PRMT5 inhibitor as well as preparation method and application thereof

Abstract

The invention discloses a PRMT5 inhibitor as well as a preparation method and application thereof. The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof, and application of the compound or the pharmaceutically acceptable salt in preparation of drugs for treating and / or preventing cancers, and the cancers can be MTAP related / mediated cancers. The PRMT5 inhibitor provided by the invention has relatively good inhibitory activity or selectivity for human colon cancer to stably knock out MTAP protein cells (HCT-116-MTAP-KO-1A2), can inhibit the proliferation of tumor cells, and shows good pharmacokinetic properties. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2023110361715 filed on August 16, 2023 and Chinese Patent Application No. 2023113327241 filed on October 13, 2023. This application cites the full text of the above Chinese patent application. 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 carries two terminal nitrogen atoms that can be monomethylated or dimethylated. PRMTs can transfer the methyl group on 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 according to 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 that is 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, ovarian cancer, etc., and is associated with the progression and poor prognosis of most cancers. PRMT5 can also inhibit the transcription of some tumor suppressor genes, including tumorigenicity suppressor factor 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. The MTAP gene is frequently deleted in many human tumors, including 53% of glioblastomas and 26% of pancreatic cancers. It is the most commonly mutated gene in cancer. In addition, MTAP often co-deletes with CDKN2A, a common tumor suppressor gene in the body. The proportion of this co-deletion in tumors can reach 9% to 15%.

[0006] Synthetic lethality refers to the phenomenon that two genes mutate simultaneously, leading to cell death, in which a single gene mutation will not cause cell death. Studies have shown that PRMT5 and MTAP form a pair of synthetic lethal combinations, and inhibition of PRMT5 can lead to synthetic lethal effects in MTAP-deficient tumor cells. MTAP is involved in the metabolism of methylthioadenosine (MTA). In cancer cells with MTAP gene deletion, due to the accumulation of MTA, it will bind to PRMT5 to form a PRMT5·MTA complex. Therefore, PRMT5 inhibitors may become a highly selective treatment for patients with MTAP deletion 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]

[0009] Although the above-mentioned new PRMT5 inhibitors have entered the clinical trial stage and have made certain progress in this field, they have not yet been approved for treatment. Therefore, it is still necessary 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. 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 to provide a novel PRMT5 inhibitor, its preparation method and use. The PRMT5 inhibitor provided by the present invention has good inhibitory activity or selectivity for human colon cancer stable MTAP protein knockout cells (HCT-116-MTAP-KO-1A2), can inhibit the proliferation of tumor cells, and shows good pharmacokinetic properties.

[0011] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0012]

[0013] R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums;

[0014] R 2 , R 4 and R 6 Each is independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 ,-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C2-C6 alkenyl, substituted by one or more R 2c Substituted C2-C6 alkynyl, substituted by one or more R 2d Substituted 3-7 membered cycloalkyl, 2e Substituted 3-7 membered cycloalkenyl, one or more R 2f substituted 4-10 membered heterocyclic group, substituted by one or more R 2g Substituted C6-C 10 Aryl or one or more R 2h substituted 5-10 membered heteroaryl;

[0015] Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2hare independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0016] R 3 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 ,-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 3a Substituted C1-C6 alkyl, one or more R 3b Substituted C2-C6 alkenyl, substituted by one or more R 3c Substituted C2-C6 alkynyl, substituted by one or more R 3d Substituted 3-7 membered cycloalkyl, 3e Substituted 3-7 membered cycloalkenyl, one or more R 3f substituted 4-10 membered heterocyclic group, substituted by one or more R3g Substituted C6-C 10 Aryl or one or more R 3h substituted 5-10 membered heteroaryl;

[0017] Each R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0018] R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5a Substituted C1-C6 alkyl, one or more R 5b Substituted C2-C6 alkenyl, substituted by one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5e Substituted 3-7 membered cycloalkenyl, one or more R 5f substituted 4-10 membered heterocyclic group, substituted by one or more R 5g Substituted C6-C 10 Aryl, one or more R 5h Substituted 5-10 membered heteroaryl or -NR 10 R 11 ;

[0019] Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 ,-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-b Substituted C2-C6 alkenyl, substituted by one or more R 5-c Substituted C2-C6 alkynyl, substituted by one or more R 5-d Substituted 3-7 membered cycloalkyl, 5-e Substituted 3-7 membered cycloalkenyl, one or more R 5-f substituted 4-10 membered heterocyclic group, substituted by one or more R 5-g Substituted C6-C 10 Aryl or one or more R 5-h substituted 5-10 membered heteroaryl;

[0020] Each R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g and R 5-h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano;

[0021] R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 7a Substituted C1-C6 alkyl, one or more R 7b Substituted C2-C6 alkenyl, substituted by one or more R 7c Substituted C2-C6 alkynyl, substituted by one or more R 7d Substituted 3-7 membered cycloalkyl, 7e Substituted 3-7 membered cycloalkenyl, one or more R 7f substituted 4-10 membered heterocyclic group, substituted by one or more R 7g Substituted C6-C 10 Aryl or one or more R 7h substituted 5-10 membered heteroaryl;

[0022] Each R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0023] R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 , by one or more R 8a Substituted C1-C6 alkyl, one or more R 8bSubstituted C2-C6 alkenyl, substituted by one or more R 8c Substituted C2-C6 alkynyl, substituted by one or more R 8d Substituted 3-7 membered cycloalkyl, 8e Substituted 3-7 membered cycloalkenyl, one or more R 8f substituted 4-10 membered heterocyclic group, substituted by one or more R 8g Substituted C6-C 10 Aryl or one or more R 8h substituted 5-10 membered heteroaryl;

[0024] Each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g and R 8h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 , C1-C6 alkyl or 3-7 membered cycloalkyl;

[0025] R 9 for hydrogen, deuterium, -C(=O)-O-CH(R 9a )-OC(O)-R 9b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2) m -OP(=O)(OR 9c )2;

[0026] R 9a and R 9b are each independently hydrogen, deuterium or C 1-20 alkyl;

[0027] Each R 9c are each independently hydrogen, deuterium or C 1-20 alkyl;

[0028] R 10 and R 11 Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 10a Substituted C1-C6 alkyl, one or more R 10b Substituted C2-C6 alkenyl, substituted by one or more R 10cSubstituted C2-C6 alkynyl, substituted by one or more R 10d Substituted 3-7 membered cycloalkyl, 10e Substituted 3-7 membered cycloalkenyl, one or more R 10f substituted 4-10 membered heterocyclic group, substituted by one or more R 10g Substituted C6-C 10 Aryl or one or more R 10h substituted 5-10 membered heteroaryl;

[0029] Each R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g and R 10h Each is independently deuterium, halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0030] R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 12a Substituted C1-C6 alkyl, one or more R 12b Substituted C2-C6 alkenyl, substituted by one or more R 12c Substituted C2-C6 alkynyl, substituted by one or more R 12d Substituted 3-7 membered cycloalkyl, 12e Substituted 3-7 membered cycloalkenyl, one or more R 12f substituted 4-10 membered heterocyclic group, substituted by one or more R 12g Substituted C6-C 10 Aryl or one or more R 12h substituted 5-10 membered heteroaryl;

[0031] Each R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g and R 12hEach is independently halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O-, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl;

[0032] n is 1 or 2;

[0033] m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0034] The heteroatoms in the 5-10 membered heteroaryl and the 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0035] And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: R 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl.

[0036] In certain preferred embodiments of the present invention, certain groups in the compound as shown in Formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any scheme of the present application (referred to as "in certain preferred embodiments of the present invention").

[0037] In certain preferred embodiments of the present invention, the compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0038]

[0039] R 1 is a C1-C6 alkyl group substituted by one or more deuteriums;

[0040] R 2 , R 4 and R 6 Each is independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 ,-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C2-C6 alkenyl, substituted by one or more R 2c Substituted C2-C6 alkynyl, substituted by one or more R 2d Substituted 3-7 membered cycloalkyl, 2e Substituted 3-7 membered cycloalkenyl, one or more R 2f substituted 4-10 membered heterocyclic group, substituted by one or more R 2g Substituted C6-C 10 Aryl or one or more R 2h substituted 5-10 membered heteroaryl;

[0041] Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0042] R 3is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 3a Substituted C1-C6 alkyl, one or more R 3b Substituted C2-C6 alkenyl, substituted by one or more R 3c Substituted C2-C6 alkynyl, substituted by one or more R 3d Substituted 3-7 membered cycloalkyl, 3e Substituted 3-7 membered cycloalkenyl, one or more R 3f substituted 4-10 membered heterocyclic group, substituted by one or more R 3g Substituted C6-C 10 Aryl or one or more R 3h substituted 5-10 membered heteroaryl;

[0043] Each R 3a , R 3b , R 3c, R 3d , R 3e , R 3f , R 3g and R 3h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0044] R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5a Substituted C1-C6 alkyl, one or more R 5b Substituted C2-C6 alkenyl, substituted by one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5e Substituted 3-7 membered cycloalkenyl, one or more R 5f substituted 4-10 membered heterocyclic group, substituted by one or more R 5g Substituted C6-C 10 Aryl, one or more R 5h Substituted 5-10 membered heteroaryl or -NR 10 R 11 ;

[0045] Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-b Substituted C2-C6 alkenyl, substituted by one or more R 5-c Substituted C2-C6 alkynyl, substituted by one or more R 5-d Substituted 3-7 membered cycloalkyl, 5-e Substituted 3-7 membered cycloalkenyl, one or more R 5-f substituted 4-10 membered heterocyclic group, substituted by one or more R 5-g Substituted C6-C 10 Aryl or one or more R 5-h substituted 5-10 membered heteroaryl;

[0046] Each R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g and R 5-h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano;

[0047] R 7is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 7a Substituted C1-C6 alkyl, one or more R 7b Substituted C2-C6 alkenyl, substituted by one or more R 7c Substituted C2-C6 alkynyl, substituted by one or more R 7d Substituted 3-7 membered cycloalkyl, 7e Substituted 3-7 membered cycloalkenyl, one or more R 7f substituted 4-10 membered heterocyclic group, substituted by one or more R 7g Substituted C6-C 10 Aryl or one or more R 7h substituted 5-10 membered heteroaryl;

[0048] Each R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0049] R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 , by one or more R 8a Substituted C1-C6 alkyl, one or more R 8b Substituted C2-C6 alkenyl, substituted by one or more R 8c Substituted C2-C6 alkynyl, substituted by one or more R 8d Substituted 3-7 membered cycloalkyl, 8e Substituted 3-7 membered cycloalkenyl, one or more R 8fsubstituted 4-10 membered heterocyclic group, substituted by one or more R 8g Substituted C6-C 10 Aryl or one or more R 8h substituted 5-10 membered heteroaryl;

[0050] Each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g and R 8h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 , C1-C6 alkyl or 3-7 membered cycloalkyl;

[0051] R 9 for hydrogen, deuterium, -C(=O)-O-CH(R 9a )-OC(O)-R 9b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2) m -OP(=O)(OR 9c )2;

[0052] R 9a and R 9b are each independently hydrogen, deuterium or C 1-20 alkyl;

[0053] Each R 9c are each independently hydrogen, deuterium or C 1-20 alkyl;

[0054] R 10 and R 11 Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 10a Substituted C1-C6 alkyl, one or more R 10b Substituted C2-C6 alkenyl, substituted by one or more R 10c Substituted C2-C6 alkynyl, substituted by one or more R 10d Substituted 3-7 membered cycloalkyl, 10e Substituted 3-7 membered cycloalkenyl, one or more R 10f substituted 4-10 membered heterocyclic group, substituted by one or more R 10g Substituted C6-C10 Aryl or one or more R 10h substituted 5-10 membered heteroaryl;

[0055] Each R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g and R 10h Each is independently deuterium, halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl;

[0056] R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 12a Substituted C1-C6 alkyl, one or more R 12b Substituted C2-C6 alkenyl, substituted by one or more R 12c Substituted C2-C6 alkynyl, substituted by one or more R 12d Substituted 3-7 membered cycloalkyl, 12e Substituted 3-7 membered cycloalkenyl, one or more R 12f substituted 4-10 membered heterocyclic group, substituted by one or more R 12g Substituted C6-C 10 Aryl or one or more R 12h substituted 5-10 membered heteroaryl;

[0057] Each R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g and R 12h Each is independently halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O-, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl;

[0058] n is 1 or 2;

[0059] m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0060] The heteroatoms in the 5-10 membered heteroaryl group and the 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0061] In certain preferred embodiments of the present invention, R 1 In the above, the C1-C6 alkyl group substituted by one or more deuteriums may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group.

[0062] In certain preferred embodiments of the present invention, R 1 In the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more deuteriums, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group.

[0063] In certain preferred embodiments of the present invention, R 1-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group.

[0064] In certain preferred embodiments of the present invention, R 6 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0065] In certain preferred embodiments of the present invention, R 3 wherein the 4-10 membered heterocyclic group and the one or more R 3f The 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group may be independently a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl, wherein the 4-10 membered heterocycloalkyl may be a 4-10 membered heterocycloalkyl in which the heteroatom is N and the number of heteroatoms is 1, or a 4-10 membered monocyclic heterocycloalkyl, preferably a 4-6 membered monocyclic heterocycloalkyl, more preferably Further optimization

[0066] In certain preferred embodiments of the present invention, each R 3f In the above, the halogen may independently be fluorine, chlorine, bromine or iodine, preferably fluorine.

[0067] In certain preferred embodiments of the present invention, R 5 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example chlorine.

[0068] In certain preferred embodiments of the present invention, R 5 wherein the C2-C6 alkynyl group and the 5cThe C2-C6 alkynyl group in the substituted C2-C6 alkynyl group may independently be a C2-C4 alkynyl group, and may also be an ethynyl group, a propynyl group or a butynyl group, preferably an ethynyl group or a propynyl group.

[0069] In certain preferred embodiments of the present invention, R 5 wherein the 4-10 membered heterocyclic group and the one or more R 5f The 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group may be independently a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl, wherein the 4-10 membered heterocycloalkyl may be a 4-10 membered heterocycloalkyl in which the heteroatom is N and the number of heteroatoms is 1, or a 4-10 membered monocyclic heterocycloalkyl, preferably a 4-6 membered monocyclic heterocycloalkyl, more preferably Further optimization

[0070] In certain preferred embodiments of the present invention, each R 5c In the above, the 3-7 membered cycloalkyl group may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0071] In certain preferred embodiments of the present invention, each R 5c wherein the 4-10 membered heterocyclic group and the one or more R 5-f The 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group may be independently a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl, wherein the 4-10 membered heterocycloalkyl may be a 4-10 membered heterocycloalkyl in which the heteroatom is N and / or O and the number of heteroatoms is 1 or 2, or a 4-10 membered monocyclic heterocycloalkyl, preferably a 4-6 membered monocyclic heterocycloalkyl, more preferably Further optimization

[0072] In certain preferred embodiments of the present invention, each R 5f In the above, the halogen may independently be fluorine, chlorine, bromine or iodine, preferably fluorine.

[0073] In certain preferred embodiments of the present invention, each R 5-f In the above, the C1-C6 alkyl group may independently be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, preferably a methyl group.

[0074] In certain preferred embodiments of the present invention, R 8 In the above, the one or more R 8a The C1-C6 alkyl group in the substituted C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, preferably a methyl group.

[0075] In certain preferred embodiments of the present invention, each R 8a In the above, the halogen may independently be fluorine, chlorine, bromine or iodine, preferably fluorine.

[0076] In certain preferred embodiments of the present invention, R 10 and R 11 wherein the C1-C6 alkyl group and the 10a The C1-C6 alkyl group in the substituted C1-C6 alkyl group may independently be a C1-C4 alkyl group, and may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example a methyl group.

[0077] In certain preferred embodiments of the present invention, R 12 wherein the 3-7 membered cycloalkyl group and the one or more R 12d The 3- to 7-membered cycloalkyl in the substituted 3- to 7-membered cycloalkyl may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0078] In certain preferred embodiments of the present invention, R 12-1 In the above, the one or more R 12d The 3- to 7-membered cycloalkyl in the substituted 3- to 7-membered cycloalkyl may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0079] In certain preferred embodiments of the present invention, each R 12d In the above, the C1-C6 alkyl group may independently be a C1-C4 alkyl group, and may also be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group.

[0080] In certain preferred embodiments of the present invention, each C1-C6 alkyl group may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

[0081] In certain preferred embodiments of the invention, each halogen may independently be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0082] In certain preferred embodiments of the present invention, each C2-C6 alkenyl group may independently be ethenyl, propenyl, butenyl or pentenyl.

[0083] In certain preferred embodiments of the present invention, each C2-C6 alkynyl group may independently be ethynyl, propynyl, butynyl or pentynyl, for example ethynyl or propynyl.

[0084] In certain preferred embodiments of the present invention, each 3-7 membered cycloalkyl group may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl.

[0085] In certain preferred embodiments of the present invention, each 3-7 membered cycloalkenyl group may independently be a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group.

[0086] In certain preferred embodiments of the present invention, each 4-10 membered heterocyclic group may independently be a saturated or unsaturated heterocyclic group, such as a saturated heterocycloalkyl group.

[0087] In certain preferred embodiments of the present invention, each 4-10 membered heterocyclic group may independently be a monocyclic heterocyclic group or a bicyclic heterocyclic group, and the bicyclic heterocyclic group may be a spirocyclic group, a bridged ring or a fused ring.

[0088] In certain preferred embodiments of the present invention, each 4-10 membered heterocyclic group may independently be a 4-6 membered monocyclic heterocyclic group or a 7-10 membered bicyclic heterocyclic group. For example

[0089] In certain preferred embodiments of the present invention, the heteroatom in each 4-10 membered heterocyclic group may independently be N and / or O, and the number of heteroatoms may independently be 1 or 2.

[0090] In certain preferred embodiments of the present invention, each C6-C 10 Aryl groups may independently be phenyl or naphthyl.

[0091] In certain preferred embodiments of the present invention, each 5-10 membered heteroaryl group may independently be a 5-6 membered monocyclic heteroaryl group or an 8-10 membered polycyclic heteroaryl group, wherein the heteroatom species is selected from one or more of N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0092] In certain preferred embodiments of the present invention, each C1-C6 alkyl-O- may independently be methyl-O-, ethyl-O-, n-propyl-O-, isopropyl-O-, n-butyl-O-, tert-butyl-O-, isobutyl-O- or sec-butyl-O-.

[0093] In certain preferred embodiments of the present invention, each -C(=O)-OC 6-10 Aryl groups may independently be -C(=O)-O-phenyl or -C(=O)-O-naphthyl.

[0094] In certain preferred embodiments of the present invention, each -C(=O)-C 1-6 The alkyl group may independently be -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-isopropyl, -C(=O)-n-butyl, -C(=O)-isobutyl, -C(=O)-sec-butyl or -C(=O)-tert-butyl.

[0095] In certain preferred embodiments of the present invention, each C1-C 20 The alkyl group may independently be a C1-C6 alkyl group, and may also be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.

[0096] In certain preferred embodiments of the present invention, the compound as shown in Formula I is a stereoisomer or a mixture thereof, and the stereoisomer may be an enantiomer or a rotation isomer. For example, when it contains one chiral center, the compound as shown in Formula I is an R configuration, an S configuration, or an R, S configuration racemate.

[0097] In certain preferred embodiments of the present invention, R 1 is C1-C6 alkyl, R 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl.

[0098] In certain preferred embodiments of the present invention, R 2 , R 4 and R 6 are each independently hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 OR 12 Preferably, R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano; more preferably, R 2 is cyano, R 4 is hydrogen, R 6 It is a halogen.

[0099] In certain preferred embodiments of the present invention, R 3 is a 4-10 membered heterocyclic group, -NR 10 R 11 、-OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 3 is a 4-10 membered heterocyclic group, -OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3fThe heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; for example, R 3 For-OR 12 .

[0100] In certain preferred embodiments of the present invention, each R 3f are independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; preferably, each R 3f are independently halogen.

[0101] In certain preferred embodiments of the present invention, R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, or one or more R 5a Substituted C1-C6 alkyl, one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group, or one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; for example, R 5 It is a halogen.

[0102] In certain preferred embodiments of the present invention, R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, or one or more R 5a Substituted C1-C6 alkyl, one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5dSubstituted 3-7 membered cycloalkyl, 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group, or one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; preferably, R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group or is replaced by one or more R 5c The substituted C2-C6 alkynyl group, wherein the heteroatoms in the 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; for example, R 5 It is a halogen.

[0103] In certain preferred embodiments of the present invention, each R 5a , R 5c , R 5d and R 5f Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 、-OR 12 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-d substituted 3-7 membered cycloalkyl or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, each R 5c and R 5f Each is independently halogen, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; more preferably, each R 5c are independently 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, -NR 10 R 11 or one or more R 5-f Substituted 4-10 membered heterocyclic group, each R 5f are independently halogen, the 4-10 membered heterocyclic group and the one or more R 5-f The heteroatoms in the 4-10-membered heterocyclic group in the substituted 4-10-membered heterocyclic group are independently selected from N and / or O, and the number of the heteroatoms is independently 1 or 2.

[0104] In certain preferred embodiments of the present invention, each R 5a , R 5c , R 5d and R 5f Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 、-OR 12 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-d substituted 3-7 membered cycloalkyl or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, each R 5c and R 5f Each is independently halogen, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; more preferably, each R 5c are independently 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, -NR 10 R 11 or one or more R5-f Substituted 4-10 membered heterocyclic group, each R 5f are independently halogen, the 4-10 membered heterocyclic group and the one or more R 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; further preferably, each R 5c Each is independently a 4-10 membered heterocyclic group, the heteroatoms in the 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2.

[0105] In certain preferred embodiments of the present invention, each R 5-a , R 5-d and R 5-f are each independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl or C1-C6 alkyl substituted by one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano; preferably, each R 5-f are independently C1-C6 alkyl.

[0106] In certain preferred embodiments of the present invention, R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; preferably, R 7 For hydrogen.

[0107] In certain preferred embodiments of the present invention, R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, -NR 10 R 11 、-OR 12 or one or more R 8a Substituted C1-C6 alkyl; preferably, R 8 For cyano, -NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl, such as R 8 For-NR 10 R 11 .

[0108] In certain preferred embodiments of the present invention, each R 8a are independently deuterium, halogen, cyano, -NR 10 R 11 or C1-C6 alkyl; preferably, each R 8aare independently halogen.

[0109] In certain preferred embodiments of the present invention, R 9 is hydrogen, -C(=O)-O-CH(R 9a )-OC(O)-R 9b or -(CH2) m -OP(=O)(OR 9c )2; preferably, R 9 For hydrogen.

[0110] In certain preferred embodiments of the present invention, R 9a and R 9b are independently hydrogen or C 1-20 alkyl.

[0111] In certain preferred embodiments of the present invention, each R 9c are independently hydrogen or C 1-20 alkyl.

[0112] In certain preferred embodiments of the present invention, R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; for example, R 10 and R 11 are independently hydrogen or replaced by one or more R 10a Substituted C1-C6 alkyl.

[0113] In certain preferred embodiments of the present invention, each R 10a are independently deuterium, halogen, cyano, -OH, -NH2 or C1-C6 alkyl; preferably, each R 10a Independently for deuterium.

[0114] In certain preferred embodiments of the present invention, R 12 is a C1-C6 alkyl group, a 3-7 membered cycloalkyl group, a 4-10 membered heterocyclic group, or a 12a Substituted C1-C6 alkyl, one or more R 12d substituted 3-7 membered cycloalkyl or one or more R 12f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 12f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl.

[0115] In certain preferred embodiments of the present invention, each R 12a , R 12d and R 12f Each is independently halogen, -OH, -NH2, C1-C6 alkyl or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl; preferably, each R 12d are independently C1-C6 alkyl.

[0116] In certain preferred embodiments of the present invention, n is 1.

[0117] In certain preferred embodiments of the present invention, R 8 It is deuterium or a deuterated group.

[0118] In certain preferred embodiments of the present invention, the compound as shown in Formula I or a pharmaceutically acceptable salt thereof has an inhibitory activity against proliferation of human colon cancer stable MTAP protein knockout cells HCT-116-MTAP-KO-1A2 of IC 50 <25nM.

[0119] In certain preferred embodiments of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof has a selectivity of >20 for inhibiting proliferation of human colon cancer cells HCT-116-MTAP-KO-1A2 with stable knockout of MTAP protein.

[0120] In certain preferred embodiments of the present invention,

[0121] R 1 is a C1-C6 alkyl group substituted by one or more deuteriums;

[0122] R 2 , R 4 and R 6 are each independently hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 OR 12 ;

[0123] R 3 is a 4-10 membered heterocyclic group, -NR 10 R 11 、-OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0124] Each R 3f are independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 or C1-C6 alkyl;

[0125] R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, or one or more R 5a Substituted C1-C6 alkyl, one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0126] Each R 5a , R 5c , R 5d and R 5f Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 、-OR 12 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-d substituted 3-7 membered cycloalkyl or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0127] Each R 5-a , R 5-d and R 5-f are each independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl or C1-C6 alkyl substituted by one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano;

[0128] R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 or C1-C6 alkyl;

[0129] R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, -NR 10 R 11 、-OR 12 or one or more R 8a Substituted C1-C6 alkyl;

[0130] Each R 8a are independently deuterium, halogen, cyano, -NR 10 R 11 or C1-C6 alkyl;

[0131] R 9 is hydrogen, -C(=O)-O-CH(R 9a )-OC(O)-R 9b or -(CH2) m -OP(=O)(OR 9c )2;

[0132] R 9a and R 9b are independently hydrogen or C 1-20 alkyl;

[0133] Each R 9c are independently hydrogen or C 1-20 alkyl;

[0134] R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl;

[0135] Each R 10a are independently deuterium, halogen, cyano, -OH, -NH2 or C1-C6 alkyl;

[0136] R 12 is a C1-C6 alkyl group, a 3-7 membered cycloalkyl group, a 4-10 membered heterocyclic group, or a 12a Substituted C1-C6 alkyl, one or more R 12d substituted 3-7 membered cycloalkyl or one or more R 12f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 12fThe heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0137] Each R 12a , R 12d and R 12f Each is independently halogen, -OH, -NH2, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl;

[0138] n is 1 or 2;

[0139] m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0140] In certain preferred embodiments of the present invention,

[0141] R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums;

[0142] R 2 , R 4 and R 6 are each independently hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 OR 12 ;

[0143] R 3 is a 4-10 membered heterocyclic group, -NR 10 R 11 、-OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0144] Each R 3f are independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 or C1-C6 alkyl;

[0145] R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, or one or more R 5a Substituted C1-C6 alkyl, one or more R 5cSubstituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0146] Each R 5a , R 5c , R 5d and R 5f Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 、-OR 12 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-d substituted 3-7 membered cycloalkyl or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0147] Each R 5-a , R 5-d and R 5-f are each independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl or C1-C6 alkyl substituted by one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano;

[0148] R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 or C1-C6 alkyl;

[0149] R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, -NR 10 R 11 、-OR 12 or one or more R 8a Substituted C1-C6 alkyl;

[0150] Each R 8a are independently deuterium, halogen, cyano, -NR 10 R 11 or C1-C6 alkyl;

[0151] R 9 is hydrogen, -C(=O)-O-CH(R 9a )-OC(O)-R 9b or -(CH2) m -OP(=O)(OR 9c )2;

[0152] R 9a and R 9b are independently hydrogen or C 1-20 alkyl;

[0153] Each R 9c are independently hydrogen or C 1-20 alkyl;

[0154] R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl;

[0155] Each R 10a are independently deuterium, halogen, cyano, -OH, -NH2 or C1-C6 alkyl;

[0156] R 12 is a C1-C6 alkyl group, a 3-7 membered cycloalkyl group, a 4-10 membered heterocyclic group, or a 12a Substituted C1-C6 alkyl, one or more R 12d substituted 3-7 membered cycloalkyl or one or more R 12f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 12f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0157] Each R 12a , R 12d and R 12f Each is independently halogen, -OH, -NH2, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl;

[0158] n is 1 or 2;

[0159] m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0160] And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: R 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl.

[0161] In certain preferred embodiments of the present invention,

[0162] R 1 is a C1-C6 alkyl group substituted by one or more deuteriums;

[0163] R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano;

[0164] R 3 is a 4-10 membered heterocyclic group, -OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1;

[0165] Each R 3f are independently halogen;

[0166] R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group, or one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1;

[0167] Each R 5c and R 5f Each is independently halogen, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-fThe heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2;

[0168] Each R 5-f are independently C1-C6 alkyl;

[0169] R 7 is hydrogen;

[0170] R 8 For cyano, -NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl;

[0171] Each R 8a are independently halogen;

[0172] R 9 is hydrogen;

[0173] R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl;

[0174] Each R 10a independently for deuterium;

[0175] R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl;

[0176] Each R 12d are independently C1-C6 alkyl;

[0177] n is 1.

[0178] In certain preferred embodiments of the present invention,

[0179] R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums;

[0180] R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano;

[0181] R 3 is a 4-10 membered heterocyclic group, -OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3fThe heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1;

[0182] Each R 3f are independently halogen;

[0183] R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group, or one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1;

[0184] Each R 5c and R 5f Each is independently halogen, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2;

[0185] Each R 5-f are independently C1-C6 alkyl;

[0186] R 7 is hydrogen;

[0187] R 8 For cyano, -NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl;

[0188] Each R 8a are independently halogen;

[0189] R 9 is hydrogen;

[0190] R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl;

[0191] Each R 10aindependently for deuterium;

[0192] R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl;

[0193] Each R 12d are independently C1-C6 alkyl;

[0194] n is 1;

[0195] And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: R 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl.

[0196] In certain preferred embodiments of the present invention,

[0197] R 1 is a C1-C6 alkyl group substituted by one or more deuterium groups (e.g. -CD3);

[0198] R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano;

[0199] R 3 For-OR 12 ;

[0200] R 5 is a halogen;

[0201] R 7 is hydrogen;

[0202] R 8 For-NR 10 R 11 ;

[0203] R 9 is hydrogen;

[0204] R 10 and R 11 are independently hydrogen or replaced by one or more R 10a Substituted C1-C6 alkyl;

[0205] Each R 10a independently for deuterium;

[0206] R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl;

[0207] Each R 12d are independently C1-C6 alkyl;

[0208] n is 1.

[0209] In certain preferred embodiments of the present invention,

[0210] R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums;

[0211] R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano;

[0212] R 3 is a 4-10 membered heterocyclic group or -OR 12 ;

[0213] R 5 is halogen, C2-C6 alkynyl, or is replaced by one or more R 5c Substituted C2-C6 alkynyl or 4-10 membered heterocyclic group;

[0214] Each R 5c are independently 4-10 membered heterocyclyl;

[0215] R 7 is hydrogen;

[0216] R 8 For-NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl;

[0217] Each R 8a are independently halogen;

[0218] R 9 is hydrogen;

[0219] R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl;

[0220] Each R 10a independently for deuterium;

[0221] R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl;

[0222] Each R 12d are independently C1-C6 alkyl;

[0223] n is 1;

[0224] And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: R 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl.

[0225] In certain preferred embodiments of the present invention,

[0226] R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums;

[0227] R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano;

[0228] R 3 is a 4-10 membered heterocyclic group or -OR 12 ;

[0229] R 5 is halogen, C2-C6 alkynyl, or is replaced by one or more R 5c Substituted C2-C6 alkynyl or 4-10 membered heterocyclic group;

[0230] Each R 5c are independently 4-10 membered heterocyclyl;

[0231] R 7 is hydrogen;

[0232] R 8 For-NR 10 R 11 ;

[0233] R 9 is hydrogen;

[0234] R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl;

[0235] Each R 10a independently for deuterium;

[0236] R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl;

[0237] Each R 12dare independently C1-C6 alkyl;

[0238] n is 1;

[0239] And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: R 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl.

[0240] In certain preferred embodiments of the present invention, the compound as shown in Formula I is a compound as shown in Formula I-1, I-2, I-3, I-4, I-5, I-6, I-7 or I-8;

[0241]

[0242] Among them, R 1-1 is a C1-C6 alkyl group;

[0243] R 3-1 For-OR 12-1 ;

[0244] R 12-1 For one or more R 12d Substituted 3-7 membered cycloalkyl.

[0245] In certain preferred embodiments of the present invention, the compound as shown in Formula I is a compound as shown in Formula I-1a, I-1b, I-2a, I-2b, I-3a, I-3b, I-4a, I-4b, I-5a, I-5b, I-6a, I-6b, I-7a, I-7b, I-8a or I-8b;

[0246]

[0247]

[0248] In certain preferred embodiments of the present invention, R 1 For -CD3.

[0249] In certain preferred embodiments of the present invention, R 1 It is -CD3 or -CH3.

[0250] In certain preferred embodiments of the present invention, R 2 It is cyano.

[0251] In certain preferred embodiments of the present invention, R 4 For hydrogen.

[0252] In certain preferred embodiments of the present invention, R6 For fluorine.

[0253] In certain preferred embodiments of the present invention, R 3 for In certain preferred embodiments of the present invention, R 5 For chlorine,

[0254] In certain preferred embodiments of the present invention, R 7 For hydrogen.

[0255] In certain preferred embodiments of the present invention, R 8 It is -NH-CD3, -NH-CH3, -CHF2 or cyano.

[0256] In certain preferred embodiments of the present invention, R 9 For hydrogen.

[0257] In certain preferred embodiments of the present invention, the compound as shown in Formula I is any of the following compounds:

[0258]

[0259]

[0260]

[0261]

[0262] In certain preferred embodiments of the present invention, the compound as shown in Formula I is any of the following compounds:

[0263] The compound that elutes first under the following conditions: HPLC analysis method, chromatographic column ChiralPak IE, HS, 150×4.6mm ID, 5μm; mobile phase: A: n-hexane, B: ethanol containing 0.1% ammonia water; gradient: B accounts for 60% by volume in the mobile phase; preferably, under the conditions, the retention time of the compound that elutes first is: 10.078 minutes;

[0264] The compound that elutes later under the following conditions: HPLC analysis method, chromatographic column ChiralPak IE, HS, 150×4.6mm ID, 5μm; mobile phase: A: n-hexane, B: ethanol containing 0.1% ammonia water; gradient: B accounts for 60% by volume in the mobile phase; preferably, under the conditions, the retention time of the compound that elutes later is: 15.034 minutes;

[0265] The compound that elutes first under the following conditions: SFC analysis method, chromatographic column OD-3 4.6*100mm 3μm column; mobile phase: A: methanol [0.2% NH3 (7mol / L ammonia methanol solution)], B: CO2; gradient: B accounts for 65% by volume in the mobile phase; preferably, under the conditions, the retention time of the compound that elutes first is: 2.024 minutes;

[0266] The compound that elutes later under the following conditions: SFC analysis method, chromatographic column OD-3 4.6*100mm 3μm column; mobile phase: A: methanol [0.2% NH3 (7mol / L ammonia methanol solution)], B: CO2; gradient: B accounts for 65% by volume in the mobile phase; preferably, under the said conditions, the retention time of the compound that elutes later is: 2.540 minutes.

[0267] The present invention also provides a pharmaceutical composition, which comprises the compound as shown in Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0268] The selection of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and can generally be conventional fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers and suspending agents in the art.

[0269] The present invention also provides the use of the compound as shown in Formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a PRMT5 inhibitor, for example, in the preparation of a PRMT5·MTA inhibitor. In the application, the PRMT5 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared as a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PRMT5.

[0270] 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 in which the MTAP (methylthioadenosine phosphorylase) gene is deleted.

[0271] The present invention also provides the use of the compound as shown in Formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a drug, such as the use in the preparation of a drug for treating and / or preventing cancer. The cancer may be a MTAP-related / mediated cancer, preferably, the MTAP-related / mediated cancer is 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), blood system cancer (e.g., leukemia, lymphoma or myeloma) or other types of cancer (e.g., melanoma or skin cancer), more preferably lymphoma, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, leukemia, glioblastoma, prostate cancer or ovarian cancer.

[0272] The present invention also provides a compound as shown in Formula I as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the preparation of a drug, for example, in the preparation of a drug for treating and / or preventing MTAP-related / mediated diseases. 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 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), blood 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.

[0273] The present invention also provides a method for treating and / or preventing MTAP-related / mediated diseases, comprising administering to a patient an effective amount of a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. The MTAP-related / mediated cancer is 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), blood cancer (e.g., leukemia, lymphoma or myeloma) or other types of cancer (e.g., melanoma or skin cancer), more preferably lymphoma, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, leukemia, glioblastoma, prostate cancer or ovarian cancer.

[0274] The present invention also provides a method for treating and / or preventing cancer, comprising administering to a patient an effective amount of a compound as shown in Formula I 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.

[0275] The compound as shown in Formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above can be a therapeutically effective amount.

[0276] The compound of formula I or a pharmaceutically acceptable salt thereof, 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).

[0277] Definition of terms

[0278] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0279] As used herein, the compound shown in Formula I of the present invention may contain one or more chiral centers or chiral axes and exist in different optically active forms. When the compound contains a chiral center, the compound comprises enantiomers. The present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be separated by methods known in the profession, such as methods such as crystallization and chiral chromatography. When the compound shown in Formula I contains more than one chiral center, diastereomers may exist. The present invention includes optically pure specific isomers and mixtures of diastereomers that have been separated. Diastereomers can be separated by methods known in the profession, such as crystallization and chiral chromatography.

[0280] 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 stereoisomer 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 an equal mixture of meso, racemate, atropisomers, and a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof.

[0281] When the compounds described in the present invention contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.

[0282] The compound as shown in Formula I or its pharmaceutically acceptable salt is intended to cover any isotopically labeled (or "radiolabeled") variant of the compound as shown in Formula I or its pharmaceutically acceptable salt. Such a variant can be a compound as shown in Formula I or its pharmaceutically acceptable salt in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually 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.

[0283] 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 vivo; 3 H or 14Compounds containing C isotopes are particularly suitable for this purpose. In addition, the inclusion of isotopes such as deuterium can produce special therapeutic benefits due to the better metabolic stability of the compound, such as extending the half-life in the body or reducing the effective dose required; therefore, 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 by the methods described below and by the methods described in the operating examples, by using corresponding isotopically modified specific reagents and / or starting compounds.

[0284] In this application, "pharmaceutical composition" refers to a preparation comprising a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0285] 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 an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0286] The term "pharmaceutical excipient" or "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations except the active ingredients. Please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition) or Handbook of Pharmaceutical Excipients (Raymond CRowe, 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 ingredients at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredients after the subject receives the composition. The pharmaceutical excipients may 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 ingredients 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.

[0287] The pharmaceutical composition 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.

[0288] When used as a drug, the compound as shown in Formula I or a pharmaceutically acceptable salt thereof can be administered in any form of a pharmaceutical composition. These compositions can be administered 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, oral or parenteral. Oral administration can 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 can be in the form of a single bolus dose, or can be by a continuous infusion pump. Conventional pharmaceutical carriers, water, powders or oily bases, thickeners, etc. may be necessary or required. The pharmaceutical composition of the present invention can also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres).

[0289] 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 leading to or causing 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.

[0290] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0291] The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."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.

[0292] The term "patient" refers to any animal that is about to or has been administered the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. 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, humans, etc., with humans being the most preferred.

[0293] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent 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 can 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.

[0294] 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).

[0295] 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.

[0296] 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 1-4Alkyl 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.

[0297] 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 is 1, 2, 3, 4, 5, 6.

[0298] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0299] The term "substituted by" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

[0300] In general, the term "substituted" or "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

[0301] In various parts of this specification, substituents of compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out 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), C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

[0302] As used herein, the terms "part", "moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0303] When a substituent is listed without indicating the atom through which it is attached to a chemical formula (including but not specifically mentioned compounds), such a substituent may be bonded via any atom thereof. Combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0304] When any variable (such as R 2a ) appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. 2a group-substituted, that is, the group may be replaced by up to 3 R 2a Substitution, where one position R 2a Definition and other positions R 2a In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0305] When a group is listed without explicitly indicating 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".

[0306] 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 as 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 linked alkylene group.

[0307] 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 is understood to be C 1-6 Alkylene.

[0308] The term "halogen" refers to fluorine, chlorine, bromine or iodine, in particular to F, Cl or Br.

[0309] In the present application, as a group or a part of other groups (for example, in haloalkyl, deuterated alkyl, etc.), the term "alkyl" refers to a saturated aliphatic hydrocarbon group including branched and straight chains with a specified number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 20 (preferably 1 to 8, more preferably 1 to 6, 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); The butyl group 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); the hexyl group 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 and 2,3-dimethylbutyl). For example, it includes, but is 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 and decyl and the like alkyl groups.

[0310] In the present application, as a group or a part of other groups, the alkyl group in the term "alkyl-O-" is as defined above.

[0311] In the present application, as a group or part of other groups, the term "alkenyl" refers to a straight 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.

[0312] In the present application, as a group or part of other groups, the term "alkynyl" 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, such as but not limited to ethynyl, 1-propynyl, n-propargyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl or pent-1,4-diynyl, etc.

[0313] In the present application, as a group or part of other groups, the term "cycloalkyl" means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) carbocyclic substituent, and it 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 3-7-membered cycloalkyl having 3 to 7 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, etc.

[0314] In the present application, as a group or part of other groups, the term "cycloalkenyl" means a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) non-aromatic carbocyclic substituent with at least one double bond, and which can be connected to the rest of the molecule by a single bond via any suitable carbon atom; such as a 3-15-membered cycloalkenyl with 3 to 15 carbon atoms, preferably a 3-12-membered cycloalkenyl with 3 to 12 carbon atoms, more preferably a 3-7-membered cycloalkenyl with 3 to 7 carbon atoms, and most preferably a 3-6-membered cycloalkenyl with 3 to 6 carbon atoms. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0315] The term "cycloalkyl" means a saturated or unsaturated monocyclic or polycyclic ring, wherein the saturated monocyclic or polycyclic ring is the same as defined in "cycloalkyl", wherein the unsaturated monocyclic or polycyclic ring is a monocyclic or polycyclic ring containing one or more double bonds, and the definition of the monocyclic or polycyclic ring is the same as that of the saturated monocyclic or polycyclic ring.

[0316] In the present application, the term "heterocyclyl", as a group or part of other groups, refers to a stable saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic 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 4-10 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, and most preferably a 4-6 membered monocyclic heterocyclyl, a 7-10 membered bicyclic heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S. When it is a bicyclic, tricyclic or more ring-ring (condensed) heterocyclic radical, it may also include forming a condensed ring (condensed ring) with a cycloalkyl, aryl, heteroaryl as defined herein, provided that the heterocyclic radical is connected to the rest of the molecule via a single bond through any suitable atom in a saturated or partially unsaturated heterocyclic ring. When it is a bicyclic, tricyclic or more ring-ring spiro heterocyclic radical, it may also include forming a spiro ring with a cycloalkyl as defined herein, provided that the heterocyclic radical is connected to the rest of the molecule via a single bond through any suitable atom in a saturated or partially unsaturated heterocyclic ring. In a certain embodiment of the present invention, heterocyclic groups include "heterocycloalkyl", "heterocycloalkenyl", heterocycloalkyl refers to a stable saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridge rings, cyclic (condensed rings) or spirocyclic systems) cyclic group consisting of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S, heterocycloalkenyl refers to a stable partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridge rings, cyclic (condensed rings) or spirocyclic systems) non-aromatic cyclic groups with at least one double bond consisting of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S. For example, the 4-10 membered heterocyclic group includes a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl. In some embodiments, "heterocycloalkyl" is a 4 to 6 membered monocyclic heterocycloalkyl. Exemplary 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl (e.g. ) or isomers and stereoisomers thereof; exemplary 5-membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl (e.g. ), or isomers and stereoisomers thereof. Exemplary 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, morpholinyl (e.g. ), piperazinyl, or isomers and stereoisomers thereof.

[0317] In the present application, as a group or part of other groups, the term "aryl" refers to an aromatic group of a conjugated hydrocarbon ring system consisting of carbon atoms that satisfies the 4n+2 rule, and each ring has aromaticity. In a certain embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6 to 10) carbon atoms. Examples of aryl include, but are not limited to, phenyl or naphthyl.

[0318] In the present application, as a group or part of other groups, the term "heteroaryl" means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and when it is a bicyclic, tricyclic or more ring system (condensed ring), it can also include condensation with a cycloalkyl or heterocyclic group as defined herein, provided that the heteroaryl group is connected to the rest of the molecule through a single bond via an atom on the aromatic ring.

[0319] In the present application, as a group or a part of other groups, the term "deuterated group" means a group formed when hydrogen atoms in the group structure are partially or completely replaced by its isotope deuterium.

[0320] 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.

[0321] It should be understood that as used herein, the singular forms, such as "a," and "an," include plural references unless otherwise specified.

[0322] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0323] Unless otherwise specified, 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.

[0324] 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 cases, standard techniques are used for chemical syntheses and chemical analyses.

[0325] In addition, it should be noted that, unless otherwise explicitly stated, the description method "... independently are" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can independently be the same or different specific groups. In more detail, the description method "... independently are" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

[0326] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0327] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0328] The reagents and raw materials used in the present invention are commercially available.

[0329] The positive and progressive effects of the present invention are: the present invention provides a class of PRMT5 inhibitors, which have good inhibitory activity or selectivity for human colon cancer stable knockout MTAP protein cells (HCT-116-MTAP-KO-1A2), can inhibit the proliferation of tumor cells, and show good pharmacokinetic properties. The compounds of the present invention have significantly better inhibitory activity on the proliferation of human colon cancer stable knockout MTAP protein cells HCT-116-MTAP-KO-1A2 than the control compounds, and the representative compounds of the present invention have better selectivity for human colon cancer stable knockout MTAP protein cells HCT-116-MTAP-KO-1A2 than the control compounds, and the selectivity is >20. DETAILED DESCRIPTION

[0330] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0331] The compound represented by formula I of the present invention can be prepared by various synthetic methods well known to those skilled in the art, without particular limitation. For example, it can be prepared by the following scheme 1 or scheme 2 provided by the present invention. It should be understood that the synthetic method of the compound represented by formula I of the present invention is not limited to this scheme, and those skilled in the art can make conventional substitutions and improvements.

[0332] Option 1:

[0333]

[0334] Scheme 1: The raw material a-1 is dehydrogenated with a strong base lithium diisopropylamide, halogen migration is performed, and then treated with carbon dioxide to obtain the carboxylic acid intermediate a-2, and the intermediate a-2 is then esterified to obtain the intermediate a-3. The intermediate a-3 is subjected to a Stille coupling reaction to obtain the intermediate a-4. The intermediate a-4 is subjected to a substitution reaction or a coupling reaction to obtain the intermediate a-5, and the intermediate a-5 reacts with N-bromosuccinimide to obtain the intermediate a-6. The intermediate a-6 is substituted with potassium acetate to obtain the intermediate a-7. The intermediate a-7 reacts with hydrazine hydrate and closes the ring to obtain the intermediate a-9. The intermediate a-9 is then halogenated to obtain the intermediate a-10, and the intermediate a-10 is then substituted with ammonia water to obtain the intermediate a-11, and finally the intermediate a-11 reacts with di-tert-butyl dicarbonate to obtain the key intermediate a-12.

[0335] The raw material b-1 undergoes substitution or coupling reaction to obtain intermediate b-2. The intermediate b-2 undergoes halogenation and coupling to obtain intermediate b-4. The intermediate b-4 is further halogenated to obtain intermediate b-5. The intermediate b-5 undergoes substitution or coupling reaction to generate intermediate b-6. The intermediate b-6 is coupled to obtain intermediate b-7. The intermediate b-7 and intermediate a-12 undergo Suzuki coupling reaction to obtain intermediate b-8; the intermediate b-8 is deprotected to obtain compound I-4.

[0336] Option 2:

[0337]

[0338] Intermediate b-5 is used as the raw material, and intermediate b-7a is obtained by coupling. Intermediate b-7a and intermediate a-12 are reacted by Suzuki coupling reaction to obtain intermediate b-8a. Intermediate b-8a is further subjected to substitution or coupling reaction to obtain intermediate b-9. Intermediate b-9 is deprotected to obtain compound I-4.

[0339] The following examples illustrate the present invention in more detail, but do not limit the present invention in any way.

[0340] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The nuclear magnetic resonance chemical shift (δ) is given in parts per million (ppm). The nuclear magnetic resonance is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS). The mass spectrum is measured using an Agilent 1260-6125B single quadrupole liquid-mass spectrometer, which uses an electrospray ionization source (ESI).

[0341] For the reversed 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.

[0342] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification used is 0.15mm-0.20mm, and the specification used for preparative thin layer chromatography is 0.4mm-0.5mm.

[0343] Preparative high performance liquid chromatography (preparative HPLC) used an AutoPurification LC preparative system equipped with an ACQUITY QDa mass spectrometer detector produced by Waters. The preparative chromatographic column used was a SunFire C18 5μm 19x250mm OBD preparative column. The mobile phase used different gradients of water (containing 0.1% formic acid)-acetonitrile to elute the compounds.

[0344] The Chinese and English abbreviations are as follows:

[0345] Boc: tert-butyloxycarbonyl; DCM: dichloromethane.

[0346] Synthesis

[0347] Intermediate a1

[0348] [({7-bromo-4-oxo-5-[(trideuterioylmethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl}methyl)amino]methane acid-tert-butyl ester

[0349]

[0350] Step 1: 6-Chloro-2-fluoro-3-iodopyridine

[0351]

[0352] Under argon protection and -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), and the reaction solution was stirred for 2 hours. Then, a solution of iodine (21.23 g, 83.65 mmol) in tetrahydrofuran (100 mL) was added to the reaction solution, and the reaction solution was stirred for 1 hour at -70°C. After the reaction was completed, saturated sodium sulfite (100 mL) was added to the reaction solution to quench the reaction, and the mixed solution was extracted with ethyl acetate (200 mL*3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether = 100%, volume ratio) to obtain a white solid product (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).

[0353] Step 2: 6-Chloro-2-fluoro-4-iodonicotinic acid

[0354]

[0355] Under argon protection and -70℃~-60℃, lithium diisopropylamide (29.96mL, 59.94mmol) was added to a solution of 6-chloro-2-fluoro-3-iodopyridine (14g, 54.74mmol) in tetrahydrofuran (20mL), and the reaction solution was stirred for 2 hours. The reaction system was replaced with a carbon dioxide balloon and continued to stir for 5 hours. After the reaction was completed, water (100mL) was added to the reaction solution, and the reaction system was extracted with ethyl acetate (50mL). The aqueous phase was adjusted to pH 6-7 with dilute hydrochloric acid (2M), and then extracted with ethyl acetate (100mL*3). The organic phase was concentrated to obtain a red solid product (16g, crude product). ESI-MS m / z: 301.9[M+1] + .

[0356] Step 3: 6-Chloro-2-fluoro-4-iodonicotinic acid methyl ester

[0357]

[0358] At 0°C, iodomethane (433 μL, 6.97 mmol) was added 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), and the reaction solution was stirred for 3 hours. After the reaction was completed, water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (ethyl acetate / petroleum ether = 0-2%, volume ratio) to obtain a yellow solid product. (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).

[0359] Step 4: 6-chloro-4-(1-ethoxyvinyl)-2-fluoronicotinate methyl ester

[0360]

[0361] Under argon protection, methyl 6-chloro-2-fluoro-4-iodonicotinate (5g, 15.873mmol), tetrakis(triphenylphosphine)palladium (917mg, 0.7936mmol), bis(triphenylphosphine)palladium dichloride (557.02mg, 0.7936mmol) and tributyl(1-ethoxyethylene)tin (5.732g, 15.873mmol) were stirred at 110°C for 24h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0-3%, volume ratio) to obtain a colorless oily product (3.4g, yield: 82.62%). 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).

[0362] Step 5: 6-bromo-4-(1-ethoxyvinyl)-2-((methyl-d3)amino)nicotinate

[0363]

[0364] Triethylamine (10 mL) and deuterated methylamine hydrochloride (5.82 g, 82.5 mmol) were added to a solution of methyl 6-bromo-4-(1-ethoxyvinyl)-2-fluoronicotinate (5.0 g, 16.5 mmol) in tetrahydrofuran (50 mL), and the mixture was sealed and stirred at 80°C for 1 hour and 15 minutes, cooled to room temperature, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 20:1, volume ratio) to obtain the product as a light yellow oil (5.2 g, yield: 99.0%). ESI-MS m / z: 317.9; 319.9 [M+1] + .

[0365] Step 6: 6-bromo-2-(tert-butyloxycarbonyl)(methyl-d3)amino)-4-(1-ethoxyvinyl)nicotinate

[0366]

[0367] Dissolve 6-bromo-4-(1-ethoxyvinyl)-2-((methyl-d3)amino)nicotinate (5.2 g, 16.3 mmol) in tetrahydrofuran (50 mL), add triethylamine (10 mL), 4-dimethylaminopyridine (4.0 g, 32.6 mmol) and di-tert-butyl dicarbonate (42.8 g, 196.1 mmol), reflux and stir for 1.5 hours under nitrogen atmosphere, cool to room temperature, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product, a yellow oil (5.74 g, yield: 83.9%). ESI-MS m / z: 317.9; 319.9 [M-Boc+1] + . 1 H NMR (400MHz, CDCl3) δ7.43 (s, 1H), 4.50 (d, J = 3.2Hz, 1H), 4.37 (d, J = 3.2Hz, 1H), 3.81 (m, 5H), 1.41 (s, 9H), 1.32 (t, J = 7.0Hz, 3H).

[0368] Step 7: 6-bromo-4-(2-bromoacetyl)-2-(tert-butyloxycarbonyl)(methyl-d3)amino)nicotinate

[0369]

[0370] Dissolve 6-bromo-2-(tert-butyloxycarbonyl)(methyl-d3)amino)-4-(1-ethoxyvinyl)nicotinate (5.74 g, 13.7 mmol) in tetrahydrofuran (75 mL), add water (25 mL) and N-bromosuccinimide (2.44 g, 13.7 mmol), stir at 25°C for 1.5 hours, pour the reaction solution into water, extract with ethyl acetate, wash the organic phase with water three times, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and chromatograph the residue on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product, a yellow oil (6.2 g, yield: 96.3%). ESI-MS m / z: 367.7; 369.7; 371.7 [M-Boc+1] + . 1 H NMR (400MHz, CDCl3) δ7.27(s,1H),4.33(s,2H),3.82(s,3H),1.44(s,9H).

[0371] Step 8: 4-(2-acetoxyacetyl)-6-bromo-2-((tert-butyloxycarbonyl)(methyl-d3)amino)nicotinate

[0372]

[0373] To a solution of potassium acetate (3.9 g, 39.6 mmol) and acetic acid (1.19 mg, 19.8 mmol) in acetonitrile (50 mL), a solution of 6-bromo-4-(2-bromoacetyl)-2-(tert-butyloxycarbonyl)(methyl-d3)amino)nicotinate (6.2 g, 13.2 mmol) dissolved in acetonitrile (50 mL) was added dropwise. After stirring at 25°C for 1.5 hours, the reaction solution was poured into 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 yellow oil (5.92 g, yield: 100.0%). ESI-MS m / z: 347.8; 349.8 [M-Boc+1] + . 1 H NMR (400MHz, CDCl3) δ7.33(s,1H),5.02(s,2H),3.81(s,3H),2.16(s,3H),1.45(s,9H).

[0374] Step 9: tert-Butyl (6-bromo-3-(hydrazinecarbonyl)-4-(2-hydroxyacetyl)pyridin-2-yl)(methyl-d3)carbamate

[0375]

[0376] Dissolve 4-(2-acetoxyacetyl)-6-bromo-2-((tert-butyloxycarbonyl)(methyl-d3)amino)nicotinate (5.92 g, 13.2 mmol) in ethanol (80 mL), add hydrazine hydrate (1.55 g, 26.4 mmol, 85%) dropwise, stir at 25°C for 6 hours, and concentrate under reduced pressure to obtain the product as a yellow solid (5.37 g, yield: 100.0%). ESI-MS m / z: 305.8; 307.8 [M-Boc+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.93 (s, 1H), 7.75 (s, 1H), 4.81 (t, J = 6.3Hz, 1H), 4.40 (s, 2H), 1.34 (s, 9H).

[0377] Step 10: tert-Butyl (7-bromo-1-(hydroxymethyl)-4-oxo-3,4-dihydropyridin[3,4-d]pyridazin-5-yl)(methyl-d3)carbamate

[0378]

[0379] Tert-butyl (6-bromo-3-(hydrazinecarbonyl)-4-(2-hydroxyacetyl)pyridin-2-yl)(methyl-d3)carbamate (5.37 g, 13.2 mmol) was dissolved in toluene (125 mL) and stirred under reflux for 12 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane / methanol = 100:3, volume ratio) to obtain the product as a yellow solid (4.3 g, yield: 83.8%). ESI-MS m / z: 287.9; 289.8 [M-Boc+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.00(s,1H),5.61(t,J=5.8Hz,1H),4.63(d,J=5.6Hz,2H),1.27(s,9H).

[0380] Step 11: {[7-bromo-1-(chloromethyl)-4-oxo-3H-pyrido[4,3-d][1,2]diazin-5-yl](trideuteriomethyl)amino}methane-tert-butyl ester

[0381]

[0382] Dissolve tert-butyl {[7-bromo-1-(hydroxymethyl)-4-oxo-3H-pyridinium[4,3-d][1,2]diazine-5-yl](trideuteriummethyl)amino}formate (2g, 5.15mmol) and thionyl chloride (3.06g, 25.76mmol) in DCM (60mL), then add N,N-dimethylformamide (0.083mL, 1.03mmol) dropwise and stir at room temperature for 1 hour. After the reaction is complete, the reaction solution is concentrated under reduced pressure to obtain a yellow solid (2g, 4.92mmol, yield: 95.47%), which is directly used in the next step. MS m / z: 406[M+1] + .

[0383] Step 12: 7-Bromo-1-(chloromethyl)-5-[(trideuterylmethyl)amino]-3,4-dihydropyrido[4,3-d][1,2]diazin-4-one

[0384]

[0385] Dissolve {[7-bromo-1-(chloromethyl)-4-oxo-3H-pyrido[4,3-d][1,2]diazin-5-yl](trideuteriummethyl)amino}methane acid-tert-butyl ester (2g, 4.92mmol) in DCM (50mL) solution, add trifluoroacetic acid (11.298mL, 147.54mmol) at room temperature, stir at room temperature for 30 minutes after addition. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is chromatographed on a silica gel column (dichloromethane / methanol=10:1, volume ratio) to obtain the product as a yellow solid (1.5g, yield: 99.49%). ESI-MS m / z: 306[M+1] + .

[0386] Step 13: 1-(Aminomethyl)-7-bromo-5-[(trideuterylmethyl)amino]-3,4-dihydropyrido[4,3-d][1,2]diazin-4-one

[0387]

[0388] Dissolve 7-bromo-1-(chloromethyl)-5-[(trideuterylmethyl)amino]-3,4-dihydropyrido[4,3-d][1,2]diazine-4-one (1.5 g, 4.89 mmol) in dichloromethane (50 mL), add dropwise into ammonia-methanol solution (20.970 mL, 7 M) at room temperature, and stir at room temperature for half an hour. After the reaction is complete, concentrate under reduced pressure to obtain a yellow solid residue (1.4 g, 4.88 mmol, yield: 99.65%). ESI-MS m / z: 287 [M+1] + .

[0389] Step 14: [({7-bromo-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl}methyl)amino]methane acid-tert-butyl ester

[0390]

[0391] 1-(Aminomethyl)-7-bromo-5-[(trideuterylmethyl)amino]-3,4-dihydropyrido[4,3-d][1,2]diazine-4-one (1.5 g, 5.22 mmol), di-tert-butyl dicarbonate (1.37 g, 6.27 mmol) and triethylamine (1.089 mL, 7.84 mmol) were dissolved in tetrahydrofuran (40 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane / ethyl acetate = 5:1, volume ratio) to obtain the product as a yellow solid (1.5 g, yield: 75%). ESI-MS m / z: 387 [M+1] + .

[0392] Intermediate a2

[0393] 7-Bromo-1-(hydroxymethyl)-5-(methylamino)-3,4-dihydropyrido[4,3-d][1,2]diazin-4-one

[0394]

[0395] Step 1: 6-bromo-4-(1-ethoxyvinyl)-2-(methylamino)nicotinate

[0396]

[0397] Triethylamine (4 mL) and methylamine hydrochloride (2.67 g, 39.6 mmol) were added to a solution of methyl 6-bromo-4-(1-ethoxyvinyl)-2-fluoronicotinate (1.2 g, 3.96 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at 80°C in a sealed tube for 1 hour and 15 minutes, cooled to room temperature, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 20:1, volume ratio) to obtain the product as a light yellow oil (1.14 g, yield 91.3%). ESI-MS m / z: 314.9 [M+1] + .

[0398] Step 2: 6-bromo-2-((tert-butoxycarbonyl)(methyl)amino)-4-(1-ethoxyvinyl)nicotinate

[0399]

[0400] Triethylamine (5 mL), 4-dimethylaminopyridine (883.8 mg, 7.2 mmol), and di-tert-butyl dicarbonate (9.5 g, 43.4 mmol) were added to a solution of methyl 6-bromo-4-(1-ethoxyvinyl)-2-(methylamino)nicotinate (1.14 g, 3.6 mmol) in tetrahydrofuran (25 mL). The mixture was stirred under reflux for 1.5 hours under a nitrogen atmosphere, cooled to room temperature, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a light yellow oil (1.41 g, yield 94%). ESI-MS m / z: 436.8 [M+Na] + .

[0401] Step 3: 6-bromo-4-(2-bromoacetyl)-2-((tert-butyloxycarbonyl)(methyl)amino)nicotinate

[0402]

[0403] Water (15 mL) and N-bromosuccinimide (604.4 mg, 3.40 mmol) were added to a solution of methyl 6-bromo-2-(tert-butyloxycarbonyl)(methyl)amino)-4-(1-ethoxyvinyl)nicotinate (1.41 g, 3.40 mmol) in tetrahydrofuran (45 mL). After stirring at 25°C for 1.5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water three times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a colorless oil (1.45 g, yield 91.8%). ESI-MS m / z: 486.7 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ7.28(s,1H),4.34(s,2H),3.82(s,3H),3.41(s,3H),1.45(s,9H).

[0404] Step 4: 4-(2-acetoxyacetyl)-6-bromo-2-((tert-butyloxycarbonyl)(methyl)amino)nicotinic acid methyl ester

[0405]

[0406] To a solution of potassium acetate (195.5 mg, 2.00 mmol) and acetic acid (59.9 mg, 1.00 mmol) in acetonitrile (5 mL), a solution of 6-bromo-4-(2-bromoacetyl)-2-((tert-butyloxycarbonyl)(methyl)amino)nicotinate (310 mg, 0.67 mmol) dissolved in acetonitrile (5 mL) was added dropwise. After stirring at 25°C for 1.0 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water three times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product as a yellow oil (296 mg, yield 100.0%). ESI-MS: 466.8 [M+Na] + .

[0407] Step 5: tert-Butyl (6-bromo-3-(hydrazinecarbonyl)-4-(2-hydroxyacetyl)pyridin-2-yl)(methyl)carbamate

[0408]

[0409] Dissolve 4-(2-acetoxyacetyl)-6-bromo-2-((tert-butoxycarbonyl)(methyl)amino)nicotinic acid methyl ester (296 mg, 0.67 mmol) in ethanol (5 mL), add hydrazine hydrate (78.2 mg, 1.33 mmol, 85%) dropwise, stir at 25°C for 6 hours, and concentrate under reduced pressure to obtain the product as a yellow solid (268 mg, yield 100.0%). ESI-MS: 424.8 [M+Na] + .

[0410] Step 6: tert-butyl (7-bromo-1-(hydroxymethyl)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-5-yl)(methyl)carbamate

[0411]

[0412] Dissolve tert-butyl (6-bromo-3-(hydrazinecarbonyl)-4-(2-hydroxyacetyl)pyridin-2-yl)(methyl)carbamate (268 mg, 0.67 mmol) in toluene (15 mL), stir under reflux for 12 hours, cool to room temperature, concentrate under reduced pressure, and chromatograph the residue on a silica gel column (dichloromethane / methanol=100:3, volume ratio) to obtain the product as a yellow solid (160 mg, yield 66.4%). ESI-MS m / z: 406.8 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),8.00(s,1H),5.61(t,J=5.9Hz,1H),4.63(d,J=5.9Hz,2H),3.25(s,3H),1.27(s,9H).

[0413] Step 7: 7-Bromo-1-(hydroxymethyl)-5-(methylamino)-3,4-dihydropyrido[4,3-d][1,2]diazin-4-one

[0414]

[0415] Dissolve tert-butyl (7-bromo-1-(hydroxymethyl)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-5-yl)(methyl)carbamate (100 mg, 0.26 mmol) in dichloromethane (5 mL) and add trifluoroacetic acid (1 mL). The reaction mixture is stirred at room temperature for 2 hours. Evaporate the solvent, alkalize with saturated sodium bicarbonate, extract with dichloromethane, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain the product (66 mg, yield 89%). ESI-MS m / z: 285.1 [M+H] +

[0416] Intermediate b1

[0417] 4-Chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteromethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0418]

[0419] Step 1: 4-Chloro-5-fluoro-2-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0420]

[0421] 1-Methylcyclopropane-1-ol (1.66g, 23.02mmol) was dissolved in dimethylformamide (40mL), nitrogen was protected, the temperature was lowered to 0°C, sodium hydride (1.38g, 34.53mmol) was added, and the reaction was stirred for 1 hour, and 4-chloro-2,5-difluorobenzene-1-carbonitrile (4g, 23.02mmol) was added, and the reaction was kept warm for 3 hours. The reaction solution was quenched with aqueous ammonium chloride solution (15mL), the reaction solution was diluted with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, volume ratio) to obtain a white solid (1.5g, yield: 28.9%). ESI-MS m / z: 226.0 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.34 (dd, J = 7.0, 6.0Hz, 2H), 1.60 (s, 3H), 1.12–1.07 (m, 2H), 0.85–0.80 (m, 2H).

[0422] Step 2: 4-Chloro-3-fluoro-2-iodo-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0423]

[0424] 4-Chloro-5-fluoro-2-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (2g, 8.86mmol) was dissolved in tetrahydrofuran (100mL), nitrogen was protected, the temperature was lowered to -78°C, diisopropylamine lithium (2mol / L, 4.88mL) was added, and the mixture was stirred for 1 hour, and iodine (3.37g, 23.02mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with saturated sodium sulfite aqueous solution (10mL), the reaction solution was diluted with ethyl acetate, the organic phase was washed with water three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was further purified by silica gel column chromatography (petroleum ether / dichloromethane = 9:1, volume ratio) to obtain a compound (2.2g, yield: 72%). ESI-MS m / z: 351.9 [M+1] + . 1 HNMR (400MHz, CDCl3) δ7.34 (d, J = 5.6Hz, 1H), 1.60 (s, 3H), 1.12–1.07 (m, 2H), 0.85–0.81 (m, 2H).

[0425] Step 3: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteromethyl)pyrazole

[0426]

[0427] Pyrazole (3 g, 44.07 mmol) was dissolved in tetrahydrofuran (80 mL), and n-butyl lithium (33.049 mL, 52.88 mmol, 1.6 M) was added under argon atmosphere at 0°C, and stirred for 5 minutes. Deuterated iodomethane (7.03 g, 48.47 mmol) was added, and stirred at 25°C for 15 hours. After cooling to 0°C, n-butyl lithium (33.049 mL, 52.88 mmol, 1.6 M) was added, and the mixture was stirred for 1 hour while keeping warm. After cooling to -78°C, 4,4,5,5-tetramethyl-2-(propane-2-oxy)-1,3,2-dioxaborane (9.84 g, 52.88 mmol) was added, and the mixture was stirred for 1 hour while keeping warm. The mixture was naturally heated to 25°C and stirred for 15 hours. The reaction was quenched with saturated ammonium chloride solution (80 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined and washed once with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oil, which was directly used in the next step. ESI-MS m / z: 212.1 [M+H] + .

[0428] Step 4: 4-Chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[2-(trideuteromethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0429]

[0430] 4-Chloro-3-fluoro-2-iodo-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (300 mg, 0.85 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole (1801.42 mg, 8.53 mmol) were dissolved in 1,4-dioxane (10 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (69.86 mg, 0.09 mmol) and potassium carbonate (235.88 mg, 1.71 mmol) in water (0.5 mL) were added, and stirred at 100° C. for 2 hours under an argon atmosphere. The reaction solution was directly spin-dried and separated by column chromatography (petroleum ether / ethyl acetate = 5:1, volume ratio) to obtain a white solid (200 mg, yield: 75.9%). ESI-MS m / z: 309.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.61(d,J=2.0Hz,1H),7.41(d,J=5.9Hz,1H),6.49(d,J=2.0Hz,1H),1.62(s,3H),1.14–1.09(m,2H),0.87–0.82(m,2H).

[0431] Step 5: 4-Chloro-3-fluoro-2-[4-iodo-2-(trideuteriomethyl)pyrazol-3-yl]-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0432]

[0433] Dissolve 4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile (200 mg, 0.65 mmol) in acetic acid (5 mL), add N-iodosuccinimide (174.89 mg, 0.78 mmol), and stir for 2 hours at 80 ° C under argon atmosphere. The reaction solution was directly spin-dried to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 5:1, volume ratio) to obtain a white solid (220 mg, yield: 78%). ESI-MS m / z: 434.9 [M+H] + .

[0434] Step 6: 4-Chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteromethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0435]

[0436] 4-Chloro-3-fluoro-2-[4-iodo-2-(trideuteriomethyl)pyrazol-3-yl]-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (220 mg, 0.51 mmol) was dissolved in 1,4-dioxane (10 mL), tri(dibenzylideneacetone)dipalladium (46.35 mg, 0.05 mmol), triethylamine (0.352 mL, 2.53 mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (48.26 mg, 0.10 mmol) were added, and pinacol borane (647.78 mg, 5.06 mmol) was added under argon atmosphere, and stirred at 100°C for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 5:1, volume ratio) to obtain a transparent oil (166 mg, yield: 75%). ESI-MS m / z:435.1[M+H] + .

[0437] Intermediate b2

[0438] 4-Chloro-6-(cyclopropyloxy)-3-fluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0439]

[0440] Step 1: 4-Chloro-2-(cyclopropyloxy)-5-fluorobenzene-1-carbonitrile

[0441]

[0442] Dissolve cyclopropanol (10g, 172.18mmol) in tetrahydrofuran (500mL), protect with nitrogen, cool to 0℃, add sodium hydride (7.23g, 180.79mmol), stir and react for 1 hour, add 4-chloro-2,5-difluorobenzene-1-carbonitrile (29.88g, 172.18mmol), and react for 2 hours. The reaction solution was quenched with aqueous ammonium chloride solution (300mL), the reaction solution was diluted with ethyl acetate (500mL), the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, volume ratio) to obtain a white solid (19g, yield: 52.14%). ESI-MSm / z: 212.0[M+1] + .

[0443] Step 2: 4-Chloro-6-(cyclopropyloxy)-3-fluoro-2-iodobenzene-1-carbonitrile

[0444]

[0445] 4-Chloro-2-(cyclopropyloxy)-5-fluorobenzene-1-carbonitrile (19g, 89.78mmol) was dissolved in tetrahydrofuran (300mL), nitrogen was protected, the temperature was lowered to -78°C, diisopropylamine lithium (58.359mL, 116.72mmol) was added, and the mixture was stirred for 1 hour, and iodine (34.18g, 134.68mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with saturated aqueous sodium sulfite solution (100mL), the reaction solution was diluted with ethyl acetate (300mL), the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. A yellow solid (19.2g, yield: 63.36%) was obtained by purification by silica gel column chromatography (petroleum ether / dichloromethane = 9:1, volume ratio). ESI-MS m / z: 337.9 [M+1] + .

[0446] Step 3: 4-Chloro-6-(cyclopropyloxy)-3-fluoro-2-[2-(trideuterylmethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0447]

[0448] Under argon protection, 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (72.76 mg, 0.09 mmol) was added to a solution of 4-chloro-6-(cyclopropyloxy)-3-fluoro-2-iodobenzene-1-carbonitrile (300 mg, 0.89 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuterylmethyl)pyrazole (938.12 mg, 4.44 mmol) and potassium carbonate (368.51 mg, 2.67 mmol) in dioxane (10 mL) and water (1 mL), and the reaction mixture was stirred at 100° C. for 12 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-15% volume ratio gradient elution) to obtain the product as a colorless oil (220 mg, yield: 83.98%). ESI-MS m / z: 295.0 [M+1] + . 1 HNMR (400MHz, CDCl3) δ7.63(d,J=2.0Hz,1H),7.50(d,J=5.8Hz,1H),6.52(d,J=2.0Hz,1H),3.94–3.85(m,1H),0.96(d,J=4.5Hz,4H).

[0449] Step 4: 4-Chloro-6-(cyclopropyloxy)-3-fluoro-2-[4-iodo-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0450]

[0451] N-iodosuccinimide (251.91 mg, 1.12 mmol) was added to a solution of 4-chloro-6-(cyclopropyloxy)-3-fluoro-2-[2-(trideuterylmethyl)pyrazol-3-yl]benzene-1-carbonitrile (220 mg, 0.75 mmol) in acetic acid (10 mL), and the reaction solution was stirred at 80°C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was diluted with saturated sodium chloride (50 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined and washed with saturated sodium sulfite solution (1×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-17% volume ratio gradient elution) to obtain the product as a white solid (300 mg, yield: 95.55%). ESI-MS m / z: 420.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.65 (s, 1H), 7.55 (d, J = 5.8Hz, 1H), 3.93–3.84 (m, 1H), 0.96 (d, J = 4.5Hz, 4H).

[0452] Step 5: 4-Chloro-6-(cyclopropyloxy)-3-fluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0453]

[0454] Under argon protection, tris dibenzylideneacetone dipalladium (65.31 mg, 0.07 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (68.00 mg, 0.14 mmol) and pinacol borane (912.77 mg, 7.13 mmol) were added to a solution of 4-chloro-6-(cyclopropyloxy)-3-fluoro-2-[4-iodo-2-(trideuterylmethyl)pyrazol-3-yl]benzene-1-carbonitrile (150 mg, 0.35 mmol) and triethylamine (0.297 mL, 2.14 mmol) in dioxane (10 mL) and the reaction solution was stirred at 100 ° C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-19% volume ratio gradient elution) to obtain the product as a colorless oil (220 mg, crude product). ESI-MS m / z: 421.1[M+1] + .

[0455] Intermediate b3

[0456] 4-Chloro-3-fluoro-6-(tetrahydro-1H-pyrrol-1-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0457]

[0458] Step 1: 4-Chloro-5-fluoro-2-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0459]

[0460] Tetrahydropyrrole (1.446 mL, 17.29 mmol) was added to a solution of 4-chloro-2,5-difluorobenzene-1-carbonitrile (2 g, 11.52 mmol) and potassium carbonate (3.98 g, 28.81 mmol) in N,N-dimethylformamide (20 mL), and the reaction solution was stirred at 75 ° C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×30 mL). The organic phases were combined and washed with saturated brine (3×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-10% volume ratio gradient elution) to obtain the product as a light green solid (2.5 g, yield: 96.56%) MS m / z: 225.0 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.23 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 6.1 Hz, 1H), 3.62–3.54 (m, 4H), 2.09–2.00 (m, 4H).

[0461] Step 2: 4-Chloro-3-fluoro-2-iodo-6-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0462]

[0463] Under argon protection and -78°C to -60°C, to a solution of 4-chloro-5-fluoro-2-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile (1 g, 4.45 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium diisopropylamide in tetrahydrofuran (2.671 mL, 5.34 mmol), and the reaction solution was stirred at this temperature for 0.5 hour. Then, a solution of iodine (1.36 g, 5.34 mmol) in tetrahydrofuran (5 mL) was added, and the reaction solution was warmed to room temperature and stirred for 0.5 hour. After the reaction was completed, a saturated sodium chloride solution (30 mL) was added to the reaction solution, the mixed solution was extracted with ethyl acetate (30 mL*3), the organic phases were combined and washed with a saturated sodium chloride solution (50 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-10% volume ratio gradient elution) to obtain the product as a light green solid (1.5 g, yield: 96.13%). ESI-MS m / z: 350.9 [M+1] + . 1 H NMR (400MHz, CDCl3) δ6.75 (d, J = 6.1Hz, 1H), 3.65–3.51 (m, 4H), 2.08–1.96 (m, 4H).

[0464] Step 3: 4-Chloro-3-fluoro-6-(tetrahydro-1H-pyrrol-1-yl)-2-[2-(trideuteriummethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0465]

[0466] Under nitrogen protection, 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (0.35 g, 0.43 mmol) was added to a solution of 4-chloro-3-fluoro-2-iodo-6-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile (1.5 g, 4.28 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuterylmethyl)pyrazole (4.5 g, 21.4 mmol) and potassium carbonate (1.77 g, 12.84 mmol) in dioxane (20 mL) and water (2 mL), and the reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (ethyl acetate / petroleum ether = 0-20%, volume ratio) to obtain the product as a yellow solid (1.7 g, crude product). ESI-MS m / z: 308.0 [M+1] + .

[0467] Step 4: 4-Chloro-3-fluoro-2-[4-iodo-2-(trideuteriomethyl)pyrazol-3-yl]-6-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0468]

[0469] Iodine (587.16 mg, 2.31 mmol) was added to a solution of 4-chloro-3-fluoro-6-(tetrahydro-1H-pyrrol-1-yl)-2-[2-(trideuterylmethyl)pyrazol-3-yl]benzene-1-carbonitrile (473 mg, 1.54 mmol) and silver nitrate (130.99 mg, 0.77 mmol) in ethanol (15 mL), and the reaction solution was stirred at 70°C for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (ethyl acetate / petroleum ether = 0-14%, volume ratio) to obtain the product as a yellow solid (200 mg, yield: 30.11%). ESI-MS m / z: 434 [M+1] + .

[0470] Step 5: 4-Chloro-3-fluoro-6-(tetrahydro-1H-pyrrol-1-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile

[0471]

[0472] The borate compound is obtained by the same method as step 6 in the above intermediate b1.

[0473] ESI-MS m / z: 434.1[M+1] + .

[0474] Intermediate b4

[0475] 6-(Cyclopropyloxy)-3-fluoro-2-[2-(trideuteriomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]-4-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0476]

[0477] Step 1: 6-(Cyclopropyloxy)-3-fluoro-2-[4-iodo-2-(trideuteriomethyl)pyrazol-3-yl]-4-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0478]

[0479] 4-Chloro-6-(cyclopropyloxy)-3-fluoro-2-(4-iodo-2-(trideuterylmethyl)pyrazol-3-yl)benzene-1-carbonitrile (200 mg, 0.48 mmol), tetrahydropyrrole (0.080 mL, 0.96 mmol), N,N-diisopropylethylamine (309.50 mg, 2.39 mmol) and N-methylpyrrolidone (4 mL) were added to a sealed tube, heated to 130 degrees Celsius, and stirred to react overnight. Cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (200 mg, 90.91%). ESI-MS m / z: 456 [M+1] +.

[0480] Step 2: 6-(Cyclopropyloxy)-3-fluoro-2-[2-(trideuterylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]-4-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0481]

[0482] 6-(Cyclopropyloxy)-3-fluoro-2-(4-iodo-2-(trideuteriomethyl)pyrazol-3-yl)-4-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile (200 mg, 0.44 mmol), pinacol borane (563.11 mg, 4.40 mmol) and triethylamine (0.184 mL, 1.33 mmol) were dissolved in dioxane (12 mL). Under argon atmosphere, tris(dibenzylideneacetone)dipalladium (40.49 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (42.16 mg, 0.09 mmol) were added and the reaction was stirred at 100°C for 1.0 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product as a white solid (170 mg, yield 85.0%). ESI-MS m / z: 456.1 [M+1] + .

[0483] Example 1

[0484] 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (Compound 1)

[0485]

[0486] (M / P) 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (Compound 1-P1 and Compound 1-P2)

[0487]

[0488] Step 1: tert-butyl {[7-(5-{5-chloro-2-cyano-6-fluoro-3-[(methylcyclopropyl)oxy]phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}carbamate

[0489]

[0490] Under argon protection, tert-butyl ({7-bromo-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl}methyl)carbamate (Intermediate a1, 147.87 mg, 0.38 mmol), 4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl}methyl)carbamate (Intermediate a1, 147.87 mg, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (31.26 mg, 0.04 mmol) was added to a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (31.26 mg, 0.04 mmol) in 1,4-dioxane (10 mL) and water (1 mL), and the reaction solution was stirred in a microwave at 120°C for 40 minutes. The reaction solution was directly spin-dried and separated and purified by column chromatography (petroleum ether / ethyl acetate = 1:3, volume ratio) to obtain a yellow solid (115 mg, yield: 49%). ESI-MS m / z: 615.2 [M+H] + .

[0491] Step 2: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0492]

[0493] Dissolve tert-butyl {[7-(5-{5-chloro-2-cyano-6-fluoro-3-[(methylcyclopropyl)oxy]phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}carbamate (115 mg, 0.19 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (1 mL), and stir at 25°C for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane (30 mL), and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The organic phase was concentrated and separated by column chromatography (dichloromethane / methanol = 10:1, volume ratio) to obtain a light yellow solid (58 mg, yield: 60%). ESI-MS m / z: 515.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.84 (s, 1H), 8.50 (s, 1H), 7.72 (d, J = 6.0Hz, 1H), 7. 19(s,1H),3.92(s,2H),1.57(s,3H),1.25–1.22(m,2H),0.95–0.91(m,2H).

[0494] Step 3: (M / P) 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (Compound 1-P1 and Compound 1-P2)

[0495]

[0496] 2-{4-[1-(Aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazine-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile was further subjected to chiral preparative separation (ChiralPak IE, 250×40mm ID, 10μm, column, mobile phase: A: n-hexane, B: ethanol containing 0.1% ammonia water; gradient: B accounted for 60% by volume in the mobile phase, elution time: 61 minutes) to obtain two products, compound 1-P1 and compound 1-P2.

[0497] Compound 1-P1: HPLC analysis method, chromatographic column ChiralPak IE, HS, 150×4.6mm ID, 5μm; mobile phase: A: n-hexane, B: ethanol containing 0.1% ammonia water; gradient: B accounts for 60% by volume in the mobile phase; retention time: 10.078 minutes.

[0498] 1 H NMR (400MHz, DMSO-d6) δ12.55(s,1H),8.84(s,1H),8.50(s,1H),7.72(d,J=6.0Hz, 1H),7.19(s,1H),3.88(s,2H),1.57(s,3H),1.27–1.21(m,2H),0.95–0.91(m,2H).

[0499] Compound 1-P2: HPLC analysis method, chromatographic column ChiralPak IE, HS, 150×4.6 mm ID, 5 μm; mobile phase: A: n-hexane, B: ethanol containing 0.1% ammonia water; gradient: B accounts for 60% by volume in the mobile phase; retention time: 15.034 minutes.

[0500] 1 H NMR (400MHz, DMSO-d6) δ12.54(s,1H),8.84(s,1H),8.50(s,1H),7.72(d,J=5.9Hz, 1H),7.19(s,1H),3.88(s,2H),1.57(s,3H),1.24–1.22(m,2H),0.95–0.92(m,2H).

[0501] Example 2

[0502] 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-6-(cyclopropyloxy)-3-fluorobenzene-1-carbonitrile (Compound 2)

[0503]

[0504] Step 1: tert-Butyl {[(7-{5-[5-chloro-2-cyano-3-(cyclopropyloxy)-6-fluorophenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate

[0505]

[0506] Under argon protection, 4-chloro-6-(cyclopropyloxy)-3-fluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile (Intermediate b2, 150 mg, 0.36 mmol), (7-bromo-5-((methyl-d3)amino)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazine 1,1-bis(diphenylphosphino)ferrocenepalladium dichlorochloride complex (29.19 mg, 0.04 mmol) was added to a solution of tert-butyl (1-yl)methyl)carbamate (intermediate a1, 124.27 mg, 0.32 mmol) and potassium carbonate (147.83 mg, 1.07 mmol) in dioxane (10 mL) and water (1 mL), and the reaction solution was stirred in a microwave at 120°C for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-dichloromethane, 0-15% volume ratio gradient elution) to obtain the product as a yellow oil (180 mg, yield: 83.99%). ESI-MS m / z: 601.2 [M+1] + .

[0507] Step 2: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-6-(cyclopropyloxy)-3-fluorobenzene-1-carbonitrile

[0508]

[0509] Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl {[(7-{5-[5-chloro-2-cyano-3-(cyclopropyloxy)-6-fluorophenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (180 mg, 0.30 mmol) in dichloromethane (6 mL), and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and subjected to preparative high performance liquid chromatography to obtain the product as a yellow solid (55 mg, yield: 36.66%). ESI-MS m / z: 501.1[M+1]+. 1H NMR (400MHz, DMSO-d6) δ12.99(s,1H),8.81(s,1H),8.53(s,1H),8.35(s,2H),7.93(d,J=6.0Hz,1 H),7.17(s,1H),4.35(s,2H),4.19(tt,J=6.1,2.9Hz,1H),1.00–0.79(m,3H),0.75–0.64(m,1H).

[0510] Example 3

[0511] 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-6-(cyclopropyloxy)-3-fluoro-4-(prop-1-ynyl)benzene-1-carbonitrile (Compound 3)

[0512]

[0513] Step 1: tert-butyl {[(7-{5-[6-cyano-5-(cyclopropyloxy)-2-fluoro-3-(prop-1-ynyl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate

[0514]

[0515] Tert-butyl {[(7-{5-[3-chloro-6-cyano-5-(cyclopropyloxy)-2-fluorophenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (150 mg, 0.25 mmol) was dissolved in dioxane (5 mL), 1-propynyl-tri-n-butyltin (821.3 mg, 2.5 mmol) was added, tetrakis(triphenylphosphine)palladium (86.5 mg, 0.07 mmol) was added under argon atmosphere, and the mixture was stirred under reflux for 22 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane / ethyl acetate = 100:20, volume ratio) to obtain the product as a yellow oil (150 mg, yield 99.4%). ESI-MS m / z: 605.3[M+1] + .

[0516] Step 2: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3Hpyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-6-(cyclopropyloxy)-3-fluoro-4-(prop-1-ynyl)benzene-1-carbonitrile (Compound 3)

[0517]

[0518] Tert-butyl {[(7-{5-[6-cyano-5-(cyclopropyloxy)-2-fluoro-3-(prop-1-ynyl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (100 mg, 0.17 mmol) was dissolved in acetonitrile (1 mL), and a solution of hydrogen chloride in 1,4-dioxane (5 mL, 20 mmol, 4 M) was added dropwise. The mixture was stirred at 25°C for 20 minutes, concentrated under reduced pressure, and separated by preparative high performance liquid chromatography to obtain the product as a yellow solid (16 mg, yield 19.2%). ESI-MS m / z: 505.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),8.78(s,1H),8.51(s,1H),7.68(d,J=5.6Hz,1H),7.16(s,1H),4.17(s,2H ),4.13(tt,J=6.0,3.0Hz,1H),2.16(s,3H),0.89(dd,J=14.0,8.1Hz,2H),0.85–0.78(m,1H),0.69–0.62(m,1H).

[0519] Example 4

[0520] 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-6-(cyclopropyloxy)-3-fluoro-4-[3-(morpholin-4-yl)prop-1-ynyl]benzene-1-carbonitrile (Compound 4)

[0521]

[0522] Step 1: tert-Butyl {[(7-{5-[6-cyano-5-(cyclopropyloxy)-2-fluoro-3-[3-(morpholin-4-yl)prop-1-ynyl]phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate

[0523]

[0524] Tert-butyl {[(7-{5-[3-chloro-6-cyano-5-(cyclopropyloxy)-2-fluorophenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]carbamate (60 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (4 mL) and N,N- Diisopropylethylamine (38.7 mg, 0.30 mmol) and 1-(4-morpholinyl)-2-propyne (125.0 mg, 1.0 mmol), under argon atmosphere, add 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (4.76 mg, 0.01 mmol) and tris(dibenzylideneacetone)dipalladium (4.57 mg, 0.005 mmol), heat to 110°C and stir to react for 12 hours. Cool to room temperature, add water, extract three times with ethyl acetate, combine the organic phases, wash three times with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and column chromatography (dichloromethane / methanol = 100:5, volume ratio) to obtain the product as a brown solid (45 mg, yield 65.4%). ESI-MS m / z: 690.3 [M+1] + .

[0525] Step 2: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3Hpyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-6-(cyclopropyloxy)-3-fluoro-4-[3-(morpholin-4-yl)prop-1-ynyl]benzene-1-carbonitrile

[0526]

[0527] Tert-butyl {[(7-{5-[6-cyano-5-(cyclopropyloxy)-2-fluoro-3-[3-(morpholin-4-yl)prop-1-ynyl]phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (45 mg, 0.065 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise, and stirred at 25°C for 30 minutes. After concentration under reduced pressure, the product was separated by preparative high performance liquid chromatography to obtain a yellow solid (10 mg, yield 26.0%). ESI-MS m / z: 590.2[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.98(s,1H),8.79(s,1H),8.51(s,1H),8.34(s,2 H),7.74(d,J=5.6Hz,1H),7.16(s,1H),4.34(t,J=4.7Hz,2H),4.17(tt,J=6 .1,2.9Hz,1H),3.77(s,2H),3.63(s,4H),2.65(d,J=13.7Hz,4H),0.90(dd ,J=10.6,5.2Hz,2H),0.82(dq,J=10.4,4.0,3.3Hz,1H),0.71–0.64(m,1H).

[0528] Example 5

[0529] 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazine-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile (Compound 5)

[0530]

[0531] Step 1: tert-butyl {[(7-{5-[5-chloro-2-cyano-6-fluoro-3-(tetrahydro-1H-pyrrol-1-yl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}formate

[0532]

[0533] Under argon protection, tert-butyl [({7-bromo-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-][1,2]diazin-1-yl}methyl)amino]formate (Intermediate a1, 400 mg, 1.03 mmol), 4-chloro-3-fluoro-6-(tetrahydro-1H-pyrrol-1-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile (Intermediate b3, 520mg, 1.20mmol) and potassium carbonate (356.88mg, 2.58mmol) in dioxane (12mL) and water (2mL), add 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) dichloromethane complex (84.56mg, 0.10mmol), microwave irradiation for 0.5h, cool to room temperature, filter, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column (methanol / dichloromethane = 2:98, volume ratio) to obtain the product as a yellow solid (347.8mg). ESI-MS m / z: 614.2[M+1] + . 1 HNMR(400MHz, CDCl3)δ10.00(s,1H),8.63(s,1H),8.19(s,1H),7.00(s,1H),6 .83(d,J=6.0Hz,1H),5.25(s,1H),4.54-4.41(m,2H),3.65–3.57(m,4H),2.02 -2.02(m,4H),1.28(d,J=14.2Hz,9H).

[0534] Step 2: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazine-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0535]

[0536] Trifluoroacetic acid (3 mL, 39.18 mmol) was added to a solution of tert-butyl {[(7-{5-[5-chloro-2-cyano-6-fluoro-3-(tetrahydro-1H-pyrrol-1-yl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (100 mg, 0.16 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the mixture was separated by preparative high performance liquid chromatography to give a white solid product (65 mg). ESI-MS m / z: 514.2 [M+1]+ .

[0537] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.78(s,1H),8.48(s,1H),8.35(s,2H),7.17–7.11(m,2H),4.34(s,2H),3.53(s,4H),1.99–1.89(m,4H).

[0538] Example 6

[0539] 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazine-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-4-(prop-1-ynyl)-6-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile (Compound 6)

[0540]

[0541] Step 1: tert-butyl {[(7-{5-[2-cyano-6-fluoro-5-(prop-1-ynyl)-3-(tetrahydro-1H-pyrrol-1-yl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3Hpyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}formate

[0542]

[0543] Under argon protection, tetrakis(triphenylphosphine)palladium (93.15 mg, 0.08 mmol) was added to a solution of tert-butyl{[(7-{5-[5-chloro-2-cyano-6-fluoro-3-(tetrahydro-1H-pyrrol-1-yl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (165 mg, 0.27 mmol) and tributyl propynylstannane (884.28 mg, 2.69 mmol) in dioxane (15 mL). The mixture was stirred at 140 °C for 27 h. The solvent was concentrated to dryness to give a crude product. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to give the product as a yellow solid (80 mg). ESI-MS m / z:618.1[M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.75(s,1H),8.28(s,1H),7.21(s,1H),6.95(d,J=5.8Hz ,1H),5.77(s,1H),4.32(d,J=6.1Hz,2H),3.49(s,4H),2.00(s,3H),1.96(s,4H),1.41(s,9H).

[0544] Step 2: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3Hpyrido[4,3-d][1,2]diazine-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-4-(prop-1-ynyl)-6-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0545]

[0546] Trifluoroacetic acid (1 mL) was added to the compound tert-butyl {[(7-{5-[2-cyano-6-fluoro-5-(prop-1-ynyl)-3-(tetrahydro-1H-pyrrol-1-yl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3Hpyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (80 mg, 0.13 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, separation by preparative high performance liquid chromatography gave a yellow solid product (20 mg). ESI-MS m / z: 518.1 [M+1] + .

[0547] 1 H NMR(400MHz,DMSO-d6)δ12.94(s,1H),8.75(s,1H),8.46(s,1H),8.34(s,2H),7.11(s,1H ),6.96(d,J=5.9Hz,1H),4.33(s,2H),3.54-3.46(m,4H),2.12(s,3H),1.98–1.88(m,4H).

[0548] Example 7

[0549] 2-{4-[1-(aminomethyl)-4-carbonyl-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]-4-[3-(morpholin-4-yl)prop-1-ynyl]benzene-1-carbonitrile (Compound 7)

[0550]

[0551] Step 1: tert-Butyl ({[7-(5-{6-cyano-2-fluoro-5-[(methylcyclopropyl)oxy]-3-[3-(morpholin-4-yl)prop-1-ynyl]phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)formate

[0552]

[0553] Under argon protection, the reaction mixture was stirred for 2 h in 4% CO 2 0 % 4-(4-(4-[4-(4-(2-((4-((2-((4-((2-chloro-6-cyano-2-fluoro-5-[(methylcyclopropyl)oxy]phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)formate (185 mg, 0.30 mmol), 4-(prop-1-yn-3-yl)-morpholine (3 76.47mg, 3.01mmol) and diisopropylethylamine (116.62mg, 0.9mmol) in N,N-dimethylformamide (10mL), tris(dibenzylideneacetone)dipalladium (27.54mg, 0.03mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (28.68mg, 0.06mmol) were added, and the reaction solution was stirred at 110°C for 20 hours. After the reaction was completed, water (20mL) was added to the reaction solution, and it was extracted with ethyl acetate (20mL*3), and the organic phase was washed with saturated brine (50mL*3), dried over anhydrous sodium sulfate, and concentrated. The residue was chromatographed on a silica gel column (ammonia methanol / dichloromethane = 0-4%, volume ratio) to obtain a red oily product (100mg, yield 47.24%). ESI-MS m / z: 704.2[M+1] + .

[0554] Step 2: 2-{4-[1-(aminomethyl)-4-carbonyl-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]-4-[3-(morpholin-4-yl)prop-1-ynyl]benzene-1-carbonitrile

[0555]

[0556] Tert-butyl ({[7-(5-{6-cyano-2-fluoro-5-[(methylcyclopropyl)oxy]-3-[3-(morpholin-4-yl)prop-1-ynyl]phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)formate (100 mg, 0.14 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative high performance liquid chromatography to obtain the product as a yellow solid (15 mg, yield 17.49%). ESI-MS m / z: 604.3[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.50(s,1H),8.32(s,1H),7.53(d,J=5.5Hz,1H),7.19(s,1H), 3.98(s,2H),3.65(s,4H),3.59(t,J=4.7Hz,6H),1.57(s,3H),1.10–1.02(m,1H),0.97–0.89(m,3H).

[0557] Example 8

[0558] 2-{4-[1-(aminomethyl)-4-carbonyl-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]-4-(prop-1-ynyl)benzene-1-carbonitrile (Compound 8)

[0559]

[0560] Step 1: tert-Butyl ({[7-(5-{6-cyano-2-fluoro-5-[(methylcyclopropyl)oxy]-3-(prop-1-ynyl)phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)formate

[0561]

[0562] Under argon protection, tetrakis(triphenylphosphine)palladium (112.72 mg, 0.1 mmol) was added to a solution of tert-butyl({[7-(5-{3-chloro-6-cyano-2-fluoro-5-[(methylcyclopropyl)oxy]phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)carboxylate (200 mg, 0.33 mmol) and tributylpropynylstannane (1070.13 mg, 3.25 mmol) in dioxane (10 mL), and the reaction solution was stirred at 120° C. for 24 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (ethyl acetate / dichloromethane = 10-20%, volume ratio) to obtain a red oily product (150 mg, yield 74.56%). ESI-MS m / z: 619.3 [M+1] + .

[0563] Step 2: 2-{4-[1-(aminomethyl)-4-carbonyl-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]-4-(prop-1-ynyl)benzene-1-carbonitrile

[0564]

[0565] Tert-butyl ({[7-(5-{6-cyano-2-fluoro-5-[(methylcyclopropyl)oxy]-3-(prop-1-ynyl)phenyl}-1-(trideuteriomethyl)pyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)formate (150 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and separated by preparative high performance liquid chromatography to obtain the product as a yellow solid (45 mg, yield 35.79%). ESI-MS m / z: 519.1[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),8.79(s,1H),8.51(s,1H),8.33(s,2H),7.50(d,J=5.7Hz,1H),7.16 (s,1H),4.35(d,J=2.6Hz,2H),2.17(s,3H),1.56(s,3H),1.05(dd,J=11.5,6.1Hz,1H),0.99–0.82(m,3H).

[0566] Example 9

[0567] 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-6-(cyclopropyloxy)-3-fluoro-4-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile (Compound 9)

[0568]

[0569] Step 1: tert-Butyl {[(7-{5-[6-cyano-5-(cyclopropyloxy)-2-fluoro-3-(tetrahydro-1H-pyrrol-1-yl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate

[0570]

[0571] 6-(Cyclopropyloxy)-3-fluoro-2-[2-(trideuteriomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]-4-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile (Intermediate b4, 100 mg, 0.22 mmol), tert-butyl[({7-bromo-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2] [1-Diazin-1-yl}methyl)amino] formate (intermediate a1) (85.61 mg, 0.22 mmol) and potassium carbonate (61.10 mg, 0.44 mmol) were dissolved in dioxane (10 mL) and water (1 mL). Under an argon atmosphere, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) dichloromethane complex (18.10 mg, 0.02 mmol) was added and microwave irradiation was performed at 120°C for 0.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (methanol / dichloromethane = 0-5%, volume ratio) to obtain the product as a yellow solid (90 mg, yield 64%). ESI-MS m / z: 636.2 [M+1] + .

[0572] Step 2: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-6-(cyclopropyloxy)-3-fluoro-4-(tetrahydro-1H-pyrrol-1-yl)benzene-1-carbonitrile

[0573]

[0574] Tert-butyl {[(7-{5-[6-cyano-5-(cyclopropyloxy)-2-fluoro-3-(tetrahydro-1H-pyrrol-1-yl)phenyl]-1-(trideuteriomethyl)pyrazol-4-yl}-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl)methyl]amino}carboxylate (90 mg, 0.14 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added dropwise, and stirred at 25°C for 30 minutes. After concentration under reduced pressure, the product was separated by preparative high performance liquid chromatography to obtain a light yellow solid (70 mg, yield 87.3%). ESI-MS m / z: 536.2[M+1] + . 1 HNMR(400MHz,DMSO-d6)δ12.94(s,1H),8.74(s,1H),8.44(s,1H),8.34(s,2H),7.09(s,1H),6.67(d,J=7.4Hz,1H), 4.33(s,2H),4.05(dt,J=6.0,3.2Hz,1H),3.50(s,4H),1.95(d,J=6.7Hz,4H),1.00–0.84(m,2H),0.80–0.58(m,2H).

[0575] Example 10

[0576] 2-{4-[1-(aminomethyl)-5-(methylamino)-4-oxo-3H-pyridin[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (Compound 10)

[0577]

[0578] Step 1: 4-Chloro-3-fluoro-2-{4-[1-(hydroxymethyl)-5-(methylamino)-4-oxo-3H-pyridin[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0579]

[0580] 4-Chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trideuteriomethyl)pyrazol-3-yl]benzene-1-carbonitrile (300 mg, 0.69 mmol), 7-bromo-1-(hydroxymethyl)-5-(methylamino)-3,4-dihydropyrido[4,3-][1,2]diazin-4-one (196.75 mg, 0.69 mmol), potassium carbonate (286.12 mg, 2.07 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (112.99 mg, 0.14 mmol) were dissolved in dioxane (8 mL) and water (2 mL) and stirred at 120 °C under microwave for 40 min. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (1×50 mL). The organic phase was 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 obtain the product, a reddish brown oil (300 mg, yield 84.75%). ESI-MSm / z: 513.1[M+1] + .

[0581] Step 2: 4-Chloro-2-{4-[1-(chloromethyl)-5-(methylamino)-4-oxo-3H-pyridin[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0582]

[0583] Dissolve 4-chloro-3-fluoro-2-{4-[1-(hydroxymethyl)-5-(methylamino)-4-oxo-3H-pyridinium[4,3-d][1,2]diazin-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (250 mg, 0.49 mmol) in dichloromethane (5 mL), add N,N-dimethylformamide (0.04 mL), add thionyl chloride (173.94 mg, 1.46 mmol), stir and react at room temperature for 1 hour. Concentrate under reduced pressure to obtain a crude product, a brown-yellow oil (300 mg, yield 96.53%). ESI-MS m / z: 531.1[M+1] + .

[0584] Step 3: 2-{4-[1-(aminomethyl)-5-(methylamino)-4-oxo-3H-pyridin[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0585]

[0586] A solution of 4-chloro-2-{4-[1-(chloromethyl)-5-(methylamino)-4-oxo-3H-pyridinium[4,3-d][1,2]diazin-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (200 mg, 0.38 mmol) dissolved in methanol (5 mL) was added dropwise to a solution of ammonia in methanol (10 mL, 7.0 mol / L) and stirred at room temperature for 5 minutes. The mixture was concentrated under reduced pressure and the residue was purified by preparative liquid phase to obtain the product as a yellow solid (10 mg, yield 4.72%). ESI-MS m / z: 512.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),8.87(d,J=4.8Hz,1H),8.51(s,1H),7.73(d,J=6.0 Hz,1H),7.20(s,1H),3.96(s,2H),2.29(d,J=4.8Hz,3H),1.58(s,3H),0.97-0.88(m,4H).

[0587] Embodiment 11

[0588] 2-{4-[1-(aminomethyl)-5-(difluoromethyl)-4-oxo-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (Compound 11)

[0589]

[0590] Step 1: 4-chloro-2-{4-[5-(difluoromethyl)-1-(hydroxymethyl)-4-oxo-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0591]

[0592] Under argon protection, 7-chloro-5-(difluoromethyl)-1-(hydroxymethyl)-3,4-dihydropyrido[4,3-][1,2]diazin-4-one (120 mg, 0.46 mmol, prepared by referring to the preparation method of intermediate a1), 4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (37.66 mg, 0.05 mmol) was added to a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (37.66 mg, 0.05 mmol) of [trideuteriomethyl]pyrazol-3-yl]benzene-1-carbonitrile (200 mg, 0.46 mmol) and potassium carbonate (190 mg, 1.38 mmol) in 1,4-dioxane (10 mL) and water (1 mL), and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was directly spin-dried and separated by column chromatography (petroleum ether / ethyl acetate = 1:2, volume ratio) to obtain a white solid (230 mg, yield: 94%). ESI-MS m / z: 534.1 [M+H] + .

[0593] Step 2: 4-Chloro-2-{4-[1-(chloromethyl)-5-(difluoromethyl)-4-oxo-3H-pyridin[4,3-d][1,2]diazin-7-yl]-2-(trideuteromethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0594]

[0595] Dissolve 4-chloro-2-{4-[5-(difluoromethyl)-1-(hydroxymethyl)-4-oxo-3H-pyrido[4,3-d][1,2]diazine-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (230 mg, 0.43 mmol) in dichloromethane (10 mL), add thionyl chloride (255.76 mg, 2.15 mmol), and stir at 45°C for 10 minutes. The reaction solution was directly spin-dried to obtain a crude product, which was directly used in the next step. ESI-MS m / z: 552.0[M+H]+.

[0596] Step 3: 2-{4-[1-(aminomethyl)-5-(difluoromethyl)-4-oxo-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0597]

[0598] 4-Chloro-2-{4-[1-(chloromethyl)-5-(difluoromethyl)-4-oxo-3H-pyridinium[4,3-d][1,2]diazine-7-yl]-2-(trideuteriomethyl)pyrazol-3-yl}-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (237 mg, 0.43 mmol) was dissolved in ammonia in methanol (5 mL, 7 M) and stirred at 25°C for 10 minutes. The reaction solution was directly spin-dried and separated by preparative liquid phase to obtain a light yellow solid (40 mg, yield: 17%). ESI-MS m / z: 533.1[M+H]+.

[0599] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.35(s,1H),8.25(s,1H),7.72(d,J=6.0Hz,1H),4.13(s,2H),1.59(s,3H),1.06–0.88(m,4H).

[0600] Example 12

[0601] 2-{4-[1-(Aminomethyl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-methylpyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (Compound 12)

[0602]

[0603] (M / P) 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-methylpyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (Compound 12-P1 and Compound 12-P2)

[0604]

[0605] Step 1: 4-Chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-(2-methylpyrazol-3-yl)benzene-1-carbonitrile

[0606]

[0607] Under argon protection, 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride complex (69.86 mg, 0.09 mmol) was added to a solution of 4-chloro-3-fluoro-2-iodo-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (300 mg, 0.85 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (355.13 mg, 1.71 mmol) and potassium carbonate (353.81 mg, 2.56 mmol) in dioxane (20 mL) and water (2 mL), and the reaction solution was stirred at 100°C for 9 h. After the reaction was completed, the reaction solution was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-15% volume ratio gradient elution) to obtain the product as a colorless oil (220 mg, 76.65%). ESI-MS m / z: 306.0 [M+1] + . 1 HNMR (400MHz, CDCl3) δ7.64(d,J=2.0Hz,1H),7.44(d,J=5.9Hz,1H),6.52(d,J =2.0Hz,1H),3.84(s,3H),1.65(s,3H),1.17–1.11(m,2H),0.89–0.85(m,2H).

[0608] Step 2: 4-Chloro-3-fluoro-2-(4-iodo-2-methylpyrazol-3-yl)-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0609]

[0610] N-iodosuccinimide (220.77 mg, 0.98 mmol) was added to a solution of 4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-(2-methylpyrazol-3-yl)benzene-1-carbonitrile (200 mg, 0.65 mmol) in acetic acid (10 mL), and the reaction solution was stirred at 80°C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was diluted with saturated sodium chloride (50 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined and washed with saturated sodium sulfite solution (1×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-17% volume ratio gradient elution) to obtain the product as a yellow solid (227 mg, 80.4%). ESI-MS m / z: 431.9 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.67(s,1H),7.50(d,J=5.9Hz,1H),3.85(s,3H),1.67(s,3H),1.20–1.14(m,2H),0.90–0.83(m,2H).

[0611] Step 3: 4-Chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]benzene-1-carbonitrile

[0612]

[0613] Under argon protection, tris dibenzylideneacetone dipalladium (48.16 mg, 0.05 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (50.14 mg, 0.11 mmol) and pinacol borane (673.06 mg, 5.26 mmol) were added to a solution of 4-chloro-3-fluoro-2-(4-iodo-2-methylpyrazol-3-yl)-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile (227 mg, 0.53 mmol) and triethylamine (0.219 mL, 1.58 mmol) in dioxane (10 mL), and the reaction solution was stirred at 100°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-15% volume ratio gradient elution) to obtain the product as a colorless oil (220 mg, crude product). ESI-MS m / z: 432.1[M+1] + .

[0614] Step 4: tert-Butyl ({[7-(5-{5-chloro-2-cyano-6-fluoro-3-[(methylcyclopropyl)oxy]phenyl}-1-methylpyrazol-4-yl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)formate

[0615]

[0616] Under argon protection, in the presence of 4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]benzene-1-carbonitrile (220 mg, 0.51 mmol), (7-bromo-5-((methyl-d3)amino)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazine-1 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (41.72 mg, 0.05 mmol) was added to a solution of tert-butyl (1-(2-(2-(4-((2-( ... + .

[0617] Step 5: 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-methylpyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0618]

[0619] Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl ({[7-(5-{5-chloro-2-cyano-6-fluoro-3-[(methylcyclopropyl)oxy]phenyl}-1-methylpyrazol-4-yl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-1-yl]methyl}amino)carboxylate (190 mg, 0.31 mmol) in dichloromethane (6 mL). The reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure and separated by preparative high performance liquid chromatography to obtain the product as a yellow solid (40 mg, yield 25.17%). ESI-MS m / z: 512.1[M+1] + .

[0620] 1H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.53(s,1H),8.04(s,2H),7.74(d,J=6.0Hz,1H),7.18(s ,1H),4.31(d,J=2.0Hz,2H),3.73(s,3H),1.58(s,3H),1.12–1.01(m,1H),1.01–0.87(m,3H).

[0621] Step 6: (M / P) 2-{4-[1-(aminomethyl)-4-oxo-5-[(trideuteromethyl)amino]-3H-pyrido[4,3-d][1,2]diazin-7-yl]-2-methylpyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile

[0622]

[0623] 2-{4-[1-(Aminomethyl)-4-oxo-5-[(trideuteriomethyl)amino]-3H-pyrido[4,3-d][1,2]diazine-7-yl]-2-methylpyrazol-3-yl}-4-chloro-3-fluoro-6-[(methylcyclopropyl)oxy]benzene-1-carbonitrile was further subjected to chiral preparative separation (OD-3 4.6*100mm 3μm column, mobile phase A: methanol [0.2% NH3 (7 mol / L ammonia methanol solution)], B: CO2; gradient: B accounted for 65% by volume in the mobile phase, elution time: 4.2 minutes) to obtain two products, compound 12-P1 and compound 12-P2.

[0624] Compound 12-P1: SFC analysis method, chromatographic column OD-3 4.6*100mm 3μm column; mobile phase: A: methanol [0.2% NH3 (7 mol / L ammonia methanol solution)], B: CO2; gradient: B accounts for 65% by volume in the mobile phase; retention time: 2.024 minutes.

[0625] 1 H NMR (400MHz, DMSO-d6) δ8.85 (s, 1H), 8.51 (s, 1H), 7.73 (d, J = 6.0Hz, 1H), 7.20 (s, 1H),3.89(s,2H),3.72(s,3H),1.58(s,3H),1.11–1.02(m,1H),0.99–0.88(m,3H).

[0626] Compound 12-P2: SFC analysis method, chromatographic column OD-3 4.6*100mm 3μm column; mobile phase: A: methanol [0.2% NH3 (7 mol / L ammonia methanol solution)], B: CO2; gradient: B accounts for 65% by volume in the mobile phase; retention time: 2.540 minutes.

[0627] 1 H NMR (400MHz, DMSO-d6) δ12.99(s,1H),8.81(s,1H),8.53(s,1H),8.36(s,2H),7.74(d,J=6.0Hz, 1H),7.18(s,1H),4.35(s,2H),3.73(s,3H),1.58(s,3H),1.10–1.02(m,1H),1.00–0.89(m,3H).

[0628] Biological Test Examples

[0629] Test Example 1: Proliferation inhibitory activity on human colon cancer cells HCT-116 and human colon cancer cells with stable MTAP protein knockout HCT-116-MTAP-KO-1A2

[0630] The PrestoBlue method was used to determine the in vitro proliferation inhibitory activity of the compounds against human colon cancer cells HCT-116 and HCT-116-MTAP-KO-1A2, in which MTAP protein was stably knocked out in human colon cancer cells HCT-116.

[0631] Cell sources: HCT-116 cells were purchased from the Institute of Cell Biology, Chinese Academy of Sciences; HCT-116-MTAP-KO-1A2 cells were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.

[0632] HCT-116 and HCT-116-MTAP-KO-1A2 cells were cultured in RPMI1640 complete medium containing 10% fetal bovine serum. HCT-116 and HCT-116-MTAP-KO-1A2 cells in the logarithmic growth phase were seeded in a 96-well plate at a cell density of 500 cells / 135 μL complete medium / well and cultured in a constant temperature incubator at 37°C containing 5% CO2 for 24 hours. Each compound was dissolved in dimethyl sulfoxide (DMSO) in advance to prepare a 10mM stock solution, and then the compound was diluted with DMSO and complete medium in turn. Take out the 96-well plate inoculated with cells, and take one of them as a no-growth control group (0-hour cell no-growth culture medium control group); add 15 μL of different concentrations of each compound to each well of the other 96-well plates, so that the final concentration is 10000, 2500, 625, 156.3, 39.1, 9.8, 2.4, 0.6, 0.15, 0.04 nM, set up three replicates for each compound concentration, and set up a negative control group (containing cells, no compound culture medium control group), and the concentration of DMSO in each well is 0.5%. The reserved no-growth control group immediately adds PrestoBlue HS cell viability detection reagent and performs subsequent detection, and the other 96-well plates continue to be cultured in a constant temperature incubator at 37°C containing 5% CO2 for 6 days, and then add PrestoBlue HS cell viability detection reagent and perform subsequent detection.

[0633] The following steps were followed for adding PrestoBlue HS cell viability detection reagent: Take out the 96-well cell culture plate from the CO2 constant temperature incubator, add 15 μL of PrestoBlue HS cell viability detection reagent (Cat. No.: P50201) to each well, and continue to incubate in a constant temperature incubator at 37°C with 5% CO2 for 3 hours. Take out the 96-well cell culture plate, and measure the relative fluorescence intensity (RFU) at 560nm excitation wavelength and 590nm emission wavelength on a microplate reader. Calculate the cell inhibition rate of each concentration of the compound according to the following formula.

[0634]

[0635] The data were analyzed using GraphPad Prism 8.3 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC 50 The results are shown in Table 1.

[0636] Table 1

[0637]

[0638]

[0639] MRTX1719 is a positive control compound (prepared according to the method in J. Med. Chem. 2022, 65, 1749–1766), A represents <25 nM, B represents 25 to 200 nM, C represents 201 nM to 1 μM, and D represents >1 μM. The selectivity value is the IC value of HCT-116 cells 50 IC values ​​of HCT-116-MTAP-KO-1A2 cells 50 The ratio of values.

[0640] The results show that the compounds of the present invention exhibit good proliferation inhibition activity and selectivity on human colon cancer stably knocked-out MTAP protein cells HCT-116-MTAP-KO-1A2.

[0641] Test Example 2: Pharmacokinetic test of the compound in SD (Sprague Dawley) rats

[0642] Intravenous administration: 3 healthy SD rats, female, weighing 200-280 g, provided by Shanghai Bikekeyi Biotechnology Co., Ltd. The compounds were administered via the tail vein according to the doses listed in the table below, and 0.2 mL of blood was collected from the jugular vein of the rats at 5 min, 15 min, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h and 24 h after administration, and plasma was prepared by separation. The concentration of the compound in the plasma was determined by LC-MS / MS to obtain the drug concentration-time curve.

[0643] Oral administration: 3 healthy SD rats, female, weighing 200-280 gg, provided by Shanghai Bikekeyi Biotechnology Co., Ltd. The compounds were administered orally by gavage according to the doses listed in the table below. 0.2 mL of blood was collected from the jugular vein of the rats at 15 min, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h and 24 h after administration, and plasma was prepared by separation. The concentration of the compound in the plasma was determined by LC-MS / MS to obtain the drug concentration-time curve.

[0644] Phoenix WinNonlin 7.0 was used to calculate the pharmacokinetic parameters. The main pharmacokinetic parameters are shown in Table 2 below:

[0645] Table 2

[0646]

[0647] The experimental results show that the compound of the present invention has a good maximum blood drug concentration and exposure in the pharmacokinetic test in rats, and also has a low clearance rate in the body, showing good pharmacokinetic properties.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 Each is independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C2-C6 alkenyl, substituted by one or more R 2c Substituted C2-C6 alkynyl, substituted by one or more R 2d Substituted 3-7 membered cycloalkyl, 2e Substituted 3-7 membered cycloalkenyl, one or more R 2f substituted 4-10 membered heterocyclic group, substituted by one or more R 2g Substituted C6-C 10 Aryl or one or more R 2h substituted 5-10 membered heteroaryl; Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 3 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 3a Substituted C1-C6 alkyl, one or more R 3b Substituted C2-C6 alkenyl, substituted by one or more R 3c Substituted C2-C6 alkynyl, substituted by one or more R 3d Substituted 3-7 membered cycloalkyl, 3e Substituted 3-7 membered cycloalkenyl, one or more R 3f substituted 4-10 membered heterocyclic group, substituted by one or more R 3g Substituted C6-C 10 Aryl or one or more R 3h substituted 5-10 membered heteroaryl; Each R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5a Substituted C1-C6 alkyl, one or more R 5b Substituted C2-C6 alkenyl, substituted by one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5e Substituted 3-7 membered cycloalkenyl, one or more R 5f substituted 4-10 membered heterocyclic group, substituted by one or more R 5g Substituted C6-C 10 Aryl, one or more R 5h Substituted 5-10 membered heteroaryl or -NR 10 R 11 ; Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-b Substituted C2-C6 alkenyl, substituted by one or more R 5-c Substituted C2-C6 alkynyl, substituted by one or more R 5-d Substituted 3-7 membered cycloalkyl, 5-e Substituted 3-7 membered cycloalkenyl, one or more R 5-f substituted 4-10 membered heterocyclic group, substituted by one or more R 5-g Substituted C6-C 10 Aryl or one or more R 5-h substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g and R 5-h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano; R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 7a Substituted C1-C6 alkyl, one or more R 7b Substituted C2-C6 alkenyl, substituted by one or more R 7c Substituted C2-C6 alkynyl, substituted by one or more R 7d Substituted 3-7 membered cycloalkyl, 7e Substituted 3-7 membered cycloalkenyl, one or more R 7f substituted 4-10 membered heterocyclic group, substituted by one or more R 7g Substituted C6-C 10 Aryl or one or more R 7h substituted 5-10 membered heteroaryl; Each R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 , by one or more R 8a Substituted C1-C6 alkyl, one or more R 8b Substituted C2-C6 alkenyl, substituted by one or more R 8c Substituted C2-C6 alkynyl, substituted by one or more R 8d Substituted 3-7 membered cycloalkyl, 8e Substituted 3-7 membered cycloalkenyl, one or more R 8f substituted 4-10 membered heterocyclic group, substituted by one or more R 8g Substituted C6-C 10 Aryl or one or more R 8h substituted 5-10 membered heteroaryl; Each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g and R 8h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 , C1-C6 alkyl or 3-7 membered cycloalkyl; R 9 for hydrogen, deuterium, -C(=O)-O-CH(R 9a )-OC(O)-R 9b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2) m -OP(=O)(OR 9c )2; R 9a and R 9b are each independently hydrogen, deuterium or C 1-20 alkyl; Each R 9c are each independently hydrogen, deuterium or C 1-20 alkyl; R 10 and R 11 Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 10a Substituted C1-C6 alkyl, one or more R 10b Substituted C2-C6 alkenyl, substituted by one or more R 10c Substituted C2-C6 alkynyl, substituted by one or more R 10d Substituted 3-7 membered cycloalkyl, 10e Substituted 3-7 membered cycloalkenyl, one or more R 10f substituted 4-10 membered heterocyclic group, substituted by one or more R 10g Substituted C6-C 10 Aryl or one or more R 10h substituted 5-10 membered heteroaryl; Each R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g and R 10h Each is independently deuterium, halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 12a Substituted C1-C6 alkyl, one or more R 12b Substituted C2-C6 alkenyl, substituted by one or more R 12c Substituted C2-C6 alkynyl, substituted by one or more R 12d Substituted 3-7 membered cycloalkyl, 12e Substituted 3-7 membered cycloalkenyl, one or more R 12f substituted 4-10 membered heterocyclic group, substituted by one or more R 12g Substituted C6-C 10 Aryl or one or more R 12h substituted 5-10 membered heteroaryl; Each R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g and R 12h Each is independently halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O-, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl; n is 1 or 2; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The heteroatoms in the 5-10 membered heteroaryl and the 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 is a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 Each is independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C2-C6 alkenyl, substituted by one or more R 2c Substituted C2-C6 alkynyl, substituted by one or more R 2d Substituted 3-7 membered cycloalkyl, 2e Substituted 3-7 membered cycloalkenyl, one or more R 2f substituted 4-10 membered heterocyclic group, substituted by one or more R 2g Substituted C6-C 10 Aryl or one or more R 2h substituted 5-10 membered heteroaryl; Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 3 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 3a Substituted C1-C6 alkyl, one or more R 3b Substituted C2-C6 alkenyl, substituted by one or more R 3c Substituted C2-C6 alkynyl, substituted by one or more R 3d Substituted 3-7 membered cycloalkyl, 3e Substituted 3-7 membered cycloalkenyl, one or more R 3f substituted 4-10 membered heterocyclic group, substituted by one or more R 3g Substituted C6-C 10 Aryl or one or more R 3h substituted 5-10 membered heteroaryl; Each R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 5a Substituted C1-C6 alkyl, one or more R 5b Substituted C2-C6 alkenyl, substituted by one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5e Substituted 3-7 membered cycloalkenyl, one or more R 5f substituted 4-10 membered heterocyclic group, substituted by one or more R 5g Substituted C6-C 10 Aryl, one or more R 5h Substituted 5-10 membered heteroaryl or -NR 10 R 11 ; Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 、-C(=O)R 12 、-C(=O)OR 12 、-OC(=O)R 12 、-C(=O)NR 10 R 11 、-NR 12 C(=O)R 12 、-NR 12 C(=O)NR 10 R 11 、-S(=O)R 12 、-S(=O)2R 12 、-P(=O)(R 12 )2.-P(=O)(OR 12 )2.-NR 12 S(=O)R 12 、-NR 12 S(=O)2R 12 、-NR 12 S(=O)NR 10 R 11 、-NR 12 S(=O)2NR 10 R 11 、-S(O)NR 10 R 11 、-S(O)2NR 10 R 11 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-b Substituted C2-C6 alkenyl, substituted by one or more R 5-c Substituted C2-C6 alkynyl, substituted by one or more R 5-d Substituted 3-7 membered cycloalkyl, 5-e Substituted 3-7 membered cycloalkenyl, one or more R 5-f substituted 4-10 membered heterocyclic group, substituted by one or more R 5-g Substituted C6-C 10 Aryl or one or more R 5-h substituted 5-10 membered heteroaryl; Each R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g and R 5-h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano; R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 7a Substituted C1-C6 alkyl, one or more R 7b Substituted C2-C6 alkenyl, substituted by one or more R 7c Substituted C2-C6 alkynyl, substituted by one or more R 7d Substituted 3-7 membered cycloalkyl, 7e Substituted 3-7 membered cycloalkenyl, one or more R 7f substituted 4-10 membered heterocyclic group, substituted by one or more R 7g Substituted C6-C 10 Aryl or one or more R 7h substituted 5-10 membered heteroaryl; Each R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -NR 10 R 11 、-OR 12 , by one or more R 8a Substituted C1-C6 alkyl, one or more R 8b Substituted C2-C6 alkenyl, substituted by one or more R 8c Substituted C2-C6 alkynyl, substituted by one or more R 8d Substituted 3-7 membered cycloalkyl, 8e Substituted 3-7 membered cycloalkenyl, one or more R 8f substituted 4-10 membered heterocyclic group, substituted by one or more R 8g Substituted C6-C 10 Aryl or one or more R 8h substituted 5-10 membered heteroaryl; Each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g and R 8h are independently deuterium, halogen, =O, cyano, -NR 10 R 11 , C1-C6 alkyl or 3-7 membered cycloalkyl; R 9 for hydrogen, deuterium, -C(=O)-O-CH(R 9a )-OC(O)-R 9b 、-C(=O)-OC 6-10 Aryl, -C(=O)-C 1-6 Alkyl or -(CH2) m -OP(=O)(OR 9c )2; R 9a and R 9b are each independently hydrogen, deuterium or C 1-20 alkyl; Each R 9c are each independently hydrogen, deuterium or C 1-20 alkyl; R 10 and R 11 Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 10a Substituted C1-C6 alkyl, one or more R 10b Substituted C2-C6 alkenyl, substituted by one or more R 10c Substituted C2-C6 alkynyl, substituted by one or more R 10d Substituted 3-7 membered cycloalkyl, 10e Substituted 3-7 membered cycloalkenyl, one or more R 10f substituted 4-10 membered heterocyclic group, substituted by one or more R 10g Substituted C6-C 10 Aryl or one or more R 10h substituted 5-10 membered heteroaryl; Each R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g and R 10h Each is independently deuterium, halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O- or 3-7 membered cycloalkyl; R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 12a Substituted C1-C6 alkyl, one or more R 12b Substituted C2-C6 alkenyl, substituted by one or more R 12c Substituted C2-C6 alkynyl, substituted by one or more R 12d Substituted 3-7 membered cycloalkyl, 12e Substituted 3-7 membered cycloalkenyl, one or more R 12f substituted 4-10 membered heterocyclic group, substituted by one or more R 12g Substituted C6-C 10 Aryl or one or more R 12h substituted 5-10 membered heteroaryl; Each R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g and R 12h Each is independently halogen, =O, cyano, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O-, 3-7 membered cycloalkyl or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl; n is 1 or 2; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The heteroatoms in the 5-10 membered heteroaryl group and the 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1)R 1 wherein the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more deuteriums is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; preferably, R 1 wherein the C1-C6 alkyl group substituted by one or more deuteriums is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; (2)R 6 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (3)R 3 wherein the 4-10 membered heterocyclic group and the one or more R 3f The 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl. The 4-10 membered heterocycloalkyl may be a 4-10 membered heterocycloalkyl in which the heteroatom is N and the number of heteroatoms is 1, or a 4-10 membered monocyclic heterocycloalkyl, preferably a 4-6 membered monocyclic heterocycloalkyl, more preferably Further optimization (4) Each R 3f wherein the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; (5)R 5 wherein the halogen is fluorine, chlorine, bromine or iodine, for example chlorine; (6)R 5 wherein the C2-C6 alkynyl group and the 5c The C2-C6 alkynyl in the substituted C2-C6 alkynyl is independently ethynyl, propynyl or butynyl, preferably ethynyl or propynyl; (7)R 5 wherein the 4-10 membered heterocyclic group and the one or more R 5f The 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl. The 4-10 membered heterocycloalkyl may be a 4-10 membered heterocycloalkyl in which the heteroatom is N and the number of heteroatoms is 1, or a 4-10 membered monocyclic heterocycloalkyl, preferably a 4-6 membered monocyclic heterocycloalkyl, more preferably Further optimization (8) Each R 5c wherein the 3-7 membered cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (9) Each R 5c wherein the 4-10 membered heterocyclic group and the one or more R 5-f The 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl. The 4-10 membered heterocycloalkyl may be a 4-10 membered heterocycloalkyl in which the heteroatom is N and / or O and the number of heteroatoms is 1 or 2, or a 4-10 membered monocyclic heterocycloalkyl, preferably a 4-6 membered monocyclic heterocycloalkyl, more preferably Further optimization (10) Each R 5f wherein the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; (11) Each R 5-f wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl; (12)R 8 In the above, the one or more R 8a The C1-C6 alkyl group in the substituted C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl; (13) Each R 8a wherein the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; (14)R 10 and R 11 wherein the C1-C6 alkyl group and the 10a The C1-C6 alkyl in the substituted C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (15)R 12 wherein the 3-7 membered cycloalkyl group and the one or more R 12d The 3-7-membered cycloalkyl in the substituted 3-7-membered cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (16) Each R 12d wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; (17)R 1-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; and (18)R 12-1 In the above, the one or more R 12d The 3- to 7-membered cycloalkyl in the substituted 3- to 7-membered cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) each C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (2) each halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; (3) each C2-C6 alkenyl group is independently ethenyl, propenyl, butenyl or pentenyl; (4) each C2-C6 alkynyl group is independently ethynyl, propynyl, butynyl or pentynyl, such as ethynyl or propynyl; (5) each 3-7 membered cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (6) each 3-7 membered cycloalkenyl group is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (7) Each 4-10 membered heterocyclic group is independently a saturated or unsaturated heterocyclic group, such as a saturated heterocycloalkyl group; (8) Each 4-10 membered heterocyclic group is independently a monocyclic heterocyclic group or a bicyclic heterocyclic group, wherein the bicyclic heterocyclic group is a spirocyclic group, a bridged ring or a fused ring; (9) Each 4-10 membered heterocyclic group is independently a 4-6 membered monocyclic heterocyclic group or a 7-10 membered bicyclic heterocyclic group, and the 4-6 membered monocyclic heterocyclic group may be For example (10) The heteroatoms in each 4-10 membered heterocyclic group are independently N and / or O, and the number of heteroatoms is independently 1 or 2; (11) Each C6-C 10 Aryl is independently phenyl or naphthyl; (12) each 5-10 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group or an 8-10 membered polycyclic heteroaryl group, wherein the heteroatom species is selected from one or more of N, O or S, and the number of heteroatoms is 1, 2 or 3; (13) each C1-C6 alkyl-O- is independently methyl-O-, ethyl-O-, n-propyl-O-, isopropyl-O-, n-butyl-O-, tert-butyl-O-, isobutyl-O- or sec-butyl-O-; (14) Each -C(=O)-OC 6-10 Aryl is independently -C(=O)-O-phenyl or -C(=O)-O-naphthyl; (15) Each -C(=O)-C 1-6 Alkyl is independently -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-isopropyl, -C(=O)-n-butyl, -C(=O)-isobutyl, -C(=O)-sec-butyl or -C(=O)-tert-butyl; (16) Each C1-C 20 The alkyl group is independently a C1-C6 alkyl group, and may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; The compound as shown in formula I described in (17) is a stereoisomer or a mixture thereof, and the stereoisomer may be an enantiomer or a rotation isomer. For example, when it contains one chiral center, the compound as shown in formula I is an R configuration, an S configuration, or an R, S configuration racemate.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1)R 2 , R 4 and R 6 are each independently hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 OR 12 Preferably, R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano; more preferably, R 2 is cyano, R 4 is hydrogen, R 6 is a halogen; (2)R 3 is a 4-10 membered heterocyclic group, -NR 10 R 11 、-OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 3 is a 4-10 membered heterocyclic group, -OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; for example, R 3 For-OR 12 ; (3) Each R 3f are independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; preferably, each R 3f are independently halogen; (4)R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, or one or more R 5a Substituted C1-C6 alkyl, one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group, or one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; preferably, R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group or is replaced by one or more R 5c The substituted C2-C6 alkynyl group, wherein the heteroatoms in the 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; for example, R 5 is a halogen; (5) Each R 5a , R 5c , R 5d and R 5f Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 、-OR 12 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-d substituted 3-7 membered cycloalkyl or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, each R 5c and R 5f Each is independently halogen, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; more preferably, each R 5c are independently 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R 5-f Substituted 4-10 membered heterocyclic group, each R 5f are independently halogen, the 4-10 membered heterocyclic group and the one or more R 5-f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; further preferably, each R 5c Each is independently a 4-10 membered heterocyclic group, wherein the heteroatoms in the 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; (6) Each R 5-a , R 5-d and R 5-f are each independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl or C1-C6 alkyl substituted by one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano; preferably, each R 5-f are independently C1-C6 alkyl; (7)R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; preferably, R 7 is hydrogen; (8)R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, -NR 10 R 11 、-OR 12 or one or more R 8a Substituted C1-C6 alkyl; preferably, R 8 For cyano, -NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl, such as R 8 For-NR 10 R 11 ; (9) Each R 8a are independently deuterium, halogen, cyano, -NR 10 R 11 or C1-C6 alkyl; preferably, each R 8a are independently halogen; (10)R 9 is hydrogen, -C(=O)-O-CH(R 9a )-OC(O)-R 9b or -(CH2) m -OP(=O)(OR 9c )2; preferably, R 9 is hydrogen; (11)R 9a and R 9b are independently hydrogen or C 1-20 alkyl; (12) Each R 9c are independently hydrogen or C 1-20 alkyl; (13)R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; for example, R 10 and R 11 are independently hydrogen or replaced by one or more R 10a Substituted C1-C6 alkyl; (14) Each R 10a are independently deuterium, halogen, cyano, -OH, -NH2 or C1-C6 alkyl; preferably, each R 10a independently for deuterium; (15)R 12 is a C1-C6 alkyl group, a 3-7 membered cycloalkyl group, a 4-10 membered heterocyclic group, or a 12a Substituted C1-C6 alkyl, one or more R 12d substituted 3-7 membered cycloalkyl or one or more R 12f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 12f The heteroatoms in the 4-10 membered heterocyclic group of the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl; (16) Each R 12a , R 12d and R 12f Each is independently halogen, -OH, -NH2, C1-C6 alkyl or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl; preferably, each R 12d are independently C1-C6 alkyl; and (17)n is 1; Preferably, R 1 for -CD3; and / or, R 8 It is deuterium or a deuterated group.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: The compound shown in Formula I is Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6, Scheme 7 or Scheme 8: Solution 1: R 1 is a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 are each independently hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 OR 12 ; R 3 is a 4-10 membered heterocyclic group, -NR 10 R 11 、-OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 3f are independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, or one or more R 5a Substituted C1-C6 alkyl, one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 5a , R 5c , R 5d and R 5f Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 、-OR 12 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-d substituted 3-7 membered cycloalkyl or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 5-a , R 5-d and R 5-f are each independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl or C1-C6 alkyl substituted by one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano; R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, -NR 10 R 11 、-OR 12 or one or more R 8a Substituted C1-C6 alkyl; Each R 8a are independently deuterium, halogen, cyano, -NR 10 R 11 or C1-C6 alkyl; R 9 is hydrogen, -C(=O)-O-CH(R 9a )-OC(O)-R 9b or -(CH2) m -OP(=O)(OR 9c )2; R 9a and R 9b are independently hydrogen or C 1-20 alkyl; Each R 9c are independently hydrogen or C 1-20 alkyl; R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; Each R 10a are independently deuterium, halogen, cyano, -OH, -NH2 or C1-C6 alkyl; R 12 is a C1-C6 alkyl group, a 3-7 membered cycloalkyl group, a 4-10 membered heterocyclic group, or a 12a Substituted C1-C6 alkyl, one or more R 12d substituted 3-7 membered cycloalkyl or one or more R 12f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 12f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 12a , R 12d and R 12f Each is independently halogen, -OH, -NH2, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl; n is 1 or 2; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Solution 2 R 1 is a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano; R 3 is a 4-10 membered heterocyclic group, -OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; Each R 3f are independently halogen; R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group, or one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; Each R 5c and R 5f Each is independently halogen, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; Each R 5-f are independently C1-C6 alkyl; R 7 is hydrogen; R 8 For cyano, -NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl; Each R 8a are independently halogen; R 9 is hydrogen; R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; Each R 10a independently for deuterium; R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl; Each R 12d are independently C1-C6 alkyl; n is 1; Solution 3 R 1 is a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano; R 3 is -OR 12 ; R 5 is a halogen; R 7 is hydrogen; R 8 For-NR 10 R 11 ; R 9 is hydrogen; R 10 and R 11 are independently hydrogen or replaced by one or more R 10a Substituted C1-C6 alkyl; Each R 10a independently for deuterium; R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl; Each R 12d are independently C1-C6 alkyl; n is 1; Solution 4: R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 are each independently hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 OR 12 ; R 3 is a 4-10 membered heterocyclic group, -NR 10 R 11 、-OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 3f are independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group, or one or more R 5a Substituted C1-C6 alkyl, one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5d Substituted 3-7 membered cycloalkyl, 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 5a , R 5c , R 5d and R 5f Each is independently deuterium, halogen, =O, cyano, C1-C6 alkyl, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 、-OR 12 , by one or more R 5-a Substituted C1-C6 alkyl, one or more R 5-d substituted 3-7 membered cycloalkyl or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 5-a , R 5-d and R 5-f are each independently deuterium, halogen, cyano, -NR 10 R 11 、-OR 12 , C1-C6 alkyl or C1-C6 alkyl substituted by one or more substituents selected from halogen, -OH, deuterium, -NH2 and cyano; R 7 is hydrogen, deuterium, halogen, cyano, nitro, -NR 10 R 11 、-OR 12 or C1-C6 alkyl; R 8 is hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, -NR 10 R 11 、-OR 12 or one or more R 8a Substituted C1-C6 alkyl; Each R 8a are independently deuterium, halogen, cyano, -NR 10 R 11 or C1-C6 alkyl; R 9 is hydrogen, -C(=O)-O-CH(R 9a )-OC(O)-R 9b or -(CH2) m -OP(=O)(OR 9c )2; R 9a and R 9b are independently hydrogen or C 1-20 alkyl; Each R 9c are independently hydrogen or C 1-20 alkyl; R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; Each R 10a are independently deuterium, halogen, cyano, -OH, -NH2 or C1-C6 alkyl; R 12 is a C1-C6 alkyl group, a 3-7 membered cycloalkyl group, a 4-10 membered heterocyclic group, or a 12a Substituted C1-C6 alkyl, one or more R 12d substituted 3-7 membered cycloalkyl or one or more R 12f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 12f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 12a , R 12d and R 12f Each is independently halogen, -OH, -NH2, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OH, -NH2 and C1-C6 alkyl; n is 1 or 2; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl; Solution 5: R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano; R 3 is a 4-10 membered heterocyclic group, -OR 12 or one or more R 3f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 3f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; Each R 3f are independently halogen; R 5 is halogen, C2-C6 alkynyl, 4-10 membered heterocyclic group, or one or more R 5c Substituted C2-C6 alkynyl, substituted by one or more R 5f Substituted 4-10 membered heterocyclic group or -NR 10 R 11 , the 4-10 membered heterocyclic group and the one or more R 5f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N, and the number of heteroatoms is independently 1; Each R 5c and R 5f Each is independently halogen, 3-7 membered cycloalkyl, 4-10 membered heterocyclyl, -NR 10 R 11 or one or more R 5-f substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group and the 5-f The heteroatoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently selected from N and / or O, and the number of heteroatoms is independently 1 or 2; Each R 5-f are independently C1-C6 alkyl; R 7 is hydrogen; R 8 For cyano, -NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl; Each R 8a are independently halogen; R 9 is hydrogen; R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; Each R 10a independently for deuterium; R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl; Each R 12d are independently C1-C6 alkyl; n is 1; And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl; Solution 6: R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano; R 3 is a 4-10 membered heterocyclic group or -OR 12 ; R 5 is halogen, C2-C6 alkynyl, or is replaced by one or more R 5c Substituted C2-C6 alkynyl or 4-10 membered heterocyclic group; Each R 5c are independently 4-10 membered heterocyclic groups; R 7 is hydrogen; R 8 For-NR 10 R 11 or one or more R 8a Substituted C1-C6 alkyl; Each R 8a are independently halogen; R 9 is hydrogen; R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; Each R 10a independently for deuterium; R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl; Each R 12d are independently C1-C6 alkyl; n is 1; And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl; Solution 7: R 1 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more deuteriums; R 2 , R 4 and R 6 are each independently hydrogen, halogen or cyano; R 3 is a 4-10 membered heterocyclic group or -OR 12 ; R 5 is halogen, C2-C6 alkynyl, or is replaced by one or more R 5c Substituted C2-C6 alkynyl or 4-10 membered heterocyclic group; Each R 5c are independently 4-10 membered heterocyclic groups; R 7 is hydrogen; R 8 For-NR 10 R 11 ; R 9 is hydrogen; R 10 and R 11 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 10a Substituted C1-C6 alkyl; Each R 10a independently for deuterium; R 12 is a 3-7 membered cycloalkyl group or is replaced by one or more R 12d Substituted 3-7 membered cycloalkyl; Each R 12d are independently C1-C6 alkyl; n is 1; And when R 1 When it is a C1-C6 alkyl group, the following conditions are met: 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl; Solution 8: R 1 is C1-C6 alkyl, R 3 For-OR 12 , R 12 For one or more R 12d Substituted 3-7 membered cycloalkyl; R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12d and n as described in any one of claims 1-4.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I is a compound as shown in formula I-1, I-2, I-3, I-4, I-5, I-6, I-7 or I-8; Among them, R 1-1 is a C1-C6 alkyl group; R 3-1 is -OR 12-1 ; R 12-1 For one or more R 12d Substituted 3-7 membered cycloalkyl; Preferably, the compound as shown in formula I is a compound as shown in formula I-1a, I-1b, I-2a, I-2b, I-3a, I-3b, I-4, I-4b, I-5a, I-5b, I-6a, I-6b, I-7a, I-7b, I-8a or I-8b; 8. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1)R 1 is -CD3 or -CH3; preferably -CD 3； (2)R 2 is cyano; (3)R 4 is hydrogen; (4)R 6 For fluorine; (5)R 3 for (6)R 5 For chlorine, (7)R 7 is hydrogen; (8)R 8 is -NH-CD3, -NH-CH3, -CHF2 or cyano; and (9)R 9 For hydrogen.

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I is any of the following compounds:

10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 9, characterized in that: The compound as shown in formula I is any of the following compounds: The compound that elutes first under the following conditions: HPLC analysis method, chromatographic column ChiralPak IE, HS, 150×4.6mm ID, 5μm; mobile phase: A: n-hexane, B: ethanol containing 0.1% ammonia water; gradient: B accounts for 60% by volume in the mobile phase; preferably, under the conditions, the retention time of the compound that elutes first is: 10.078 minutes; The compound that elutes later under the following conditions: HPLC analysis method, chromatographic column ChiralPak IE, HS, 150×4.6mm ID, 5μm; mobile phase: A: n-hexane, B: ethanol containing 0.1% ammonia water; gradient: B accounts for 60% by volume in the mobile phase; preferably, under the conditions, the retention time of the compound that elutes later is: 15.034 minutes; The compound that elutes first under the following conditions: SFC analysis method, chromatographic column OD-3 4.6*100mm 3μm column; mobile phase: A: methanol [0.2% NH3 (7mol / L ammonia methanol solution)], B: CO2; gradient: B accounts for 65% by volume in the mobile phase; preferably, under the conditions, the retention time of the compound that elutes first is: 2.024 minutes; The compound that elutes later under the following conditions: SFC analysis method, chromatographic column OD-3 4.6*100mm 3μm column; mobile phase: A: methanol [0.2% NH3 (7mol / L ammonia methanol solution)], B: CO2; gradient: B accounts for 65% by volume in the mobile phase; preferably, under the said conditions, the retention time of the compound that elutes later is: 2.540 minutes.

11. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10, and at least one pharmaceutical excipient.

12. Use of a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11, in the preparation of a PRMT5 inhibitor, for example, in the preparation of a PRMT5·MTA inhibitor.

13. Use of a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11, in the preparation of a drug, for example, in the preparation of a drug for treating and / or preventing cancer.

14. The use according to claim 13, characterized in that The application meets one or more of the following conditions: (1) The cancer is a MTAP-related / mediated cancer, preferably, the MTAP-related / mediated cancer is head and neck cancer, respiratory cancer, digestive cancer, urinary cancer, bone cancer, gynecological cancer, blood 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 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is in a therapeutically effective amount.

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