaction was stirred at 0°C for 0.5 hours. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a colorless oil (400 mg, yield 89.6%). ESI-MS m / z: 382.0 [M+1] + .

[0894] Step 3: 4-(2-acetoxyacetyl)-6-chloro-2-(2-fluoro-2-methylpropoxy)nicotinate

[0895] Potassium acetate (85 mg, 0.87 mmol), acetic acid (26 mg, 0.42 mmol), and acetonitrile (10 mL) were added to a reaction flask. A solution of methyl 4-(2-bromoacetyl)-6-chloro-2-(2-fluoro-2-methylpropoxy)nicotinate (110 mg, 0.28 mmol) in acetonitrile (5 mL) was slowly added dropwise. The mixture was stirred at 20°C for 4 hours. Water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (100 mg, 99% yield). ESI-MS m / z: 362.0 [M+1] + .

[0896] Step 4: Methyl (7-chloro-5-(2-fluoro-2-methylpropoxy)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-1-yl)acetate

[0897] Methyl 4-(2-acetoxyacetyl)-6-chloro-2-(2-fluoro-2-methylpropoxy)nicotinate (100 mg, 0.28 mmol) was dissolved in ethanol (4 mL), and hydrazine hydrate (16 mg, 0.28 mmol, 85%) was added. The mixture was stirred at 25°C for 48 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a white solid (61 mg, yield 64.2%). ESI-MS m / z: 343.1 [M+1] + .

[0898] Step 5: 7-Chloro-5-(2-fluoro-2-methylpropoxy)-1-(hydroxymethyl)pyridin[3,4-d]pyridazin-4(3H)-one

[0899] Methyl (7-chloro-5-(2-fluoro-2-methylpropoxy)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-1-yl)acetate (224 mg, 0.65 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (2.5 mL). Lithium hydroxide monohydrate (55 mg, 1.3 mmol) was added and stirred at 20°C for 3 hours. Water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a white solid (195 mg, 99% yield). ESI-MS m / z: 302.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),7.56(s,1H),5.54(t,J=5.8Hz,1H),4.60(d,J=5.8Hz, 2H),4.47(s,1H),4.42(s,1H),1.53(s,3H),1.48(s,3H).

[0900] Step 6: 4-chloro-6-cyclopropyloxy-3-fluoro-2-(4-(5-(2-fluoro-2-methylpropoxy)-1-(hydroxymethyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)benzonitrile

[0901] 7-Chloro-5-(2-fluoro-2-methylpropoxy)-1-(hydroxymethyl)pyridin[3,4-d]pyridazin-4(3H)-one (91 mg, 0.3 mmol), 4-chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzonitrile (197 mg, 0.33 mmol), potassium carbonate (125 mg, 0.9 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (22 mg, 0.03 mmol), dioxane (6 mL), and water (1.5 mL) were added to a reaction flask and stirred at 80 °C under argon atmosphere for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain the product as a yellow solid (110 mg, yield 65.9%). ESI-MS m / z: 557.1 [M+1] + .

[0902] Step 7: 4-chloro-2-(4-(1-(chloromethyl)-5-(2-fluoro-2-methylpropoxy)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile

[0903] 4-Chloro-6-cyclopropyloxy-3-fluoro-2-(4-(5-(2-fluoro-2-methylpropoxy)-1-(hydroxymethyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)benzonitrile (110 mg, 0.2 mmol) and thionyl chloride (5 mL) were added to a reaction flask and stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure to obtain the product as a yellow solid (115 mg, 99% yield). ESI-MS m / z: 575.1 [M+1] + .

[0904] Step 8: 4-chloro-6-cyclopropyloxy-2-(4-(1-((1,3-dioxoisoindolin-2-yl)methyl)-5-(2-fluoro-2-methylpropoxy)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile

[0905] Potassium phthalimidate (83 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2 mL) and slowly added dropwise to a solution of 4-chloro-2-(4-(1-(chloromethyl)-5-(2-fluoro-2-methylpropoxy)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile (172 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 15°C for 0.5 hour. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed twice with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1, volume ratio) to afford the product as a white solid (120 mg, 58.3% yield). ESI-MS m / z: 686.1[M+1] + .

[0906] Step 9: 2-(4-(1-(aminomethyl)-5-(2-fluoro-2-methylpropyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0907] 4-Chloro-6-cyclopropyloxy-2-(4-(1-((1,3-dioxoisoindolin-2-yl)methyl)-5-(2-fluoro-2-methylpropoxy)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (69 mg, 0.1 mmol) was dissolved in ethanol (4 mL), and hydrazine hydrate (12 mg, 0.2 mmol, 85%) was added. The mixture was stirred at 25°C for 20 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography to obtain the product as a white solid (22 mg, yield 39.5%). ESI-MS m / z: 556.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.45 (s, 1H), 8.59 (s, 1H), 7.94 (d, J = 6.1Hz, 1H), 7.75 (s, 1H) ),4.15-4.07(m,3H),4.01(s,2H),3.74(s,3H),1.50-1.30(m,6H),0.95-0.75(m,4H).

[0908] Example 13

[0909] 2-(4-(1-(aminomethyl)-5-(difluoromethoxy)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 13)

[0910] Step 1: Methyl 6-bromo-4-iodo-2-((4-methoxybenzyl)oxy)nicotinate

[0911] To a solution of 4-methoxybenzyl alcohol (84.456 mg, 0.6112 mmol) and sodium hydride (44.45 mg, 1.111 mmol, 60% purity) in tetrahydrofuran (4 mL) was added a solution of methyl 6-bromo-2-fluoro-4-iodonicotinate (200 mg, 0.5557 mmol) in tetrahydrofuran (4 mL) at 0°C. The reaction mixture was stirred for 0.5 hours. After completion, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-7%, v / v) to afford the product as a yellow oil (300 mg, crude product). ESI-MS m / z: 499.8 [M+Na] +

[0912] Step 2: Methyl 6-bromo-2-hydroxy-4-iodonicotinate

[0913] To a solution of methyl 6-bromo-4-iodo-2-((4-methoxybenzyl)oxy)nicotinate (300 mg, 0.6275 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL), and the reaction mixture was stirred for 0.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water (5 mL) was added to the residue. The pH of the mixture was adjusted to 6-7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%, volume ratio) to afford the product as a white solid (170 mg, yield 75.69%). ESI-MS m / z: 357.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.64 (s, 1H), 4.00 (s, 3H).

[0914] Step 3: Methyl 6-bromo-2-(difluoromethoxy)-4-iodonicotinate

[0915] Under argon protection at 0°C, a solution of methyl 6-bromo-2-hydroxy-4-iodonicotinate (500 mg, 1.397 mmol) and anhydrous sodium sulfate (19.8 mg, 0.1397 mmol) in acetonitrile (20 mL) was added with a solution of fluorosulfonyldifluoroacetic acid (522.43 mg, 2.9335 mmol) in acetonitrile (4 mL). The reaction mixture was stirred for 24 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-4%, volume ratio) to afford the product as a white solid (260 mg, 45.63% yield). ESI-MS m / z: 407.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.80(s,1H),7.58–7.17(m,1H),3.98(s,3H).

[0916] Step 4: Methyl 6-bromo-2-(difluoromethoxy)-4-(1-ethoxyvinyl)nicotinate

[0917] Under argon, 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (35.85 mg, 0.0490 mol) was added to a dioxane solution of methyl 6-bromo-2-(difluoromethoxy)-4-iodonicotinate (200 mg, 0.490 mmol) and tributyl(1-ethoxyethylene)tin (194.77 mg, 0.5393 mmol). The reaction mixture was stirred at 90°C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-4%, v / v) to afford the product as a yellow oil (110 mg, 63.72% yield). ESI-MS m / z: 352.0 [M+H] + .

[0918] Step 5: Methyl 6-bromo-4-(2-bromoacetyl)-2-(difluoromethoxy)nicotinate

[0919] To a solution of methyl 6-bromo-2-(difluoromethoxy)-4-(1-ethoxyvinyl)nicotinate (780 mg, 2.215 mmol) in tetrahydrofuran (15 mL) and water (5 mL) at 0°C was added a solution of N-bromosuccinimide (394.24 mg, 2.215 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 0.5 hours. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-5%, volume ratio) to afford the product as a white solid (500 mg, yield 62.42%). ESI-MS m / z: 403.8 [M+H] +

[0920] Step 6: 6-Bromo-2-(difluoromethoxy)-4-(dimethylglycyl)nicotinic acid hydrazide

[0921] To a solution of methyl 6-bromo-4-(2-bromoacetyl)-2-(difluoromethoxy)nicotinate (200 mg, 0.4964 mmol) in tetrahydrofuran (20 mL) at 0°C was added a solution of dimethylamine in tetrahydrofuran (248 μL, 0.4964 mmol). The reaction mixture was stirred for 0.5 hours, followed by the addition of a solution of hydrazine hydrate (49.696 mg, 0.9927 mmol) and a further stirring for 0.5 hours. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%, volume ratio) to afford the product as a yellow oil (80 mg, 43.96% yie...

Claims

1. A compound as shown in formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, in, X 1 and X 2 Each independently CR 5 or N; Each R 5 are independently deuterium, hydrogen, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 alkoxy; R 1 is a 3-8 membered cycloalkyl group, which is occupied by one or more R 1a Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 1b Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 1c Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 1d substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 1b The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. R 1a 、R 1b 、R 1c and R 1d are independently deuterium, hydroxyl, halogen, cyano, -N(R 6 )2、C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3 to 8-membered cycloalkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, 4-10 membered heterocyclic group, -Z 1b -U 1a -3- to 8-membered cycloalkyl in a 3- to 8-membered cycloalkyl group, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1- a Substituted; the 4 to 10 membered heterocyclic group, -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)-, (halogenated C 1-6 alkyl) 2N-C(=O)-, -NH2 or -OH; the number of heteroatoms in the 4- to 10-membered heterocyclic group and the 4- to 10-membered heterocyclic group substituted with halogen is independently 1, 2 or 3, and the heteroatoms are independently selected from N, O and S; When X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, R 2c Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2d Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2d The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Or, when X 1 and X 2 are each independently CH, and R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different; When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 For hydrogen, cyano, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2l The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m and R 2n are independently deuterium, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -N(R 6 ) 2, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or 5-10 membered heteroaryl; the number of heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S; R 3 and R 4 are independently deuterium, hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2)m-OP(=O)(OR 3c )2; R 3a and R 3b are each independently deuterium, hydrogen or C 1-20 alkyl; Each R 3c are independently deuterium, hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group or C 6-10 Aryl; the number of heteroatoms in the 4- to 10-membered heterocyclic group is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S; R 4a is deuterium, H or a 3- to 8-membered cycloalkyl group; m is an integer from 0 to 10; Y, Z 1a 、Z 1b 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-; L, U 1a and U 1b Each independently a chemical bond or C 1-3 alkylene; Each R 6 are independently hydrogen or C 1-6 alkyl.

2. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, characterized in that: The compound of formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt satisfies any one of the following conditions: (1) The compound shown in formula I is not (2) When X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c Substituted 3-8 membered cycloalkyl, one or more R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 Halogen, C 1-6 Alkyl, one or more R 2g replace C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5-10 membered heteroaryl; the 4-10 membered heterocyclic group, replaced by one or more R 2l The 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the substituted 4- to 10-membered heterocyclic group replaced by one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Or, when X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 Alkoxy, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is hydrogen; Alternatively, the compound shown in formula I is 3. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet any one of the following conditions: (1) When X 1 and X 2 are each independently CH, and R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-O- C(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)-, (halogenated C 1-6 alkyl)2N-C(=O)-, -NH2 or -OH; Z 1a 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-; U 1b independently a chemical bond or C 1-3 alkylene; Each R 6 are independently hydrogen or C 1-6 alkyl; (2) When X 1 and X 2 are each independently CH, and R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group, C 1-6 Alkyl-C(=O)-O-, C 1- 6-alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)- or (halogenated C 1-6 alkyl)2N-C(=O)-; Z 1a 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-; U 1b independently a chemical bond or C 1-3 alkylene; Each R 6 are independently hydrogen or C 1-6 alkyl; (3)R 1a 、R 1b 、R 1c and R 1d Each independently -Z 1d -11 to 20 membered heteroaryl, said -Z 1d -11 to 20 membered heteroaryl groups are optionally substituted with one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, halogenated C 1-6 Alkyl-OC(=O)-, deuterated C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group, C 1-6 Alkyl-C(=O)-O-, C 1- 6-alkyl-NH-C(=O)-, (C 1-6 alkyl) 2N-C(=O)-, deuterated C 1-6 Alkyl-NH-C(=O)-, halogenated C 1-6 Alkyl-NH-C(=O)-, (deuterated C 1-6 Alkyl) 2N-C(=O)- or (halogenated C 1-6 alkyl)2N-C(=O)-; Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-; U 1b independently a chemical bond or C 1-3 alkylene; Each R 6 are independently hydrogen or C 1-6 alkyl.

4. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1) When X 1 CR 5 And X 2 N, X 1 N and X 2 CR 5 、X 1 N and X 2 N or X 1 and X 2 Each independently CR 5 And R 5 For deuterium, halogen, -N(R 6 )2、C 1-6 Alkyl or C 1-6 When alkoxy, R 2 is cyano; (2) When X 1 and X 2 are each independently CH, and R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced When there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; Z 1a 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-; U 1b independently a chemical bond or C 1-3 alkylene; Each R 6 are independently hydrogen or C 1-6 alkyl; (3)R 1a 、R 1b 、R 1c and R 1d Each independently -Z 1d -11 to 20 membered heteroaryl, said -Z 1d -11 to 20 membered heteroaryl groups are optionally substituted with one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -O-, -S-, -NR 6 -、-NR 6 C(=O)-, -SO-, -SO2-, -CH(OH)- or -C(=O)-; U 1b independently a chemical bond or C 1-3 alkylene; Each R 6 are independently hydrogen or C 1-6 alkyl.

5. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1)R 1-a In the -Z 1f -U 1b - The 3- to 8-membered cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl; (2)R 2 wherein the 3- to 8-membered cycloalkyl group is replaced by one or more R 2c The 3- to 8-membered cycloalkyl in the substituted 3- to 8-membered cycloalkyl and the 3- to 8-membered cycloalkyl in the substituted 3- to 8-membered cycloalkyl 2k The 3- to 8-membered cycloalkyl groups in the substituted 3- to 8-membered cycloalkyl groups are independently cyclopropyl, cyclobutyl, or cyclopentyl; (3)R 2b wherein the 3- to 8-membered cycloalkyl groups are each independently cyclopropyl, cyclobutyl, or cyclopentyl; (4)R 2j wherein the 3- to 8-membered cycloalkyl groups are each independently cyclopropyl, cyclobutyl, or cyclopentyl; (5)R 4a wherein the 3- to 8-membered cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl; (6)R 1 、R 1a 、R 1b 、R 1c 、R 1d 、R 2a 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2k 、R 2l 、R 2m 、R 2n and R 3c wherein the 3- to 8-membered cycloalkyl group is replaced by one or more R 1a 3- to 8-membered cycloalkyl in substituted 3- to 8-membered cycloalkyl, and -Z 1b -U 1a - The 3- to 8-membered cycloalkyl groups in the 3- to 8-membered cycloalkyl group are independently cyclopropyl, cyclobutyl, or cyclopentyl; (7)R 1 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m 、R 2n and R 3c In the embodiment, the 4-10 membered heterocyclic group is replaced by one or more R 1b The 4- to 10-membered heterocyclic group in the substituted 4- to 10-membered heterocyclic group is replaced by one or more R 2d The 4- to 10-membered heterocyclic group in the substituted 4- to 10-membered heterocyclic group and the substituted 4- to 10-membered heterocyclic group 2l The 4- to 10-membered heterocyclic groups in the substituted 4- to 10-membered heterocyclic groups are independently 4- to 6-membered heterocyclic groups, such as piperidinyl, piperazinyl or pyrrolidinyl; (8)R 1d In the -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl is independently phenyl or naphthyl; (9)R 1 、R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 and R 3c In the C 6-10 Aryl, one or more R 1c Substituted C 6- 10 C in aromatic groups 6-10 Aryl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, one or more R 2e Substituted C 6-10 C in aromatic groups 6-10 Aryl, and one or more R 2m Substituted C 6-10 C in aromatic groups 6-10 Aryl is independently phenyl or naphthyl; (10)R 1 wherein the 5- to 10-membered heteroaryl group and the one or more R 1d The 5- to 10-membered heteroaryl groups in the substituted 5- to 10-membered heteroaryl groups are independently 5- to 6-membered monoheteroaryl groups or 8- to 10-membered fused heteroaryl groups; the 5- to 6-membered monoheteroaryl groups may independently be pyrazole or triazole, for example (11)R 1 wherein the 5- to 10-membered heteroaryl group and the one or more R 1d The 5- to 10-membered heteroaryl in the substituted 5- to 10-membered heteroaryl independently has 2 or 3 heteroatoms; the heteroatoms can be independently selected from N; (12)R 2 wherein the 5- to 10-membered heteroaryl group is replaced by one or more R 2f The 5- to 10-membered heteroaryl in the substituted 5- to 10-membered heteroaryl, and the ... 2n The 5- to 10-membered heteroaryl groups in the substituted 5- to 10-membered heteroaryl groups are independently 5- to 6-membered monoheteroaryl groups or 8- to 10-membered fused heteroaryl groups; the 5- to 6-membered monoheteroaryl groups may independently be pyrazole or triazole, for example (13)R 2 wherein the 5- to 10-membered heteroaryl group is replaced by one or more R 2f The 5- to 10-membered heteroaryl in the substituted 5- to 10-membered heteroaryl, and the ... 2n The 5- to 10-membered heteroaryl in the substituted 5- to 10-membered heteroaryl independently has 2 or 3 heteroatoms; the heteroatoms can be independently selected from N; (14)R 2a wherein the 5- to 10-membered heteroaryl groups are independently 5- to 6-membered single heteroaryl groups or 8- to 10-membered fused heteroaryl groups; The membered heteroaryl groups may independently be pyrazole or triazole, for example (15)R 2a In the above, the 5- to 10-membered heteroaryl group independently has 2 or 3 heteroatoms; the heteroatoms can be independently selected from N; (16)R 2i In the above, the 5- to 10-membered heteroaryl group is independently a 5- to 6-membered single heteroaryl group or an 8- to 10-membered fused heteroaryl group; the 5- to 6-membered single heteroaryl group may independently be a pyrazole or a triazole, for example (17)R 2i In the above, the 5- to 10-membered heteroaryl group independently has 2 or 3 heteroatoms; the heteroatoms can be independently selected from N; (18)R 1a 、R 1b 、R 1c 、R 1d 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2j 、R 2k 、R 2l 、R 2m and R 2n wherein the 5- to 10-membered heteroaryl and -Z 1d - The 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl is independently a 5- to 6-membered single heteroaryl or an 8- to 10-membered condensed heteroaryl; the 5- to 6-membered single heteroaryl may independently be pyrazole or triazole, for example (19)R 1a 、R 1b 、R 1c 、R 1d 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2j 、R 2k 、R 2l 、R 2m and R 2n wherein the 5- to 10-membered heteroaryl and -Z 1d - The 5- to 10-membered heteroaryl group in the 5- to 10-membered heteroaryl group independently has 2 or 3 heteroatoms; the heteroatoms can be independently selected from N; (20)R 1-a wherein the halogen is independently fluorine, chlorine, bromine or iodine; (21)R 2 wherein the halogen is independently fluorine, chlorine, bromine or iodine; (22)R 2c wherein the halogen is fluorine, chlorine, bromine or iodine; (23)R 2g wherein the halogen is fluorine, chlorine, bromine or iodine; (24)R 2k wherein the halogen is fluorine, chlorine, bromine or iodine; (25)R 1a 、R 1b 、R 1c 、R 1d 、R 2a 、R 2b 、R 2d 、R 2e 、R 2f 、R 2h 、R 2i 、R 2j 、R 2l 、R 2m 、R 2n and R 5 wherein the halogen is independently fluorine, chlorine, bromine or iodine; (26)R 1a 、R 1b 、R 1c 、R 1d and R 1-a In the C 1-6 The hydroxyalkyl groups are independently C 1-4 Hydroxyalkyl, for example -CH2OH, -CH2CH2OH, -CH(CH3)OH or -CH(CH3)CH2OH; (27)R 1a 、R 1b 、R 1c 、R 1d 、R 1-a 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m 、、R 2n and R 5 In the C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, halogenated C 1-6 C in the alkoxy group 1-6 Alkoxy and deuterated C 1-6 C in the alkoxy group 1-6 Alkoxy is independently methoxy, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -O(CH2)3CH3, -OCH2CH(CH3)2, -OCHCH3CH2CH3 or -OC(CH3)3; (28)R 2 In the C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 C in alkenyl 2-6 Alkenyl, and one or more R 2i Substituted C 2-6 C in alkenyl 2-6 Alkenyl is independently C 2-4 Alkenyl groups, such as vinyl, (29)R 3c In the C 2-6 Alkenyl is independently C 2-4 Alkenyl groups, such as vinyl, (30)R 2 In the C 2-6 Alkynyl, one or more R 2b Substituted C 2-6 C in the alkynyl group 2-6 Alkynyl, and one or more R 2j Substituted C 2-6 C in the alkynyl group 2-6 Alkynyl is independently C 2-4 Alkynyl groups, such as ethynyl, (31)R 1a 、R 1b 、R 1c 、R 1d and R 3c In the C 2-6 Alkynyl is independently C 2-4 Alkynyl groups, such as ethynyl, (32)R 1d In the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (33)R 2 In the C 1-6 Alkyl, and one or more R 2g Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (34)R 2b In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (35)R 2j In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (36)R 1a 、R 1b 、R 1c 、R 1-a 、R 2a 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2k 、R 2l 、R 2m 、R 2n 、R 3 、R 4 、R 3c 、R 5 and R 6 In the C 1-6 Alkyl, -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl and -C(=O)-C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (37)R 1-a and R 3c wherein the halogenated C 1-6 Alkyl and -Z 1e -Halogenated C 1-6 Halogenated C in alkyl 1-6 Alkyl is independently halogenated C 1-4 Alkyl groups, such as -CF3, -CHF2 or -CH2CF3; (38)R 2 wherein the halogenated C 1-6 Alkoxy is halogenated C 1-4 Alkoxy, such as -OCF3, (39)R 2 In the above, the deuterated C 1-6 Alkoxy is deuterated C 1-4 Alkoxy, such as -OCD3 or -OCD2CD3; (40)R 3a and R 3b In the C 1-20 The alkyl groups are independently C 1-6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (41) In L, the C 1-3 Alkylene is methylene, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-; (42)U 1a In the C 1-3 Alkylene is methylene, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-; (43)U 1b In the C 1-3 Alkylene is methylene, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-.

6. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1)R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; (2) Each R 1d Independent-Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a replace; (3) Each R 1-a are independently deuterium, cyano, halogen, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; (4) When X 1 and X 2 When each is independently CH, R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c substituted 3-8 membered cycloalkyl, or one or more R 2f substituted 5- to 10-membered heteroaryl; (5) When X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2 For hydrogen, halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl; (6)R 2a 、R 2b 、R 2c 、R 2f 、R 2g 、R 2i 、R 2j 、R 2k 、R 2m and R 2n are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3-8 membered cycloalkyl or 5-10 membered heteroaryl; (7)R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2; (8)R 3a and R 3b are each independently hydrogen or C 1-6 alkyl; (9) Each R 3c are independently hydrogen; (10)R 4a is H or a 3- to 8-membered cycloalkyl group; (11) m is 1, 2 or 3; (12) Each R 5 are independently hydrogen, halogen or -N(R 6 )2; (13) Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f are each independently a chemical bond, -O- or -S-; (14) L and U 1b Each independently a chemical bond or C 1-3 alkylene; (15) Each R 6 are independently hydrogen.

7. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1)R 1 wherein the 5- to 10-membered heteroaryl group and the one or more R 1d When the 5- to 10-membered heteroaryl groups in the substituted 5- to 10-membered heteroaryl groups are independently 5- to 6-membered monoheteroaryl groups, the 5- to 6-membered monoheteroaryl groups are independently pyrazolyl or imidazolyl, for example (2)R 1d In the -Z 1d -When the 5- to 10-membered heteroaryl group in the 5- to 10-membered heteroaryl group is an 8- to 10-membered fused heteroaryl group, the 8- to 10-membered fused heteroaryl group is independently (3)R 1d In the -Z 1d - The 5- to 10-membered heteroaryl group in the 5- to 10-membered heteroaryl group independently has 1, 2 or 3 heteroatoms; the heteroatoms may be independently selected from N and O; (4)R 1d In the -Z 1d The 11-20 membered heteroaryl in the -11-20 membered heteroaryl is independently an 11-16 membered heteroaryl, such as a 12-membered heteroaryl, a 13-membered heteroaryl or a 15-membered heteroaryl, and for example (5)R 1d In the -Z 1d - The 11-20 membered heteroaryl in the 11-20 membered heteroaryl independently has 2, 3 or 4 heteroatoms; the heteroatoms can be independently selected from N and O; (6) Each R 1d Independent-Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5-10 membered heteroaryl in 5-10 membered heteroaryl, or -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; for example, each R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced (7) Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3~8 yuan Cycloalkyl; (8) When X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2 Halogen, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl; Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is hydrogen; (9)Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-,R 6 For H.

8. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1)R 1-a wherein the 4- to 10-membered heterocyclic group and the 4- to 10-membered heterocyclic group substituted with halogen are 4- to 6-membered heterocyclic groups, such as oxetane, oxetanyl, piperidinyl, piperazinyl or pyrrolidinyl; (2)R 1d In the -Z 1d The 11-20 membered heteroaryl in the -11-20 membered heteroaryl is independently an 11-16 membered heteroaryl, such as a 12-membered heteroaryl, a 13-membered heteroaryl, a 14-membered heteroaryl or a 15-membered heteroaryl, and for example (3)R 1-a In the C 1-6 Alkyl, deuterated C 1-6 C in the alkyl group 1-6 Alkyl, C 1-6 C in alkyl-C(=O)- 1-6 Alkyl, C 1-6 C in alkyl-SO2- 1-6 Alkyl, C 1-6 C in alkyl-OC(=O)- 1-6 Alkyl, halogenated C 1-6 C in alkyl-OC(=O)- 1-6 Alkyl, deuterated C 1-6 C in alkyl-OC(=O)- 1-6 Alkyl, C 1-6 C in alkyl-C(=O)-O- 1-6 Alkyl, C 1-6 C in alkyl-NH-C(=O)- 1-6 Alkyl, (C 1-6 C in alkyl)2N-C(=O)- 1-6 Alkyl, deuterated C 1-6 C in alkyl-NH-C(=O)- 1-6 Alkyl, halogenated C 1-6 C in alkyl-NH-C(=O)- 1-6 Alkyl, (deuterated C 1-6 C in alkyl)2N-C(=O)- 1-6 Alkyl and (halogenated C 1-6 C in alkyl)2N-C(=O)- 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

9. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1) Each R 1-a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, 4-10 membered heterocyclic group, 4-10 membered heterocyclic group substituted by halogen, -NH2 or -OH, preferably, each R 1- a are independently deuterium, cyano, oxo (=O), halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterium Generation C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, -NH2 or -OH; (2) Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O-, -S- or -C(=O)-, R 6 is H; (3) Each R 1d Independently by one or more R 1-a Replaced By one or more R 1- a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced 10. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound represented by Formula I, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by Formula Ia, Formula Ib, or Formula Ic, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, Preferably, the compound represented by Formula I, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof is a compound represented by Formula II-a, Formula II-b or Formula II-c, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, Among them, R 1 、R 2 、R 3 、R 4 、R 4a 、R 1d , Y and L are as defined in any one of claims 1-3.

11. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, characterized in that: The compound represented by Formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound represented by Formula Ia', Formula Ib' or Formula Ic', its stereoisomer, its tautomer or its pharmaceutically acceptable salt, Among them, R 1d’ -Z 1a -C 1-6 Alkyl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 The alkyl group is optionally replaced by one or more R 1-a replace; Ring B is (1) In formula Ia', when R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c Substituted 3-8 membered cycloalkyl, R 2e Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2f In the case of a substituted 5- to 10-membered heteroaryl group, R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace; (2) In Formula Ia', R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1d for By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced (3) In formulas Ib' and Ic', R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R 2h Substituted C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k Substituted 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, one or more R 2l Substituted 4- to 10-membered heterocyclic group, C 6-10 Aryl, one or more R 2m Substituted C 6-10 Aryl, 5-10 membered heteroaryl, or one or more R 2n When substituted 5-10 membered heteroaryl, or Y is -NR 6 -, R 6 is H, L is a chemical bond, R 2 When it is hydrogen, R 1d -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20 membered heteroaryl; said -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a replace; Z 1a 、Z 1c and Z 1d Each is independently a chemical bond; R 1-a 、R 2a 、R 2b 、R 2c 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j 、R 2k 、R 2l 、R 2m 、R 2n 、R 3 、R 4 、R 4a , Y and L are as defined in claim 1 or 2.

12. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, wherein: The compound of formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt satisfies any one of the following conditions: (1)X 1 and X 2 Each independently is CH; R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and or multiple R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -5 to 10 membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -5-10 membered heteroaryl in the 5-10 membered heteroaryl is optionally substituted by one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-NH-C(=O)- or 4- to 10-membered heterocyclic group; R 2 Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkenyl, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2f substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2f The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Or, when R 2 H, C 1-6 Alkyl or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced R 2a 、R 2b 、R 2c and R 2f are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S; R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2; R 3a and R 3b are each independently hydrogen or C 1-6 alkyl; Each R 3c are independently hydrogen; m is 1, 2, or 3; R 4a is H or a 3- to 8-membered cycloalkyl group; Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-; Each R 6 independently H; L and U 1b For chemical bonds or C 1-3 alkylene; (2)X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ; R 1 is a 5- to 10-membered heteroaryl group, or is replaced by one or more R 1d substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, halogen, oxo (=O), C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkyl-NH-C(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, -NH2 or -OH; R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 2i Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl, one or more R 2k substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, or one or more R 2n substituted 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl and one or more R 2n The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. R 2g 、R 2i 、R 2j 、R 2k and R 2n are independently deuterium, halogen, C 1-6 Alkyl, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S; R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2; R 3a and R 3b are each independently hydrogen or C 1-6 alkyl; Each R 3c are independently hydrogen; m is 1, 2, or 3; R 4a is hydrogen or a 3- to 8-membered cycloalkyl group; Each R 5 are independently H, halogen or -N(R 6 )2; Y, Z 1a 、Z 1c 、Z 1e 、Z 1d and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-; Each R 6 independently H; L and U 1b Each independently a chemical bond or C 1-3 alkylene; Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H; (3)X 1 and X 2 Each independently is CH; R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Each R 1d Independently -Z 1a -C 1-6 Alkyl or -Z 1c -C 6-10 Aryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl and -Z 1c -C 6-10 C in aromatic groups 6-10 Each aryl group is optionally substituted by one or more R 1-a replace; Each R 1-a are independently cyano, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 Halogenated C 1-6 Alkoxy, one or more R 2a Substituted C 2-6 Alkenyl, one or more R 2b Substituted C 2-6 Alkynyl, one or more R 2c a substituted 3- to 8-membered cycloalkyl or 5- to 10-membered heteroaryl group; the number of heteroatoms in the 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and each heteroatom is independently selected from N, O, and S; when there are multiple substituents, they may be the same or different; Or, when R 2 H or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced R 2a 、R 2b and R 2c are each independently halogen, -N(R 6 ) 2, 3 to 8-membered cycloalkyl or 5 to 10-membered heteroaryl; the number of heteroatoms in the 5 to 10-membered heteroaryl is independently 1, 2 or 3, and the heteroatoms are each independently selected from N, O and S; R 3 and R 4 Each independently is hydrogen or -(CH2)m-OP(=O)(OR 3c )2; Each R 3c are independently hydrogen; m is 1; R 4a is H; Y, Z 1a 、Z 1c 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-; Each R 6 independently H; L and U 1b For chemical bonds or C 1-3 alkylene; (4)X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ; R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5~10 yuan for miscellaneous items 5- to 10-membered heteroaryl and -Z in aryl 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-NH-C(=O)-, 4- to 10-membered heterocyclic group, 4- to 10-membered heterocyclic group substituted with halogen, -NH2 or -OH; R 2 For halogen, cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 2j Substituted C 2-6 Alkynyl, 3-8 membered cycloalkyl or one or more R 2k substituted 3- to 8-membered cycloalkyl; R 2g 、R 2j , and R 2k are independently deuterium, halogen, C 1-6 Alkyl or -N(R 6 )2; R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2; R 3a and R 3b are each independently hydrogen or C 1-6 alkyl; Each R 3c are independently hydrogen; R 4a is hydrogen or a 3- to 8-membered cycloalkyl group; Each R 5 independently H; Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-; Each R 6 independently H; L and U 1b Each independently a chemical bond or C 1-3 alkylene; Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H; (5)X 1 and X 2 Each independently is CH; R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. When R 2 H or deuterated C 1-6 When alkyl, R 1 For at least two R 1d Substituted 5- to 10-membered heteroaryl, wherein at least one R 1d Independently -Z 1a -C 1-6 Alkyl, at least one R 1d Independently by one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently cyano, halogen, C 1-6 Alkyl or -Z 1e -Halogenated C 1-6 alkyl; R 3 and R 4 are each independently hydrogen; R 4a is H; Y, Z 1a and Z 1e Each independently is a chemical bond or -NR 6 -; R 6 is H; L is a chemical bond; (6)X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ; R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl, -Z 1d -5- to 10-membered heteroaryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d -5- to 10-membered heteroaryl and -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently deuterium, cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)- or 4- to 10-membered heterocyclic group; R 2 For cyano, C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3- to 8-membered cycloalkyl; when there are multiple substituents, they may be the same or different; R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen, -C(=O)-O-CH(R 3a )-OC(O)-R 3b or -(CH2)m-OP(=O)(OR 3c )2; R 3a and R 3b are each independently hydrogen or C 1-6 alkyl; Each R 3c are independently hydrogen; R 4a is hydrogen; Each R 5 independently H; Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -, -O- or -C(=O)-; R 6 is H; L and U 1b Each is independently a chemical bond; Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H; (7)X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 ; R 1 For one or more R 1d substituted 5-10 membered heteroaryl; said substituted one or more R 1d The number of heteroatoms in the 5- to 10-membered heteroaryl group of the substituted 5- to 10-membered heteroaryl group is independently 1, 2, or 3, and the heteroatoms are independently selected from N, O, and S. When there are multiple substituents, they may be the same or different. Each R 1d Independently -Z 1a -C 1-6 Alkyl, -Z 1c -C 6-10 Aryl or -Z 1d -11 to 20-membered heteroaryl, wherein the -Z 1a -C 1-6 C in the alkyl group 1-6 Alkyl, -Z 1c -C 6-10 C in aromatic groups 6-10 Aryl and -Z 1d -11-20 membered heteroaryl groups in the 11-20 membered heteroaryl group are each optionally substituted with one or more R 1-a Substitution; said -Z 1d - the number of heteroatoms in the 11- to 20-membered heteroaryl group is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S; when there are multiple substituents, they may be the same or different; Each R 1-a are independently cyano, halogen, oxo, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, 4 to 10 -membered heterocyclic group, 4- to 10-membered heterocyclic group substituted by halogen, -NH2 or -OH; R 2 For one or more R 2g Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 2g independently for deuterium; R 3 and R 4 are each independently hydrogen; R 4a is hydrogen; Each R 5 independently H; Y, Z 1a 、Z 1c 、Z 1d 、Z 1e and Z 1f Each independently represents a chemical bond, -NR 6 -or-O-; R 6 is H; L and U 1b Each is independently a chemical bond.

13. The compound of formula I according to claim 1 or 2, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by Formula I, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by Formula IIIa, Formula IIIb, Formula IIIc, or Formula IIId, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, (1) In formula III-a, each R 1-a are independently deuterium, cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 Halogenated C 1-6 Alkoxy; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond; Z 1f -O-; L and U 1b are independently chemical bonds; n is 2, 3, 4 or 5; For example, each R 1-a are independently cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 Halogenated C 1-6 Alkoxy; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond; Z 1f -O-; L and U 1b are independently chemical bonds; n is 4; (2) in formula III-b, each R 1-a Independently C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 H, C 1-6 Alkyl or deuterated C 1- 6 alkyl; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently chemical bonds; L and U 1b independently a chemical bond; For example, each R 1-a Independently C 1-6 Alkyl; R 2 H; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond; L is a chemical bond; (3) In formula III-c, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently deuterium, cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond; Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H; For example, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently cyano, halogen or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond; Alternatively, Y is -NR 6 -, where R 6 When H and L are chemical bonds, R 2 is H; (4) In formula III-d, R 1d for By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1- 6-alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, or one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently chemical bonds; L and U 1b independently a chemical bond; For example, R 1d For one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently cyano, oxo, halogen, C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1f is a chemical bond; L and U 1b are independently chemical bonds.

14. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, wherein: The compound of formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt satisfies any one of the following conditions: (1) The compound of formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is as shown in formula The compound represented by III-c, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, Among them, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently deuterium, cyano, halogen, 4- to 10-membered heterocyclic group, halogen-substituted 4- to 10-membered heterocyclic group, or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond; Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H; For example, R 1d -Z 1c -C 6-10 Aryl, wherein the -Z 1c -C 6-10 C in aromatic groups 6-10 The aryl group is optionally substituted with one or more R 1-a Replacement; each R 1-a are independently cyano, halogen, 4- to 10-membered heterocyclic group, halogen-substituted 4- to 10-membered heterocyclic group, or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 C 1-6 Alkyl, one or more R 2g Substituted C 1-6 Alkyl or 3-8 membered cycloalkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond, -NR 6 -or-O-,R 6 H; Z 1c is a chemical bond; Z 1f -O-; L and U 1b independently a chemical bond; Alternatively, Y is -NR 6 -, where R 6 When H and L are chemical bonds, R 2 is H; (2) The compound of formula I, its stereoisomer, its tautomer or its pharmaceutically acceptable salt is a compound of formula IIId, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, Among them, R 1d for By one or more R 1-a Replaced or by one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group or -OH; R 2 C 1-6 Alkyl, or one or more R 2g Substituted C 1-6 Alkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b independently a chemical bond; For example, R 1d for By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, deuterated C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-OC(=O)-, 4-10 membered heterocyclic group or -OH; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g are independently deuterium or halogen; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is a chemical bond or -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b independently a chemical bond; For example, R 1d For one or more R 1-a Replaced By one or more R 1-a Replaced By one or more R 1-a Replaced or by one or more R 1-a Replaced Each R 1-a are independently deuterium, cyano, oxo, halogen, C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl, -Z 1f -U 1b -3 to 8-membered cycloalkyl, C 1-6 Alkyl-OC(=O)- or C 1-6 Alkyl-SO2-; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1e and Z 1f are independently a chemical bond or -C(=O)-; L and U 1b independently a chemical bond; (3) The compound represented by formula I is a compound represented by formula III-e-1 or formula III-e-2, Among them, each R 1-a are independently cyano, halogen, -Z 1f -U 1b -3- to 8-membered cycloalkyl, 4- to 10-membered heterocyclic group, or halogen-substituted 4- to 10-membered heterocyclic group; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1f -O-; L and U 1b are independently chemical bonds; n is 4; (4) The compound shown in formula I is a compound shown in formula III-f-1 or formula III-f-2, in, Indicates a single bond or a double bond; when When representing a double bond, W is CR 1-a ;when When it represents a single bond, W is C=O, CH2 or NR 1-a ; Each R 1-a Independently C 1-6 Alkyl, -Z 1e -Halogenated C 1-6 Alkyl or -Z 1f -U 1b -3 to 8-membered cycloalkyl; R 2 For one or more R 2g Pick Generation C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H or a 3- to 8-membered cycloalkyl group; Y is -NR 6 -, where R 6 H; Z 1e and Z 1f are independently chemical bonds; L and U 1b independently a chemical bond; For example, each R 1-a Independently C 1-6 Alkyl or -Z 1e -Halogenated C 1-6 Alkyl; R 2 For one or more R 2g Substituted C 1-6 Alkyl; each R 2g independently deuterium; R 3 and R 4 are each independently hydrogen; R 4a is H; Y is -NR 6 -, where R 6 H; Z 1e and L are independently a chemical bond.

15. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1)X 1 and X 2 are each independently CH or N; (2)R 1 for (3) When X 1 and X 2 When each is independently CH, R 2 for (4) When X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2 For H, F, Cl, -CF3, -CH2CF3, (5)R 3 For H, (6)R 4 H or (7)R 4a H or (8) Y is a chemical bond or -O-; (9) L is a chemical bond or C 1-3 alkylene; (10) Each R 5 are independently H.

16. The compound of formula I according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The compound of formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1)R 1 for (2) When X 1 CR 5 And X 2 N or X 1 N and X 2 CR 5 When R 2 For triazole, pyrazolyl, -CH3, cyano, -CH2CHF2, -CH2CD3, -CD2CD3 or -CD2CH3; Alternatively, Y is -NR 6 -, R 6 When H and L are chemical bonds, R 2 is H; (3) Y is -NR 6 -, where R 6 For H.

17. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, wherein: R 1 for 18. The compound of formula I according to claim 1, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, wherein: The compound shown in formula I is selected from any of the following structures:

19. A pharmaceutical composition comprising the compound of formula I according to any one of claims 1 to 18, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, and at least one pharmaceutical excipient.

20. Use of the compound of formula I according to any one of claims 1 to 18, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 19 in the preparation of a PRMT5 inhibitor, for example, in the preparation of a PRMT5·MTA inhibitor.

21. Use of the compound of formula I according to any one of claims 1 to 18, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament, for example, in the preparation of a medicament for treating and / or preventing cancer.

22. The use according to claim 21, characterized in that The application meets one or more of the following conditions: (1) The cancer is an MTAP-related / mediated cancer, preferably, the MTAP-related / mediated cancer is head and neck cancer, respiratory system cancer, digestive system cancer, urinary system cancer, bone cancer, gynecological cancer, blood system cancer, melanoma or skin cancer, more preferably lymphoma, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, leukemia, glioblastoma, prostate cancer or ovarian cancer; (2) The compound of Formula I, its stereoisomers, its tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition is in a therapeutically effective amount.

23. A compound as shown below,

Images